Ion Exchange Mechanisms in the Nephron
By ROBERTW . BERLINER, MI.D.
Accumnulating evidenee favors the view that in biologic systemws, the active transport of
strong electrolytes involves coupled exchanges of ions, usually of sodium for potassium.
In the present paper, the author considers the renal exchange of potassium, sodium and
hydrogen in this light, and reviews current concepts concerning the mechanisms involved
in the secretion of these ions by the kidney. He indicates that new investigative teehnies
will be required to establish that the kidney behaves with respect to coupled ion exchanges
as do nerves, red blood cells and frog skin. He concludes by cautioning against extrapolation of experimental results froimi one species to another.
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T HE TITLE "Ion Exchange Mechaniisms
in the Nephron" permits a more or less
wide ralnge of subject matter depenlding upon
the interpretation of the phrase ' ion exchange
mechanisms." This presentationl will be concerned with a few aspects of the processes
reabsorptive process is essen-tial for the evaluationi of the secretory sodium-potassium exchange, sinlce only the differenee between reabsorptioni and secretioni can be measured. To
quantify secretion, it is first niecessary to assign some value to reabsorption. Gilman was
the first to propose that reabsorption of potassium was equal to the filtrationi of potassiumthat is, that the filtered potassium was completely reabsorbed before the potassium destinied for exeretioni was added bv secretion.5
At the time, 10 or 12 years ago, this seemed
a rather unlikely possibility; but as time has
passed and mnore data have been accumulated,
it first became useful to adopt this as a working hypothesis,0 and then as a view for which
there is a considerable body of experimental
involved in the excretion of acid aiid potassium which are the processes which have been
shown to result in the replacement of 1 ion
in the urine by another. However, as knowledge inereases coneerninig the traiisport of
strong electrolytes generally, the evideniee increasingly favors the concept that all such
active-transport processes inivolve coupled exchanges-usually of sodium for potassiuni. At
least such exchanges appear to be implicated
in nerve' in red blood cell2 and in frog
skin,3 and it seems reasonable to expect that
when adequate investigative technics have
been devised for the more definitive study of
renal tubular processes, simnilar nmechanisms
will be encountered. Inideed, the carrier inechanisni now widely adopted as the model for
ion transport implies ion exchange.4
With respect to potassium exeretion, nio attemept will be made to review the entire field
certain aspects related to relativelv recent
work will be considered. Onie of these aspects
(concerns the site anid extent of potassiunm reabsorption in the tubule. Wlhile very little
is known about the mechanism concerned in
this process and it is not, strictly speaking.
one which can be identified with the ion
exchange processes, some knowledge of the
evidence.
The evidence for this view is based largely
oni 2 phenomena: first, the dependence of the
excretion of potassium on the excretion of
sodium and secomid, the lack of relationship
between the glomerular filtration rate and the
excretion of potassium when the excretion of
sodium is maintained. Although earlier data
illustrating the depenidence of the excretion
of potassium on the exeretioni of sodiuni will
be considered later, the most striking demonstration of this phenomenon is to be seen in
stop-flow studies.
Figure 1, taken from some recent studies
by Jaenike and Berliner,7 shows the usual
patterii of electrolyte concentrationis in stopflow studies. In this particular instance the
first few samples collected, shown at the left
of the figure, differ from the usual because in
From the National Heart Institute, National Institutes of Health, Bethesda, MNld.
891-
9Circulation,
Volume XXI, May 1960
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CUMULATIVE VOLUME ML.
