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Causes and evaluation of hyperkalemia in adults

AUTHOR: David B Mount, MD
SECTION EDITOR: Richard H Sterns, MD
DEPUTY EDITOR: John P Forman, MD, MSc

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

Literature review current through: Mar 2024.

This topic last updated: Mar 06, 2023.

INTRODUCTION

Hyperkalemia is a common clinical problem. Potassium enters the body via oral intake or
intravenous infusion, is largely stored in the cells, and is then excreted in the urine. The
major causes of hyperkalemia are increased potassium release from the cells and, most
often, reduced urinary potassium excretion ( table 1).

This topic will review the causes and evaluation of hyperkalemia. The clinical manifestations,
treatment, and prevention of hyperkalemia, as well as a detailed discussion of
hypoaldosteronism (an important cause of hyperkalemia), are presented elsewhere:

● (See "Clinical manifestations of hyperkalemia in adults".)

● (See "Treatment and prevention of hyperkalemia in adults".)

● (See "Etiology, diagnosis, and treatment of hypoaldosteronism (type 4 RTA)".)

BRIEF REVIEW OF POTASSIUM PHYSIOLOGY

An understanding of potassium physiology is helpful when approaching patients with

hyperkalemia. Total body potassium stores are approximately 3000 mEq or more (50 to 75
mEq/kg body weight) [1]. In contrast to sodium, which is the major cation in the extracellular
fluid and has a much lower concentration in the cells, potassium is primarily an intracellular
cation, with the cells containing approximately 98 percent of body potassium. The
intracellular potassium concentration is approximately 140 mEq/L compared with 4 to 5
mEq/L in the extracellular fluid. The difference in distribution of the two cations is

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maintained by the Na-K-ATPase pump in the cell membrane, which pumps sodium out of and
potassium into the cell in a 3:2 ratio.

The ratio of the potassium concentrations in the cells and the extracellular fluid is the major
determinant of the resting membrane potential across the cell membrane, which sets the
stage for the generation of the action potential that is essential for normal neural and
muscle function. Thus, both hyperkalemia and hypokalemia can cause muscle paralysis and
potentially fatal cardiac arrhythmias. (See "Clinical manifestations of hyperkalemia in adults"
and "Clinical manifestations and treatment of hypokalemia in adults", section on
'Manifestations of hypokalemia'.)

The causes of hyperkalemia can be best understood after a brief review of normal potassium
homeostasis. The plasma potassium concentration is determined by the relationship among
potassium intake, the distribution of potassium between the cells and the extracellular fluid,
and urinary potassium excretion.

Regulation of urinary potassium excretion — In normal individuals, dietary potassium is

absorbed in the intestines and then largely excreted in the urine, a process that is primarily
determined by potassium secretion by the principal cells in the two segments that follow the
distal tubule: the connecting segment and cortical collecting tubule ( figure 1) [2-5]. There
are three major factors that stimulate principal cell potassium secretion [2-5]:

● An increase in plasma potassium concentration and/or potassium intake

● An increase in aldosterone secretion
● Enhanced delivery of sodium and water to the distal potassium secretory sites

Ingestion of a potassium load leads initially to the uptake of most of the excess potassium by
cells in muscle and the liver, a process that is facilitated by insulin and the beta-2-adrenergic
receptors, both of which increase the activity of Na-K-ATPase pumps in the cell membrane [4-
7]. Some of the ingested potassium remains in the extracellular fluid, producing a mild
elevation in the plasma potassium concentration.

The increase in plasma potassium stimulates the secretion of aldosterone, which directly
enhances sodium reabsorption and indirectly enhances potassium secretion in the principal
cells ( figure 1). The increase in sodium reabsorption is mediated primarily by an increase
in the number of open sodium channels in the luminal membrane of the principal cells. The
reabsorption of cationic sodium makes the lumen more electronegative, thereby enhancing
the electrical gradient that promotes the secretion of potassium from the cells into the
tubular fluid via potassium channels in the luminal membrane ( figure 1). Additionally, the
aldosterone-independent activation of apical secretory potassium channels by dietary
potassium loading increases the capacity for potassium secretion [5,8]. Aldosterone also
increases the number and activity of basolateral Na-K-ATPase pumps in principal cells, which

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facilitates both sodium reabsorption and potassium secretion. The net effect is that most of
the potassium load is excreted within six to eight hours.

Both cellular uptake and urinary excretion of an acute potassium load are impaired in
patients with advanced acute or chronic kidney disease. (See 'Acute and chronic kidney
disease' below.)

Potassium adaptation — Hyperkalemia is a rare occurrence in normal individuals because

the cellular and urinary responses prevent significant potassium accumulation in the
extracellular fluid. Furthermore, the efficiency of potassium excretion is enhanced if
potassium intake is increased, thereby allowing what might otherwise be a fatal potassium
load to be tolerated. This phenomenon, called potassium adaptation, is mostly due to the
ability to more rapidly excrete potassium in the urine [4,5].

Studies in rats have shown that potassium adaptation begins after a single potassium-
containing meal. In one study, for example, rats fed a meal with potassium, when compared
with rats given a potassium-free meal, were better able to excrete a potassium load several
hours later, leading to a lesser rise in the plasma potassium concentration after the second
potassium load [9]. The net effect is that adapted animals excrete more potassium at a given
plasma potassium concentration than animals that have not adapted ( figure 2).

