Osmotic Concentration and Dilution
in the Mammalian Nephron
By CARL WILLIAM GOTTSCHALK, M.D.
The micropuncture evidence relating to the location and the mechanism for concentration
and dilution of the urine is reviewed. As required by the countercurrent hypothesis for
urine concentration, these data demonstrate that in the presence of antidiuretic hormone,
the tubular urine is first concentrated in the descending limb of the loop of Henle and
then diluted in the ascending limb of the loop before its final concentration in the collecting ducts. The loop of Henle is believed to function as a countercurrent multiplier
system, and the vasa recta as countercurrent diffusion exchangers. Additional data are
required during water diuresis before the course of events in this condition is established.
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THE micropuncture technic which was
originally applied to the study of kidney
function by Wearn and Richards' has been
particularly fruitful in elucidating the course
of events as they occur in concentration and
dilution of the urine. Over 20 years ago
Walker and his collaborators2 demonstrated
that proximal tubular fluid in frogs and Necturi was isosmotic with plasma, and that the
hypo-osmotic urine characteristic of these animals first appeared in the distal tubule. In
1941 Walker, Bott, Oliver and MacDowell3
demonstrated that a large percentage of the
glomerular filtrate was reabsorbed proximally* by an isosmotic process in rats, guinea
pigs, and 1 opossum. They were able to collect
only 3 samples of fluid from distal convolutions. One of these was isosmotic, but the other
2 were hypo-osmotic. This latter observation
was rather surprising, as the final urine was
hyperosmotic. They were reluctant to attach
too much significance to their few analyses of
distal fluid, but pointed out that the findings
suggested that the site of active chloride re-
absorption was proximal to that of pure water.
More recently, Wirz4 reported that proximal tubular fluid was also isosmotic in rats
undergoing a water diuresis, and that fluid in
the early distal convolution was hypo-osmotic
under all conditions. During water diuresis,
the fluid remained hypo-osmotic throughout
the distal convolution and collecting ducts, but
became isosmotic by the end of the distal convolution when the final urine was hyperosmotic. Miss Mylle and I have been able to confirm most of the above results, and to extend
them.5 This is fortunate, for the 3 groups have
worked independently and have been widely
separated, either by the years, or by many
miles, and this confirmation lends credence to
the results. It is only proper to point out that
although the results obtained by micropuneture may be very helpful, the methods are so
difficult that they present many potential pitfalls.
We have also found (fig. 1) the proximal
tubular fluid to be isosmotic, regardless of
whether the final urine was hyper- or hypoosmotic. In hydropenic rats elaborating
markedly concentrated urine, the fluid in the
early distal convolution is consistently hypoosmotic, and in the second half of the distal
convolution, isosmotic, but never hyperosmotic
(fig. 2). Clearly, the hyperosmotic phase of
urine concentration is established in the collecting ducts.
The hypotonicity of the fluid entering the
early distal convolution can be explained on
From the Department of Medicine, University of
North Carolina School of Medicine, Chapel Hill, N. C.
Dr. Gottschalk is an Established Investigator of
the American Heart Association.
*In these and the subsequent studies, the proximal
tubule is considered to extend from the glomerulus
to the thin deseending segment of the loop of Henle;
the distal convolution, from the macula densa-where
the ascending limb of the loop touches its own
glomerulus-to its junction with one or more other
distal convolutions to form a collecting duct.
Circulation, Volume XXI, May 1960
861
862
GOTTSCHALEh
U/P
9.0
OSMOLALITY
8.0
* HYDROPENIA
o
-
MANNITOL DIURESIS
SALINE DIURESIS
GLUCOSE DIURESIS
o UREA DIURESIS
*DIABETES INSIPIDUS
*
a
9.0
8.0
70
OSMOLALITY
7.0
HYDROPEN I A
6.0
60
S
6 RATS
50
5.0
A
4.0
4.0
0
A
18 RATS
0
3.0
p
2.0
0
1.5
3.0
2.0
~~~~~~0
F/P
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0
3
OSMOLALITY
F/
.5
P
OSMOLALI TY
o
1.1
1.0
0.9
0.8
0.7
0.8
0.7
0.6
0.6
.0
1.0
0.9
VV
0.9
0.8
0.7
0.5
0.41
04
0.3-
0.3
I.0
~
0
T
06
A
0.5
0.5
~
*
'
0.4
*
.
