Clinical Science and Molecular Medicine (1978), 54, 661-666
Factors related to potassium transport in chronic stable
renal disease in man
T. KAHN, D. M. KAJI, G. NICOLIS, L. R. KRAKOFF AND R. M. STEIN
Departments of Renal Disease, Hypertension and Endocrinology, Bronx Veterans Administration Hospital and Mount Sinai School of
Medicine, City University ofNew York, New York, U.SA.
(Received 26 September 1977; accepted 7 February 1978)
Summary
1. The inter-relationships between plasma aldosterone, plasma renin activity, potassium excre­
tion and plasma potassium were evaluated in
subjects with normal and decreased glomerular
filtration rate.
2. In seven studies of healthy control subjects
and 12 studies of patients with renal disease, daily
urine collections, plasma aldosterone and plasma
renin activity were measured on a free diet for 5-^10
days and subsequently during the addition of 50
mmol of potassium chloride daily for 5 days.
Plasma aldosterone was also measured in 22
hospital patients with normal glomerular filtration
rate and 24 patients with reduced glomerular filtra­
tion rate.
3. Plasma aldosterone was similar in base-line
conditions in patients with or without renal disease
and increased similarly during the administration
of potassium chloride, suggesting that potassium
excretion in patients with reduced glomerular filtra­
tion rate probably does not depend primarily upon
increased aldosterone.
4. Plasma renin activity increased similarly in
control subjects and patients with renal disease
during the administration of 50 mmol of potas­
sium chloride/day, but plasma renin activity did
not increase when 100 mmol of potassium
chloride/day was given to control subjects.
5. With the administration of 50 mmol of potas­
sium chloride/day mean daily potassium excretion
Correspondence: Dr Thomas Kahn, Renal Section, D-236,
Bronx Veterans Administration Hospital, 130 West Kingsbridge
Road, Bronx, New York 10468, U.S.A.
increased similarly in control subjects and patients
with renal disease but plasma potassium increased
significantly (4-7 to 5·4 mmol/1) only in patients
with renal disease, suggesting that their uptake of
potassium into cells was impaired.
Key words: aldosterone, plasma potassium,
potassium excretion, renin.
Abbreviations: GFR, glomerular filtration rate;
PRA, plasma renin activity.
Introduction
Patients with chronic stable renal disease usually
maintain a normal plasma potassium. The mechan­
isms whereby they are able to excrete normal
quantities of potassium despite a marked reduction
in functioning nephrons remain uncertain. Earlier
studies indicated that increased aldosterone main­
tained potassium excretion (Cope & Pearson,
1963; Kleeman, Okun & Heller, 1966), but more
recent studies have not confirmed this (Schrier &
Regal, 1972; Weidmann, Maxwell, Rowe, Winer &
Massry, 1975). We have found similar plasma
renin activities for a given level of sodium excre­
tion in patients with chronic renal disease and in
subjects with normal renal function; plasma renin
activity was also appropriately suppressed in
response to volume expansion (Kahn, Mohammad,
Bornia, Stein & Krakoff, 1975). We have now
further investigated the relationship between potas­
sium excretion, plasma potassium, plasma renin
activity and aldosterone in control subjects and in
661
662
T. Kahn et al.
patients with chronic stable renal disease not
requiring dialysis.
Methods
Group 1
Patients with chronic renal disease. (1) Base-line
studies. Ten patients with chronic renal disease and
normal plasma potassium were studied. They were
clinically stable, had no oedema, and maintained a
steady weight on their free diet. No patient was
receiving any treatment known to affect the
variables being studied. Twenty-four hour urine
collections were made for 5-10 days. Blood for
aldosterone, plasma renin activity (PRA) and
plasma potassium was obtained on several oc­
casions at noon preprandially after the subject had
been ambulatory. (2) Addition of 50 mmol of
potassium. Twelve studies were performed on the
10 subjects, one subject being studied on three
separate occasions. Each subject ingested 25 mmol
of potassium chloride at 08.00 hours and 15.30
hours for 5 days.
Normal subjects. Six subjects with no known
renal disease were studied on a free diet. (1) Base­
line studies. Twenty-four hour urine collections
were made for 5-10 days. (2) Addition of 50 mmol
of potassium. Seven studies were performed on the
six subjects who ingested 25 mmol of potassium
chloride at 08.00 hours and 15.30 hours for a
period of 5 days. (3) Addition of 100 mmol of
potassium. Seven studies were performed on the six
subjects who ingested 25 mmol of potassium
chloride at 08.00, 12.30, 15.30 and 19.30 hours
for 5 days. Blood was obtained at noon, pre­
prandially, after ambulation.