The efficacy of potassium adaptation in humans was demonstrated in a study evaluating the
response of healthy adults to increasing potassium intake from 100 to 400 mEq/day [10].
Urinary potassium excretion rose to equal intake by the end of the second day, an effect that
was accompanied by an elevation in both aldosterone secretion and the plasma potassium
concentration (from 3.8 to 4.8 mEq/L) ( figure 3). At day 20, urinary potassium excretion
continued to match the high level of intake, but plasma aldosterone levels had returned to
near baseline, and the plasma potassium concentration had fallen to 4.2 mEq/L ( figure 3).

The increased efficiency of potassium excretion with potassium adaptation appears to be

mediated by three changes that occur in the potassium-secreting principal cells in the
connecting segment and cortical collecting tubule ( figure 1):

● A largely aldosterone-independent increase in the density and activity of apical

secretory potassium channels [3,8,11].

● Increased Na-K-ATPase activity, which enhances potassium uptake into the cell across
the basolateral (peritubular) membrane, thereby increasing the size of the potassium
secretory pool [12,13].

● Increased activity of apical epithelial sodium channels (ENaC), through both

aldosterone-independent and aldosterone-dependent mechanisms [8,11,14]. This
induction increases the electrogenic driving force for apical potassium excretion.

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Additionally, by inhibiting the function of the thiazide-sensitive Na-Cl cotransporter (NCC)

within the distal convoluted tubule, potassium loading and hyperkalemia increase the
delivery of sodium to principal cells within the downstream connecting tubule, thereby
increasing potassium secretion. NCC is tightly regulated by complex interactions among
potassium, the renin-angiotensin-aldosterone system, and the chloride-sensitive WNK
signaling system [5,15-17].

Conclusions — The preceding observations lead to the following conclusions concerning the
causes of hyperkalemia:

● Increasing potassium intake alone is not a common cause of hyperkalemia unless it

occurs acutely. Acute hyperkalemia can rarely be induced (primarily in infants because
of their small size) by the administration of potassium penicillin as an intravenous
bolus, the accidental ingestion of a potassium-containing salt substitute, or the use of
stored blood for exchange transfusions. In addition, moderate increases in potassium
intake can be an important contributor to the development of hyperkalemia in patients
with impaired potassium excretion due, for example, to hypoaldosteronism and/or
kidney function impairment. (See 'Reduced urinary potassium excretion' below.)

● The net release of potassium from the cells (due to enhanced release or decreased
entry) can, if large enough (eg, increased tissue breakdown), cause a transient elevation
in the serum potassium concentration. (See 'Increased potassium release from cells'
below.)

● Persistent hyperkalemia requires impaired urinary potassium excretion. In view of

the factors described above, this is generally associated with a reduction in aldosterone
secretion or responsiveness, acute or chronic kidney disease, and/or diminished
delivery of sodium and water to the distal potassium secretory sites. (See 'Reduced
urinary potassium excretion' below.)

● Potassium secretion is tightly regulated by a complex interplay among individual

mediators in the renin-angiotensin-aldosterone system, sodium and potassium
transport pathways, and the chloride-sensitive WNK signaling system [5,15-17]. Due to
aldosterone-independent regulatory pathways in potassium homeostasis,
hyperkalemia is not a universal feature of hypoaldosteronism.

Many of the causes of hyperkalemia are discussed in detail elsewhere and will only be listed
below ( table 1).

INCREASED POTASSIUM RELEASE FROM CELLS

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Pseudohyperkalemia — Pseudohyperkalemia refers to those conditions in which the

elevation in the measured serum potassium concentration is usually due to potassium
movement out of the cells during or after the blood specimen has been drawn [18]. The
possible presence of pseudohyperkalemia should be suspected when there is no apparent
cause for the hyperkalemia in an asymptomatic patient who has no electrocardiographic
manifestations of hyperkalemia.

Technique of blood drawing — Pseudohyperkalemia can be seen in a variety of settings.

The most common causes are related to the technique of blood drawing and can involve one
or both of the following mechanisms:

● Mechanical trauma during venipuncture can result in the release of potassium from red
cells and a characteristic reddish tint of the serum due to the concomitant release of
hemoglobin.

Red serum can also represent severe intravascular hemolysis rather than a hemolyzed
specimen [19]. When intravascular hemolysis is present, the measured serum
potassium may represent the true circulating value.

● Potassium moves out of muscle cells with exercise. As a result, repeated fist clenching
during blood drawing can acutely raise the serum potassium concentration by more
than 1 to 2 mEq/L in that forearm [20]. (See 'Exercise' below.)

In these settings, venipuncture without a tourniquet, repeated fist clenching, or trauma will
demonstrate the true serum potassium concentration [21]. If a tourniquet is required, the
tourniquet should be released after the needle has entered the vein, followed by waiting for
one to two minutes before drawing the blood sample.

Less common causes of an increase in serum potassium related to collection and storage
include cooling of the sample and specimen deterioration because of prolonged length of
storage [18,22].