.
k
0.3
% DISTAL CONVOLUTION
l
I
|
o
|
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20
40
60
0
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IJ
80
loo
Figure 1
Osmnolality ratios of proximal tubular fluid and
urine in rats. (Republished by permission of the
American Journal of Physiology.5)
URINE
I
20
40
60
80
I
100
Figure 2
Osmolality ratios of fluid from the distal convolution and of urine during hydropenia. Different
symbols refer to different ralts. (Republished by
permission of the American Journal of Physiology.5)
the basis of hyperosmotic reabsorption of
solute in the loop of Henle, or secretion of
water into the loop. If it is due to reabsorption of solute in excess of water, the only
solute present in sufficient quantity to explain
this degree of hypotonicity is sodium chloride.
Accordingly, in an attempt to differentiate between these 2 possible mechanisms, osmotic
diuresis was induced with the nonreabsorbable
solute, mannitol, and with sodium chloride
(fig. 3).
When a 25 per cent solution of mannitol
was infused intravenously, the rate of urine
flow increased
up
to 80 times that of the hy-
dropenic state, and the urine/plasma osmnolality ratios were correspondingly low. Again,
early distal fluid was hypo-osmotic, but the
osmolality ratio was not less than 0.6, and
late distal samiples were isosmotic or nearly
so. Similar results were obtained during glucose diuresis.
When sodium chloride, given as a 5 or 7
cent solution, was the loading solute, comparable urine flows were achieved, but the
degree of hypotonicity of the fluid in the
early distal convolution increased. Here, a
large percentage of the samples had fluid/
per
Circulation,
Volume
XXI, May 1960
-
OSMOTIC REGULATION IN THE MAMMALIAN NEPHRON
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plasma osmolality ratios less than 0.6; the
minimum fluid/plasma ratio was 0.3. As before, fluid from the late distal convolution
was isosmotic. The increase in the degree of
hypotonicity with sodium chloride is impressive and constitutes, we believe, strong evidence that the hypotonicity of the fluid in the
early distal convolution is due to hyperosmotic
reabsorption of sodium chloride in the loop of
Henle.
All of the data so far can be explained by
the conventional theories6 for the reabsorption
of sodium and water, i.e., the proximal "obligatory" reabsorption and the distal "facultative" reabsorption of sodium and water,
with the hyperosmotic phase probably resulting from active transport of water by the cells
of the collecting ducts. This interpretation,
however, neglects the countercurrent hypothesis of Kuhn and collaborators, which was
first proposed in 1942,7 but which had few
proponents until recently. This new and
revolutionary theory, treated in detail in 1951
by Hargitay and Kuhn,8 proposes that the
hairpin-like loop of Henle functions as a
countercurrent multiplier system in which a
small concentration gradient, at any giveni
level in the loop, is multiplied as the tip of
the loop is approached. This system was believed to result in an increasing osmotic pressure in the medulla of the kidney. The theory
further proposes that the concentration of the
urine results from the passive withdrawal of
water from the collecting ducts as they
traverse this area. Their original experimental
evidence, gained in conjunletion with Wirz,
was a cryoseopic study of rat kidney slices.9
They found that, at any given level, the osmotic pressure of the fluid was identical in the
lumen of all the tubules. There was also an
increasing osmotic gradient from the cortex,
which was isosmotic with arterial plasma, to
the tip of the papilla. Although the recent
analyses of distal tubular fluid4' 5do not invalidate the concept of an inereasing osmotic
gradient from cortex to papilla in at least
some of the medullary structures, they do
demonstrate that all tubular fluid at a given
level in the kidney does not have exactly the
Circulation, Volume XXI, May 1960
863
N a C I v s. MANNITOL a GLUCOSE
DIURESIS
U/P
OSMOLALITY
4.0
3.0
NoCI
2.0
A
FS
OSMOLALITY
1.1
1.0
-
Mannitol a
Glucose
I.5
i-
0.9
0.8
0.7
191.0
"-Mannitol a
Glucose
0.6
0.5
0.4
0.3
% DISTAL CONVOLUTIC)N
URINE
I
I
J
j0 20 40 60 80 100
Figure 3
Compatrison of the osmolality ratios of fltid froin
the distal convolution and of urine during hypertonic sodium. chloride diuresis 'with the ratios
during hypertonic mannitol and glucose diuresis.
