THE PHYSIOLOGY OF THE KIDNEY
THE PHYSIOLOGY OF
THE KIDNEY
BY
HOMER W. SMITH, A.B., Sc.D., M.S. (HON.)
Profusor oj Physiology and Dimtor of
the Physiological Laboratoriu,
New rork University College of Medicine
OXFORD UNIVERSITY PRESS
LONDON
NEW YORK
1937
TORONTO
COPYRIGHT
1937 BY
OXFORD UNIVERSITY PRESS, NEW YORK, INC.
NLVS/IVRI
1111111111111111111'11111111
00331
.---.-~
PRINTED IN THE UNITED STATES OF AMERICA
To
CARWTTA GREENE SMITH
ACKNOWLEDGEMENT
author gratefully wishes to acknowledge his indebtedness to Dr. Allan L. GrafHin for his assistance in the preparation of chapter II, to Dr. Robert F. Pitts and Dr. James
A. Shannon for critically examining the manuscript, and to
numerous generous colleagues who have advised him in the
preparation of special portions.
THE
CONTENTS
I
PART
I.
II.
INTRODUCTION
•
1
5
ANATOMY
III. THEORIES OF RENAL FUNCTION
16
IV. GLOMERULAR FILTRATION
27
34
43
V. TUBULAR REABSORPTION
VI. TUBULAR EXCRETION
.
IX. CREATININE CLEARANCE
5I
72
92
X. CREATINE CLEARANCE
102
VII. INULIN CLEARANCE .
VIII. PHENOL RED CLEARANCE
XI. GLUCOSE CLEARANCE
XII. UREA CLEARANCE
.
110
.
119
XIII. THE EVIDENCE FOR THE USE OF INULIN AS A MEASURE OF GLOMERULAR FILTRATION
PART
II
145
158
XIV. COMPOSITION OF THE PLASMA.
XV. SODIUM, POTASSIUM AND CHLORIDE
XVI. ACID-BASE EQUILIBRIA IN PLASMA AND URINE
XVII. CALCIUM, PHOSPHATE AND SULPHATE
.
XVIII. HIPPURIC ACID, URIC ACID, DIODRAST, ETC. .
PART
DIURETICS
169
183
192
III
XIX. THE EXCRETION OF WATER
XX.
135
.
.
XXI. THE ROLE OF THE RENAL NERVES IN UR1NE FORMATION
XXII. RENAL BLOOD FLOW
XXIII. COMPARISON OF RENAL ACTIVITY IN MAMMALS.
201
235
241
250
257
ILL USTRATIONS
/rontis.
PLATE I. ANGLOMERULAR KIDNEY OF TOADFISH
FIGURE
I. DIAGRAM OF THE HUMAN NEPHRON.
.
.
..
6
2. TUBULAR REABSORPTION OF CHLORIDE, ETC. IN AMPHIBIA 35
3. TUBULAR REABSORPTION OF GLUCOSE, ETC. IN AMPHIBIA 37
4. PRINCIPLES OF RENAL CLEARANCE
57
5. DIFFUSlON COEFFICIENTS OF INULIN, ETC.
63
6. INULIN CLEARANCE IN MAN . .
65
7. INULIN CLEARANCE IN THE DOG .
66
8. INULIN CLEARANCE IN THE RABBIT . • •
69
9. PROTEIN BINDING OF PHENOL RED IN HUMAN PLASMA. 77
10. PHENOL RED CLEARANCE IN MAN .
79
I I. PHENOL RED CLEARANCE IN THE DOG.
•
•
82
12. PHENOL RED CLEARANCE IN THE CHICKEN .
83
13. TUBULAR EXCRETION OF PHENOL RED IN THE DOG
85
14. TUBULAR EXCRETION OF PHENOL RED IN THE CHICKEN
86
15. CREATININE CLEARANCE IN MAN. ....
96
16. CREATININE CLEARANCE IN THE CHICKEN • • .
97
17. CREATININE CLEARANCE IN THE DOGFISH, S. acanthias
98
18. CREATINE CLEARANCE IN THE DOG AND MAN..
105
19. CREATINE CLEARANCE IN THE TELEOST, E. moria .
108
20. TUBULAR REABSORPTION OF GLUCOSE IN THE DOG.
.
113
21. DIAGRAM OF STANDARD AND MAXIMUM UREA CLEARANCE 123
22. UREA REABSORPTION IN THE DOG .
u8
23. UREA REABSORPTION IN MAN.
.
.
.
.
132
24. SUMMARY OF CLEARANCE DATA IN THE DOG.
142
25. SUMMARY OF CLEARANCE DATA IN MAN.
143
26. WATER AND ISOTONIC SALT DIURESIS.
156
27.' PHOSPHATE CLEARANCE IN THE DOG. . . . . . 187
28. OSMOTIC PRESSURE OF HUMAN PLASMA l)URING WATER
DIURESIS
.
.
.
.
•
.
.
.
-.
.
..
209
29. RE~PONSE OF NORMAL AND DENERVATED KIDNEY TO
WATER DIURESIS AND PITUITARY EXTRACT.
"
219
30. RESPONSE OF NORMAL AND DENERVATED KIDNEY TO
EXERCISE .
.
.
.
•
.
.
.
.
.
.
.
• 220
31. ANATOMICAL RELATIONSHIPS OF THE PITUITARY GLAND 227
32. EFFECT OF CONSTRICTION OF THE AFFERENT AND EFFERENT GLOMERVLAR ARTERIOLES UPON GLOMERULAR
PRESSURE •
248
PART. I
I
INTRODUCTION
years ago Claude Bernard * 27 pointed out that the
higher animals "have really two environments: a milieu
exterieur in which the organism is situated, and a milieu interieur in which the tissue elements live. The living organism does not really exist in the milieu exterieur (the atmosphere if it breathes, salt or fresh water if that is its element)
but in the liquid milieu interieur formed by the circulating
organic liquid which surrounds and bathes all the tissue elements; this is the lymph or plasma. • . . The milieu interieur surrounding the organs, the tissues and their elements
never varies; atmospheric changes cannot penetrate beyond
it and it is therefore true to say that the physical conditions
of environment are unchanging in a higher animal: each one
is surrounded by this invariable milieu which is, as it were,
an atmosphere proper to itself in an ever-changing cosmic
MANY
*
The contributions of Claude Bernard (1813-1878) to physiology
were marly and varied and entitle him to a place of high honor in the history of this science. Among his discoveries were the vasomotor nerves,
glycogen and the nervous control of glycogen storage in the liver, COhemoglobin, and ~he action of curare in blocking nerve impulses. His
concept of the constancy of the internal environment was, however, perhaps his greatest contribution: Haldane has said, "No more pregnant sentence was ever framed by a physiologist."
2
THE PHYSIOLOGY OF THE KIDNEY
environment. Here we have an organism which has enclosed
itself in a kind of hot-house. The perpetual changes of
external conditions cannot reach it i it is not subject to them,
but is free and independent. • . . All the vital mechanisms,
however varied they may be, have only one object, that of
preserving constant the conditions of life in the in~ernal environment. "
Though Bernard arrived at his view of the constancy of
the internal environment from relatively few facts, investigations since his time have repeatedly confirmed and broadened the application of his principle.
Cannon,80 in his study of the autonomic nervous system,
has been led to extend Bernard's principle by recognizing
that the constancy of the internal environment, which he
designates as a homeostatic state, is in itself evidence that
physiological agencies are acting, or ready to act, to maintain this constancy. These physiological agencies are themselves excited to action by some slight deviation of the homeostatic state. Thus in Cannon's view the compensation, direct
or indirect, is itself automatically elicited by the environmental change. The term "constancy" is, of course, used to
signify" limited variability." Incidental or cyclical variations in the composition of the body fluids do occur, and in
fact such variations play an important role as motivating
factors in the organism i but on the whole these variations
are of a small order of magnitude because of the regulatory
powers of the organism.
The principles formulated by Bernard and Cannon are
especially pertinent to the problems of renal function. In
all the higher animals the plasma has indeed a remarkably
INTRODUCTION
3
constant composition, not only from individual to individual,
but between distantly related groups. This constancy is in
large part a consequence of the activity of the kidneys, which
under all conditions excrete a urine of such a composition as
to offset any tendency towards deviation in the composition
of the plasma.
For example, the water content of the plasma varies
scarcely at all in a normal animal j and it varies little between the extremes of the fishes that live in fresh or salt
water and the reptiles, birds and mammals that live under
the most arid conditions on the land. Or, to choose a more
immediate example, on one day a man may ingest a large
quantity of water, on another he may sweat profusely without drinking j yet the composition of the plasma is regulated
so effectively that the most precise methods of examination
are required to detect the change in its water content. Under the first condition the kidneys compensate for the large
intake of water by excreting a large quantity of very dilute
urine, while under the second condition they excrete a small
quantity of very concentrated urine, and thus compensate
for the large water loss. And so with innumerable salts
and other substances: sodium, potassium, calcium, chloride,
phosphate, etc. j the kidneys compensate for variations in
the quantities ingested by excreting them in variable amounts.
On the other hand, certain plasma constituents, such as
glucose, numerous proteins, amino-acids and hormones, are
never excreted in significant quantities under normal conditions; on the contrary, the kidneys operate constantly to conserve these valuable materials. The hydrogen-ion concentration of the blood is in part regulated by respiration, but
THE PHYSIOLOGY OF THE KIDNEY
4
the kidneys contribute to this regulation by excreting vari~
able quantities of bicarbonate and a more or less alkaline
urine. In addition, when non-volatile acids are produced
during acidosis, ammonia is formed for their neutralization
in order to conserve the inorganic bases of the blood. One
might say that it was only incidentally in the performance
of these complex tasks of conservation and regulation that
the kidneys carry out their most obvious function, the excretion of the numerous waste products of metabolism, as
well as foreign substances which are always being absorbed
through the gastro-intestinal tract and skin. Indeed, the
kidneys excrete many foreign substances with remarkable
efficiency, even though these substances have never been encountered before.
In the last analysis, the composition of the" internal environment" is determined not by what the body takes in,
but by what is retained and what is excreted. The living
organism frequently achieves its end by working backwards.
There is no more striking example of this than the kidneys,
which begin their task by tentatively excreting everything
through the glomeruli, only to salvage the valuable materials
in the tubules while permitting the waste products to escape.
The kidneys work in this manner not necessarily because it
is the best manner, but because, like other organs of the body,
their functional architecture has been shaped by the long
and varied evolutionary history of the vertebrates.
II
ANATOMY
THE function of the kidney in man and other vertebrates
would suggest that this organ had an extraordinarily complex structure, but on close analysis it is found to be made
up of a very large number of structurally similar and relatively simple functional units. These units, or nephrons,
consist typically of a capillary tuft or glomerulus which is directly attached to an unbranched tubule, the latter being differentiated into possibly no more than three distinct portions. There are about one million nephrons in each human
kidney, which drain by way of a series of collecting tubules
into the renal pelvis and thence by the ureter into the bladder. The essential features of a typical nephron in the
human kidney are illustrated diagrammatically in Figure I.
The formation of urine begins in the glomerulus, which
consists of an elaborate, almost spherical, tuft of capillaries
supplied with blood through a short, wide afferent arteriole.
This capillary tuft is formed by the abrupt division of the
afferent arteriole into 2 or 4, rarely up to 10, primary
branches, which in turn subdivide again, at times into as
many as 50 capillary loops, each loop having a length 2 or
3 times the diameter of the whole tuft.. The original branch·
ing of the primary capillaries tends to give the tuft a lobulated structure. The capillaries do not anastomose with
each other, but coalesce into an afferent arteriole, which in
6
THE PHYSIOLOGY OF THE KIDNEY
PROXIMAL
TUBULE --------------------
. ..
..
DISTAL
TUBULE - - - - - 1 l I
..
'
THIN SEGMENT - - FIGURE I
Diagram showing the essential features of a typical nephron in the
human kidney
ANATOMY
7
turn breaks up again into a second capillary system around
the tubules.
The true relation of the glomerulus to the tubule is perhaps best expressed by saying that the capillary tuft is thrust
so far into the expanded but closed end of the tubule that the
tuft has come to be enveloped by a double layer of tubular
epithelium; the inner or visceral layer being closely applied
to the capillaries, extending in between all the loops, and surrounding each loop almost completely i the outer or parietal
layer forming a smooth spherical capsule (Bowman's capsule) about the tuft as a whole. The space within this capsule is continuous with the lumen of the tubule, the arrangement being such that any fluid passing through the capillaries
drains from the capsular space down the tubule. Between
the visceral layer of the capsule and the capillary endothelium there is a thin glomerular basement membrane, which
is anatomically continuous with the basement membrane
bounding the outer surface of the tubule cells. These three
layers, the capillary endothelium, the basement membrane
and the capsular epithelium, are usually stated to be continuous, in the sense of having no openings or defects."'" However, some anatomists contend that the visceral epithelium
is discontinuous, and that the individual cells are highly
irregular in shape, exhibiting delicate discrete processes
(" Deckzellen ") which invest the glomerular capillaries in
the manner of the pericytes which are applied to capillaries
elsewhere in the body.
The above and other details of the organization of the
nephron are best upderstood in the light of embryological
development. The capillary tufts and the renal tubules de-
8
THE PHYSIOLOGY OF THE KIDNEY
velop out of different anlage and for a time grow independently in the embryonic kidney. When the tuft and
tubule first make connection, the latter is a short S-shaped
tube, closed at ·both ends. While one end of the S is establishing connection with the collecting duct, the other end
expands and, by invagination, develops a concavity on one.
side into which the capillary tuft grows, ultimately becoming
completely enfolded within the invaginated tubule wall.
Thus the basement membrane, which originally covered the
outer surface of the tubule cells, comes to occupy an intermediate position between the capillaries and the tubular
epithelium in the fully developed glomerulus.
In the adult kidney each tubule, after extensive convolutions near the glomerulus (proximal convoluted tubule),
passes by a more or less straight course towards the pelvis
of the kidney where it abruptly reverses its direction (loop
of Henle) and returns to the region of its own glomerulus
to undergo a second series of convolutions (distal convoluted
tubule), and subsequently to join a collecting duct. The
proximal and distal convoluted segments of a particular tubule are closely intertwined about the glomerulus of origin,
which circumstance arises from the fact that they have developed in situ as a unit. While the S-shaped tubule is
anchored at both ends, the middle portion grows by elongation towards the renal pelvis, thus forming the loop of
Henle. Similarly the extremely complex convolutions of
both the proximal and distal segments arise out of the
tendency of the anchored ends of the tubule to elongate
locally.
The gross organization of the mammalian kidney into
ANATOMY
9
lobes is not of physiological importance, since it is an incidental consequence of the developmental pattern of the minor
calyces and papillary ducts. In man and the dog the tendency to lobulation is evident only when one inspects the crosssection of the adult organ, but in many mammals the kidney
is externally divided into almost independent lobes. Similarly, the convolutions of the proximal and distal tubules,
the disposition of the nephrons in the kidney into a series of
pyramidal lobes, each of which may be divided grossly into a
" cortex" and" medulla" (which are respectively composed
of convoluted tubules and -the extended portions of the loops
of Henle), and other gross anatomical features, may be set
aside as incidental consequences of organogenesis, without
particular physiological significance. For this reason the
term " convoluted" has been omitted from our designation
of the proximal and distal tubular segments.
The tubular portion of the nephron is divisible, on the
basis of cytological structure, into three segments: * (I) the
proximal tubule (which includes both the pars convoluta
and the pars recta as far as the transition in the medulla to
the thin segment of Henle's loop); (2) the thin segment;
and (3) the distal tubule (which includes the pars recta, or
the thick, ascending limb of Henle's loop, as well as the pars
convoluta) . A subdivision of the ptoximal and distal segments can be made on cytological grounds but nothing is
gained by attempting that subdivision at the present time.
In addition, we must recognize a short segment or " neck "
*
"Loop of Henle" is commonly used to include the pars recta of the
proximal, the thin segment, and the pars recta of the distal tubule. Since
this usage must obviously lead to confusion in the discussion of function, it
has been abandoned here in favor of the description given above.
10
THE PHYSIOLOGY OF THE KIDNEY
joining the glomerulus to the proximal tubule; this is of
variable length and may be almost absent.
The proximal segment has the widest diameter of any
portion of the tubule, and is made up of large cuboidal or
truncated pyramidal cells having abundant protoplasm and
large spherical nuclei. The cell boundaries are mostly invisible, due to the fact that they are fluted in a plane perpendicular to the basement membrane, these flutings being
interdigitated with the flutings of the adjacent cells. The
cystosomes of the cells are coarsely granular, and the granules help to obscure the cell boundaries. The cells usually
bulge into the lumen, giving it an irregular contour. In all
vertebrates, so far as is known, the cells of the proximal
segment are distinguished by the presence of brush border
on the inner or luminal aspect. In common with the cells
of the distal segment, they possess at their basal margins
peculiar, parallel striations perpendicular to the basement
membrane, this striated appearance being due either to the
mitochondria or to the spaces between the mitochondria, depending upon the method of fixation and staining. The
striations become less marked as the thin segment is approached.
As the tubule emerges from its initial convolutions near
the glomerulus it descends in a more or less straight path
into the medulla where it completes a sharp hair-pin turn
and then returns upon its course to the neighborhood of its
glomerulus. At a slightly variable position along this" loop
~f Henle" the thick cells of the proximal portion are replaced by the highly attenuated cells of the thin segment.
This segment is of smaller diameter than either the proximal
ANATOMY
II
or distal tubules, and is made up of flattened epithelium with
clear protoplasm containing a slightly compressed nucleus
which bulges the cell wall into the lumen. The length of this
segment varies considerably, depending upon the position of
the glomerulus to which it belongs, and upon how far the
tubule penetrates into the medulla. In the human kidney
short loops are about seven times as numerous as long ones,
and in some instances, when the glomeruli are located near
the surface of the kidney, the thin segment may be absent
entirely. Where present the thin segment may occupy only
the descending limb of Henle's loop, or it may extend around
the loop and for some distance along the ascending limb;
but whatever its position or length, its structure is the same
and there is no doubt that it should be looked upon as a discrete functional unit. It is significant that this thin segment
is present only in the mammals (with the possible exception
of a similar segment in a small percentage of the nephrons
of the bird), and that its average length in different mammals is highly variable. It is least developed in the more
primitive forms.
In the ascending limb of the loop of Henle the cells are
at first cuboidal, with indistinct cell boundaries, but as the
cortex is approached they again become cuboidal to columnar
and acquire irregular projections into,the lumen. The nuclei
are spherical or slightly oval, and the epithelium is more
finely granular than in the proximal segment. All portions
of the distal segment lack brush border, but show more or
less distinct basal striations. Near the glomerulus the
tubule undergoes _a second ser_ies of tortuous convolutions
from which it emerges to join with its neighbors the tree-
12
THE PHYSIOLOGY OF THE KIDNEY
like system of collecting ducts. It is believed by some that
the distal segment always makes contact with the glomerulus
of origin; at the point of contact the cells are slightly and
characteristically flattened.
The renal tubules and the excretory ducts are enveloped
externally by a well-developed and distinct basement membrane which is probably formed embryologically by condensation of interstitial connective tissue. It is doubtful
whether this basement membrane plays any active role in
excretion, but its interposition between the capillaries and
the tubules is a matter of moment, for it must be traversed
by all solutes moving from the blood to the tubule cells, or
vice versa. The presence of the basement membrane is particularly significant in the glomerulus, where it is interposed
between the capillaries and the visceral layer of Bowman's
capsule. All water and solutes must therefore traverse this
membrane, as well as the capillary endothelium and the
capsular epithelium, in order to gain access to the capsular
space. Here this membrane is normally so thin as to be discernible only with special stains, but there is evidence that
proliferation and thickening may play an important role in
renal deficiency due to glomerular disease.
The collecting tubules consist of epithelium which is quite
different from the other parts of the nephron, a distinction
in keeping with its separate embryological origin. The cells
vary in height in different portions of the cQllecting system,
but are almost universally arranged in a single, smooth layer
with the dark staining, spherical nuclei all in the same relative position. The cytology of the collecting tubules does
not suggest any specialized function in the mammalian kidney other than service as conduits.
ANATOMY
13
In view of the role of the kidney in regulating the composition of the body fluids, its blood supply is of special
importance. After the renal artery enters the hilus of the
kidney it divides into two sets of end·arteries, a ventral and
a dorsal set, which progressively subdivide into three further
orders, the interlobar, arcuate and interlobular arteries.
Numeous short arterial twigs, the afferent arterioles, are
given off from the last, each of which directly supplies a
glomerulus. From the glomerular capillaries the blood is
carried off by a vessel, the efferent arteriole, that has the
structure of an .arteriole, but which subsequently breaks up
into a second network of capillaries closely applied to the
external surface of the tubules. The arrangement of blood
vessels is such that the near.by convolutions of the proximal
and to a lesser extent the distal tu'bules of a particular glomerulus tend to be supplied with blood by the efferent arteriole
of that glomerulus, though this is probably significant only
as an incident of organogenesis. The tubules of the medulla,
comprising the thin segment and the ascending limb of the
distal tubule, are supplied with efferent blood from glomeruli
located in the region of the cortex nearest the medulla. In
this instance the efferent arterioles do not subdivide into
capillaries in the cortex, but descend by a straight radial
course into the medulla and there branch profusely into a
capillary network with elongated meshes conforming to the
radial arrangement of the medullary tubules. Since the capillaries from neighboring glomeruli undergo some anastomosis
it is improbable that the tubular blood supply in the medulla
is derived to any ~ignificant extent from the glomerulus of
orlgm.
In both the cortex and the medulla the peritubular capil-
14
THE PHYSIOLOGY OF THE KIDNEY
laries converge into veins whose distribution follows more
or less the local tubular pattern; in the cortex the confluent
veins have a stellate arrangement, while in the medulla their
course is straight, paralleling the tubules. The interlobular
veins converge into the arcuate veins paralleling the arcuate
arteries, and these finally join to form the renal vein which
emerges, in the hilus of the kidney, adjacent to the renal
artery.
It is to be noted that in the mammals no major arterial
vessels go directly to the tubules, so that most of the blood
supplied to the tubules must first pass through the glomeruli.
This point is of the utmost importance in relation to the
pathology of the kidney since obstructive changes in the
glomeruli must tend to obliterate the tubular circulation.
Several investigators have described exceptional capillary
plexuses about certain tubules which were derived directly
from the arterial tree, and which could supply the tubules
with blood without the interposition of the glomerular capillaries. One of these direct arterial connections is Ludwig's
artery, an infrequent and relatively' small twig branching
from the afferent arteriole. In other instances an interlobular artery may terminate, with or without subdivision,
in a capillary plexus around the cortical tubules. These instances of a direct arterial supply to the tubules are certainly
rare in the normal kidney, and probably have negligible
functional significance; but it is worthy of note that recent
studies indicate that in chronic renal disease involving glomerular obliteration such devices may maintain some degree
of tubular circulation.
In apparently all glomerular vertebrates below the mam-
ANATOMY
15
mals the tubules receive blood from two sources: by way of
the efferent arterioles of the glomeruli, and also by way of
the renal-portal vein. The latter supplies a system of peritubular capillaries that ultimately are confluent with the
postglomerular capillaries, either by direct anastomoses
or by emptying into common venous sinuses. This circumstance is responsible for demonstrated differences in renal
function, particularly as concerns tubular activity, in the
lower animals as 'compared with the mammals.
There is an elaborate network of lymphatic capillaries
between the tubules, especially in the cortex. These lymphatics converge into a lymph vessel that leaves the kidney
with the major blood vessels at the hilus.
The quantity of connective tissue in the normal mammalian
kidney is small. Its branching and anastomosing fibers form
diffuse networks everywhere in the narrow spaces between
the tubules, the fibers being especially numerous and thick
in the pyramids. A few strands of connective tissues enter
the glomerulus along the blood vessels. Proliferation of
connective tissue throughout the kidney plays an important
part in disease.
The kidney receives an abundant supply of sympathetio
nerves by way of the thoracico-lumbar outflow, as well as
parasympathetic fibers by way of the vagus. Both sensory
and motor endings are demonstrable in the adventitia and
muscular portions of the arterioles, in such physiological
relationship as to mediate changes in blood flow through the
kidney as a whole, and perhaps locally within the glomeruli.
Nerve endings h~ve also been demonstrated around the tubules and between the epithelial cells.
III
THEORIES OF RENAL FUNCTION
theories of renal function have, of course, been based
upon the structure of the nephron ......It was first suggested
by Ludwig in 1844 Ul that urine formation begins with a
passive process of filtration of a protein-free fluid in the
glomeruli, effected by the ·hydrostatic pressure of the blood.
This supposition is strongly supported by the structure of
the glomerulus itself. The membranes to be traversed (the
endothelial capillary walls, the basement membrane and the
visceral layer of capsular epithelium) are all so thin and
structureless as to argue against specific activity. In this
view the filtrate, essentially identical in composition with the
plasma except for the absence of protein, must undergo its
final elaboration into urine during its passage down the
tubules.
But when we consider the function of the tubules the above
concept of filtration is no longer adequate. The tubule in
its ~ntire length is supplied by blood that, having been
through the capillary tuft of the glomeruli, has lost a great
part of its pressure, and it has lost, therefore, the driving
force necessary to effect filtration, especially against the
osmotic pressure of the plasm proteins. Moreover, the cells
of the tubule are high cuboidal cells of such a nature as to
argue not only against filtration, but also against the easy
diffusion of solutes. Their structure suggests that they are
ALL
THEORIES OF RENAL FUNCTION
17
capable of carrying out complex chemical operations analogous to those carried out by glandular cells in other organs,
as well as of establishing and maintaining considerable differences in composition between the peri tubular blood or
lymph and the urine within the lumen. The possible operations which might be carried out by these tubule cells can, in
the first approximation, be divided into three categories.
( I) They might absorb substances from the fluid in the
lumen and return thel!l to the blood, a process which we may
designate as tubular reabsorption (gl!lcose, etc.).
(2) They might remove substances from the blood and
discharge them into the tubular fluid, a process which we
may designate as tubular excretion * (phenol red, etc.).
(3) They might manufacture from raw materials, obtained either from the blood or the tubular fluid, new sub. stances which could be discharged either into the blood or
*
The term" secretion" has long been used in renal physiology as synonymous with" excretion," but in recent years it has come into a more restricted use to denote tubular excretion in particular, essentially as defined
above. Unfortunately, there is still frequently attached to the word the
implication of "vital activity." When one attempts to give a definition
to " secretion" as it is currently used by non-vitalistic physiologists, perhaps
the best that can be done is to say that it is the transportation of a substance from a low concentration to a high concentration, under such conditions that work must be performed; in the case of the renal tubules, the
energy for this work is supplied locally by the metabolism of tke tubule celli.
But even so, no fundamental distinction is involved, for work must also
be performed in glomerular filtration (in the form of increasing the osmotic
concentration of the plasma proteins), only in this instance the energy is
supplied by the metabolism of tke heart and is transmitted to the kid_ney by
the blood. Although we are entirely ignorant of how energy is made available or utilized in tubular excretion, there is in our concept of it no implication of vitalism} .and the term " secretion," stripped of its older ambiguity, may serve as a convenient synonym for it.
18
THE PHYSIOLOGY OF THE KIDNEY
into the tubular fluid; such processes we may designate as
chemical transformation (ammonia and hippuric formation,
~-oxidation, etc.).
Our problem, then, is this: To what extent does filtration,
tubular reabsorption, tubular excretion or chemical transformation enter into the conservation or excretion of any
particular substance? The difficulties in answering this
question are obviously great, for even where we are certain
that a substance is not synthesized by the kidney (i.e., phenol
red) all three processes, filtration, reabsorption and tubular
excretion, may possibly be involved, with the relative participation of each entirely unknown. It would be possible to
erect an elaborate theory to explain the formation of urine
in terms of filtration plus reabsorption, or filtration plus
reabsorption plus tubular excretion, without being able to
prove its validity at any point. And two investigators, viewing the same evidence, might disagree emphatically about
how that evidence should be interpreted. Such, in fact, has
been the history of theories of renal function until quite
recent years.
Bowman 46 in the classical paper in which he described the
true relation of the glomerulus to the tubule, suggested on
purely morphological grounds that the former excreted only
water and salts, the other components of the urine (urea,
uric acid, etc.) being excreted by the tubules. Two years
later Ludwig 241 advanced a more definite formulation which,
as subsequently elaborated by himself and his students, consisted essentially of a simple physical or mechanical theory.
He suggested that a protein-free filtrate was pressed out of
the glomerular capillaries by the hydrostatic pressure of the
THEORIES OF RENAL FUNCTION
I9
blood, and that this fluid was subsequently concentrated in
the tubules by the diffusion of water and various solutes.
The activity of the tubules, he believed, could be explained
simply in terms of the relative osmotic pressure and protein content of the tubular urine and peritubular blood.
In I 874 Heidenhain 183 modified the original Bowman
theory by positing that the glomeruli" secreted" water and
salts, which glomerular secretion was in turn enriched with
various additional salts, waste products and foreign substances by the specific activity of the tubule cells. In Heidenhain's views the tubular epithelium was charged with the
major responsibility of removing from the blood most of
the solids that appear in the urine, and a certain amount
of the water as well, in accordance with the needs of the
body at the moment. The protagonists of the Ludwig
theory had performed numerous experiments indicating that
the rate of urine formation paralleled the blood pressure; in
rebuttal Heidenhain asserted that it was not blood pressure,
but the rate of blood flow, that was important; he adduced
evidence that the tubules could at least excrete certain dyes
quite independently of the glomeruli, and he argued that
the filtration theory required an incredible quantity of filtrate
to be formed to account for the known excretion of urea.
For many years the two points of view remained irreconcilable. Ludwig's theory, although physiologically inadequate, had the advantage of physical simplicity; Heidenhain's theory, although physiologically adequate, demanded
great discrimination on the part of the tubule cells, and
appeared to invok~ some" vital" force to propel water,
waste products, etc., through the tubule cells and into the
20
THE PHYSIOLOGY OF THE KIDNEY
lumen. "Vitalism" was fast being driven out of respiration, digestion and other physiological phenomena, and the
" intelligence" of the tubule cells, implicit in Heidenhain's
theory, seemed to give" vital" forces a fresh lease in urine
formation. The choice of theory in this matter was influenced nearly as much by the bias of the investigator on this
philosophical question as by the experimental evidence.
During the next fifty years the respective natures of
glomerular and tubular activity were debated back and
forth, with no really conclusive evidence to settle the argument. One opinion did come to be widely held: namely,
that urine formation begins with the simple ultra-filtration
of plasma in the glomeruli. But on'the fate of this filtrate
in the tubules, and on the relative importance of tubular
reabsorption and tubular excretion, there was little agreement, for the evidence seemed full of unintelligible contradictions.
When Cushny 82 wrote his well known monograph, "The
Secretion of Urine," in I9 I7 he stated in his prefatory letter
to Starling:
" It is often complained that the physiology of the kidney
given in textbooks is made up of a wrangle between the two
great views of its activity. • • • I have not avoided the
controversy, but I have at any rate given the ascertained
facts apart from the discussion, so that they at least may
remain, whatever theory of kidney activity may survive.
The different views are presented, and one is advocated
which differs in some respects from any that has been accepted hitherto, and which embraces some of the features
of each of its precursors. Since it has been developed gradu-
THEORIES OF RENAL FUNCTION
2I
ally from the work of many, it would not be fair to attach
to it the name of anyone investigator, and I have therefore
called it 'the modern view' j • • • If it serves as an advanced post from which others may issue against the remaining ramparts of vitalism, its purpose will be attained.
" You will pro,bably complain that instead of presenting
the facts and following them to the: theoretical principle to
which they point, I have just stated the theory and then discussed how far each set of observations can be brought into
accord with it. • • . The facts are so multitudinous that
unless the student were first given some general scheme on
which he could arrange them, he would be lost in detail and
might fail to appreciate where the path was leading."
When the second edition of Cushny's monograph appeared in I926 the issue of "vitalism" was dead, but the
" wrangle" concerning the role of tubular excretion was
not. The processes that once had savored so strongly of
" vital" activity were still warmly defended by many in~
vestigators on quite mechanistic grounds. But the" modern
theory" had accomplished one thing in the interim, the
chief thing which Cushny had desired for it: it had served
to guide investigators so that they could, in a well known
phrase, put intelligent questions to the kidney and hope for
intelligible answers. Which is, of course, the chief function of any theory.
A brief review of Cushny's theory will serve to introd-ace the student to the more recent investigations in this
field. tV'Cushny supposed, as had Ludwig in 1844, that the
initial step in urine f,ormation ~s the separation in the glomerulus of a fluid essentially identical in composition with
THE PHYSIOLOGY OF THE KIDNEY
22
plasma except for the absence of the plasma proteins, to
which the capillaries of the glomerular tuft were presumed
to be impermeable. This capsular fluid is formed at the
expense of the hydrostatic pressure of the blood, and hence
the energy for its formation is supplied in the last analysis
by the heart. The chief endothermic reaction is due to the
circumstance that the plasma proteins must be concentrated
osmotically when protein-free capsular fluid is expelled from
the plasma. The capsular fluid is supposed to contain all
the filterable constituents of the plasma (Na, K, CI, SO"
urea, amino-acids, glucose, etc.) in the same concentration
per unit volume of water * as these are present in the plasma,
except for such inequalities in the distribution of ions as
might arise from the presence of non-filterable proteins
(Donnan effect). Just what molecules P!lss into the filtrate
and what molecules do not, must remain a matter of speculation until the porosity or permeability of the glomerular
tuft is actually measured. But that the great majority of
plasma solutes pass through the glomerulus must be accepted on the grounds that if they did not, the total osmotic
pressure, by tending to draw water back into the capillaries
from the capsular space, would oppose and effectively prevent the process of filtration itself.
JIt follows in principle that such substances as are present
in the plasma but absent from the urine must be reabsorbed
by the tubules as the glomerular filtrate passes along them
on its way to the bladder. It must also be supposed that a
*
The solutes in the filtrate would he more concentrated per unit
volume of solution, in consequence of the abstraction of the plasma proteins, which occupy from 5 to 7 per cent of the plasma volume.
THEORIES OF RENAL FUNCTION
23
large fraction of the water present in the filtrate is also reabsorbed by the tubules, since certain waste products, such
as creatinine, urea, ~tc., may be present in the urine in many
times the concentration that they are present in the plasma,
and therefore in lhe capsular fluid. Cushny, denying the
role of tubular e1cretion, supposed that this increased concentration is effe/-ted only by the reabsorption of water. In
view of the fact that different substances are concentrated
to a different extent, it was supposed that some or all of
these substances are reabsorbed by the tubules in varying
degree. Substances which need to be conserved by the organism, such as sugar, amino-acids, Cl, etc., are perhaps
reabsorbed completely or nearly so, while some waste products, such as creatinine, are possibly not reabsorbed at all.
Cushny believed that substances in the first group are completely reabsorbed so long as the plasma concentration is
below a certain critical or threshold level, and therefore he
called these" threshold" substances, a term first used by C.
Bernard in describing the excretion of glucose. Waste products, such as creatinine, are rejected by the tubules independently of their plasma level, and these he called "no-threshold" substances.
At first sight, the process whereby water and the many
threshold substances which escape frolJl the plasma into the
capsular fluid are reabsorbed appears to be extraordinarily
complex, but Cushny attempted to resolve this complexity by
a simplifying assumption: namely, that what is actually reabsorbed by the tubules is a fluid of constant composition, a
perfected" Locke's solution" or protein-free plasma. The
tubule cells are so constructed, he supposed, that they draw
24
THE PHYSIOLOGY OF THE KIDNEY
from the glomerular filtrate optimal quantities of a fluid
having an optimal composition, and return this fluid to
the plasma, thus maintaining the optimal composition of the
latter. Everything left behind in the tubular urine after the
removal of this optimal fluid passes into the collecting ducts
as the final urine. "The formation of the glomerular filtrate
is due to a blind physical force, the absorption in the tubules
is equally independent of any discrimination, for the fluid
absorbed is always the same, whatever the needs of the organism at the moment." V
It is open to question if the hypothesis of the tubular ab-sorption of a fluid of optimal composition is really a simplification. In order that the tubules may reabsorb a fluid of optimal composition containing a large number of chemical substances in different concentrations, there would seemingly be
required just as elaborate physical-chemical apparatus as for
them to reabsorb each of these constituents separately and
independently. And a preferential choice between tubular
reabsorption and tubular excretion of particular chemical
entities can scarcely be based on physical-chemical grounds,
for this would appear" to be merely a matter of the physiological orientation of the cell. So the advantage of this part
of Cushny's theory is slight. In principle, however, the
theory as a whole was very attractive to most investigators
because it treated the kidney as an organ of fixed and predictable function, like muscle and nerve. But where this
forthright, mechanistic interpretation was its strength, its
weakness lay in its over-simplification, which was achieved
by the a priori exclusion of tubular excretion. True, there
was no incontrovertible proof of the existence of this process;
THEORIES OF RENAL FUNCTION
but neither was there any incontrovertible proof of the existence of either filtration or reabsorption. Every single fact
known about the kidney could have been explained in at least
two ways. The exclusion of tubular excretion was based in
no small measure upon the belief that such a process must
readmit " vitalism," with its uncontrolled and inexplicable
forces, into the domain of renal physiology. In retrospect,
we see that this fear was quite unjustified. Tubular excretion, viewed as a consequence of the physical-chemical organization of the tubule cells, can be looked upon as being as
mechanistic as filtration itself. In fact, in the absence of any
knowledge of how the tubules could absorb the " optimal" .
fluid, Cushny was forced to ascribe this process to " vital
activity," even though this activity was reduced to attractively constant and definable proportions.
So while physiologists were generally prepared to accept
glomerular filtration and tubular reabsorption, at least in
principle, they remained divided on the issue of tubular excretion. The" wrangle" of disagreement, which Cushny
had justly deplored, was little abated until recent years, when
Richards and his collaborators demonstrated beyond question the existence of glomerular filtration and tubular reabsorption, and Marshall and his collaborators demonstrated
the existence of tubular excretion, thus· showing that both
schools were right. Our current knowledge of renal physiology leads us to believe that though glomerular filtration
plays an important part in urine formation, this process is
supplemented by tubular excretion in all animals, including
man. Cushny's idea of the reabsorption of an " ideal fluid"
of constant composition has been confounded by the dis-
THE PHYSIOLOGY OF THE KIDNEY
co very that the reabsorption of water, glucose, chloride,
phosphate and perhaps other substances are more or less
independent processes, and that in addition considerable
quantities of waste products, such as urea, uric acid and S04
are normally, though perhaps incidentally, reabsorbed as
well. For the time being we are forced to premise that the
kidneys of different species will handle various substances
in quite different ways. Thus the simplification which the
Cushny theory strove to achieve has momentarily been lost.
It is not inappropriate to point to the history of renal
physiology as typical of the history of science, and particularly of the history of medicine. It has been a history of
rival theories, each based upon inconclusive evidence. Its
errors have been compounded of over-simplification in the
matter of theory and under-examination in the matter of
critical investigation.
IV
GLOMERULAR FILTRATION
IN RECENT years new methods for the examination of the
kidney have been devised that demonstrate, as Ludwig and
Cushny had supposed, that the initial process in the formation of urine consists of simple physical filtration in the
glomeruli. The chief of these methods are those developed
since 1924 in the laboratory of Professor :Richards for determining the actual composition of the capsular fluid of
the frog (R. pipiens) , the mud-puppy (N. maculosus) and
other cold-blooded animals. Richards and his collaborators
have adapted the Chambers microdissection technique so
that the capsular fluid can be withdrawn as fast as it is
formed in the glomerular capsule. This fluid, and also the
plasma obtained simultaneously from the same animal, have
been analyzed for various constituents by biochemical methods adapted to quantities no larger than 0.5 cubic mm.cr. 861,870
" Capsule puncture" was first applied by Wearn and Richards,4811 to the demonstration that the glomerular fluid normally contains no protein, thus substantiating a central point
of the filtration theory. It was also shown that the capsular
fluid may contain glucose and chloride when the bladder
urine is free of these substances, thus demonstrating the
actuality, in these two instances at least, of tubular reabsorption.
THE PHYSIOLOGY OF THE KIDNEY
Subsequent investigations have shown that in both the
frog and Necturus the osmotic pressure of the capsular
fluid and of the blood plasma from which it is formed are
the same, as is also the electrical conductivity.l8· 45B The
chloride content of the capsular urine in both animals is on
the average a little higher than that of plasma; although
the difference is within the error of the method it may
be a real one explicable by a Donnan equilibrium.ll8• 486. 469
Urea/ 57 glucose/82 inorganic phosphate/56 creatinine 48 and
uric acid 42 (the last also studied in the snake) are present
in the capsular fl~id in the frog in the same concentration as
in plasma. The capsular fluid also has the same pH as the
plasma.8ol ,830 Moreover, it is possible to collect filtrate fromt:
a single capsule at such a rate that, when the total number of
glomeruli in the two kidneys is taken into account, the quantity of water filtered is well above the maximum rate of urine
excretion. * In certain details these results have been confirmed by White and Schmitt 488 and Ekehorn.105
That the blood pressure in th,e glomerular capillaries is
adequate to effect filtration against the colloid osmotic pressure of the blood has been shown by the observations of
Hayman 170 on the frog and of White 477 on Necturus.
It is therefore established that the capsular fluid in the
frog and Necturus is, in its chief features, a protein-free
fluid such as would be formed by physical filtration from the
*
This calculation indicates that glomerular filtration could adequately
account for all the water excreted, but similar calculations must be applied
with caution to the excretion of other substances where a range, not of
several hundred per cent, but of 25 or 50 per cent, is critical in answering
the question of whether or not glomerular filtration is the sole process in~
volved in their excretion.
tiLOMERULAR FILTRATION
29
blood, and that this filtrate is sufficient in quantity to account for all the water excreted. So we may dismiss from
consideration, in these animals at least, the possibility that
the glomerular apparatus performs anything in the nature
of a specific excretory oper~tion.
One might infer that a similar process of filtration occurs
in the mammals, since the structure of the glomeruli in the
mammals and Amphibia is so much alike. But such an inference is perhaps dangerous in view of the great phylogenetic gap between the cold- and warm-blooded animals. We
must therefore consider' brieHy the independent evidence
bearing on glomerular filtration in the higher forms. Direct
analysis of glomerular filtrate in mammals has not been
made, since the glomeruli are not close enough to the surface of the kidney to be accessible, and the evidence is therefore of an indirect nature. The chief experimental approach to this problem has been the observation of the effect
of perfusion pressure on urine formation, in various semimechanical preparations where the pressure can be accurately
controlled.
The first experiments along this line were performed by
Starling 480 in 1899. In 1914 Bainbridge and Evans 11 developed a method of providing a denervated and isolated
kidney with blood from a heart-lung circulation so that renal
function could be observed under controlled but widely
varying conditions. This heart-lung-kidney preparation has
been used by Starling, Verney and others to examine the
effects of blpod pressure, blood How, etc., upon urine forma tion. 84, 192, 481 In ~ 9 I 5 Richards and Drinker 882. designed
an apparatus for the continuous perfusion of the kidney,
THE PHYSIOLOGY OF TH~ KIDNEY
30
which was subsequently used by Richards and Plant 88'. 885. 888
to study the action of adrenaline upon the renal circulation.
The original heart-lung-kidney preparation has been elaborated into a heart-lung-double kidney '50 and a double heartlung-double kidney 81 preparation, and Hemingway 189 has
designed a pump-lung-kidney, the lung being retained to filter
certain toxic or vasoconstrictor substances out of the blood.10'
Although these semi-mechanical preparations have been valuable in the early stages of renal investigation, they suffer
severe limitations. Normal function has never been obtained
with either the perfused kidney or the heart-lung preparation, renal activity being easily impaired by ischemia,
asphyxia, traces of hemolysis, anticoagulants, hemoconcentration, the appearance of vasoconstrictor substances in defibrinated blood, the absence of hormones, etc. But, although
the method appears to be incapable of answering the finer
questions of renal physiology, certain of the results offer
evidence in favor of glomerular filtration.
When the rate of blood flow an.d other factors are kept
as constant as possible the rate of urine formation varies in
the same sense as the arterial blood pressure, and variations
in urine flow induced by adrenaline, etc., are paralleled by
variations in the perfusion pressure. Thus, when the systemic blood pressure is reduced to about 75 mm. urine formation is arrested,9' presumably because the hydrostatic
pressure in the glomeruli _is insufficient to overcome the
osmotic pressure of the plasma proteins and filtration no
longer takes place. Or again, when the ureteral (urine)
pressure is raised to about 30 mm. above atmospheric pressure, urine formation stops; here one presumes that the
GLOMERULAR FILTRATION
31
ureteral pressure, transmitted back to the tubules, opposes
the filtration pressure in the glomeruli.11I2• 490 As a rough
approximation, these are the results to be expected under the
filtration hypothesis; we may assume a mean arterial pressure of 110 mm. of Hg., and a normal fall of 55 mm. by
the time the blood reaches the glomerular capillaries; deducting 25 mm. as due to the colloid osmotic pressure of the
plasma proteins,. we have left an effective filtration pressure of 30 mm., and any change in arterial pressure will result in a change in the filtration pressure and, therefore, in
the rate of filtration.
But under the terms of the filtration-reabsorption theory,
which these experiments are designed to test, it is irrational
to expect changes in filtration rate to be perfectly reBected
by changes in urine _flow. Since it is assumed that a great
fraction of the filtered water is reabsorbed by the tubules, it
must be recognized that proportionally very small changes
in this reabsorbed fraction, due to variations in pressure,
blood composition or other variable factors during the experiment, could lead to marked changes in urine How which
might either simulate or obscure changes in the rate of filtration itself. Among other functions of the tubules which are
disturbed in the heart-lung or isolated kidney is the capacity
to excrete a concentrated urine, and it-- is likely that such
parallels between perfusion pressure and urine flow as have
been observed are in part due to this circumstance. The
general results do, however, support the filtration hypothesis,
and indicate that the glomerular pressure is about two-thirds
of the arterial pressur_e.481 , 499
The selective excretion of large molecules is further evi-
THE PHYSIOLOGY OF THE KIDNEY
32
dence that the glomerular membrane is acting as a simple
filter. Bayliss, Kerridge and Russell 17 have shown that when
various proteins are injected intravenously in cats and rab.
bits, or added to the defibrinated blood which is perfused
through the isolated dog kidney, hemoglobin (mol. wt. =
67,000), egg albumin (35,000), Bence-Jones protein (35,·
000) and gelatin (35,000) are excreted; while serum al.
bumin (72,000), serum globulin (17°,000), casein (200,000), edestin (200,000) and hemocyamin (5,000,000) are
not excreted. This selective excretion of large molecules
is what would be expected of a simple filter. Fixed sections
of isolated kidneys which have been perfused with egg albumin for half an hour show a deposit of protein in the
capsular space as well as in the lumen of the tubules, indicating that the protein has escaped through the glomeruli.