Other causes — There are several other settings in which pseudohyperkalemia can occur:

● Potassium moves out of platelets after clotting has occurred. Thus, the serum
potassium concentration normally exceeds the true value in plasma by 0.1 to 0.5 mEq/L
[23]. Although this difference in normal individuals is not clinically important, the
increase in the measured serum potassium concentration can be much greater in
normokalemic patients with thrombocytosis, rising by approximately 0.15 mEq/L per
100,000/microL elevation in the platelet count [23]. In one study, hyperkalemia in a
serum sample occurred in 34 percent of patients with a platelet count above
500,000/microL compared with 9 percent of patients with a platelet count less than

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250,000/microL [23]. The concentration of potassium in plasma (obtained by

centrifugation of heparinized, unclotted blood) was normal.

A similar phenomenon has been reported in acute myeloid leukemia [24]. However,
hypokalemia is more common in this disorder, due to movement of potassium into
rapidly proliferating cells after the blood has been drawn (pseudohypokalemia) or to
renal potassium wasting (true hypokalemia). (See "Acute myeloid leukemia: Overview of
complications", section on 'Hypokalemia'.)

● High white blood cell counts (>120,000/microL) caused by chronic lymphocytic leukemia
can lead to falsely elevated potassium concentrations due to cell fragility. Unlike
thrombocytosis, this form of pseudohyperkalemia occurs in both serum and plasma
samples and may be more prominent when blood is sampled in heparinized tubes [25].
Centrifugation of a heparinized tube causes in vitro cell destruction and release of
potassium as these cells are freely suspended in plasma.

Accurate assessment of the potassium concentration in this setting can be achieved by

allowing clotting to separate serum (plasma without the clotting factors) from cells
before centrifugation. The fibrin clot entraps and protects fragile leukemic cells,
minimizing cell lysis.

Pseudohyperkalemia in patients with very high white blood cell counts due to leukemia
or lymphoma has also been reported after mechanical disruption of white blood cells
during transport of blood samples via pneumatic tube systems [26,27].

● Potassium can move out of red cells after the specimen is collected in patients with
hereditary (familial) forms of pseudohyperkalemia, which are caused by an increase in
the passive potassium permeability of erythrocytes. Pseudohyperkalemia may be the
only manifestation of the disorder, or it may be accompanied by abnormal red cell
morphology (eg, stomatocytosis), varying degrees of hemolysis, and/or perinatal
edema in specific kindreds. This genetically heterogeneous condition is discussed in
detail elsewhere. (See "Hereditary stomatocytosis (HSt) and hereditary xerocytosis (HX)",
section on 'Clinical manifestations'.)

Metabolic acidosis — In patients with metabolic acidosis other than organic acidosis due to
lactic acidosis or ketoacidosis, buffering of excess hydrogen ions in the cells leads to
potassium movement into the extracellular fluid, a transcellular shift that is obligated in part
by the need to maintain electroneutrality ( figure 4). (See "Potassium balance in acid-base
disorders", section on 'Metabolic acidosis'.)

Although this shift will tend to raise the plasma potassium concentration, some patients
have concurrent potassium losses due to gastrointestinal disease (eg, diarrhea) or increased
urinary losses (eg, renal tubular acidosis [RTA]). In these settings, the measured serum
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potassium concentration may be normal or reduced despite the presence of metabolic

acidosis. However, the plasma potassium will be higher than it would have been if the same
degree of potassium loss had occurred in the absence of metabolic acidosis. (See "Overview
and pathophysiology of renal tubular acidosis and the effect on potassium balance".)

Absent effect in lactic acidosis or ketoacidosis — In contrast to the above finding,

hyperkalemia due to an acidosis-induced shift of potassium from the cells into the
extracellular fluid does not occur in the organic acidoses lactic acidosis and ketoacidosis [28-
31]. A possible contributory factor in both disorders is the ability of the organic anion and the
hydrogen ion to enter into the cell via a sodium-organic anion cotransporter. The transport
mechanisms involved and how they minimize potassium movement out of the cells are
discussed in detail elsewhere [29].

As described below, the development of hyperkalemia in patients with diabetic ketoacidosis

is primarily due to insulin deficiency and hyperosmolality, not acidemia. (See 'Insulin
deficiency, hyperglycemia, and hyperosmolality' below and "Diabetic ketoacidosis and
hyperosmolar hyperglycemic state in adults: Clinical features, evaluation, and diagnosis",
section on 'Serum potassium'.)

Smaller effect in respiratory acidosis — Hyperkalemia due to respiratory acidosis is not a

common clinical problem. The effect of respiratory acidosis on the plasma potassium
concentration has been primarily evaluated in acute rather than chronic respiratory acidosis.
In a review of the available human data, respiratory acidosis produced no significant effect
on the plasma potassium, although the degree of acidemia in the reviewed studies was
usually mild (fall in plasma pH approximately 0.1); in addition, the increase in plasma
potassium for a given reduction in pH was smaller when the fall in pH was induced by
respiratory as compared with metabolic acidosis [28]. The effect of respiratory acidosis on
the plasma potassium is greater with more severe acidosis and with a longer duration of
acidosis [32]. The mechanisms responsible for the lesser increase in plasma potassium in
respiratory acidosis compared with metabolic acidosis are not well defined [29].