Figure 1
Stop-flow pattern obtained during mannitol diuresis in the dog. The dead space had been
filled with mineral oil.7 First specimens collected appear a!t the left of the figure. (Republished by permission of the Journal of Clinical Investigation.7)
Circulation, Volume XXI, May 1960
893
l
894
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these studies the pelvic dead space was filled
with oil. The first samples, therefore, differ
from free flow because they are derived from
the tubule system and have been modified
during the period of stop-flow. This is not
important for present purposes, but will explain the different appearance of these data
from the figures of Vander, Sullivan, Malvin,
and Wilde." 10 With this exception, the pattern of potassium concentration seen here does
not differ significantly from that previously
published by others.8 " The concentration of
potassium shows a minimum in samples which,
from their very low concentrations of sodium
and chloride, are identified as having sojourned in distal tubules during the period
of stop-flow. This low potassium concentration might be due to reabsorption of potassium at the indicated site. However, the samples
from that site must traverse the remainder
of the tubule system before they are collected
and the more distal parts of the tubule certainly can and do secrete potassium.9n 10 The
low concentrations of potassium might also
be interpreted as being due to failure to
secrete potassium into those particular samples. There is a logical explanation for this
possibility in that they contain virtually no
sodium to be exchanged for potassium. These
2 explanations have been distinguished in
experiments by Walker and Cooke and their
associates at Johns Hopkins." The results
of these experiments very clearlv indicate
that the latter interpretation is correct, that
is, that the low potassium concentrations are
due to inability of the more distal parts of
the tubules to add potassium to the virtually
sodium-free distal tubule samples. The experiments were done using a modification of the
stop-flow technic devised by Murdaugh and
Robinson.'2 This modification consists of interrupting the stop-flow at the end of 4 minutes to permit samples from 1 site to move
down to another. Flow is then stopped for an
additional 4 minutes following which the
usual type of collection is made. If, during
the interruption of stop-flow, about 3 or 4 ml.
is permitted to escape from the tubules, most
of the high potassium samples leave the tu-
BERLINER
bules and the low sodiunm-low potassium
samples are moved into the region in which
potassium concentration was previously high.
WVhen the pattern from this second oeclusion
is examined, there is no distal potassiumi peak.
Furthermore, if the secretion of potassium
is markedlv enhanced by the adininistration
of the carbonic anhydrase inhibitor, acetazoleamide, the marked distal peak observed
in the initial collection is still obliterated in
the second part of the interrupted stop-flow.
On the other hand, if chlorothiazide is used
so that the ininimal concentration of sodium
in distal tubule samples is mnuch higher, the
potassium peak, although somewhat reduced,
is still present. The question arises whether
the failure to observe a potassiumi peak during
the second occlusion does not stem from either
damage to, or exhaustion of, the secretory
mechanism during the prolonged period of
stop-flow. This problem was tested by permitting 8 to 10 ml., rather than 3 to 4 ml., to
escape between occlusions so that the low
sodium samples could move out of the tubules;
the results indicate that under this circumstance the potassium peak in the second occlusion was indistinguishable from the first.
Several conelusions can be drawn from
these observations: (1) potassium can be
secreted only into fluids which initially contain sodium; (2) the potassium minimum in
stop-flow experiments owes its localization
primarily to the absence of sodiumn in the same
samples. Had the urine, in the monients preceding stop-flow, arrived at this site already
freed of potassium but not of sodium, the result would be exactly that observed. Both
more distal and more proximal samples would
contain higher concentrations of sodium amid
therefore gain potassium in passing the secretory site after reinstatement of flow, while
those around the sodium concentration minimum would remain free of potassium. It can
be concluded, concerning the site of potassium
reabsorption, that it may be at the region
which is marked by the low conceintrations
of potassiuni in stop-flow pattermis, but it niay
also be anywhere proximal to it. Furthermore, the concentration of potassium in these
Circulation, Volume XXI, May 1960
ION EXCHANGE IN THE NEPHRON
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low potassium samples reveals nothing about
how much potassium was left in them by the
reabsorptive process, since they subsequently
gain potassium while passing the secretory
site. If some intervention, such as the administration of chlorothiazide or the infusion of
sulfate, results in a higher concentration of
potassium in the low potassium samples, it
does not warrant the conclusion that the reabsorption of potassium has been inhibited ;8 13
this reservation is particularly pertinent if
the intervention increases the concentration
of sodium in these samples, in which case it
will enhance their capacity to accept potassium after flow is reinstituted. As a matter
of fact, data to be presented shortly, much
of it derived after just such interventions,
strongly support the view that even under
these conditions all of the filtered potassium
is reabsorbed.
It is apparent from the data already considered that in some tubule segments all, or
nearly all, the potassium can be reabsorbed.
