Cireulation Research
MAY
1971
VOL. XXVIII NO. 5
SUPPLEMENT NO. II
An Official Journal at the American Heart Association
Function of the Chronically Diseased Kidney
THE ADAPTIVE NEPHRON
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By Carl W. GoMscholk, M.D.
ABSTRACT
Adaptive morphological and functional changes in the chronically diseased
kidney are described in historical perspective and their correlation is stressed.
The consequences of decreased glomerular filtration rate (GFR} in the
presence of unchanged dietary intake on the mechanisms of excretion of
substances passively reabsorbed, actively reabsorbed, and secreted are
reviewed. Under these circumstances the plasma concentrations of creatinine
and urea are necessarily elevated, but not that of electrolytes with regulated
tubular transport. In the case of sodium, fractional excretion and GFR are
reciprocally related in order to maintain unchanged rates of excretion and
plasma concentration. With phosphate, regulated tubular reabsorptioii can
prevent an increase in plasma concentration provided the GFR does not fall
below approximately 25 ml/mih. In the case of potassium, tubular secretion
becomes apparent at marked decreases infiltrationrate.
These adaptive regulatory changes are considered predictable and necessary
in order for the patient to survive, and are supported by compensatory
morphological changes in some of the surviving nephrons. Heterogeneity in size
of the surviving nephrons, particularly the proximal tubules and glomeruli, is
documented and the prediction is made .that these structural changes are
associated with appropriate changes in rates of transport. Data are presented
demonstrating marked heterogeneity of nephron filtration rates and proximal
tubular transit times in experimentally diseased kidneys. The necessity of
utilizing appropriate methods of study to obtain data on individual nephrons is
stressed, as is the lack of knowledge concerning the mechanisms that lead to
the compensatory structural and functional changes.
It is concluded that the adaptive changes exhibited by the kidney with
chronic renal disease are another and a special example of adaptive growth and,
therefore, that it is more appropriate to think in terms of "adaptive nephrons"
and not "intaet nephrons."
KEY WORDS
creatinine clearance
urea clearance
potassium excretion
phosphate excretion
tubular transport
electrolyte concentration
• This review will concern certain general
aspects of the excretory function of the
chronically diseased kidney and the correlaDr. Gottschalk is Kenan Professor of Medicine and
Physiology, University of North Carolina School of
Medicine, Chapel Hill, North Carolina 27514; and a
Career Investigate! for the American Heart Assooiation.
Supplement
11 to Circulation Research, Voli. XXVlll
and XXIX,
sodium excretion
renal disease
tion of structure and function in this situation,
The ideas I will present are not new or
original and I shall quote liberally from the
literature in order to trace their historical
"
'
This study was supported by a grant-in-aid from
the American Heart Association, and by Grant HE02334 from the National Institutes of Health.
Ma} 1971
11-1
II2
GOTTSCHALK
but differ, of course, in their handling by the
tubule and are illustrative of the several
mechanisms of tubular transport.
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The fundamental pathophysiological disorder in chronic Bright's disease is the loss of
nephrons. This is so obvious that it sometimes
escapes us. Destructive morphological changes
cause the fall in glomerular filtration rate
(GFR) and tubular transport capacities and
evoke compensatory morphological and functional responses. In general, structure and
function are correlated in biological systems,
and I see no reason to believe that such a
correlation does not hold in chronic kidney
disease but, in fact, many reasons to believe
that it does hold. For the patient to survive,
the kidney must exhibit appropriate and
adaptive functional changes. These are supported by adaptive morphological changes
that occur in some of the surviving nephrons.
And since I consider this only a special
example of adaptive growth I prefer to speak
of "adaptive nephrons" and not "intact nephrons."