Other experiments involving the dilution of the plasma
proteins, the use of poisons such as cyanide, anoxia, cold,
etc., to destroy the activity of the tubule cells are necessarily ambiguous and need not be reviewed here.
Though none of the above evidence is absolutely conclusive, it has been sufficient to convince most investigators
that the filtration of a relatively large quantity of fluid occurs in the glomeruli of the mammals, as of the Amphibia. *
However, a contrary view is held by O'Connor and Conway,
who believe that the rate of glomerular filtration is approximately equal to the rate of urine formation, and that the
concentration of various substances in the urine can be accounted for by a diffusion-secretion process. 78, 1'4 Lack of
*
For summaries of the older investigations reference may be made
to Cushny's monograph (znd edition, 19Z6) or to the papers by Richards 8fi7, Bfi9, 870 and Marshall. 2GS
GLOMERULAR FILTRATION
33
space prevents a detailed criticism, but this theory appears
to be at variance with all the known facts.
A new line of evidence in favor of filtration, entirely inferential, but having the advantage of being more precise
and applicable to the intact and normal animal, lies in the
recent demonstration that several substances may be excreted at an identical rate, relative to their respective plasma
concentrations (chapter XIII). In the normal dog, for
example, this is true of inulin, creatinine and ferrocyanide;
and, after the administration of phlorizin to block the reabsorption of sugars, it is also true of glucose, xylose and
sucrose. It is difficult to believe that six different substances
could be handled in precisely the same manner by specific
cellular processes; on the other hand, the result is consonant
with the belief that all of these substances are simply filtered
at the glomerulus and pass down the tubules without the
filtered material being either reabsorbed or supplemented by
tubular excretion.
It is significant in considering the question of ~lomerular
filtration in the Amphibia and mammals to observe that
the blood pressure in the latter is much higher than in the
former. In man the mean systolic pressure may be taken as
110 mm. Hg. and t~e average osmotic pressure of the
plasma p.roteins as 24 mm.,887, 484 in COt;ltrast to the figures
29 mm. and 7.7 mm, respectively, in the frog. so, 170, 2S8, 476,47'1'
Assuming that the blood pressure is reduced by one-third to
one-half in the glomeruli of both animals, one would expect
a considerable higher filtration pressure in the warm-blooded
form, and therefore a greater volume of filtrate relative to
each unit volume of blood.
v
TUBULAR REABSORPTION
THE methods developed for the collection and analysis of
glomerular fluid have also been applied by Richards and
Walker 871 and their co-workers to the study of the tubular
fluid of frogs and Necturi. Tubules have been punctured
at various levels and fluid removed for analysis, or fluid of
known composition has been perfused through a tubule by
two micropipettes, the lumen of the tubule to either side being closed by the injection of a globule of mercury or mineral
oil.
The extent of the reabsorption of water, the most important constituent in the glomerular filtrate, is the most difficult to determine, and for this reason it is uncertain whether
a change in the concentration of a particular substance as it
passes down the tubule is due to the addition or subtraction
of water, or of the substance itself. Since no fluid can be
collected from a tubule when the glomerulus is cut off by
compression it is assumed that no water is excreted by the
tubule. The question whether evidence on the tubular reabsorption or excretion of water can be obtained from studies
on the degree of concentration of various solutes as they
pass down the tubules is considered below.
Since the Amphibia live in fresh water, they normally excrete a very dilute urine in order to compensate for the large
quantities of water absorbed through the skin. The forma-
TUBULAR REABSORPTION
35
tion of a dilute urine necessitates the reabsorption of the
sodium chloride and other osmotic constituents in the tubules. The data in figure 2, adapted from Walker, Hudson,
Findley and Richards,'81 show that there is essentially no
PROXIMAL TUBULE
o
ISTAL TUBULE URETE
o
0
o
o 1.00~~~~~....---:,.....-~""""~i'f-i-----i---;
«
o
a:
i=
«.80
•
~
If)
«
~ .60
"
w
~ 40
o
:::::>
o
o
.20
FIGURE 2
The glomerular filtrate is essentially identical with plasma, so
far as chloride and molecular concentration' are concerned. This
identity is preserved throughout the length of the proximal tubule,
the reabsorption of chloride (and necessarily sodium) occurring in
the distal tubule. (Adapted from Walker, Hudson, Findley and
Richards, 461.)
change in the osmotic pressure of the tubular urine during
its passage along. th~ proximal tubule; the typically hypotonic urine is formed in the distal tubule. Under the as-
THE PHYSIOLOGY OF THE KIDNEY
sumption that there is no tubular excretion of water, the
progressive loss in osmotic pressure observed in the distal
tubule must be due to the reabsorption of osmotically active
constituents, the chief of which is sodium chloride. The
data on the chloride concentration of tubular urine given in
figure 2 supplement the data on osmotic pressure, and indicate that the reabsorption of chloride with its attendant
sodium, and perhaps of other inorganic constituents, occurs
in the distal tubule, the reabsorption of chloride apparently
occurring throughout its entire length.
The urine in Amphibia is typically acid in comparison with
the blood. Montgomery and Pierce,302 using the microquinhydrone electrode to measure the pH of the tubular
urine, have shown that acidification takes place exclusively
in the distal tubule. These precise measurements confirm
the earlier observations of Richards 8S8 that phenol red solution introduced into the tubule changes from red to yellow
only after it has entered the distal segment. The cells which
possess the power of acidificati-on occupy slightly less than
one-fifth of the extent of this segment, and are situated somewhat nearer the distal than the proximal end. Though they
show no outstanding histological features, their location usually coincides with an abrupt widening of the lumen. Their
activity is remarkable, for they can change the reaction of a
0.33 M sodium phosphate buffer from 7.5 to 6.8 in one
minute; this is equivalent to adding one-fourth volume of
0.33 N Hel to this buffer, and exceeds by roo fold the
change in buffering capacity required to effect acidification
of normal tubular urine. The nature of the acidification
process is discussed further in chapter XVI.
TUBULAR
REABSORPTIO~
37
Since glucose is present in the glomerular filtrate when
it is simultaneously absent from the urine, it follows that,
like chloride, it must he reabsorbed by the tubules. That
this reabsorption occurs in the proximal tubule of N ectufus
1(>
PROXIMAL TUBULE
cno·.
0
01..20
••••
a: l.00 •
<{
~
~
en
<{
.80 l-
-'
a.
~ 60
z
iX
::::>
.40
0
....~4.
•
• •
......
i
••
~
0
••
I>
~
•••
••
•
o.
:.
~.
0
•
o •
0
20
•
-.••
.,
•
0
o
•
•
• •• • •••
•
• ••••
0
i=
<{
DISTAL TUBULE URETER
GLUCOSE NECT. FROG
0
NORMAL
0
PHLORIZIN
• •
•
0
1.40
=
~
. ·0....
0
eo
•
o •
o •
•
0
0
•
~
a.
FIGURE 3
The glucose contained in the glomerular fi,ltrate is reabsorbed in
the proximal tubule of the normal frog and Necturus. After adequate doses of phlorizin, this reabsorptive process is blocked and
the giucose is concentrated in the proximal tubule to a slight extent by the reabsorption of water. (Adapted from Walker and
Hudson, 458.)
was first shown by White and Schmitt.488 Data from the
more extensive experiments of Walker and Hudson 4G8 con-
THE PHYSIOLOGY OF THE KIDNEY
firming this are given in figure 3. It may be observed that
whereas glucose is present in the glomerular filtrate in the
same concentration as in plasma, the concentration diminishes rapidly as the filtrate moves down the proximal tubule.
When this has been half traversed the concentration may be
as low as it is in the ureteral urine. However, the capacity
to reabsorb glucose is not limited to the proximal half of
the proximal tubule, for when Ringer's solution containing
glucose is slowly perfused through the distal half of the
proximal tubule the sugar is also reabsorbed. On the contrary, when a glucose solution is perfused through the distal
tubule, its concentration remains the same or increases. The
sole site of the selective reabsorption of glucose appears,
therefore, to be the proximal tubule.
The reabsorption of glucose is decreased by raising the
concentration of glucose in the plasma; the reason for this
threshold effect will be considered in a later chapter. It has
long been known that the drug phlorizin causes glucose to
be excreted in mammals and other animals, a phenomenon
attributed on the basis of other evidence to a specific action
in blocking tubular reabsorption. Phlorizin does not affect
the concentration of glucose in the glomerular filtrate of
N ecturus, but it does abolish the capacity of the proximal
tubule to reabsorb it. In fact, in the phlorizinized animal
the glucose concentration increases perceptibly as the fluid
traverses the proximal tubule itself (figure 3). This fact
cannot be attributed to the tubular excretion of glucose,
since all the available evidence in Amphibia as well as
other animals argues to the contrary; but it may be attributed
to the reabsorption of water. In this view, it must be con-
TUBULAR REABSORPTION
39
eluded that the reabsorption of water in the proximal tubule, as compared to the distal tubule, is slight since under
phlorizin glucose may be present in the ureteral urine in
concentrations 2.5 times as great as in the plasma. If one
could assume that the phlorizin had completely blocked the
reabsorption of glucose one could calculate from the relative degree of concentration (or U IP ratio) of glucose the
relative amount of water reabsorbed from the glomerular
filtrate, but Walker and Hudson do not believe that such is
the case; on the basis of experiments in which glucose solutions are perfused through the tubules of phlorizinized N ecturi they conclude that some of the sugar escapes through
both the proximal and distal tubule by diffusion. But an
approximate idea of the locus and degree of water reabsorption is given by these experiments.
In contradistinction to chloride, phosphate, which is ingested as such in food and also formed as a waste product in
the combustion of protein and fat, is usually concentrated
by the kidneys of the frog and N ecturus. Walker and
Hudson 480 have shown that the U IP ratio of phosphate
rises progressively as the urine passes through the proximal
and distal tubule, concentration being effected most rapidly
in the latter. The final U/P ratios of phosphate (3.3) and
of glucose (3.1) in phlorizinized Necturi-are so nearly alike
that one may conclude that there is sufficient reabsorption
of water to account for the concentration of phosphate,
even if some of the glucose is diffusing back, as is suggested
above.
It should be noted that although phosphate is usually concentrated by the tubules (though never to an extent greater
THE PHYSIOLOGY OF THE KIDNEY
40
than glucose under phlorizin) it may sometimes be absent
from the urine. In such instances it is reabsorbed by the
proximal tubule. Thus phosphate resembles glucose in that
it may at one time be reabsorbed by the tubule, and at another time rejected.
That in the frog urea is excreted in part by tubular activity
was first suggested by Marshall. 26T This conclusion is based
upon the observations that urea may be concentrated in the
urine, as compared to the plasma, as much as 20 to 34 times,
whereas the pentose, xylose, which is only slightly reabsorbed, * is never concentrated more than three times. The
progressive rise in the concentration of urea along the tubule, as observed by Walker and Hudson,41S9. 460 is so marked
that this substance is, on the average, 7.8 times more concentrated in the bladder urine than in the plasma. In contrast, glucose under phlorizin and· phosphate in normal animals are concentra ted to a l~sser degree (2.7 times). This
discrepancy is so great that Walker and Hudson conclude
that in the frog some urea is excreted by tubular activity.
This conclusion is fortified by two additional facts: the observed rate of urea excretion in frogs requires an average
glomerular filtration rate greater than is normally observed;
and the rate of excretion is not directly proportional to the
plasma level. For reasons which will be discussed in chap.
ter VIII, this last point strongly indicates tubular excretion,
In marked contrast to the situation in the frog, in phlorizinized N ecturi the U IP rati~ of urea is rarely greater than
*
Reasons for believing that there is very little reabsorption of xylose,
even in the normal animal, are given .in chapter XIII.
TUBULAR REABSORP1iON
41
that of glucose or phosphate; the reabsorption of water
appears to be sufficient in this animal to account for the
maximal tubular concentration of urea.
The above experiments demonstrate the existence of glomerular filtration and tubular reabsorption in the Amphibia;
specifically they show that the reabsorption of certain substances is a function of certain parts of the tubule and in a
single instance, urea in the frog, they constitute good evidence of tubular excretion. But in the final analysis, ambiguity again enters into their interpretation since it is impossible to determine exactly how much water is reabsorbed.
To put the problem in general terms: in order to know
whether any substance undergoes tubular reabsorption or
tubular excretion, it is necessary to have as a standard of
reference some substance which is known not to undergo reabsorption or tubular excretion; then the change in concentration which that substance undergoes in passing down the
tubule will reveal the extent of water reabsorption, since this
will be dependent only upon water reabsorption. If any
other substance present in the blood and urine at the same
time is concentrated to a lesser or greater extent than the
first, this can only be due to the tubular reabsorption or tubular excretion of the second substance. In the above experiments it might be assumed that the reabsorption of glucose is completely blocked by phlorizin, thus satisfying the
above requirements. But even so, there would remain the
possibility that phlorizin might also impair other important
tubular processes and the use of such a drug would be physiologically unsound. It will be. our task in a later chapter to
THE PHYSIOLOGY OF THE KIDNEY
inquire if an ideal substance for this purpose can be found,
but first it is necessary to consider the question of tubular
excretion. We have seen evidence in the above discussion
that this process may occur, and we will now turn to evidence
that demonstrates its existence beyond doubt.
VI
TUBULAR EXCRETION
A GREAT part of the older evidence. adduced for tubular
excretion was based upon experiments with the frog's kidney.
This organ in the Amphibia, as in the fishes, reptiles and
birds, receives a double supply of blood, the renal artery
exclusively supplying the glomeruli while part of the tubular
system is supplied by the renal-portal vein. In 1878 Nussbaum proposed to take advantage of this double circulation by ligating the aorta or the renal artery and injecting
into the renal-portal vein various substances, the excretion
of which he wished to follow. In 1906 Cullis improved the
experiment by the perfusion of the arterial and venous systems separately. The original Cullis experiment has been
perfected to permit the perfusion of arteries, veins, or both,
at definite pressures; in one modification or another it has
been widely used to obtain evidence on the relative function
of the glomeruli and tubules, and an enormous literature
has accumulated on this subject.ot.los However, it has
been shown by Richards and Walker,8s8 Hayman 177 and
others that the glomeruli are available to the portal perfusion fluid by way of anastomoses within the kidney, and
Kempton 224 has shown that after the renal artery is ligated
the perfusion fluid can reach glomeruli by way of collateral
arteries from the ureters. Consequently any experiment in
THE PHYSIOLOGY OF THE KIDNEY
44
which restriction of the perfusion fluid to definite parts of
the kidney is assumed must be interpreted with caution.
In addition to perfusion experiments, a large literature has
accumulated on the microscopic observation of the renal
tubules during the excretion of dyes. But all experiments
i"n which dyes are demonstrated to be present in the tubule
cells of glomerular kidneys are suspect since the dye may
gain access to the cell by way of the lumen. Dyes may
also be taken up by the tubule cells from the external surface without subsequently being excreted into the lumen i
i.e., their properties are such that they act as vital stains
and are stored in the cell.84 Consequently phenomena of
vital staining and the mere renal extraction of dyes from
the blood have an uncertain bearing upon tubular excretion. 183• 819.820.4,011 Both because of lack of space and because
of their possible ambiguity, experiments such as the above
will not be considered here.
AGLOMERULAR KIDNEY
In 1902 Huot discovered that the kidneys of certain marine teleosts contain no glomeruli, and subsequent investigations have considerably extended the list of aglomerular species. In some families of marine teleosts there
may be numerous and well-developed glomeruli, in other
families the glomeruli may be very few or very poorly developed, and in still others they may be entirely absent. 28o
In, some fishes there are a few glomeruli that are functional in
the young animal, but that degenerate in the adult stage. l6lI• 156
The evolution of the aglomerular kidney in the marine
teleost has been interpreted by Marshall and Smith 280. 418 as
TUBULAR EXCRETlON
45
an adaptation to an oliguria associated with a sea-water
habitat, which medium is considerably hypertonic to the
blood of vertebrates. The aglomerular condition may be
viewed as a terminal state in the progressive degeneration
of glomerular function; there is no reason to believe that
the functional capacities of the aglomerular tubules are essentially different from those of the glomerular kidney. In
accordance with a sound principle of comparative physiology
we may look for continuity of function in the renal tubules,
as in other homologous organs.
In 1928 Marshall and Graffiin lBO. 273 and Edwards DD undertook the re-examination of the aglomerular kidney. Marshall and GrafHin serially sectioned the kidney of the goosefish (Lophius piscatorius) and demonstrated that it can be
considered to be truly aglomerular, although it contains about
one non-functional, pseudo-glomerulus to every 2000 tubules.
A little later the kidney of the adult toadfish (Opsanus tau)
was shown by GrafHin m to be entirely aglomerular, and
Armstrong (personal communication) has shown that a
glomerulus does not develop in the embryonic pronephros
in either this fish or the pipefish. The whole function of this
kidney is performed by blind tubules made up of high or
cuboidal epithelium possessing brush border and corresponding closely to the proximal segment Qf the Amphibian and
mammalian tubule. It has a structure that points strongly
in the direction of highly specialized chemical operations,
with nothing comparable to the filtration apparatus of the
glomerulus. The blood supplied to these aglomerular tubules is venous and probably has a hydrostatic pressure lower
than the osmotic pressure of the plasma proteins, so that it
THE PHYSIOLOGY OF THE KIDNEY
is difficult to imagine how filtration could occur. A microphotograph of a cross section of the kidney of the aglomerular toadfish is given in plate I (see frontis.).
It has been shown in the above studies of the kidney of
the goosefish, in Marshall's subsequent study of the toadfish,StU. 274. and in Edwards and Condorelli's 102 study of the
pipefish and sea horse, that the aglomerular kidney can
excrete most of the ordinary urinary constituents: water,
creatine, creatinilte, urea, uric acid, magnesium, sulphate,
potassium and chloride: and, among foreign substances,
iodides, nitrates, thiosulphates, sulphocyanides and the dyes,
indigo-carmin, neutral red and phenol red.
In view of this highly developed excretory capacity for
some substances, it is all the more significant that the aglomerular kidney is unable to excrete certain other substances,
among which are ferrocyanide, glucose 265.289 and cyanol,201
all of which are readily excreted by the glomerular kidneys
of other animals, and albumin,82 which under certain circumstances, at least, may be excreted by glomerular kidneys.
Even when large doses of glucose are given to raise the blood
level, along with maximal doses of phlorizin, the urine of the
aglomerular fish remains sugar-free. Subsequent investigations have shown that other carbohydrates (xylose, sucrose
and inulin), which are readily excreted by glomerular kidneys, are not excreted in the urine of the aglomerular
fish.403. 419
The aglomerular kidney shows the phenomenon of a
" threshold": i.e., chloride may disappear from the urine
under some conditions, and under others it may be present
in large amounts. Other substances (creatine, phenol red,
TUBULAR EXCRETION
47
sulphate, magnesium) may be present in the urine in concentrations many times the simultaneous concentrations in the
plasma, a circumstance requiring the expenditure of energy
in the excretory process, energy which is presumably derived
from the local metabolism of the tubule cells. The rate at
which phenol red can be excreted by the toadfish kidney has
an upper limit 88 implying some physiological limitation in
the excretory mechanism. The urine may be excreted against
a hydrostatic pressure higher than the dorsal aortic pressure, indicating that the excretion of water is an active rather
than a passive proces~.81 Certain excreted substances (magnesium sulphate,. creatinine, etc.) induce an increased excretion of water, or diuresis, by local action on the kidney.a4. 85
One might suppose that substances could diffuse into the
lumen of the aglomerular tubule at one point and then be
concentrated by reabsorption of water at another point.
But its structure is inconsistent with this idea, the cells being
high cuboidal epithelium, and essentially uniform throughout the length of the tubule. The idea of diffusion is further controverted by the inability of the aglomerular tubule
to excrete certain very diffusible substances, such as glucose,
xylose, ferrocyanide, etc., all of which are readily excreted
by the glomerular kidney. Instead, one is forced to believe
that the tubules have, in the course of their evolution, acquired the ability to withdraw directly from the blood the
normally occurring waste products as well as certain foreign
substances which resemble these waste products in some particular respect, and to excrete them into the lumen. For
other substances (carb_ohydrates, etc.) an excretory capacity
has never been evolved, and the general permeability of the
THE PHYSIOLOGY OF THE KIDNEY
tubules is so low that no significant quantity of these nonexcreted substances can diffuse across the cells to appear in
the urine.
IN
VITRO CULTURES OF THE CHICK TUBULE
Chambers and Kempton 85 have shown that the tubules of
the mesonephros of the chick can be cultured in vitro. During the first few hours of incubation, the open ends of fragmented proximal tubules become closed, and the lumen
gradually becomes distended with fluid, forming a spherical
or elongate cyst. When phenol red is added to the culture
medium in small amounts the dye is taken up by the tubule
cells and discharged into the fluid of the distended lumen
in high concentration. There is no storage of the dye in the
tubule cells during this process of excretion. When the dye
is injected directly into the lumen no detectable quantity of it
is taken up by the cells, even though the lumen is dilated by
the force of the injection. The absence of a glomerulus or
any aperture through which the dye might enter the sealed
tubule, the fluid of which may actually be under pressure i
the transportation of dye from a low concentration to a high
concentration i and the apparent uni-directional " permeability" (which perhaps merely reflects the tendency to establish
a high concentration gradient between plasma and urine)
afford a direct visualization of the process of tubular excretion. This phenomenon is displayed only by the cells of the
proximal tubule, the distal tubule showing no capacity to
excrete phenol red or other dyes.
Lowering the temperature of the culture to 3-6 0 C. stops
the excretion of both water and phenol red, as also do
TUBULAR EXCRETION
49
cyanide, hydrogen sulphide, anoxia and sodium iodoacetate,
but carbon dioxide has little effect.lll, 82 The pH of the cyst
fluid in which the phenol red is concentrated is greater than
8.0, while the cytoplasm of normal tubule cells appears to be
nearly neutral, pH 6.8 ± 0.2. The cyst fluid is normally
nearly isosmotic with the culture medium, and its formation
is accelerated by the presence of phenol red or magnesium
sulphate in the medium.225 After injury the cells become acid
(pH 5.2).83
The above evidence leaves no doubt that tubular excretion is a reality, and although many more problems have
been raised by this discovery than can be quickly answered,
tubular excretion must be admitted as a possibility in the
higher animals. We must assume, in the absence of. evidence to the contrary, that the mammalian tubule may excrete at least some waste products and foreign substances.
But we must also recognize that, although filtration, reabsorption and tubular excretion may all have played a role
in the primitive kidney, as filtration becomes increasingly or
decreasingly dominant tUbular excretion may undergo a con,
comitant change in functional importance. It has been seen
that two such closely related animals as the frog and Necturus may differ in respect to the tubular excretion of urea;
even gr~ater functional differences would be expected to
exist between the fish or Amphibian and man. In respect
to the relative importance of glomerular filtration, tubular
reabsorption and tubular excretion, the human kidney must
be examined on its own rights - and, in fact, the normal
human kidney may be expected to differ considerably from
the kidney that is alte~ed by disease. ,It is of interest to
THE PHYSIOLOGY OF THE KIDNEY
50
note that the recent investigations of MacNider 250 and
Oliver and his co-workers cr. 240 indicate that aglomerular tubules, which from their structure appear to possess some
excretory function, may be formed in the dog and human
kidney during the course of experimentally induced or naturally occurring chronic nephritis. Though the discussion of
the function of the kidney in disease lies beyond the scope of
this book, it will be our task in subsequent chapters to examine methods by which the importance of both glomerular
and tubular function may be evaluated.
VII
INULIN CLEARANCE
IT
.
WILL
THE CONCEPT OF RENAL CLEARANCE
.
facilitate future discussion of a1l phases of renal
physiology if we introduce at this time the concept of renal
"clearance," an expression that has come into widespread
use as a quantitative statement of the excretory activity of
the kidney.
The term clearance was first used in connection with the
excretion of urea by Moller, McIntosh and Van Slyke 299 in
1928, who defined it as the volume of blood which one
minute' s ~xcretion of urine suffices to clear of urea. Since
all the blood flowing through the kidneys is partially cleared
of urea, this is of course a virtual rather than a real volume.
It is obtained by dividing the quantity of urea excreted per
minute by the quantity contained in each cubic centimeter of
blood; i.e., if U = concentration of urea in urine, V = cc.
of urine formed per minute and B = concentration of urea
in the blood, the clearance is given by the expression UVlB.
Moller, McIntosh and Van Slyke did not attempt to explain the urea clearance in terms of any particular process
in the kidney. They were primarily interested in obtaining
a mathematical expression to describe the capacity of the
diseased as compared with the normal kidney to excrete
urea, and it appt:_ared that when the urine flow exceeded a
certain minimum rate (the augmentation limit), the urea
THE PHYSIOLOGY OF THE KIDNEY
clearance was fairly constant in anyone individual, and independent of the rate of urine formation. However, it is
convenient to dissociate the concept of clearaf?ce from this
historical connection with urea, and since 1932 the term has
been widely used to describe the excretory activity of the
kidneys for other substances.
We may say that one function of the kidneys is to" clear"
the blood of waste products and foreign substances. The
virtual volume of blood which is completely cleared of a
particular substance by the kidneys in one minute's time is
given by the expression UV/B, where these terms have the
meaning defined above. Since U x V equals the quantity of
substance excreted per minute, if one divides this quantity
by the amount, B, contained in each ~olume of blood, the
result gives the virtual volume of blood cleared, or, as it is
commonly called, the" clearance." It should be noted that
the clearance is also the minimum volume of blood required
to furnish the quantity of substance excreted in the urine in
one minute's time. This notion of clearance is perhaps more
useful for some purposes than the definition in terms of
virtual volume.
Whether the clearance is a whole blood or a plasma clearance depends upon whether one uses the whole blood or
plasma concentration in the calculation. The result will be
different in proportion as the substance under investigation
is unequally distributed between plasma and the cells. In any
case, physiological reasons favor the choice of the plasma
clearance. The accurate comparison of whole blood clearances in the case of different individuals or of different substances is in part vitiated by variations in the hematocrit,
INULIN CLEARANCE
53
unless this is measured and the actual distribution of the substance under investigation is taken into account. Moreover,
the process of filtration is the central excretory process in the
glomerular kidney, and this is fundamentally independent of
the hematocrit; since only the plasma is filtered, the filtration
process is necessarily a plasma clearance, and this method
of expression for other substances permits a direct and uncomplicated comparison. The plasma clearance should of
course be written UV/P inst~ad of UVlB. Throughout this
book· the term It clearance" refers to plasma clearance
(UP / P) unless otherwise indicated.
In the measurement of a consecutive series of renal clearances the urine is collected at frequent intervals, preferably
by catheter, and samples of blood are drawn at stated periods
during the course· of the experiment. After analysis the
several plasma concentrations are plotted against time and
the precise values at the middle of each urine-collection
period are determined by interpolation. This procedure is
particularly necessary if the plasma concentration is changing rapidly, as is likely to be the case where foreign substances have been administered by any route. *
*
It is unnecessary to enlarge upon possible sources of error in clearance determinations, but due consideration should be given to the appropriate method of calculating the mean concentration existing in the plasma
during each urine-collection period. One of the simplest methods is to
use a semi-logarithmic graph, plotting the plasma concentration logarithmically against time, and then to interpolate to the mid-period. Although this
method does not yield the mean concentration it approximates it more closely
than simple linear interpolation, particularly after single intravenous injections.
Creatinine, which is readily ab!!Orbed from the intestinal tract, may be
administered by stomach; inulin, which would be destroyed by digestive
enzymes, and phenol red, which is not absorbed to any significant extent
THE PHYSIOLOGY OF THE KIDNEY
54
TABLE I
Two
(E.B., SURFACE
The first column gives the elapsed time from the ea.d
of the rapid priming infusion and the beginning of the slow infusion.
SERIES OF TYPICAL CLEARANCES ON A NORMAL SUBJECT
AREA
= 1.92
11=
~
~
·cII
SQ. M.).
Urea
Phenol Red
Inulin
Clearance
"
:::0
..!l"
.......
-- -- --- -- --~ -cc. -------- -J :g...."
mgm. mgID.
mgID. mgm.
eCo
mgm. mgm.
ce.
cc.
P
U
U/p
u
P
;:::l
per
per
min. 100cc. 1DOc,,-
u/p
per
per
l00ee. l00cc.
per
- - --
P
UjP
U
Urea Inulin
Phenol
Red
min.
per
min.
1i!: .......~
- -
122
134
120
147
137
ISS
380
413
339
418
398
435
3.11
3.08
2.82
2.84
2.88
2.81
0.53
0.43
0.45
0.47
0.44
0.48
71.7
70.3
62.7
70.5
72.6
131
132
120
125
125
421
418
399
437
454
3.21
3.16
3.33
3.49
3.64
0.55
0.53
0.52
0.56
0.58
Average 69.6
127
426
per
per
10Occ. l00ee.
per
per
min.
Observations on November 9, 1936
33
SO
60
72
82
94
104
Bladder emptied and washed with saline
U
1.7
1.3
1.9
1.8
2.5
16.7
16.8
16.8
16.2
15.8
15.9
257
572
704
592
533
478
15.4
34.0
41.9
36.5
33.7
30.0
95
96
97
98
98
98
2762
7550
8980
7600
7430
6070
29.1
78.6
92.6
77.6
75.8
62.0
0.940
0.920
0.915
0.910
0.905
0.890
85.0
223.7
238.4
200.2
200.2
154.8
90.4
243.2
260.6
220.0
221.3
174.0
64.6
57.8
54.5
69.4
60.7
75.0
-- --136
397
Average 63.7
Observation. on November 13, 1936
36
4513.8 13.7 71.2 52.0
5411.5 13.5 82.5 61.1
65 6.7 13.5 126.4 93.6
76 6.2 13.6 154.5 113.6
84 4.9 13.7 203 148.1
Bladder emptied and washed with saline
89
92
96
102
106
846
1058
1720
2055
2695
9.5
11.5
17.9
20.1
25.4
1.01
0.99
0.96
0.92
0.90
30.8
36.0
57.2
64.8
83.3
30.5
36.4
59.6
70.4
92.6
- - -- --
To illustrate by specific examples, two series of urea, inulin
and phenol red clearance determinations in man are sumfrom the intestine, must be administered parenterally. Since inulin is not
absorbed quickly from subcutaneous injections it is administered intravenously, dissolved in I per cent saline, and this same practice has been foun~
to be most convenient for phenol red and other substances. The most accurate results are obtained when the plasma concentrations of various substances under investigation are kept as nearly constant as possible, and for
this reason continuous intravenous infusion is now used by the author and his
collaborators in nearly all observations on man.
INULIN CLEARANCE
55
marized in table I. No urea was administered in this instance because there was a sufficient concentration of this
substance already present in the plasma. A rapid infusion
of saline containing inulin and phenol red was given for
about 10 minutes as a priming dose, after which a more
dilute solution was infused at the rate of 4 cc. per minute,
the infusion being continued throughout the observations.428
The urine was collected from the bladder by catheter, which
was left in place throughout the observations. A few minutes
before the end of each urine-collection period the bladder
was emptied, washed out with a known volume of saline
and the wash-fluid expelled by insufflation with air. The
volume of the wash fluid was deducted from the total volume
of the urine in each period in order to obtain the true urine
flow. It is unnecessary to describe here the chemical procedures used for the analysis of the plasma and urine, which
must, of course, be adapted to yield the highest possible
accuracy.
Without, for the moment, dwelling upon the absolute
values of these clearances, attention is called to the fact that
their values do differ considerably. To apply the definition
of clearance, it may be said that in the first series of observations the average minimum volumes of circulating plasma
required to supply the excreted urea, inulin and phenol red
were, respectively, 63.7, 136 and 397 cc. per minute.
PHYSIOLOGICALLY POSSIBLE EXCRETORY OPERATIONS
The actual value of the renal clearance of a particular sub~
stance reveals nothing about the physiological operations by
which it is excreted. - But the very fact that the clearances
THE PHYSIOLOGY OF THE KIDNEY
of various substances do differ reveals that the kidney must
handle these substances by different means. Excluding
chemical transformations, such as deamination, oxidation,
etc., with which we need not be concerned at the moment,
the excretion of a particular substance might in theory be
effected by filtration alone, filtration plus tubular excretion,
or filtration plus tubular reabsorption. Let us consider first
a substance that is completely filtered at the glomerulus, and
that is present only in the plasma. In spite of the fact that
this substance is present in the glomerular filtrate, if the tubules completely reabsorb it, its clearance will be zero (see
A in figure 4). If now the extent of tubular reabsorption is
decreased, the substance will appear in the urine, i.e., its
clearance will increase (B and C) until, if there is no reabsorption at all (D), the clearance will be equal to the rate
of filtration (glomerular clearance) itself. On the other
hand, if a substance is excreted by tubular activity in addition
to being filtered, its clearance will be greater than the rate
of filtration by an amount equal to the extent of the tubular
clearance (V, W, X). Obviously there is an upper limit to
the possible range of clearance value~, for the kidneys cannot excrete more of a substance in any period of time than
is brought to them by the blood; the upper limit of the renal
clearance is therefore a figure determined by the blood flow
through the kidneys. For example, if X is a substance undergoing tubular excretion and, further, if all of the X contained
in the plasma coming to the kidneys is being removed and
concurrently transferred to the urine, then the clearance
will be a " complete" one. A complete clearance must necessarily be equal to the volume of plasma supplied to the kid-
INULIN CLEARANCE
57
neys per minute. To make this clear it is only necessary to
go through a simple calculation: if each cc. of plasma contains I mgm. of X, and if 500 cc. of plasma Bow through
the kidneys each minute and are completely cleared of X,
1000~ _
-
500,
~
_.
==-x
= ~R~N;~~i~~:~o.~
=~ :
~
C~M~LE'Tf'j~~f'CLEARANC£' = = ~ -:OR
RE NAL PLASMA
fLOW
~
~400
U
U
6
t
a:
~
W
~ 300
«
- ---
~
~
d 200
~
.-- - - - - - - - - - - .--------- -----------
IV
«
~
100 '_____
o
~ - - w- - - .. - - ... - - - - - - - - - - - - - - - - - -... ~ ...
...J
:J
a:
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0
flLTRATtON
RATE
c_, ____ ,.- ___. ___________.'-.., ___
,
.~
- - - - -~
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~
.
~A
4Schema illustrating the physiological concept Qf renal clearances.
For discussion see page 56.
FIGURE
then 500 mgm. of X will be excreted -each minute. The
possibility of any substance having a complete clearance in
the human kidney cannot be answered as yet one way or the
other, and it is mentioned here only to round out the concept of clearance. Actually the efficiency of the kidney in
excreting most substances is of a very low order, so that
their clearances are considerably less than the plasma Bow.
58
THE PHYSIOLOGY OF THE KIDNEY
THE INULIN CLEARANCE AS A MEASURE OF
GLOMERULAR FILTRATION
It will be clear from the foregoing discussion that, with at
least three and perhaps more processes involved in the formation of urine, little progress can be made until the initial
and central process of glomerular filtration can be measured
under strictly physiological conditions in the intact animal.
Once this is done, the extent of tubular reabsorption and
tubular excretion is open to precise quantitation. A substance suitable for measuring the glomerular clearance must
fulfil certain specifications. It must be completely filterable
at the"glomerulus (i.e., its molecular size must not be so
great as to prevent its passing through the glomerular membranes, and it must not combine with the plasma proteins,
which are themselves unfilterable) t and it must not be reabsor14ed, excreted or synthesized by the tubules. * As a
matter of practical importance it must be physiologically
inert, so that its administration does not have any disturbing
effect upon the body, and particularly upon the kidney itself.
* It may be noted parenthetically that in the case of any substance
excreted solely by filtration and without tubular reabsorption or tubular
excretion the clearance must be constant or independent of the plasma concentration. This consideration arises from the fact that the concentration
of the substance in the filtrate is equal to the concentration in the plasma,
regardless of the value of the latter; consequently the quantity excreted
per minute (UV) will increase in simple proportion to the plasma concentration (P). That is, UV = KP, which is equivalent to saying that the clearance, UV/P, is constant regardless of the value of P. In later chapters it
will be seen that this condition does not hold for substances excreted in
part by tubular activity, and therefore the examination of the effects of
increasing the plasma level upon the rate of excretion (or upon the clearance) affords a valuable means of demonstrating tubular participation.
INULIN CLEARANCE
59
And it must, of course, be of such a nature that its concentration in plasma and urine can be determined accurately.
In order to eliminate physiological and chemical errors, it is
desirable that the plasma concentration be kept as constant
as possible during observation.
Most of the subsidiary points enumerated above present
little difficulty. In regard to filterability, numerous lines of
evidence indicate that the upper limit of permeability of the
glomerular membranes in mammals may be set at a molecular size som~what under the plasma proteins. There is no
difficulty about excluding tubular synthesis, especially in the
excretion of foreign substances. It is in regard to the possibility of tubular reabsorption and tubular excretion that the
greatest difficulty is encountered, for there is no way to examine these processes directiy, and our conclusions must be
based upon the relative behavior of several substances under
a variety of conditions.
When the author and his co-workers undertook to discover a substance which would fulfil the specifications for
measuring glomerular filtration, they were guided by the
following a priori considerations. Since it has been shown
that the tubules of the aglomerular kidney can excrete magnesium, sulphate, chloride, creatinine, uric acid, phenol red,
etc., one had to assume, in the absence of evidence to the contrary, that the tubules of other animals might also be able to
excrete these, and perhaps related, substances. On the other
hand, the fact that the aglomerular tubules cannot excrete
glucose, although it does not prove that this substance cannot
be excreted by glomerular tubules, offered a promising line
of investigation. On broad principles it may be supposed
.
60
THE PHYSIOLOGY OF THE KIDNEY
that, being a food and not a waste product, glucose has been
conserved by the vertebrates throughout their evolution, and
at no time continuously excreted from the body. Consequently the tubules have never been called upon to excrete
it, and remain incapable of doing so. The presence of glucose in the urine of glomerular kidneys during hyperglycemia
or phlorizin poisoning may be attributed to the incomplete
reabsorption of this substance from the glomerular filtrate.
Inasmuch as glucose is normally reabsorbed by the tubules it
can furnish no evidence itself on the rate of glomerular filtration, unless the reabsorptive process is blocked by phlorizin ~
and since this drug may have other and perhaps deleterious
effects upon the kidney, its use is of dubious value. It seemed,
however, that if glucose were not excreted by the renal
tubules, other sugars might not be excreted by them, and that
among the metabolically inert carbohydrates one or more
might be found which were not reabsorbed as was this physiologically important foodstuff. With this thought we began
our examination of the excretion of non-metabolized carbohydrates, xylose, sucrose and raffinose, in normal and phlorizinized animals, in relation to the simultaneous excretion
of urea, creatinine, etc. The evidence is now-convincing that
in the glomerular, as in the aglomerular kidney, these substances are not excreted by the tubules j but the inference that
there would be no tubular reabsorption has proved to be
incorrect.
Our earlier investigations 212, 418 did, in fact, indicate that
there was no reabsorption of these inert sugars in the normal animal, but this conclusion had to be modified when
the investigations were extended to inulin, and it was found
INULIN CLEARANCE
61
that the inulin clearance in normal animals is about 25 per
cent higher than the simultaneous xylose clearance (cf. chapter XIII). It is now thought that this discrepancy between
the clearances of the lower sugars and inulin is due to the entanglement, so to speak, of the former in the reabsorption of
glucose, since the discrepancy is removed by phlorizin.
There are, however, good reasons for believing that this is
not the case with inulin.
Experiments with inulin were begun independently by Professor Richards and his co-workers 812 shortly before our
own investigations were started. In both laboratories the
line of investigation was directed by the desire to obtain a
very large molecule, in order to minimize tubular diffusion,
so that the tubular reabsorption of water could be measur~d
as accurately as possible.
The evidence is now fairly convincing that the polysaccharide, inulin, fulfils the specifications for measuring glomerular filtration in all vertebrates. Since this evidence can
best be appreciated after the consideration of the clearances
of several substances, we will defer its discussion to chapter
XIII. We append here only a few remarks on the properties
of inulin itself.
PROPERTIES OF INULIN
Inulin is a starch-like polymer, prin?ipally of fructose,
which is almost insoluble in cold water. It dissolves readily
in hot water, however, and on cooling forms supers,aturated
solutions which may be administered intravenously. After
intravenous injecti<?n it is quantitatively excreted in the urine
in a short time. There are no enzymes in the blood capable
THE PHYSIOLOGY OF THE KIDNEY
of hydrolyzing it, and therefore no way in which the body
can metabolize it. When properly prepared it is physiologically inert, and its administration produces no detectable
change in renal function, circulation, etc.
The true molecular weight of inulin is about 5,000, 4TO
showing that it contains about 32 hexose molecules. This
large molecular weight is important because it results in low
diffusibility j though, actually, the diffusion coefficient of inulin is considerably less than would be expected from its true
molecular weight, in consequence of the fact that it is a very
elongate molecule and elongation increases the effective radius under conditions of random orientation. The effect of
elongation in the case of inulin is such as to produce a diffusion coefficient equivalent to a molecular weight of about
15,000. 50 The diffusion coefficient of several substances of
physiological interest are shown graphically in figure 5.
Hemoglobin fails to pass through the glomerular membranes, presumably because of its large molecular size.1T
Since the diffusion coefficient of hemoglobin is about one-half
that of inulin, it would appear that for the purpose of measuring glomerular filtration little could be gained by seeking a
molecule larger than inulin.
On the physiological side, Hendrix, Westfall and Richards 194 have shown that inulin passes into the capsular fluid
of frogs and N ecturi in the same concentration as it is present in the plasma. It is completely filterable from plasma
through collodion membranes, showing that it is not bound
to plasma proteins, and it is readily amenable to chemical
analysis. 408 In spite of its large molecular weight and low
diffusion constant, it is copiously excreted by man and other
INULIN CLEARANCE
mammals and all the evidence indicates that it is completely
filterable at the glomerulus. In man and in the dog it fulfils
the condition, set forth on page 58, that the rate of excretion
(UV) increases in simple proportion to the plasma concentration (P), i.e., the clearance is independent of the plasma
M.W
60
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0.85
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113
lcREATININE
342
354
. 'SUCROSE PHENOL RED
0.55
0.54
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W
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z
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en::>
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,5100
INULIN
0.177
_____
? ____ ~I~!I_Q.F_ ~L.9.!v1_E:8~Lf..F
i:5 0,086
PERMEABILITY
FIGURE
Hb.
68000
1
5
The diffusion coefficients at 37 0 C. of substances of physiological
interest. (Bunim, Smith and Smith, 50.)
concentration.
Without further comment until .chapter
XIII, it will be assumed that the inulin clearance is at the
level of glomerular filtration in all vertebrates.
GLOMERULAR CLEARANCE
Numerous observations on the excretion of inulin and
other substances in man and the dog have shown that, under
THE PHYSIOLOGY OF THE KIDNEY
physiologically basal conditions, the rate of glomerular filtration in these species is relatively constant. This might be
expected on the assumption of a constant blood flow to the
kidney, and a constant arterial pressure. There are, however, slight variations in all clearances from period to period,
of about the order of magnitude of those shown in table 1.
These variations are in part due to unavoidable errors in
the timing of urine samples and in the analyses of plasma and
urine j but it appears that in addition the actual renal blood
flow, rate of filtration, etc., are not perfectly constant but
auctuate within a narrow range from moment to moment.
Such fluctuations in physiological activity would be expected
in view of the spontaneous fluctuations in the arterial pressure itself.
Data showing inulin clearances at various urine flows in
man and aog are given in figures 6 and 7.* In the data on
man given in figure 6 88 each point represents a single clearance period of 10 to 40 minutes duration, the observations
being made in groups of 5 to 10 at about weekly intervals,
under basal conditions (i.e., before breakfast and with the
subject recumbent in bed) . A wide range in urine flows was
obtained by keeping the subject on a low or high water intake, and by the administration of varying quantities of
water on the morning of observation. t The data in figure 7
*
The simultaneous urea clearances are included in these figures to show
that these behave in a manner roughly parallel to the inulin clearance. The
fact that the urea clearance is lower than the inulin clearance indicates that
a considerable fraction of the filtered urea is reabsorbed by the tubules.
This process of reabsorption is discussed in chapter XII.
t The necessity for making such observations under highly controlled
conditions is obvious, since numerous factors can disturb renal activity by
altering the cardiac output, blood pressure, etc. It is known, for example,
INULIN CLEARANCE
are from Shannon's 400 earlier study of the dog in which the
creatinine clearance (which in this species is equal to the
inulin clearance) was taken as a measure of the rate of
glomerular filtration. Except for the fact that the dog can:2
~
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.
2
4
6
14
16
10
8
12
URINE FLOW CC PER 173 sa M PER MINUTE
6
Simultaneous inulin and urea clearances in man at varying urine
flows. All data are corrected to 1.73 sq. meters body surface area.
(Chasis, 68.)
FIGURE
not be observed under strictly basal conditions, the arrangement of the experiments was much the same as in man.
In both dog and man, the rate of glomerular filtration at
that even the administration of water per os may increase the cardiac output
for an hour or more/ 05 and for this reason the first clearance period in all
the above observations was--not made earlier than forty-five minutes after
the last dose of water.
66
THE PHYSIOLOGY OF THE KIDNEY
low urine flows tends to decrease below the average level,
probably because of an increase in concentration of plasma
proteins, decrease in blood volume, or other factors attending excessive dehydration. At very high urine flows the fil-
•
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24
URINE' F1..0W CCJ SQ....M./MIN.
FIGURE
6
7
Simultaneous creatinine and urea clearances in the dog at varying urine flows. Open circles: urea clearances observed without
the administration of creatinine. (Shannon, 400.)
tration rate tends to increase above the average because of
increased cardiac output, dilution of plasma proteins, etc.,
attending excessive hydration. But apart from these extreme conditions, the filtration rate is fairly constant at
low and high rates of urine formation. *
*
The filtration rate in the dog can be raised or lowered by altering the
protein content of the diet, an effect due partly to changes in the circu-
INULIN CLEARANCE
The av~rage rate of glomerular filtration in ideal man
(1.73 sq. meters) is about 120 cc. per minute.42S Out of this
120 cc. of filtrate a large fraction of the water is reabsorbed,
leaving only a small and variable quantity to be excreted as
urine. Complete reabsorption of the glomerular filtrate is
prevented by the osmotic activity of non-reabsorbed solutes
contained therein, the minimum urine flow in man under
normal conditions being about 0.5 cc. per minute. And for
reasons as yet undetermined, the excretion of the entire
glomerular filtrate never occurs, the maximum urine flow in
man being about 20 cc. per minute.
The two human kidneys contain about 2,000,000 glomeruli/os, 412 each having an average volume of 0.0042 cmm.
