Renal Division, National Defense Medical Center, Taipei, Taiwan, Republic of China; McGill Nutrition and Food Science Centre, Royal Victoria Hospital, McGill University, Montreal, Quebec; and Division of Nephrology, St. Michael's Hospital, University of Toronto, Toronto, Ontario, Canada M5B 1A6
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ABSTRACT |
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A deficit of
K+ of close to 300 mmol develops
in the first 2 wk of fasting, but little further excretion of
K+ occurs, despite high levels of
aldosterone and the delivery of ketoacid anions that are not reabsorbed
in the distal nephron. Our purpose was to evaluate how aldosterone
could have primarily NaCl-retaining, rather than kaliuretic, properties
in this setting. To evaluate the role of distal delivery
of Na+, four fasted subjects
recieved an acute infusion of NaCl to induce a natriuresis. To assess
the role of distal delivery of , five fasted subjects were given an infusion containing
NaHCO3. The natriuresis induced by
an infusion of NaCl caused only a small rise in the rate of excretion
of K+ (0.8 ± 0.1 to 1.9 ± 0.3 mmol/h); in contrast, when
replaced Cl
in the
infusate, K+ excretion rose to 8.3 ± 2.2 mmol/h, despite little excretion of
(urine, pH 5.8) and similar rates
of excretion of Na+. The
transtubular K+ concentration
gradient was 19 ± 3 with
and
6 ± 2 with NaCl. We conclude that the infusion of
NaHCO3 led to an increase in
K+ excretion, likely reflecting an
increased rate of distal K+
secretion. With a low distal delivery of
, aldosterone acts as a
NaCl-retaining, rather than a kaliuretic, hormone.
aldosterone; bicarbonate; ketoacidosis; sodium
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INTRODUCTION |
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DEVELOPMENT OF physiological mechanisms to adapt to prolonged periods of total lack of food is one of the most primitive yet essential strategies that have permitted the human species to survive. Understanding the basis for these critical adaptive responses could reveal the importance of control mechanisms that operate in a variety of clinical settings. In this study, we addressed the control of K+ homeostasis in prolonged total fasting.
A key element in the physiology of prolonged fasting is the need to
provide a fat-derived fuel (fat stores are abundant) to displace the
need of the brain for glucose as an energy substrate (a supply of
glucose now depends on gluconeogenesis from indispensable protein;
reviewed in Ref. 2). The water-soluble, fat-derived fuel is, for the
most part, the ketone bodies, -hydroxybutyrate (
-HB
). It takes <1
wk to develop the near steady state characterized by a modest degree of
ketosis (
-HB
in the
5-7 mM range) and acidemia (pH 7.34, 19-21 mM
) (2, 21). Subsequently, renal
adaptive mechanisms become paramount (6, 11, 15, 18, 21, 23). The
kidney filters 750-1,000 mmol of
-HB
each day, and
15-20% of this filtered load is excreted (21). The consequences
of the excretion of
-HB
on the excretion of cations such as
Na+,
K+, and
NH+4 in chronic fasting have been well
characterized (6, 11, 15, 18, 21, 23). They can be summarized as follows: during the first 2 wk of fasting, a large deficit of Na+ develops (close to 350 mmol),
but over the subsequent period of fasting, there is little additional
excretion of Na+. Similarly, there
is also a large initial kaliuresis (close to 300 mmol) (7, 22).
However, renal mechanisms for conservation of
K+ are less efficient than for
Na+, and there is a continuing
mild progression in the negative balance for
K+. Without a
K+ supplement, a mild degree of
hypokalemia develops despite the relative hypoinsulinemia, a hormonal
setting characterized by a shift of
K+ from cells (30).
The question we address in this study is, what is responsible for the
low rate of kaliuresis in subjects who have continued their total
caloric deprivation for 2 wk? This low rate of kaliuresis occurred
despite the presence of two factors that should augment it: high levels
of aldosterone (4, 6, 18) and the delivery to the distal nephron of
anions (-HB
) that are
not reabsorbed in these nephron segments (13, 29). Results indicate
that two factors seemed to limit the excretion of
K+ in these subjects: a low distal
delivery of Na+ (minor factor) and
a low distal delivery of
(major
factor). These results will be discussed in a fashion that integrates
K+ and acid-base physiology with
the aim of suggesting how aldosterone can continue to promote the
electroneutral reabsorption of NaCl while avoiding its kaliuretic
action in prolonged total fasting.