Studies in animal models of acute respiratory acidosis have shown variable increases in
plasma potassium with the severity and duration of the acidosis. The following illustrates the
range of findings:

● In a study in dogs, severe acute respiratory acidosis (a decrease in mean plasma pH

from 7.4 to 7) had no effect on the plasma potassium at 10 minutes but, at two and six
hours, the plasma potassium had increased from 4 to 6 mEq/L (approximately 0.5
mEq/L per 0.1 reduction in plasma pH) [33]. The increase in plasma potassium was due
to potassium movement out of cells and was approximately twice as large when the
ureters were ligated, suggesting a role for urinary excretion of some of the excess
potassium.
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● As might be expected, other studies in dogs with less severe acute respiratory acidosis
found no [34] or only small elevations in the plasma potassium concentration [35].

Insulin deficiency, hyperglycemia, and hyperosmolality — Insulin promotes potassium

entry into cells. Thus, the ingestion of glucose (which stimulates endogenous insulin
secretion) minimizes the rise in the serum potassium concentration induced by concurrent
potassium intake ( figure 5) [36], while glucose ingestion alone in patients without
diabetes modestly lowers the serum potassium ( figure 6) [37].

The findings are different in uncontrolled diabetes mellitus. In this setting, the combination
of insulin deficiency (either impaired secretion or insulin resistance) and hyperosmolality
induced by hyperglycemia frequently leads to hyperkalemia even though there may be
marked potassium depletion due to urinary losses caused by the osmotic diuresis
( figure 6) [37-39]. (See "Diabetic ketoacidosis and hyperosmolar hyperglycemic state in
adults: Clinical features, evaluation, and diagnosis", section on 'Serum potassium'.)

The increase in plasma osmolality results in osmotic water movement from the cells into the
extracellular fluid. This is accompanied by potassium movement out of the cells by two
proposed mechanisms:

● The loss of cell water raises the cell potassium concentration, thereby creating a
favorable gradient for passive potassium exit through potassium channels in the cell
membrane.

● The friction forces between solvent (water) and solute can result in potassium being
carried along with water through the water pores in the cell membrane. This
phenomenon of solvent drag is independent of the electrochemical gradient for
potassium diffusion.

Causes other than diabetes mellitus — Disorders other than diabetes mellitus have been
associated with hyperkalemia due to insulin deficiency and/or hyperosmolality. As examples:

● Insulin levels fall in response to therapy with somatostatin or the somatostatin agonist,
octreotide, and can lead to elevations in serum potassium [40-43]. The magnitude of
this effect varies with the clinical setting. In one study, for example, the mean increase
in serum potassium was 0.5 to 0.6 mEq/L in normal individuals and patients with type 2
diabetes; in contrast, there was no change in serum potassium in patients with type 1
diabetes since they make little or no insulin [40]. The effect of somatostatin or
octreotide is much greater in patients with end-stage kidney disease (ESKD) requiring
dialysis in whom the serum potassium can rise above 7 mEq/L [41,42].

● Fasting is associated with an appropriate reduction in insulin levels that can lead to an
increase in plasma potassium. This may be a particular problem in patients on dialysis.

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(See 'Acute and chronic kidney disease' below.)

The risk of hyperkalemia during preoperative fasting can be minimized by the

administration of insulin and glucose in patients with diabetes, or glucose alone in
patients without diabetes ( figure 6) [37].

● In addition to hyperglycemia induced by insulin deficiency, hyperkalemia induced by

hyperosmolality has also been described with hypernatremia [44], sucrose contained in
intravenous immune globulin [45], radiocontrast media [46], and the administration of
hypertonic mannitol [47]. Most of the reported patients had kidney failure. (See
"Complications of mannitol therapy", section on 'Volume expansion, hyponatremia,
hyperkalemia, hypokalemia, and metabolic acidosis'.)

Increased tissue catabolism — Any cause of increased tissue breakdown leads to the
release of intracellular potassium into the extracellular fluid. Hyperkalemia can occur in this
setting, particularly if kidney failure is also present. Clinical examples include trauma
(including noncrush trauma), rhabdomyolysis, the administration of cytotoxic or radiation
therapy to patients with lymphoma or leukemia (the tumor lysis syndrome), and severe
accidental hypothermia [48-50]. (See "Crush-related acute kidney injury", section on
'Biochemical abnormalities' and "Tumor lysis syndrome: Pathogenesis, clinical
manifestations, definition, etiology and risk factors", section on 'Clinical manifestations' and
"Accidental hypothermia in adults", section on 'Pathophysiology'.)

Beta blockers — Increased beta-2-adrenergic activity drives potassium into the cells and
lowers the serum potassium. (See "Causes of hypokalemia in adults", section on 'Elevated
beta-adrenergic activity'.)

Beta blockers interfere with the beta-2-adrenergic facilitation of potassium uptake by the
cells, particularly after a potassium load ( figure 7) [51,52]. An increase in serum potassium
is primarily seen with nonselective beta blockers (such as propranolol and labetalol). In
contrast, beta-1-selective blockers such as atenolol have little effect on serum potassium
since beta-2 receptor activity remains intact [53].