It follows that in each glomerulus about 0.001 cmm. of
filtrate is formed per second, or 25 per cent of its own
volume. This is close to the upper limit of the rate of filtration in the capsule of the frog, as observed by micro-collection. 870 If we assume that the blood flow through the two
kidneys is approximately 1000 cc. per minute, this requires
that 0.0075 cmm. of blood, or an amount about 80 per cent
greater than the total volume of the glomerulus, flow through
each glomerulus per second. Vimtrup 4.520 has calculated
that with an average of 25 capillary loops per glomerulus,
the velocity of the blood is about 0.1'25 mm. per second,
which corresponds well with velocities observed in the frog's
glomerulus. The total surface area of the glomerular capillary loops is estimated to be 1.56 sq. m., or nearly equal
to the surface area of an ideal man (1.73 sq. m.). It is
lation rate. This phenomenon is not ·nearly so marked in man (cf. chapter XXII).
68
THE PHYSIOLOGY OF THE KIDNEY
not difficult to imagine that under a pressure of 50 mm. of
Hg 2 cc. of water could be filtered through this area of
endothelium per second. It amounts to no more than one
drop per second through a membrane 20 x 20 cm.
The question of whether changes in filtration rate are
physiologically important in controlling the rate of urine
formation is one which cannot be answered with certainty
at the present time. One might suppose that the tubules
are so organized as to reabsorb a constant volume of fluid
per minute, a volume close to, but slightly less than, the
minimum filtration rate. A slight increase in filtration rate
would then leave an excess quantity of water to be excreted.
Shannon <1000. and Chasis 68 have considered this question in
the case of water diuresis in the dog and man and have
concluded that changes in the filtration rate are not the essential means of regulating the excretion of water. The
problem is a very complex one, but we may provisionally accept the hypothesis that in these species changes in the rate
of urine formation are effected primarily by variations in
the quantity of water reabsorbed by the tubules, this reabsorptive process being controlled by means of the antidiuretic hormone of the pituitary gland.
It seems likely, however, that the rabbit possesses some
means of adjusting glomerular activity to the rate of
water excretion. Kaplan and Smith 217 have found that in
this animal the filtration rate is highly variable, and both the
creatinine and inulin clearances decrease very markedly at
low urine flows (see figure 8). Since these two clearances
remain identical at all urine flows, it is highly improbable
that the observed ~hange in clearances can be attributed to
INULIN CLEARANCE
69
reabsorption. Walker, Schmidt, Elsom and Johnson 483 and
others find no consistent change in renal blood flow in either
the rabbit or the dog during water diuresis, but this does not
exclude local changes in the glomerular apparatus.
The only other animals on which extensive information is
•
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URINE fLOW CC./SQ.M./MIN.
FIGURE
~
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8
Inulin clearances in the rabbit at varying urine flows. The data
are from several animals, each observed at high and low urine flows.
(Kaplan and Smith, 217.)
available are the sculpin (M. octodecimspinosus) 11 and the
dogfish (S. acanthias).895 The former resembles the rabbit,
in that the filtration rate varies with the urine flow; so
marked is this relation that one is led to suspect that in the
marine teleost variations in urine flow are mediated in great
THE PHYSIOLOGY OF THE KIDNEY
part by variations in glomerular activity. It may be noted
that the filtration rate is much greater in fresh water than
in marine fishes,289 paralleling the much greater rate of
water excretion in the former. The frog appears to behave
like a sculpin,B· 287 but the available information does not
justify a final conclusion.
The indirection of the filtration-reabsorption mechanism
has some rather surprising consequences. One of the chief
processes which involve the expenditure of energy in the
formation of urine is the tubular reabsorption of water
against the osmotic pressure of the urinary constituents.
Neglecting the energy expended in the reabsorption of specific constituents (glucose, N aCI, etc.), it follows that, so
long as the quantity of osmotically active constituents remains
constant, the smaller the rate of urine excretion the greater
is the energy which must be expended in the reabsorption of
water. As the urine volume increases, the kidney does less
work, and if the urine volume in man were increased to the
impossible figure of 120 cc. per minute, the kidney would be
doing no work at all in this respect. Under this condition
the energy for the formation of urine would be furnished
entirely by the heart and expended in the filtration process.
It may be calculated that in man 170 liters of water are
filtered from the plasma per day, or over 50 times the volume of plasma in the body. From this large quantity of filtrate the renal tubules must reabsorb 168.5 liters of water
and something like 1000 grams of sodium chloride, 360
grams of sodium bicarbonate and 170 grams of glucose, not
to mention the filtered phosphate, amino-acids, etc., in order
INULIN CLEARANCE
to excrete about 60 grams of sodium chloride, urea and
other waste products in 1.5 liters of urine.
Summary. Using the inulin clearance as a measure of the
rate of glomerular filtration, it is found that in the dog and
man the filtration rate is essentially constant under basal
conditions. In ideal man (1.73 sq. m.) the average figure
is about 120 cc. per minute (or 70 cc. per sq. m. per minute) .
Regulation of the rate of water excretion in the dog and in
man is effected primarily by regulation of the fraction of
water reabsorbed by the tubules, rather than by regulation
of the filtration rate itself. In other mammals (rabbit)
and in cold-blooded animals the filtration rate may increase
or decrease with the urine flow, indicating some physiological association between water excretion and the activity of
the glomerular apparatus.
VIII
PHENOL RED CLEARANCE
IT
advantageous to consider next the process of tubular
excretion in mammals. It has been demonstrated that the
tubules of the human kidney participate in the excretion of
creatinine, phenol red, diodrast and hippuran. The excretory capacity for the last three is, in fact, developed to an
extraordinary degree, which is rather surprising since they
are entirely foreign to the body. But one may suppose that
they are related in some physical-chemical manner to other
substances, as yet unidentified, which normally occur in
blood and urine and which are excreted with equal efficiency.
The fact that they are foreign substances does not diminish
their physiological importance, for they have afforded valuable information on the dynamics of tubular excretion. Because of the fundamental principles involved, and because
our knowledge of its excretion is rather more complete,
phenol red (phenolsulphonphthalein) has been chosen for
extended consideration in this chapter. The following comments on the history of this problem and on protein-binding
of this dye will aid in orientation.
Phenol red was introduced by Rowntree and Geraghty 884, S8G in 19 I 0 as a renal function test after these investigators had found that, among a large number of dyes
tested in normal animals, this was excreted most rapidly by
the kidneys. It was further shown that the rate of its exIS
PHENOL RED CLEARANCE
73
cretion was greatly reduced in man in advanced nephritis.
Rowntree and Geraghty's" phthalein test," which consists
of injecting a small, accurately known quantity of dye intramuscularly and noting the fraction recovered in the urine in
the next one or two hours, has been widely used to test renal
function in man. The value of this test rests upon empirical
correlation with other clinical data, and does not involve any
consideration of how the dye is excreted.
The question of whether phenol red is excreted exclusively
by filtration, or in part by tubular excretion, was long a subject of controversy. Any consideration of this problem must
take into account the fact that, like many other substances,
it enters into combination with plasma proteins. Whether
or not this is chemical combination or physical absorption is
not known, but an answer to this question is not necessary in
the present discussion. It is enough to note that the combination is a perfectly reversible one, the equilibrium between free and bound dye depending upon the concentration
of both dye and protein. The binding of phenol red by
plasma proteins was first noted by de Haan 88 and Marshall
and Vickers,281 who measured the fraction of free dye in the
plasma by filtering the latter through collodion membranes
impermeable to proteins. De Haan believed that in order
to explain the observed excretion of th,e dye one had to postulate that the protein-dye complex as a whole passed through
the glomeruli, the proteins being reabsorbed by the tubules.
Marshall and Vickers rejected this explanation in favor of
the belief that the tubules took up the dye from its reversible
combination with the proteins and excreted it by their cellular activity. In subsequent papers Marshall and his col-
THE PHYSIOLOGY OF THE KIDNEY
74
laborators 288, 271 advanced several arguments in favor of
tubular excretion, the most cogent of which, perhaps, are the
following: (I) If it is accepted that the glomerular filtrate is
protein-free, and if reasonable assumptions are made concerning the rate of blood flow through the kidney, there is an
insufficient quantity of free dye in the plasma to account for
its excretion by filtration j (2) at low plasma levels of dye,
the phenol red clearance greatly exceeds the simultaneous
creatinine clearance in the dog, and there is good evidence
that in this animal creatinine is excreted only by filtration
( chapter IX) i and (3) the phenol "red clearance is not independent of plasma level, as would be expected for a substance e:l{creted only by filtration, but decreases as the plasma
level is raised. Since de Haan's belief that the plasma proteins pass through the glomerular membranes may be rejected on the grounds cited in earlier chapters, the experiments adduced by Marshall and his co-workers constitute the
first credible demonstration of tubular excretion in the mamma~. It will be recalled that phenol red is also copiously
excreted by the aglomerular kidney and by the mesonephric
tubules of the chick when cultured in vitro.
PROTEIN BINDING
It is important to recognize the limitations which protein
binding of phenol red imposes upon its excretion. When the
total concentration of dye in human plasma is I mgm. per
cent, about 20 per cent of the dye is free and 80 per cent is
bound to the plasma proteins. So long as it is held that the
glomerular fluid is protein-free, and that it is elaborated from
the plasma solely by filtration, there is no way in which the
PHENOL RED CLEARANCE
75
bound dye can be excreted by the glomeruli. During the process of filtration no change occurs in the concentration of free
dye in the unfiltered plasma to alter the equilibrium between
the free and bound dye, and thus liberate the latter. On the
other hand, the total concentration of dye in the filtrate cannot be greater than the concentration of the free dye in the
plasma, because to suppose that the dye can be transported
across the glomeruli by combination with the proteins of the
glomerular membranes, or by any other means, requires that
the concentration of free dye in the capsular fluid be raised
to a higher level than the free dye in the plasma, which is to
postulate an endothermic reaction incompatible with the definition of filtration. In point of fact, Richards and Walker 889
find that the concentration of dye in the capsular fluid of the
frog approximates the concentration of free dye in the
plasma, as would be demanded by theory and the collateral
evidence on the nature of glomerular activity.
But in considering tubular excretion it must be recognized
that the tubular cells, by taking up the free dye that has escaped from the capillaries, must necessarily reduce the concentration in the peritubular interstitial fluid; this reduction
in concentration will in turn promote diffusion of free dye
from the capillaries, and with the reduction of the concentration of free dye in the capillaries th~ bound dye will dissociate-;- so that in theory all the dye, both bound and free,
is available for excretion. The only limiting factor is the
speed of diffusion of free dye from capillary to tubule cell.
When we note the great expanse of peritubular capillaries
we may suppose that tubular activity might well be able to
remove a large fraction of the dye from the blood flowing
THE PHYSIOLOGY OF THE KIDNEY
through them, before this blood emerges into the renal
vems.
GroUman 161, 162 has shown that it is the plasma albumin
that combines with the dye, and that the equilibrium between
free and bound dye is influenced by pH, temperature, etc.
Under otherwise constant conditions the combination be':'
tween dye and protein in most species may be described by
the usual adsorption isotherm, xjm = Kc1/ n , where x is the
milligrams of dye absorbed by m grams of albumin, c is the
equilibrium concentration of free dye and K and ljn are constants. The equilibrium between free and bound phenol red
has been studied at 37° C. in man,US, 423 dog,89T rabbit (unpublished) and chicken.881 The values of Ijn for these
species are, respectively, 0.94, 0.83, 0.58 and 0.67. The
values of Kjm are 3.55, 2.32, 17.20 and 1.78. K has been
determined only in man, in whom it has the value of 0.85,
and this value appears to be unaffected by disease. Since the
constant l/n is less than 1.0 in all four species, the fraction
of free dye in a given sample of plasma increases as the total
concentration of dye is increased. The equilibrium distribution of free in relation to total dye in human plasma having
different albumin contents is portrayed in figure 9.
PHENOL RED/INULIN CLEARANCE RATIO
The phenol red clearance should not be confused with the
familiar Rowntree and Geraghty" phthalein test." As with
any other clearance, it is based upon the simultaneous determination of the concentration of the dye in the plasma
(P) and the rate of its excretion (UV), and expresses the
minimum volume of plasma required to supply the dye ex-
PHENOL RED CLEARANCE
77
creted in one minute. Apart from a limited number of
observations by Marshall 266 on the dog, the first systematic
studies of the phenol red clearance were those of Shannon 897
on this same animal, and of Goldring, Clarke and Smith 143
on man. * These investigations have shown, first, that the
2
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fE
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.~
18
16
-
6
I
-
'--"
!.o= I--
-
-
j....-
I--
I--
I--!--
--
6
8 10
- -- --
f-
-
I--
.'-- '--
~
~~
r--
~
-
I-- I--
.-
_f- f- I-- f -
~
~
j....- I--
l- I--
-1.0
~
j....- f- ~ I-"
l- I-""
..-
I-- ~
l - I--
I-" I-
4
t5
I--
f-r-
l - I--
14
3
f- l - I - l-
l- I-"
t....-
--
-~
I-- f- r--
2
81
l - I-- ~
22
1:::120
'--
4
f-
I - f~
W 24
a:
l-
30
..J 28
3
,...-
~
-P2!
~
----
~
l- I-" ~
- r-
f-
'--
3.5
&J
~
5.0
50!:
:.ru:
t-
-05
0
05
TOTAL PI-ENOL RED - LOG MGM. PER CENT
FIGURE
1.0
9
The relationship between total phenol red, free phenol red and
albumin in human plasma at 37°C., pC02 = ca. 40 mm. (Smith,
Goldring and Chasis, 42 3.)
'"
phenol red clearance is much larger than the inulin clearance,
and second, that its absolute value, all other things being
*
MacKay 246 injected one gram of phenol red intravenously and calculated the Addis excretory ratio in three successive periods and obtained
values greatly in excess of the simultaneous urea values.
THE PHYSIOLOGY OF THE KIDNEY
constant, is dependent upon the concentration of phenol red
in the plasma.
Before discussing the phenol red clearance further, attention is called to the difficulties inherent in any attempt to
compare absolute clearances. Because of differences in the
size and development of the kidneys, we cannot expect the
absolute clearance of any substance to be the same in two
individuals, and no more will one individual show the same
clearance under all circumstances. In short, independent
absolute values of renal clearances are of little value; it is
essential, even under the best physiological conditions, to
observe the simultaneous clearances of the two or more substances which we wish to compare. Though the clearance
of any substance may be used as the standard of reference,
it is logical to take the glomerular clearance (= inulin clearance) for this purpose. Slight variations in absolute renal
activity, as well as errors due to collection of urine, dilution, etc., are then eliminated by considering the ratio of
the simultaneous phenol red and inulin clearances, rather
than their absolute values. Wherever two clearances are
compared, it is understood that they are simultaneous
clearances.
In man, when the plasma phenol red level is below a critical concentration (1.0 mgm. per cent) the phenol red/inulin
clearance ratio has a maximum and fairly constant value
which averages 3.3.4.23 As the plasma level is raised, the
phenol red/inulin clearance ratio is depressed, due to depression of the phenol red clearance, until at high plasma levels
of the dye this ratio may be considerably less than 1.0.143
These two points will be discussed separately. Since the
PHENOL RED CLEARANCE
79
phenol red clearance is independent of the rate of urine formation, this factor may be omitted from consideration.
Low PLASMA LEVELS
The above relationships will be made clearer by reference
to the left-hand side of figure 10, in which data are given for
Q
L R
o
~
2/14/35
6 AFTER 2.0 GMS.
.. AFTER 3.0 GMS. ADD.
2/21/35
o AFTER 1.5 GilliS.
._AFTER 3.~_GMS. ADD.
a:
w
Z
o
U
I
<[3.0
I
I
a:
<[
:l
S:t:i
~:5
:::>
I-JX
....
''
o
w
a:
AFTER 0.3-0.5 GMS,
<'Q
:J2.0
~
0
I
cr,Z
U
z
:,
0
11&1
'
:
5,·0 - - :, - - - 3I 0
L
~
GLOMERULAR EXCRETION
~~~~~~~~~~~~~LL~~~~~~~~~~
0.5
1.0
PLASMA PHENOL RED
FIGURE 10
The phenol red/inulin clearance rotio in man in relation to the
concentration of phenol red in the plasma. Left, at plasma concentrations below 1.0 mgm. per cent; r:ight, at plasma concentrations above 1.0 mgm. per cent. For discussion see pages 79-81.
(Adapted from Goldring, Clarke and Smith, 143 and 423.)
a normal subject, L.R. In the series of observations from
which this figure is drawn, the inulin clearance averaged
I IS cc. per minute and the phenol red clearance, when the
plasma phenol red level ranged from o. I to 1.0 mgm. per
80
THE PHYSIOLOGY OF THE KIDNEY
cent, averaged 402 cc. per minute, both corrected to 1.73 sq.
m. body surface area. The average phenol red/inulin clearance ratio in this case was 3.5. The free phenol red was
determined by ultrafiltration, and at plasma levels of o. I to
1.0 mgm. per cent this fraction was close to 20 per cent. We
may therefore say, since only the free dye is filterable, that
the filtration clearance of the dye is equal to 20 per cent of
the inulin clearance (23 cc. per minute) , and that the tubular
clearance of the dye is equal to the difference between this
value and the total clearance, i.e., 379 cc. Thus, only 6 per
cent ( &) of the total dye excreted in each minute was excreted by filtration, and 94 per cent by tubular activity. Expressed as the inulin clearance ratio, the fraction excreted
by filtration is indicated by the sloping line at the bottom of
figure 10.
HIGH PLASMA LEVELS
When the plasma level of dye is raised, the phenol red
clearance, and therefore the phenol red/inulin clearance
ratio, is progressively depressed (see right of figure 10).
Raising the plasma level of dye has two effects: (a) it increases the fraction of free dye in the plasma according to
the equation given on page 76, and (b) it depresses the tubular excretion of the dye. Thus while (a) tends to increase
the filtration clearance, (b) offsets this increase and, in fact,
greatly decreases the total clearance of dye, and therefore
the phenol red/inulin clearance ratio. The lowest value for
this ratio obtained in normal man has been 0.89 at a plasma
level of 28.2 mgm. per cent, but presumably if the plasma
level were raised still higher the ratio would approach asymptotically to the fraction of free dye in the plasma. The
PHENOL RED CLEARANCE
81
depression of the clearance is perfectly reversible; i.e.,
the same relations exist with an ascending or descending
plasma concentration, showing that it is not a toxic phenomenon and that there is no storage of the dye in the
tubule cells.
To say that the clearance is depressed by raising the
plasma level amounts to saying that the rate of excretion,
UV, does not increase in direct proportion to P. We have
already pointed out (page 58) that constant proportionality between UV and P, all other things being equal, is an
essential criterion for a substance excreted exclusively by
filtration, and that this relationship holds true for inulin in
all animals so far examine~. We will now inquire why it
does not hold true for the tubular excretion of phenol red.
MAXIMUM RATE OF TUBULAR EXCRETION
The phenomenon of the depression of the rate of excretion of a substance by elevation of plasma level was first
noted by Marshall and Crane 211 in the excretion of phenol
red by the dog. There can be no doubt that it is a tubular
phenomenon. Marshall and GrafHin 274 and Bieter 3S have
shown that the efficiency of the aglomerular kidney of the
toadfish in excreting both creatinine and phenol ned is
markedly lower after a large dose than a·-small one. There
seems to be no explanation of this phenomenon in terms of
glomerular filtration, although it is readily interpreted in
terms of tubular excretion, since one would suppose a priori
that there is some physiological limit to the quantity of dye
which can be handled py the tubule cells in unit time, a consideration that does not apply to filtration. In the case of
THE PHYSIOLOGY OF THE KIDNEY
82
tubular excretion one might suppose that the tubules were
doing a constant amount of physiological work per minute
in transporting the phenol red from a low concentration in
the plasma to a high concentration in the lumen; or, altero
~ ~.:.
W
~
«
a
«
1.5
E)
0
•
o
•
•
,
••
00
W
•
d
I.oI----~""-..".o,--------------i
•••
~
•
• • •
•
~.......
o • •
o
o
8 .5
a
•
0
0' •
~
W
if
0 Ro----'~r---~IO~---~I.I~~--~2~O~--~2~5O---~3~O~~
PLASMA PHENOL RED MGM. PER CENT
FIGURE II
The phenol red/inulin clearance ratio in the dog. Dots, as observed; open circles, recalculated from phenol red/xylose ratios.
(Shannon, 397.)
natively, that there was an upper limit to the quantity of
phenol red which they could handle in unit time.
This question has been examineq by Shannon 387 in the
dog and by Pitts 337 in the chicken, in which animals the situation is qualitatively the same as in man. Data on the phenol
red/inulin clearance ratio in the dog and chicken are given
PHENOL RED CLEARANCE
in figures II and 12. At low plasma levels of dye in man
this ratio averages about 3.3, in comparison with 1.7 in the
dog and 13 in the chicken. In small part the difference between the three species may be due to differences in the spe-
•
o
.:
i=
16
<!
C!
-:
~ 14.~
2
~
U
10 .. _
~ 12'
2
S
I..
8 ... •
~ ~,\
....1.
ll!
5
6
4
Z
w
a:
2
i. "~••
~
••
•
e)~_ ...
.,.......~.
•• ••
:.:."1"',.. ••• • ... .
Ir-------------------~··~~-~·-L~~·~~~·-·~·~~.-~--_d
••
·1
OL_
o ____~~--~~----~~-----~--~~~----~
20
40
60
80
. ·,00
PLASMA PHENOL RED
MGM. PER Cf:NT
FIGURE 12
The phenol red/inulin clearance ratio in the chicken. The large
magnitude of this ratio, as compared to dog and man, indicates the
relative preponderance of tubular as compared to glomerular function. (Pitts, 337.)
cific excretory capacity of the tubules, but in greater part
it is unquestionably due to differences in the relative development of the glomeruli and tubules. Man has only half as
many glomeruli per _gram of renal tissue as the dog. And
it will be recalled that in the birds the tubules receive an
THE PHYSIOLOGY OF THE KIDNEY
independent supply of blood by way of the renal-portal vein,
which circumstance gives rise to a preponderance of tubular
function.
There are no data available to permit a comparison of
renal function in these animals except in terms of some
arbitrary standard of reference, and it is convenient to use
the rate of glomerular filtration as that standard. By taking due account of the rate of filtration and the percentage
of free dye in the plasma, it is possible to calculate the absolute quantities of dye excreted by the tubules relative to
each cc. of glomerular filtrate. (This calculation is of course
more significant in comparing the same individual, or different individuals of the same species under different conditions,
than it is for comparing the bird and the mammal, where
there is such a difference in the development of glomeruli
and tubules.) Such calculations show that in both dog and
bird, as the plasma level is raised, the tubules excrete more
and more dye up to a certain limit, after which the quantity
excreted per minute remains approximately constant. (See
figures 13 and 14.) The value for the quantity of dye excreted by the tubules per cc. of glomerular filtrate for the
dog is 0.079 mgm.; for man, about 0.21 mgm.; and for the
chicken, 0.62 mgm. Here again, the differences in these figures reflect both differences in excretory capacity per unit
weight of tubule and differences in the relative development
of the glomeruli and tubules in the different species. It is impossible at the present time to separate these factors, but it is
to be expected that different species will show marked differences in respect to inherent tubular capacity as well as relative tubular development. Marshall,288 by sampling arterial
PHENOL RED CLEARANCE
85
and renal venous blood in the dog, has found that the maxi.
. (
conc. in renal venous blood)
mal renal extractIon ratIo I .
· I bi00 d
ar terla
conc. 10
averaged about 65 per cent, which figures have been confirmed by Sheehan 401 who has further shown that this re-
r
c
1
4
6
6
10
12
14
16
fR.EE PLASMA PHENOL RED MGM. PER tENT
FIGURE 13
Filtration and tubular excretion of phenol red in the dog. (A)
total phenol red excreted; (B) phenol red filtered; (C) phenol red
excreted by the tubules. The above data are from a single experiment. The rate of excretion of dye by the t)Jbules does not increase
in direct proportion to P, but approaches and ultimately reaches an
upper, maximal, limit. For this reason the total excretion by
tu buIes and glomeruli, UV, does not increase in proportion to P; i.e.,
the clearance, UV/P, is depressed as the plasma level of dye is
raised above a critica'l value, as shown in fig. II.
moval of dye is accompanied by concomitant excretion in the
urine. In the rabbit the maximum extraction ratio averages
86
THE PHYSIOLOGY OF THE KIDNEY
about 37 per cent.408 It is probable that the maximum extraction ratio in man is at least as high as in the dog.
The existence of an upper limit to the rate of tubular
excretion of phenol red may be taken, then, to explain why
the clearance is depressed as the plasma level is raised. This
o
30
40
50
60
PHENOL RED MGM. PER CENT
FI(;uRE 14
Filtration and tubular excretion of phenol red in the chicken.
The above data are averages of those in fig. IZ. Legend as in fig. 13.
depression phenomenon has been demonstrated for urea
in the frog,271. 4GB for creatinine in' the dogfish,894. S96
chicken,4oob and man 868 and for diodrast and hippuran in
dog :107 and man 428 and it is possibly a universal characteristic of tubular excretion. But it can be demonstrated,
however, only if the plasma concentration of the sub-
PHENOL RED CLEARANCE
stance under consideration is varied over a sufficiently wide
range.
Little is known concerning the cellular mechanism involved
in tubular excretion. The experiments of Chambers and
Kempton 65 with fragments of the mesonephric proximal
tubules of the chick offer a beautiful and direct demonstration of the process, which we may imagine is not very different in the aglomerular tubule, the chicken tubule and the
mammalian tubule. Apparently the dye is picked up from
the surrounding medium and transported across the tubule
cells without storage, to be discharged into the tubular urine
at a higher concentration. Whatever the mechanism, the
transportation of dye from a low concentration in the blood
to a higher concentration in the tubular urine is a physicalchemical process that will not proceed spontaneously, since
it requires the expenditure of energy. There is no reason
to believe that the energy of the circulation can be used for
this purpose, and it is more likely that the energy is supplied
entirely by the metabolism of the tubule cells.
VVHOLE BLOOD PHENOL RED CLEARANCE AT
Low PLASMA LEVELS
Returning now to the phenol red clearance at low plasma
levels, we may reiterate the definition'·of a plasma clearance
as the minimum volume of plasma required to supply the
quantity of a particular substance excreted in the urine in
one minute. It has been demonstrated that when phenol
red is added to whole blood it does not penetrate the red
cells, but is confined to the plasma. It follows that all the
phenol rea is carried to the kidneys by the plasma. But
88
THE PHYSIOLOGY OF THE KIDNEY
if, in the subject, L.R., 402 cc. of plasma How through the
kidneys each minute (as is demanded by the phenol red
clearance) and the blood contains only 59.6 per cent plasma
(40.4 per cent cells), it follows that 402/0.596 or 674 cc.
of whole blood must flow through the kidneys in each minute's time. This conclusion follows irrespective of how the
phenol red is excreted, how much of it is bound by plasma
proteins, or of any 9ther subsidiary consideration.
In a recent series of observations on man the inulin clearance averaged about 120 cc., the plasma phenol red clearance about 400 cc., and the whole blood phenol red clearance
about 665 cc. per minute, corrected to I. 73 sq. m.'2S Thatthe
phenol red clearance does not approach a "complete clearance " is indicated by observations on the clearances of other
substances.
Elsom, 'Bott and Shiels 107 and Landis, Elsom, Bott and
Shiels 284 have shown that the organic iodine compounds,
diodrast and hippuran, are copiously excreted by the tubules
in the dog and man (cf. 196), and the rabbit. loB The
excretion of these and other organic iodine compounds in
man has recently been re-examined by the author and his
co-workers in relation to the simultaneous inulin and phenol
red clearances.428 The hippuran and diodrast clearances are
independent of the plasma concentration of these substances
when this is below a certain level, as is' the case with phenol
red. It is particularly interesting that increasing the plasma
concentration of these iodine compounds not only depresses
their own clearances, bllt it also depresses the simultaneous
clearance of phenol red in a systematic and reversible manner, indicating that all three substances are excreted by a
PHENOL RED CLEARANCE
common tubular mechanism. When precautions are taken
to eliminate the error occasioned by the dead space of the
bladder, ureters and tubules, by maintaining a high urine
flow and by keeping the plasma concentration constant, these
clearances are just as constant and reproducible as are the
inulin or phenol red clearances. This fact, and the reversibility of the depression phenomenon, indicate that there is
no storage of either phenol red, hippuran or diodrast in the
human kidney. Apparently these substances are transmitted
with great speed and uniformity across the tubules to be
discharged into the tubular lumen. It is possible that a high
concentration is built up only in the tubular urine, rather
than in the tubule cells. A series of simultaneous inulin,
phenol red, hippuran and diodrast clearances in a normal
man are given in table II: Since all three substances are carried only in the plasma, the minimum renal plasma flow is at
least as large as the largest of these clearances. From a
limited series of observati"ons made under basal conditions
on nine normal men, it appears that the hippuran and diodrast whole blood clearances in ideal man will average
slightly above 1000 cc. per minute, as compared to a whole
blood phenol red clearance of 665 cc. If the removal of
these substances from the renal blood is not complete, then
of course the renal blood flow must,be greater than this.
This figure, surprisingly large as it is, is in agreement with
data on the dog and rabbit (chapter XXIII). If we assume
that the hippuran clearance is essentially complete, then an
average of 120 cc. out of 600 cc., or ,one-fifth, of the plasma
flowing through the human kidney is filtered through the
glomeruli.
THE PHYSIOLOGY OF THE KIDNEY
TABLE II
SIMULTANEOUS CLEARANCES OF
Two
ORGANIC IODINE COMPOUNDS, HIPPURAN
(UPPER TABLE) AND DIODRAST (LOWER TABLE) IN NORMAL SUBJECT (H.C.,
S.A. = 1.70 SQ. M.). The first column gives the elapsed time (rom the end of
the rapid priming infusion and the beginning of the slow infusion.
~
.
.~
Phenol Red
Inulin
ii;
P
u u/p
P
u
U/p
Iodine
P
u
Plasma aearanee
U/P Inulin
Phenol
Iodine
Red
~
..9
11
~
-------~
------cc. --...
..._
mgm. mgm.
mgm. mgm.
1I18m. mll!l1.
~
;!
min. lOOcc. l00cc.
::I
~
-
per
per
per
per
per
10Occ. loocc.
."
u
"8 ~
per
per
10Uec. l00cc.
u
..d
Po<
..s
- -
Hematocrit: 38.7 per cent cell.
28
37
47
56
67
76
84
Bladder e",pried and wa.hed with aaline
8.5
5.7
3.6
2.8
2.9
2.4
123
122
123
125
129
130
1584
2235
3530
4630
5330
5490
12.9
18.3
2B.7
-37.1
41.3
42.2
0.965
0.960
0.955
0.960
0.970
D.98S
44.1
61.2
9B.l
123.8
145.4
150.0
45.7
63.8
102.7
129.0
149.9
152.3
0.64 49.6 77.4
0.60 67.4 112.4
0.5B 98.9 170.5
0.59 132.1 224.0
0.60 156.5 261.0
0.60 159.0 265.0
Averase
109
105
103
104
120
101
389
364
370
361
435
366
658 3.55
641 3.48
614 3.57
627 3.47
756 3.63
636 3.60
6.02
6.13
5.94
6.06
6.31
6.27
118
100
131
132
346
311
415
404
674
590
787
774
5.7
5.9
6.0
5.8
120
369
706
----107
387
655
Hematocrit: 3B.9 per cent cella
25
35
45
57
69
6.0
3.1
3.5
3.4
134
135
138
136
Bladder e",pried and waehed with ealine
2640 19.7 1.15 66.3 57.6 0.74 83.2
4360 32.3 1.08 108.2 100.3 0.75 142.7
5150 37.3 1.05 124.5 118.5 0.76 171.0
5300 39.0 1.03 122.5 119.0 0.76 173.1
112.5
190.5
225.0
228.0
Average
------
2.93
3.11
3.18
3.05
Summary. The phenol red clearance at plasma levels of
dye below I.O mgm. per cent averages about 400 cc. per
minute in normal man, in contrast to the inulin clearance,
which averages about I20 cc. Only about 20 per cent of the
dye in the plasma is free and filterable, the rest being bound
to plasma protein. Therefore the volume of blood which
can be cleared by filtration amounts to only 20 per cent of
I20 cc., or 24 cc. per minute, leaving 376 cc. of the phenol
red clearance, or 94 per cent of the total dye excreted, to be
PHENOL RED CLEARANCE
accounted for by tubular excretion. Since the phenol red is
confined to the plasma, all the excreted dye must be carried
to the kidneys by the plasma. In order to obtain the whole
blood clearance it is only necessary to divide the plasma
clearance by the percentage of plasma in the blood. The figure so obtained averages 665 cc. in ideal man.
Hippuran and diodrast, which are handled by the kidney
in much the same manner as is phenol red, have in a more
limited series of observations in man an average plasma
clearance of about 600 cc., and a whole blood clearance of
1000 cc. Since the renal blood flow cannot be less than this
value, it follows that the clearance of phenol red is no more
than 66 per cent complete.
IX
CREATININE CLEARANCE
IT HAS long been known that of a:ll substances which the kidney is normally called upon to excrete, and for which adequate analytical methods are available, creatinine is concentrated in man to the greatest extent - i.e., has the highest
UjP ratio. This fact led Rehberg 860 to suggest that the rate
of excretion of exogenous creatinine could be used to calculate the rate of glomerular filtration.
It should be noted particularly that exogenous creatinine
is specified. It is questionable if the substance or substances
in normal plasma which give the Jaffe reaction are actually
creatinine. In I922 Behre and Benedict pointed out that
there are present in blood filtrates substances which give a
color with alkaline picrate, but which are apparently not
creatinine since they are not adsorbed by kaolin under conditions in which creatinine itself is removed. The value of the
Jaffe reaction for creatinine determination, although upheld
by some;'''' 181 must be seriously questioned on several lines of
evidence. 2o, 21. ~O, lU. m. 128 The problem is further complicated by the fact that Gaebler 12~ has found that there is present in blood a substance which is not creatinine, but which
yields creatinine after adsorption on Lloyd's reagent with
subsequent elution with magnesium oxide. The problem has
not so far been clarified by the introduction of the more specific 3,s-dinitrobenzoic acid reagent. 21 ,296 Although the
CREATININE CLEARANCE
93
clearance of "apparent creatinine," and also the renal extraction ratio, are of the same order of magnitude as exogenous creatinine/,s.119 this fact itself has little meaning.
The non-adsorb able chromogenic substance or substances
present in normal plasma are not excreted to any great extent
in the urine, either because they fail to be filtered or because
they are reabsorbed by the·tubules.,o2
For the above reasons all investigators interested in the
excretion of creatinine have administered it in sufficient quantities to raise the plasma level to 7- IS mgm. per cent or
higher. All subsequent mention in this book of the creatinine
clearance refers to exogenous creatinine.
Although a very high or even maximal U IP ratio might
be taken as a superficial indication that there is no tubular reabsorption, it does not exclude the participation of tubular
excretion. Convincing evidence of the tubular excretion of
creatinine was lacking when Rehberg made his suggestion,
but shortly afterwards it was shown that creatinine is excreted not only by the aglomerular tubules of the teleost
fishes, but also by the glomerular tubules of the dogfish. T2• 89'.896 This is all the more significant since creatine,
rather than creatinine, normally predominates in fish urine.
If creatinine can be excreted by the aglomerular and the dogfish tubule, the presumption is immediat~ly raised that it may
be excreted by the tubules of higher forms, and evidence
against tubular excretion must be adduced in any ariimal before creatinine excretion can be accepted as a measure of
glomerular filtration. Extensive information is now available on the excretion of creatinine in several mammals, and
it appears that Rehberg's inference is correct for the dog and
I
THE PHYSIOLOGY OF THE KIDNEY
94
some other mammals, but not for man, the anthropoid apes,
the birds, or cold-blooded animals.
It may be noted that in both dog and man the creatinine
clearance is essentially independent of the rate of urine formation, as are the inulin and phenol red clearances, a fact
which may be attributed to the relative constancy of filtration. Consequently we may neglect the variable factor..of
urine volume in these animals and proceed to the consideration of the creatinine clearance in terms of the simultaneous
inulin clearance. (In the rabbit the creatinine clearance
varies with urine flow in the same manner as the inulin
clearance. )
It will be convenient to consider first those animals in
which creatinine is excreted in part by tubular activity. The
evidence of tubular participation may be summarized as
follows:
( I) The creatinine clearance is greater than the inulin,
clearance in man,898 the apes,m the chicken"oob the teleost
fishes 888 and the dogfish. 89B This fact is prima facie evidence
of tubular excretion. In man the creatinine/inulin ratio at
low plasma levels of creatinine averages 1.40, indicating that
about 29 per cent (0.40/1.40) of the total creatinine is excreted by the tubules. In the dogfish and teleost the creatinine/inulin ratio is greater, ranging from 4.0 to 7.0 or above,
indicating that here 75 to 85 per cent is excreted by the
tubules. (Relative preponderance of tubular excretion may
be expected in cold-blooded animals, since the circulatory
rate is smaller and glomerular development is poorer than in
the mammals, and since blood is supplied directly to the
tubules by way of the renal-portal vein.)
CREATININE CLEARANCE
95
( 2) The creatinine clearance in the above species is depressed, both absolutely and relative to the inulin clearance,
by raising the plasma l'evel. This phenomenon has already
been discussed in connection with the excretion of phenol red,
and it has the same significance here; it is inexplicable in
terms of filtration, and may be taken as independent evidence
of tubular excretion. It has been demonstrated to occur in
man, the chicken and the dogfish.
(3) The creatinine clearance in the above species is depressed, relative to the inulin clearance, by phlorizin. Apparently this drug impairs the tubular excretion of creatinine* and therefore reduces the creatinine clearance to approximately the level of the inulin clearance.
The relations between the creatinine/inulin clearance
ratio and the plasma concentration of creatinine in man, the
bird and the dogfish are illustrated in figures IS, 16 and 17.
Attention is called to the action of phlorizin in all these animals. It is possible that tire tubules are only capable of excreting a certain maximal quantity of creatinine per unit
time, as is the case with phenol red, but, if so, this limiting
factor is approached only at very high plasma levels.cf• 898
*
Phlorizin also blocks the tubular excretion of creatine (page 107).
It so disturbs the clearances of all substances (probably by reducing the
blood flow through the kidney, etc.) that changes in the absolute clearance
values do not reveal which clearance is being specifically affected; but since
(in man) the urea/inulin clearance ratio is not affected by this drug 898
one may conclude that the creatinine clearance has been lowered, rather than
the inulin clearance raised, by its action. The action of phlorizin in blocking the tubular excretion of creatinine was first noted in the dogfish by
Clarke and Smith 72 and Shannon. 894.
THE PHYSIOLOGY OF THE KIDNEY
FILTRATION OF CREATININE
Turning now to other mammals, the evidence indicates
that there is no tubular excretion of creatinine in the dog, the
rabbit, sheep and seal. The evidence is as follows:
o
a:~ 1,4
,,_•
u
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a: 1.3
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w
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.
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............
.
... '.......
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,I
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w
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.... .
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.... .. .. .
....
..
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..
..
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__~~____~~__~~____~--~7.b~__~~~
20
40
0
80
100
120
PLASMA CREATININE MGM, PER CENT
FIGURE
15
•
Creatinine/inulin clearance ratio in normal man (dots) and after
phlorizin (triangles). (Shannon, 398.)
In the dog 818,898, 899. "~'a the creatinine and inulin clearances
are identical within the limit of the experimental error, un·
der all conditions so far examined. Raising the plasma level
of either inulin or creatinine has no effect upon this identity,
and neither does phlorizin. The sheep (Shannon, unpub.)
and seal m have not been examined as extensively as the
dog and rabbit au but the identity of the clearances implies
that in all these animals creatinine is excreted solely by filtra·
tion.
CREATININE CLEARANCE
97
In interpreting the above facts, it should be noted that
creatinine is completely filterable from the plasma through
membranes impermeable to protein, and it may be presumed
that it is completely filterable at the glomerulus in all mam-
01.6
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a: 1.5
:••r
•.,
·•~,
• ••
w
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• :a...
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. ,.
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••
.
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4
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••
•
~O.9
~
o
40
80
120
160
200
240
PLASMA CREATININE MGM. PER CENT
FIGURE 16
Creatinine/inulin clearance ratio in normal chickens (dots) and
after phlorizin (triangles). (Shannon,4oob.)
,
mals, as has been demonstrated to be the case in the Amphibia. We must recognize, therefore, that the glomerular
filtrate will carry its full complement of this substance, i.e.,
that the filtration clearance of creatinine will be equal to the
glomerular clearanc~. The tubular clearance of creatinine
can then be taken to be the difference between the inulin
THE PHYSIOLOGY OF THE KIDNEY
clearance and the creatinine clearance. The average creatinine clearance in man may be taken to be 170 cc.; deducting
120 cc. for filtration, there is left a tubular clearance of only
50 cc. This is much smaller than the tubular clearance of
.
o
0.<8
0
o
00
O~
o
__~~__~~____~____~____~~'__~~__~~_J
20
40
60
P!..~SMA CREATINI~E
FIGURE
60
100
120
140
MGM. PER CENT
17
Creatinine/inulin clearance ratio in the normal dogfish, S. acan-thias, as directly determined (solid dots) and recalculated from
the creatinine/xylose clearance ratio (open circles). After phlorizin (solid triangles). (Shannon, 394, 395.)
phenol red (376 cc.), indicating that the excretory capacity
of the tubules for creatinine is much less than for phenol
red. This same difference obtains in all animals studied.
At first sight it seems surprising that the tubular excretion
CREATININE CLEARANCE
99
of creatinine should occur in some animals and not in others,
but such must be the conclusion on the basis of the evidence.
There is no a priori reason to believe that tubular activity
is constant, even in all members of a particular species. Since
the tubular excretion of creatinine is most highly developed
in the fishes, one is tempted to view it as a primitive character, and to believe that it persists as such in some of the higher
animals and not in others. However, it is not impossible
that this character has been acquired in the primates quite
independently of any ancient heritage. Considerably more
information must be gained on the comparative physiology
of the kidney before questions such as this can be answered
with any certainty.
IMPERMEABILITY OF THE TUBULES
Some of the investigations referred to above throw considerable light upon an important question in renal physiology: namely, the extent to' which various substances may
escape from the tubular urine by diffusion, in consequence of
the high concentration gradient established by the reabsorption of water. Shannon 898, 899 has found that there is no
detectable difference between the creatinine and inulin clear:
ances in the dog, even when the urine flow is very low (U jP
ratios up to 574). The diffusion coefficient of creatinine is
five times as large as that of inulin (page 63) ; if as little as
2 per cent of the inulin which is contained in the glomerular
filtrate diffused back through the tubules, one would expect
the back diffusion of at least 10 per cent of the filtered creatinine, which would cr~ate a det~~table difference in the clearances. Since 'no such difference is observed, one must con-
100
THE PHYSIOLOGY OF THE KIDNEY
clude that the tubules of the dog are relatively impermeable,
in the sense of passive diffusion, to both inulin and creatinine,
and we may justifiably extend this conclusion to those animals
where creatinine is excreted in part by tubular excretion,
especially in view of the identity of the creatinine and inulin
clearances after phlorizin.
Summary. Exogenous creatinine is excreted by the tubules
of the aglomerular fish, ,thus demonstrating the possibility
of the tubular excretion of this substance. That creatinine
is in part excreted by the tubules of some other animals is
indicated by the following considerations: the exogenous
creatinine clearance is greater than the simultaneous inulin
clearance in (a) man, the anthropoid apes, the chicken, the
teleost and the dogfish, while these clearances are identical
in (b) the dog, rabbit, sheep and seal. Raising the pla$ma
level of creatinine in (a) lowers the creatinine/inulin clearance ratio towards 1.0, but has no effect on the unitary ratio
normally observed in (b). Phlorizin lowers the creatinine/
inulin clearance ratio towards 1.0 in (a) but does not alter
the unitary ratio normally observed in (b). It is concluded
that in (a) some creatinine is excreted by tubular excretion
in addition to that which is excreted by filtration, while no
tubular excretion occurs in (b). In the latter, the creatinine
clearance, like the inulin clearance, may be taken as a measure of glomerular filtration. There is apparently no tubular
reabsorption of creatinine in either dog or man.
In the absence of an adequate method for creatinine determination at low plasma levels it is impossible
to say
..,.
whether creatinine as such is nO){IJllJ:l1y present in plasma: so
CREATININE CLEARANCE
101
that it remains to be determined whether the creatinine normally excreted in the urine is derived from preformed creatinine in the blood, and, if so, whether this endogenous
creatinine is handled by the kidney in the same manner as
exogenous creatinine.
x
CREATINE CLEARANCE
problems in biochemistry have presented more per·
plexities than the origin and relationship of urinary creatine
and creatinine. Although these questions do not immediately concern the physiology of the kidney it will be profitable
to review them briefly.
Interest in the excretion of creatine et. 20B, 881 is enhanced
by the fact that this substance plays an important role in the
metabolism of skeletal muscle. 'It is generally believed that
creatine is an anabolic product synthesized and conserved
for this specific end (muscle metabolism) in the same sense
as glucose or protein are conserved. Although sevel'al
amino-acids have been suggested as the precursor, there is
no certain evidence in favor of anyone. It is thought that
muscle creatine is the ultimate source of urinary creatinine,
though the conversion is possibly not a direct one.
As judged by the Jaffe reaction, creatine normally predominates over creatinine in the urine of birds and reptiles,122, 20B, 488 fresh-water and marine teleosts 184, 285,213, 415, 418
and elasmobranchs.4011 Conversely, creatinine commonly predominates over creatine in the urine of mammals/ 22 ,205, 353
but the latter may appear in large quantities in the urine of
apparently normal herbivores/oB, 323, m though it should be
noted that the creatine content of herbivorous diets has not
been extensively studied.
FEW
0..
PLATE I
Aglomerular kidney ·of toadfish, Ops.amts tau.
The aglomerular tubUles, wbich cdns ist entir.ely of
the proximal segment, are nearly separated from
each other b y lymphoid tissue . The cuboidal nature of the cells, which are essentially uniform
throughout the tubule, is particularly to be noted as
cont raindicating a process of filtI·ation such as occurs in th e capillary tuft of the glomerular kidney.
(See page 4 6 )
CREATINE CLEARANCE
103
In man, creatine is a constant but variable component of
the urine in both sexes from birth to puberty, although creatinuria is more marked in girls than boys after the first few
years. After adolescence creatine disappears from the urine
of man, but creatinuria recurs intermittently in women in relation to the oyarian cycle, and it reappears in old men and
becomes more marked in women after the climactic. It has
been suggested that the male sex hormone inhibits its excretion. Creatinuria also occurs where there is perturbed
carbohydrate metabolism, as in phosphorus or phlorizin intoxication and in diabetes, and it is usually associated with
hyperthyroidism, in which condition it disappears after the
administration of iodine. Conversely, hypothyroidism in
children is accompanied by a diminished creatine excretion.
Creatinuria frequently appears where there is rapid destruction of muscle, and attention has recently been directed towards the persistent excretion of creatine in myasthenia
gravis. Here, as in hyperthyroidism, small doses of creatine
are in great part excreted in the urine, in contradistinction to
normal individuals in whom moderat~ doses lead to no increased excretion. The administration of various aminoacids also causes an augmented excretion of creatine in myasthenia gravis and other muscular atrophies, but it has not
been shown that this is due to the direct eonversion of the
amino-acid to creatine.