Group 2
Forty-six hospital patients with a range of
glomerular filtration rates of 4-189 ml/min, and
not receiving any treatment known to affect PRA
or aldosterone, were studied. They were on a free
diet, were clinically stable with steady weight and
no oedema. Twenty-four hour urine collections
were made for 3-5 days. Blood for PRA and
plasma aldosterone was taken between 07.00 and
09.00 hours while the patient was fasting and had
remained in bed since midnight. PRA values in
these subjects have been previously reported (Kahn
et al, 1975). Signed informed consent was ob­
tained from each subject and this study was
approved by the Human Experimentation Com­
mittee of this institution.
Urine and plasma were analysed for sodium and
potassium by flame photometer, and creatinine by
Technicon Auto-analyzer. PRA and plasma
aldosterone were analysed by radioimmunoassay
(Krakoff, 1973; Varsano-Aharon & Ulick, 1975).
Endogenous creatinine clearance was used as a
measure of glomerular filtration rate (GFR).
Results were analysed by using a paired /-test.
Results
Group 1
Results are summarized in Table 1 and Figs. 13. Plasma values are averages of two to five speci­
mens obtained in each period and urinary values
are an average of all collections in that period.
Weight and blood pressure remained stable in all
subjects. In the normal control subjects base-line
potassium excretion averaged 62 mmol/24 h, and
with the addition of 50 mmol of potassium chloride
potassium excretion increased by an average of 30
mmol/24 h (Fig. 1, Table 1). In the patients with
chronic renal disease potassium excretion averaged
45 mmol/24 h in base-line studies and with the
administration of 50 mmol of potassium chloride
the mean increase in potassium excretion was 31
mmol/24 h, the same as in control subjects. During
the administration of 50 mmol of potassium
chloride plasma potassium did not change signifi­
cantly in control subjects but increased signifi­
cantly in patients with renal disease from mean
value of 4·7 mmol/1 to 5-4 mmol/1 (P < 0-001).
Even with the administration of 100 mmol of
potassium chloride to control subjects plasma
potassium increased only from 4-7 to 4-9 mmol/1
(Table 1).
The response of plasma aldosterone to a supple­
ment of 50 mmol of potassium chloride is shown in
Fig. 2. The mean plasma aldosterone of control
subjects increased from 41-7 to 51-0 pmol/100 ml
but the increase was not statistically significant. In
patients with renal disease the mean plasma aldo­
sterone increased from 35-2 to 50-0 pmol/100 ml
(P < 0-001). Neither the base-line plasma al­
dosterone values nor the values obtained with the
administration of potassium differed significantly
between these two groups. The plasma aldosterone
concentrations obtained with the administration of
100 mmol of potassium chloride to normal sub­
jects were not significantly higher than those noted
with the administration of 50 mmol of potassium,
but in six of seven studies plasma aldosterone
increased (P < 0-10) (Table 1).
Potassium in renal disease
663
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Mean base-line PR A values were also similar in
both groups although the range was much larger in
those with renal disease (Fig. 3, Table 1). In
response to the administration of 50 mmol of
potassium chloride PRA increased significantly in
both groups. The administration of 100 mmol of
potassium chloride to control subjects did not,
however, result in a significant increase in PRA
(Table 1).
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FIG. 1. Average values for plasma potassium (top) and daily
urinary potassium excretion (bottom) in each normal subject
and subject with chronic stable renal disease during the base-line
state and during the daily administration of 50 mmol of
potassium chloride. The horizontal bars represent mean values
for the entire group.
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Group 2
The studies were made in 22 subjects who had a
GFR above 80 ml/min (mean 119 ± 36 ml/min)
and 24 subjects with a GFR below 80 ml/min
(mean 36 + 23 ml/min). Plasma aldosterone con­
centrations were similar in the 'low GFR' group
and the 'normal GFR' group (Fig. 4). No relation­
ship was noted between plasma aldosterone and the
level of base-line potassium excretion with or with-
T. Kahn et al.
664
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Normal
subjects
Chronic
renal disease
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FIG. 2. Average plasma aldosterone values for each individual
in normal subjects and subjects with chronic stable renal disease
during base-line conditions and during the addition of 50 mmol
of potassium chloride/day. Mean values for the entire group are
represented by horizontal bars.