The rise in serum potassium with nonselective beta blocker therapy is usually less than 0.5
mEq/L. True hyperkalemia is rare unless there is a large potassium load, marked exercise (as
described in the next section), or an additional defect in potassium handling that prevents
excretion of the excess extracellular potassium, such as hypoaldosteronism or kidney failure
[52,54]. In one report, for example, three kidney transplant recipients developed severe
hyperkalemia after the administration of labetalol for postoperative hypertension [52].

Exercise — Potassium is normally released from muscle cells during exercise. The increase in
plasma potassium is rarely important clinically, with the one major exception that fist
clenching during blood drawing can interfere with accurate assessment of the serum
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potassium concentration. Repeated fist clenching during blood drawing can acutely raise the
serum potassium concentration by more than 1 mEq/L in that forearm, thereby representing
a form of pseudohyperkalemia [20]. (See 'Pseudohyperkalemia' above.)

The increase in plasma potassium during exercise may be mediated by two factors:

● A delay between potassium exit from the cells during depolarization and subsequent
reuptake into the cells via the Na-K-ATPase pump.

● With marked exercise, an increased number of open potassium channels in the cell
membrane. These channels are inhibited by ATP, an effect that is removed by the
exercise-induced decline in ATP levels [55].

The release of potassium during exercise may have a physiologically important role. The
local increase in potassium concentration has a vasodilator effect, thereby increasing blood
flow and energy delivery to the exercising muscle.

The degree of elevation in the plasma potassium concentration in the systemic circulation
is less pronounced and varies directly with the degree of exercise: 0.3 to 0.4 mEq/L with slow
walking; 0.7 to 1.2 mEq/L with moderate exertion (including prolonged aerobic exercise with
marathon running); and as much as 2 mEq/L following exercise to exhaustion [54,56-59],
which may be associated with both ECG changes [58] and lactic acidosis [59].

The peak increase in plasma potassium during exercise is less pronounced with prior
physical conditioning (perhaps due to increased Na-K-ATPase activity) [60] and more
pronounced in patients treated with nonselective beta blockers [56] or those with ESKD even
though there is often a lesser degree of attained exercise [61]. (See 'Beta blockers' above.)

The rise in plasma potassium concentration induced by exercise is reversed after several
minutes of rest and is typically associated with a mild rebound hypokalemia (averaging 0.4 to
0.5 mEq/L below the baseline level) [57-59]. It has been suggested that the changes in
plasma potassium might be arrhythmogenic in susceptible patients, such as those with
angina pectoris [58].

Hyperkalemic periodic paralysis — Hyperkalemic periodic paralysis is an autosomal

dominant disorder in which episodes of weakness or paralysis are usually precipitated by
cold exposure, rest after exercise, fasting, or the ingestion of small amounts of potassium.
The most common abnormality in hyperkalemic periodic paralysis is a point mutation in the
gene for the alpha subunit of the skeletal muscle cell sodium channel. (See "Hyperkalemic
periodic paralysis", section on 'Pathogenesis'.)

Other — Other rare causes of hyperkalemia due to translocation of potassium from the cells
into the extracellular fluid include:

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● Digitalis overdose, due to dose-dependent inhibition of the Na-K-ATPase pump [62].

Hyperkalemia can also occur after poisoning with structurally related digitalis
glycosides, as may occur after ingestion of the plants, common oleander or yellow
oleander [63], or extracts of the cane toad, Bufo marinus (bufadienolides) [64]. (See
"Digitalis (cardiac glycoside) poisoning", section on 'Electrolyte abnormalities' and
"Potentially toxic plant ingestions in children: Clinical manifestations and evaluation",
section on 'Cardiac glycosides (eg, oleander, foxglove)'.)

● Red cell transfusion, due to leakage of potassium out of the red cells during storage.
Hyperkalemia primarily occurs in infants and with massive transfusions. (See "Red
blood cell transfusion in infants and children: Administration and complications",
section on 'Metabolic toxicity'.)

● Administration of succinylcholine to patients with burns, extensive trauma, prolonged

immobilization, chronic infection, or neuromuscular disease [65-67]. Acetylcholine
receptors are normally concentrated within the neuromuscular junction, and the efflux
of intracellular potassium caused by depolarization of these receptors is confined to
this space. Hyperkalemia occurs when succinylcholine is given under conditions that
cause upregulation and widespread distribution of acetylcholine receptors throughout
the entire muscle membrane [65].

● Administration of arginine hydrochloride, which is metabolized in part to hydrochloric

acid and has been used to treat refractory metabolic alkalosis. The entry of cationic
arginine into the cells presumably obligates potassium exit to maintain
electroneutrality [68]. The drug aminocaproic acid can cause hyperkalemia by the same
mechanism since it is structurally similar to arginine [69,70]. (See "Treatment of
metabolic alkalosis", section on 'Hydrochloric acid in selected patients'.)

● Use of drugs that activate ATP-dependent potassium channels in cell membranes, such
as calcineurin inhibitors (eg, cyclosporine and tacrolimus), nicorandil, and isoflurane
[71]. In particular, there are multiple reports of hyperkalemia from nicorandil in
susceptible patients [72-74]. As described elsewhere, other mechanisms are also
involved in calcineurin inhibitor-induced hyperkalemia, including hyporeninemic
hypoaldosteronism and inhibition of the luminal potassium channel through which
potassium is secreted ( figure 1). (See 'Reduced aldosterone secretion' below and
"Cyclosporine and tacrolimus nephrotoxicity", section on 'Hyperkalemia'.)