Let me introduce my remarks by quoting
from the Preface of Pitts' splendid book The
Physiology of the Kidney and Body Fluids.1 In
stressing the importance of the regulatory
function of the kidneys, Pitts poses this
question (pp. 6-7):
"Consider two persons, one with normal renal
function, the other a patient with long-standing,
chronic, bilateral renal disease. Suppose both
individuals ingest identical diets containing 70
grams of protein, 250 grams of carbohydrates,
and 100 grams of fat (2,200 cal). Suppose each
diet contains 5 g of sodium chloride, 2 g of
potassium and 1 g each of phosphorus and sulfur;
suppose fluid intakes are equal and generous.
How, then, will the composition of the urine of
these two individuals differ? The answer is: They
will not differ.
"Each person will excrete per day 12 g of
nitrogen, 5 g of sodium chloride, 2 g of potassium
and 1 g each of phosphorus and sulfur. If fluid
intake is high, the urine volumes will be the same.
True, the patient with chronic renal disease may
excrete a little protein, some red blood cells and
casts, but die major excretory products will be the
same."
Creatinine Clearance
The simplest relationships hold for a substance which is excreted only as a result of
glomerular filtration without tubular reabsorption or secretion. For this purpose I will make
the simplifying assumptions that this is true
for creatinine in man and that the amount of
creatinine produced per day is the same in the
person with serious renal disease as it was
during health. Consider the relationships
which must be present for the person to be in
a steady state. If the normal GFR is 120
ml/min and the normal plasma creatinine
concentration is 1 mg%, then 1.2 mg of
creatinine are excreted in the urine per
minute. For these to be steady-state values the
rate of excretion must equal the rate of
production. If either rate changes, the plasma
creatinine concentration will change appropriately so that the amount of creatinine
excreted will equal that produced. If the
filtration rate is reduced by disease to one-half
of normal, the plasma creatinine concentration
will rise to 2 mg%, and to 4 mgS? if the filtration
rate is one-fourth of normal, and so on, since
the GFR and plasma concentrations must be
reciprocally related in order for the amount
excreted to remain unchanged. Because of
deviations from the simplifying assumptions I
have just made, one cannot interpret endogenous creatinine determinations on patients in
these precise terms, but qualitatively the
relationship holds and the plasma creatinine
determination is a useful and simple clinical
tool.
Urea Clearance
The relationship between the plasma urea
concentration and the urea clearance is quite
similar. Although the urea clearance is always
less than the GFR due to tubular reabsorption, it is a relatively constant fraction of the
filtration rate so long as the rate of urinary
flow is approximately 1.5 to 2.5 ml/min. For a
steady state to be present the product of the
urea clearance and plasma concentration must
How does this happen? I should like to
review with you as prototypes the mechanisms
of excretion of creatinine, urea, sodium, and
potassium in the presence of a reduced mass
of nephrons. These substances are all filtered
Supplement
I
Ito Circulation Research, Voli. XXVIll
and XXIX,
May
1971
11-3
HYPERTENSION XIX—SALT, HORMONES, AND HYPERTENSION
creatinine, there is no regulation of plasma
concentration and there is no adaptation of
the mechanisms of excretion. I use the word
adaptation to mean an adjustment or modification in response to changes in the internal
environment.
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equal the amount of urea being made
available for excretion. The latter will be
constant if protein intake and metabolism are
constant.
Goldring and Chasis2 demonstrated over 25
years ago that these relationships hold in
patients with glomerulonephritis and hypertension (Fig. 1). In the figure the coordinates
are logarithmic plots, so that their product, the
amount of urea excreted, forms a straight line.
The upper diagonal line describes the relation
when the rate of urea excretion equals 24 mg
and the lower line when it equals 8 mg/min,
which would result from daily protein intakes
of approximately 100 and 34 g/day, respectively.