(Republished by permission of the American Journal of Physiology.5)
same osniolality. They also suggest to us that
postmortem diffusion probably accounted for
this aspect of the results of Wirz, Hargitay
and Kuhn.9 Since some doubt remained that
the osmolality in all of the medullary structures exceeds that of the cortex, additional
direct sampling and measurement of osmolality seemed to be required. Wirz10 accomplished this for the medullary blood vessels
864
GOTTSCHALK
II
I
I
I
I
-
T
*
* LOOP OF HENLE FLUID
14001 o VASA RECTA BLOOD
7~
//
*
1200-
*
/
/4
/~~~~~
49/
'V
o
1000 .0C
/
* /0
C7*
0
-l/
o
0
O/
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En
10/
/(
/p
800[ C>E
0
Aw~~
600[
,,.,o'
4001
/0
/ 0
DLLECTING DUCT FLUID mOsm / kg H20
1000 1200 1400
600
800
a
400
a
I
AL
I
Figure 4
Relation betwceen the osmolality of collecting duct fluid, fluid from the loops of Ilenle,
and vasa recta blood in various desert rodents. (Republished by permission of the American Journal of Physiology.5)
by demonstrating that blood from the vasa
recta at the tip of the hamster papilla had
the same osmolality as that of the final urine.
More recently, we accomplished the same for
fluid from the loop of Henle. Under conditions
of proper illumination, it is possible to identify loops of Henle in the living hamster
papilla and to sample their contents. Fluid
from the bends of the loops, or very close
thereto, had essentially the same osmolality as
that from a collecting duct at the same level
(fig. 4). These results demonstrate that the
urine is first concentrated and then diluted
before its final concentration, as required by
the countercurrent hypothesis. AWe were also
able to confirm Wirz 's observation that the
osmolality of blood from the
same as that of fluid from
recta is the
collecting duct
vasa
a
at the
same level.
These observations indicate to us that a
countercurrent mechanism is operative in the
nephrons of the kidney, as well as in the vasa
recta. The details of the mechanism remain to
be established, and one can propose numerous
variations of the countercurrent hypothesis
that will explain the facts that are now available. We agree that the active transport on
which the system depends is performed by the
nephron, and that the loop of Henle functions
as a countercurrent multiplier svstem. The
exchanges in the vasa recta, as in other blood
vessels, are probably passive and they are beCirculation, Volume XXI, Ma-y 1960
OSMOTIC REGULATION IN THE MAMMALIAN NEPHRON
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lieved to function as countercurrent diffusion
exchangers, making the concentrating mechanism far more efficient. According to this view,
the loop of Henle functions as a source of
sodium ions for the medullary interstitium,
and as a result of its hairpin-like shape and the
nature of its permeability, an osmotic gradient
is established in it as well as in the other
medullary structures. Another general feature
is that all exchanges are believed to take place
between the lumina of the various structures
and the adjacent interstitium, and not directly
between tubular lumina. Fortunately, with
such a mechanism, one is able to explain all
movement of water as being secondary to
previous movement of solute. Our present
working hypothesis,5 which is based on the
assumption that there is no active transport
of water, follows:
" Sodium, by an unknown active mechanism,
and chloride, as a result of the electrochemical
gradient established, are believed to be transported out of the relatively water impermeable ascending limb of the loop of Henle
into the interstitium of the medulla until a
gradient of perhaps 200 mOsm. per Kg. of
water has been established between the fluid
of the ascending limb and interstitium. This
single effect is multiplied as the fluid in the
thin descending limb comes into osmotic
equilibrium with the interstitial fluid by the
diffusion of water out of, and probably the
diffusion of some sodium chloride into, the
descending limb, thus raising the osmolality
of the fluid presented to the ascending limb.
In this fashion, an increasing osmotic gradient
is established in the direction of the tip of the
papilla, and yet at no level is there a large
osmotic difference between luminal and interstitial fluid. In contrast, the epithelium of the
collecting ducts in the presence of antidiuretic hormone is believed to be water permeable
and functionally sodium impernmeable (net
transport is probably small although there
may be diffusion into, and active transport
out of, the collecting ducts). This results in
diffusion of water out of the collecting ducts
into the hyperosmotic medullary interstitium
until the fluid remaining in the collecting
Circulation, Volume XXI, May 1960
865
ducts becomes correspondingly concentrated.