REDUCED URINARY POTASSIUM EXCRETION

Urinary potassium excretion is primarily mediated by potassium secretion in the principal

cells in the two segments that follow the distal tubule: the connecting segment and cortical

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collecting tubule ( figure 1). Three major factors are required for adequate potassium
secretion at these sites: adequate aldosterone secretion, adequate responsiveness to
aldosterone, and adequate distal sodium and water delivery [75]. The widely used term
hypoaldosteronism applies to both reduced aldosterone secretion and reduced response to
aldosterone. (See 'Brief review of potassium physiology' above.)

The four major causes of hyperkalemia due to reduced urinary potassium secretion are:

● Reduced aldosterone secretion

● Reduced response to aldosterone (aldosterone resistance)
● Reduced distal sodium and water delivery as occurs in effective arterial blood volume
depletion
● Acute and chronic kidney disease in which one or more of the above factors are present

Other mechanisms for reduced urinary potassium secretion have rarely been described. (See
'Other mechanisms of impaired potassium secretion' below.)

In addition to directly causing hyperkalemia, impaired urinary potassium excretion can also
contribute to hyperkalemia induced by potassium release from the cells ( table 1). (See
'Increased potassium release from cells' above.)

Reduced aldosterone secretion — Any cause of decreased aldosterone release, such as

that induced by hyporeninemic hypoaldosteronism or certain drugs, can diminish the
efficiency of potassium secretion and lead to hyperkalemia and metabolic acidosis (called
type 4 renal tubular acidosis [RTA]) ( table 2). Drugs commonly implicated include
angiotensin inhibitors [76], nonsteroidal antiinflammatory drugs, calcineurin inhibitors, and
heparin. (See "Etiology, diagnosis, and treatment of hypoaldosteronism (type 4 RTA)", section
on 'Etiology'.)

Hyperkalemia is a common problem in patients treated with the calcineurin inhibitors,

cyclosporine and tacrolimus. These drugs can induce hyporeninemic hypoaldosteronism and
can also interfere with the effect of aldosterone on the potassium-secreting cells in the
connecting segment and cortical collecting tubule. (See "Cyclosporine and tacrolimus
nephrotoxicity", section on 'Hyperkalemia'.)

The rise in plasma potassium concentration induced by reductions in aldosterone secretion

or aldosterone response directly stimulates potassium secretion, partially overcoming the
relative absence of aldosterone. The net effect is that the rise in the plasma potassium
concentration is generally small in patients with normal kidney function but can be clinically
important in the presence of underlying kidney function impairment and/or other causes of
hyperkalemia ( table 1).

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Reduced response to aldosterone — There are a number of causes of hyperkalemia that

are due to a reduced response to aldosterone, also called aldosterone or mineralocorticoid
resistance. The most common are the administration of potassium-sparing diuretics and
acute and chronic kidney disease in which other factors may also contribute. (See 'Acute and
chronic kidney disease' below.)

Potassium-sparing diuretics — Two classes of diuretic medications impair renal potassium

secretion despite normal or high levels of aldosterone: aldosterone antagonists that
compete with aldosterone for receptor sites (spironolactone and eplerenone), and drugs that
directly block the sodium channels in the apical (luminal) membrane of the principal cells in
the collecting tubule (amiloride and triamterene) ( figure 1).

The antibiotics trimethoprim (TMP) and pentamidine share structural similarity with
amiloride and also inhibit apical sodium channels [77,78]; in perfused cortical collecting
ducts, TMP inhibits both sodium reabsorption and potassium secretion [79]. Hyperkalemia
associated with TMP was initially reported in patients with HIV treated for Pneumocystis
pneumonia with high doses of trimethoprim-sulfamethoxazole [80]. Standard doses of TMP
may also produce hyperkalemia; in one study of hospitalized patients, for example,
hyperkalemia occurred in greater than 50 percent, with serum potassium concentrations
>5.5 mmol/L in 21 percent [81]. (See "Trimethoprim-sulfamethoxazole: An overview" and
"Etiology, diagnosis, and treatment of hypoaldosteronism (type 4 RTA)", section on
'Antibiotics'.)

Risk factors for hyperkalemia in patients treated with potassium-sparing diuretics include
kidney function impairment, hyporeninemic hypoaldosteronism, and treatment with
angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs).

Voltage-dependent renal tubular acidosis — In some patients with distal RTA, the primary
defect is impaired sodium reabsorption in the principal cells in the two segments that follow
the distal tubule (the connecting segment and the cortical collecting tubule). The movement
of sodium from the lumen into the principal cells makes the lumen electronegative, thereby
promoting the secretion of both hydrogen ions and potassium ( figure 1). In contrast, an
impairment in sodium reabsorption will reduce both hydrogen and potassium secretion,
which will promote the development of metabolic acidosis and hyperkalemia. This disorder,
which has been called voltage-dependent RTA, has been associated with urinary tract
obstruction [82], lupus nephritis [83], sickle cell disease [84], and renal amyloidosis [85]. (See
"Overview and pathophysiology of renal tubular acidosis and the effect on potassium
balance".)