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METHODS |
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Human subjects. The study protocols were approved by the ethics committee for experiments in human subjects. Seven females and two males [age, 33 ± 2 (range 21-48 yr), initial body weight, 122 ± 7 kg] were admitted for prolonged (2-4 wk) therapeutic fasting for a severe degree of obesity. They volunteered for the study after being informed of its purpose, nature, and possible consequences. None had diabetes mellitus, gout, renal, hepatic, or cardiovascular disorders, nor had they received medications that could have influenced the present results.
During fasting, subjects maintained a daily oral intake of at least 1,500 ml of water. They were also given 16 mmol KCl (SlowK; Ciba Pharmaceuticals, Dorval, PQ, Canada) to avoid a severe degree of hypokalemia; they also received a daily multivitamin preparation (Beminal; Ayerst Laboratories, Don Mills, ON, Canada). Measurement of electrolytes and metabolites in venous blood, renal function tests, and an electrocardiogram were performed each week. Blood pressure and pulse rate were monitiored twice daily with patients lying down and standing.
Infusion studies. The purpose of the
first study was to examine whether a low distal delivery of
Na+ is the limiting factor for
K+ secretion in the cortical
collecting duct (CCD) after 2 wk of fasting. To control for possible
mixing of urines with different Na+ and
K+ excretion rates, an acute
infusion protocol was used. Four of the subjects were given an acute
infusion of 2 liters containing 300 mmol
Na+, 80 mmol
K+, and 380 mmol
Cl over 6 h, with all the
infusions starting at 0900 h. Prior to the infusion, subjects drank at
least 0.5 liter of water so that they could void hourly on request for
the 6-h period. To evaluate whether distal delivery of
was also a factor that might
influence the excretion of K+ in
this setting, five additional subjects were given an intravenous infusion of 2 liters containing 300 mmol
Na+, 80 mmol
K+, 230 mmol
Cl
, and 150 mmol
over 6 h in a second study.
Analytic techniques. Blood samples
were drawn anerobically for immediate assay of pH and
PCO2. Urine was collected without
preservative, and its pH and PCO2
were measured immediately; the concentration of
in the urine was calculated using
a pK of 6.10, and a solubility factor for
CO2 corrected for ionic strength
as previously described (3). A portion of blood and urine were each
mixed immediately with an equal volume of 10% perchloric acid at
4°C for determination of
-HB
. Assays for
Na+,
K+,
Cl
, pH,
PCO2, total
CO2, urea, creatinine, osmolality,
-HB
, and
NH+4 were performed as previously described (11, 12).
Calculations. The transtubular K+ concentration ([K+]) gradient (TTKG) was calculated using the following formula (8)
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RESULTS |
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At 2 wk of fasting, the subjects had a mild degree of metabolic
acidosis (pH 7.34 ± 0.01, 21 ± 1 mM
), hypokalemia (3.5 ± 0.1 mM),
and an elevated level
-HB
in plasma (4.6 ± 0.4 mM). Their urine pH was close to 6.0, in agreement with previous
observations (18, 22), and NH+4 and
-HB
were the predominant
urine solutes in the 24-h period (Table 1).
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To evaluate whether a low distal delivery of Na+ might limit secretion of K+ in the collecting ducts, subjects were given an intravenous load of NaCl. Prior to the administration of Na+, the rate of excretion of Na+ was 0.4 ± 0.1 mmol/h, whereas that of K+ was 0.8 ± 0.1 mmol/h. When the rate of excretion of Na+ rose to 1.6 mmol/h, there was a small rise in the rate of excretion of K+ to 1.9 mmol/h and a significant decline in urine pH from 5.7 to 5.2 (Fig. 1 and Table 2). Net K+ secretion in the terminal CCD was evaluated using the noninvasive semiquantitative tool, TTKG. The TTKG rose from 2 ± 1 to 6 ± 2 with the infusion of NaCl, and there was no significant change in the urine flow rate (Table 2).