It is well known that the creatinine output of a given individual on a creatine-creatinine free diet is remarkably uniform from day to day, even when the diet is protein-free, and
there is abundant evidence to indicate that the creatinine excretion in anyone species of mammal bears a close relation-
104
THE PHYSIOLOGY OF THE KIDNEY
ship to the total muscle mass. On the other hand Chanutin
and Kinard 88 have found that in various species there is no
correlation between creatinine excretion and the creatine
content of the muscles, and these authors have questioned
the strict validity of the above assumption. With regard to
the formation of creatinine, the system creatine p creatinine
is a reversible one and it has been pointed out that the velocity of the reaction at pH 7.2 and 35° III is such that about
one per cent of the active mass of creatine would spontaneously revert to creatinine in 24 hours. If the active mass of
creatine is taken to be 0.5 per cent of the muscle mass of the
body, the spontaneous dehydration of creatine could account
for the daily excretion of creatinine. The difficulty with this
calculation is that muscle creatine is not free, but combined
with phosphate, and nothing is known about the formation
of creatinine from phospho-creatine. One may, however,
suppose that spontaneous dehydration of creatine occurs at
some stage in the hydrolysis and re-formation of this labile
compound. In any case there would seem to be no reason to
look elsewhere than to muscle creatine for the mediate precursor of urinary creatinine, even though it should be shown
that the conversion is not a direct one.
The examination of the normal excretion of creatine is
rendered difficult, as in the case of creatinine, by the lack of a
specific analytical method. Where creatinine is invariably
present in the urine of mammals, creatine is usually absent,
and this raises the question of whether the absence of creatinuria is due to reabsorption by the renal tubules, or to the
fact that there is no creatine in the plasma. The last interpretation has been accepted by Wilson and Plass 488 and
CREATINE CLEARANCE
10 5
others, while Hunter and Campbell 206 have concluded that
if, indeed, creatine is normally present, the plasma" threshold" above which excretion occurs does not exceed 0.4 mgm.
per cent.
Since ingested creatine is in part stored in the tissues or deQ
!:i
0:.
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','
;.........
.. ~• I!a ...
• -•
•
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~ ... "fl'. •.••
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..... (1
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• MAN
f
~Q~---~20~---~40~----6~O~----80~-----~IOO~---~I20~~
R....ASMA
C~ATrNE
MGM
PE~
CENT
FIGURE 18
Creatine/inulin clearance ratio in normal dog and man.
(Pitts,
33 2 .)
stroyed 67 fairly large doses must be administered to normal
animals before creatinuria occurs. When the quantity administered is sufficient to raise the plasma level detectably,
creatine appears in the urine of both normal dogs and men.
In figure 18 there are given data obtained by Pitts 882, 888 on
the creatine/inulin cle~rance ratio in the dog and man in relation to plasma level of creatine. It will be noted that in
106
THE PHYSIOLOGY OF THE KIDNEY
both species a very slight elevation of plasma creatine suffices
to induce a creatine clearance which is about 80 to 90 per
cent of the inulin clearance, the difference between these two
clearances not being perceptibly decreased at the highest
creatine plasma levels! The possibility that part of the
creatine of the plasma may be combined in an unfilterable
complex has not been excluded, nor has. the possibility that
some of the creatine, even at high plasma levels, exists in a
complex that is filterable, but which is handled by the tubules
in a different manner than free creatine. Some such factor
may possibly account for the fact that the creatine clearance
never rises as high as the inulin clearance, and we cannot
definitely conclude that tubular reabsorption occurs.
The fact that the creatine clearance rises so rapidly with
increasing plasma level might be held to argue against the
existence of a renal threshold, * and therefore against tubular
reabsorption. But this question cannot be answered satisfactorily until more specific methods are available for analysis
at low plasma levels. In any case, the use of the term" lowered threshold" to describe the tendency of persons with
myasthenia gravis and hyperthyroidism to excrete creatine
is inappropriate, since it implies that the reabsorptive capacity of the kidney is altered, which mayor may not be true.
It is rather more probable that abnormal creatinuria reBects
a reduced capacity to store creatine in the skeletal muscles,
or to metabolize it, in consequence of which the plasma concentration, and therefore the rate of excretion, increases
*
The fact that intermediate creatine clearances were obtained by Pitts
in both the normal and phlorizinized dog at plasma levels below 5.0 mgm.
per cent may not have been due to a threshold effect, but to the error introduced by non-creatine bodies in the total apparent creatine determinations.
CREATINE CLEARANCE
10 7
rapidly when small quantities, endogenous or exogenous, are
introduced into the blood.
Phlorizin has no apparent effect upon the immediate excretion of creatine in the dog at any plasma level,s88 although
prolonged phlorizinization leads to excessive protein destruction and hence to creatinuria.
In marked contrast to the dog and man, where the creatine
clearance is always less than the filtration clearance, the
glomerular teleost excretes this substance in part by the
tubules.838 This might be expected, since creatine is readily
excreted by the aglomerular fish. It must be supposed that
in the glomerular teleost tubular excretion supplements
glomerular filtration. This is the first instance where a substance which is possibly actively reabsorbed by the mammalian tubules is excreted by the tubules of the cold-blooded
animals. * This paradoxical situation arises perhaps from
the circumstance, as mentioned above, that in the vertebrates
below the mammals creatine, rather than creatinine, is the
nor.bal constituent of the urine. Data on the creatine/inulin
ratio, from Pitts' recent study of the red grouper, E. morio,
are given in figure 19.
As the plasma level of creatine is raised the creatine clearance, and therefore the creatine/inulin ratio, is depressed.
Thus creatine, like creatinine and phenol red, shows this
phenomenon which seems to be invariably associated with
tubular excretion. Phlorizin lowers the creatine/inulin ratio
towards 1.0, indicating that this drug blocks the tubular excretion of creatine, as of creatinine. When both creatine and
creatinine are administered, the clearances of these two sub-
* A similar situation may exist in the case of phosphate.
1G
4.
108
THE PHYSIOLOGY OF THE KIDNEY
stances are not identical, the substance with the lower plasma
level having the higher clearance.
Summary. When creatine is administered to mammals in
sufficient doses to raise the apparent plasma level to a detect-
~
ki
7
W'6
~ .
~5
<l
~
~4
~
53
"
~2
~
i=
«
w
.0::
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•
• •
•
...........
... ...
1~~------------~---------------------------4
Ok---____
~----~~----~~~--~db~--~~
o
I
200
250
PLASMA
MGM. PER CENT
FIGURE 19
Creatine/inulin clearance ratio in the normal teleost, Epinephelus
morio (dots), and after phlorizin (triangles). Each dot represents
the average of ten observations; each triangle is a single observation.
(Pitts,3j8.)
able degree, this substance appears in the urine in relatively
large amounts. In both man and dog the creatine clearance
at plasma levels of 5 to 120 mgm. per cent is 80 to 90 per
cent of the filtration clearance. It is impossible on the evidence to decide whether or not creatine is reabsorbed by the
renal tubules either at low or high plasma levels, because
CREATINE CLEARANCE
109
of the lack of a specific analytical method. In any case there
is no tubular excretion.
Exogenous creatine is excreted by the aglomerular fish.
The creatine/inulin clearance ratio in the glomerular teleost is greater than 1.0, and is depressed by raising the plasma
level, and by the administration of phlorizin, indicating that
here creatine is excreted in part by tubular excretion in addition to filtration. The paradox of tubular excretion in a
lower vertebrate, as against possible tubular reabsorption in
mammals, is perhaps related to the fact that creatine is a normal constituent of the urine in all vertebrates below the
mammals, but appears in the urine of mammals only under
special circumstances.
XI
GLUCOSE CLEARANCE
PHYSIOLOGICAL GLYCURESIS
IT HAS long been known that whenever the plasma level of
glucose is elevated, sugar is excreted in the urine in considerable quantities. Hyperglycemia sufficient to cause glycuresis
attends a large number of diverse circumstances which may
be considered entirely physiological, i.e., after a large carbohydrate meal, during severe exercise. or accompanying
marked sympathetic activity, as in emotional excitement, etc.
The most noteworthy instance, however, of glycuresis is in
diabetes mellitus. It was, in fact, from the sweet taste of
the urine that this disease derived its name (honey diabetes)
and the urinary test for sugar still constitutes one of its chief
diagnostic signs. Here the failure to metabolize carbohydrates leads to a cyclical or persistent hyperglycemia, and
this in turn may result in glycuresis; but in this instance, as in
physiological glycuresis, the appearance of glucose in the
,urine is to be considered incidental to the elevation of the
plasma glucose and to the failure of the tubules to reabsorb
all the glucose contained in the glomerular filtrate, rather
than to any impairment of renal function.
The concept of a renal" threshold" is more commonly associated with glucose than with any other constituent of the
plasma. The term may be slightly misleading, however,
inasmuch as it implies a fairly sharp limit above which gly-
GLUCOSE CLEARANCE
I II
curesis will occur. There are traces of glucose in the urine
at almost all times/TO and the apparent threshold in man is
itself rather variable, ranging from 100 to over 200 mgm.
per cent, although 80 per cent of normal individuals fall
within the range of 140 to 190 mgm. per cent. G8 , 80, 188, 4.08 It
would appear that this problem has been complicated by the
use of venous blood. Where a substance is utilized by the
tissues, as in this instance, a considerable difference may exist
between the concentration in the arterial (renal) blood and
the venous blood, and the use of the latter may lead to a deceptive value for the renal threshold, especially if the concentration of glucose in the blood is changing rapidly.
In the pathological condition called renal diabetes the
threshold is lowered, for glycuresis occurs at normal plasma
glucose levels.
The nature of the glucose" threshold" mechanism of the
kidney can be examined by the simultaneous determination
of the rate of glucose filtration and the glucose clearance.
The quantity of glucose filtered per minute will be the filtration clearance (in the dog, the creatinine clearance) multiplied by the concentration of glucose in the plasma; the difference between this quantity and the quantity excreted per
minute gives the quantity reabsorbed by the tubules. Tqe
glucose clearance is essentially zero u~til the plasma level
reaches a critical value (the" threshold") ; above this level
glucose begins to be excreted, the clearance increasing rapidly with rising plasma level and approaching the filtration
rate as its asymptote. Ni and Rehberg,818 assuming that
reabsorption takes place in the proximal tubule before any
reabsorption of water occurs, calculated the equilibrium con-
I 12
THE PHYSIOLOGY OF THE KIDNEY
centrations in the blood and .urine at various levels of hyperglycemia, and concluded that the reabsorptive process is
limited by a maximal concentration difference between these
two fluids. They recognized, however, that the quantity of
glucose which the tubule cells could reabsorb per minute
might have some upper limit. But in point of fact, so long
as the rate of filtration remains constant, the reabsorption of
a constant quantity of glucose will lead to a constant concentration difference between tubular urine and blood, under
their assumption, so that this latter relationship may be
purely fortuitous.
This problem has recently been re-examined by Fisher and
Shannon (unpublished) in the dog, the arterial plasma
level of glucose being maintained by the constant intravenous
infusion of a glucose-saline solution. An experiment from
the work of these investigators is given in figure 20. Frank
glycuresis appeared when the plasma level rose above 300
mgm. per cent; the quantity of glucose reabsorbed by the
tubules of both kidneys (as calculated by the difference between the quantity filtered and the quantity excreted) remained constant at 200 mgm. per minute, although the
plasma level was raised from 300 to 2400 mgm. per cent.
It would appear that the glucose" threshold" has its origin
in the fact that the tubules can reabsorb glucose up to some
constant, maximal quantity per unit time; if presented in
excess of this quantity, the remainder is allowed to escape
into the urine. This situation recalls the fact that the tubules of the dog, bird and apparently man can excrete a
constant maximal quantity of phenol red per unit time.
Translating the above results in the dog to man, we may
GLUCOSE CLEARANCE
II3
estimate that the maximal rate of reabsorption is about 200
mgm. per minute, i.e., 120 cc. filtrate per m~nute x 165 mgm.
per cent, the latter figure being the average of the threshold
values cited above. Glucose is normally filtered at about
1200
~IOOO
"
~800·
~
IX 600
8
3400
(9
t
c
+
1200
1800
2400
GLUCOSE MGM. PER CENT
FIGURE 20
The rate of excretion of glucose (UV) in relation to plasma concentration in the dog. The tubules are apparently capable of reabsorbing approximately all the glucose up to a certain constant
quantity (C) per unit time. Consequently, as the plasma level rises
the quantity excreted (A) is determined by the difference between
this quantity (C) and the quantity filtered (B). (Shannon and
Fisher, unpub.)
half this rate (120 cc. X 100 mgm. per cent), but, if the concentration in the plas~a is raised to 165 mgm., all the excess
glucose in the filtrate passes down the tubules into the urine.
114
THE PHYSIOLOGY OF THE KIDNEY
Cushny believed that the tubules reabsorbed a perfected
Locke's fluid, a solution containing glucose, amino-acids and
other similar food substances, chloride, sodium, potassium,
urea, uric acid and phosphate in approximately the proportions in which they are of advantage in normal plasma, the
fluid absorbed being" always the same, whatever the needs
of the organism at the moment."
But there is no reason to believe that the reabsorption of
glucose is teleologically related to the reabsorption of any
other substance, or that the reabsorption of any solute is
teleologically related to the reabsorption of water. The several reabsorptive processes are probably carried on more or
less independently, and no doubt occur at different positions
along the tubule. In the Amphibia, glucose is reabsorbed
in the proximal tubule and chloride in the distal, and it is
likely that this is also the case in mammals; whereas it
is equally probable that in the mammals much more water is
reabsorbed in the thin segment and in the distal tubule than
in the proximal tubule. The reabsorptive processes by which
glucose and other solutes are returned to the blood must
depend on highly specific cellular mechanisms, as in the case
of tubular excretion. The problem is undoubtedly a very
complex one; in our ignorance the term " threshold," as descriptive of the more or less critical relationships between
plasma level and excretion, is too convenient to be abandoned.
PHLORIZIN GLYCURESIS
Of particular interest in connection with the excretion of
carbohydrates, is the action of the drug, phlorizin, a glucoside obtained from the bark and the roots oOf apple, pear and
GLUCOSE CLEARANCE
115
other fruit trees, in blocking the tubular reabsorption of
glucose. Shortly after its isolation by deKonick in 1846, this
investigator tried phlorizin in the treatment of malaria on
the grounds that it was bitter like other remedies which were
effective in this disease. This prescription was short-lived,
however, and it was not until 1885 that von Mering discovered that phlorizin caused a transient glycuresis. In 1899
Minkowsky and von Mering demonstrated that diabetes
mellitus could be produced. experimentally in dogs by the
extirpation of the pancreas, and they correctly attributed
this disease to a deficiency of the internal secretion of this
organ. Because the action of phlorizin was accompanied by
the excretion of glucose in the urine it came to be called
phlorizin" diabetes," and it was many years before the
fundamental differences between the two conditions were
fully recognized.
Ever since von Mering's discovery of the glycuretic action
of phlorizin, this drug has been used experimentally to force
the excretion of glucose in connection with various biochemical investigations, and it was early introduced for this purpose in renal physiology.212, 288, 84.1, 472: Much has been
learned about its action in recent years by the study of renal
clearances. In sufficient doses (200 mgm. per kg. intravenously) it completely blocks the reabsor-ption of glucose in
dogfish, m teleost,838 chicken,887, tOOb sheep (unpub.) and
dog; 3D6 in the largest doses given man 408 (100 mgm. per
kg.) it raised the glucose/inulin clearance ratio to 0.91, and
it is quite probable that larger doses would produce complete
glycuresis. It is poor!y absorbed from the gastro-intestinal
tract and complete glycuresis cannot be obtained by this
I
16
THE PHYSIOLOGY OF THE KIDNEY
route.l4B The administration of phlorizin causes a marked
reduction in all renal clearances, presumably due to circulatory disturbances, which fact makes it necessary to judge its
effects in terms of clearance ratios rather than absolute
values.146. 810. 338,482 In the sculpin it causes the glomerular
circulation to shut down entirely, thus temporarily rendering
the animal aglomerular. 214 Earlier investigations on the
measurement of glomerular filtration carried out in the author's laboratory were concerned with the excretion of xylose
and sucrose. After intravenous injection there is little if any
metabolism of xylose 81. 2111 and sucrose is rapidly and quantitatively excreted in the urine. lllll. 222 A large number of data
are now available on the excretion of these substances in both
normal and phlorizinized animals, which have been detailed
in chapter XIII. The simultaneous clearances of xylose and
sucrose are essentially identical in the normal dogfish, dog
and man/Ill. 381, 894,419 and it has been shown that in these
animals, as well as in the sculpin and rabbit, the xylose clearance is lower than the inulin clearance by 20 to 30 per cent.
Phlorizin raises these clearances to equality with the inulin
clearance, indicating that the reabsorption of xylose and
sucrose is an active process, probably associated with the
reabsorption of glucose.
Little is known concerning the mechanism of action of this
substance, which is primarily confined to the kidney and does
not include any direct effect upon the body as a whole. 8B. 218, 801
It does not inhibit the metabolism of excised renal tissue 410
or the fermentation of yeast,86 though it aoes inhibit the selective absorption of sugars from the intestine. 1I2, 801.468 In
sufficient concentration it inhibits phosphorylation of glu-
GLUCOSE CLEARANCE
II7
cose 242 and Lundsgaard once suggested that it is because of
this action that it blocks the reabsorption of glucose in the
kidney,24S but he later abandoned this explanation because
it appears that the phlorizin concentration in the kidney is
not high enough to act in this manner.2", 824 A similar negative conclusion concerning the mechanism of renal action has
been reached by Walker and Hudson. 458 Arbutin, a glucoside obtained from the bearberry, also induces marked glycuresis, but amygdalin (bitter almonds) and salicin (willow)
are without marked glycuretic effect.1, 298
There is no other active reabsorptive process which is
known to be blocked by phlorizin, but it would be expected
that the drug might have other and perhaps deleterious effects upon the kidney. The outstanding effects which have
been identified at the present time are the paralysis of the
tubular excretion of creatinine in all animals (dogfish,S94, 896
chicken,4oob man,R9S) and the paralysis of the tubular
excretion of creatine in fish.8s8 Relative to the inulin clearance, it has no effect upon the clearance of creatine sss or
hexamethylene tetramine 885 in the dog, or upon the excretion
of chloride.402
..
Phlorizin glycuresis in all animals is accompanied by some
diuresis, but this is apparently due simply to the osmotic resistance offered by the urinary glucose to the reabsorption of
water. Prolonged administration leads to a rise in protein
combustion, ketosis and other sequelae associated with deficient carbohydrate metabolism.
Summary. Glucose, which we may presume is present in
the glomerular filtrate in mammals in the same concentration
as in plasma, is normaily almost completely reabsorbed by
II
8
THE PHYSIOLOGY OF THE KIDNEY
the tubules. When the plasma level is elevated some of the
glucose escapes reabsorption and appears in the urine, although even under conditions of marked hyperglycemia, glycuresis is not complete. This" threshold" mechanism appears to be due to the fact that the renal tubules tend to
reabsorb all the filtered glucose up to a certain constant,
maximal quantity per unit time.
Phlorizin produces glycuresis by blocking the tubular reabsorption of glucose in all animals. It similarly blocks the reabsorption of xylose and sucrose, the reabsorption of which
is slight, and apparently due to entanglement with the reabsorption of glucose. This drug also blocks the excretion of
creatinine and creatine where this has been observed to occur.
XII
UREA CLEARANCE
IN UREA we encounter a substance which 'in the mammals is
excreted solely by glomerular filtration, but which in addition
is reabsorbed to a considerable extent by the tubules. It
therefore falls roughly in category C of figure 4, page 57.*
Of all substances in the urine, urea has been of the greatest
interest to both the physiologist and the clinician. It is the
chief nitrogenous end-product of the combustion of protein
and, apart from water, the chief constituent of the urine.
Because the urea clearance is one of the most widely used
indices in diagnosis of renal disease, the physiological factors
involved in its excretion are of the utmost importance. A
brief review of the history of investigations on the excretion
of urea is essential to an understanding of the present status
of the problem.
Urea was first prepared by Rouelle in 1773 by the alcoholic extraction of evaporated human urine. This investigator was also one of the first to extend biochemical investigations to the lower animals, for he alsp demonstrated that
*
In the marine elasmobranch fishes urea is actively reabsorbed by the
tubules until the plasma concentration rises to 2000-2500 mgm. per cent;
this physiological uremia serves to elevate the osmotic pressure of the blood
and promote water equilibrium.'20 In the aglomerular fish there is possibly slight tubular excretion, though in the glomerular teleost filtration appears to be the only pz:.ocess involved.lIs It is excreted in part by tubular
activity in the frog, but not in Necturus (cf. page 40). In the chicken
it i.s handled much as in the mammal.sslt
120
THE PHYSIOLOGY OF THE KIDNEY
this substance was present in the urine of the camel, horse
and cow. In the hands of Scheele, Proust, Fourcroy al}.d
others the separation and identification of the nitrogenous
constituents of urine progressed rapidly in the early years of
the 19th century, and uree, as it was named by Fourcroy to
avoid confusion with urique (uric acid), received its full
share of attention. Of urea, Fourcroy wrote in 1804,
. . . its expulsion is the principle and, the most necessary, the
most remarkable purpose of the urinary evacuation.
It was only a few years after Prout had established its empirical formula that Wohler in 1828 demonstrated that this
" organic" compound could be prepared artificially from
ammonium cyanate. The effect of this discovery upon the
science of the past century can scarcely be appraised even at
this date, for it constituted one of the first and also one of the
most effective blows ever delivered against the doctrines of
vitalism, which had dominated natural philosophy up to the
19th century. It was due less to coincidence than to the fact
that chemistry and medicine were developing hand in hand,
that in the year before Wohler's work Richard Bright first
described the disease which is named after him. It was
known that urea was present in the blood, that there was a
deficiency of urea in the urine of dropsical patients, that
dropsy is frequently associated with albuminuria and at
times with diseased kidneys. It was Bright's achievement
to demonstrate the accumulation of excess urea in the blood
in dropsy, and to correlate this unusual circumstance with its
decreased concentration in the urine, with albuminuria, and
with abnormal kidneys. When, in 1842, Dumas and Cahours showed that urea was a product of the combustion of
UREA CLEARANCE
121
protein food (the essential principles of metabolism having
been formulated by Lavoisier a generation before) the naturalistic description of renal disease was complete.
The term" uremia" early became associated with renal
insufficiency. It is now thought that few if any of the pathological changes associated with renal insufficiency are due
specifically to the accumulation of urea in the body, for urea
is one of the least toxic of all nitrogenous comp~unds; but
this in no way diminishes the importance of this substance to
the physician, and the capacity of the kidney to excrete it still
constitutes a valuable test of renal function.
Until the close of the century physicians relied for diagnostic purposes chiefly upon the accumulation of urea in the
blood. During the next two decades the determination of
the blood urea content was supplemented by the determination of the non-protein nitrogen, creatinine and uric acid
content, since these all tend to rise above normal values in
advanced renal disease. It is now clear, however, that all
indices which are based simply upon the retention of urea or
any other waste product are inadequate to detect early
changes in excretory function, since these may be greatly reduced before marked retention occurs. Some investigators
have placed emphasis on the urea content of the urine under
more or less constant conditions, while others have believed
that the degree to which urea could be concentrated (i.e.,
the U /P ratio) constituted a better functional test. But it
was not until 1912 that Ambard and Weill 8 attempted to
evaluate renal activity by what we may call a "dynamic"
test, i.e., one which related the quantity of urea excreted in
unit time to the plasma concentration. Ambard and Weill
122
THE PHYSIOLOGY OF THE KIDNEY
arrived at an equation which, though it described the facts
fairly well at low urine flows, was difficult to interpret physiologically. With numerical constants omitted, this equation
is K=
v'U where Band U are the concentration of
urea in the blood and urine, respectively? and D is the rate of
urea excretion. The relationship of Ambard's formula to
the standard urea clearance is discussed by Peters and Van
Slyke. S27
A little later some degree of simplification in this problem
was effected in the demonstration by Marshall and Davis 272
and Addis and Drury:l that the rate of urea excretion is directly proportional to the blood urea content, providing the
urine flow is fairly large. It is this fact that constitutes the
central principle of the Addis" urea excretion ratio," according to which the quantity of urea excreted in one hour's urine
(uv) divided by the concentration in the blood (b) is constant for anyone individual under standard conditions.
(The Addis excretion ratio is really nothing other than an
hourly, rather than a minute, clearance.) But the Addis excretion ratio had a limited applicability, since the" standard
conditions" required maximum diuresis, or at least a very
large urine flow. er. 327
In 192 1 Austin, Stillman and Van Slyke 10 re-examined the
influence of urine flow on the excretion of urea and found
that the expression UV IB (they preferred one minute rather
than one hour as their unit of time, and they used the concentration of urea in whole blood) is constant until the urine
flow falls below a certain critical value, which they called the
"augmentation limit." Below this point the rate of urea
excretion relative to the blood level appeared to vary in pro-
vr:
UREA CLEARANCE
12 3
portion to the square root of the rate of urine flow; that is,
the above equation must be written (UV/B) V I IV = K.
This is equivalent to writing UVVIB = K. It was in a subsequent extension of this work that Moller, McIntosh and
Van Slyke 299 applied the term, "clearance"; the expression
,
I
________________ 1, _______
STANDARD:
CLEARA~,:
Iffii C
---pa
S
.
.
_F.!.L!~T_IQ~ _R_~Tf
1
__________ _
MAXIMUM·
CLEARANCE
UV
-p=CM
,
1
'I-
i~
IJ
IZ
'Q
I~
1'IW2
:~
1«
,,
I
URINE
2
3·
4
9
VQl....UM~ - Cc. / M.INUTE
4
16
FIGURE 21
The" standard" and" maximal" urea clearance interpreted on
the basis of a constant rate of glomerular filtration.
UV/B they called the "maximum" clearance (Cm), and
U VVIB they called the " standard " clearance (Cs).
It is convenient to visualize these standard and maximum
clearances against the background of knowledge of the kidney which we have obtained thus far. This has been done
in figure 2 I where the filtration rate is taken to be 125 cc. per
minute and, as we have seen, independent of the rate of urine
124
THE PHYSIOLOGY OF THE KIDNEY
excretion. The" maximum" whole blood urea clearance
(UV/B) is given its average value in normal man of 75 cc.
per minute. This holds until the urine flow falls to the augmentation limit (which averages in man about 1.5 cc. per
minute), after which die clearance as calculated in the ordinary manner begins to decrease, and the formula U VV/B
(" standard" clearance) must be substituted in order to obtain a constant. The mean normal value of the" standard"
whole blood urea clearance in normal man is 54 cc. per minute, compared with the 75 cc. maximum clearance. In order
to place the two formulae on a mathematically equivalent
basis, the urea clearance, whether maximum or standard, is
commonly expressed as per cent of normal (i.e., of 54 and 75
cc., respectively).
A series of urea clearances in the dog and man, observed
simultaneously with the inulin clearance, have been given in
figures 6 and 7, which the reader may review for the following points. It will be observed, first, that the urea clearance is considerably less than the inulin clearance, and, second, that w~ere the inulin clearance shows no systematic
downward drift at low urine flows, the urea clearance does.
It is this variability of the urea clearance in relation to urine
flow that was the physiological basis for the empirical distinction between the "standard" and "maximum" clearances of Moller, McIntosh and Van Slyke.
We can restate the facts concerning urea excretion in the
following manner. At moderate to high urine flows the urea
clearance is nearly constant, in the sense of being independent
of urine flow, but it is, nevertheless, considerably less than the
rate of filtration. Urea is completely filterable, and there is
UREA CLEARANCE
as yet no evidence that it is destroyed in the tubular urine, so
we must interpret the deficit in the urea clearance to mean
that a considerable fraction of the filtered urea is reabsorbed
by the tubules. As the urine flow decreases the urea clearance decreases relative to the rate of filtration, indicating
that the amount of urea reabsorbed increases as the urine becomes more concentrated. A priori, one might suppose that
the reabsorption of urea at all urine flows is due to a unitary
process somehow related to the rate of urine formation; but
on the contrary the investigations cited below indicate that
at least two processes are involved, one of which accounts
for the deficit at high urine flows (amounting to about 40
per cent of the glomerular clearance) and a second process
that becomes significant chiefly at low urine flows. Nothing
is known of the processes by which urea is reabsorbed except
that they are not influenced by the plasma level of urea. *
The following paragraphs relate to investigations bearing
upon the above points, but since the outcome of these investigations has been to reveal further complexities in the problem, rather than any immediate simplification, it will be appropriate for the student to consider them 'merely as a
collateral discussion.
The applicability of the concept of standard and maximum
clearances to the dog was accepted by Jolliffe and Smith 214, 2111
and by Summerville, Hanzal and Goldblatt 434 without criticism, and it has been assumed in the recent studies of Van
*
Sheehan and his co-workers 97, 219 find that the renal extraction ratio
for both urea and creatinine is decreased when the plasma level is raised,
in contradiction to others who have found that the rate of excretion of these
substances is indc;pendent of .plasma level. For a discussion of tp.ese experiments see Van Slyke et a1. 448
126
THE PHYSIOLOGY OF THE KIDNEY
Slyke, Rhoads, Hiller and Alving. 446 Dominguez 91 has formulated an equation to describe the changes in the urea clearance relative to the rate of urine formation, intended to be
applIcable at all urine flows. To do this he had arbitrarily
to assume that the maximum clearance was an asymptote
which the urea clearance approached as the urine flow increased, and whicn was approximated at the augmentation
limit.
In all these studies it would seem that data obtained under
a variety of physiological conditions had been treated together indiscriminately. Shannon 400& re-examined the problem in individual dogs on the assumption that different dogs
might behave in a different manner, and that even the same
dog might behave differently at different times. His experiments were so arranged that the rate of urine flow varied
throughout the entire physiological range in each series of
observations and returned at least once during the experiment to the initial rate, or .as near to it as possible. The
creatinine clearance was used as a measure of glomerular filtration, on the evidence cited in chapter IX. For convenience of discussion his experiments may be divided into two
groups: first, those in which the urine flow was either con.stant or falling, and, second, those in which the effect of a
rising urine flow was examined against a background afforded by the first group. In the first group of experiments
the initial observation period was removed at least one hour
from the administration of water, in order to avoid the disturbing effects which this procedure might have had upon the
systemic circulation, as well as locally upon renal function.
The data obtained upon a single dog (C) are illustrated in
UREA CLEARANCE
12
7
figure 7. It should be noted that the absolute value of the
urea clearance at any urine flow is the same in the presence
(solid dots) or absence (open circles) of creatinine.
In Shannon's data there appears to be no particular urine
flow in the dog which may properly be designated as an augmentation limit; the urea clearance increases systematically
with the rate of urine formation up to the highest values obtainable. Variations in the urea clearance are partly due to
variations in the rate of filtration, and partly to variations
in the fraction of the filtered urea that is reabsorbed. The
variations in the rate of filtration can be eliminated by considering the urea/inulin (or creatinine) clearance ratio, as
has been done in the case of phenol red and other substances.
In analyzing the effect of urine flow upon the reabsorption of
urea it is convenient to relate the fraction: 1.00 - urea/
creatinine clearance ratio (which indicates the fraction of
the filtered urea which has been reabsorbed) to the U /P
ratio of creatinine, which indicates the degree to which the
glomerular filtrate has been concentrated in the renal tubules.
When this is done, it is found that the changes in urea/creatinine clearance ratio are roughly in inverse proportion to the
logarithm of the U /P ratio of creatinine, as is shown in figure 22. The value of this ratio at any urine flow is indipendent of the rate of filtration, w_gen this is elevated or
lowered by a high or low protein diet.
It was suggested by Rehberg 850 that the progressive depression of the urea clearance as the urine flow decreases is
due to passive diffusion of urea in consequence of the concentration gradient across the tubules which results from the reabsorption of water. It will be observed, however, that at
128
THE PHYSIOLOGY OF THE KIDNEY
the highest urine flows obtainable (i.e., at the lowest U /P
ratio of creatinine, which is about 10) 40 per cent of the filtered urea is reabsorbed. If the linear relationship is extra-
2 .60
«
a:
~ 50
z
«
a:
«
w
..J
U
W
Z
Z
I-
«
W
a:
u
co
"
«
w
a:
:>
o
.10
o
DOG C
10
CREATININE
RATIO
FIGURE 22
The tubular reabsorption of urea (urea/creatinine clearance
ratio) in the dog in relation to the degree of concentration of the
urine (creatinine V/P ratio). Circles, high protein diet, avg. filtration rate = about 113 cc. per minute; dots, low protein diet, avg.
filtration rate = about 65 cc. per minute, both on constant or falling urine flows. The solid triangles represent observations on rising
urine flows. (Shannon,4ooa.)
UREA CLEARANCE
12 9
polated back to a U IP ratio of 1.0, it would cut the ordinates
at about 0.7, indicating that about 30 per cent of the filtered
urea would be reabsorbed even under conditions where there
would be no reabsorption of water, and therefore no concentration gradient to cause back-diffusion of urea. Although
such an extended extrapolation is by no means warranted,
one is led to infer from these experiments that some reabsorptive process, not related to the concentration gradient of
urea across the tubules, is ·responsible in part for the deficit
in the urea clearance at a creatinine U IP ratio of 10. This
inference is further supported by the following considerations.
In setting up a description of a simple diffusion process,
there must be taken into account the concentration gradient
of urea, the volume of the tubule from which reabsorption is
occurring in relation to the area of permeable surface, and
the time during which the' concentrated urine is in contact
with the tubule cells. After considering these- factors Shannon concluded that if the deficit in the urea clearance at a
creatinine U/P ratio of 10 is in fact due to a process of passive diffusion, and if this process is of the same nature as that
which occurs at low urine flows, then at a creatinine U/P
ratio of 100 the conditions would be such as to permit complete back diffusion, i.e., an approximately. equal distribution
of urea between urine and blood. Such a simple diffusion hypothesis therefore appears to be inadequate to explain the
facts. If, however, one supposes that something like 40 per
cent of the filtered urea is reabsorbed at high urine flows by
some process not depen.ding on diffusion, then the additional
reabsorption which comes into play at low urine flows might
13 0
THE PHYSIOLOGY OF THE KIDNEY
be explicable under the combined terms of increasing concentration gradient and prolongation of the time of contact.
Turning now to the second group of experiments, in which
the excretion of urea was observed on rising urine flows, it is
found that a further complication enters. The solid triangles in figure 22 illustrate an experiment in: which the urin~
How was caused to increase during the experiment by the administration of water. Other experiments show that if the
rate of increase is very slow the urea/creatinine clearance
ratio may retrace the course set on constant or falling urine
Hows. But if the positive acceleration of urine How is more
rapid, as in this particular instance, the urea clearance tends
to increase, to an excessive degree, relative to the creatinine
clearance, so that the ratio rises to abnormally high values.
This phenomenon of the relative exaltation of the urea clearance is temporary, but it can be elicited repeatedly and in
response to other agents causing a rapid increase in rate of
urine flow.
Although it must be inferred that more than one reabsorptive process is responsible for the deficit in the urea clearance,
there is no reason to believe that there is any active reabsorption of urea in the sense in which glucose is actively reabsorbed by the tubules, or in the sense in which urea itself is
reabsorbed by the tubules in the elasmobranch fishes j 420 i.e.,
there is no reason to interpret this reabsorption as a conservation of urea, in the teleological sense. It seems more likely
that it is incidental to other operations going on in the tubule.
With the information gained from Shannon's observations on the dog, Chasis 88 has re-examined the excretion of
urea in man. The same precautions have been taken to avoid
UREA CLEARANCE
13 1
the disturbing influence of water administration, and to
achieve as great physiological constancy as possible. The
results obtained in a single individual (T.G.) on constant or
falling urine flows have been illustrated in figure 6, and the
urea/inulin clearance ratios from these data, as well as data
for a second individual, C.B., have been plotted as open
circles against the U /P ratio of inulin in figure 23. It was
not possible to get the urine How down to as low values as in
the dog, but it would appear that in these subjects the deficit
in the urea clearance increases roughly in proportion to the
logarithm of the inulin U /P ratio throughout the range
studied. In a third subject, T.B., the behavior of the urea
clearance conforms more closely to the Moller, Mcintosh
and Van Slyke description than in the other two. The human kidney also shows an exaltation of the urea clearance,
relative to the inulin clearance, on rising urine flows, as is
shown by the solid trian~;Ies in figure 23. This is an important practical consideration in the determination of urea
clearances in man; a veritable or reproducible urea clearance can be obtained only if the rate of urine formation is
constant or falling.
It is apparent that the excretion of urea is complicated by
several factors which are neither analyzable nor controllable
at the present time. In view of this fact, it would seem desirable for the time being to adhere, for man at least, to the
description of this process in terms of standard and maximum clearances, using the latter wherever practicable.
It will be of interest, before leaving the discussion of the
excretion of urea, to r_efer to clinical data on nephritis relating the urea clearance to the urea content of the blood, on the
13 2
THE PHYSIOLOGY OF THE KIDNEY
one hand, and the creatinine content on the other.827 The
urea clearance must fall to below 50 per cent of the average
normal value before the blood urea rises above the normal
level, the upper limit of which may be set at about 23 mgm.
o
.62
oi= .54
~
<{
a::
0
00
o
w· 46
6J
o
u
z
~
38
<{
w
_j
u
z
~0
00
0
00
~
8
T.G.
o
.70
_J
~ .62
C8.
10
20
50
100
INULIN U/P RATIO
200
23
The tubular reabsorption of urea (urea/inulin
clearance ratio) in man in relation to the degree
of concentration of the urine (inulin V/P ratio), as
observed on falling (circles) and rising (triangles)
urine flows. (Chasis, 68.}
FIGURE
of urea nitrogen per 100 cc. of blood. With urea clearances
between 20 and 40 per cent of normal, more than one-half
UREA CLEARANCE
133
the blood urea contents will still be within the normal range.
It is only when renal function, as measured by the urea
clearance, has fallen to 20 per cent of normal that the concentration of urea in the blood becomes definitely elevated. Similarly, it is not until the urea clearance is decreased to approximately 20 per cent of the normal that the
blood creatinine exceeds its average normal concentration
(2 mgm. per cent). There can be no doubt that, despite the
reabsorption which complicates the excretion of urea, the
urea clearance is a very sensitive index of renal function and
that it merits its widespread clinical popularity. It must
be recognized, however, that disturbances of the circulation
may cause a decrease in the urea clearance, due primarily
to decreased filtration and quite apart from primary renal
impairment.
Summary. The urea clearance is invariably less than the
rate of glomerular filtration in both dog and man, even when
the rate of urine formation is very large, indicating that a
considerable fraction of the urea originally present in the
glomerular filtrate is reabsorbed during the passage of this
filtrate down the tubules. As the rate of urine formation
decreases the fraction of filtered urea reabsorbed increases,
which circumstance leads to a progressive lowering of the
urea clearance. There is no evidence at; the present time
that there is any active reabsorption of urea, in the sense that
glucose .is actively reabsorbed by the tubules; rather it seems
better to view the deficit in the urea clearance as due to the
escape of urea from the lumen of the tubules back into the
blood in consequence of a high concentration gradient established by the reabsorption of water, supplemented by an
as yet unknown reabsorptive process which takes up some-
134
THE PHYSIOLOGY OF THE KIDNEY
thing like 40 per cent of the filtered urea at the highest urine
flow obtainable. During the time when the urine flow is
increasing, the urea clearance may be raised to abnormally
high values, relative to the rate of urine formation. In view
of the multiplicity of the factors influencing the rate of excretion of urea, it appears best to adhere to the empirical
description of this process in terms of standard and maximum
clearances, using the latter wherever practicable.
XIII
THE EVIDENCE FOR THE USE OF INULIN
AS A MEASURE OF GLOMERULAR
FILTRATION
A PAUSE may conveniently be made at this point to summarize the evidence justifying the use of inulin, or any other substance, for the measurement of glomerular filtration. This
evidence consists of a comparison of simultaneous clearances
of various substances in different species, and since its final
appraisal requires an authoritative knowledge not only of
the physiological conditions of the experiments, but also of
the analytical methods used, it is not to be expected that
anyone unpractised in the technique of clearance determination could critically evaluate it. But since the measurement
of filtration rate is a matter of such great theoretical and
practical importance, an understanding of the general principles is valuable.
We may begin by stating certain of the specifications, formulated in the light of the knowledge of renal function
gained so far, which a substance, X, suitable for measuring
glomerular filtration, must fulfil.
.
I. Any substance, X, to be completely filterable through
the glomeruli, must be completely filterable from plasma
through artificial membranes impermeable to plasma proteins but permeable to smaller molecules.
13 6
THE PHYSIOLOGY OF THE KIDNEY
II. As presumptive evidence against tubular excretion, X
should not be excreted by the aglomerular fish kidney.
III. a. The rate of excretion of X (UV) should increase
over wide limits in simple, direct proportion to the plasma
concentration (P) ; i.e., the clearance, UVIP, should be independent of the plasma concentration. This condition in
large measure excludes the possibility of tubular excretion
and tubular reabsorptio~.
b. Where III. a. cannot be demonstrated, because of inconstancy in the rate of filtration itself, it is of equal force to
show that the clearance of X is constant, relative to the
clearance of some other substance, at various plasma levels
of X.
IV. Assuming that adequate doses of phlorizin completely block the tubular reabsorption of glucose, then in the
phlorizinized animal the clearance of X should be equal to
the glucose clearance. (This, of course, is not evidence that
phlorizin does not block the tubular excretion or reabsorption of X itself.)
V. Where the simultaneous clearances of two or more
substances are identical under a wide variety of conditions
(plasma level, urine flow, etc.), this may be taken as evidence
that both substances are excreted by the glomeruli, without
interference from the variable factors of tubular reabsorption or tubular excretion. .
VI. Where a completely filterable substance is excreted in
part by tubular activity, the clearance of that substance when
depressed by elevating the plasma level should approach the
clearance of X as the limiting asymptote.
The following paragraphs detail the behavior of inulin in
the above respects:
MEASUREMENT OF GLOMERULAR FILTRATION
137
1. Inulin is not bound by plasma proteins, and is completely filterable in the Amphibia.104,895
ii. Inulin is not excreted by the aglomerular tubules of the
toadfish 872,895 or goosefish i 895 and in the author's laboratory it has recently been shown that the urine of a newly discovered aglomerular fish, the batfish (Ogcocephalus radiatus) , contained no inulin (i.e., less than 5 mgm. per cent)
when the plasma had contained something like 1600 mgm.
per cent for some hours.
iii. a. The rate of excretion of inulin, UV, is proportional
to P in the dog 898 and in man. 408
b. The inulin/creatinine clearance ratio (1.00) is independent of the plasma level of inulin in the dog. 878• 808
iv. The inulin clearance is equal to the simultaneous glucose clearance in the phlorizinized dogfish,885 teleost,888
dog 398 and bird/s7, 400b and nearly equal in man (to whom
large doses of phlorizin have not been given. 408
v. a. The simultaneous inulin and creatinine clearances are
identical (0.99 ± .03) in the dog,878. 898,399, 444a rabbit (.99 ::I::
.04) ,21T sheep (Shannon, unpub.) and seal.'21 There is no
independent evidence of tubular excretion of creatinine in
the dog and rabbit (sheep and seal not examined). The
above identity does not obtain in the dogfish, chicken, ape
and man, in most of which independent, evidence for the
tubular excretion of creatinine has been adduced, as cited in
chapter IX. These clearances are identical, however, in
the chicken and man after sufficient doses of phlorizin, which
presumably blocks the tubular excretion of creatinine.
Approximate identity is obtained in the phlorizinized
dogfish.
b. The simultaneous inulin and ferro cyanide clearances
THE PHYSIOLOGY OF THE KIDNEY
are identical in the dog ~~"'a (cf. page 197). The lack of identity between inulin and the ferrocyanide clearances in man
is attributed to tubular reabsorption of ferrocyanide. 297
Vl.
The creatinine clearance in the dogfish,395 bird,,,,oob
and man 898 apparently approaches the inulin clearance as
the limiting asymptote as the plasma level of creatinine is
raised.
In order to supplement the above summary, there is included below a brief review of evidence on the clearance
ratios and excretion of other substances, whose clearances
have lie en extensively studied in the author's laboratory.
Similar comparisons for intact animals are given by White
and Monaghan,~81, ~2 Cope,78, 77 * Richards et al.,873 Keith et
aI.,221 and by Hemingway 100 for the perfused kidney.
vii. The xylose/inulin clearance ratio = 0.78 in the normal doglish,89I 0.81 in the sculpin. (Clarke, unpub.), 0.73
in the dog 898 and 0.79 in man,"'08 indicating that about 2S per
cent of the filtered xylose is reabsorbed. This ratio is
slightly lower and variable in the rabbit.217
viii. The sucrose/xylose ratio = 0.99 in the normal dog-
*
Cope's observations on cyanol,77 a dye which is not excreted by the
aglomerular fish,201 are complicated by the possibility that the dye is bound
by the plasma proteins. If only So per cent of the dye were free, it would
appear that the clearance of the free dye would be equal to the rate of
filtration in both normal and phlorizinized rabbits. Like many dyes, this
is highly absorbed on collodion, which fact renders the measurement of
protein binding difficult.
The human red cell is freely permeable to glucose 221,818 but this is not
true of the rabbit and perhaps other animals. In such cases care must be
exercised in determining glucose clearances, since the differential movement
of water or glucose between cells and plasma, especially when an anticoagulant is used, may introduce considerable error.
MEASUREMENT OF GLOMERULAR FILTRATION
r39
fish,894 Lor in the dog 212, 219,881 and L08 in man,221,419 indicating that xylose and sucrose are reabsorbed to about the
same extent.
ix. In the normal animal, glucose is of course absent from
the urine. After phlorizin, the glucose/inulin ratio rises to
r .00 in the dogfish,991 dog,806 sheep (unpub.) and chicken 887,
400b indicating that phlorizin completely blocks the reabsorption of glucose in these animals. The failure of the ratio to
rise above 0.89 in man 408 is perhaps attributable to the fact
that the dose of phlorizin was roo mgm. per kg., whereas in
the other animals a minimum dose of 200 mgm. per kg. was
given.
x. After phlorizin, the xylose/inulin ratio rises to L02 in
the dogfish,895 indicating that phlorizin completely blocks the
reabsorption of Hlose, as of glucose. (The failure of the
xylose/inulin ratio to rise above 0.9 r in the dog 896 is perhaps
due to analytical error; it should be noted moreover that the
number of observations is small and it must be concluded that
phlorizin can completely block the reabsorption of xylose in
this animal, since in a much larger series, glucose/inulin =
r.o r 898 and glucose/xylose = r .02; 212, 881, 402 crea tinine/
inulin = 0.9 8 898 and xylose/creatinine = 0.97.831. 885,402) The
failure of the ratio to rise to r .00 in man is perhaps due
to the small dose of phlorizin (see ix) .
xi. After phlorizin, the glucose/sucrose ratio rises to 0.99
in the dogfish,S04 and the xylose/sucrose ratio to 0.99 in
man,80 indicating that phlorizin also blocks the reabsorption
of sucrose.
xii. In the normal dog, in specific experiments, the ureal
inulin ratio was about 0.58, and this value was unaffected by
.