However, this reabsorption, which occurred
during the relatively prolonged stasis of stopflow, might not occur during free flow. The
data of Davidson, Levinsky, and Berliner14
show that the same extensive reabsorption of
potassium does occur in free flow. The pertinent experiments involved the separate collection of urine from each kidney of the
trained, unanesthetized dog which had been
previously prepared by a bladder-splitting
procedure.15 At appropriate times the filtration rate in the right kidney was reduced by
inflation of a cuff previously placed around
the right renal artery and connected to the
outside by a fine polyethylene catheter.16 This
made it possible to use the left kidney as a
control for the right and thus to compensate
for changes with time in the excretion of potassium from the control kidney. When no
attempt was made to provide a high rate of
sodium excretion, reduction of the filtration
rate produced a sharp drop in sodium exeretion and with it a marked, although lesser,
drop in potassium excretion. This is illustrated
in figure 2. Since sodium excretion frequently
fell to quite low levels, the results were consistent with the interpretation that the obCirculation, Volume XXI, May
1960
895
served effect was due, not primarily to the
change in filtered potassium, but to the decrease in the sodium available for exchange
with potassium in the more distal parts of
the nephron.
Accordingly, measures of various sorts were
taken to increase sodium excretion to such
an extent that a high rate of sodium excretion
was maintained even when glomerular filtration was reduced. The procedures which were
used were the administration of the mercurial
diuretic, salyrgan, the carbonic anhydrase
inhibitor, acetazoleamide, and the poorly reabsorbed anion, sulfate, in the form of sodium sulfate. The result obtained, as shown
in figure 3, was independent of the procedure
used to maintain sodium excretion. Reduction
of glomerular filtration rate by up to 35 per
cent was entirely without effect on the excretion of potassium, although sodium excretion
fell to an extent equal to or greater than the
reduction of filtration rate. The excretion of
potassium was maintained at the same level
as in the control kidney whether that level
represented only 15 to 20 per cent of the concurrent rate of filtration of potassium at the
glomeruli, as was frequently the case wheii
salyrgan was administered, or, as was usual
when acetazoleamide was used, when the rate
of excretion of potassium exceeded the rate at
which it was filtered. The only reasonable interpretation of these data is that the filtered
potassium makes no appreciable contribution
to that excreted in the urine. If only a few
per cent of the filtered potassium were excreted, the total excretion of potassium should
have been detectably modified by the change
in filtration rate. It should also be noted that
the data can be explained only if the reabsorption precedes the secretion.
The data derived from micropuneture studies are the only ones which pertain directly
to the localization of the site of potassium
reabsorption. These data are conflicting. Wirz
and Bott,'7 in the only micropuncture study
of potassium in the mammal, found that in the
rat the concentration of potassium fell markedly in the first half of the proximal tubule.
At about the same time, Bott also found
that the concentration of potassium was
896
BERLINER
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Figure 2
Potassium (left) and sodium excretion (right) during reduction of the glomerular filtration rate in dogs in which no attempt was made to maintain sodium excretion. Ordinate:
ratio of potassium or sodium excretion of the right (experimental) kidney to that of
the left (control) kidney; Abscissa: ratio of inulin clearances right kidney to left kidney.
Open symbols: conttrol periods (before inflation of cuff
right renal artery); Solid
symbols: experimentol periodls. (Repvblished by permission of the Journal of Clinical
on
Inrcestigation.14)
markedly reduced in the proximal tubule of
Necturus.'8 But, subsequently, using different
and probably more reliable methods, Bott did
not find an appreciable reduction in the concentration of potassium in the proximal tubule of Necturus.19 Nevertheless, in view of
the opposing electrical potential,20 even the
maintenance of an unchanged concentration
requires active transport of potassium-l (or a
very considerable solvent drag effect) ;21
otherwise, if active transport were not involved, the potassium concentration should
iise to almost twice that in plasma in order
for the chemnical gradient to balance the electrical gradient. It may be, thein, that reabsorption of potassium is completed in some
distal segment, but for the reasons
stated earlier, the site cannot be identified
by the stop-flow technic.