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Because excretion is associated
with a higher rate of excretion of
K+ (3) and the infusion of NaCl
led to a fall in
excretion (fall
in urine pH, Fig. 1), a second protocol was employed to determine
whether distal delivery of
could
be an important modulator of the excretion of
K+ in these subjects. When the
rate of excretion of Na+ was not
statistically significantly different during the infusion of NaCl and
the one containing
, there was no
significant change in the urine flow rate (Table 2). The kaliuresis was
greater when
was added to the
infusate (8.3 vs. 1.9 mmol/h, respectively, Table 2). The TTKG was much higher in the subjects infused with the solution containing
(19 ± 3 and 6 ± 2, respectively, Table 2); there was no change in plasma
[K+]. These data
suggest that the delivery of Na+
to the CCD was only one factor that influenced the rate of excretion of
K+ in this setting.
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DISCUSSION |
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The principal focus of this study was to examine factors that might
limit the rate of excretion of K+
during chronic fasting. This model is of interest for three major reasons. First, the adaptations developed for survival during prolonged
deprivation of food are critically important and therefore must have
been established very early on in human evolution. Second, this is an
example of a clinical setting where the rate of excretion of
K+ is low, but there are factors
present that could augment the excretion of
K+: a high level of aldosterone
(4, 6, 18) and the delivery of anions (-HB
) that
are not reabsorbed in the distal nephron. Third, by revealing the
control mechanisms that operate in this setting, perhaps insights can
be gained into understanding the pathophysiology of clinical disorders
with a dyskalemia resulting from an altered rate of excretion of
K+.
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Balance data for Na+ and K+ during total fasting place the antinatriuresis and the antikaliuresis in perspective. Subjects who fast for >1 wk have cumulative negative balances that are close to 350 mmol for Na+ (6, 15, 23) and close to 300 mmol for K+ (7, 22). Although these subjects typically have normal values for plasma Na+ concentration ([Na+]), they are modestly hypokalemic if no supplements of K+ are given (7).
The physiological response to a deficit of
Na+ is to have a maximum renal
conservation of Na+ and
Cl. Indeed, the rate of
excretion of Na+ in our subjects
was very small (3-8 mmol/day, Table 1) and typical of that found
in other studies (6, 15, 23). Part of this renal response for maximal
conservation of Na+ involves
aldosterone. The well-established mechanism begins with extracellular
fluid volume contraction, which leads to the release of
renin and thereby an increase in the production of angiotensin II
(reviewed in Ref. 14). This latter compound stimulates the zona
glomerulosa of the adrenal cortex to release aldosterone (19).
Aldosterone acts primarily on the principal cell of the CCD, and the
response is activation of the epithelial
Na+ ion channel in its luminal
membrane (29). If Cl
are
reabsorbed along with Na+, this
system will be absolutely beneficial for survival (electroneutral reabsorption for Na+; Fig.
2A).
Alternatively, if Na+ were
reabsorbed in an electrogenic fashion (i.e., without
Cl
), there could be
continued excessive excretion of
K+, and this response is not a
desirable one (Fig. 2B). How
aldosterone could "select" electroneutral rather than
electrogenic reabsorption of Na+
in the CCD during chronic fasting will be considered here.
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The simplest possible mechanism to limit the excretion of Na+ and K+ is to limit the delivery of Na+ to the distal nephron. For this to be an effective mechanism, the [Na+] in the luminal fluid would have to be considerably less than 10-15 mM, the concentration that results in half-maximal secretion of K+ in the CCD of the rat (9). It is possible, however, that such a low distal delivery of Na+ could compromise the excretion of NH+4 or that of K+, if a need for its excretion arose (e.g., cell necrosis). As shown in Table 2, when distal delivery of Na+ was present (Na+ excretion rose), there was only a modest rise (0.8 to 1.9 mmol/h) in the rate of excretion of K+. Hence, other mechanisms were probably operating to curtail the rate of excretion of K+.