140
THE PHYSIOLOGY OF THE KIDNEY
phlorizin.898 In man, similarly, the ratio was 0.62, and this
ratio was likewise unaffected by phlorizin.403
xiii. The hexamethylenetetramine/creatinine ratio =
0.76 in the dog and is unaffected by phlorizin. 381
xiv. At elevated plasma levels of creatine, the creatine/
creatinine ratio in the dog = 0.90, and this is unaffected by
phlorizin.882, 883
In man this ratio = 0.67 j since creatinine/inulin = about
1.39,898 this suggests that the creatine/inulin ratio in man
(which has not been examined) would be about 0.90, as in
the dog.
xv. The xylose/creatinine ratio in the dog -;- 0.76886,401
which confirms the independent figures reported in v. a. and
vii above. After phlorizin this ratio rises to 0.97, confirming
v. a. and x.
xvi. After phlorizin the glucose/xylose ratio is 1.00 in the
dogfish,72, 89' 1.02 in the dog 212, 831, 888, 402 and 1.0 I in
man. G9,408 This is to be expected from ix, x and xv.
Included in the above is a reference to the hexymethylenetetramine clearance in the dog, recently studied by
Pitts.83& The clearance of this substance is less than the
inulin clearance, and is independent of plasma level over a
wide range.
From the above data it appears that in the phlorizinized
dog the clearances of inulin, creatinine, glucose, xylose, sucrose and ferrocyanide are precisely equal. To assume that
the excretion of these substances involves either tubular excretion or reabsorption is to invoke a highly improbable coincidence that the degree of tubular excretion or reabsorption
is likewise precisely the same.
MEASUREMENT OF GLOMERULAR FILTRATION
141
In the normal dog, the inulin, creatinine and ferrocyanide
clearances are equal, the first two with a high degree of precision (0.99 ± .04). Glucose is absent from the urine, and
the xylose and sucrose clearances are less than the inulin
clearance. One infers, therefore, that the first three clearances are still at the level of filtration, and that glucose is
being completely, and xylose and sucrose partly, reabsorbed
by the tubules. Phlorizin completely blocks the reabsorption
of all the sugars.
In the normal dog the urea, creatine and hexamethylenetetramine clearances are less than the inulin and/or creatinine clearance, and the relative values of these clearances in
respect to the inulin and/or creatinine clearance are unaffected by phlorizin. One infers, therefore, that they are
in part reabsorbed, but that, unlike the sugars, this reabsorptive process is unaffected by phlorizin.
The evidence as set forth in the last three paragraphs is
given diagrammatically in figure 24.
The data on man are less satisfactory than they are on
the dog; ferrocyanide is apparently reabsorbed to some extent, and creatinine is excreted in part by the tubules. Consequently in normal man there is as yet no known substance
which has the same clearance as inulin. In phlorizinized
man, however, the inulin, glucose, xylosel,.sucrose and creatinine clearances are all identical, so that here there can be no
doubt that all clearances are at the level of filtration. When
we recognize the independent evidence for the tubular excretion of creatinine, the constancy of the urea/inulin ratio
before and after phlorizin, and the degree to which the
creatinine clearance approaches the inulin clearance at high
14 2
THE PHYSIOLOGY OF THE KIDNEY
plasma levels of creatinine, the evidence is fairly convincing
that in normal man, as in the dog, inulin is excreted without
either tubular excretion or reabsorption. This evidence is
given diagrammatically in figure 25.
Summary. Taking all available data into consideration,
oi= 1.0
«c:
INULIN
CRt:ATININE
CREATINE
I
INULIN
•••. .~~E~~~
/FCREATIIIIINE···········GLUCOSr=""
J.'.7:
~ ~_~R<"~lCT-""
- - - - SUC.OsE--3~ !
« .8
m
XYLOSE-
CREATINE----i
HEXAME:TH.,-----i
.
c:
5.
d6
r-------UREA-----~!~-------UREA-----~
:z
~.4
:::::>
:z
~.2
PHLORI%INIZED
o ......... ,.r-._~!..V.(:.Q,$f; ................
FIGURE 24
Diagrammatic summary of the evidence, based on clearance
ratios, indicating that the inulin clearance is at the level of glomerular filtration in the dog.
we conclude that in all vertebrates the inulin clearance is
at the level of glomerular filtration.
Glucose (at low plasma levels) is completely, and xylose
and sucrose are partly (about 25 per cent) reabsorbed, and
this reabsorption is completely blocked by phlorizin.
Exogenous creatinine is excreted in part by the tubules in
MEASUREMENT OF GLOMERULAR FILTRATION
143
the elasmobranch, teleost, bird, ape and man, but not in
the dog, rabbit, sheep or seal. There is no reabsorption of
creatinine in the last four animals, and therefore in these the
creatinino clearance can be used as a measure of the filtration
rate.
o
1.4 Ie-
"ltl--~REATININE
""",Cit
i=
<l:
0:
1.2 ~
-1\
LOW PLASMA LEVELsJ
~L4SM
u
-..:.: ~ -h.E~L~
U
Z 1.0I----INULIN
<l:
\
\
l'-..lIf"CREAT'N'NE-.m"uuGLUCOSE."·
_INULIN
-~~t§~~~
I
II
0:
.8 - - - - - SUCROSE----_.YI :
w
=-----XYLOSE--l!
<{
..:J
<J
z
.6
.
.
~------UREA-----~.~-------UREA-----~
_J
~
.4
"x
~2
z
!
PHLORIZINIZED
NORMAL
o ____ .... ____
c,;;_L,.ll~_Q~_e;
______ •.••...
FIGURE 25
Diagrammatic summary of the evidence, based on clearance
ratios, indicating that the inulin clearance is at the level of glomerular filtration in man.
Urea is partly reabsorbed by some complex but probably
passive process in the chicken and all the mammals, while it
is excreted by tubular excrotion in the frog but not in N ecturus, and actively and almost completely reabsorbed in the
elasmobranch (in which it is handled almost as glucose or
chloride are handled in-mammals.)
144
THE PHYSIOLOGY OF THE KIDNEY
Exogenous creatine is partly reabsorbed (?) in the dog
and man, but copiously excreted by tubular excretion in the
teleost.
Hexamethylenetetramine is partly reabsorbed in the dog.
Phenol red is copiously excreted by the tubules in all vertebrates so far examined.
PART II
XIV
COMPOSITION OF THE PLASMA
THE FLUID COMPARTMENTS OF THE BODY
IN PREVIOUS chapters attention has been directed chiefly towards the excretion of waste products or foreign substances
whose ultimate fate it is to be removed from the body as
completely and as quickly as possible. As we turn to the
consideration of electrolytes, emphasis must be directed
from the processes of excretion to the processes of conservation, and to the role which the kidney plays in the regulation
of the composition of the plasma. Consequently attention
must be shifte_d for a moment to the body fluids. *
A discussion of the composition of the body fluids can appropriately begin with water. This is the chief constituent
of the blood and tissues and some physiological provision
must exist to prevent the water content of the body from being excessively increased or decreased. That such provision
does exist is attested by the remarkable constancy of the
water content of the tiss~s and body fluids. But it is not
*
In the interests of brevity, specific bibliographic references will not
be cited in the discussion of the general features of body-fluid regulation.
A complete bibliography of this and related subj ects is given by Peters and
Van Slyke 827 and Peters,828 to which reference should be made for a more
detailed exposition.
14 6
THE PHYSIOLOGY OF THE KIDNEY
merely the water content in terms of total solids of which
we must think. In every solution the concentration of solvent, as well as the several concentrations of the various
solutes, is an important factor in determining the system's
reactivity, and the " concentration" of water in the plasma
and tissues in this physical-chemical sense is physiologically
of great importance. In the higher vertebrates the kidney
is the chief effector organ that regulates the concentration
of water in the body by virtue of its capacity to excrete
greater or lesser quantities of this substance. Yet, obvious
as are the evidences of such regulation, the questions that
arise in attempting to discover how it is effected are among
the most perplexing in physiology.
The most fundamental consideration in this connection is
the fact that water moves freely between all parts of the
body, by way of the circulating plasma, and under conditions
of equilibrium is distributed in such a manner that the osmotic pressure of all tissues and internal body fluids is the
same, except in so far as a difference is maintained dynamically by differences in hydrostatic pressure or tissue tension.
This generalization does not, of course, apply to the urine,
for the urine is a highly specialized external excretion and
it is by the elaboration of a hypotonic or hypertonic urine that
the kidney maintains the composition of the body fluids.
But within the confines of the body, so to speak, osmotic
work on water is never done. The lymph, tissue fluids, gastric and intestinal secretions, bile, cerebrospinal fluid, etc.,
are all essentially isosmotic with the plasma. The only exceptions to this rule are the saliva and sweat, both of which
are hypotonic. The hypotonicity of the sweat possesses cer-
COMPOSITION OF THE PLASMA
I47
tain physiological advantages, and the hypotonicity of the
saliva is perhaps functionally related to the role of this secretion in the control of water ingestion through the mechanism of thirst.
The mere fact that water is, in the osmotic sense, uniformly distributed throughout the body does not place any
limitation upon the actual volume of water, or of isotonic
fluid, contained either within the body as a whole or in the
plasma. It must be emphasized at the beginning that we are
concerned with two problems: the regulation of the composition of the body fluids, and the regulation of their volume.
Failure to keep this distinction in mind can only lead to
confusion.
It is convenient to recognize in this discussion that the
body is divided into several partially isolated "compartments " between which the movement of solutes is more or
less restricted.
First, there is the compartment of the circulating plasma,
which serves as a medium for the transportation of water
and solutes to all the tissues, or, more properly speaking, to
the interstitial fluid which separates the vascular bed from
the tissues. Within the plasma is the subsidiary compartment of the blood cells. Between the blood cells and the
plasma only a limited interchange of, solutes occurs.168 It
is of course the plasma with its contained cells which is directly presented to the kidneys, and upon which these organs
must operate.
Immediately beyond the vascular bed, between this and
the tissues, is the compartment of the interstitial fluid. In
one sense this compartment is in almost free communication
14 8
THE PHYSIOLOGY OF THE
KID~EY
with the plasma, since apparently all the more diffusable constituents of the latter - water, O 2 , CO2 , salts, glucose, urea,
amino-acids, etc. - pass readily through the capillary endothelium, and it is by virtue of this free communication that
the plasma is enabled to maintain continuous chemical and
physical interchange between different tissues, as well as the
ultimate interchange between the tissues and the environment. But in one respect the interstitial fluids are isolated
from the plasma: the capillary endothelium is poorly permeable, and perhaps sometimes impermeable, to the plasma
proteins, and since these are osmotically active, a limitation
is thereby placed upon the free migration of water. Where
the hydrostatic pressure of the plasma tends to force water
out of the vascular bed, the osmotic pressure of the plasma
proteins (oncotic pressure) tends to draw water back into
the vascular bed; on the other hand, the hydrostatic pressure
and protein content of the interstitial fluid work in the opposite direction, so that the movement of water at any moment and the ultimate equilibrium are determined by the resultant of these several forces. This generalization was
formulated many years ago by Starling, and although difficulties arise in applying it in special instances, we may accept this balance of forces as the fundamental factor determining the distribution of water between the plasma and the
interstitial fluid. The total water in the body comprises
about 70 per cent, the interstitial fluid plus the plasma (i.e.,
the extracellular water) about 20 per cent, and the plasma
itself about 5 pet cent of the body weight. 2S7 The volume of
fluid contained in each of these three compartments may
vary more or less independently. The interstitial fluid and
COMPOSITION OF THE PLASMA
149
the plasma contain nearly all the chloride and 90 per cent of
the sodium (excluding the bones) in the body.
Beyond the interstitial fluid there is the compartment or
compartments of the tissues. Between these and the inter-·
stitial fluid there is such a limited interchange of ordinary
solutes that for our present purposes these two compartments may be considered as isolated from each other, except
in respect to water itself. For example, the base of the tissues is composed mostly of K and Mg, and there appears
to be little exchange of these cations for the N a of the extracellular fluid.l7l When injected intravenously N a, CI, SO",
and CNS do not penetrate the tissues, only CNS penetrating
the red cells."'4.
As has been said above, the regulation of the osmotic pressure of these compartments does not per se impose any limitation upon their respective volumes; so long as the diffusion
pressure of water is maintained at equilibrium, each compartment is still free to vary in volume. It must be concluded,
therefore, that some regulation is superimposed upon the respective volumes of the plasma, the interstitial fluid and the
cellular fluid independently of the regulation of their composition. There seems to be no better view than to suppose
that in the tissues the number of osmotically active constituents, and therefore the total volume of fluid, is regulated by
those as yet unknown forces which determine cell volume and
other fixed cell characters, in a manner analogous to the regulation of cell volume in unicellular organisms. The regulation of the volume of the interstitial fluids and the plasma,
on the other hand, is effected by mechanisms which chiefly
have to do -with the mechanical aspects of the peripheral
15 0
THE PHYSIOLOGY OF THE KIDNEY
circulation, tissue tension, the physiological properties of
the capillary endothelium, etc. These determinants for the
most part fall outside the scope of this book, and in any case
are so poorly understood that in the interests of economy
they must be dismissed summarily in favor of the regulation
of plasma composition. It should be recognized that while
the plasma proteins are one of the important factors regulating the plasma volume, they are not directly concerned
in the regulation of the volume of the interstitial fluid. And
while the kidney, by excreting greater or lesser quantities of
water, can reduce or enlarge the volume of the plasma and
the interstitial fluid, such changes are, as it were, accidental
or incidental; they occur because the mechanisms of regulation of extracellular fluid volume are comparatively soft,
sluggish or limited, and unable to cope with the activity of
the kidney, which meantime is operating solely to maintain
the plasma composition. The kidney itself is not concerned
with whether two or five liters of plasma are circulating in
the vascular bed, so long as that plasma has the proper composition. And this organ, in attempting to regulate the composition of the plasma, will frequently enlarge or reduce the
volume of that fluid, and, indirectly, of the interstitial ~uid,
.beyond physiological limits, and sometimes to fatal excess.
ELECTROLYTE COMPOSITION OF THE PLASMA
The electrolyte pattern of the plasma is made up typically
of the constituents shown in table III. The sum of the inorganic or " fixed" bases is slightly greater than the sum of
the inorganic acids, about 22mEq. of base being combined
with the polyvalent protein anions or with organic acids.
COMPOSITION OF THE PLASMA
151
TABLE III
COMPOSITION OF TYPICAL HUMAN PLASMA
Base
mEq. per liter
Na+
143.4
K+
5.1
Ca+
5.0
Mg+
2.5
Acid
mEq. per liter
ClHCOaHP0 4 =
S04Organic
PrTotal
15 6.0
130,262
103.0
27.0
3.0
1.0
2.0
20.0
15 6.0
Osmotically eq. NaCl, grams per 100 cc. of water:
Men:
0.9447 probable individual deviation: ±0.0049S
Women: 0.9269 probable individual deviation: ±0.0059
Freezing point lowering (.6.)
Men:
0.SS3
Women: 0.543
Since the sum of the anions must equal the sum of the cations,
the total electrolyte content is usually designated in terms of
the total fixed base, which has the advantage of being easily
determined analytically.
The electrolyte composition of the plasma is one of its
most finely regulated features. Gross dilution after the ingestion of large quantities of water is pl'evented by the rapid
excretion of water and the production of a very dilute urine,
and gross concentration following dehydration is prevented
by the retention of water and the excretion of a highly concentrated urine. The electrolyte composition is so secured
that it varies by a sC3:rcely detectable amount under the most
extreme conditions. But the interpretation of this fact, and
15 2
THE PHYSIOLOGY OF THE KIDNEY
of many related phenomena, is rendered difficult because we
do not know what particular feature it is in the composition
of the plasma that is the chief desideratum towards which
physiological regulation is directed. It is scarcely enough
to say that the kidneys are operating to maintain a constant
water content in the plasma, for this expression has no precise meaning. The water content of the plasma can be expressed only in relation to some standard of reference. It
is natural, in the first instance, to look for our standard of
reference to the total osmotic pressure itself, yet there are
certain difficulties in this interpretation. A constant osmotic
pressure merely reflects the constancy of the several osmotically active constituents, and therefore the constancy of the
osmotic pressure of the plasma may simply be a passive consequence of the independent regulation of the concentration
of the several solutes contained within it. It is true that the
osmotic pressure of the plasma in all the terrestrial vertebrates is not only constant in any phyletic order, but is much
the same in all orders, whether they live in fresh or salt
water or upon the land. Nevertheless it varies widely in
some forms under strictly physiological conditions. In the
e1asmobranch fishes, for example, it seems to be a matter of
indifference, so far as the internal affairs of the organism
are concerned, whether the osmotic pressure (as measured by
the freezing-point depression) is set at a level of - 0.5 0 C.
or - 2.0 0 C.m Though the evidence in man is too slight
to permit a definite conclusion, a notable exception such as occurs in the elasmobranch fishes engenders caution against accepting osmotic pressure, per se, as the essential goal of body
fluid regulation.
COMPOSITION OF THE PLASMA
153
Gamble and his associates 180 have suggested that the complex adjustments involved in the regulation of the acid-base
balance of the blood have as their chief end the preservation
of a constant total fixed base, and it may be that this serves
as the standard of reference for water regulation. In point
of fact, the total base is regulated to extreme constancy (it
may be for this reason that the osmotic pressure is so constant), but it is difficult to see how the" sum" of the inorganic cations could be of physiological importance, or how
it could be integrated physiologically for the purposes of
regulation. If the electrolytes alone are to be considered, it
would seem more likely that the ionic strength would.be the
essential feature. This enters into and influences the reactivity of all electrolyte systems, and therefore of all physiological systems; and it is not difficult to imagine that a particular value in the ionic strength of the plasma might be the
physiological standard of reference. The ionic strength of
the plasma parallels closely but not perfectly the total base;
but it is a value which at present must be calculated from the
concentrations of all ions of either charge and their respective valencies, for there is no simple method of measuring it.
From still another point of view it might appear that the
kidney is operating to maintain a constant concentra'tion
of water in the plasma relative to some..-specific constituent,
and that the dilution or concentration of this constituent is
the effective stimulus that leads directly or indirectly to the
excretion or retention of water in the blood. It is known,
for example, that the actual excretion of water by the kidneys
from moment to moment is governed in part- by the concentration in the plasma of the antidiuretic hormone of the
154
THE PHYSIOLOGY OF THE KIDNEY
pituitary gland. In this view the plasma concentration of
protein and of individual salts, as also the total base, would
be maintained within the major frame of water regulation
by secondary reference and control.
Until more information is available, we must be content
simply to recognize that the total osmotic pressure, the total
base and the ionic strength of the body fluids are all maintained within narrow limits in the mammals i but which one
of these, if indeed any of them, constitutes the essential
physiological standard of reference in the regulation of the
water concentration is as yet unknown.
The difficulty of defining the most fundamental feature of
body-fluid regulation, as set forth in the above paragraphs,
is reflected in the interpretation of numerous observations.
First, there is the extraordinarily fine balance between the
thirst mechanism, on the one hand, and loss of water by way
of the urine, respiration, sweat and feces, on the other. This
balance is such that the organism maintains what might
roughly be called an " optimal" water intake and output:
the urine, which is the most variable avenue of water loss,
is normally neither extremely concentrated nor extremely
dilute. It would seem that.the electrolyte-water pattern of
the body fluids is at the heart of this physiological maintenance of water equilibrium. During forced dehydration,
water can be conserved by the kidneys to a sufficient extent
to maintain both the composition and the volume of the body
fluids i but if the dehydration is prolonged, electrolytes are
sacrificed and consequently the volume of the body fluids is
reduced in order, apparently, to maintain their composition.
Again, if both water and electrolytes are lost by vomiting,
COMPOSITION OF THE PLASMA
ISS
diarrhoea, or excessive sweating, the volume of the body
fluids is sacrificed in preference to their composition. In the
disease, diabetes insipidus, the kidney fails to conserve water,
the urine output rising to 10 to 20 liters per day; if water
ingestion, under control of the thirst mechanism, proves
inadequate, the volume of the body fluids is reduced, as
against the alternative of permitting the electrolytes to become more concentrated.
On the other hand, so long as their composition is preserved, there is in general little resistance to expansion of
body-fluid volume; in fact, expansion appears to be a matter
of such indifference that, at least under certain circumstances,
a considerable period of time may pass before restitution is
effected. This is illustrated by the long recognized difference in response to the ingestion of water and isotonic N aCI
solution, as shown in figure 26. Water per os produces after
a short interval a copious diuresis, the extra water excreted
in a few hours being equal to the ingested volume. But
when isotonic NaCl solution is administered either per os
or intravenously, no immediate diuresis results; both the salt
and water may be retained in the body for hours or days.
It has been shown that under these conditions there is little
dilution of the plasma, the salt solution being distributed
throughout all the extracellular fluid ·almost at once. This
circumstance is commonly said to be the reason why diuresis
fails to occur. Yet ingested water is distributed not only
in the extracellular fluid, but also in the tissues, and it escapes from the plasma as readily as does salt solution. It
would appear more reasonable to suppose. that the salt solution fails to be excreted simply because it is a salt solution,
15 6
THE PHYSIOLOGY OF THE KIDNEY
essentially identical with plasma itself, so far as ionic
strength and osmotic pressure are concerned. In sharp contrast to the behavior of an isotonic solution, hypertonic
N aCI induces marked diuresis which may actually overshoot the mark and drain an excess quantity of water from
14
~ 12
~
"'-
8 10
.3 8
9LL
6
w
z
(( 4
~
FIGURE 26
The response of the kidneys in man to 1000 cc. of water or, alternatively, 1000 cc. of I per cent NaCI solution, ingested at zero
minutes. In this experiment 92 per cent of the water was recovered
within 180 minutes. (Expt. by J. A. S.)
the body. Again we may suppose that the diuresis results,
not because of the failure of the excess salt to escape from
the plasma, but because the kidney rejects the salt as a superfluous addition to the plasma's normal composition.
Summary. The composition of the plasma in respect to
water and total electrolytes is remarkedly constant, which
COMPOSITION OF THE PLASMA
157
fact is reflected in a corresponding degree of constancy in
the osmotic pressure, the total base and ionic strength. It
is not known which of these three features, if indeed any
of them, is the essential physiological desideratu~ in bodyfluid regulation, but so long a,s the s~btle composition of the
plasma with respect to water and electrolytes is not disturbed, fluid can be added to and subtracted from it without
any immediate effort on the part of the kidneys to effect
restitution. In such instances, in consequence of the almost
free communication between the plasma and the interstitial
fluid, the resulting changes in volume are distributed between
these compartments, the " softness" of the confines of the
latter permitting relatively great expansion. It is' only
where the composition of the plasma tends to be changed
by the addition of either water or salt that the kidney responds immediately by the increased excretion of the component presented in excess.
Except as it participates in the regulation of their composition, the kidney is not actively concerned with regulation
of the volume of the body fluids, which is governed by extrarenal factors. But while operating to maintain the composition of the plasma the kidney may retain or excrete large
quantities of salt and water, and thus inadvertently cause
expansion or reduction of body-fluid yolume. This is, of
course, not a denial of the obvious fact that the kidney is a
rnalor portal (in addition to the lungs, skin and gastrointestinal tract) through which salts and water are normally
excreted and which may, under certain conditions, be the
locus of the abnormal excretion or retention of either.
xv
SODIUM, POTASSIUM AND CHLORIDE
excretion of electrolytes presents numerous complexities that do not enter into the excretion of non-electrolytes,
for here we are dealing, not with independent molecular
species, but with paired ions the individual excretion of
which is usually conditioned by some other obligation.
In view of the nature of strong electrolytes, it is incorrect
to treat any pair of ions, such as Na+ and CI-, as though
they existed in the plasma in the form of a molecule. Yet
because these two are the predominant ions in both plasma
and urine, and because CI- always carries with it an equivalent quantity of cation, mostly Na+, while Na+ carries with
it an equivalent quantity of anion, mostly CI-, we are accustomed to think of N aCI as an entity. But it is no more
a physiological entity than a physical-chemical one. It is
because the analytical methods for CI are simpler than those
for N a that nearly all investigations concerning the excretion of N a and CI have followed the behavior of CI, with
the assumption that it is accompanied by an equivalent quantity of N a. It is a better convention, since the nature of the
cation is unknown, to designate the unidentified base as B.
Na, K, Ca, CI, HPO" etc., each play quite different roles
in various physiological processes and, as might be expected,
are dealt with separately by the kidney as far as is possible.
But the mere necessity of maintaining equivalent quantities
THE
SODIUM, POTASSIUM AND CHLORIDE
159
of cations and anions in the blood and urine imposes a limitation upon the independent excretion of anyone. In addition, as has been pointed out above, the retention or excretion of N aCl is subordinated to the retention or excretion
of water, or vice versa. Lastly, there is a well developed
tendency in the organism to distinguish N a from K or Li,
and Cl from Br or CNS, Ca from Sr, etc., yet the separation of these ions is never perfect. When we recognize that
the excretion of a single ion such as N a is the resultant of
several factors, - i.e., the tendency to conserve this particular cation and to reject other cations, the availability of
Cl or HCOs , the total electrolyte content of the plasma, etc.,
- it is not surprising that the problem presents many complex features. It is only where the electrolyte pattern is
markedly altered in one respect, while essentially normal in
all others, that simple relations between plasma level and
excretion of any particular ion can be demonstrated.
Although the chief electrolyte in the blood is N aCl, it
should be noted that N a and Cl do not exist in plasma in
equivalent or necessarily dependent concentrations. In addition to Cl, large and variable quantities of other anions
are present, the chief of which is HCO s, with plasma proteins, HPO" H 2 PO, and organic acids such as lactic and
~-hydroxybutyric playing a lesser role . .; Within the specification that the sum of the anions shall always equal the sum
of the cations, considerable substitution of various anions is
possible. Interchangeability is particularly evident in the
case of CI and HCO a• Loss of HCI by vomiting may cause
half the Cl to be replaced by HCOs and other anions. Short
vigorous exercise may replace half the HCOs with lactate.
160
THE PHYSIOLOGY OF THE KIDNEY
Increase in CO2-tension may raise HCOs at the expense of
Cl, while reduction of C02~tension may have the reverse
effect. Accumulation of keto-acids during fasting or in diabetic acidosis may replace HCOa with the anions of these
acids. Except as such substitutions may cause a change in
pH and CO 2-tension, and thus lead to respiratory embarrassment, they apparently occasion no immediate distress. Interchangeability is much less evident on the side of the cations, N a, K, Ca, and Mg, but the normal concentrations
of the last three are so small, relative to Na, that permissible
substitution would extend through only a small absolute
range. It is perhaps because of their greater physiological
activity that the plasma concentrations of K, Ca, Mg,
H 2 PO" and more particularly H, are more closely regulated than is the case with N a, CI and HCO a•
There is at present no conclusive evidence that any of the
inorganic electrolytes commonly present in plasma are excreted by tubular activity in the mammals. It has been seen
in chapter IV that CI is present in the capsular fluid of Amphibia in approximately the same concentration as in plasma,
and there is no reason to doubt that this is equally true in
the mammal. In fact, we may presume that the glomerular
filtrate carries its full complement of all the filterable ions,
subject only to the conditions of a Donnan equilibrium arising from the presence of proteins on one side of the glomerular membranes . .xThe role of the kidney in the regulation
of the inorganic composition of the plasma therefore depends upon the tubular reabsorption of these ions. Most
of the electrolytes normally present in plasma behave like
" threshold" substances, in that they are almost completely
SODIUM, POTASSIUM AND CHLORIDE
161
retained when the plasma level is lowered, and copiously excreted when the plasma level is raised.
rIn the case of CI, for example, the urine may be almost
Cl-free at low plasma levels. It must be inferred, therefore,
that CI with an equivalent quantity of B is reabsorbed from
the glomerular filtrate by the tubules. It is not known at
what point in the tubule of the mammal this reabsorption
occurs, though it may be in the distal segment as in the Amphibia. As in the case of glucose, the use of the term
" threshold" is misleading in so far as it implies that CI is
almost completely reabsorbed when the plasma level is
below, and almost completely rejected when the plasma level
is above, a certain value. On the contrary, it appears that
CI is reabsorbed in variable amounts at all times, the reabsorption being maximum at low, and minimum at high plasma
levels. ~t has been shown by Aitken 7 that when the plasma
CI in man is reduced below 95 mM. per liter the rate of exc;retion in the urine is fairly constant at about 5 mgm. of
NaCl per hour. Above this level CI excretion increases rapidly, but at the highest plasma levels does not become constant. Similarly Rehberg 861 has found in man that when the
plasma CI is below 106 mM. per liter the rate of excretion
is small and essentially constant. At plasma levels above
this the excretion rate is markedly affected by the rate of
urine formation; the greater the urine volume, the larger
the fraction of the filtered CI which escapes reabsorption.
MacKay and MacKay 249 have shown that Cl-free urine
is excreted by rabbits depleted of CI at a plasma level below
85 mM. per liter; yet on other occasions CI is present in
the urine at plasma levels considerably below this, a circum-
162
THE PHYSIOLOGY OF THE KIDNEY
stance which they attribute to the lsimultaneous excretion of
K. Nevertheless these investigators retain the word
" threshold" and assign it a value of 84.5 mM. per liter.
Little is known about the specific response of the kidney
to N a except in so far as we accept the observations on the
excretion of CI as reflecting the resultant tendency to conserve both N a and Cl. ~And our knowledge of the quantitative response of the kidney to K is still less advanced. It is
known that the kidney distinguishes N a from K, as is shown
by the precision with which the plasma concentration of
these ions is regulated. When KCI is ingested or injected,
K is rapidly and completely excreted, in sharp contrast to
N aCI, which may be retained for considerable periods of
time. The renal threshold for K in man averages about 3.5
mM. per liter/80 and it may be that this rapid excretion reflects the greater percentage change in the normal plasma
level brought about by the administration of small quantities,
in contrast to N a, the normal plasma concentration of which
is about 143 mM. per liter. Water diuresis tends to carry
considerable quantities of both ions out of the body, while K
is lost in NaCI diuresis and Na is lost in KCI diuresis. This
failure to completely separate Na and K perhaps reflects
some degree of imperfection on the part of the renal mechanism, rather than indifference to the nature of the cation
lost. But on the whole the kidneys are so efficient in distinguishing these two cations that marked, persistent changes
in their relative concentrations in the plasma are observed
only in seriously abnormal conditions.
-lThe problem of the renal conservation of electrolytes,
and of Na in particular, has recently developed new interest
SODIUM, POTASSIUM AND CHLORIDE
163
in relation to the syndrome produced by a deficiency of the
hormone of the adrenal cortex. Within a few days after removal of the adrenal glands, animals begin to lose weight
rapidly and become extremely weak; the metabolic rate is
decreased, the body temperature falls and anorexia, vomiting and diarrhoea appear. Untreated animals invariably
die within one to two weeks, after passing into a state of
profound circulatory shock. Numerous theories have been
propounded to explain the physio~ogical role of the hormone, cortin, and no complete description can as yet be
given ;~ut it has been suggested by Loeb and his coworkers 289 that one important factor in cortical deficiency is
the loss of N a from the body through the kidneys. It is
known that early after adrenalectomy there is an increased
excretion of NaCI and water; a little later marked hemoconcentration and oligemia appear, accompanied by renal
insufficiency and, ultimately, impairment of other physiological functions. The administration of sodium salts may
delay the onset of shock for months, though this treatment
appears to be unable to permanently forestall it.lT2 Although it is possible that deficiency of the cortical hormone
leads to a shift of water from the extracellular to the intracellular compartments, Loeb has suggested that the oligemia
is in part due to the loss of N aCI from the body. Mfhe kidney, in operating to maintain the electrolyte-water balance
of the plasma, allows water to escape simultaneously, until
the resulting dehydration and hemoconcentration lead to
circulatory insufficiency. -The administration of cortin leads
to N aCl retention and xestoration of plasma volume. This
theory has been affirmed by Harrop and his co-workers,172
164
THE PHYSIOLOGY OF THE KIDNEY
who point specifically to the kidney as the site of action of
the hormone. It is suggested that in the absence of the hormone the renal threshold for N a is lowered. It is interesting
to note that in cortical deficiency there is not a corresponding
excretion of K; apparently the local renal action is cation
specific. Strangely enough, in spite of the profound effects
of adrenalectomy, the injection of cortical extracts of proved
potency into normal animals has little effect, either upon
any physiological function or upon the electrolyte pattern of
the plasma. This inactivity of the hormone when administered in more than minimal maintenance doses finds a parallel only among the vitamins .
. It is believed that Addison's disease in man involves a deficiency of the cortical hormone, only the onset is slower and
therefore the effects more insidious than in acute ablation.
This disease presents many features closely paralleling the
above picture, especially in the muscular weakness and the
terminal circulatory shock. The injection of cortin in patients suffering from Addison's disease leads to the retention of NaCl.441
It is also pertinent to this discussion to note that symptoms
resembling those of cortical deficiency follow the acute reduction of the N aCI content of the body in normal men.
This can be accomplished by a low salt diet combined with
diuresis and sweating. In a recent study of acute salt deficiency by McCance and his co-workers 261 one subject lost 30
per cent of his body Cl in a few days. His plasma N a fell
from 154 to 139 mM. per liter and his Cl from 100 to 80
mM. During the early part of salt depletion there was an
equivalent loss in weight in spite of the fact that water was
SODIUM, POTASSIUM AND CHLORIDE
16 5
taken ad libitum,tsfrowing that in endeavoring to maintain
the electrolyte composition of the plasma the kidney was
incidentally reducing the total body fluid. There was profound muscular weakness, excessive fatigue, mental apathy
and confusion, anorexia, nausea and loss of the sense of
taste. There was no acute thirst, in spite of the loss of body
fluid. Slight muscular activity produced cramps, and any
muscle suddenly brought into action was liable to spasm,
even the muscles of the chest and cheeks. One of the most
interesting results, from the point of view of the kidney,
was the abnormal diuretic response to water. Where in the
normal individual the ingestion of a large quantity of water
leads immediately to marked diuresis, in salt depletion the
excretion of this water may be delayed twelve hours. vthis
may be tentatively interpreted as due to the fact that the
plasma was already so diluted by loss of electrolyte that
further dilution by addition of water failed to produce the
typical physiological response. A second interesting feature
was the inability of the kidney to excrete HeOs • Normally,
when alkalosis is induced by over-ventilation, the kidney responds by excreting BHeO s and thus aids in the maintenance
of the H ion concentration of the plasma. But because the
maintenance of the total base of the plasma takes precedence
over the maintenance of the concentration of a single ion,
and therefore over the maintenance of the acid-base balance, in salt deficiency there is no N a available for the excretion of BHeO s , and the kidney fails to make its usual
compensatory response by excreting this salt. Similarly the
kidney fails to excrete BHeOs after prolonged. vomiting or
other measures which .deplete the total base of the plasma,
166
THE PHYSIOLOGY OF THE KIDNEY
and in such instances the administration of N aCI, by restor~
ing the total base, leads to the renewed excretion of BRCO a•
A converse effect to the above, in which water and salt
a!:e retained in excessive quantity, is observed in various
1:ypes of edema. It has been said that the regulation of the
volume of fluid retained in the body does not devolve pri~
marily upon the kidney, but upon extra-renal factors.
Where the circulation is inadequate, as in cardiac failure,
there is a primary impairment of those mechanisms which
normally regulate the 'Volume of the interstitial fluid; and
when an excess of salt is ingested the kidney retains it, along
with a physiologically equivalent quantity of water, and this
gradual expansion of the body fluids leads to edema as the
retained saline accumulates in the interstitial spaces. The
volume of the interstitial fluid, rather than the volume of
the plasma, is augmented, because the regulators of the
former are, so to speak, " softer" and under conditions of
deficient circulation fail t~~sr enlargement of their domain. Deprivation of salt may lead to abrupt excretion of
some of the edema fluid; increased ingestion of salt augments it. It is doubtful if the kidney is to be blamed for the
edema in this instance; this organ is merely carrying on in
its task of regulating the electrolyte-water balance of the
circulating plasma.
The relative rates of excretion of water and salt are
rarely acutely unbalanced to a degree to produce marked
changes in the composition of the blood. It is possible, however, to inducc;,/'water intoxication" by the administration
of water, in quantities above a critical value, more rapidly
SODIUM, POTASSIUM AND CHLORIDE
167
than the kidneys can excrete it, or by stimulating the tubular
reabsorption of water in conjunction with its administration
by the injection of the antidiuretic hormone of the pituitary
gland. Although the syndrome presented by water intoxication presents great physiological interest, little is known
about it. The first symptoms involve the central nervous
system and, following convulsions, death occurs from cardiac
failure. 888 Alkalosis and loss of Cl by vomiting or accumulation of gastric juice in the stomach appear to play an important part in producing the untoward reaction.4I!6
Another condition in which the electrolyte-water equilibrium is disturbed is presented in Uoll'eat cramps," a syndrome
marked by painful spasms of the voluntary muscles following prolonged muscular activity at high environmental temperatures. The pathogenesis of this condition is principally
the excessive loss of N aCI in the sweat, with a consequent
reduction of these ions in the plasma and presumably a reduction of K and CI in the muscles . ..Moderate dehydration
of the body (1.5 per cent of body weight) can be accomplished without marked disturbance of salt balance, but in
more marked dehydration (5 per cent) plasma electrolytes
(N aCI) are sacrificed, and later KCI from the tissues.48T
The depletion of plasma electrolytes is accompanied by the
continued excretion of water so that the body fluids are ultimately reduced and the plasma proteins are excessively concentrated. The ill-effects of profuse sweating may be almost
instantly ameliorated by the administration of salt solution,
whereas ordinary drinking water may aggravate the symptoms because of the rapid osmotic dilution of the blood.486
168
THE PHYSIOLOGY OF THE KIDNEY
Subjects become acclimatized to high temperatures by virtue of the fact that the concentration of NaCl in the sweat
is reduced by adaptation. ss
Summary. Although the differentiation is imperfect and
liable to failure during stress, the kidney normally distinguishes between Na and K and between Cl and HCO B, as
well as between other cations and anions. It tends to maintain a specific pattern of various ions in the plasma, conserving each separately when the supply is deficient, excreting
each separately when the supply is excessive. But the composition of the plasma in respect to total electrolytes and
water appears to take precedence over the regulation of
specific ions and subsidiary processes such as the maintenance of the H ion concentration. In its role of regulating
the total electrolyte composition of the plasmtt the kidney
will go to the extreme of reducing the volume of body fluid
to lethal limits, as occurs in cortical deficiency. Or, conversely, if excessive salt is available, and if other circumstances permit, the kidney will for the same reason enlarge
the volume of body fluid to the extent of producing serious
edema. The renal retention of Na appears to he governed
in part by the adrenal cortical hormone, though this hormone has slight action in the normal animal.
XVI
ACID-BASE EQUILIBRIA IN PLASMA
AND URINE
most carefully guarded feature of the electrolyte
pattern of the plasma is the H ion concentration, which is
maintained close to pH 7.4 by the buffering action of the
salts of weak acids. (We may omit the hemoglobin of the
red cells from the following discussion; although this constitutes the chief source of alkali for the respiratory transportation of CO 2 , it participates in renal function only indirectly through the plasma, since the kidney cannot operate
upon it directly.) Within the plasma all the acid-base components or buffers - H 2 CO S ' HPr, H,P04 , etc., - are necessarily in equilibrium with the same H ion concentration, and
it is improper to say that the latter is determined by anyone
buffer system. But because CO2 is excreted by the lungs and
BHCOa is excreted by the kidney, this acid plays a unique
role in acid-base equilibria. * H 2 COa is the chief acid formed
in the oxidation of food; the quantity produced by a normally active man amounts to over 20· mols per day, which
is equivalent to 2 liters of concentrated HCI, or over 20
times the total available base in the body, which may be
ANOTHER
* Because of its great importance in the neutralization of acids other
than H 2COa, t.he plasma BHCOs is frequently called the" alkali reserve."
For the neutralization of HzCOs itself the other buffers Qf the blood and
tissues, and chiefly the BHb of the cells, afford a supply of base which is
commonly designated at " total available base."
170
THE PHYSIOLOGY OF THE KIDNEY
taken as 1000 mEq. Because of the volatility of its anhydrid, CO 2 , this acid is excreted almost entirely by the
lungs. Thus, in the first instance, the respiratory center is
charged with the chief responsibility for regulating the H ion
concentration of the plasma by regulating its COa-tension.
But according to the mass law, BHCOa plays stoichiometrically an equal part with H 2 COa in determining the H ion
concentration, and respiration has no power to regulate the
concentration of BHCOs in the plasma; this is done entirely
by the kidneys. So that in the final analysis, the regulation
of the H ion concentration of the plasma, or more broadly,
of the acid-base equilibria of the body fluids, is as much a
renal as a respiratory problem.
In addition to the regulation of BRCOs, the kidney must
excrete such non-volatile acids (HsPO" HaSO" lactic,
~-hydroxybutyric, etc.) as are produced under normal or abnormal conditions. The daily metabolism of 100 grams of
protein produces on the average 60 mEq. of sulphate by the
oxidation of the protein S, and a quantity of phosphate by
the oxidation of protein P which requires 50 mEq. of base
for its naturalization to pH 7.4. An additional 50 mEq.
of base are required to neutralize the phosphate from
100 gm. of fat containing 10 per cent lecithin. Although
most proteins bind considerable fixed base at pH 7.4 and
meat contains some NaHCOa, this base is inadequate for
the neutralization of these fixed acids. In severe ketosis an
additional burden of 500 mEq. or more of ~-hydroxybutyric
acid may be added from the incomplete oxidation of fatty
acids, and half of this requires base for its neutralization at
the maximal acidity of the urine (pH 4.8). Since the total
ACID-BASE EQUILIBRIA IN PLASMA AND URINE
17 1
available base in the body is but slightly over 1000 mEq., it
will be seen that the draught of these " fixed" acids upon
this av:ailable base may be relatively severe.
V·n contributing to the regulation of the hydrogen ion concentration of the plasma, the kidney excretes a urine which
is at one time more acid and at another more alkaline; but
the variable excretion of free fixed acids as such is negligible
in comparison with the excretion of the salts of these
acids. Since sulphuric, phosphoric and organic acids (lactic,
~-hydroxybutyric, etc.) are produced de novo in the tissues
by the metabolism of protein, carbohydrate or fat without
an equivalent quantity of base, they appropriate base from
BHCOu to form neutral salts in the plasma, while the liberated CO2 is excreted by the lungs. The pH of the urine is
usually about 6.0, although this value may vary under extreme conditions of acidosis and alkalosis between 4.8 and
8.2.* At pH 4.8 all sulphate is present as B2 S04 99 per
cent of phosphate is present as BH2 P04 and 90 per cent of
lactate is present as B-Iactate; consequently at the maximum
acidity of the urine these acids carry almost an equivalent
quantity of base out of the body as salts. The one notable
instance in which the excretion of free acid is physiologically
significant is that of ~-oxybutyric acid, since at pH 4.8 about
55 per cent is present as the free acid and only 45 per cent
as the salt. Consequently a shift in pH of the urine from
7.0 to 4.8 saves one-half mol of base for the body for each
*
The inability of the kidney to elaborate a more acid or alkaline urine
is in sharp contrast to other glands; the gastric and intestinal mucosae, for
example, may secrete HCl and NaHCO s solutions almost equivalent in concentration to the total base of the. plasma, and strong H 2 S04 solutions are
secreted by the salivary glands of some invertebrates.
17 2
THE PHYSIOLOGY OF THE KIDNEY
mol of this acid excreted. The largest quantity of total free
acid which can be excreted per day amounts to 125-150
mEq., whereas the free and combined acid may amount to
over four times this quantity. The kidney is therefore
called up on to excrete such free fixed acid as it can at pH
4.8, and to excrete the rest in the form of salts; and inasmuch as these salts tend to be formed at the expense of the
BHCOs of the plasma, this salt must be maintained by one
means or another.
This last operation - the maintenance of the plasma
BHCOs in the face of the invasion by fixed acid - is affected in part by renal conservation of exogenous base and
in part by the synthetic substitution of NHa for fixed base
in the neutralization of the fixed acids in the urine. During
the excretion of large quantities of acid, NHs is formed in
the kidney from protein or amino nitrogen, and in so far as
this cation is available for the neutralization of urinary acid
it permits the reabsorption of an equivalent quantity of fixed
base, which, by combination with CO 2 , re-forms BHCO s
and replenishes this salt in the plasma. Thus, the excretion
of H, HCOs, B2 S04 , BH2 P04 and the salts of organic acids,
the formation of NHs in the kidney and the conservation.
of fixed base, B, are intimately tied up with each other. It
is therefore inaccurate, though convenient, to consider these
processes as though they were separable physiological functions.
BICARBONATE
When the plasma level of BHCOs is lowered in acidosis,
the excretion of BHCOs is reduced to negligible proportions
and the urine becomes acid (pH 4.8). Conversely, after
ACID-BASE EQUILIBRIA IN PLASMA AND URINE
173
large doses of NaHCO s or in alkalosis, the ensuing elevation of the plasma BHCOa is accompanied by an increased excretion of this salt and the urine becomes alkaline
(pH 8.2). Since it must be supposed that BHCOa is present in the glomerular filtrate in the same concentration as in
plasma, decreased or increased excretion must be due either
to increased or decreased tubular reabsorption. N euschlosz a12 has applied the Cushny filtration-reabsorption
theory to the excretion of HCO s and believes that his results show that the concentration of this salt in the reabsorbed fluid is constant, but some of his assumptions are
open to serious question. For the time being it is perhaps
best to recognize that HCOs , like CI, glucose, PO" and other
substances, are reabsorbed independently of the reabsorption of water, and probably in different segments of the
tubule.
It may be noted, in this connection, that the excretion of
bicarbonate presents a unique situation. If we assume that
CO2 is always in equilibrium with H 2 COa, we may apply the
mass law:
(C02)
(H+) (HCOa-) = k
to both plasma and tubular urine, where it is understood
that (C0 2 ) = total un-ionized carbonic acid plus free CO 2 •
In accordance with this equation, the equilibrium concentration of anyone of the three species involved is determined by the existing concentrations of the other two.
This is true, with due consideration to thermodynamic activities, for both blood and urine, and wholly apart from
the consideration of whether one or more of these species
174
THE PHYSIOLOGY OF THE KIDNEY
may be transferred from urine to blood, or vice versa. It
follows that if the U /P ratios of two of these species
are given (for example, (CO a )u/(C0 2 )p and (HCOs-)u/
(HCOa-h), then the ratio of the third, «H+)u/{H+)p)
is thereby fixed. For this reason we cannot speak of the
independent excretion of all three species, H+, HCOs- and
CO2 • In the example given above, the U/P ratio of H+ is
pre-determined in the physical-chemical sense, and physiologically the kidney can do nothing about it.