60
Normal
subjects
Chronic
renal disease
10
20
30 40 50 60 70
UKy (mmol/24 h)
80
90 100
FIG. 4. Plasma aldosterone concentration plotted against mean
daily potassium excretion in 19 subjects with GFR > 80 ml/min
(A) and 19 subjects with GFR < 80 ml/min ( · ) . The equation
for the linear regression line of the high GFR group is y =
-0-025* + 55, for the low GFR group is y = 0-125x + 42, and
for the groups taken together is y = 0- \x + 47. None of these
lines has significant correlation coefficients.
out renal disease. No relationship between plasma
aldosterone and PRA was detected. Similarly, there
was no apparent relationship between plasma aldo­
sterone and PRA or potassium excretion in the
group 1 studies under base-line conditions.
Discussion
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Base
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. 50 mmol
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Base
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t 50 mmol
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FIG. 3. Average plasma renin activity (PRA: pmol of angiotensin T h _l ml-1) in each individual in normal subjects and
normokalaemic subjects with chronic stable renal disease during
base-line conditions and during the administration of 50 mmol
of potassium chloride/day. Mean values for the entire group are
shown by horizontal bars.
The interrelationship between potassium excretion,
plasma potassium, aldosterone and PRA has not
been studied extensively in patients with chronic
stable non-oliguric renal disease. The present
studies were performed on subjects ingesting their
normal diet and with the addition of 50 mmol of
potassium chloride to the daily intake. The lower
mean values of sodium and potassium excretion in
the patients with chronic renal disease in the base­
line studies reflect their lower intake of electro­
lytes, as others have observed (Gonick, Kleeman,
Rubini & Maxwell, 1971; Knolph, Gauntner,
VanStone & Bauer, 1977). Restricting the electro­
lyte intake in control subjects or increasing the
electrolyte intake in patients with chronic renal
disease to obtain similar levels of electrolyte excre­
tion would necessarily alter the base-line condi­
tions and might change the responsiveness to a
stimulus such as potassium administration. We
therefore chose to study these subjects under base­
line conditions on their usual electrolyte intake.
Plasma aldosterone concentration was similar
under basal conditions in control subjects and in
Potassium in renal disease
the patients with chronic renal disease both in the
upright and recumbent position. No relationship
was observed under basal conditions between
plasma aldosterone and potassium excretion what­
ever the GFR (Fig. 4). With 50 mmol of potassium
chloride plasma aldosterone values were still similar
in both groups. The fact that the increase in
plasma aldosterone in response to 50 mmol of
potassium chloride reached statistical significance
only in patients with renal disease may indicate a
difference in responsiveness of plasma aldosterone
in the two groups. These studies confirm that aldo­
sterone is normal in patients with chronic renal
disease (Schrier & Regal, 1972; Weidmann et al.,
1975) and support the view that other factors play
a major role in maintaining potassium excretion
when GFR is reduced (Schultze, Taggart, Shapiro,
Pennell, Caglar & Bricker, 1971).
A supplement of 50 mmol of potassium chloride
resulted in an increase in PRA in both normal and
azotaemic patients. Earlier studies found that
potassium-loading depressed PRA (Brunner, Baer,
Sealey, Ledingham & Laragh, 1970; Dluhy,
Underwood & Williams, 1970). The conflict of
evidence may be explained by the larger amounts
of potassium given in earlier studies and by the fact
that their PRA was generally stimulated by a low
sodium intake. The fact that a supplement of 100
mmol of potassium chloride did not significantly
increase the PRA of our control subjects suggests
that the response may depend upon the precise
amount of potassium given. Studies of Addisonian
patients found that the administration of 200 mmol
of potassium chloride did not depress PRA, and
suggested therefore that a fall in PRA in response
to a large potassium supplement depends upon an
increase in aldosterone provoked by the large dose
of potassium (Miller, Waterhouse, Owens &
Cohen, 1975). A supplement of 50 mmol of potas­
sium chloride administered to normal subjects on a
zero electrolyte diet did not alter PRA (Bauer,
Gauntner, Nolph & VanStone, 1977). Inhibition of
PRA in response to potassium chloride loading
may specifically depend primarily upon more
chloride reaching the macula densa (Kotchen,
Galla & Luke, 1976). It seems reasonable therefore
to suggest that a small amount of potassium
chloride may increase PRA by one mechanism and
a larger load may depress PRA by another.