When examining the excretion of K+
in normal subjects, we were struck by the fact that the presence of
bicarbonaturia was strongly correlated with the rate of excretion of
K+ provided that aldosterone was
present (3, 25). In more detail,
led to a high [K+] in
the terminal CCD, whereas a rise in flow rate in the CCD was not a
consistent finding. For example, the maximum value for the TTKG was
close to 10 in
-free urine, whereas it was close to 20 when there was bicarbonaturia (3, 27). In
the diurnal period, the time of highest excretion of K+ was near 1200 h, the time of
the alkaline tide (25). Moreover, giving 9-
-fludrocortisone in the
evening did not lead to a high TTKG, unless the subjects consumed
NaHCO3 or took a carbonic
anhydrase inhibitor type of diuretic (acetazolamide) (25). Accordingly, we wished to evaluate whether delivery of
to the distal nephron in
prolonged fasting could make the endogenous aldosterone increase the
kaliuresis by raising the
[K+] of CCD.
When NaHCO3 was infused, the rate of excretion of Na+ was not statistically significantly different from that of the NaCl series, but there was now a high kaliuresis (1.9 vs. 8.3 mmol/h with NaCl and NaHCO3 infusions, respectively, Table 2). Nevertheless, frank bicarbonaturia was not seen (urine, pH 5.8), and this probably reflects the continuing presence of acidemia, which stimulated the H+-adenosinetriphosphatase (H+-ATPase) units downstream in the medullary collecting duct, a nephron system with a high density of these proton pumps (reviewed in Ref. 17).
Integrative physiology. It would be
desirable in prolonged total fasting to avoid a kaliuresis by having
aldosterone promote the electroneutral reabsorption of
NaCl. This was accomplished in small part by having a low
distal delivery of Na+ and the
previously suggested effect of a deficit of
K+, which leads to electroneutral
reabsorption of NaCl in the CCD (27). We speculate that another and
very important component of this picture is to have a low distal
delivery of . Components of this
picture are the effects of a mild metabolic acidosis, which both lowers
the filtered load of
and
stimulates the reabsorption of
(reviewed in Ref. 1). Having this lower plasma
concentration
([
]) will ensure a
subnormal plasma level of
even if
HCl is secreted by the stomach (cephalic phase of gastric
H+ secretion) during a fast; this
can cause close to a 5 mM rise in the plasma
[
] (reviewed in Ref.
20). Finally, having angiotensin II as the stimulator of aldosterone release helps avoid distal delivery of
, because angiotensin II
stimulates proximal (5) and distal (16) reabsorption of
(Fig.
2A). In fact, Stinebaugh and
Schloeder (26) demonstrated a markedly enhanced capacity for proximal
reabsorption of
in chronic fasting. In addition, having a mild degree of
K+ depletion could augment the
reabsorption of
in the proximal
convoluted tubule (PCT) even further (5). Whatever the
mechanism, having both a K+
deficit and the presence of angiotensin II reduce the distal delivery
of
could explain why aldosterone could support electroneutral NaCl retention while avoiding a large kaliuresis during chronic fasting (Fig.
2A).
In the prolonged fasted state, distal delivery of
Na+ is accompanied by
-HB
anions, and
reabsorption of Na+ would be
expected to augment a kaliuresis. We envision two additional mechanisms
operating now. First, to the extent
K+ was secreted in the CCD, it
must be reabsorbed downstream in the medullary collecting
duct because its excretion was low even when NaCl was
infused (Table 2). An
H+-K+-ATPase
can carry out this function (28), albeit at a cost of extra ATP
turnover. For this process to function, there must be a
luminal H+ ion acceptor, and, in
this case, the acceptor for H+ is
NH3. The net result would be the
excretion of NH+4 and
-HB
in a 1:1
stoichiometry, while minimizing a further deficit of Na+ or
K+.
The second area to consider with respect to the distal delivery of
Na+ and
-HB
is distal
H+ secretion. The fact that the
urine pH fell when Na+ excretion
rose (Fig. 1, Table 2) suggests that a low distal delivery of
Na+ could also limit distal
H+ secretion in steady state.
Again, the secretion of H+, which
are largely converted to NH+4, permits the
eventual urine to be Na+ and
K+ poor, having
NH+4 plus
-HB
as its principal
constituents.
Perspectives for Disease States
The results of this study underscore the possible importance ofTo summarize, when aldosterone is to function as a hormone which should
enhance the electroneutral reabsorption of NaCl, having angiotensin II
as its secretagogue is a logical choice (Fig.
2A). In contrast, when the function
of aldosterone is to promote the excretion of
K+, having hyperkalemia as its
secretagogue is also logical, because hyperkalemia can augment the
delivery of to the distal nephron
(Fig. 2B).