Not unexpectedly, the experimental findings
conform to the predicted results. The tubular
handling of urea is largely, but perhaps not
exclusively, a process of passive reabsorption,
and when the rate of filtration is decreased the
plasma urea concentration will rise until the
amount of urea filtered is sufficiently great
that the amount of urea excreted equals the
amount produced. Thus, with both urea and
Sodium Excretion
With sodium the situation is completely
different in two respects: (1) the body cannot
tolerate large changes in plasma sodium
concentration; and (2) tubular reabsorption
of sodium is regulated. But again, what
happens in the chronically diseased kidney is
predictable, since the amount of sodium
excreted must equal that ingested, otherwise
the person will either swell up and burst or
wither away and die. When the kidneys can
no longer make the appropriate adjustments
the patient is no longer available for study
except to the pathologist. The arithmetic
involved is quite simple. In order for the
amount of sodium excreted to remain the
same when the GFR diminishes, the fraction
of filtered sodium excreted must increase. If
eoo
\
400
400
\
;
\
200
200
\
*>o
°\
*
X
100
100
\"°
75
A5
8
. \
\ '
•••
45
X?
35
35
\
25
IS
75
25
15
HYPERTENS ION
CLOMERULONEPHRITIS
2
3
5
0
20
O
60 SO »1
Relationship of blood urea concentration to the urea clearance in 103 observations in patients
with hypertension and glomerulonephritis (urinary flows above 1.5 ml/min). See text for
interpretation. (Reprinted from Goldring and Chasis,* by permission.)
Supplement II to Circulation Research, Voli. XXVlll and XXIX, May 1971
GOTTSCHALK
11-4
NoCI Diet:
» 7.0 9/day
*3.5g/day
fluorohydrocortisone
Theoretical
Curves
0
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40
30
60
90
120
Glomcrular Filtration Rate (ml/min)
60
80
100
120
GLOMERULAR FILTRATION RATE (ml/m
FIGURE 2
Predicted and observed relationship between glomerular filtration rate and percentage of
filtered sodium excreted under steady-state conditions in patients on 3.5-g and 7.0-g sabdiets.Pre dictedandobservedrelationsh
(Reprinted from the Journal of Clinical Investigation,* by permission.)
the dietary intake demands that 1% of the
filtered load of sodium be excreted in order for
the person with a normal GFR to remain in
balance, fractional excretion will double to 2%
when the GFR falls by one-half. When the
GFR is only one-fourth of normal, excretion of
sodium must equal 4% of the filtered load, and
so on. Kleeman and associates3 were the first
to present data showing this relationship in
patients with various types of kidney disease.
Although there was considerable variation in
results, due at least in part to differences in
dietary intake, the relationship was abundantly clear.
These relations have been confirmed and
extended by Slatopolsky, Bricker, and colleagues,4 and Figure 2 shows both theoretical
curves and curves drawn from actual determinations on patients with dietary intakes of
7.0 g or 3.5 g salt/day. The larger intake
requires, of course, a somewhat greater
fractional excretion at any given filtration rate.
Under their closely controlled conditions, the
observed values on the two diets agree very
well with the predicted ones. The relationship
still held when 9-a-fluorohydrocortisone was
Supplementil t
given. Schultze, Shapiro, and Bricker8 have also
made the important observation that fractional excretion by a remnant kidney in dogs
was similar to that of the opposite kidney
when the latter was in place and functioning,
but that fractional excretion of sodium by the
remnant kidney increased rapidly and appropriately when the dog's filtration rate was
reduced by removal of the contralateral
kidney. Unfortunately, I do not know the
mechanism responsible for this adaptive
change in reabsorption following change in
GFR. I agree with Bricker that it is unlikely
that the increase in sodium excretion results
merely from a urea diuresis. To the contrary,
sodium excretion appears to be more directly
and precisely regulated.