Potassium excretion increased similarly in con­
trol subjects and patients with renal disease in
response to 50 mmol of potassium chloride. Never­
theless, plasma potassium increased significantly
from 4·7 to 5-4 mmol/1 in the azotaemic subjects
665
and did not change significantly in the control sub­
jects. Indeed, the plasma potassium increased only
minimally in the control subjects in response to 100
mmol of potassium chloride when potassium excre­
tion increased by a mean of 72 mmol/24 h. The
higher plasma potassium in the patients with renal
disease cannot be attributed to progressive reten­
tion of potassium since mean daily potassium
excretion was similar in both groups and faecal
losses are if anything increased in patients with
renal insufficiency (Hayes, McLeod & Robinson,
1967). Plasma aldosterone concentrations were
similar in both groups but reduced responsiveness
to aldosterone in renal failure cannot be excluded.
In normal animals (Hiatt, Miller & Katayanagi,
1975; Petit, Vick & Swander, 1975) and man
(Moore-Ede, Meguid, Fitzpatrick, Ball & Boyden,
1976) the initial response to the administration of
potassium appears to be rapid uptake into the cells
before excretion in the urine. The higher plasma
potassium 4 h after the administration of potas­
sium thus probably indicates a defect in transport­
ing potassium into cells. Several observations
suggest a potassium transport defect in renal
failure: potassium concentration is reduced in
leucocytes (Patrick, Jones, Bradford & Gaunt,
1972), sodium concentration is elevated in erythrocytes (Welt, Smith, Dunn, Czerwinski, Proctor,
Cole, Balfe & Gitelman, 1967) and muscle potas­
sium concentration is low in azotaemic patients
(Bilbrey, Carter, White, Schilling & Knöchel,
1973). Uraemic dogs have impaired cellular potas­
sium uptake (Hiatt, Chapman, Davidson, Schein­
kopf & Miller, 1976). Our studies of azotaemic
patients whose plasma potassium is persistently
high despite normal concentrations of aldosterone
and normal potassium excretion also suggest a
potassium transport defect (Kahn, Kaji, Krakoff,
Stein & Nicolis, 1976).
Although a direct correlation between PRA and
plasma aldosterone has been reported in patients
with end-stage renal failure before dialysis (Weid­
mann, Maxwell & Lupu, 1973; Vetter, Zarubar,
Armbruster, Beckerhoff, Nussberger, Furrer, Fon­
tana & Siegenthaler, 1977) we did not find a
significant correlation between PRA and plasma
aldosterone values in subjects with normal or
reduced GFR.
Acknowledgments
We thank John Torelli, Bernice Middleton, Linda
Conception and Katherine Felton for technical
assistance and Evelyn Shapiro for secretarial
T.Kahn et al.
666
KNOLPH, K.D., GAUNTNER, W.C., VANSTONE, J. & BAUER,
assistance. This work was supported by the
J.H. (1977) Effects of potassium chloride on the response to
General Medical Research Service of the Veterans
sodium restriction in normal subjects and patients with
Administration, NIH USPHS HL 13595 and NIH
chronic renal failure. Journal of Laboratory and Clinical
Medicine, 90,361-372.
AM-16317.
KOTCHEN, T.A., GALLA, J.H. & LUKE, R.G. (1976) Failure of
References
BAUER, J.H., GAUNTNER, W.C., N O L P H , K.D. & VANSTONE,
J.C. (1977) Effects of potassium chloride on plasma renin
activity during sodium restriction in normal man. Journal of
Laboratory and Clinical Medicine, 90,312-317.
BILBREY, G.L., CARTER, N.W., WHITE, M.G., SCHILLING, J.F.
& KNÖCHEL, J.P. (1973) Potassium deficiency in chronic
renal failure. Kidney International, 4,423-430.
BRUNNER, H.R., BAER, L., SEALEY, J.E., LEDINGHAM, J.G.G. &
LARAGH, J.H. (1970) The influence of potassium administra­
tion and of potassium deprivation on plasma renin in normal
and hypertensive subjects. Journal of Clinical Investigation,
49,2128-2138.
COPE, C.L. & PEARSON, J. (1963) Aldosterone secretion in
severe renal failure. Clinical Science, 25, 331-341.
DLUHY, R.G., UNDERWOOD, R.H. & WILLIAMS, G.H. (1970)
Influence of dietary potassium on plasma renin activity in
normal man. Journal of Applied Physiology, 28,299-302.
GONICK, H.C., KLEEMAN, C.R., RUBINI, M.E. & MAXWELL,
M.H. (1971) Functional impairment in chronic renal disease.
III. Studies of potassium excretion. American Journal of
Medical Sciences, 261,281-290.
HAYES, C.P., JR, M C L E O D , M.E. & ROBINSON, R.R. (1967) An
extrarenal mechanism for the maintenance of potassium
balance in severe chronic renal failure. Transactions of the
Association of American Physicians, 80,207-216.
