5/7/2020 Potassium balance in acid-base disorders - UpToDate

Author: David B Mount, MD

Section Editor: Richard H Sterns, MD
Deputy Editor: John P Forman, MD, MSc

Contributor Disclosures

All topics are updated as new evidence becomes available and our peer review process is complete.

Literature review current through: Apr 2020. | This topic last updated: Dec 03, 2019.

INTRODUCTION

There are important interactions between potassium and acid-base balance that involve both
transcellular cation exchanges and alterations in renal function [1]. These changes are most
pronounced with metabolic acidosis but can also occur with metabolic alkalosis and, to a lesser
degree, respiratory acid-base disorders.

INTERNAL POTASSIUM BALANCE

Acid-base disturbances cause potassium to shift into and out of cells, a phenomenon called
"internal potassium balance" [2]. An often-quoted study found that the plasma potassium
concentration will rise by 0.6 mEq/L for every 0.1 unit reduction of the extracellular pH [3]. However,
this estimate was based upon only five patients with a variety of disturbances, and the range was
very broad (0.2 to 1.7 mEq/L). This variability in the rise or fall of the plasma potassium in response
to changes in extracellular pH was confirmed in subsequent studies [2,4].

Metabolic acidosis — In metabolic acidosis, more than one-half of the excess hydrogen ions are
buffered in the cells. In this setting, electroneutrality is maintained in part by the movement of
intracellular potassium into the extracellular fluid (figure 1). Thus, metabolic acidosis results in a
plasma potassium concentration that is elevated in relation to total body stores. The net effect in
some cases is overt hyperkalemia; in other patients who are potassium depleted due to urinary or
gastrointestinal losses, the plasma potassium concentration is normal or even reduced [5,6]. There
is still a relative increase in the plasma potassium concentration, however, as evidenced by a further
fall in the plasma potassium concentration if the acidemia is corrected.

A fall in pH is much less likely to raise the plasma potassium concentration in patients with lactic
acidosis or ketoacidosis [7,8]. The hyperkalemia that is commonly seen in diabetic ketoacidosis
(DKA), for example, is more closely related to the insulin deficiency and hyperosmolality than to the
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degree of acidemia. (See "Diabetic ketoacidosis and hyperosmolar hyperglycemic state in adults:
Clinical features, evaluation, and diagnosis".)

Why this occurs is not well understood. Two factors that may contribute are the ability of the organic
anion to accompany the hydrogen ion into the cell, perhaps as the lipid-soluble, intact acid [9], and
differential effects on insulin and glucagon secretion [4,10].

Just as metabolic acidosis can cause hyperkalemia, a rise in the plasma potassium concentration
can induce a mild metabolic acidosis. In patients with hypoaldosteronism, for example, the mild
metabolic acidosis is primarily due to the associated hyperkalemia [11]. Two factors contribute to
this phenomenon:

● A transcellular exchange occurs as the entry of most of the excess potassium into the cells is
balanced in part by intracellular hydrogen ions moving into the extracellular fluid [12]. The net
effect is an extracellular acidosis and an intracellular alkalosis.

● Normally, the kidney increases ammonium excretion after an acid load, an effect that is
stimulated in part by a fall in intracellular pH [13]. In hyperkalemia, the associated intracellular
alkalosis diminishes ammonium generation by the proximal tubule [14]. Hyperkalemia reduces
the expression of ammonia-generating enzymes in the proximal tubule and upregulates
expression of the ammonia-recycling enzyme glutamine synthetase [15]. Normally, ammonium
exiting the proximal tubule is reabsorbed in the thick ascending limb via the apical Na+-
K+/NH4+-2Cl- cotransporter (NKCC2), after which it crosses the interstitium and is excreted into
the urine by the collecting duct [16-18]. However, potassium competes with ammonium for
reabsorption by NKCC2, and therefore, elevated tubular potassium concentrations can impair
normal renal ammonium handling, resulting in acidosis [19]. In addition, hyperkalemia reduces
expression of the ammonia transporter family member Rhcg and decreases apical expression
of H-ATPase in the inner stripe of the outer medullary collecting duct, further compromising
urinary ammonium excretion [15].

The net effect of these changes in cation distribution and renal function is that metabolic acidosis
and relative hyperkalemia are often seen together.

Metabolic alkalosis — For similar reasons in which the above ionic changes are reversed,
metabolic alkalosis and hypokalemia are commonly associated. Metabolic alkalosis causes
potassium movement into the cells, and hypokalemia causes hydrogen movement into the cells
[20,21]. With metabolic alkalosis, the plasma potassium concentration falls, although the change in
potassium is smaller in magnitude than is observed in metabolic acidosis [7].