The recent observations of Hilger, KlIumper
and Ullrich22 based on microcatheterization
of the hamster papilla, have suggested, although they did not unequivocally establish,
that potassiumn secretion occurs in the collecting ducts. Data from the stop-flow experimenits of Jaenike and Berliner7 suggest that
the same is true in the dog. However, it should
be pointed out that the secretioni of potassium
cannot be confin:ed to the collecting ducts but
must, in large measure, be contributed by cortical portions of the nephron. It is not difficult
to produce, and maintain over extended pemore
Circulation, Volume XXI, May 1960
ION EXCHANGE IN THE NEPHRON
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riods, potassium clearances twice the rate of
glomerular filtration, which in the dog would
be about half the renal plasma flow. Since,
barring synthesis by the kidney, no substance
can long be cleared at a rate exceeding the
blood flow, this means that the potassium secretory site must receive a flow of blood which
can supply the requisite potassium. Even assuming that there is no reabsorption of the
filtered potassium, and disregarding the probable relative exclusion of potassium from the
iedulla by the countercurrent flow of the
blood, the most generous estimates of medullary blood flow would not include enough potassium to supply the secreted potassium.
Similar considerations probably also apply to
the availability of ammonia precursors to the
collecting ducts, but the necessary data for
the calculation are less easily obtained.
There is little information concerning the
mechanism by which the potassium-sodium
exchange is accomplished. It appears not unlikely that potassium-sodium exchange underlies the sodium extrusion mechanism which
characterizes virtually all animal cells. However, except for the red blood cell, potassium
seems to be close to electrochemical equilibrium23 in those cells that have been studied.
This may be due to a high permeability to
potassium which enables potassium to be distributed in such a way that there is little
departure from an electrochemical potential
gradient of zero. The known low permeability
of the red blood cell to cations will adequately
explain its departure from the behavior of
other cell types. In the case of membranes
such as frog skin and renal tubule epithelium,
which perform oriented transport, there is an
additional requirement for a differential permeability of the 2 surfaces of the cell facing
the exterior and interior of the body. This is
essentially the model of Ussing and KoefoedJohnsen,3 in whieh potassium is close to
electrochemical equilibrium across the inwardfacing surface of the cell, but not across the
outward-facing surface which has a low permeability to potassium. The common sensitivity of all the sodium-potassium transport
mechanisms, including that of the renal tubules, to strophanthidin and other cardiotonie
Circulation, Volume XXI, May
1960
897
steroids suggests, as pointed out by Orloff and
Burg,24 that a similar sodium-potassium exchange process at the basal surface of the
tubule epithelial cells underlies the monovalent electrolyte transport systems of the rena]
tubules. Whether or not any additional process is required to explain the secretion of potassium into the urine is uncertain, since the
value of the electrical potential gradient between tubule lumen and peritubular fluid has
Inot been measured at the right place and under the right conditions. However, the conicentration ratio (urine to interstitial fluid)
for potassium probably rarely exceeds 20 or
30 and the required 80 to 100 mV may well
be presenit at these times. It should be noted
that so long as the cell membranes are pernmeable to chloride, and chloride is present in
appreciable coneen-tration in the lumen, there
would be a continuous flow of chloride from
lumen to the peritubular fluid. This current
of chloride ion would short-circuit the poten tial, keeping it relatively low and tending to
suppress the accumulation of potassium in the
lumen.
Although there is some virtue in simple
hypotheses, the fact that a relatively simple
model to explain net sodium-potassium exchange can be devised does not mean that
nothing more is involved. One circumstanee
that makes this model seem incomplete arises
in consideration of the problem of acidification. The ratio of hydrogen ion coneentration
in urine to that in plasma may reach 1,000 or
more and a transtubular potential of 180 mY
or more would be required to establish such
a gradient passively. This suggests, although
it does not prove, the existence of some more
specific exchange mechanism, presumably at
the luminal face of the cell as proposed in
the model of Pitts9 (fig. 4). The addition of
such an exchanger to the model would account
for the exchange of potassium for sodium and
explain the competitive relationship between
potassium and hydrogen ion,6 a phenomenoln
which is a little more difficult to fit in with
the simple model of a single pump.