Although the quantitative verification is
recent, the concept itself is not new and was
presented in detail by Platt in 1950.6 After
explicitly describing the mathematical relationship between the amount of sodium
filtered and excreted and the fact that the
latter must remain constant for a person with
unchanged dietary intake to survive as renal
o
Circulation Research, VOLT. XXVIII and XXIX, May
1971
HYPERTENSION XIX—SALT, HORMONES, AND HYPERTENSION
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failure advances, Platt presented data and
described them as follows (pp. 369-370):
"The percentage of sodium excreted is charted
against serum creatinine as an indication of the
degree of renal failure. It would have been
preferable to chart it against creatinine clearance
but this would have excluded a large number of
outpatient observations in which accurate timing
of urine could not be carried out and so the
creatinine clearance could not be calculated. The
chart clearly shows that as renal failure advances
there is a general tendency for the percentage of
sodium excreted to increase. It is also clear that
most of the eases in which heart failure coexisted
with renal failure were exceptional in showing a
percentage excretion of sodium which was not
commensurate with the degree of renal failure."
Potassium and Phosphate Excretion
Platt also described the relationship regarding potassium excretion and phosphate
excretion with advancing renal failure, which
I shall discuss shortly. The concept goes back
even further, however, and Gamble7 states in
the fifth edition of his Chemical Anatomy,
Physiology and Pathology of Extracellular
Fluid:
"The integrity of the ionic structure of blood
plasma requires that the concentration of its
individual components be held at closely stationary values. This is accomplished by regulated
reabsorption from glomerular filtrate."
Gamble discussed the relationships with
reference to phosphate, potassium, and sodium chloride. His calculated values for potassium demonstrate that when the GFR is
reduced to 10% of normal the filtrate would
contain less than the daily intake of potassium
as long as the serum potassium value remained at 5 mm/L. Gamble did not suggest
that potassium is secreted, perhaps because of
the variations seen in serum potassium in
severe renal disease and because variations in
dietary intake affected his calculations. This
was written slightly before Berliner, Mudge,
and colleagues demonstrated that the tubules
can, in fact, secrete potassium.8' 9
PHOSPHATE
Gamble's calculations of the amount of
phosphate filtered per day at various filtration
rates and their implications for the rate of
Supplement
II to Circulation Research, Vols. XXVIII
and
11-5
reabsorption are of great interest, and his
predictions have been abundantly confirmed
in recent years. Gamble emphasized that by
regulated reabsorption from the glomerular
filtrate the plasma phosphate level is kept
within normal limits over a wide range of
filtration rates and does not rise until GFR is
reduced to approximately 20% of its normal
volume. He states:
"The chart* explains the absence of rise in plasma
HPO4 in the early stages of renal disease. It may
be noted that eventual elevation of P is not
progressive for a given reduction of filtration rate;
it remains at the position required for removal of
dietary load in the filtrate. Rise in phosphate is
not, however, as in the case of urea, a harmless
event since it disturbs the normal electrolyte
structure of the plasma. The therapeutic implication of reduction of load is shown in the chart."
By "load" Gamble meant dietary intake.
Goldman and Bassett10 were apparently the
first to confirm in man Gamble's predictions
concerning phosphate. They found that the
serum phosphorus remained within the normal range until the GFR was reduced to 25
ml/min or less, and showed convincingly that
these normal phosphate values resulted from
appropriate reductions in phosphate reabsorption as the GFR fell. The latter observations
were confirmed by Slatopolsky and colleagues.11 As with sodium, the St. Louis
workers have also demonstrated that the
percentage of filtered phosphate excreted by a
unilaterally diseased kidney changes appropriately when the contralateral nondiseased
kidney is removed.12 Again, the exciting thing
is not that a particular relationship holds in
advancing renal failure, since we knew that it
must, but that a regulatory mechanism leads
to appropriate changes in tubular reabsorptive
activity.
POTASSIUM
Although Gamble considered the appropriate model, it remained for Leaf and Camara
to demonstrate in 1949 the process of renal
tubular secretion of potassium in man.13 They
accomplished this in studies on four patients
XXIX, May
•Chart 17-D.