On this assumption we are led to inquire what species, or
what two species, the kidney operates upon in the regulation
of the acidity of the urine and the excretion of bicarbonate.
Gamble and others have shown that if the urine is promptly
removed from the bladder with precaution against loss of
CO 2 , the CO2 tension may be several times as great as in
venous blood.lIlf• 280. 89S In explanation of this fact Sendroy,
Seelig and Van Slyke,893 suggest, first, that the acidity of the
urine is regulated by the specific tubular reabsorption of
BRCOs, and, second, that it is because BRCO a is reabsorbed
more rapidly than R 2 COS that the CO2 tension of the urine
is higher than that of the venous blood.
That R 2 COa is not "actively" reabsorbed, but merely
escapes back into the blood by diffusion, is indicated, as they
point out, by the fact that the CO2 tension in the urine never
is found below that in the arterial blood. And if, as is suggested, the active reabsorption of BHCOa proceeds more
rapidly than the passive diffusion of R 2 C08, the urine
must tend to become progressively more acid as the ratio,
BRCOa/H2 COa is decreased. But any increase in acidity
must affect the acid-salt ratios of the other buffers in the
ACID-BASE EQUILIBRIA IN PLASMA AND URINE
175
urine, and consequently the active reabsorption of BHCOa
must lead to the conversion of B2HPO" ~-hydroxybutyrate,
etc., to the corresponding free acids until equilibrium has
been attained. Assuming that little H 2 CO a is reabsorbed,
there is an adequate quantity of this acid in the glomerular
filtrate to account for the total free acid excreted. The
plasma contains about 1.3 mM. per liter of H 2 CO S , and 170
liters of glomerular filtrate would carry 220 mM. into the
urine per day, whereas the maximum free acid which can
be excreted (as judged by titrating the urine to pH 7.4) is
not over ISO mEq. Since the unabsorbed, unneutralized
H 2 COS in the tubular urine would be concentrated by the
reabsorption of water, this theory would explain the high
CO2 tensions observed in freshly drawn bladder urine.
Furthermore, if NHs is excreted as NH,HCO a by the tubules, the interaction of this salt with the salt (BA) of any
other acid in the filtrate would form NH,A and the BHCO s
could be reabsorbed. Thus one essential tubular process,
the reabsorption of BHCOa, would suffice to effect the
conservation of this salt, to regulate the acidity of the urine
and the relative distribution of the various acid-base components contained within it, and to explain the high CO 2
tension of the urine itself. Though it is not so stated, it
is implicit in this view that the kidney is r:egulating the U IP
ratio of BHCPs, and essentially indifferent to the U IP
ratio of both Hand H 2 COa•
The chief objection that might be raised to the above
theory is in regard to the assumption that the tubules are
impermeable to free c~rbonic acid, for this substance penetrates all known tissues and living cells with great ease.
17 6
THE PHYSIOLOGY OF THE KIDNEY
In point of fact, it diffuses through tissues more rapidly than
any other known substance with the exception of O 2 • But
a clear distinction must be drawn here between the molecular
species R 2 COS and CO2 • The physical properties of CO 2
are such as to endow it with great penetrating power,
whereas in the light of our knowledge of the permeability
of living cells to aliphatic acids, it would be inferred that
the species R 2 COS would penetrate very slowly, even more
slowly than lactic or glycollic acid. In simple aqueous solutions 99.9 per cent of the total free CO 2 exists as CO2 , and
this is probably true of plasma and of tubular urine. The
distinction between the two species would be less important
if the equilibrium, CO2 R 2 0pR 2 CO S were rapidly readjusted, but such is not the case. The component velocities
are relatively slow and are catalyzed in the red cells by
carbonic anhydrase. S82 There is no reason to believe that
this catalyst is present in the glomerular filtrate or tubular
urine, and in its absence the delay in hydration of CO 2 , combined with the fact that the greater part of the total CO 2
is present as free CO 2 , might afford ample opportunity for
diffusion of this species to occur.
The difficulties raised by postulating impermeability of
the tubules to CO 2 lead us to' suggest an alternative hypothesis to explain the regulation of the acidity of the urine,
an hypothesis which will permit us to assume that CO2 does
diffuse across the tubules readily, and that its U /P ratio
tends to approach 1.00. It may be supposed that the urine
is acidified by the tubular excretion of R+ in exchange for
B+. By this exchange BRCOs would be converted to RaCOa
and any other buffers present would in part be converted to
+
ACID-BASE EQUILIBRIA IN PLASMA AND URINE
177
free acids; in the absence of carbonic anhydrase, the newly
formed H 2 COa would fail to undergo dehydration to CO 2
and, failing therefore to escape from the tubule, would appear in the urine in excessive concentration. In this view the
tubules would be supposed to govern the U/P ratio of H+,
and would be indifferent to the VIP ratio of HCOa-; the
apparent reabsorption of this salt, both normally and in
acidosis, would actually be effected by conversion to CO2
and the diffusion of this substance back into the blood. This
interpretation has the further advantage that it agrees more
satisfactorily with the phenomenon of acidification as it occurs in the frog tubule. Montgomery and Pierce S02 have
recently shown that 0.33 M sodium phosphate solution of
pH 7.5, and containing phenol red, when held in contact
with the distal tubule of the frog, becomes yellow (pH 6.8)
in 60 seconds. Interaction of H 2 COS from the glomerular
filtrate and the specific reabsorption of HCOs are here excluded from consideration. Acidification of this buffer mixture to pH 6.8 might be effected by reabsorbing 182 out of
227 mEq. (or 80 per cent) of the B2 HP0 4 , or by substituting H ions for B in 126 out of 227 mEq. (or 56 per cent).
The distal tubule can apparently reabsorb this quantity of
base from the tubular urine in less time than 60 seconds,
and therefore neither mechanism is beyond the range of possibility. But since P04 is very slightly reabsorbed by the
frog tubule when the concentration in the plasma, and hence
in the glomerular filtrate, is elevated by only a few mEq.,
such extensive reabsorption from 0.33 M solution appears
unlikely.
But whatever the mechanism of acidification of the urine,
17 8
THE PHYSIOLOGY OF THE KIDNEY
it is probable that the renal tubules operate on only one of
the four species: H 2COa, CO 2 , HCO a- or H+, and that they
are essentially impermeable to, or indifferent to, the U /P
ratio of the other three. In view of what has been said in
previous chapters, it is not surprising that reciprocal relationships can be demonstrated between the excretion of
CI and HCOa• For example, the administration of large
amounts of NaHCO s , while increasing the excretion of
HCO a, tends to reduce the excretion of Cl. And as has been
noted, the excretion of HCOa may be slight and the urine
may be acid in spite of alkalosis induced by prolonged vomiting, excessive salt deprivation or sweating. In all these instances dehydration with simultaneous reduction of plasma
electrolytes is present, and the kidney preserves the total
electrolyte content of the plasma even if a severe alkalosis
remains uncompensated.
The administration of the neutral alkali salts of mineral
acids (N aCI, KCI, N a2S0~, etc.) has little effect upon the
acid-base equilibrium of the blood, as might be expected, but
the salts of organic acids, such as lactic, acetic, citric, tartaric, etc., increase the alkali reserve temporarily because
the anion is oX'idized to CO 2 and H 2 0, and the salt reappears
as BHCOa• Conversely, ammonium salts of mineral acids
decrease the alkali reserve because the NHs is almost completely converted to urea, leaving CI to combine with base
at the expense of HCOa• The administration of NH~CI is
an effective method of producing acidosis experimentally or
for therapeutic purposes. The mineral salts (CI, S04' etc.)
of the alkaline earths (Ca, Mg and Sr), are acidotic because the basic ion is largely excreted in the feces as the
ACID-BASE EQUILIBRIA IN
PLAS~A
AND URINE
179
phosphate, carbonate or fatty acid soap, leaving the mineral
acid to displace base from BHCO a•
Finally, the phenomenon of the " alkaline tide II may be
briefly noted here. It has long been known that the urine
becomes more alkaline than normal an hour or so after
a meal. Although other factors contribute to the phenomenon,49 the alkaline tide reflects a decreased excretion
of acid and ammonia, coincident with a tide of alkalinity in
the blood which in turn is due in part to the excretion of
gastric HCI. The formation of HCl from BCI leaves an
excess of base in the plasma which combines with the CO 2
of concurrent metabolism. Thus the plasma BHCOa is
slightly elevated, marked elevation being prevented by the
excretion of alkaline pancreatic and intestinal fluids. Subsequently the HCI is reabsorbed from the intestine, the
plasma BHCOa and CO2 return to normal and the urine
becomes more acid. Where the gastric secretion of HCI is
reduced or absent (in achlorhydria or after a fat or carbohydrate meal, etc.) the alkaline tide is diminished or fails
to appear.
AMMONIA
The significance of NHs excretion in the urine in relation
to conservation of fixed base has been discussed on page 172.
In 1921 Nash and Benedict S03 demonstrated that urinary
NHs is formed in the kidney, a fact that has been amply
confirmed by numerous investigators. This conclusion was
based upon the facts that the concentration of NHs in the
arterial blood is too small to account for the quantity excreted in the urine, that the concentration in the renal venous
blood is higher than that in the arterial blood, and that the
180
THE PHYSIOLOGY OF THE KIDNEY
arterial concentration is unchanged in acidosis, alkalosis or
after nephrectomy. The nature of the precursor in the
blood is still undetermined. N ash and Benedict, as numerous others, inferred that the urinary NHa is formed from
urea, but there is no evidence that such is the case. The
only reason for thinking that urea might be the precursor
is that in acidosis a rough reciprocal relation sometimes
exists between the excretion of urea and NHa, such that any
increased output of NHa is accompanied by a decreased output of urea. But increased NHa excretion may be accompanied by an increase in the excretion of total nitrogen with
no change in urea excretion; and even if a reciprocal relation could invariably be demonstrated, it might be due to the
early deflection of N in intermediate metabolism, rather than
to the direct hydrolysis of urea.
NHa is a very toxic substance if injected directly into the
venous stream, for under these circumstances it reaches the
central nervous system upon which it has a strong convulsive action. Yet comparatively large doses may be given
intra-arterially because it is quickly removed and bound by
the tissues. When taken per os its toxicity is equally low,
because in this case it is carried directly to the liver and converted to urea, the hepatic conversion being so efficient that
there is no appreciable elevation of the NHa content of the
systemic blood. It is impossible to increase the excretion of
NHa by the oral administration of NHa salts, except through
the secondary induction of acidosis. Krebs 281 has recently
demonstrated that the hepatic conversion of NHa to urea is
not by the direct dehydration of (NH,) 2eOa, as was once
thought, but indirectly through union with some amino-acid.
ACID-BASE EQUILIBRIA IN PLASMA AND URINE
I 8I
The type reaction which he suggests is the union of a molecule of ornithine with NHa and CO2 to form citrulline, which
by the addition of another molecule of NHa would form
arginine; arginine is split by hepatic arginase to urea and
ornithine, and the latter would again he available in the
manner of a catalyst to react with more NHa. It is possible
that in an analogous manner some nitrogenous substance in
the plasma furnishes the N for the formation of NH3 in the
kidney. Bliss a8 has suggested that amide nitrogen of protein serves this purpose, but Williams and Nash 488 appear
to have effectively refuted the experimental evidence upon
which this claim is based. From Krebs' work it appears that
one or more amino-acids in the plasma constitutes the precursor. The renal cortex is the most active de aminating
tissue per unit weight in the body and, according to Krebs,
if more NHa is formed in the kidneys than is required to neutralize excreted acids, the excess is removed by way of the
venous blood. Both Krebs 2S1 and Schneller,S92 who have recently reviewed this problem, consider the theory that urea
is the precursor of urinary ammonia to be definitely disproved.
This question is not only of theoretical interest but also
of some practical importance. Van Slyke, Page, Hiller and
Kirk,441l accepting urea as the precursoI: of NH3, have recommended that the sum of the urea NHsN in the urine be
used, in place of the urea alone, in calculating the urea clearance in man in acidosis. The assumption here is that the
deflection of N to NHs will create a deficit in the urea clearance. This circumstance. could arise only if some of the
filtered urea were converted to NHa, either in the tubule
+
182
THE PHYSIOLOGY OF THE KIDNEY
lumen or in the tubule cells after the reabsorption of a fraction of the urea from the glomerular filtrate. But Pitts aa8
has shown in the dog that the difference between the urea
clearance and the glomerular clearance, which exists under
all normal conditions, is unchanged in extreme acidosis and
alkalosis j if the clearance in acidosis is calculated on the
urea + NHsN, it may exceed the rate of glomerular filtration by a considerable amount, particularly if the ratio,
NHa-N/urea-N is large, whereas the clearance calculated
on urea alone maintains its normal value relative to the rate
of filtration. It may be concluded from these observations
that the precursor of NHa is not the urea in the tubular
urine, but otherwise they throw no light on the nature of the
precursor.
An increased excretion of NHs by the kidney follows the
induction of acidosis only after an interval of hours or days,
and in recovery from acidosis increased NHs excretion persists for a considerable period, perhaps until the general
electrolyte pattern has been restored. Gambell, Ross and
Tisdale 180 have suggested that the stimulus to NHs excretion is the reduction of the alkali reserve of the blood rather
than the increased H ion concentration. Such a view would
in part explain why NHs excretion is delayed, and why it
should present numerous inter-relationships with the availability and simultaneous excretion of fixed base, CI, RCO a,
R 2 PO" and of water itself.
XVII
CALCIUM, PHOSPHATE AND SULPHATE
CALCIUM
is known concerning the specific renal features of
Ca excretion, except for the facts that the total excretion
can be increased or decreased by varying the Ca intake and
by certain physiological means such as the administration of
parathyroid hormone. The deficiency in our knowledge on
how Ca is handled by the kidneys arises in part from the
complexity of the physical-chemical state of this substance in
the plasma.
The total Ca content of normal human plasma ranges
from 9 to II.S mgm. per cent (2.3 to 3.0 mM. per liter).
Rona and Takahashi 880 discovered in I9I3 that only about
half of this is diffusible, and they concluded that the rest was
combined with plasma proteins. (The formation of protein salts is not unique with Ca, for such salts are also formed
by K, N a and Mg, only the ionic activity of Ca under
these conditions is much less than the activity of the other
cations.) Since several lines of evidence indicate that the
physiological activity of the plasma Ca depends upon its
physical-chemical state, this problem has been the subject of
numerous investigations. The essential question concerns
the degree of ionization of various Ca salts. In the light of
modern chemical the~ry, CaCII may be thought of as completely dissociated into Ca++ and Cl- ions, whereas it is
LITTLE
184
THE PHYSIOLOGY OF THE KIDNEY
known that the Ca salt of citric acid is a largely undissociated
complex in which the Ca has lost its physical-chemical and
physiological activity. Ca-citrate is diffusible and therefore cannot be distinguished from Ca ions by filtration.
Most investigators have favored the belief that a significant
fraction of the plasma Ca is in the form of a non-ionized,
non-protein salt of such a nature as Ca_citrate.228 . " 0 This
fraction is sometimes designated as Ca-X. In addition,
it has been suggested that part of the diffusible Ca is in the
form of a Ca-phosphorus complex.22
The problem has recently been reinvestigated by McLean
and Hastings 26& using the excised frog heart, which is extremely sensitive to the ionic composition of the perfusing
fluid, as a test for Ca ions. With this biological method
McLean and Hastings have concluded that the quantity of
Ca-X (probably citrate) is normally no greater than o.s
mgm. per cent; of the remaining Ca about half is present as
Ca-proteinate and half as Ca ion. The dissociation of the
Ca-proteinate conforms roughly to the mass law, the equilibrium being affected not only by the protein- and Ca-ion concentration but also by pH, temperature, albumin/globulin
ratio, etc.
It would appear that the organization of the body is such
as to tend to maintain, not so much a constant concentration
of total Ca in the plasma, as a constant concentration of the
physiologically active Ca ions. 440 One of the chief mechanisms involved in this regulation is the hormone of the parathyroid glands, which influences the equilibrium between
plasma Ca and the Ca in the bones. But once Ca is in the
plasma, the distribution in the form of ions and proteinate
CALCIUM, PHOSPHATE AND SULPHATE
ISS
is determined solely by those physical-chemical factors which
influence this local equilibrium. The elevation of the plasma
P04. increases the relative amount of Ca bound in the colloidal phosphate complex, but since this tends to be removed
as fast as it is formed it is doubtful if it is of immediate
interest in problems of excretion. It would be expected
from the above considerations, that the excretion of Ca
would not be related in any simple manner to the total Ca
of the plasma. That portion combined with protein is unavailable for filtration, as is also the colloidal phosphate
complex, and one cannot say in advance that Ca-X would be
handled by the kidney as are Ca ions.
Ca differs from N a and K by the fact that when ingested
most of it escapes through the bowel, only a small part appearing in the urine. This is due to the circumstance that
it is precipitated as insoluble salts in the alkaline intestinal
fluids. For this reason CaCII produces acidosis; in the net
ionic balance it is as though NaCI + HCI were absorbed
and the Ca excreted as the carbonate, phosphate or soap.
There is also some actual excretion of Ca by the bowel and
consequently CaCI I when administered intravenously also
produces acidosis, the Ca escaping via the gut, the NaCI +
HCI remaining to be excreted in the urine.
The kidney roughly distinguishes Ca from Sr, the latter
being excreted more rapidly.202
PHOSPHATE
The urine, contains chiefly inorganic phosphate,288 and it is
commonly assumed that all the acid-soluble phosphate in
the plasma is also in the inorganic form. Of the ionically
186
THE PHYSIOLOGY OF THE KIDNEY
active inorganic phosphate in the plasma, about 80 per cent
is present at pH 7.4 as B2HPO~ and 20 per cent as BH2PO~.
There appears to be a calcium-phosphate complex 22 in the
plasma which in theory should be in equilibrium with the
free phosphate ions. All the plasma inorganic phosphate is
normally filterable 168, ~66, m and since the urine may be almost phosphate-free we must infer that either the H 2PO,or HPO,= ions, or both, are reabsorbed by the tubules. It
will be recalled that phosphate is reabsorbed in the distal
tubule of the frog '60 and it may be inferred, though without
great certainty, that reabsorption similarly occurs in the distal tubule of the mammal. It is perhaps not too inaccurate
to think of PO, as an entity the excretion of which is increased or decreased in relation to the body's need to conserve it, and to view the distribution between B2HPO~ and
BH2PO, in urine as incidental consequences of the H ion
concentration of this fluid.
There is, as yet, no convincing evidence of the tubular excretion of PO~ in the mammal. It is known to be excreted
under certain circumstances by the tubules of the aglomerular
fish,t6', 276 although it is uncertain whether the precursor is
organic or inorganic phosphate. Though on general principles it would not be expected in anyone species that a substance which was reabsorbed by the renal tubules under most
circumstances would be excreted by them under others, yet
such tubular excretion might occur, not from the inorganic
phosphate of the plasma, but from some organic form. lOS
This possibility is enhanced by the presence in the kidney
of a rich supply of phosphotase capable of splitting inorganic phosphate from organic compounds, though it is not
18 7
CALCIUM, PHOSPHATE AND SULPHATE
demonstrated that this phosphotase plays any part in the
excretion of the inorganic salt. It may be that the enzyme
is concerned with the local metabolism of the tubule cells,
or in some such process as the reabsorption of glucose.
o
~
CI I.e
~
~
<t
.s
•
w
do
......
..
•
..
I
•
•••
• •
•
"
.
•
•
•• •• •
••••
••
.,
~.d.
()
...
,••..
._
..
••
•••
# ••
o
-
5
10
A....ASMA P04
,,,,,M.
FIGURE
15
20
I LITER
27
The POJinulin clearance ratio in the dog, in relation to plasma
P04, concentration. (Recalculated from Pitts' P0 4 /xylose clearance ratios, 33 I.)
The excretion of inorganic phosphate in relation to
plasma level has been examined by Pitts 331 whose data on
phosphate clearances in the dog are presented in figure 27.
When the plasma level is normal (1.1 to 1.5 mM. per liter)
the phosphate clearance is nearly zero. As the plasma level
is raised by the intravenous administration of a phosphate
solution of pH 7.4, the clearance rises rapidly, to approach
188
THE PHYSIOLOGY OF THE KIDNEY
an asymptote somewhat below the level of glomerular filtration. Marshall and GrafHin 275 have found that in the frog
the phosphate clearance at high plasma levels is approximately identical with the simultaneous xylose clearance.
Phosphate excr~tion in the mammal is grossly influenced
by a large number of factors, many of which are known to
produce disturbances in the plasma level. Where the clearance rises as rapidly with increasing plasma level as it does
in this case, it is a difficult matter to rule out slight changes
in plasma level as the essential factor underlying marked
variations in the rate of excretion. The increased excretion
of phosphate which has been observed to follow the administration of parathyroid hormone and of various organic phosphorus compounds, or the decreased excretion
attending the administration of glucose, insulin and adrenalin are quite possibly referable entirely to this cause.
It would appear, however, that the normal threshold of the
kidney can be altered, as for example in acidosis where
phosphate excretion is markedly increased, although the
plasma level may be below normal, and the ensuing drain
may be so great as to draw upon the stores of the bones and
tissues. Phlorizin does not block the normal reabsorption
of phosphate,402 though after prolonged phlorizination increased excretion may occur in consequence of the degradation of tissue. Yet the phosphate clearance at high plasma
levels is irregularly reduced in the phlorizinized dog,881 an
unexplained result which may be due to action on the kidney, or to a change in the composition of labile phosphate
compounds in the plasma. The normal excretion of phos-
CALCIUM, PHOSPHATE AND SULPHATE
18 9
phate is slightly increased in salt 198 but not in water diuresis/ n , 209, '85 and it is decreased by pituitary ablation."
SULPHATE
In
Mayrs 281 found in the rabbit that the VjP ratio
of exogenous SO, was from I.5 to 2.25 times the VjP ratio
of urea, and about equal to the V jP ratio of exogenous
PO, and creatinine. He concluded that all of these substances were excreted by filtration under the conditions of
his experiments. Mayrs' observations are of special interest
because he was the first to adduce quantitative evidence in
favor of a common mechanism (glomerular filtration) for
the excretion of several substances, and also because his experiments were the first to indicate, contrary to Cushny's
theory, that about 50 per cent of the filtered urea was reabsorbed. Subsequently Mayrs and Watt 290 measured the
blood flow in the rabbit's kidney and, using the SO, excretion as a means of calculating the filtration rate, concluded
that about 20 to 25 per cent of the plasma is filtered through
the glomeruli.
White 472, '78, m failed to confirm Mayrs' results in the
phlorizinized dog i in White's data the V jP ratio of SO,
was less than that of glucose and only slightly greater than
the V jP ratio of urea. Subsequent investigations show that
the discrepancy was due in part to the plasma level of SO,.
Hayman and Johnston/so Cope/" M acy 258 and Keith, Powers and Peterson 221 have shown that when the plasma SO, is
at normal levels, the SO, clearance in man, although highly
variable, is always less than the creatinine clearance, and
1922
19 0
THE PHYSIOLOGY OF THE KIDNEY
usually less than the urea clearance. Keith et al. give as
average clearance figures, 35 cc. per minute for SO" as compared with 70 for urea, 100 for xylose and sucrose, and 150
for creatinine. However , Hayman and Johnston found that
when Na2S0, is injected intravenously to elevate the plasma
SO" the clearance rises, approaching but never exceeding
the creatinine clearance.ct. 209 Since SO, is completely filterable from plasma 180 it follows that it must be reabsorbed
by the tubules. Although it must be recognized that SO, is
a waste product and there is no apparent reason for its
conservation, the behavior of this substance may be likened
to that of PO, (figure 25), in that both clearances are increased by raising the plasma level. It is interesting that at
elevated plasma SO, levels the creatinine/SO, clearance
ratio averages 1.38 in Hayman and Johnston's data; the
fact that the creatinine/inulin ratio in man a-verages 1.39
suggests that under these conditions the SO, clearance approaches the inulin clearance. This supposition is supported by the fact that Mayrs found the U jP ratio of
exogenous SO, (and PO,) to be about equal to that of
creatinine in the rabbit.
White and Monaghan '81 have more recently reported SO,
clearances in the phlorizinized dog which range from onesixth to two times the creatinine clearance. Though it is
possible that phlorizin influences the excretion of SO" it
seems probable that the SO, clearance never in fact exceeds
the glomerular clearance in either dog or man.
The above evidence indicates that at normal plasma levels
of SO" the SO, clearance is very low, presumably due to
reabsorption of the salt. As the plasma level is raised the
CALCIUM, PHOSPHATE AND SULPHATE
19 1
clearance rises, approaching the filtration clearance as an
upper limit. It is possible that variations in the rate of urine
formation, or in the concentration of other salts in the urine,
are in part responsible for the observed variations in the
endogenous SO, clearance.
XVIII
HIPPURIC ACID, URIC ACID, DIODRAST, ETC.
HIPPURIC ACID
THE discovery of hippuric acid synthesis in the kidney by
Bunge and Schmiedebe~g in 1876 is a frequently cited landmark in biochemistry. These investigators showed that
when N a benzoate and glycine are injected simultaneously
into dogs with the renal circulation intact, hippuric acid accumulates in the blood, but no hippuric acid is formed if the
renal blood vessels are first tied off. They were also able
to demonstrate that hippuric acid synthesis occurs if blood
containing benzoic acid and glycine is perfused through the
excised dog kidney. They correctly concluded that in the
dog benzoic acid is conjugated with glycine only in the kidney. This observation is especially noteworthy since it was
the first molecular transformation, of significance to general
metabolism, to be revealed in this organ. Subsequent investigations have amply confirmed this discovery. Although
the kidney is not the exclusive site of benzoic acid conjugation in man, it has been demonstrated by perfusion experiments to be capable of carrying out this operation.8~&, 8&8,427
When the higher homologues of benzoic acid are fed to
mammals they undergo various degrees of oxidation before
conjugation. This proceeds in general by ~-oxidation, and
Snapper and Griinbaum m have demonstrated that this oxidation can itself be carried out by the renal tissue. By per-
HIPPURIC ACID, URIC ACID, DIODRAST, ETC.
193
fusion of the kidney of sheep and calves these authors have
demonstrated that where phenylacetic acid is combined directly with glycine to yield phenylaceturic acid, phenylproprionic and phenylvalerianic yield hippuric acid, while phenylbutyric yields phenylaceturic acid. The dog's kidney
however, oxidizes phenylproprionic acid only to cinnamic
acid, which is then conjugated to cinnamoglycine, this organ
being unable to oxidize cinnamic acid as do the kidneys of the
sheep and calf.
The maximum excretion of hippuric, and probably of
other conjugated acids, is dependent on the availability of
glycine. s44- Benzoic acid is also conjugated with glycuronic
acid to form glycuronic acid-monobenzoate, but it has not
been established that the kidney participates in this process. S4S It should be noted that the liver is capable of ~-oxida­
tion, and that fats with even numbers of carbon atoms are
degraded at least to ~-hydroxybutyric acid in this organ.
Snapper and Griinbaum have adduced evidence that the
kidney can oxidize ~-hydroxybutyric acid to CO2 and H 2 0,
and they suggest that this substance, after being formed in
the liver, is completely degraded in the muscles and the'
kidney. The extent to which the latter organ participates
in the induction of diabetic acidosis is undetermined.
It has also been shown that the bird kidney can convert
hypoxanthine to uric acid by virtue of a xanthine oxidase,281
a fact which is particularly significant in view of the existence of tubular excretion of uric acid in the bird, as described
below.
Although the few re,actions listed above, together with the
formation of NHs , are the only molecular transformations
194
THE PHYSIOLOGY OF THE KIDNEY
which have been demonstrated in renal tissue, it is unlikely
that they are the only ones of which the kidney is capable,
and it is quite likely that further investigations will reveal
other important operations of a similar nature.
URIC ACID
For a century after the discovery of uric acid by Scheele
in 1776 this compound occupied an important place in biochemical research. It has been of special interest because it
is frequently the material of renal calculi and gouty deposits,
and because of the peculiarities of its metabolism.
In insects, reptiles and birds uric acid is the chief form
in which waste nitrogen is excreted, a circumstance which
has been interpreted as an adaptation to arid terrestrial life,
for the properties of this substance are such that it may
be excreted with a minimum of water. 420 In the mammals,
however, waste nitrogen is excreted chiefly as urea, and uric
acid appears in the urine only in consequence of the ingestion of the purine bases normally contained in nucleoproteins, and of endogenous metabolism. The nucleic acids are
degraded to nucleotides and ultimately to the purine bases,
which are then converted to uric acid. In most mammals
the uric acid is then oxidized to allantoin, but in man, the
anthropoid apes, the New World monkeys 863 and the Dalmatian coach-hound a great fraction of the uric acid is excreted as such. The failure to oxidize uric acid in the coachhound has been shown to be a genetic character obeying the
Mendelian law.
There is no doubt that uric acid is excreted in large part
by tubular activity in the bird. This was early suggested
HIPPURIC ACID, URIC ACID, 'DIODRAST, ETC.
195
by Mayrs 289 who analyzed ureteral urine and showed that
the U IP ratio of uric acid was considerably greater than
the U/P ratios of exogenous P04 or S04' Later Gibbs 188
showed that the U IP ratio might reach enormous values
(3, IIO?) and affirmed Mayrs' conclusion. More recently
Marsha1l 288 has examined the simultaneous clearances of
glucose and uric acid in the phlorizinized bird and the iguana,
and concluded that in both animals the greater part of the
uric acid is excreted by tubular activity.
It appears from Gibbs' figures that the uric acid is excreted into the tubular urine in a highly super-saturated solution, from which it readily precipitates. The water of the
urine is then reabsorbed (isosmotically) from the cloaca
and the uric acid is defecated as a semi-solid past~.189
Berglund and Frisk 21 have shown that the uric acid clearance in man is roughly only one-fifth as great as the simultaneous creatinine clearance, and is only slightly increased
by salyrgan, novatophan and euphyllin. These authors incorrectly -assume that this low clearance is due to the fact
that only a minor fraction of the plasma uric acid is available for filtration: on the contrary, uric acid is filterable
from frog's blood,42 bird's blood 188, 289 and human blood (author's unpublished observations) and its failure to be excreted must be attributed to tubular reabsorption. Gersh 186
was unable to demonstrate uric acid in the tubules of the
rabbit, and from this concluded that it was excreted solely
by the glomeruli, but the adequacy of histological methods
to reveal either tubular reabsorption or tubular excretion is
open to question. W4en injected intravenously it has a very
toxic action on the kidneys and accumulates in these organs
19 6
THE PHYSIOLOGY OF THE KIDNEY
in large quantities; 118 though it is not demonstrated that
this is cellular storage, it is possible that like many dyes 84 it
may tend to accumulate within the tubule cells without actual
excretion.
DIODRAST, HIPPURAN AND SKIODAN
Recently introduced'into clinical urology, these organic
iodine compounds, because of their opacity to x-rays and
the high concentration in which they appear in the urine,
have been found useful in urography. (Diodrast or neoskiodan is 3:5 diiodo-4-pyridon-N-acetic acid, dissolved with
the aid of diethanolamine; hippuran is sodium ortho-iodohippurate; skiodan is sodium mono-iodo-methane sulphonate.)
Elsom, Bott and Shiels 101 have shown that diodrast and
hippuran are excreted in part by the tubules in the dog,
the diodrast or hippuran/creatinine clearance ratios being
greater than 1.0 at low plasma levels and depressed to approximately 1.0 as the plasma level is raised. Similarly, the
diodrast and hippuran clearances exceed the creatinine clearance in man,2B4 the clearance ratios averaging 2.3 and 3.9,
respectively, and the clearance ratio is depressed at elevated
plasma levels. Hippuran is also excreted by the tubules of
the rabbit. loB
The skiodan clearance, on the other hand, is approximately equal to the creatinine clearance at all plasma levels
in the dog. This would indicate that there is no tubular
excretion of this substance; in fact, there may be a slight reabsorption, for the clearance ratios average 0.89. The behavior of skiodan in man is less certain; in four clearance
HIPPURIC ACID, URIC ACID, DIODRAST, ETC.
197
comparisons reported by Landis et al.lI84 the skiodan/creatinine clearance ratio ranged from 0.82 to I.14 and averages
0·95·
Diodrast and hippuran are of particular interest because
like phenol red they are excreted chiefly by the tubules, and
with very high clearances. Unlike phenol red, they are completely filterable from the plasma.
We have referred in an earlier chapter (page 88) to our
later examin!1tid'n of the hippuran clearance at low plasma
levels in man, and to the fact that from the value of this
clearance it appears that the renal blood flow in ideal man
cannot be less than 1,000 cc. per minute. 4l18
FERRO CYANIDE
It will be recalled that Marshall m found that ferrocyanide is not excreted by the aglomerular kidney except in
traces. Gersh and Stieglitz 181 have concluded that there is
no reabsorption of this substance by the tubules of the glomerular kidney. Their evidence is based upon the histochemical demonstration of this substance in the capsular
fluid and lumen of the tubules in rabbit kidneys which have
been rapidly dehydrated at low temperatures. Since they
find no evidences of ferro cyanide in the cells of the tubules
they conclude that there is no reabsorption.
Van Slyke, Hiller and Miller 444a, 444b have found that the
simultaneous ferrocyanide, inulin and creatinine clearances
in the dog are equal, a fact which affirms the conclusion that
the last two represent the level of glomerular filtration.
But in a subsequent investigation, Miller and Winkler liST
found that in man the ferrocyanide clearance is at the level
19 8
THE PHYSIOLOGY OF THE KIDNEY
of the urea clearance, or usually about half of the creatinine
clearance, and they conclude that about 40 per cent of the filtered ferrocyanide is reabsorbed by the tubules. They point
out that this might be due to a specific difference in the kidney of man and dog, or it might be due to the fact that the
observations on the dog were made at higher plasma levels
than in man.
AMINO-AcIDS
The "amino-acid " clearance in normal man has a very
low value, ranging from 1 to S cc. per minute; after the administration of glycine the clearance rises as high as 25 cc.
It is obvious that filtered amino-acids are extensively reabsorbed, the available data indicating a threshold at about
4 mgm. per cent of amino-nitrogen in plasma. us It would
seem probable, however, that different amino-acids are
handled by the kidney in a different manner.
OTHER INORGANIC ANIONS
Bromides, iodides, sulphocyanates, nitrates and chlorates
are extensively.reabsorbed by the tubules, the first three being excreted very slowly and the last two rather rapidly.82
The iodide clearance in the dog, at plasma levels of about
5 mM. per liter, is about 17 per cent of the filtration rate.1O'l
Investigations in Peters' laboratory on man (personal communication) and in the author's laboratory on dogs (Pitts,
unpub.) show that the eNS clearance is extremely small
and highly variable, ranging from 0.3 to 2.0 per cent of the
filtration rate. A small fraction (about 10 per cent) of the
salt is un filterable from plasma, perhaps because it combines
with lipoids (Peters), but it is clear that the filtered por-
HIPPURIC ACID, URIC ACID, DIODRAST, ETC.
199
tion is almost completely reabsorbed by the tubules. It is
possible that the variations in the CNS clearance are due
to simultaneous variations in CI excretion, or to the disturbing influence of urine How.
Summary. The manner in which various normal, foreign
and waste electrolytes are handled by the kidney is at the
moment very puzzling. CNS, I, PO~, SO, and uric acid are
all reabsorbed by the tubules of the mammalian kidney to
a considerable extent. CNS is a foreign invader j I is present
(in the observations referred to here) in great excess over
any normal concentration, PO, is available in slight but constant excess, while SO~ and uric acid are waste products.
It might be supposed that the tubules failed to distinguish
I and SCN from CI, but this line of reasoning would scarcely
apply to such dissimilar ions as PO, and SO" or to any of
these ions and uric acid.
There is, again, no obvious physical-chemical similarity
between phenol red, diodrast and hippuran, all of which are
excreted by the tubules with remarkable efficiency. It is all
the more surprising that these substances, which are entirely
foreign to the body, should be excreted so much more
efficiently than urea and creatinine, the chief nitrogenous
waste products of metabolism.
Lastly, ferrocyanide and skiodan are both excreted by
filtration, with no apparent tubular excretion or reabsorption in the dog, while the former is reabsorbed to a considerable degree by the tubules of man.
No simple hypothesis can explain the diversified manner
in which the kidney handles these substances. In view of the
identity of the creatinine and inulin clearances in the normal
200
THE PHYSIOLOGY OF THE KIDNEY
dog and in phlorizinized fish, bird and man, and of the
identity of the xylose and inulin clearances in all phlorizinized animals, it is difficult to invoke simple passive diffusion
across the tubules to explain the reabsorption of SO" ferrocyanide and other substances which do not diffuse at all
through ordinary cells. The evidence as it stands jndicates
that passive diffusion is almost non-existent in the mammalian kidney, except for the very diffusible substance, urea,
and such lipoid soluble substances as alcohol, acetone, etc.,
which are notoriously able to penetrate most cells. Before
passive diffusion can be invoked to account for the reabsorption of non-penetrating electrolytes, the effects of the rate
of urine formation and of the concentrations of other urinary
electrolytes upon the reabsorptive process must be carefully
examined.
PART!!!
XIX
THE EXCRETION OF WATER
""THE substance present in greatest amount, and from many
points of view the most important constituent in the urine,
is water; and the control of water excretion is one of the
most vital functions of the kidneys, especially in the mammals. It is also one of the most complicated. In the ultimate analysis of this problem we must take into consideration the relative importance of glomerular and tubular
function in bringing about variations in urine flow; and, in
relation to tubular function, we must consider further the
maximal concentration of the urine against which water can
be reabsorbed, the role of blood dilution as the essential
stimulus controlling water reabsorption, and the role of the
antidiuretic hormone of the pituitary gland as at least one
essential mechanism by which changes in the tubular reabsorption of water are mediated ...
THE RELATIVE IMPORTANCE OF GLOMERULAR AND
TUB ULAR FUNCTION IN WATER EXCRETION
~It was pointed out in an earlier chapter that, although
the rate of glomerular filtration in both dog and man is relatively constant under controlled conditions, it is impossible
202
THE PHYSIOLOGY OF THE KIDNEY
on the available data to definitely conclude that variations
in filtration play no part in the integrated regulation of water
excretion.s8• 400a * Nevertheless, there are good reasons for
believing that urine flow is essentially controlled by varying
tubular reabsorption", For example, dog C (figure 7, p. 66)
on a high protein diet had a filtration rate of about 113 cc.
per minute; on a low protein diet the filtration rate was only
65 cc. per minute; yet before the administration of water
the urine flow in both 'instances was below 0.5 cc. per minute,
and increased during water diuresis to a maximum of about
7 cc. per minute . ., In man the filtration rate may vary from
90 to 130 cc. and show no correlation with the rate of urine
formation. ss There is no evidence in either species that the
tubules tend to reabsorb a constant volume of water per
minute, nor does the evidence support the idea that they
tend to reabsorb a constant fraction of the filtrate. Rather
it appears that they tend to return water to the peritubular
blood until that blood has some specific composition, or until
the urine itself has reached some specific concentration.
When we seek for the factors that govern water reabsorption, it appears probable that both blood and urine composition, acting locally upon the tubules, are concerned, and
that the reabsorptive process is carried out under these determinants more or less independently of the rate of filtration. It would appear from the recent experiments of Shannon and Winton 404 that there is ample time at the normal
*
Handovsky and Samaan 189 have recently asserted that there is an increased renal blood flow in the dog during water diuresis, but this is no doubt
due to the effect of the administration of large quantities of water upon the
circulation rate and is not a necessary concomitant of water diuresis.
THE EXCRETION OF WATER
203
rate of glomerular filtration for equilibrium across the tubules to be reached.
On the side of the blood, it may be said that the remote
stimulus to increased water excretion is the dilution of the
plasma, but there is as yet no evidence that this acts directly
upon the kidney. Water reabsorption by the renal tubules
is immediately controlled by the antidiuretic hormone secreted by the pituitary gland, which serves to accelerate the
reabsorptive process; and it is apparently because of variations in the concentration of this hormone in the blood that
the rate of urine formation varies during water diuresis.
On the side of the urine, it appears that the essential factor
limiting the reabsorption of water is somehow related to
either the total or the specific concentration of the various
solutes contained therein. It is convenient to discuss these
urinary factors first.
THE LIMITING CONCENTRATION OF THE URINE
In the mammals the extensive reabsorption of water from
the glomerular filtrate results at times in the production of
urine having considerable osmotic pressure. Neglecting the
thermodynamics of the numerous specific processes, the mere
elaboration of a fluid hypertonic to the blood represents a
considerable expenditure of energy which is presumably furnished by the local metabolism of the tubules themselves.
On the other hand, when the reabsorption of water is slight
but the reabsorption of glucose, CI, N a, etc., is nearly complete, the urine may be markedly hypotonic to the blood.
Osmotic work must also be done in this case, only here the
energy is expended in elaborating a fluid more dilute than
204
THE PHYSIOLOGY OF THE KIDNEY
the blood. The processes by which hypertonic and hypotonic urine are formed appear to be separate and independent. All the vertebrates are capable of excreting urine
which varies from marked hypotonicity to isotonicity with
the blood, whereas apparently only the mammals can excrete
a urine hypertonic to the blood. 417 The physiological task
involved in this operation is, from the point of view of
energetics, no doubt one of the most expensive operations in
the mammalian kidney.
It might be assumed, as a first approximation, that the extent to which the urine can be concentrated is limited by the
total osmotic pressure. So long as the rate of glomerular
filtration remains relatively large, the osmotically active
constituents contained in this filtrate, and which are themselves not reabsorbed, will prevent the complete reabsorption of water and thus place a lower limit upon the rate of
urine formation. The chief osmotically active constituent
of the urine is urea, and it is perhaps to the advantage of the
organism that at very low urine Hows a considerable fraction of the filtered urea is reabsorbed, for under'conditions
of extreme dehydration this circumstance permits the rate
of water excretion to decrease to lower levels than it otherwise could. Conversely, the introduction into the blood, and
hence into the glomerular filtrate, of any osmotically active
substance which itself is not reabsorbed, tends to increase
the rate of urine formation by passively preventing the reabsorption of water. Thus, urea itself is frequently used
as a diuretic, and the fact that the urine volume on a high
protein diet tends to be higher than on a low protein diet
is commonly attributed to the osmotic action of the urea pro-
THE EXCRETION OF WATER
20 5
duced by the degradation of protein. Sucrose, sulphate and
similar substances when given intravenously produce diuresis
for the same reason.
No quantitative description of the osmotic limitations of
the urine in anyone species, or of the osmotic capacities of
different species of mammals, can be given at the present
time. In man the maximum urinary concentrations of Bel
or BReOa, or of mixtures of these salts, is about 0.33 M, a
value which appears to be independent of the urea content
of the urine. 87 A higher electrolyte "ceiling" (0.50 M)
can be obtained if BRPO,= is mixed with Bel or BReOa,
but this might be due to differences in the osmotic activity
of these salts. 261 Adolph S.' has found that the maximum
osmolar equivalent of the urine after the administration of
Bel or BReOs , or of mixtures of these, in man is slightly
lower than when urea is the predominant solute.
Gamble and his coworkers 128. 129 have found that rats
which were allowed water ad libitum, and to which
various salts and non-electrolytes (Na, K, el, ReO s , PO"
SO" glucose, galactose and creatinine) were administered,
excreted urine of essentially constant osmotic pressure. If
urea was the predominant constituent of the urine distinctly
more concentrated urine was formed. But the interpretation of these experiments is rendered qifficult, first by the fact
that the kidney is not under stress to reabsorb water, and
second by the fact that the water intake may be governed by
the mechanism of thirst without reference to the ability of
the kidney to excrete a more or less concentrated urine. It
is reasonably certain that the kidney can excrete a more
concentrated urine than was observed in any of the fore-
206
THE PHYSIOLOGY OF THE KIDNEY
going experiments, and it is open to question if that limit
is ever reached with water ad libitum. *
It is clear that the same question is faced in discussing the
maximal concentration of the urine as was encountered in
discussing the composition of the plasma: it is difficult to
distinguish the relative importance of the specific electrolyte content (total base?) , the osmotic pressure and the ionic
strength. It is not beyond possibility that there are two
limiting terms to the concentration "ceiling," an osmotic
ceiling (urea, sucrose, etc.) and an ionic strength ceiling
(NaCl, Na 2 SQ.. , etc.), and that the maximal concentration
of the urine represents a resultant of these two terms. But
whatever the factor or factors involved, there is no reason
to suppose that they operate only to limit the maximal urine
concentration: it may be that they operate at all times in
opposition to the reabsorptive processes activated by the antidiuretic hormone in the blood, the varying balance between
these two forces leading to a greater or lesser concentration
of the urine; i.e., to greater or lesser water reabsorption.
Such a view is entirely speculative, its chief advantage being
that it is not in conflict with too many facts. This subject is
discussed further on page 230.
BLOOD DILUTION DURING DIURESIS
Earlier investigators were divided on the question of
whether or not dilution of the blood occurred during water
*
Gilman (Amer. J. Physio!., vol. 119) has recently concluded that the
difference in water excretion in the experiments of Gamble et aP29 is due
to a difference in the water intake, due in turn to a difference in the osmotic
effect of urea, which penetrates all the tissues of the body, and other sub·t::nces which do not.
THE EXCRETION OF WATER
20 7
diuresis, but it is now clear that such dilution does occur,
although the changes are of a very small order of magnitude. Rioch,877.878 Bayliss and Fee/ 8 Margaria,1I811 Baldes
and Smirk 12 and Smirk 418 have shown that the administration of water in large quantities to dogs and man produces
a perceptible decrease in the protein content, electrical conductivity and total osmotic pressure of the plasma, and of
the iron, Hb and CI of whole blood. Apparently the decreased protein content is not the effective factor in diuresis,
since protein dilution occurs after the ingestion of isotonic
salt solution, which does not cause diuresis. Smirk 411 has
found the following average maximum changes in the blood
of rabbits which had received 40 cc. of water per kilogram
given by stomach:
Total solids
Haemoglobin
Cell volume
Plasma protein
Plasma chloride
-3.5 per cent
-2.0"
-I·9
"
-5. 2
"
-I.6
"
"
"
"
But in individual rabbits the degrees of blood dilution,
as estimated by various constituents, are not uniform and
may be in excess of, or less than, the dilution calculated
on the basis of an equal partition of the added water among
the tissues of the body. In Smirk's experiments none of the
dilution phenomena correlated consistently with diuresis i
on the contrary, the dilution of the blood was partly determined by the fact that diuresis was inadequate, or failed
entirely to occur. The rabbit is peculiar in that simple
water diuresis is frequently difficult to obtain 217 and Smirk's
results do not argue against the broad principle that dilu-
208
THE PHYSIOLOGY OF THE KIDNEY
tion of one or more components in the blood is the normal,
if indirect, stimulus to diuresis. But apart from experimental variability, it is clear now that there is no relationship between the rate of water excretion and the degree of
blood dilution that is present when the urine is formed.