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ACKNOWLEDGEMENTS |
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We are extremely grateful to Dr. Harald Sonnenberg for very helpful discussions and suggestions during the preparation of this manuscript. We are also indebted to Stella Tang and Eleanor Singer for expert technical assistance and Jolly Mangat for expert secretarial assistance.
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FOOTNOTES |
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This work was supported by Grant no. 5623 from the Medical Research Council of Canada.
Address for reprint requests: M. L. Halperin, Division of Nephrology, St. Michael's Hospital, 38 Shuter St., Toronto, Ontario, Canada M5B 1A6.
Received 18 February 1997; accepted in final form 16 July 1997.
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REFERENCES |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
1.
Alpern, R. J.,
O. W. Moe,
and
P. A. Preisig.
Chronic regulation of the proximal tubular Na/H antiporter: from HCO3 to SRC.
Kidney Int.
48:
1386-1396,
1995[Medline].
2.
Cahill, G. F. J.
Starvation in man.
N. Engl. J. Med.
282:
668-675,
1970[Medline].
3.
Carlisle, E. J. F.,
S. M. Donnelly,
J. Ethier,
S. E. Quaggin,
U. B. Kaiser,
S. Vasuvattakul,
K. S. Kamel,
and
M. L. Halperin.
Modulation of the secretion of potassium by accompanying anions in humans.
Kidney Int.
39:
1206-1212,
1991[Medline].
4.
Chinn, R. H.,
J. J. Brown,
and
R. Fraser.
The natriuresis of fasting: relationship to changes in plasma renin and plasma aldosterone concentration.
Clin. Sci. (Lond.)
39:
437-455,
1970[Medline].
5.
Cogan, M. G.
Regulation and control of bicarbonate reabsorption in the proximal tubule.
Semin. Nephrol.
10:
115-121,
1990[Medline].
6.
Cooke, C. R.,
M. D. Turin,
A. Whelton,
and
W. G. Walker.
Studies of marked and persistent sodium retention in previously fasted and sodium-deprived obese subjects.
Metabolism
36:
609-615,
1987[Medline].
7.
Drenick, E. J.,
W. H. Blahd,
F. R. Singer,
and
M. Lederer.
Body potassium content in obese subjects and potassium depletion during prolonged fasting.
Am. J. Clin. Nutr.
18:
278-285,
1966[Medline].
8.
Ethier, J. H.,
K. S. Kamel,
P. O. Magner,
J. J. Lemann,
and
M. L. Halperin.
The transtubular potassium concentration in patients with hypokalemia and hyperkalemia.
Am. J. Kidney Dis.
15:
309-315,
1990[Medline].
9.
Good, D. W.,
H. Velazquez,
and
F. S. Wright.
Luminal influences on potassium secretion: low sodium concentration.
Am. J. Physiol.
246 (Renal Fluid Electrolyte Physiol. 15):
F609-F619,
1984
10.
Halperin, M. L.,
S. Cheema-Dhadli,
and
L. E. Phillip.
Potassium excretion: a story that is easy to digest.
J. Am. Soc. Nephrol.
5:
S23-S28,
1994[Abstract].
11.
Hannaford, M. C.,
L. A. Leiter,
R. G. Josse,
M. B. Goldstein,
E. B. Marliss,
and
M. L. Halperin.
Protein wasting due to the acidosis of prolonged fasting.
Am. J. Physiol.
243 (Endocrinol. Metab. 6):
E251-E256,
1982
12.
Kamel, K.,
J. Ethier,
B. Stinebaugh,
F. Schloeder,
and
M. L. Halperin.
The removal of an inorganic acid load in subjects with ketoacidosis of chronic fasting: the role of the kidney.
Kidney Int.
38:
507-511,
1990[Medline].
13.
Kamel, K. S.,
M. L. Halperin,
M. D. Faber,
S. P. Steigerwalt,
C. W. Heilig,
and
R. G. Narins.
Disorders of potassium balance.
In: The Kidney, edited by B. M. Brenner,
and F. C. Rector. Philadelphia, PA: Saunders, 1996, p. 999-1037.
14.
Kamel, K. S.,
B. J. Stinebaugh,
F. X. Schloeder,
and
M. L. Halperin.
Kidney in starvation.