In the further consideration of hydrogen
ion exchange, a problem of definition exists.
It has been fairly generally accepted that the
BERLINER
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Figure 3
Potassium (left) and sodium excretion (right) during reduction of the glomerular filtration rate in dogs with maintained sodium excretion from the experimental kidney. See
legend figure 2. (Republished by permission of the Journal of Clinical Inrestigation.14)
reabsorption of bicarbolnate anid the formation of titratable acid are effected by the secretion of hydrogen ion in exchange for sodium (fig. 5).4, 2, 26 The secreted hydrogen
ion is assumed to coimbine with bicarbonate
to yield carbonie acid which in turn yields
CO2 and water which mtiay diffuse from the
urine. There has been little direct evidence
to support this view, but because this unitary
hypothesis is simplest and there is no evidence
to the contrary, it seems expedient to retaini
it. This view has, indeed, been somewhat
strengthened by the recen:t fildings of Gottschalk and Giebisch and their respective associates27' 28 that the pH of proximal tubule
urine in the rat does niot, as had long been
considered to be the case, remuain the same as
that of plasma. Instead, it is lowered appreciably. Thus, one assumned difference between
bicarbonate reabsorption in the proximal, and
acidification in the distal tubule has been
largely eliminated from consideration. One
little-recognized consequence of the concept
that bicarbonate reabsorption is effected by
Circulation, Volume XXI, May 1960
ION EXCHANGE IN THE NEPHRON
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hydrogen-sodium exchange is that considerably more hydrogen ion is secreted in the
proximal tubule where most of the bicarbonate is reabsorbed than in the more distal regions where the extremes of acidity are
reached. This consequence is made all the
more one-sided by the observation that bicarbonate concentration, as well as volume flow,
is reduced in the proximal tubule.
One other very interesting consequence
which may make possible the experimental
verification of the hypothesis has been pointed
out by Walser and Mudge.29 It can be caleulated that if proximal bicarbonate reabsorption involves the formation of carbonic acid
and its subsequent dehydration to carbon dioxide, as would be the case with hydrogen ion
secretion, the latter step can proceed at a
rate equal to the rate of bicarbonate reabsorption only if: (1) there is carbonic anhydrase
in the surface of the proximal tubule cells so
that the reaction of carbonic acid to C02 and
water in the lumen is catalyzed; or (2) there
is appreciable accumulation of carbonic acid
in the fluid in the tubule-enough to bring the
pH down approximately 1 pH unit below
its equilibrium value. Unfortunately, the type
of pH measurement which has been made,
since it involves withdrawal or at least isolation of an element of fluid, does not exclude
(although it does make it improbable) the
possibility that the pH of the fluid in situ is
as low as required by hydrogen ion secretion
in the absence of carbonic anhydrase. In the
interval required to do the analysis, uncatalyzed dehydration of carbonic acid might have
raised the pH to the observed value.
The third effect of hydrogen-sodium exchange is the accumulation of ammonia in the
acidified urine. The process is believed to involve the formation of ammonia from appropriate precursors in the cell of the renal tubule and the diffusion of the nonionic ammonia, that is NH3, into the urine; in the
urine it combines with hydrogen ion to fornm
ammonium ion to which the tubule cell is
presumed to be relatively impermeable. There
are those who prefer to believe that the excretion of ammonium ion involves direct exCiTrculation, Volume XXI, May 1960
899
TUBULAR URINE
PERITUBULAR FLUID
pH 4.6
No4
K
pH 74
-_ Na
-
f
HHCOH
HCOO
HZC03
Figure 4
Schematic representation of distal tubule exchange
mechanisms. (Republished by permission of the
American Journal of Medicine.9)
change of ammonium and sodium ions.30 31
This view, however, fails to account for one of
the most striking features of ammonia exeretion (at least in man and in the dog) -its
dependence upon the pH of the urine.32'33
The argument advanced that glutamine hydrolysis yields, at the pH within cells, glutamate and ammonium ions31 is without cogency
since even if free ammonia is formed, it must
be considered to be instantaneously in equilibrium with its ionic form which greatly
predominates at all physiologic pH's. This
has, however, little bearing on the form in
which the ammonia crosses the cell membrane.