1971
11-6
GOTTSCHALK
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FIGURE 3
Nephron from a patient with, chronic glomerulonephritis showing extreme atrophy of the proximal convolution. The loop of Henle and distal convolution are
not markedly changed. (Reprinted from Oliver,15
by permission.)
with severe chronic renal insufficiency by
demonstrating that the amount of potassium
excreted exceeded that filtered. More recently
Kleeman and colleagues3 demonstrated in
patients with advancing degrees of renal
insufficiency • that the amount of potassium
excreted is equal to an increasingly large
percentage of the filtered potassium, but in
only a rare individual did it actually exceed
the amount that could be accounted for by
filtration. Allison and Kennedy, however, in
their studies of the effects of furosemide in
patients with severe renal insufficiency, found
abundant evidence of tubular secretion of
potassium and demonstrated that under these
conditions the amount of potassium excreted
may exceed the amount filtered by up to
sevenfold.* Again, the renal response is a
•Personal communication.
FIGURE 4
Nephron from a patient with chronic glomerulonephritis showing marked hypertrophy and hyperplasia of
the proximal convolution. (Reprinted from Oliver,11
by permission.)
predictable one, and the intriguing question of
the control mechanisms remains and requires
explanation. These questions stimulate many
investigations, but it is beyond the purview of
this presentation to attempt to review them
here.
Functional and Structural Adaptations
in the Diseased Kidney
I should like to turn now to a consideration
of some aspects of the structure of the
chronically diseased kidney. I consider that
the basic disorder, the specific defect if you
will, in the garden variety of chronic kidney
disease is the loss of nephrons and not damage
to some one or another of their specific parts.
SapplemM 11 u Circulation Research, Volt. XXVlll mi XXIX, May 1971
11-7
HYPERTENSION XIX—SALT, HORMONES, AND HYPERTENSION
A r
B
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This leads to certain compensatory morphological and functional changes. Fundamentally, and as so well put by Dr. Jean Oliver,14 I
believe that structure and function are inseparably correlated as two aspects of the
biological process. Thus we can characterize
structure and function individually, but we
must not separate them..
First, I wish to stress something not fully
appreciated by many functionalists but which
has been emphasized by Oliver,15 namely, that
not all of the morphological changes in the
nephrons of chronically diseased kidneys are
destructive ones. Obviously many are, and in
fact lead to actual disappearance of the
nephrons. But compensating for these changes
are progressive changes in many of the
remaining nephrons—changes of hypertrophy
and hyperplasia, particularly of the proximal
convoluted tubule and of the glomerulus,
changes which are similar to those seen in the
remaining kidney after unilateral nephrectomy. Structurally these are supernephrons,
and I believe the morphologist is justified in
suspecting that they are likely to be accompanied by increases in functional capacity as
well.
This morphologically adaptive process was
well recognized by Platt,16 and in his Lumleian Lectures of April 1952 he described it in
detail and compared the morphological and
functional adaptations in patients with chronic
renal disease with those seen after subtotal
nephrectomy in animals. Furthermore, there is
no basis for concern with the question of
whether or not structurally altered nephrons
produce urine. Oliver has demonstrated in
exquisite detail that all remaining nephrons in
the end-stage kidney exhibit structural alterations. There are no morphologically unaltered
nephrons left to produce urine. I do not use
FIGURE 5
Mosaic photomicrograph of three proximal tubules
and attached glomeruli (A, B, C) microdissected from
a case of juvenile familial nephrophthisis. The arrows
mark the ends of the proximal tubules. (Reprinted
from Fetterman et al.,17 by permission.)
Siptlemsnl U <o OrnlMim Re,e*rcb. Voli. XXVIll Md XXIX, May 1971
11-8
GOTTSCHALK
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the pejorative term "damaged nephrons" but
"altered nephrons," since as Oliver15 stresses,
the changes in nephrons are of two basic
types: either an increase or a decrease in size.
To quote from his 1939 book entitled Architecture of the Kidney in Chronic Bright's
Disease (p. 8):
"Two such nephrons, the one large (hypertrophied) and the other small (atrophied), can
therefore be considered the basic architectural
units from which the kidney of chronic Bright's
disease is built. It is true, as we shall see later,
that an infinite number of modifications of these
types is found in the abnormal kidney, but always
there is present the fundamental variation of
increase or decrease in some part at least of the
altered structure."