It is apparent that in order for the urine to
be significantly concentrated, the flow through
the loops of Henle must considerably exceed
the flow through the collecting ducts.8 This is
accomplished under the influence of ADH by
diffusion of water out of the distal convolution into the interstitium of the cortex, reducing the volume and increasing the osmolality
to the isosmotic level of the fluid presented to
the collecting ducts. As suggested by SehmidtNielsen,1 urea is probably also involved in
some unknown fashion. It appears most likely
to us that urea diffuses into the descending
limb, contributing to the osmotic gradient
established in the loop, and diffuses out of
and/or is actively transported out of the ascending limb. Unlike sodium, depending on
the circumstances, there may be net diffusion
of urea from the interstitium into the collecting ducts (exaltation), or vice versa, as water
is extracted from them.
"Recent work by Hilger, Kliimper and
Ullrich12 indicates that active reabsorption of
sodium by the epithelium of the collecting
duct also occurs. This reabsorption may play
an important role in maintaining a high concentration of sodium in the interstitium of
the medulla by preventing loss of sodium in
the urine. In the presence of ADH, reabsorption of sodium or other solute by the cells of
the collecting duct would lead to the isosmotic
reabsorption of water at the level at which
the reabsorption of the solute oceurred, and
a reduction in the volume of fluid presented
to any more distal portion of the eollecting
ducts. In the absence of ADH, reabsorption
of solute would lead to further dilution of
the collecting duct fluid; this view is consistent with the observations of Wirz4 and ourselves (unpublished observations) on the osmolality of fluid from the end of the distal
convolution and of urine.
"The vasa recta also participate in this
mechanism, as first shown by Wirz'0 and now
confirmed by us, and apparently function as
countercurrent diffusion exchangers as shown
in figure 5. (See Scholander13 for a discussion
of this general biologic principle.) They make
866
GOTTSCHALK
TRANSPORT
Active Possive
SODIUM
UREA
WATER
m
o
m
--
'4
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Figure 5
Diagram depicting the co untercurrent mechanism as it is believed to operate in a
nephron with a long loop and in the rvasa recta. The num)tbers represent hypothetic
osmolality valtues. No quantitative significance is to be attached to the number of arrows
and only net mnovements are indicated. As is the case with the vascular loops, all loops
of Henle do not reach the tip of the papilla, aiid hence the fluid in themn does not become
as concentrate(1 as thait of the final urine, but on.ly as concentrated as the medullary interstitial fluid at the same level. The active sodium transport by the epithelium of the
collecting duct is based on the work of Rilger, Kliimper and Ullrich.'2 Kuhn17 has
recently considered the theoretic aspects of the activation of the counter-cutrrent multiplier by active sodium transpsort. (Republished by permission, of the Americaln Journal
of Physiology.5)
the enitire mechanism far more effective, resulting in a higher osmotic gradient, by telndinig to trap sodiumi, urea and other diffusible
solutes in the medulla. This aspect of the
imiechanism has recently been clearly diseussed
by Berliiner and his co-workers,14 who have
emphasized the imnportanee of a low effective
medullary blood flow in establishinlg a high
osnmotic gradient. We would poinlt out, however, that the osmotic equilibration of the
blood in the vasa reeta with medullarv interstitial fluid in all likelihoo(d is niot due only to
the diffusion of solute into their descendiug,
and out of their ascending limubs, but also
results in large part fromn the diffusion of
water in the opposite direction. This shorteircuitinog of water across the tops of the
vascular loops may be, at least in part, responlsible for the seemingly rich content of
red cells in the vasa recta at the tip of the
papilla. The efficiency of the countercurrent
exchange in the vasa recta is critical, for they
probably renmove not only the blood entering
the medulla, but also the water that diffuses
Circulation, Volume XXI, May 1960
OSMOTIC REGULATION IN THE MAMMALIAN NEPHRON
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from the thin descending limbs of the loops
of Henle and the collecting ducts. This water,
with solutes isosmotic for the particular level
of the medulla, presumably moves into the
vasa recta because of the gradient of its chemical potential established by the colloid osmotic
pressure of the plasma proteins, since the hydrostatic pressures in the capillaries and interstitium are the same.15 The more nearly the
osmotic pressure of the blood leaving the
medulla approaches that of the blood entering
it, the less solute will be lost from the medulla,
and hence the higher the osmotic gradient established. "
As noted above, many hypotheses are consistent with the presently established facts.