HIATT, N., CHAPMAN, L.W., DAVIDSON, M.B., SHEINKOPF, J.A.
& MILLER, A. (1976) Inhibition of transmembrane K transfer
in ureter-ligated dogs infused with KC1. American Journal of
Physiology, 231,1160-1664.
NaHCOj to inhibit renin in the rat. American Journal of
Physiology, 231,1050-1056.
KRAKOFF, L.R. (1973) Measurement of plasma renin substrate
by radioimmunoassay of angiotensin. I. Concentration in
syndromes associated with steroid excess. Journal of Clinical
Endocrinology and Metabolism, 37,110—117.
MILLER, P.D., WATERHOUSE, C , OWENS, R. & COHEN, E.
(1975) The effect of potassium loading on sodium excretion
and plasma renin activity in Addisonian man. Journal of
Clinical Investigation, 56,346-353.
MOORE-EDE, M . C , MEGUID, Μ.Μ., FITZPATRICK, G., BALL,
M.R. & BOYDEN, C M . (1976) Circadian variation in intra­
venous potassium tolerance (Abstract). Clinical Research,
24,644A.
PATRICK, J., JONES, N.F., BRADFORD, B. & GAUNT. J. (1972)
Leucocyte potassium in uraemia: Comparisons with erythrocyte potassium and total exchangeable potassium. Clinical
Science, 43.669-678.
PETIT, G.W., VICK, R.I. & SWANDER, A.M. (1975) Plasma Κ+
and insulin: Changes during KC1 infusion in normal and
nephrectomized dogs. American Journal of Physiology, 228,
107-109.
SCHRIEB, R.W. & REGAL, E.M. (1972) Influence of aldosterone
on sodium, water and potassium metabolism in chronic renal
disease. Kidney International, 1,156-168.
SCHULTZE, R.G., TAGGART, D.D., SHAPIRO, H., PENNELL,
J.P., CAGLAR, S. & BRICKER, N. S. (1971). On the adapta­
tion of potassium excretion associated with nephron reduc­
tion in the dog. Journal of Clinical Investigation, 50, 1061—
1068.
VARSANO-AHARON, N. & ULICK, S. (1974) Further simplifica­
tion in the immunoassay of plasma aldosterone. Journal of
Clinical Endocrinology and Metabolism, 37,110-117.
HIATT, N., MILLER, A. & KATAYANAGI, T. (1975) Kaliuresis
VETTER, W., ZARUBAR, K., ARMBRUSTER, H., BECKERHOFF,
R., NUSSBERGER, J., FURRER, J., FONTANA, A. &
and diuresis after administration of antidiuretic hormone to
hyperkalemic dogs. American Journal of Physiology, 228,
1108-1112.
SIEGENTHALER, W. (1977) Control of plasma aldosterone
during hemodialysis in patients with terminal renal failure.
Nephron, 18,114-132.
KAHN, T„ KAJI, D., KRAKOFF, L.R., STEIN, R.M. & NICOLIS,
WEIDMANN, P., MAXWELL, M.H. & LUPU, A.N. (1973) Plasma
G. (1976) Hyperkalemia in chronic stable renal disease
(Abstract). Clinical Research, 2 4 , 4 0 3 A .
aldosterone in terminal renal failure. Annals of Internal
Medicine, 78,13-18.
KAHN, T., MOHAMMAD, G., BORNIA, M.E., STEIN, R.M. &
WEIDMANN, P., MAXWELL, M.H., ROWE, P., WINER, R. &
KRAKOFF, L.R. (1975) Control of plasma renin activity in
chronic stable renal disease. Journal of Laboratory and
Clinical Medicine, 85,637-644.
MASSRY, S.G. (1975) Role of the renin-angiotensin-aldosterone system in the regulation of plasma potassium in
chronic renal disease. Nephron, 15,35-49.
KLEEMAN, C.R., OKUN, R.O. & HELLER, R.J. (1966) The renal
WELT, L.G., SMITH, E.K.M., DUNN, M.J., CZERWINSKI, A.,
PROCTOR, H., COLE, C , BALFE, J.W. & GITELMAN, H.J.
regulation of sodium and potassium in patients with chronic
renal failure (CRF) and the effect of diuretics on the excre­
tion of these ions. Annals of the New York Academy of
Science, 139,520-539.
(1967) Membrane transport defect: the sick cell. Trans­
actions of the Association of American Physicians, 80, 2 0 7 216.