Examples of such nephrons dissected from
diseased human kidneys are shown in Figures
3 and 4. Figures 5 and 6 show the marked
variation in size of proximal convolutions from
kidneys of patients with hereditary nephritis
studied by Fetterman et al.17
It would certainly come as a great surprise
to me if there were not differences in function
associated with such differences in structural
configuration. The changes in function that I
anticipate are changes in rates of transport
and probably some permeability properties.
Since there is greater structural heterogeneity
among the surviving nephrons of the chronically diseased kidney than in normals, one
who believes in correlation of structure and
function must expect greater functional heterogeneity as well. Great heterogeneity of rates
of function—yes, but chaos, no. To the
contrary, Oliver,14 for instance, believes that
there is exquisite correlation of structure and
function. And, without question, in order for
the patient to survive the remaining nephrons
in the diseased kidney must be responsive to
the changing needs of the patient. With
progression of the renal disease the range of
V
•
\
FIGURE 6
Mosaic photomicrograph of two proximal tubules and
glomemli (A, B) microdissected from a patient with
hereditary nephritis. (Reprinted from Fetterman et
al.,17 by permission.)
Supplement
II to Circulation Research, Vols. XXVlll
and XXIX,
May
1971
11-9
HYPERTENSION XIX—SALT, HORMONES, AND HYPERTENSION
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flexibility in response to dietary and other
demands diminishes and the patient will no
longer survive when the nephrons are no
longer sufficiently responsive.
Unfortunately, data on the function of
structurally altered nephrons are very scarce,
and even more scarce is information on the
structure and function of the same individual
nephron. Some of the earliest such information was furnished by Oliver et al.18 in a 1941
study of dogs with chronic nephritis. Nephrons were isolated by microdissection following vital staining with trypan blue. The dye
content of enlarged nephrons appeared to be
increased in proportion to their proximal cell
mass. In other proximal convolutions, atrophic
stretches of epithelium contained no dye,
whereas hypertrophic segments were dyefilled. These results provide a clear-cut correlation between structure and function at the
individual nephron level.
I should like to emphasize the latter point
and state the obvious. If one wishes to gain
information about the structure and function
of individual nephrons, individual nephrons
must be studied. This requires the use of such
techniques as microdissection and micropuncture. Kidney clearances are not adequate for
this purpose. Let me remind you of what
Homer Smith19 said about this:
"Since there are 2 million-odd nephrons in the
kidneys it is self-evident that no overall method of
examination can directly reveal what is occurring
in individual nephrons. Impairment in any
clearance function may be the result of a partial
reduction of function in all nephrons or the
complete reduction of function in a few.
Conversely, constancy of function does not imply
constancy in all contributing nephrons, since
function may be increased in some nephrons at a
time when it is decreased in others."
Results of some clearance studies by
Baines20 demonstrate the type of conceptual
error that they may lead to. The inulin
clearance and tubular transport maximum for
glucose (TmG) were measured in rats 3 to 20
days after injection of dichromate. TmG was
reduced from 3 to 15 days after dichromate
injection (Fig. 7). We know from other
studies on these and similarly treated rats21
that the individual nephrons do not function
R A T - T m 6 DURING RECOVERY FROM DICHROMATE
INDUCED RENAL DAMAGE
mg/min
lOOmg
_ M E A N OF CONTROLS
(13) 1 S.O. * #
lOOmg
Kldniy 1-0
dry «rt.
mg/mlo
KXJ
2-0
Kidney
DNA-P 1 0
— MEAN OF CONTROLS (IS) ± S.O.
CONTROLS
3
7
11
15
19
doys after dichromate injection
Comparison of tubular transport maximum for glucose (TmG) in rats following injection of
potassium dichromate with that of control rats. (Reprinted from Baines,10 by permission.)