A somewhat similar defect is induced by hypoaldosteronism since aldosterone normally

increases the number of open sodium channels in the luminal membrane. In contrast to
hypoaldosteronism, voltage-dependent RTA is associated with normal or even high
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aldosterone levels and an inability to normally acidify the urine, as the urine pH is above 5.5.
(See 'Reduced aldosterone secretion' above and "Etiology and diagnosis of distal (type 1) and
proximal (type 2) renal tubular acidosis".)

Pseudohypoaldosteronism type 1 — Pseudohypoaldosteronism type 1 is a rare hereditary

disorder that is characterized by aldosterone resistance. The autosomal recessive form
affects the collecting tubule sodium channel (ENaC) ( figure 1), and the autosomal
dominant form in most patients affects the mineralocorticoid receptor. (See "Etiology,
diagnosis, and treatment of hypoaldosteronism (type 4 RTA)", section on
'Pseudohypoaldosteronism type 1'.)

Reduced distal sodium and water delivery — Even in the presence of normal or increased
plasma aldosterone levels, potassium secretion and therefore urinary potassium excretion
can be impaired if there is a substantial reduction in sodium and water delivery to the
potassium secretory sites in the distal nephron (connecting segment and cortical collecting
tubule). As an example, potassium secretion by perfused rabbit cortical collecting ducts is
dramatically inhibited at a luminal sodium concentration of 8 mmol/L and essentially stops at
a luminal sodium concentration of 0 mmol/L [86]. Dietary sodium intake also influences
potassium excretion; the potassium secretory capacity is enhanced by excess sodium intake
and reduced by sodium restriction [87].

The most common cause of reduced distal sodium and water delivery is effective arterial
blood volume depletion, which may be accompanied by other factors that promote the
development of hyperkalemia. Measurement of urinary sodium concentration, combined
with a therapeutic response to saline hydration, can help confirm this pathophysiology.

Effective arterial blood volume depletion — The effective arterial blood volume (also
called effective circulating volume) refers to the arterial blood volume that is effectively
perfusing the tissues. Effective arterial blood volume depletion includes any cause of true
volume depletion (eg, gastrointestinal or renal losses) as well as heart failure and cirrhosis in
which decreased tissue perfusion is due to a reduced cardiac output and vasodilation,
respectively. (See "General principles of disorders of water balance (hyponatremia and
hypernatremia) and sodium balance (hypovolemia and edema)", section on 'Effective arterial
blood volume'.)

Any cause of effective arterial blood volume depletion can lead sequentially to decreased
delivery of sodium and water to the sites of potassium secretion in the distal nephron
(connecting segment and cortical collecting tubule), impaired potassium secretion into the
tubular lumen, and hyperkalemia ( figure 1) [88,89]. (See 'Brief review of potassium
physiology' above.) However, the effect of impaired potassium secretion can be minimized or
overcome, possibly resulting in hypokalemia, if there are concurrent potassium losses, as in
patients with vomiting or diarrhea, or those treated with diuretic therapy.
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In addition to decreased distal delivery of sodium and water, other potentially important
contributing factors to hyperkalemia in patients with heart failure and cirrhosis include
angiotensin inhibitor therapy in heart failure (but not cirrhosis) and aldosterone antagonists
in both heart failure and cirrhosis. (See "Renal effects of ACE inhibitors in heart failure",
section on 'Hyperkalemia' and "Ascites in adults with cirrhosis: Initial therapy", section on
'Avoidance of angiotensin inhibition' and "Ascites in adults with cirrhosis: Initial therapy",
section on 'Diuretic regimen' and "Primary pharmacologic therapy for heart failure with
reduced ejection fraction", section on 'Mineralocorticoid receptor antagonist'.)

Acute and chronic kidney disease — Hyperkalemia is a common complication of acute and
chronic kidney disease. In patients with acute kidney injury, hyperkalemia is most prevalent
in oliguric patients who also have increased potassium release from cells due, for example,
to rhabdomyolysis or tumor lysis syndrome.

In patients with chronic kidney disease, the ability to excrete potassium at near-normal levels
without the development of hyperkalemia generally persists as long as both the secretion of
and responsiveness to aldosterone are intact and distal delivery of sodium and water are
maintained [90]. Hyperkalemia is most commonly seen in patients who are oliguric or have
an additional problem such as a high-potassium diet, increased tissue breakdown, reduced
aldosterone secretion or responsiveness, or fasting in patients on dialysis, which may both
lower insulin levels and cause resistance to beta-adrenergic stimulation of potassium uptake
[38,90-92]. In patients on dialysis who fasted prior to surgery, the administration of insulin
and glucose or, to a lesser degree, glucose alone in patients without diabetes can minimize
the elevation in the serum potassium concentration [92]. (See 'Insulin deficiency,
hyperglycemia, and hyperosmolality' above.)

Impaired cell uptake of potassium also contributes to the development of hyperkalemia in

advanced kidney failure ( figure 5). Diminished Na-K-ATPase activity may be particularly
important in this setting. How this occurs is not clear, but retained uremic toxins may
decrease the transcription of mRNA for the alpha1 isoform of the Na-K-ATPase pump in
skeletal muscle [91,93,94].