In: The Kidney. Physiology and Pathophysiology, edited by D. W. Seldin,
and G. Giebisch. New York: Raven, 1992, p. 3457-3470.
15.
Kolanowski, J.,
A. Bodson,
P. Desmecht,
S. Bamelmans,
F. Stein,
and
J. Crabbe.
On the relationship between ketonuria and natriuresis during fasting and upon refeeding in obese patients.
Eur. J. Clin. Invest.
8:
277-282,
1978[Medline].
16.
Levine, D. Z.,
M. Iacovitti,
S. Buckman,
and
K. D. Burns.
Role of angiotensin II in dietary modulation of rat late distal tubule bicarbonate flux in vivo.
J. Clin. Invest.
97:
120-125,
1996
17.
Levine, D. Z.,
and
H. R. Jacobson.
The regulation of renal acid secretion: new observations from studies of distal nephron segments.
Kidney Int.
29:
1099-1109,
1986[Medline].
18.
Rapoport, A.,
G. L. A. From,
and
H. Husdan.
Metabolic studies in prolonged fasting. I. Inorganic metabolism and kidney function.
Metabolism
14:
31-46,
1965.
19.
Rossier, B. C.,
and
L. G. Palmer.
Mechanisms of aldosterone action on sodium and potassium transport.
In: The Kidney. Physiology and Pathophysiology, edited by D. W. Seldin,
and G. Giebisch. New York: Raven, 1992, p. 1373-1409.
20.
Rubin, S. I.,
B. Sonnenberg,
R. Zettle,
and
M. L. Halperin.
Metabolic alkalosis mimicking the acute sequestration of HCl in rats: bucking the alkaline tide.
Clin. Invest. Med.
17:
515-521,
1994[Medline].
21.
Sapir, D. G.,
and
O. E. Owen.
Renal conservation of ketone bodies during starvation.
Metabolism
24:
23-33,
1975[Medline].
22.
Schloeder, F. X.,
and
B. J. Stinebaugh.
Defect of urinary acidification during fasting.
Metabolism
15:
17-25,
1966[Medline].
23.
Schloeder, F. X.,
and
B. J. Stinebaugh.
The natriuresis of fasting. II. Relationship to acidosis.
Metabolism
15:
838-846,
1966[Medline].
24.
Sebastian, A.,
E. McSherry,
and
R. C. J. Morris.
Renal potassium wasting in renal tubular acidosis (RTA): its occurrence in types 1 and 2 RTA despite sustained correction of systemic acidosis.
J. Clin. Invest.
50:
667-678,
1971[Medline].
25.
Steele, A.,
H. deVeber,
S. E. Quaggin,
A. Scheich,
J. Ethier,
and
M. L. Halperin.
What is responsible for the diurnal variation in potassium excretion?
Am. J. Physiol.
267 (Regulatory Integrative Comp. Physiol. 36):
R554-R560,
1994
26.
Stinebaugh, B. J.,
and
F. X. Schloeder.
Glucose induced alkalosis in fasting subjects: relationship to renal bicarbonate reabsorption during fasting and refeeding.
J. Clin. Invest.
51:
1326-1336,
1972[Medline].
27.
Vasuvattakul, S.,
S. E. Quaggin,
A. M. Scheich,
A. Bayoumi,
J. M. Goguen,
S. Cheema-Dhadli,
and
M. L. Halperin.
Kaliuretic response to aldosterone: influence of potassium in the diet.
Am. J. Kidney Dis.
21:
152-160,
1993[Medline].
28.
Wingo, C. S.,
and
F. E. Armitage.
Potassium transport in the kidney: regulation and physiologic relevance of H+-K+-ATPase.
Semin. Nephrol.
13:
213-224,
1993[Medline].
29.
Wright, F. S.,
and
G. Giebisch.
Regulation of potassium excretion,
In: The Kidney. Physiology and Pathophysiology, edited by D. W. Seldin,
and G. Giebisch. New York: Raven Press, 1992, p. 2209-2247.
30.
Zierler, K.,
and
D. Rabinowitz.
Effect of very small concentrations of insulin on forearm metabolism: persistence of its action on potassium and free fatty acids without its effect on glucose.
J. Clin. Invest.
43:
950-962,
1963.