Supplement 11 u CircuUlitm Rtiarcb. Volt. XXVUl md XXIX, May 1971
11-10
GOTTSCHALK
RAT-COMPARISON OF Tm6 a C,n AFTER
DICHROMATE INJECTION
— H U H 0 * COMTMHS -
0
3
7
II
15
19
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days after injection of potassium dichromate
Comparison of TmQ/Cin (tubular transport maximum
for glucose/simultaneous inulin clearance) ratios of
rats following injection of potassium dichromate with
those of control rats. (Reprinted from Baines,*0 by
permission.)
normally during this time. Glucosuria at
normal plasma glucose concentrations persists
for two weeks after dichromate treatment
because dichromate produces necrosis of the
proximal pars convoluta and the rate of
reabsorption of salt and water and the
secretion of PAH are markedly reduced in the
proximal convolution. Yet, as is shown in
Figure 8, when these values for TmG were
divided by the simultaneous inulin clearance,
the ratios of TmG/Ci n in the dichromateinjected animals were the same as in the
normal control rats. Such a result could be
interpreted as indicating persistence of normal
function in a reduced number of normal
glomerulotubular units. We know very surely,
however, that this is not the correct explanation in this case since microdissection shows
that every nephron has been damaged and
micropuncture has shown the expected functional disturbances. The existence of glucosuria
at normal plasma glucose concentration also
indicates that this is not the correct interpretation. The normalization of the glucose Tm
produced by factoring by the inulin clearance
in these kidneys must be interpreted as being
due either to reduction of both functions or to
redistribution of function to non-necrotic
tubular segments if the nephron filtration rates
are unchanged in the contributing glomerulo-
tubular units. This circumstance does not, of
course, exclude some alternative interpretation, including persistence of normal function
in a reduced number of normal nephrons,
under other circumstances. It merely bears out
what one knows is surely a fact; there are
alternative explanations for such results as
these, and one cannot choose among them on
the basis of the clearances alone.
I should like to comment on the filtration
rate of individual glomeruli in the chronically
diseased kidney. The experimental literature
in animals, and now the clinical literature,
give abundant evidence that following uninephrectomy the filtration rate of the remaining kidney increases until it approximates that
of the normal condition when two kidneys
were present, and microdissection studies in
animals have shown increases in size of the
nephron, especially the glomerulus and proximal tubule. 22 ' 23 More recently, Fetterman et
14.0
ISO
1M
26.0
300
LENGTH OF PROXIMALS-mm.
Histogram comparing lengths of 30 proximal tubules
of nephrons microdissected from a donor control
kidney with those of 30 proximal tubules from the
rejected aUograft kidney. (Reprinted from Fetterman
et al.,17 by permission.)
Supplement 11 to Orc^uim Raarcb, Volt. XXVU1 end XXIX, May 1971
HYPERTENSION XIX—SALT, HORMONES, AND HYPERTENSION
11-11
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0 10 &0 30 40 50 60 70 80 90 100
"0 10 ZO 30 40 50 60 70 80 90 100
Per cent of original number oP glomeruli remaining after operation.
FIGURE 10
Relation between reduction in the number of glomeruli and reduction in clearances following
subtotal nephrectomy. (Reprinted from the Journal of Clinical Investigation,* i by permission.)
al.17 have presented a fascinating microdissection study of two normal kidneys removed at
autopsy, one of which was transplanted and
functioned for four years. Compared with the
nephrons of the nontransplanted kidney, the
proximal tubules of the transplanted kidney
showed a marked increase in average length
as well as a striking heterogeneity of length
(Fig. 9).
Hayman and colleagues24 studied the relationship between the percentage of glomeruli
remaining after subtotal nephrectomy in dogs
and their creatinine and urea clearances. The
operation involved partial surgical removal of
one kidney and complete removal of the
opposite kidney. They found that the creatinine clearance was reduced much less than
the number of glomeruli (Fig. 10). With
approximately 50% of the glomeruli remaining,
the creatinine clearance was approximately
75% of normal; and with approximately 25% of
the glomeruli remaining, the creatinine clearance was reduced to only 50%. There was a
somewhat similar relationship between the
urea clearance and the number of glomeruli.