Rioch was the first to note the fact, which has been confirmed by several subsequent investigators using different
methods, that the peak of greatest blood dilution occurs IS
to 20 minutes before the maximum diuresis in the rabbit,
guinea pig, rat, dog and man. 12 , 229, 412,413 This latent period
is still evident when water is given intravenously.S14 But
even allowing for the latent period, the rate of urine formation is not proportional to the degree of hydration of either
tissues or blood. m An almost normal diuretic response may
be obtained when the tissues or blood are dehydrated m
or when the total osmotic pressure of the blood is elevated
by salt administration.12 On the other hand, the reduction
of the total osmotic pressure by chronic salt deprivation
does not of itself induce diuresis. It would appear that it
is not the absolute value of total osmotic pressure, but a
relatively rapid change in that value which produces the
diuretic response. A series of observations from Baldes
and Smirk 12 on a subject who had drunk a liter of water is
shown in figure 28. The maximum fall in total osmotic pressure under these conditions is between 1.5 and 2.75 per cent,
and is reached about 25 to 45 minutes after water ingestion.
It has been suggested that the absorption of a diuretic
hormone from the gastro-intestinal tract is necessary to induce diuresis; this gastro-intestinal hormone was supposed
to act upon the pituitary gland, causing this in turn to excrete
THE EXCRETION OF WATER
20 9
a "diuretic" hormone. But hypotonic saline and, with
proper precautions, pure water administered intravenously
produce diuresis 148,230,814 so that it seems the postulation of
a gastro-intestinal hormone influencing renal function is superfluous.
10
w
I-
:::>
8
Z
~
"-
NACL
PER CENT
U
U
0.904
w
z
q
•,\
\
o
a:
• ....0
,
,,
0,
:>
'0
o~~~~__~~~~~~__~~~~~~~
30
60
90
120
150
210
MINUTES
FIGURE 28
Blood dilution and diuresis resulting from the ingestion of
cc. of water. The blood dilution is indicated by the change
in vapor pressure in terms of an equivalent NaCI solution. (After
Baldes and Smirk, 12.)
1000
The above evidence is convincing that a relatively abrupt
blood dilution is the remote physiological stimulus to water
diuresis, but whether the essential change is reduction of the
osmotic pressure, total base, ionic strength or of some other
feature can scarcely be decided as yet. We will now turn
to evidence which shows that blood dilution acts not directly
2 10
THE PHYSIOLOGY OF THE KIDNEY
upon the kidneys, but through the intermediation of the
pituitary gland.
l\.NTIDIURETIC HORMONE OF THE PITUITARY GLAND
. It has been known for two decades that lesions associated
with the pituitary gland on the floor of the third ventricle
may result in the production of diabetes insipidus, a condition in which there is a tremendously increased urine flow
(polyuria) and an insatiable thirst (polydipsia). The urine
flow may amount to 20 to 50 liters per day, and without
treatment the condition may persist for years. The polyuria
and polydipsia are both relieved by injections of pituitary
extracts which contain the antidiuretic hormone, so called
because in normal animals it prevents the typical diuresis
which ordinarily follows the administration of water. The
relationship of the pituitary gland to diabetes insipidus and
to the excretion of water have been the subject of numerous
investigations, many of which have led to contradictory results and theories, and it is only within the past few years
that certain fundamentals have emerged into the realm of
certainty. /
It is beyond the province of this book to discuss the full
history of this and related subjects. For the earlier work,
and for investigations dealing with the experimental neurology of the pituitary gland and related areas, reference may
be made to recent reviews. s1, 128, 182, 8~9, 429 A few longdebated points will be covered briefly in the following paragraphs.
It is typical of the history of this problem that the first
observations of the action of pituitary extracts upon urine
THE EXCRETION OF WATER
2II
formation, reported by Magnus and Schafer lllf in I90I, indicated (falsely, it will be seen) a marked diuretic action.
During the next fifteen years numerous investigators confirmed this, and it was not until 1913-1916 that the
characteristic antidiuretic action was first noted by Von
den Velden, 4&8a to be confirmed quickly by many investigators.2I2,80', 81'1, '21, "8b, 454. In 1 9 I 7 Motzfeldt 804 presented evidence that the diuretic action was a physiologically fallacious
phenomenon due to unsuitable methods of observation, but
it long continued to be accepted as of equal importance with
the antidiuretic action, and it is still not uncommon to find
reference to the "diuretic-antidiuretic" hormone of the
pituitary." There is, in fact, scant evidence for the existence
of a diuretic principle in any part of the pituitary gland,
and the essential action of the only renal hormone so far
isolated is an antidiuretic one. We will return later to
this alleged diuretic action, but throughout this entire discussion it should be kept in mind that ordinary pituitary extracts contain, besides the antidiuretic principle, considerable quantities of the vasopressor hormone, vasopressin, and
of the smooth-muscle stimulant, oxytocin. These have different effects upon the circulation, blood pressure, ureteral
tone, etc., of different animals 2~4 and their invariable admixture with the renal hormone complic3tes the study of the
latter.
Two general theories of the action of the antidiuretic
hormone have been proposed: that it acts extra-renally,
causing a redistribution of water between blood and tissues,
and that it acts locally upon the kidney.12B, 182,44:1 In mammals the evidence for the first theory is slight. Pituitary
2 12
THE PHYSIOLOGY OF THE KIDNEY
extract causes a change in the rate of water movement across
the skin of the intact frog,482 and various investigators have
noted changes in the composition of the blood following
pituitary administration, either with or without fluid, but it
appears that the latter are due to inhibition of urine formation, exaggerated dilution of the blood resulting from the
failure of diuresis to occur, or to profound vasomotor reactions. There has been no convincing demonstration of a
specific effect upon the organic or inorganic composition of
the plasma, and the distribution of water between blood and
tissues appears to be unchanged. 140, 188, 109, 258, 25~. 8~2. 843, ~1~, ~04
The antidiuretic hormone does not significantly delay the
absorption of water from the intestine 186, 280, m and it inhibits the diuresis produced by the intravenous injection of
water.81' It exerts its typical action in decerebrate animals 112 and to some extent in the heart-Iung-kidney/a1. ~49 in
which preparation the urine is typically dilute. Veroey ~~8
has shown that the diuresis normally observed in the heartlung-kidney is reduced if the blood is switched through the
head of a dog with the pituitary intact, but not if this gland
has been removed. From the above facts most investigators
have concluded that the hormone acts directly upon the
kidney.
The antidiuretic hormone is immediate and constant in its
action, which is best revealed by its effects upon the diuresis
following standard quantities of water. In adequate doses
it completely prevents diuresis, even after large doses of
water, and under its influence blood dilution may occur to
the point of producing hemolysis, and water intoxication is
readily obtained.142, 467 The excretion of water is delayed
THE EXCRETION OF WATER
21 3
for two tp ten hours, depending upon the dose of hormone
given. VThe essential mode of action in man and other
mammals appears to be the acceleration of the reabsorption
of water from the tubular urine, for it has no consistent
effect upon the rate of glomerular filtration. 51, 842, 891, 488
Such effects as have been noted upon filtration rate or renal
blood flow 169 are probably due to the action of vasopressin
or oxytocin. The hormone does not accelerate the reabsorption of water in the fish, frog or alligator, its action in this
respect being evident only in the mammals and to a lesser
degree in the birds:s_" • Reduction of glomerular activity in
the alligator and chicken 61 and in the pithed frog 5 may
perhaps be ascribed to contaminating vasomotor hormones.
The antidiuretic hormone induces a slight and variable
increase in the excretion of el, but apart from this, and
perhaps including this effect, its action on the excretion of
salts is so inconstant that one suspects it is non-specific.1S , 254, 828, 848, 879 But what "is most significant, it is incapable of accelerating the reabsorption" of water if the concentration of salts in the urine is very great, as was first
shown by Motzfeldt.804 This may be due to the limiting
concentration ceiling against which the tubules can reabsorb
water (page 203). The data of Nelson and Woods 811 on
mice would indicate that in this species the maximal N aCI
concentration reached under its influence is about 0.3 molar.
Returning now to the alleged diuretic action reported by
earlier investigators, we find that the observations were almost invariably made in anesthetized animals or in decerebrate animals which had received an anesthetic. The diuresis was of very slight magnitude and not reproducible,
21+
THE PHYSIOLOGY OF THE KIDNEY
and in many instances it consisted of an increase in urine flow
lasting over such a short period (I to 5 minutes) as to have
little meaning. It was frequently preceded by a period of
complete anuria. In explaining this phenomenon it is to be
noted that in anesthetized animals the urine flow is very low
and the urine is very concentrated; there are reasons for
believing that this oliguria is itself partly due to increased
secretion of the antidiuretic hormone,lll but in addition it
must be recognized that in such animals there is likely to be
hyperglycemia, hemoconcentration and oligemia, and the
conditions of the circulation with respect to vasomotor tone,
venous pressure, etc., are most likely to be highly abnormal.
In so far as glomerular filtration occurs at all, salts, urea,
glucose, etc., continue to pass into the filtrate, and under the
existing oliguria are maximally or nearly maximally concentrated by tubules. When moderate doses of pituitary
extracts containing vasopressin and oxytocin are given to
such animals an increase in both blood pressure and renal"
blood flow may occur 180, 241 and smaller doses cause constriction of the efferent glomerular arterioles,s88 all of these
effects tending to increase the rate of filtration; a slight decrease in the reabsorption of CI or other salts may add to
the already maximal concentration of the urine; and frequently contraction of smooth muscle in the ureters may
force the extrusion of a small quantity of urine: in short,
these and other effects may produce a momentary and slight
increase in urine flow. It appears that such non-specific
effects have been responsible for the alleged" diuretic" action of pituitary extracts. Essentially this explanation has
been given by Melville 208 and Macdonald/4s and implicitly
THE EXCRETION OF WATER
21 5
assumed by others to account for the variable and uncertain
action of such extracts in anesthetized animals.
It has also been asserted, erroneously we think, that the
antidiuretic hormone has no influence upon the" normal"
excretion of urine. But Motzfeldt,804 who was perhaps the
first to make systematic and well controlled observations in
this problem, found that the rate of urine excretion in
normal, unanesthetized rabbits might be reduced markedly
for several hours. He found it was impossible to produce
anuria in this way, the antidiuretic action being absent or
only slightly marked when the urine flow was initially very
low or during salt diuresis. Similar conclusions may be
reached from Buschke's G8 observations on dogs and Poulsson's 848 observations on men; the hormone produces at most
a slight decrease in urine flow if the urine is already concentrated, as might be expected in theory.
Similarly it has been shown repeatedly that the hormone
.will not prevent salt diuresis; 8, ~, 79, 262, 298, 811 this is consonant with the view that an excess will not effect the further
concentration of an already concentrated urine.
Nelson 809 has recently demonstrated that pituitary extract has a diuretic effect in rabbits anesthetized with morphine and urethane and already rendered diuretic by the
rapid intravenous infusion of sucrose or by phlorizin. The
diuresis is paralleled by an increased rate of glomerular
filtration and by an increased excretion of chloride.
These results are difficult to interpret; glomerular activity in the rabbit is different from what it is in dog and
man in relation to ordinary diuresis (page 68), and the
glomerular action of vasopressin and oxytocin in this animal
2I6
THE PHYSIOLOGY OF THE KIDNEY
are undetermined; moreover the above experiments include
the complication of both osmotic diuresis and anesthesia.
In the normal rabbit pituitary extract exerts a typical antidiuretic action.142 Its effect upon glomerular filtration in
the normal rabbit has not been examined. Nelson and
Woods 811 have also shown that excessive doses may have
less effect than moderate doses, and explain this as due to
the increased excretioJ} of chloride. But their experiments
must have been complicated by the profound vasomotor
effects of vassopressin .
..J' Motzfeldt 804 found that various organic bases (~-imada­
zolylethylamine and ~oxyphenylethylamine), possessing
sympaticomimetic action, also check diuresis, while adrenalin
is without significant effect.cr. 98, 496,488,497
Reference may be made here to a theory advanced by
Molitor and Pick, that pituitary extract acts upon a hypothetical water center in the hypothalamus, which in turn by
nervous or humoral influences controls the distribution of
water between the plasma and tissues. The experiments
upon which this theory is based were performed mostly
upon anesthetized animals. They have been examined and
criticized by Theobald,438 who concludes that there is no
evidence for the existence of a water center in the sense of
Molitor and Pick, and that the antidiuretic hormone acts
directly upon the kidney.
The antidiuretic hormone is customarily associated with
the intermediate and posterior portions of the pituitary
gland, but it also occurs in the anterior portion, although
in lesser quantities. Downes and Richards 88 and Kamm
and his co-workers 218 have prepared it free of vasopressor
THE EXCRETION OF WATER
21 7
action and it appe~rs therefore to be erroneous to identify
it with pitressin or vasopressin, the pressor principle of the
posterior lobe, as is commonly done.1s1, 191, 200, 29B In aqueous
solution it is ultrafilterable, but it is adsorbed on some colloidal constituent in the blood, from which it is liberated
(or preferentially adsorbed by the tubule cells) in the kidney. It is excreted in part in the urine, but within a certain
range the amount excreted is highly independent of the concentration in the blood, the excreted fraction paradoxically
decreasing as the amount injected is increased.9 ,184
Lastly, it should be noted that denervation of the kidney
does not influence its action. 68, no, 2S0, 818, 888, U8
THE SITE OF WATER REABSORPTION
Investigators have variously considered the proximal
tubule, the distal tubule and the collecting ducts as the site
of reabsorption of water. In 1909 Peter S2B suggested that
the thin segment was largely responsible for this operation,
and attempted to correlate the length of the thin segment in
the kidneys of various mammals with the concentration of
the urine. Later Crane,80 recognizing that hypertonic urine
is formed only in the mammals and birds where the thin segment is present, suggested that here was where the reabsorption of water against the osmotic pressure of the urine occurred. If such is the case, however, it does not preclude
some reabsorption in other parts of the tubule. The observations of Walker and Hudson 4B8 on phlorizinized frogs
show that some water is reabsorbed in the proximal tubule
of these animals, and this is probably also true in mammals.
In fact, sections of kidneys fixed during the excretion of
2I8
THE PHYSIOLOGY OF THE KIDNEY
ferrocyanide, Hb, etc., reveal that some water reabsorption
does occur in the proximal tubule. The data do not permit
any exact description, but it is in the thin segment that
marked concentration of urinary constituents first occurs,
and it appears that a slight further concentration is effected
in the distal tubule. 24, 80, 100, 101,185, 138,187,208,4.16
It seems unlikely that hypertonic urine is formed in the
proximal tubule of mammals j and even if electrolytes are
not reabsorbed until the distal tubule, as in the Amphibia,461
isotonic reabsorption of water in the proximal is no doubt
made possible by virtue o.f the reabsorption of glucose, etc.
Since Burgess, Harvey and Marshall ll1 found that accelerated water reabsorption is induced by the antidiuretic
hormone only in the birds and mammals, and since the thin
segment of the loop of Henle is present only in the mammals
and in a small fraction of the tubules of the bird, they suggest that this thin segment is the site of the hormone's action.
The tendency to reabsorb water, as well as perhaps all
other tubular activity, is suppressed in the perfused kidney
by lowering the temperature. 2D
PHYSIOLOGICAL REGULATION OF WATER EXCRETION
The question of whether or not the plasma concentration of the antidiuretic hormone varies between normal and
diuretic conditions has been a difficult one to answer because
of the absence of a suitable method to measure it. But that
such is the case is strongly indicated by indirect evidence.
Klisiecki, Pickford, Rothschild and Verney 229 have exteriorized the ureters of a dog so that the urine from each kidney could be collected separately. They have observed that
THE EXCRETION OF WATER
21 9
the response of the two kidneys during water diuresis is
generally closely parallel, though one kidney may on occasion lag behind or run ahead of the other throughout the
diuretic response. The denervation of one kidney does not
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Left. Simultaneous diuretic response of normal and denervated
'kidney in dog to water per os. Right. Effect of pituitary extract
subcutaneously. (After Klisiecki, Pickford, Rothschild and Verney, 229, 230.)
affect the diuretic response in that kidney as compared with
the control. It has been pointed out that denervation of the
kidneys does not influence the action of the antidiuretic hormone. Tw~ experiments taken from the work of the above
investigators, illustrating these two points, are given in
figure 29. Vigorous muscular exercise momentarily inhibits
water diuresis, and here again the intact kidney and dener-
220
THE PHYSIOLOGY OF THE KIDNEY
vated kidney respond in the same manner, as shown in
figure 30. Theobald and Verney 489 have shown that afferent
nerve stimuli, which inhibit diuresis, also affect the intact
and denervated kidney in the same manner. From these
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facts Verney and his co-workers conclude that the control of
water excretion is effected by some humoral factor, and
more particularly by variations in the concentration of the
antidiuretic hormone in the plasma, since other changes in
THE EXCRETION OF WATER
221
the composition of the latter brought about by exercise and
afferent nerve stimulation must be very slight.
It may be supposed that at low water loads the concentration of the hormone in the plasma is high, and that
at high water loads this concentration is low or possibly
zero. Pickford 829 has shown that when pituitary extract
is administered intravenously in constant doses the degree
of inhibition of water excretion is roughly inversely proportional to the existing water load in the body, which result
is consonant with the belief that the total effect is due to
the summation of the endogenous and exogenous moieties
of hormone.
l.Ftom all considerations, Verney and his co-workers conclude that the facts are best interpreted as follows: the
excretion of water is normally controlled by the presence in
the blood of the antidiuretic hormone of the pituitary. The
secretion of this hormone is itself controlled, through the
intermediation of the nervous system, by the" concentration of water in the blood and tissues." Evidence previously cited indicates that the hormone acts by accelerating
the reabsorption of water from the tubular urine, possibly
chiefly at the thin segment. During water diuresis the quantity of the hormone in the blood is decreased, and during
exercise, increased, under both circumstances a certain time
being required to obtain maximal effects. The delay between
maximum hydration of the body and maximum diuresis is
attributable to the time required for the hormone to disappear from the blood. This delay time is reduced in a diuretic
animal, due to the shorter time required for the water-load
to reach the level requisite for inhibition of pituitary secre-
222
THE PHYSIOLOGY OF THE KIDNEY
tion; and in a dehydrated animal the delay time IS mcreased, due to the longer time required for the higher concentration of hormone in the blood to fall to the level at
which water excretion is released.
It is in agreement with this view that Marx 283 and
others 197 have been able to check diuresis in dogs by infusing the blood of other dogs whose urine flow was normal,
while the blood of diuretic dogs does not affect the urine
flow of non-diuretic dogs. Gilman and Goodman 141 have
demonstrated that the urine of dehydrated rats and dogs
contains an antidiuretic substance which in its general properties resembles the pituitary hormone. The urine of hypophysectomized or diuretic animals does not show this antidiuretic activity. Melville 294 has recently demonstrated
that it is possible to extract what appears to be the pituitary
antidiuretic hormone from the blood by appropriate methods; when such extracts are given intravenously to dogs
with explanted ureters, they have an unquestionable antidiuretic action.
From quantitative studies Hart and Verney 173 conclude
that spontaneous diuresis in man is due to a fall in the concentration of the antidiuretic hormone of less than I part
of substance in 15,000,000,000 parts of plasma.
There are, however, certain difficulties in the way of
accepting the above view, at least in its simplest form.
Fee 112, 113 and Newton and Smirk,315 taking special precautions to avoid the effects of anesthetics, have shown that the
urine flow may remain at a low level for hours in decerebrate dogs and cats from which the pituitary has been removed. The enteral administration of water to such prepa-
THE EXCRETION OF WATER
223
rations may lead to a typical diuretic response. Diuresis
may be elicited several times and it invariably shows an appreciable delay after maximum hydration; it lasts for a
considerable period and then the urine flow returns to very
low levels, the greater portion of the administered water
being recovered during the diuresis. The urine flow increases from low values to 1.0 to 2.0 cc. per minute, a rate
of flow which corresponds well with water diuresis in the
normal animal. The diuretic urine is dilute iIi CI and the
diuresis can be inhibited by pituitary extract. It is difficult
to understand why polyuria should be absent for hours after
hypophysectomy, why the urine flow should increase after
giving water, not once but repeatedly, if the presence of
the antidiuretic hormone in the blood is the only factor in
the regulation of water excretion. Newton and Smirk believe that the pituitary gland and its hypothalamic connections " are not indispensable parts of the mechanism controlling water diuresis."
But the hypothesis of pituitary control as formulated by
Verney and his co-workers appears to explain most of the
known facts very well. It has been tacitly suggested or accepted by several workers, although it reaches definitive
form only in the hands of the Cambridge investigators.
Whatever modifications this hypothe~is may suffer in the
future, its present form is adequate to explain several interesting phenomena, among which are the existence of
conditioned reflexes influencing diuresis, the action of anesthetics, and the diuresis associated with lesions in the hypothalamus or the pituitary stalk.
224
THE PHYSIOLOGY OF THE KIDNEY
CONDITIONED REFLEXES
Marx 282 and others have shown that diuresis can be induced in man by hypnotic suggestion. It has further been
shown that dogs which are repeatedly given water under
special circumstances may respond to a conditioned stimulus,
when this is applied unaccompanied by water, by a marked
diuresis, even in a denervated kidney; B4, 66, B8, 148, 168-284
and Eagle 98 has shown that the normal diuretic response
to water may be inhibited by a conditioned reflex. Although the higher centers of the nervous system are themselves not necessary for either the induction of diuresis or
the action of the antidiuretic hormone,1l2, 118, 210,448 one must
suppose that the intermediate and posterior lobes of the
pituitary gland are under nervous control, since they have
abundant connections with the hypothalamus. It is therefore possible that it is some remote portion of the central
nervous system, rather than the pituitary gland itself, which
is acted upon by changes in the composition of the blood
during water diuresis, and that through these central connections changes in the secretion of the hormone may be
effected by changes in the activity of the cerebral associative
tracts.
ANESTHESIA
It is now well established that anesthetics may have a
profound effect upon the excretion of water, the effect varying with the anesthetic, the depth of anesthesia and the
animal used. 88 , 95, '98, :111, 112, 188, 252, 488, 484 But in general the
diuretic response to large quantities of water is almost entirely absent when morphine or non-volatile anesthetics have
THE EXCRETION OF WATER
225
been administered, and as long as they are still present in the
body. Though absorption from the gastro-intestinal tract
may be delayed by the anesthetic, Heller and Smirk 187 have
shown that this does not account for the inhibition of diuresis, whifh is still present when water is given intravenously.814, Fee 111 has suggested that in the normal animal
there is some mechanism that inhibits the secretion of the
pituitary hormone, and that under anesthesia this secretion
is released. It seems not unlikely that the oliguria observed
in water intoxication 119, 217 may also be due to the release
of excessive antidiuretic hormone. But in addition it must
be recognized that anesthesia has marked effects upon the
composition of the plasma,827 tending to produce hemo-concentration, oligemia and other abnormal changes.
It is unfortunate that many of the early observations on
renal function were made upon animals in a state of anesthesia. The use of morphine and other anesthetics has
vitiated many observations' in physiology, but in no field has
it led to more confusion than in the present one. It is not
inappropriate to remark that many investigators have coneluded that anesthetized animals are so highly abnormal that
the results obtained on them have very little bearing upon
the normal, and they are learning to make their observations
by methods which can be used upoq.. unanesthetized animals, without pain or excessive psychical or physiological
disturbance.
EXPERIMENTAL POLYURIA
Although diabetes insipidus and experimental polyuria
have long been associated with lesions in or near the pituitary
226
THE PHYSIOLOGY OF THE KIDNEY
gland, the location of the most effective lesions is still a subject of dispute. 22s • 2GB We tentatively accept here the description of Fisher, Ingram, Hare and Ranson. llG According to
these investigators the only hypothalamic lesions that will
give a permanent polyuria are those which destroy the supraoptic nuclei or the tractus supraoptico-hypophyseus leading
to the gland, or the pars posterior and pars intermedia of
the gland itself j i.e., those lesions which separate the gland
from its connections with the supraoptic nucleus, or which destroy the chief glandular site of secretion of the antidiuretic
hormone. The neural relations of the pituitary gland and
the anterior hypothalamus are illustrated in figure 31.
It may be safely accepted that diabetes insipidus is due to
a deficiency of the antidiuretic hormone, since no matter how
caused, it can be relieved by the administration of this hormone. It may also be accepted that the polyuria is the
primary feature, the polydipsia being entirely a secondary
consequence. ST8 But one puzzling fact remains, and that is
that the removal of the entire pituitary gland fails to produce
consistently the permanent, marked polyuria which is typical
of diabetes insipidus. Earlier investigations were complicated by the fact that in some species posterior pituitary
tissue may extend upward into the floor of the hypothalamus,
but even where it has been demonstrated that the removal of
glandular tissue has been complete, polyuria fails to develop.
This condition has been produced more consistently, perhaps,
by injury to the supraoptic tract or to the posterior lobe itself.
This paradoxical situation has seemed to many investigators
a substantial argument against the theory that deficiency of
the antidiuretic hormone is solely responsible for the poly-
THE EXCRETION OF WATER
227
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THE PHYSIOLOGY OF THE KIDNEY
uria. But Richter 874 has recently shown that if the anterior
lobe is left intact when the posterior and intermediate portions of the gland are removed, polyuria results with impressive constancy. It would seem that the essential factor is a
lesion severing the connection between the posterior lobes
and the supraoptic nucleus in the hypothalamus, provided
that at least some of the anterior lobe remains. Richter
points to two possible, explanations for the role of the anterior lobe in the induction of polyuria: this lobe might itself secrete a diuretic hormone, or it might be necessary for
the maintenance of other metabolic activities which are themselves essential to the intake or excretion of large quantities
of water.
The evidence in favor of the first of these suggestions is
as yet unconvincing. Bourquin 44b reported the extraction of
a substance from the mammillary bodies of dogs which had a
diuretic action and which was apparently present in larger
quantities in dogs suffering from experimental diabetes insipidus than normal animals. It also appeared to be present
in the blood and urine of polyuric dogs. However, the
diuresis produced by these extracts was so small, in comparison with water diuresis or diabetes insipidus, that its
significance is questionable. Teel,487 'Barnes, Regan and
Buena,18 Biasotti 28 and others have also reported diuresis
in animals receiving injections of anterior pituitary extracts,
but it seems likely, as Barnes, Regan and Buena suggest,
that the diuresis is non-specific, i.e., due to changes in general
or inorganic metabolism. * Ingram and Barris 207 find in
*
It would seem that for the demonstration of a diuretic principle
from any source one may demand that it consistently and reproducibly
THE EXCRETION OF WATER
229
cats anesthetized with pentobarbital that electrical stimulation of the pituitary at the juncture of the intermediate and
anterior lobes may produce a marked, rapid diuresis without
glycosuria, but the possibility that diuresis might be due to
decreased secretion of the antidiuretic hormone from the
intermediate lobe was not considered. It is suggestive that
Mahoney and Sheehan 2GB find that the polyuria caused by
occlusion of the pituitary stalk is abolished by thyroidectomy,
and re-established by administration of thyroid gland, an
observation which has been confirmed by White and Heinbecker .4BO The explanation of this fact is obscure, though it
cannot be taken to mean that the thyroid itself exerts a
diuretic action, since total thyroidectomy has no demonstrable effect upon the water exchange of the otherwise normal
dog, nor does the administration of thyroid produce polyuria in dogs from which either the entire pituitary or the
pituitary and thyroid have been removed. White and Heinbecker believe that they have prepared a diuretic principle
from the anterior pituitary, for the action of which thyroid
is necessary. In view of the widespread participation of the
anterior pituitary in the regulation of other endocririe and
metabolic functions, and until the effects of these extracts
upon general metabolism and salt and water equilibria are
clarified, it is perhaps best to avoid the terms" diuretic principle," because of the implications that such a principle is
elevate the urine flow, as determined by catheterized specimens in well
controlled experiments, from moderate, rather than very low levels; that the
diuresis should reach a rate at least comparable to that observed after a
moderate dose of water, and that it should persist for a period of at least
30 minutes. Urine-collection periods of" either a few minutes, or 24 hours,
duration can scarcely be held to have a meaning in this problem.
23 0
THE PHYSIOLOGY OF THE KIDNEY
specific, that it participates in a positive rather than permissive manner in ordinary diuresis and in diabetes insipidus,
and that it acts in opposition to the antidiuretic principle of
the posterior portion of the gland.
In contrast to the fact that diabetes insipidus is by no
means rare, only a few instances have been reported in which
there was presumably over-secretion of the antidiuretic hormone.lII8, 828
~n
accepting the hypothesis that the variable concentration of the antidiuretic hormone in the blood regulates the
reabsorption of water under ordinary conditions, it must be
recognized that this hypothesis fails to explain one very
important fact. This is, that under no known condition,
either in extreme water diuresis or in diabetes insipidus, does
the rate of water excretion rise to the level of the rate of
glomerular filtration. For example, in man the rate of
filtration is about l20 cc. per minute, whereas the maximum
urine flow in water diuresis is about 20 cc. per minute. This
is close to the figure usually reported in severe diabetes insipidus, in which condition the rate of urine excretion cannot markedly be increased by the ingestion of water. 114 It
is clear that in the normal kidney about four-fifths of the
water in the glomerular filtrate are reabsorbed under any
and all circumstances. We might designate this moiety,
which is always reabsorbed, and which amounts to about
lOO cc. per minute, as the obligatory reabsorption. In addition to this obligatory reabsorption is the facultative reabsorption of the remaining 20 cc. of water. It is by variations in this facultative reabsorption, under the influence of
THE EXCRETION OF WATER
23 1
the antidiuretic hormone, that the water content of the
plasma and tissues is regulated.
It will be recalled that the capacity to excrete a hypertonic urine is present onlYln the mammals, where it has been
evolved independently of the capacity to excrete an isotonic
or hypotonic urine, an operation which is carried out in all
vertebrates. The excretion of a hypertonic urine is associated with the antidiuretic hormone, this hormone apparently
producing the hypertonic urine, so to speak, by accelerating
the tubular reabsorption of water against the osmotic gradient between the blood and urine. It seems highly probable
that the reabsorption of water to produce a hypertonic urine
occurs only after the bulk of the osmotically active substances in the glomerular filtrate have been reabsorbed, and
that the site of the former operation in the tubule is distinct
from, and distal to, that of the latter. One might suppose
that the first steps in the tubular elaboration of the urine are
the reabsorption of glucose and most electrolytes; this reabsorption is accompanied by, or at least permits, the isotonic reabsorption of a great fraction of the water in the
glomerular filtrate. We may, for the sake of discussion,
suppose that the total waste products (i.e., those which will
undergo no reabsorption) account for 2 per cent of the
osmotic pressure of the plasma. After the removal of
all the other substances the bladder urine can then be concentrated tenfold, and still have only one-fifth the osmotic
pressure of the plasma. With a filtration rate of 120 cc. per
minute, this would permit 108 cc. of water to be reabsorbed,
leaving 12 cc. of still very dilute urine to be excreted. We
23 2
THE PHYSIOLOGY OF THE KIDNEY
may imagine that this is the circumstance in extreme diabetes
insipidus or at the peak of water diuresis when the concentration of the antidiuretic hormone in the plasma is zero.
The second step in the elaboration of the urine we may
imagine to be the further and independent reabsorption
of water under the influence of the antidiuretic hormone,
whereby a hypertonic urine is formed. If the maximal
osmotic concentration of the urine is taken to be 5 times the
osmotic pressure of the blood, the tubular urine may now
be concentrated a further twenty-fivefold; that is, 11.5 cc. of
additional water may be reabsorbed, leaving 0.5 cc. of water
to be excreted. This we may take to be the circumstance in
a normal individual under conditions of extreme dehydration, or after the administration of large doses of the antidiuretic hormone.
In this view the obligatory reabsorption of a large fraction of the water in the glomerular filtrate may be identified
with, in the sense that it is made possible by, the reabsorption
of glucose and electrolytes from the tubular urine. One
might suppose that it occurs early in the tubule, though not
necessarily at the same point, as the reabsorption of glucose
and electrolytes. * It is perhaps not advancing the hypothesis
too far to suggest that this process of water reabsorption
*
Reabsorption of Bel to maintain a UjP ratio of 1.0 occurs in the
proximal tubule of the frog, and complete reabsorption of Bel occurs in
the sculpin 162& in which only the proximal segment is present. There seems
to be ho evidence conflicting with the view that in the mammal a great part
of the water might be reabsorbed in the proximal tubule, along with glucose
and Bel, before osmotic concentration is effected in the thin segment. In
this view the distal tubule would be concerned with operations most economically performed on the concentrated urine, such as regulation of
H ion concentration, etc.
THE EXCRETION OF WATER
233
was evolved with, and entailed by, the evolution of glomerular filtration, which itself entailed the tubular conservation
of water, glucose and electrolytes. The facultative reabsorption of water, on the other hand, may be identified with the
production of a hypertonic urine, under the stimulus of the
antidiuretic hormone; it would appear to be physiologically
and anatomically independent of the obligatory process.
An earlier comment may be recalled in this connection: that
the degree of concentration of the urine (we would now say
in this facultative reabsorption) may be determined by the
balance of forces between the antidiuretic hormone, on the
side of the blood, and the osmotic pressure or ionic strength,
or both, on the side of the urine. But again this view is entirely speculative, and we would repeat a remark made in an
introductory chapter. The history of renal physiology has
erred, more often than not, by attempts at over-simplification. The problems of water and salt excretion appear to
be e~tremely complex, and especially liable to this danger •
....summarizing the still very conflicting evidence in the problem of water regulation, we would begin with the demonstrated action of the only hormone so far separated from the
pituitary gland which has a specific renal action. This hormone is "antidiuretic," in that it prevents the normal diuretic response to water. It acts dirt:!ctly upon the kidney,
causing an accelerated reabsorption of water from the glomerular filtrate. In its absence about four-fifths of the water
in the glomerular filtrate are reabsorbed isosmoticallYi it is
by the variable reabsorption of the remaining fifth, under the
influence of this hormone, that the urine is raised to levels
hypertonic to the blood, and that the water content of the
234
THE PHYSIOLOGY OF THE KIDNEY
plasma is regulated. The secretion of the hormone is under
neural control in which the cerebral cortex may participate
(hypnosis and conditioned reflexes) and the oliguria characteristic of anesthesia is presumably a release phenomenon.
A deficiency of the hormone is responsible for diabetes insipidus. The hormone is incapable of reducing the urine flow
if the urine is very concentrated or during salt diuresis.
When the urine flow is small and the urine is concentrated a
diuretic effect may be produced by the administration of pituitary extracts containing the vasopressor and oxytocic principles, but no true diuretic action is possessed by the antidiuretic hormone itself.
Whether or not the reabsorption of water by the tubules
is amenable to physiological control by changes in the composition of the plasma, apart from the antidiuretic hormone,
is not known. N or is it known how or where changes in the
composition of the plasma act to bring about changes in the
secretory activity of the pituitary gland. During water
diuresis the plasma as a whole is diluted, and presumably
this dilution may serve as a stimulus either to the gland itself, or to some central nervous receptor in or connected with
the hypothalamus, but it remains to be determined what
particular feature of plasma dilution (total osmotic pressure, total base, ionic strength, etc.) constitutes the effective
stimulus.
For reasons as yet undetermined the ablation of the entire pituitary gland does not consistently produce permanent
polyuria and it appears that the continued function of the
anterior lobe is essential for this result.
xx
DIURETICS
THE term diuretic is used to describe any agent which will
produce an increased excretion of water by the kidneys.
Where there is circulatory failure, drugs (digitalis) or
other remedial measures which improve cardiac action or
arterial pressure may restore deficient renal function and
thus indirectly lead to the excretion of any excess water, salt,
etc., which may have been retained in the body. Though
there is no objection to speaking of such drugs as diuretics,
this usage does not imply a specific action, so far as renal function is concerned. We will confine this discussion to those
substances which produce diuresis in the normal animal. In
theory, such substances might act (I) by changing the composition of the plasma, (2) by increasing the rate of filtration, or (3) by decreasing the rate of water absorption in
the tubules. In reference to (I) it has frequently been
suggested that some diuretics act by altering the "water
binding" power of the plasma proteins, or by causing a shift
of electrolytes and water between plasma and tissues, but
the evidence for this mode of action is meager and the possibility may be set aside as unproved.
In regard to (2), an increased filtration rate might be
brought about, apart from an increase in systemic circulation rate or pressure, by increasing the number of active
glomeruli or the number of active capillary loops in indi-
23 6
THE PHYSIOLOGY OF THE KIDNEY
vidual glomeruli, or by an increase in the glomerular pressure. The latter could result from either dilatation of the
afferent arterioles or constriction of the efferent arterioles.
Whether the action of any diuretic is primarily glomerular
will be discussed below.
Decreased reabsorption of water might be brought about
by a decreased tendency on the part of the tubules to carry
out this operation, either in consequence of some direct action by the diuretic on the tubules, or indirectly by interfering with, or inhibiting the secretion of, the antidiuretic hormone. Or it might be the result of obstruction of water
reabsorption by virtue of the osmotic opposition of the constituents of the urine. The last-named mechanism presents
perhaps the simplest features of all the possibilities mentioned, and will be discussed first.
OSMOTIC DIURESIS
When substances which are not reabsorbed by the tubules
to any considerable degree are injected intravenously, or, if
they are absorbed from the gastro-intestinal tract, given by
mouth, the rate of water excretion increases, rises to a maximum, and decreases again when the concentration of the
diuretic agent in the urine falls to negligible values. Urea,
sucrose, sodium sulphate and other salts act in this manner.
There is no reason to believe that, in mammals at least; the
diuresis 'is due to anything more than the opposition which
these substances offer, by virtue of their osmotic pressure or
ionic strength, to the reabsorption of water. It is clear,
however, that the resulting diuresis will be determined by
the balance of forces between the concentration of the urine
DIURETICS
2.37
and the tendency of the tubules to reabsorb water, and that
the latter may be inconstant in consequence of variations in
the secretion of the antidiuretic hormone. It is not to be expected, therefore, that the diuretic response produced by any
osmotic agent will necessarily be constant from time to time.
To what extent the diuresis caused by acidifying salts such
as NH~CI and CaCl2 is a simple osmotic one, or due in part
to subtle changes in the composition of the plasma, is unknown.
XAN:rHINE DIURETICS
Caffeine, theobromine and theophylline (thephyldine)
have a marked diuretic action in the rabbit, a moderate action
in man, a very slight action in the dog and no action in the cat,
and these compounds may fail to produce diuresis even in the
rabbit if the animal is markedly dehydrated.82 It can be
questioned if they merit their reputation as true diuretic
agents. The mechanism of their action is complicated by the
fact that they profoundly influence both the systemic circulation, and the central nervous system. Though it has been
shown repeatedly that an increased renal blood flow may
accompany xanthine diuresis, Richards and Plant 863 demonstrated that caffeine increased the output of urine in the
perfused rabbit's kidney when the rate of blood flow was
kept constant. They concluded that the increased blood flow
was not essential to diuresis. Moreover, since caffeine acts
upon the isolated perfused kidney, the action cannot be due
to a shift of electrolytes from tissues to plasma, as some have
suggested. The conclusion that xanthine diuretics act locally
in the glomeruli, increasing the filtration rate by one or
another method, has been reached by several workers whose
23 8
THE PHYSIOLOGY OF THE KIDNEY
experiments were inadequately controlled or executed. Caffeine diuresis in the heart-lung-kidney has been so interpreted <In but it is doubtful if the results obtained on this
preparation are applicable to the normal animal. Davenport et al.,88 using moderate doses of theophylline in dogs,
and Chrometzka and Unger,TO were able to obtain diuresis
with no increase in creatinine clearance, and thIs and other
xanthine derivatives have no consistent influence on the urea
clearance.l2l , 821 Using the thermostromuhr method, Walker
et al.<l88 found that theophylline may produce an increased
renal blood flow and creatinine clearance in unanesthetized
rabbits and dogs, but the diuresis always outlasted the blood
flow and did not correlate consistently with the increased
rate of filtration. The urine excreted during xanthine diuresis is dilute. These diuretics are said to depress the
plasma phosphate and decrease its excretion 41 and may cause
an increased excretion of chloride. l2l
Bartram U injected small doses of various xanthine diuretics into the renal artery of anesthetized dogs, and found
that caffeine, theobromine and theophylline produced bilateral diuresis, while theocin had no effect on the injected
kidney (theocin is a synthetic brand of theophylline). He
concluded that the action of the first group was in part extrarenal. Against this conclusion is the fact that caffeine and
theophylline induce an increased urine flow in the perfused
kidney,888, 4G1 although here the effects upon the glomerular
apparatus have not been ruled out. It may be concluded
that, although the xanthine derivatives tend to increase the
filtration rate, either by increasing the systemic circulation
or by local action of the glomerular apparatus, this is not
DIURETICS
239
an essential factor in their diuretic action, which is to be attributed to decreased reabsorption of water. But it is undetermined whether or not the decreased reabsorption of
water is wholly the result of a direct action on the tubules.
It should be remembered that in the unanesthetized animal
caffeine in particular, and to a lesser extent the other xanthine
derivatives, have a marked excitatory effect upon the central
nervous system, and it is conceivable that part of their action
is due to a diminished secretion of the antidiuretic hormone.
Much remains to be done in clarifying this problem.
MERCURIAL DIURETICS
All soluble mercury compounds tend to produce some degree of diuresis. Among the organic derivatives some are
more potent than others, the diuretic activity apparently
being correlated with differences in the solubility of the
salts.l17 The fact that, per unit of mercury, ionized compounds are much more active than un-ionized compounds
suggests that the action of all of them is due to mercury
ions.,z8 The action of the mercurials is definitely augmented by the simultaneous administration of acidotic salts,
particularly NH,CI zzo and although acidotic salts themselves tend to produce diuresis, the combination with organic
mercurials appears to be a real syner-gism.1T8
It has been suggested frequently that the action of the
mercurial diuretics is extra-renal, but there is no convincing
evidence that such is the case. On the centrary, by crossed
circulation experiments Govaerts liT has shown that once
diuresis is induced in a kidney by novasurol, perfusion with
normal blood does not check it, which indicates a local ac-
240.
THE PHYSIOLQGY QF THE KIDNEY
tion. This conclusion is supported by the facts that the mercurials act on the isolated kidney 118 and that small doses of
salyrgan and novasurol, when injected into the renal artery
of anesthetized dogs, produce marked diuresis on the injected side with no effect on the other.14 Salyrgan does not
increase the filtration rate in man 8D or dogs,86,8D1 nor the
standard urea clearance: 121, 821 nor does it affect the renal
blood flow in the do.g in any constant manner.88D, 468 It may
be concluded that the mercurials act locally in the kidney by
reducing the tubular reabsorption of water.
Various investigators have found that the excretion
o.f chloride is markedly increased during mercurial diuresis,cr. 121,800,889 and in fact the concentration o.f chloride
in the diuretic urine is such as to indicate that the salt itself
may promote the diuresis by its osmotic effect. Every form
of diuresis tends to sweep considerable salt out of the body,
to. lower the total base of the plasma and to. deplete the
plasma BReOa, but it appears that the mercurial diuretics
are particularly active in this respe·ct, for the chloride content
of the urine may rise at the peak of diuresis to a level above
that of the plasma. It is not surprising, therefore, that excessive mercurial diuresis may lead to profound physiological
disturbances, apparently due to depletion of water and
NaCl, rather than mercury poisoning. 840 The excretion of
water may be so marked as to perceptibly reduce the blood
volume.10D
XXI
THE ROLE OF THE RENAL NERVES IN
URINE FORMATION
THE kidney receives a rich supply of autonomic nerves, said
to be second in bulk only to the adrenal gland. Most of
these nerves are sympathetic, arising from the 4th dorsal to
the 4th lumbar nerves, although the most important segments functionally in the dog appear to be the last four
dorsal segments. Minor and rather variable fibers are also
derived from the vagus. A combination of these fibers from
the splanchnic and abdominal ganglia makes up the renal
plexus, a network lying along the renal artery from the
aortic plexus to the hilum, from which fibers enter the kidney with the renal vessels and terminate along the afferent
and efferent arterioles and between the cells of the renal
tubules. Some of the preganglionic sympathetic fibers undergo synaptic junction in the lateral ganglia, others in the
colateral ganglia, and still others in the kidney itself, and it
is impossible at the present time to distinguish any segmental
or localized pattern in the thoracico-Iumbar: renal innervation. There are also afferent fibers, at least from the renal
pelvis and ureters, some of which on excitation give rise to
renal pain and may cause anuria by reflex vasoconstriction.48. 187
It has long been known that changes in the renal blood
flow can be brought about by excitation of the renal nerves,
_242
THE PHYSIOLOGY OF THE KIDNEY
and it has frequently been suggested that these nerves also
control the specific excretion of various substances. That
the kidney can function without neural connections has been
amply demonstrated. It has been removed completely and
re-implanted, and, after removal of the other kidney, shown
to be adequate for the maintenance of life for apparently
indefinite periods. But in spite of the physiological sufficiency of the denervated kidney, the possibility remains that
the renal nerves may play some part in the finer regulation of
urine formation.
SPECIFIC NEURAL FUNCTIONS
Since the secretion of saliva, sweat and gastric juice are
indubitably under neural control, the possibility of neural
mediation in tubular activity cannot be overlooked. The
most notable feature of renal function for which evidence
of neural control has been advanced is the excretion of water.
Since the first experiments of Bernard on this subject, many
investigators have reported that denervation results in
" diuresis." 67, 298, 822, 841 We will confine this discussion to
the more recent experiments along this line in which the observations have been better controlled. In 1919 Marshall
and Kolls 276 found, in dogs anesthetized with paraldehyde,
that section of the splanchnic nerves or stripping of the nerve
plexus from the renal pedicle caused that kidney to excrete
urine which was larger in quantity and more dilute in chloride
than that excreted on the unoperated side. It made no
difference whether the observations were made immediately,
or some days after denervation. The difference between
the normal and denervated kidney was accentuated during
RENAL NERVES
243
the osmotic diuresis caused by lactose and N aCI, but not
by Na 2 SO,. Since these differences could be duplicated, at
least so far as urine volume was concerned, by compression
of the renal artery, and since they could be abolished by
nicotine, which was presumed to act only by paralyzing the
intact splanchnic pathways, it was concluded that the effects
of denervation were entirely attributable to changes in blood
flow and pressure. ll7O, 211, 218, 219 Granting this interpretation,
the fact remains that Marshall and his co-workers consistently obtained a relative" diuresis" in the denervated kidney, and marry others have obtained the same result.
In 1929 Fee 118 found, as we have mentioned on page 222,
that the urine How in dogs remained at a low level for some
hours after hypophysectomy and decerebration. But when
one kidney was denervated a "diuresis" resulted on that
side which could be inhibited by pituitary extract. Shortly
afterwards Bayliss and Fee 11 repeated these experiments
on kidneys perfused in situ by the heart-lung-circuit i here
again, denervation produced an increase in urine flow which
was checked by pituitary extract.