With regard to the latter question there is
a very considerable body of evidence indicating that cell membranes are very much more
permeable to nonpolar, nonionized substances
than to their ions.
In closing, it seems warranted to mention a
need for some caution in accepting data obtained in rats as quantitatively applicable to
all mammals. While it is unlikely that similar
mechanisms in different species differ in their
qualitative nature, and indeed we have reason
to hope that the fundamental similarities of
transport mechanisms extend from tissue to
tissue as well as from one animal type to another, nevertheless, it may be misleading to
extend quantitative considerations from one to
another. This is well illustrated in some of
the disagreements concerning the determinants of ammonia excretion. These disagreements have certain of the features of the old
story about the blind men and the elephant.
900
BERLINER
MECHANISM OF URINARY ACIDIFICATION
PLASMA
TUBULE CELL
URINE
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Figure 5
Schematic representation of hydrogen-sodium exchange and its effects on the composition
of fluid in the tubule lumen.
Those who have studied ammonia excretion
in the rat have been impressed with the
nmarked and easily demonstrable increases in
the glutaminase activity of the renal cortex,
which over any relatively extended period are
highly correlated with the rate of ammonia
excretion.30 34 However, adaptation to acidosis in the dog is not associated with any such
change in glutaminase activity,35 and in this
species the relationship of ammonia excretion
to the pH of the urine is much more striking
and reproducible.33 3 Furthermore, the increase in ammonia excretion, which occurs in
rats along with an increase in glutaminase
activity in response to carbonic anhydrase inhibitors, is absent in both dog36 and man.
It is important, therefore, to extend the
basis of our knowledge over as wide a range
as possible anid, particularly with regard to
quantitative aspects, to hold some reservations, until our investigations have been extended to the specific eircumstances coneerning whieh we wish to draw conclusions.
References
1. HOGKIN, A. L., AND KEYNES, R. D.: Active
transport of cations in giant axons from Sepia
and Loligo. J. Physiol. 128: 28, 1955.
2. GLYNN, I. M.: Action of cardiac glycosides on
sodium and potassiumn movements in human
red cells. J. Physiol. 136: 148, 1957.
3. KOEFOED-JOHNSEN, V., AND USSING, H. H.: Nature of frog skin potenitial. Acta physiol.
scandinav. 42: 298, 1958.
4. BERLINER, R. W.: Renial secretion of potassium
and hydrogen ions. Fed. Proe. 11: 695, 1952.
5. GILMAN" A.: Personal communication.
6. BERLINER, R. W., KENNEDY, T. J., JR., AND ORLOFF, J.: Factors affecting transport of potassium and hydrogen ions by renal tubules.
Arch. internat. pharmnaeodyn. 97: 299, 1954.
7. JAENIKE, J. R., AND BERLINER, R. W.: Study of
distal renal tubular functions by a miodified
stop flow technique. J. Clin. Invest. 39: 481,
1960.
8. VANDER, A. J., MALVIN, R. L., WILDE, W. S., AND
SULLIVAN, L. P.: Localization of the site of
action of chlorothiazide by stop-flow analysis.
J. Pharmaeol. & Exper. Therap. 125: 19, 1959.
9. PITTS, R. F.: Some reflections on mechanisms of
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ION EXCHANGE IN THE NEPHRON
10.
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action of diuretics. Am. J. Med. 24: 745,
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SULLIVAN, L. P., WILDE, W. S., MALVIN, R. L.,
AND VANDER, A. J.: Site of renal transport of
potassium as revealed by stop flow analysis.
Fed. Proe. 17: 158, 1958.
WALKER, W. G., AND COOKE, R.: Personal communication.
MURDAUGH, H. F., JR., AND ROBINSON, R. R.:
Magnesium excretion studied by stop-flow
analysis. J. Clin. Invest. 38: 1028, 1959.
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Ion Exchange Mechanisms in the Nephron
ROBERT W. BERLINER
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Circulation. 1960;21:892-901
doi: 10.1161/01.CIR.21.5.892
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