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Respiratory acid-base disorders — Respiratory acidosis and alkalosis induce relatively small
changes in potassium balance [7]. The reason for this minor effect is not well understood.

CONCURRENT DISORDERS OF POTASSIUM BALANCE

The preceding discussion has emphasized the effect of pH on potassium distribution between the
cells and extracellular fluid. However, patients with acid-base disturbances commonly have
concurrent disorders of external potassium balance that can affect this relationship.

Concurrent metabolic acidosis — In metabolic acidosis caused by diarrhea, fecal loss of alkali is
accompanied by gastrointestinal loss of potassium. The net result is a normal anion gap metabolic
acidosis with potassium depletion and hypokalemia. (See "Causes of hypokalemia in adults",
section on 'Lower gastrointestinal losses'.)

In several organic acidoses, the acid anion is excreted in the urine with sodium or potassium as the
accompanying cation. Hypokalemia may result despite the concurrent shift of potassium out of cells
in response to acidemia. The metabolic acidosis caused by glue sniffing is the most dramatic
example of this phenomenon. Inhaled toluene is metabolized to hippuric acid, and the acid anion
(hippurate) is eliminated in the urine by both filtration and secretion, commonly resulting in
hypokalemia [22]. (See "The delta anion gap/delta HCO3 ratio in patients with a high anion gap
metabolic acidosis".)

Renal potassium wasting also occurs in diabetic ketoacidosis (DKA) and occasionally may lead to
hypokalemia (6 percent of patients with DKA in one study) [23]. However, in contrast to toluene
inhalation, many patients with DKA may develop hyperkalemia. Hyperkalemia in such patients
results from profound potassium shift out of cells caused by hyperosmolality and insulin deficiency,
and not, as noted above, by the metabolic acidosis. The administration of insulin typically leads to
hypokalemia, unmasking the true state of potassium balance. (See "Diabetic ketoacidosis and
hyperosmolar hyperglycemic state in adults: Treatment".)

Renal potassium wasting can result in severe hypokalemia in untreated distal renal tubular acidosis
(RTA) and in patients with proximal RTA who are treated with sodium bicarbonate. On the other
hand, true hyperkalemia (ie, increased body potassium stores) is present in patients with
hypoaldosteronism (type 4 RTA) due to impaired urinary potassium excretion. (See "Overview and
pathophysiology of renal tubular acidosis and the effect on potassium balance".)

Concurrent metabolic alkalosis — Renal potassium wasting resulting in potassium depletion and
hypokalemia is a feature of most causes of metabolic alkalosis (eg, vomiting, diuretics, Bartter and
Gitelman syndromes).

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SUMMARY

● In metabolic acidosis, more than one-half of the excess hydrogen ions are buffered in the cells.
In this setting, electroneutrality is maintained in part by the movement of intracellular potassium
into the extracellular fluid (figure 1). Thus, metabolic acidosis results in a plasma potassium
concentration that is elevated in relation to total body stores. The net effect in some cases is
overt hyperkalemia. (See 'Metabolic acidosis' above.)

● Just as metabolic acidosis can cause hyperkalemia, a rise in the plasma potassium
concentration can induce a mild metabolic acidosis. This is due to transcellular exchange as
most of the excess potassium enters the cells with intracellular hydrogen ions moving into the
extracellular fluid. The net effect is an extracellular acidosis and an intracellular alkalosis. In the
kidney, hyperkalemia diminishes ammonium excretion, thereby preventing excretion of the daily
acid load and contributing to the metabolic acidosis. (See 'Metabolic acidosis' above.)

● For reasons that are similar but reciprocal, metabolic alkalosis and hypokalemia are commonly
associated. Metabolic alkalosis causes potassium movement into the cells, and hypokalemia
causes hydrogen movement into the cells. (See 'Metabolic alkalosis' above.)

● Some patients with metabolic acid-base disorder have concurrent disorders of potassium
balance which can produce hypokalemia or hyperkalemia through mechanisms other than
those dependent upon cellular exchange. Examples include diarrhea, renal tubular acidosis,
and diabetic ketoacidosis (DKA). (See 'Concurrent disorders of potassium balance' above.)

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REFERENCES

1. Aronson PS, Giebisch G. Effects of pH on potassium: new explanations for old observations. J
Am Soc Nephrol 2011; 22:1981.