Hayman and colleagues25 found the opposite
relation in patients in whom clearance determinations were made shortly before death.
These studies are more difficult to interpret,
however, since it was impossible to be sure
Supplement
II to Circulatu.
• c b ,
Volt. XXVlll
and XXIX,
that the glomeruli counted had been functional.
Much more recently, Bank and Aynedjian26
reported that in experimental bilateral pyelonephritis in rats, individual nephron filtration
rates averaged 160% of normal; but even more
striking was the marked heterogeneity in
filtration rate in individual nephrons. Heterogeneity of individual nephron filtration rate
was also very evident in collaborative studies
with Dr. Oliver of rats with chronic renal
insufficiency following administration of potassium dichromate and mercuric chloride one
month earlier. Single nephron filtration rates
ranged from 10 to 150 nl/min, with a control
range of 15 to 60 nl/min. An even more
strikingly heterogeneous function in these rats
was the proximal transit time. In normals the
transit time varied from 3 seconds for a
relatively early to 15 seconds for a late
proximal puncture. In the damaged kidney
there were numerous values within this range,
but the variation was from 3 to 111 seconds. In
still other nephrons it was infinite. When
converted to velocity per unit tubular length
the heterogeneity was just as marked. I
believe that the available evidence is overwhelmingly in favor of increased heterogeneity of rates of function in the remaining
nephrons of chronically diseased kidneys.
May
1971
11-12
GOTTSCHALK
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In speculating on the correlation of the
morphological form of the nephrons seen in
Blight's disease with their probable functional
behavipr, Oliver15 states in his book on renal
architecture (pp. 23-24):
"The question is perhaps simpler in the case of
the atrophied unit. Surely few would deny the
likelihood that its functional ability has been
decreased. Not only is its internal surface, the
seat of exchange between cell and urine, greatly
reduced, but its epithelium in a reversion towards
the more primitive type has lost all those
morphological attributes that are generally indicative of functional ability. And granting such a
reduction in function as its structure suggests,
leads almost as a corollary to the supposition that
in the hypertrophied unit an increase in function
accompanies increased size. . . . A provisional
conclusion . . . can be that, though the disturbing
factors operating in Blight's disease may well
decrease the functional ability of these large
elements, they are nevertheless the only visible
mechanisms that remain carrying on the work of
the kidney. They are in this sense a phenomenon
compensatory to the regressive changes that are
slowly destroying the 'organ.'"
This leads me to a statement of what I
consider the two most interesting aspects of
the chronically diseased kidney. They are (1)
the mechanisms that result in the compensatory structural changes, and (2) the control
systems that permit and lead to the appropriate functional changes. In respect to the
morphological aspects, I conclude that the
adaptive structural changes that occur in
residual nephrons represent yet another and a
special example of adaptive growth. What is it
that leads one nephron to hypertrophy when
another has been removed? This is largely an
unknown area. We do not even know what
the mechanisms are that lead to increase in
size of the glomerulus and tubule during
growth and development in the normal
animal. Axe they determined independently?
Or is only one primarily determined, and does
this in turn determine the changes in the
other? Adaptive growth in surviving glomeruli
and nephrons is essential in permitting functional adaptations and survival of the patient
with chronic kidney disease. Recognition of
this places consideration of the structure and
function of the chronically diseased kidney in
Supplement
a different and broader perspective—that of
adaptive growth in general and the unknown
mechanisms which underlie it. It also leads me
to conclude that it is more appropriate to
think in terms of adaptive nephrons rather
than intact nephrons.
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Function of the Chronically Diseased Kidney: The Adaptive Nephron
CARL W. GOTTSCHALK
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Circ Res. 1971;28:II-1-II-13
doi: 10.1161/01.RES.28.5_Suppl_2.II-1
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