For example, the hypothesis of Berliner et
al.,14 in which both the descending and ascending limbs of the loop of Henle were postulated to be relatively water-impermeable and
actively to transport sodium from lumen to
interstitium, is compatible with present information if the thin descending limb is assumed to be water-permeable in the presence
of antidiuretic hormone. In such a system, the
volume of fluid reaching the tip of the loop
would be somewhat smaller than in the hypothesis detailed above, because transport of
sodium out of the thin descending limb would
lead to further extraction of water.
Ullrich16 has proposed that the active transport of sodium in the medulla is limited to the
epithelium of the thick ascending limb and
collecting ducts, and that exchanges in the
thin limbs are passive. He visualizes that the
osmolality of the loop and of the interstitial
fluids is the same throughout the inner medulla, and that osmotic equilibration with
collecting duct fluid lags behind so that the
fluids in the loop and in the collecting duct
have the same osmolality only at the tip of
the papilla. We believe this hypothesis is unlikely, since we have recently been able to
demonstrate in a few loops in the papilla of
the desert rodent, Psammomys obesus,* an
increase in osmolality in the direction of their
tips.
*Kindly supplied by Dr. Bodil Schmidt-Nielsen.
Circulation, Volume XXI, May 1960
867
Micropuncture data on the diluting kidney
are few and difficult to obtain, but proximal
fluid is certainly isosmotic and early distal
fluid, hypo-osmotic. In rats in which the final
urine was quite dilute, Wirz4 found that the
fluid remained dilute throughout the distal
convolution, and perhaps was diluted a bit
further in the collecting ducts. In a small
series of observations on animals elaborating
urine which was only slightly hypo-osmotic,
we found that the fluid was isosmotic by the
end of the distal convolution and that the final
dilution occurred in the collecting ducts, presumably the result of the active reabsorption
of sodium chloride by a water-impermeable
membrane. Additional data are obviously
needed before one can be confident of the
course of events in this situation.
Antidiuretic Hormone
The micropuncture findings are consistent
with the hypothesis that the epithelium of the
collecting ducts, and perhaps the distal convolution, is rendered freely permeable to water
by the presence of antidiuretic hormone,4' 14
but we agree with Wirz4 that antidiuretic
hormone may have an additional effeet on the
concentrating mechanism. If a change in the
permeability to water of the epithelium of the
collecting duct and of the distal convolution
were its only effect, the interstitium of the
medulla could be even more hyperosmotic during water diuresis than during hydropenia,
for less water is probably extracted from the
collecting ducts during water diuresis than
during hydropenia. Among other possible
mechanisms whereby antidiuretic hormone
could facilitate the operation of the countercurrent system are 1 or more of the following
actions: (1) increased transport of sodium
by the thin, ascending limb; (2) increased
permeability to water of the thin, descending
limb; or (3) decreased medullary blood flow.
References
1. WEARN, J. T., AND RICHARDS, A. N.: Observations oii the composition of glomerular urine,
with particular ref erence to the problem of
reabsorption in the renal tubules. Am. J.
Physiol. 71: 209, 1924.
GOTTSCHALK
868
2. WALKER, A. M., HUDSON, C. L., FINDLEY, T., JR.,
AND RICHARDS, A. N.: Total molecular con-
3.
4.
5.
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6.
7.
8.
centration and chloride concentration of fluid
from different segments of the renal tubule of
amphibia: The site of chloride reabsorption.
Am. J. Physiol. 118: 121, 1937.
--v BOTT, P. A., OLIVER, J., AND MACDOWELL, M.:
Collection and analysis of fluid from single
nephrons of the mammalian kidney. Am. J.
Physiol. 134: 580, 1941.
WIRz, H.: Location of antidiuretic action in the
mammalian kidney. In The Neurohypophysis.
Heller, H., Ed. Proceedings of the Eighth
Symposium of the Colston Research Society.