It is in sharp but perhaps not ine~plicable contrast to the
above observations that other investigators have found that
denervation has no effect upon the excretion of water. This
was the conclusion of Bykow and Alexejew-Berkmann 58 who
exteriorized the ureters of a dog so that urine could be collected from the kidneys separately. One kidney was then
denervated at a later date. The urine flow, as observed in
the unanesthetized animal, was essentially the same in the
normal and dener~ated kidney, and the response to water
diuresis was almost identical on the two sides. A condi-
244
THE PHYSIOLOGY OF THE KIDNEY
tioned reflex inhibition of water excretion affected both the
kidneys equally, as did the extinction of the conditioned reflex. Klisiecki, Pickford, Rothschild and Verney,229 whose
experiments have been referred to on page 2 I 8, used a
similar technique for observing the effect of denervation.
The ureters were exteriorized and one kidney denervated,
and observations were made later without the use of anesthesia. The normal urine flow was nearly the same in
both the normal and denervated kidney, and the response on
both sides was strikingly parallel, not only to water diuresis
but also to the antidiuretic hormone, and to exercise and
afferent nerve stimulation.2so.439 Data from these experiments have already been given in figures 29 and 30. It was
concluded by these investigators that the renal nerves play
no part in the excretion of water.
In reconciling the above conflicting results it is to be noted
that Marshall and Kolls worked with animals anesthetized
with paraldehyde. The urine flow was very low, and in no
instance did the flow during " diuresis " rise to levels comparable with water diuresis. These same criticisms apply to
the experiments of Fee and of Bayliss and Fee, even though
the direct action of anesthesia was here avoided. Low urine
flows are likely to mean a highly and perhaps maximally
concentrated urine, and a slight or moderate increase in rate
may reflect nothing more than osmotic diuresis. The mechanism for this osmotic diuresis is evident. Marshall and Kolls
themselves emphasized the role of increased blood flow in
the denervated kidney, and Bayliss and Fee, in their perfusion experiments, showed that the "diuretic" response
was actually accompanied by a very marked increase in blood
RENAL NERVES
245
flow. It would seem that this increased blood flow, by promoting filtration and the excretion of osmotically active substances, would induce diuresis, especially in view of the fact
that the renal blood Bow before denervation may have been
considerably reduced. The fact that the response was inhibited by pituitary extract only implies that there was not a
maximal concentration of the antidiuretic hormone in the
blood prior to its administration.
In view of the evidence presented by Verney and others
it seems necessary to conclude that in the normal, unanesthetized animal renal denervation has no effect upon
water excretion, or upon the more involved control thereof.
"Denervation diuresis" appears to be a fallacious phenomenon. The long period experiments upon which its
existence has been argued are so uncontrolled as to have no
meaning, and the acute experiments have been complicated
by the fact that the urine volume was very low and the urine
very concentrated, due to anesthesia and other abnormal
conditions (hemoconcentration, oligemia, etc.) ; under these
circumstances a transient diuresis may occur in consequence
of changes in blood flow, glomerular activity, etc. The phenomenon does not occur, nor does it have any bearing on
the excretion of water, in the normal, unanesthetized animal.
Several investigators have believed that they had demonstrated the existence of specific secretory nerves in connection with the urinary excretion of various substances other
than water,cf. 149,1&1,181 but their experiments have been inadequately controlled and were performed without knowledge of the cQncomitant changes in blood Bow, rate of filtration, etc. For t~e ni"oment it may be said that substantial
24 6
THE PHYSIOLOGY OF THE KIDNEY
evidence of the neural control of either the tubular excretion
or reabsorption of any urinary constituent is lacking.
GLOMERULAR ACTIVITY
The invariable presence of circularly arr~nged smooth
muscle fibers in the afferent arterioles furnishes tl)e anatomical means of varying local glomerular pressure, and Bensley 28 has described a network of cells (pericytes) investing
the efferent arterioles in man and other mammals, which he
considers to be admirably adapted for this purpose. Both
Ludwig and Starling recognized that differential variations
in the caliber of these vessels might bring about changes in
the rate of filtration, more or less independently of the renal
blood flow and systemic pressure. That the activity of the
glomeruli is under neural control, mediated by the profuse
supply of autonomic nerves to the glomerular vessels, is
beyond question, though our knowledge of the details of this
control is extremely meager.
It has commonly been stated that the efferent is smaller
than the afferent arteriole, which might be due to the fact
that there is considerable diminution in the volume of the
blood (or, more accurately, plasma) as it passes through the
tuft; or, alternatively, it might be considered as a device for
regulating the pressure in the glomerular capillaries. The
difference in size between the afferent and efferent arteriole
is not a constant finding, however, and perhaps has been overemphasized. In any case, the lumen of these two vessels
can vary independently.
The classical instance of this independent activity is in the
action of the sympaticomimetic hormone, adrenaline. Rich-
RENAL NERVES
247
ards and Plant 885,888 found that when the perfused kidney
is supplied with blood at a constant rate of flow, adrenaline
causes a rise in the perfusion pressure and at the same time
swelling of the kidney. At first sight the rise in perfusion
pressure would indicate vasoconstriction, but generalized
vasoconstriction should lead to a decrease in kidney volume.
The paradoxical increase in kidney volume was explained
by them as due to the fact that adrenaline preferentially constricts the efferent arterioles; this leads to engorgement of
the glomeruli and swelling of the kidney. Presumably there
occurs at the same time a rise in glomerular pressure and
increase in the rate of filtration. A similar result may follow
sympathetic stimulation. The effect of partial efferent constriction would of course be augmented by simultaneous dilatation of the afferent arterioles, which would tend to equalize
systemic and glomerular pressure. If, on the other hand,
the afferent arterioles were partially constricted, the increased resistance offered to the blood as it enters the glomeruli would reduce the glomerular pressure. Large doses
of adrenaline presumably have this effect, and may produce
complete renal ischemia and consequent anuria, due to the
cessation of filtration.
Working with the heart-lung-kidney, Winton 490, 498 has
confirmed the above view and concluded that the glomerular
pressure can be varied over the wide range of 30 to 90 per
cent of the arterial pressure. The action of adrenaline on
glomerular pressure is distinct at a concentration of I part
to IO,OOO,ooo. An idealized schema illustrating the effects
of variations in affer~nt-eff~ren~ arteriolar tone on glomerular pressure is given in figure 32.
248
THE PHYSIOLOGY OF THE KIDNEY
Variations in glomerular activity are well demonstrated
in cold-blooded animals. Richards and Schmidt 881 found
fiLTRATION
PRESSURE
w
CI
~
1"-"
1____
..J :._____ •• ____________
j:!
~
~--.--
OSMOTIC PRESSURE OF PLASMA PROTEINS
FIGURE 32
Theoretical effect of vasoconstriction of the glomerular arterioles upon the effective filtration pressure in the glomerulus. Dilatation of the afferent
and constriction of the efferent arteriole leads to a
high glomerular pressure, as indicated by the upper
curve. Constriction of the afferent and dilatation
of the efferent arteriole leads to a low glomerular
pres~ure, as indicated by the lower curve.
by the direct microscopic examination of the frog kidney
that only a certain proportion of the glomeruli, or of the
capillaries in a particular glomerulus, may exhibit a free
RENAL NERVES
249
blood flow at anyone moment. This intermittency of circulation appears to be controlled by changes in the arterioles
at the point where these give rise to the capillaries, and
vasoconstrictor and vasodilator agencies may decrease or increase the number of active glomeruli. G, 80,860, 8eG 418 Bieter 30
has described a short capillary loop in the frog which acts as
a shunt, permitting blood to flow across the glomerulus without extensive exposure in the longer capillaries. Actual capillary s)1unts have not been demonstrated in mammals as yet,
and there are reasons for believing that intermittency of
glomerular activity is more highly developed in the lower
vertebrates than in the mammals, but evidence obtained by
the intravenous injection of hemoglobin and dyes, with subsequent histological examination of the kidney, indicates that
alternation of glomerular activity may occur in the higher
forms as well.182 ,405 Unfortunately, most of the evidence
so far has been obtained on rabbits, in which glomerular activity is not as constant as it is in the dog or man i but even
if intermittency as such is lacking it must be recognized that
the differential tone of the afferent and efferent arterioles
may alter the filtration rate under a variety of physiological
conditions.
It remains to be determined to what extent variations in
glomerular activity do occur. At the moment, about the only
evidence on this question is to be obtained from observations
on the total renal blood flow, which is considered in the following chapter.
XXII
RENAL BLOOD FLOW
IT has long been known that stimulation of the splanchnic
nerves peripherally leads to renal vasoconstriction and
anuria, and it would be inferred that these motor pathways
are normally in tonic activity. However, the evidence on
this point "is very unsatisfactory, a situation which arises in
part from the difficulty of measuring renal blood flow in
the normal, unanesthetized animal. The classical method
of following blood flow was by observing changes in the volume of an organ by means of a plethysmograph. Although
easily adapted to the kidney because of this organ's shape,
one suspects that the method is deceptive because of the
mechanics of the glomerular circulation. Herrick, Essex
and Baldes 1911 find that an increased blood flow, as measured
by the thermostromuhr method, is accompanied by an increase in volume, and vice versa. But the observations of
Richards and Plant, which have been referred to above, in..
dicate that this relationship between blood flow and renal
volume is not a constant one. Without control of the perfusion pressure, it is impossible to say whether an increase
in renal volume is due to afferent dilatation or efferent constriction, or whether it reflects a decrease or increase in blood
flow. For example, Reid,8113 utilizing a plethysmograph
which could be left in dogs to be healed in situ, observed
that the administration of caffeine, theobromine, theophyl-
RENAL BLOOD FL~W
lin, pituitrin, merbaphen, glucose and NaCI all produced a
sustained increase in renal volume which might or might not
be preceded by a transi:ht decrease, while adrenalin, nitroglycerine and nitrites invariably caused a decrease in volume.
In addition to the fact that these results are complicated by
changes in the volume of urine in the tubules (glucose, N aCI)
and changes in the systemic circulation rate (caffeine, adrenalin, etc.), it is clear that afferent dilatation and efferent
constriction cannot readily be distinguished by plethysmographic means.
Numerous observations have been made on the renal
blood How' in anesthetized or decerebrate animals,cf. 408, 448
but since the venous pressure, cardiac output, vasomotor
tone, etc., in anesthetized, and especially in operated animals, must be assumed to be abnormal, these results are of
uncertain value physiologically. Several methods which appear to avoid at least some of these difficulties have recently
been devised for determining the renal blood flow in unanesthetized animals. Rhoads 814 has developed a technique
in dogs for explanting one kidney under the skin, in such a
position that the renal arteries and veins are readily accessible. This operation has been improved in certain respects by Sheehan. 407 Such explanted kidneys function normally and after removal of the remaining kidney undergo
hypertrophy. SI5 Van Slyke, Rhoads, Hiller and Alving 448
have measured the blood flow through such explanted kidneys, both with and without the other kidney in the body,
by determining the A-V difference of urea and the urea excreted per miuute. 'Xhe method of determination is in principle a simple one: if 10.3 per cent of the whole blood urea
25 2
THE PHYSIOLOGY OF THE KIDNEY
is removed in one circulation through the kidneys (as determined by the analyses of simultaneous samples of ~enal
arterial and venous blood) and if the simultaneous urea
clearance is 44.6 cc., then the renal blood flow must equal
44.6/0.103 = 433 cc. Similar measurements of renal blood
flow have been made by Sheehan 407 using the simultaneous
extraction ratio and clearance of phenol red.
Janssen and Rein,211 Walker, Schmidt, Elsom and Johnson 880,488 and others have used thermoelectric stromuhrs of
various types which could be attached to the renal artery or
vein and left in situ so that observations could be made after
recovery from operation.
The results obtained by such methods indicate that there
is no consistent relation between renal blood flow and water,
salyrgan, or xanthine diuresis or pituitary antidiuresis. The
O 2 consumption of the kidney increases in proportion to
blood flow, but it is not related to urine flow. It is wen
known that when one kidney is removed the other undergoes hypertrophy, and this hypertrophy is accompanied by
about a So per cent increase in blood flow. 188 , 211,865,448,489
Adrenaline causes a decrease in blood flow and in large doses
may produce anuria.188 , 385, 490 Similarly, pituitary extracts
cause renal vasoconstriction/Bs, 211. 888 an effect probably referable to the va sop res sure hormone and one which is not
without further evidence to be attributed to the antidiuretic
hormone.
DIET
One of the most interesting phenomena involving the renal
circulation is the influence of diet. Jolliffe and Smith 214, 211
showed that the urea clearance in dogs which were observed
RENAL BLOOD FLOW
253
in the post-absorptive condition varied with the protein content of the maintenance diet, and subsequently it was shown
that the changes in urea clearance, effected by increasing or
decreasing the protein content of the diet, are paralleled by
changes in the creatinine and xylose clearances. 401 ,402 Van
Slyke, Rhoads, Hiller and Alving m have shown that the
change in the urea clearance is accompanied by an increase
in renal blood flow. The available data do not enable one
to determine to what extent this increased renal blood How
is brought about by local changes in the kidney, or by an increase in the systemic circulation. The effect of protein upon
renal function can be duplicated by the administration of
amino-acids, or by increasing endogenous protein metabolism by thyroxin or phlorizin. When the diet has a high
content of protein there can be distinguished both an immediate post-prandial action and a sustained elevation of
renal function in the post-absorptive state. 884 For this reason quantitative studies of renal clearances in dogs must not
only be performed in the post-absorptive state, but they
must also take into account the composition of the maintenance diet. The effect of high and low protein diets on renal
activity in man is much less than in the dog,78,144 though
children are more susceptible.110
Dfl:NERVATION
Beginning with the observations of Bradford,48 it has been
believed that the kidney receives both vasoconstrictor
and vasodilator fibers via the thoracico-Iumbar autonomic
nerves; and, since tp.e denervation of most other organs
leads to at least transient vasodilatation, it would be expected
254
THE PHYSIOLOGY OF THE KIDNEY
that the same would be true for the renal arterioles. In fact,
the observations of Burton-Opitz and Lucas,62 who used a
mechanical stromuhr for measuring blood flow in the renal
vein, showed that vasodilatation may occur following denervation. Bradford also obtained reflexly a marked expansion of the kidney volume in anesthetized dogs, and
Reid 852 obtained similar evidence of vasodilatation in unanesthetized dogs using spinal anesthesia. More recently
Handovsky and Samaan,189 using a thermostromuhr in unanesthetized dogs, found that unilateral splanchnotomy was
followed immediately, or after a brief period of reduced
flow, by a distinct increase, which amounted to I.S to 4.0
times the control flow. On the other hand, Rhoads, Van
Slyke, Hiller and Alving aa6 found that novocainization of
the renal vessels in unanesthetized dogs, and denervation of
the kidney in dogs under full anesthesia, produced no consistent change in either blood flow or urea clearance. However, these observations were made on single, explanted,
hypertrophied kidneys, the other kidney having been removed two years before.
There are numerous reports in the literature on the effects
of paravertebral anesthesia on renal function in man, but
none of them contains indubitable evidence that the renal
blood flow has been increased. It has been shown that the
creatinine clearance falls during spinal anesthesia, a result
attributable to the concomitant fall in arterial and therefore glomerular pressure; the creatinine clearance does
not fall if the arterial pressure is maintained at normal
levels. liB, 288,201 Renal denervation has been practiced in man
as a therapeutic measure in chronic nephritis and hyperten-
RENAL BLOOD FLOW
sion, but this procedure does not lead to any marked alteration in renal function, as revealed by the urea clearance,
except in so far as the ensuing reduction of arterial pressure
may favorably influence the course of disease. 12O ,822 It is
well established that the peripheral arterioles in man become sensitized to adrenalin after post-gangliqnic denervation; ct. 119 this increased sensitivity, combined perhaps with
other factors, leads to a restoration of partial constriction
in the denervated area, and to excessive vasoconstriction
under conditions where increased adrenalin secretion occurs. If a similar phenomenon occurs in the kidney, it would
complicate the effects of chronic denervation. It is of interest that Hartmann, 0rskov and Rein,174 using thermostromuhrs on the renal vein and femoral artery of anesthetized dogs, find that the renal circulation is relatively stable
and uninfluenced by factors that produce profound changes
in the blood flow through the leg. The renal circulation, for
example, does not participate in the vasoconstriction induced
reflexly from the carotid sinus. The threshold of the renal
circulation for adrenalin is stated to be 100 times as high as
in the muscle and skin vessels, but this threshold may vary
considerably during a short period of time, and it is lowered
with fair regularity by denervation. Marked renal vasoconstriction was observed by these inv:estigators only after
the administration of high concentrations of COz•
In the absence of further evidence it must be presumed
that the renal vasomotor nerves are tonically active, though
their chief function may be the regulation of the glomerular
filtration pressure. The results which are elicited reflexly.
or by acute denervation, will in any instance be complicated
256
THE PHYSIOLOGY OF THE KIDNEY
by the unique afferent-efferent arteriolar mechanism in the
renal circulation, by the distribution of blood between the
kidney and the other splanchnic viscera and the skin, and
perhaps by endogenous activity of the renal arterioles. This
subject is one of great interest, but its development can 0!1ly
proceed pari passu with our knowledge of the autonomic
nervous system and its functional activity in normal man.
XXIII
COMPARISON OF RENAL ACTIVITY
IN MAMMALS
IT IS interesting at this point to make some comparisons on
renal activity in relation to the size of the kidneys, the number of glomeruli, the probable blood Bow, etc., in the unanesthetized rabbit, dog and man, the three species on which
most information is available. Data bearing on this subject
have been compiled in table IV, and are discussed in detail
below.
The relative size of the two kidneys in these three species
is unquestionably very different. According to the data of
Taylor, Drury and Addis 438 the rabbit has 89 grams of
kidney per square meter of surface area. This figure in the
dog is given as 85 grams by MacKay,248 113 grams by
Stewart 483 and 13 0 grams by Kunkel,282 the last figure appearing to agree best with the functional data. The mass
of the kidneys in man has been recalculated from reliable
data in the literature by MacKay; 241 for ideal man of 1.73
square meters, the value as given by this author would be
294 grams, or 1'70 grams per square meter.
Compared in terms of either kidney weight or body surface area, the rabbit and the dog 282 have relatively many
more glomer.uli than does man; 462 but, since the glomeruli
vary in size and vascuJ3.rization"mere number is not of great
significance.
25 8
THE PHYSIOLOGY OF THE KIDNEY
The average renal blood flow per gram of kidney per
minute, as observed by Walker et al., '68 in the rabbit is
3.2 cc., and in the dog 2.8 cc. Excluding from the data of
Van Slyke et al. "8 one experiment on dog D9, in which the
blood flow was unusually high, and also those dogs which
had been fed meat or given urea solution just before observation, the figures range from 1.9 to 4.7 cc., and average 3.3 cc.,
which value we have taken in table IV. Sheehan's 407 average
figure is higher than this, perhaps because his dogs were
maintained on a high protein diet. From a functional point
of view, it would appear that dogs on a low protein diet are
more nearly comparable to man. Handovsky and Samaan 189
state that their values range from 1.75 to 3.80 cc. Figures
of this same order of magnitude have been obtained by
Levy and Blalock ll88 and Mason, Blalock and Harrison,286
both by this method and by means of a venous sound stromuhr. The minimum figure for the renal blood flow in
ideal man may be taken as close to 1000 cc. per minute
(page 89) ; since ideal man has 294 grams of kidney, this
gives the figure 3.4 cc. per gram of kidney per minute.
Data for the rabbit on the basis of surface area are lacking, and our estimate of 285 cc. per minute (3.2 X 89, as
above) may be considerably too low. The figure 433 cc. for
the dog is the average of the data of Van Slyke et al.,448
selected as above; it is fortified by two other calculations:
3.3 cc. per gram X 130 grams of kidney per sq. m. =
429 cc. j and a whole blood urea clearance of 52.2 cc. (cf. below) divided by a urea extraction ratio m of 0.105 = 495 ce.
The figure 580 cc. for man is calculated as 1000/1.73
sq. m.42S
COMPARISON OF RENAL ACTIVITY IN MAMMALS
259
The figures for the filtration rate and urea clearance in
the rabbit are based on the data of Kaplan and Smith 217 and
exclude very low urine flows. The data of Taylor, Drury
and Addis <188 give a urea clearance of 25.5 cc. during urea
diuresis; but at moderate urine flows, without a diuretic, the
value will probably be 20 cc. or less. The data on the filtration rate in the dog are too meager to warrant direct use,
but a fairly accurate estimate may be obtained if1.uirectly.
Several investigations afford data on the urea clearance in
dogs maintained on a mixed diet. In 49 plasma clearances
on 10 dogs Jolliffe and Smith 21&,2111 obta'ined 55.6::1::13.7 cc.
per sq. m. per minute. In 2 I whole blood clearances on
17 dogs Summerville, Hanzal and Goldblatt 484 obtained
53.1::1:: I I; Ralli, Brown and Pariente 848 in 20 whole blood
clearances on 6 dogs obtained 57.7; Rhoads, Alving, Hiller
and Van Slyke SBG in 26 whole blood clearances on 5 dogs
obtained 49.8, and in 103 observations on 13 dogs with one
kidney explanted and the other in situ, 48.1. In the majority
of the above recalculations the urine flow exceeded 0.5 cc.
per sq. m. per minute. The average whole blood urea clearance in the above data is 52.2; with an hematocrit of 0.40,
the equivalent plasma clearance would be about 47 cc. (In
23 observations on 2 dogs maintained on a low protein diet
the plasma clearance averaged 33.6 =1:3-:''1; this figure may
rise to above 70 cc. on a meat diet.) 215,447 We may take the
average plasma urea/creatinine ratio at urine flows above
0.5 cc. per sq. m. per minute as 0.5; <lOOa this figure, combined
with the aver,age plasma urea clearance on a mixed diet of
47 cc., as obtained ab?ye, would give a filtration rate of 94 CC.
per sq. m. per minute. The figures for the filtration rate and
260
THE PHYSIOLOGY OF THE KIDNEY
urea clearance in man are taken from Smith, Goldring and
Chasis.428
The maximal plasma phenol red clearance in man averages 231 cc. per sq. m. In the dog this figure may be taken
to be 1.7 X 94 = 160 cc. (i.e., the phenol red/inulin ratio X
the filtration rate).
It cannot be assumed that all the data in table IV were
obtained under strictly comparable physiological conditions; nonetheless they permit several interesting deductions. First, it may be noted that renal blood flow per gram
of kidney weight is much the same in the three species. Although the identity of the figures given here is perhaps fortuitous, the data suggest that the vascularization of the renal
parenchyma is essentially uniform. It would seem that the
functional capacities of the three species can safely be compared in terms of the surface area of the body, particularly
in view of the success of this method of computation in
metabolism. On this basis, man has the largest kidneys
but the smallest number of glomeruli, while the rabbit has
the smallest kidneys and the largest number of glomeruli. It
is clear that the relative quantities of glomerular and tubular
tissue in the three species differs greatly. Since there is no
significant number of aglomerular tubules in the normal
mammal, the relative number of glomeruli may be taken as
an index of the relative number of nephric units; i.e., man
has 'the smallest number of nephrons, and the rabbit the
largest number. But since the human kidney is the largest,
man's nephrons must be larger than the rabbit's or the dog's.
The mass of the nephron is composed chiefly of tubules, and
therefore we may say that the human kidney, as compared
COMPARISON OF RENAL ACTIVITY IN MAMMALS
261
with the dog and more particularly with the rabbit, has a
preponderance of tubular tissue.
In spite of the differences in the number of glomeruli, the
three species maintain a filtration rate of the same order
of magnitude. This is primarily a consequence of the fact
that the blood flow per glomerulus is so much larger in man
than in the rabbit.
The fraction of urea reabsorbed in the dog and man is
nearly the same at comparable urine flows, which fact leads
to similar values for the urea clearance in these two species.
The reabsorption of urea in the rabbit is somewhat greater;
this, combined with a lower filtration rate, leads to a lower
urea clearance.
If the data on renal blood How in the three species are of
equal accuracy and represent similar physiological conditions
in the circulation, there can be no doubt that this value is
highest in man, when comparison is made on the surface area
basis.
If it is assumed, in each case, that 60 per cent of the blood
is plasma, we may calculate from these figures the fraction
of plasma which is filtered. The figure 29 per cent in the
rabbit agrees with the observations of Walker et al.,488 who
found that the creatinine clearance in this animal usually
ranged from 23 to 40 per cent of the plasma flow, and averaged 30 per cent. In the dog Medes and Herrick 282 found
that the average creatinine clearance in different animals
ranged from 14 to 48 per cent, and averaged 3 I per cent
of the plasma. flow. Too much significance should not be
attached to the estima~es of the filtration fraction given in
table IV for the dog and rabbit, however, since they are not
262
THE PHYSIOLOGY OF THE KIDNEY
based upon simultaneous observations, but contain the multiplied errors in two groups of data. A filtration fraction of
20 per cent in man is subject to the qualification that it may
be smaller; it can scarcely be larger, for the datum on blood
flow is minimum.
TABLE IV
COMPARATIVE DATA ON MAMMALS
<
en
El
i
8.
l
~
Rabbit
Dog
Man
El
Renal Blood Flow
!t
c:i
8.
'"
~
~
c;
.8<
a.
c:i
'il
'ij
1I
8.
II
a
Ji
...:g"to
>.
...:g
E
8
Ii.
'"E
~
..9
ci
...i!!
ia
"Ul
Z
Cl
89
130
170
2,030,000
1,920,000
1,120,000
33,000
13,350
6,600
8
.. i!>
8,-
x
u
1.4
2.3
5.2
'"
a
II
It'"
·sc:i
II
..:'"
Plaama Clearance
Urea Phenol
Red
II
'"
1
- - --..:
it 8. .
Inulin
en
.!I
q;;
El
El
1
!t
id
!t
Ii.
.8-
~.~
i
~.~
"fl" ~
94
70
47
36
160
231
en
Ii
El
Ii.'~
<
en
en
..:
c;
f8
f!
f!
f!
It
""
---- - - -- --3.2 285 50
20
29
3.3
3.4
433
580
36
20
The above evidence would suggest, then, that man, as compared with the dog and rabbit, has large kidneys made up
of fewer nephrons, each nephron having a relatively greater
amount of tubular as compared to glomerular tissue. The
blood flow to each nephron is nearly four times as great as
in the rabbit, and over twice as great as in the dog; this relative hyperemia of the glomeruli raises the rate of filtration
in each glomerulus and keeps the total filtration rate on a
parity with the other species.
The specific excretory capacity of the tubules in the dog
and human kidney, at least so far as phenol red is concerned,
is about the same (Le., in ce. of plasma cleared of phenol red
COMPARISON OF RENAL ACTIVITY IN MAMMALS
26 3
per gin. of kidney per min.) ; but the fact that man possesses
a greater mass of tubular tissue, with a proportionally increased blood flo'\'V to this tissue by way of the glomeruli,
gives him an advantage, in respect to tubular excretion (as
judged by the phenol red clearance) of about 50 per cent
over the dog. The suggestion cannot be avoided that the
relatively few nephrons in the human kidney, the preponderance o~ tubular tissue, and the relatively greater blood flow
through each glomerulus are functionally related features in
the pattern o~ the renal parenchyma.
BIBLIOGRAPHY
Since it is impossible within the scope of this book to include
references to all papers which bear directly upon renal function, and
which have appeared since 1920, an effort has been made to limit
the following list to the arbitrary number of five hundred. In many
instances, therefore, it has been necessary to omit all except the last
of a series of articles by one author on a particular subject, and in
o~her instances to refer only to recent reviews which have an adequate bibliography.
I.
2.
3.
4.
5.
6.
7.
8.
9.
ABERHALDEN, E. and G. EFFKEMANN. 1934. Ober den
Einfluss von a-und ~-Glucosiden auf die Phosphorylierung von Traubenzucker. Biochem. Ztschr., 268.
461-468 . . . . . . . . . . . . . . . . . . . . II?
ADDIS, T. and D. R. DRURY. 1923. The rate of urea excretion. V. The effect of changes in blood urea concentration on the rate of urea excretion. J. BioI.
Chem., 55. 105-1 I I . . . . . . . . . . . . . . . I22
ADOLPH, E. F. 192;2. The excretion of chloride, urea
and water by the human kidneys. Am. J. Physio!.,
59. 460-461 . . . . . . . . . . . . . . . . . . 205
ADOLPH, E. F. 1923. The excretion of water by the kidneys. Am. J. Physio!., 65.419-449 . . . . . . . . 205
ADOLPH, E. F. 1936. Control of urine formation in the
frog by the renal circulation. Am. J. PhysioI., I I 7,
366-379 . . . . . . . . . . . . . . . . ?oJ 2z3J 2 49
ADOLPH, E. F. and G. ERICSON. 1927. Pituitrin and diuresis in man. Am. J. Physio!., 79. 377-388. . . . . 2z5
AITKEN, R. S. 1929. On the renal threshold for chloride
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AMBARD, L. and A. WEILL. 1912. Les lois numeriques
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ANSE~MINO, K. J. and FR. HOFFMANN. 1936. Ober den
Nachweis von Hypophysenhinterlapp~nhormonen im
Blut mit Hilfe von Ultrafiltrationenmethoden. Klin.
Wchnschr., IS. 1750-1751
. . . . . . . . . . . 2I7
266
THE PHYSIOLOGY OF THE KIDNEY
10. AUSTIN, J. R., E. STILLMAN and D. D. VAN SLYKE. 1921.
Factors governing the excretion rate of urea. J. BioI.
Chern., 46, 91-112 . . . . . . . . . . . . . . . I22
II. BAINBRIDGE, F. A. and C. L. EVANS. 1914. The heart,
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12. BALDES, E. J. and F. H. SMIRK. 1934. The effect of water
drinking, mineral starvation and salt administration on
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in relation to the problems of water absorption and
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13· BARNES, B. 0., J. F. REGAN and J. G. BUENO. 1933. Is
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14. BARTRAM, E. A. 1932. Experimental observations on
the effect of various diuretics when injected directly
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1197-1219 . . . . . . . . . . . . . . . . . 238,240
15. BAYLISS, L. E. and A. R. FEE. 1930. Studies on water
diuresis. III. A comparison of the excretion of
urine by innervated and denervated kidneys perfused
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135-143 . . . . . . . . . . . . . . . . . . 2I3,243
16. BAYLISS, L. E. and A. R. FEE. 1930. Studies on water
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60-66 . . . . . . . . . . . . . . . . . . . . . 207
17. BAYLISS, L. E., P. M. T. KERRIDGE and D. S. RUSSELL.
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18. BAYLISS, L. E. and A. M. WALKER. 1930. The electrical
conductivity of glomerular urine from the frog and
from Necturus. J. BioI. Chem., 87, 523-540. . . . . 28
19. BECK, L. V. and R. CHAMBERS. 1935. Secretion in tissue
culture. II. Effect of Na iodoacetate on the chick kidney. J. Cell. & Compo PhysioI., 6, 4..P-455· . . . . 49
20. BEHRE, J. A. and S. R. BENEDICT. 1922. Studies in creatine and creatinine metabolism. IV. On the question
of the occurrence of creatinine and creatine in blood.
J. BioI. Chem., 52, I1-33· . . . . . . . . . . . . 92
BIBLIOGRAPHY
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24. BENSLEY, R. R. and W. B. STEEN. 1928. The functions
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25. BERGLUND, H. and A. R. FRISK. 1935. Uric acid elimination in man. Acta Med. Scandinav., 86, 233-267. . I95
26. BERGLUND, H., G. MEDES, T. Q. BENSON and A. BLUMSTEIN. 1935. Effects of spinal anesthesia on glomerular function in hypertension. Acta Med. Scandinav.,
86, 292-301 . . . . . . . . . . . . . . . . . . 254
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I
28. BIASOTTI, A. 1933. Tiroides y aCclon diuretica del extracto de l6bulo anterior de la hip6fises. Rev. Soc.
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29. BICKFORD, R. G. and F. R. WINTON. 1937. The influence of temperature on the isolated kidney of the dog.
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3 I. BIETER, R. N. 193 I. The secretion pressure of the
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32. ,BIETER, R. N. 1931. Albuminuria in glomerular and
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407-412 . . . . . . . . . . . . . . . .. . . . 46
33. Bieter, R. N. 1933. Excretion of phenol red by the
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30, 981--984 .' -. . . . . -. . . . . . . . . . . 47,8I
268
THE PHYSIOLOGY OF THE KIDNEY
34. BIETER, R. N. 1933. Further studies concerning the action of diuretics upon the aglomerular kidney. J.
Pharm. &; Exper. Therap., 49. 25cr256 . . . . . . . 47
35. BIETER, R. N. 1935. The action of diuretics injected
into one kidney of the aglomerular toadfish. J.
Pharm. &; Exper. Therap., 53, 347-349 . . . . . . . 47
36. BIETER, R. N. and F. H. Scott. 1929. Blood pressure
and plasma protein determinations in the same fr:og.
Am. J. Physiol., 91, 265-274 . . . . . . . . . . . 33
37. BLATHERWICK, N. R., P. J. BRADSHAW, O. S. CULLIMORE,
M. E. EWING, H. W. LARSON and S. D. SAWYER. 1936.
The metabolism of d-xylose. ]. BioI. Chem., II3,
405-410 . . . . . . . . . . . . . . . . . . . . u6
38. BLISS, S. 1930. The amide nitrogen of blood. V. A
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39. BLUMGART, H. L., D. R. GILLIGAN, R. C. LEVY, M. G.
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Arch. Int. Med., 54. 4cr81 . . . . . . . . . . . . 240
40. BOHN, H. and F. HAHN. 1933. Untersuchungen zum
Mechanismus des blassen Hochdrucks. VII. Ober das
wahre und falsche Kreatin und Kreatinin des Blutes.
Die Erniedrigung des Blutkreatinspiegels beim blassen
Hochdruck. Ztschr. f. Klin. Med., 125,458-474. . . 92
41. BOLLIGER, A. 1928. The influence of the purine diuretics on inorganic phosphates of blood and urine. J.
Biol. Chem., 76, 797-807. . . . . . . . . . . . . 238
42. BORDLEY, J. 3rd, and A. N. RICHARDS. 1933. Quantitative studies of the composition of glomerular urine.
VIII. The concentration of uric acid in glomerular
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193-221 . . . . . . . . . . . . . . . . . . 28, I95
43· BORDLEY, J. 3rd, J. P. HENDRIX and A. N. RICHARDS.
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101, 255-267 . . . . . . . . . . . . . . . . . . 28
44a. BOURDILLON, J. and P. H. LAVIETES. 1936. Observa-
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#b. BOURQUIN, H. 1929. Studies on diabetes insipidus.
III. The diuretic substance, further observation. Am.
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45. BOWMAN, W. 1842. On the structure and use of the
Malpigian bodies of the kidney, with observations on
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57-80 . . . . . . . . . . . . . . . . . . . . . I8
46. BRADFORD, J. R. 1888. The innervation of the renal
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48. BRUNN, F. 1920. Beitrage zur Diuresefrage. II. Ober
diuresehemmende und diuretische Wirkung des Pituitrins. Zentralbl. f. Innere Med., 41, 674-679. . . . 2I5
49. BRUNTON, C. E. 1933. The acid output of the kidney
and the so-called alkaline tide. Physio!. Rev., 13, 372397 . . . . . . . . . . . . . . . . . . . . . . I79
50. BUNIM, J. J., W. W. SMITH and H. W. SMITH. 1937.
The diffusion coefficient of inulin and other substances
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667-677 . . . . . . . . . . . . . . . . . . . 62, 63
51. BURGESS, W. W., A. M. HARVEY and E. K. MARSHALL,
JR. 1933. The site of the antidiuretic action of pituitary extract. J. Pharm. & Exper. Therap., 49, 237249 . . . . . . . . . . . . . . . . . . . . 2I3,2I8
52. BURTON-OPITZ, R. and.D. R. LUCAS. 1908. Ober die
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5S3-595 . . . . . . . . . . . . . . . . . . . . 254
53. BUSCHKE, F. 1928. Experimentelle Beitrage zum
Wirkungsmechanismus des Hypophysins auf den
Wasser- und ChloridwechseI. I. Einfluss der Narkose auf !fie Kochsalzausschwemmende Wirkung des
Hypophysins. Arch. f. Exper. Path. u. Pharmakol.,
136.43-51 . . . . . . . . . . . . . . . . . 2IS, 224
27 0
THE PHYSIOLOGY
OF THE KIDNEY
54. BYKOW, K. M. and I. A. ALEXEJEW-BERKMANN. 1927.
Creation des reflexes conditionnels sur la diurese.
Compt. Rend. Acad. d. Sci., 185, 1214-1216. . . . . 224
55. BYKOW, K. M. and I. A. ALEXEJEW-BERKMANN. 1930.
Die Ausbildung bedingter Reflexe auf Harnausscheidung. Arch. f. d. Ges. Physio!., 224, 710-721. . . . 224
56. BYKOW, K. M. and I. A. ALEXEJEW-BERKMANN. 1931.
Die Ausbildung bedingter Reflexe auf die Hamausscheidung. II. Bedingte Reflexe bei denervierter
Niere. Arch. f. d. Ges. Physio!., 227, 301-308 2I7, 224, 243
57· CALDWELL, J. M., H. MARX and L. G. ROWNTREE. 1931.
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58. CAMPBELL, R. A., E. E. OSGOOD and H. D. HASKINS.
1932. Normal renal threshold for dextrose. Arch. Int.
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60. CANNON, W. B. 1929. Organization for physiological
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2
61. CANNY, A. J., E. B. VERNEY and F. R. WINTON. 1930.
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62. CHAMBERS, R., L. V. BECK and M. BELKIN. 1935.
Secretion in tissue cultures. I. Inhibition of phenol
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Physio!., 6,425-439. . . . . . . . . . . . . . . 49
63. CHAMBERS, R. and G. CAMERON. 1932. Intracellular
hydrion concentration studies. VII. The secreting
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Physio!., 2, 99-103 . . . . . . . . . . . . . . . . 49
64. CHAMBERS, R. and G. CAMERON. 1937. Tissue culture
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J. Cell. &. Compo Physiol., In Press. . . . . . . 44, I9 6
65. CHAMBERS, R. and R. T. KEMPTON. 1933. Indications
of function of the chick mesonephros in tissue culture
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48,87
66. CHANUTIN, A. and F. W. KINARD. 1932. The relation-
BmLIOGRAPHY
ship between muscle creatine and creatinine coefficient.
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67. CHANUTIN, A. and H. SILVETTE. 1929. A study of creatine metabolism in the nephrectomized white rat. J.
Biol. Chem., 85, 179-193 . . . . . . . . . . . . . IOS
68. CHASIS, H. 1937. The excretion of urea in relation to
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64, 65,68, I30, I32,202
69. CHASIS, H., N. JOLLIFFE and H. W. SMITH. 1933. The
action of phlorizin on the excretion of glucose, xylose,
sucrose, creatinine and urea by man. J. Clin. Invest.,
12, 1083-1090 . . . . . . . . . . . . . . . I39, I40
70. CHROMETZKA, F. and K. UNGER. 1931. Untersuchungen
iiber die Grosse des Glomerulusfiltrats unter dem Einfluss von Diuretics und Hormonen. Ztschr. f. d. Ges.
Exper. Med., 80, 261-273 . . . . . . . . . . . . 238
71. CLARKE, R. W. 1934. The xylose clearance of Myoxocephalus octodecimspinosus under normal and diuretic
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72. CLARKE, R. W. and H. W. SMITH. 1932. Absorption
and excretion of water and salts by the elasmobranch
fishes. III. The use of xylose as a measure of the
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73· CONWAY, E. J. 1925. The relation in diuresis between
volume of urine and concentration of a diuretic with
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30-40 . . . . . . . . . . . . . . . . . . . . . 32
74. CONWAY, E. J. and F. KANE. 1926. The equation expressing the excretion of a diuretic and its relation to
diffusion processes. J. Physiol., 61, 595-607 . . . . 32
75. COPE, C. L. 1932. Inorganic sulph_ate excretion by the
human kidney. J. Physiol., 76, 329-338. . . . . . I89
76. COPE, C. L. 1933. The excretion of non-metabolized
sugars by the mammalian kidney. . J. Physiol., 80,
238-251 . . . . . . . . . . . . . . . . . . . . Ij8
77. COPE, C. L. 1933. The excretion of cyanol by the mammalian kidney. J. Physiol., 80, 253-260 . . . . . . Ij8
78. COPE, C. L. 1933. Studies of urea excretion. VIII. The
effects on the urea clearance of changes in protein and
salt contents of the diet. J. Clin. Invest., 12, 567-572 2Sj
27 2
THE PHYSIOLOGY OF THE KIDNEY
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THE PHYSIOLOGY OF THE KIDNEY
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THE PHYSIOLOGY OF THE KIDNEY
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THE PHYSIOLOGY OF THE KIDNEY
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INDEX
Acid-base equilibria, 169
Acidification of urine, 36, 171, 173
Acidosis, 178
Acids, fixed, 170
Addison's disease, 164
Adrenal cortex, 163
Aglomerular kidney (see Tubules)
Alkaline tide, 179
Amino-acids, 198
Ammonia, 179
Anesthesia, 224
Arteries, renal, I 3
Augmentation limit, 122
Basement membrane, 7, 12
Bicarbonate, 169
Blood How, renal, 250, 258
dilution in diuresis, 206
supply, renal, 13
Bromide, 198
Brush border, 10
Calcium, 183
Capsular fluid (see Glomerular filtrate)
Capsule, Bowman's, 7, I 2
Carbohydrates, 46
Chlorate, 198
Chloride, 1 58
Clearance, complete, 57, 59, 89
definition of, 52
history of, 51, 121
physiological significance of, 56
Collecting tubules, ~ 2
Connective tissue, I 5
Cortex, renal, 9
Creatine, 102.
Creatinine, 92.
urinary, origin of, 103
Cushny's theory, 2.0
Cyanol, 46, 1 38
"Deckzellen," 7
Denervated kidney, 2.19, 2.53
Diabetes insipidus, 2.2.5
Diabetes mellitus, 1 10
Diet, effect on clearances, 2. 52.
Diffusion coefficients, 62,
Diodrast, 88, 196
Distal tubule, 8, 35, 2.32
Diuresis, 47, 2.35
" denervation," 2.42.
hypertonic, 156, 2.04, 236
isotonic saline, I 5 5
mercurial, 2.39
osmotic, 2.04, 2.36
water, 155
~nd blood dilution, 2.06
xanthine, 2.37
Diuretics, 2.35
" Diuretic"· hormone, 2.08, 2.11,
2.13, 2.28
Dyes, tubular storage of, 44
Edema, 166
Electrolytes, filtration of, 2.8, 160
reabsorption of, 35, 160
plasma, ISO, 154
interchangeabilitf of, 159
Environment, internal, 2.
308
INDEX
Ferrocyanide, 46, 197
Glomerular clearance, 56, 63
filtrate, composition of, 27
filtration, 18, 21
(For data on magnitude in dogfish, teleost, chicken and
mammals see references in
Chapters XIII and XXIll.
For frog and a,lligator see
references 267 and 268.)
Evidence for, in mammals, 29,
135
Fraction of plasma, 89, 261
measurement of, 58, 135
and urine flow, 63, 68, 201
permeability, 22, 32
pressure, 28, 30, 33, 247
Glomeruli, regulation of, 246
Glomerulus, 5
Glucose, 46, 110
permeability of red cells, 1 38
Heart-lung-kidney, 29
Heat cramps, 167
Hexamethylenetetramine, 140
Hippuran, 88, 196
Hippuric acid, 192
Inulin, 58
clearance, ratios to other clearances, 137
properties of, 61, 137
Iodides, 198
Ketosis, 170
Kidney, anatomy of,S
Kidney, size of, 257
Loop of Henle, 8
Lymphatics, renal, 15
Medulla, renal, 9
Mercurial diuretics, 239
Nerves, renal, 15,241
Nitrates, 198
Nussbaum's experiment, 43
Oxidations, renal, 193
Oxygen consumption, renal, 252
Phenol red, 72
clearance, high plasma levels, 80
low plasma levels, 18, 87, 260
whole blood, 87
protein binding, 73, 76
Phlorizin, 14
action on chloride excretion, 1 17
creatine clearance, 107, I I 7,
140
creatinine clearance, 96, 117,
140
glucose clearance, 114
hexamethylenetetramine clearance, 117, 140
phosphate clearance, 188
renal blood flow, 95, 116
sucrose clearance, 116, 139
xylose clearance, 116, 139
Phosphate, 185
Pituitary gland, anatomy of, 225
antidiuretic hormone, 153, 2 I 0,
233
and diabetes insipidus, 22 5
Plasma, composition of, 145
electrolytes, 1 50
ionic strength, 153
osmotic pressue, 1 5 1
total fixed base, 1 53
water, 145
Polyuria, experimental, 225
Potassium, 158
INDEX
Proteins, glomerular excretion of,
32
plasma, osmotic pressure of, 28,
30
Proximal tubule, 8, 35, 21 7, 232
Reflexes, conditioned, 224
Renal-portal vein, 15
&.It de.6ciency~ 164Skiodan, 196
Sodium, 158
Sucrose, 60, 116, I 38
Sulphate, 189
Sulphocyanate, 198
Thin segment, 9,10,217,232
Threshold substances (see Cushny's
theory)
Tubular acidification of urine, 36,
17 1
Tubular clearance, 80
Tubular excretion, 17, 43
of chloride, 46
of creatine, 46, 107
of creatinine, 46, 94
of diodrast, 196
of hippuran, 196
of hydrogen ion, 176
of indigocarmine, 46
of iodide, 46
of magnesium, 4-6
of neutral red, 46
of nitrite, 46
of phenol red, 46, 48, 72
maximal rate, 81
of phosphate, 186
of potassium, 46
of sulphate, 46
of sulphocyanate, 46
of thiosulphate, 46
of urea, 40, 46, 119
of uric acid, 46, 194
of water, 46
Tubular reabsorption, 1 7
of amino-acids, 198
of bicarbonate, 36, 173
of chloride, 35, 161
of electrolytes, 23 I
of glucose, 37, 110,23 1
of inorganic anions, I 98
of phosphate, 39, 186
of sulphate, 189
of urea, 119, 125
of uric acid, 195
of water, 34, 38, 202, 230
Tubular secretion, I 7
Tubules, structure of, 10
aglomerular, in fish, 44
in mammals, 14, 50
excretion by, 46
blood supply of, 13
chemical transformations in, 17,
179, 19 2
chick, in vitro cultures of, 48
impermeability of, 99
Urea, 119
clearance, effect of urine flow on,
12 5
comparisons of, 259
effect of diet on, 252
" standard and maximum,"
~23
Urea excretion in lower animals,
119
Uric acid, 194
Urine, acidity of, 36,171
limiting concentration of, 203
osmotic pressure of, 204, 231
Urine flow (see Water)
Veins, renal,
13
INDEX
3 10
" Water center," :u6
Water excretion, 201, 208, 218,
230
intoxication, 166
reabsorption, obli~atory and facultative, 231
isotonic and hypertonic, 203,
23 1
Xylose, 60, 116,
13~