2. Sterns RH, Cox M, Feig PU, Singer I. Internal potassium balance and the control of the
plasma potassium concentration. Medicine (Baltimore) 1981; 60:339.

3. BURNELL JM, SCRIBNER BH, UYENO BT, VILLAMIL MF. The effect in humans of
extracellular pH change on the relationship between serum potassium concentration and
intracellular potassium. J Clin Invest 1956; 35:935.

uptodate.searchbox.science/contents/potassium-balance-in-acid-base-disorders?search=diabetic ketoacidosis children&topicRef=5809&source=see_l… 4/7

5/7/2020 Potassium balance in acid-base disorders - UpToDate

4. Adrogué HJ, Madias NE. PCO2 and [K+]p in metabolic acidosis: certainty for the first and
uncertainty for the other. J Am Soc Nephrol 2004; 15:1667.

5. Magner PO, Robinson L, Halperin RM, et al. The plasma potassium concentration in
metabolic acidosis: a re-evaluation. Am J Kidney Dis 1988; 11:220.

6. Wiederseiner JM, Muser J, Lutz T, et al. Acute metabolic acidosis: characterization and
diagnosis of the disorder and the plasma potassium response. J Am Soc Nephrol 2004;
15:1589.

7. Adrogué HJ, Madias NE. Changes in plasma potassium concentration during acute acid-base
disturbances. Am J Med 1981; 71:456.

8. Fulop M. Serum potassium in lactic acidosis and ketoacidosis. N Engl J Med 1979; 300:1087.

9. Graber M. A model of the hyperkalemia produced by metabolic acidosis. Am J Kidney Dis

1993; 22:436.

10. Adrogué HJ, Chap Z, Ishida T, Field JB. Role of the endocrine pancreas in the kalemic
response to acute metabolic acidosis in conscious dogs. J Clin Invest 1985; 75:798.

11. Szylman P, Better OS, Chaimowitz C, Rosler A. Role of hyperkalemia in the metabolic
acidosis of isolated hypoaldosteronism. N Engl J Med 1976; 294:361.

12. Altenberg GA, Aristimuño PC, Amorena CE, Taquini AC. Amiloride prevents the metabolic
acidosis of a KCl load in nephrectomized rats. Clin Sci (Lond) 1989; 76:649.

13. Rose BD, Post TW. Clinical Physiology of Acid-Base and Electrolyte Disorders, 5th ed, McGra
w-Hill, New York 2001. p.347.

14. DuBose TD Jr, Good DW. Effects of chronic hyperkalemia on renal production and proximal
tubule transport of ammonium in rats. Am J Physiol 1991; 260:F680.

15. Harris AN, Grimm PR, Lee HW, et al. Mechanism of Hyperkalemia-Induced Metabolic
Acidosis. J Am Soc Nephrol 2018; 29:1411.

16. Good DW. Ammonium transport by the thick ascending limb of Henle's loop. Annu Rev
Physiol 1994; 56:623.

17. Attmane-Elakeb A, Mount DB, Sibella V, et al. Stimulation by in vivo and in vitro metabolic
acidosis of expression of rBSC-1, the Na+-K+(NH4+)-2Cl- cotransporter of the rat medullary
thick ascending limb. J Biol Chem 1998; 273:33681.

uptodate.searchbox.science/contents/potassium-balance-in-acid-base-disorders?search=diabetic ketoacidosis children&topicRef=5809&source=see_l… 5/7

5/7/2020 Potassium balance in acid-base disorders - UpToDate

18. Bourgeois S, Meer LV, Wootla B, et al. NHE4 is critical for the renal handling of ammonia in
rodents. J Clin Invest 2010; 120:1895.

19. DuBose TD Jr, Good DW. Chronic hyperkalemia impairs ammonium transport and
accumulation in the inner medulla of the rat. J Clin Invest 1992; 90:1443.

20. Sabatini S, Kurtzman NA. The maintenance of metabolic alkalosis: factors which decrease
bicarbonate excretion. Kidney Int 1984; 25:357.

21. COOKE RE, SEGAR WE, CHEEK DB, et al. The extrarenal correction of alkalosis associated
with potassium deficiency. J Clin Invest 1952; 31:798.

22. Carlisle EJ, Donnelly SM, Vasuvattakul S, et al. Glue-sniffing and distal renal tubular acidosis:
sticking to the facts. J Am Soc Nephrol 1991; 1:1019.

23. Arora S, Cheng D, Wyler B, Menchine M. Prevalence of hypokalemia in ED patients with

diabetic ketoacidosis. Am J Emerg Med 2012; 30:481.

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