New York, Academic Press, 1957, p. 137.
GOTTSCHHALK, C. W., AND MYLLE, M.: Micropuneture study of the mammalian urinary concentrating mechanism: Evidence for the countercurrent hypothesis. Am. J. Physiol. 196: 927,
1959.
SMITH, H. W.: Principles of Renal Physiology.
New York, Oxford University Press, 1956, pp.
95ff.
KSUHN, W., AND RYFFEL, K.: Herstellung konzentrierter Losuingen aus verdiinnten durch blosse
Membranwmirkung: Ein Modellversuch zur Funktion der Niere. Hoppe Seyler Ztschr. 276:
145, 1942.
HARGITAY, B., AND KUHN, W.: MAultiplikationsprinzip als Grundlage der Harnkonzeatrierung
in der Niere. Ztschr. Elektrochem. 55: 539,
1951.
9. WIRZ, H., HARGITAY, B., AND KUHN, W.: Lokalisation des Konzentrierungsprozesses in der
Niere durch direkte Kryoskopie. Helvet.
physiol. et pharmacol. acta 9: 196, 1931.
1 0. -: Der osnlotisehe Druek des Blutes in der
Nierenpapille. Helvet. physiol. et pharmacol.
acta 11: 20, 1953.
11. SCHMIDT NIELSEN, B.: Urea exeretion in mammals. Physiol. Rev. 38: 139, 1938.
12. HILGER, H. H., KLUMPER, J. D., AND ULLRICH.
K. J.: Wasserriickresorption und Ionentransport durch die Saiimmelrohrzellein der Sdugetierniere. Pfluigers Arlch . ges. Physiol. 267:
218, 1958.
1.3. SCHOLANDER, P. F.: The woinderful Ilet. Scient.
Am. 196: 96, 1957.
14. BERLINER, R. WA., LEVINSKY, N. G., DAVIDSON,
D. G., AND EDEN, M.: Dilution and conicentration of urine and action of antidiuretic hormone. Am. J. Med. 24: 730, 1938.
15. GOTTSCHALK, C. W., AND MYLLE, M.: Micropuneture study of pressures in proxinmal tubules and
peritubular capillaries of the rat kidney and
their relation to ureteral arid renal venous
pressures. Am. J. Physiol. 185: 430, 1956.
16. ULLRICH, K. J.: tber die Funktion des Nierenmarkes. Deutsche mned. Wehnschr. 84: 1197,
1959.
17. KUHN,AW., AND RAMEL, A.: Aktiver Salztransport als m6glicker (uand wahrscheinlicher) Eimzeleffekt bei der Harnkonzentrierung in der
Niere. Helvet. chim. acta 42: 628, 1959.
The First Micropuncture Studies of the Kidney
In the spring of 1921 I had the privilege of seeing a demonstration of Professor Robert
Chambers of New York in which, by means of micropipettes, he injected various substances into the cell bodies of amoebae. It excited mne to believe that the frog's kidney,
already made accessible to direct vision, might becolne accessible also to instrumental
mnanipulation. Dr. J. T. WVearn, learning of this thought, crystallized it bv suggesting
that it ilight be possible to dr-aw fluid from the intracapsular space within the malpighian
body and thus to compare its ehemnical composition with that of the blood plasma froln
which it is derived. If such a project could be successfully and comprehensively accomplished, we should gain knowledge of the miost direct character by which to estimate the
nature of the processes concerned in the separation from the blood within the glomerulus
of the fluid which is eventually to becomne urine: and a far more satisfactory basis for
study of function of the tubules would be laid than existed previously because, until we
are definitely certain concerning the amount and composition of the fluid which constitutes the head water of the stream-l flowing down the tubule, we can scarcely hope to
decide with certainty concerning the changes to which this fluid is subjected during its
passage through the tubule.-A. N. Richards. Methods and Results of Direct Investigations of the Function of the Kidney. The Beaumont Foundation Lectures, series 8.
Baltimore, Williams and Wilkins, 1929, p. 13.
Circulation, Volu me XXI, May 1960
Osmotic Concentration and Dilution in the Mammalian Nephron
CARL WILLIAM GOTTSCHALK
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Circulation. 1960;21:861-868
doi: 10.1161/01.CIR.21.5.861
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