Multiple factors — The presence of multiple factors that impair potassium secretion can
lead to more severe and possibly life-threatening hyperkalemia. One setting in which this can
occur is in patients with moderate to severe heart failure [95-99]. These patients often have
reduced distal sodium and water delivery due to the associated kidney hypoperfusion,
relatively decreased aldosterone release (from treatment with ACE inhibitors and/or ARBs),
and reduced aldosterone effect (from treatment with spironolactone or eplerenone) [98].
(See "Major side effects of angiotensin-converting enzyme inhibitors and angiotensin II
receptor blockers", section on 'Hyperkalemia' and "Overview of the management of heart
failure with reduced ejection fraction in adults" and "Primary pharmacologic therapy for

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heart failure with reduced ejection fraction", section on 'Mineralocorticoid receptor

antagonist'.)

Other mechanisms of impaired potassium secretion — In addition to the common

mechanisms of hyperkalemia due to reduced urinary potassium excretion described above,
there are other, less common causes of hyperkalemia in which urinary potassium excretion is
impaired due to mechanisms not directly related to reduced secretion of or response to
aldosterone or to reduced distal sodium and water delivery.

Selective impairment in potassium secretion — Some patients with hyperkalemia have

impaired urinary potassium excretion despite normal aldosterone release and normal distal
sodium and water delivery. This seemingly selective impairment in potassium secretion,
which does not respond to exogenous mineralocorticoid, has been described with lupus
nephritis, acute transplant rejection, and sickle cell disease [100-102]. These patients do not
have sodium wasting and have a normal antinatriuretic response to mineralocorticoids,
indicating a selective potassium defect, not aldosterone resistance [101,102]. In at least
some cases, the potassium secretory defect may be due to interstitial nephritis [100].

A selective impairment in potassium secretion can also occur in patients treated with
cyclosporine or tacrolimus. One or more mechanisms involved in tubular potassium
secretion may be impaired. (See "Cyclosporine and tacrolimus nephrotoxicity", section on
'Hyperkalemia'.)

Pseudohypoaldosteronism type 2 (Gordon's syndrome) — An inherited syndrome of

hyperkalemia, volume expansion, hypertension, and otherwise normal kidney function has
been called pseudohypoaldosteronism type 2, Gordon's syndrome, or familial hyperkalemic
hypertension. The reduction in aldosterone secretion represents an appropriate response to
volume expansion. (See "Etiology, diagnosis, and treatment of hypoaldosteronism (type 4
RTA)", section on 'Pseudohypoaldosteronism type 2 (Gordon's syndrome)'.)

Ureterojejunostomy — A rise in the serum potassium concentration can occur in patients

with a urinary diversion procedure in which the ureters are inserted into the jejunum (called
a ureterojejunostomy). Hyperkalemia in this setting is presumably due to absorption of
urinary potassium by the jejunum [103]. (See "Acid-base and electrolyte abnormalities with
diarrhea".)

EVALUATION

Evaluation of the patient with hyperkalemia usually begins with a careful history, evaluation
for clinical manifestations of hyperkalemia such as muscle weakness and characteristic

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changes on the electrocardiogram, and laboratory testing for the causes of hyperkalemia
( algorithm 1). (See "Clinical manifestations of hyperkalemia in adults".)

Exclude pseudohyperkalemia — Pseudohyperkalemia, which is discussed above, refers to

those conditions in which the elevation in the measured serum potassium concentration is
due to potassium movement out of the cells during or after the blood specimen has been
drawn. It is usually related to the technique of blood drawing, but it can also occur in
patients with marked elevations in platelet or white blood cell counts. (See
'Pseudohyperkalemia' above.)

Pseudohyperkalemia should be suspected when there is no apparent cause for the

hyperkalemia in an asymptomatic patient who has no clinical or electrocardiographic
manifestations of hyperkalemia. One clue to the possible presence of pseudohyperkalemia is
wide variability in repeated measurements of the serum potassium concentration (eg, from 5
to 6.5 mEq/L, often including some normal values). In contrast, patients with normokalemia
and those with true chronic hyperkalemia, most often due to hypoaldosteronism or chronic
kidney disease, tend to have stable values over the short term, although higher values can
occur over time if there is progression of the underlying disease.

If an artifact of blood drawing is suspected or there is no apparent cause for hyperkalemia,

venipuncture without a tourniquet, repeated fist clenching, or trauma will demonstrate the
true serum potassium concentration [21]. If a tourniquet is required, the tourniquet should
be released after the needle has entered the vein, followed by waiting for one to two minutes
before drawing the blood sample. The diagnosis of pseudohyperkalemia in patients with
thrombocytosis or markedly elevated white blood cell counts is described above. (See 'Other
causes' above.)

Acute rise in serum potassium — In the absence of pseudohyperkalemia or recent

potassium administration, an acute rise in serum potassium is often due to increased release
of potassium from the cells, and the cause is identified from the history and laboratory data.
Increased tissue catabolism is a classic example that is most often due to trauma or cytotoxic
or radiation therapy in patients with lymphoma or leukemia (the tumor lysis syndrome).
Diabetic ketoacidosis is another cause of an acute rise in serum potassium, a change that is
more pronounced if kidney function is impaired. (See 'Increased tissue catabolism' above and
'Insulin deficiency, hyperglycemia, and hyperosmolality' above and 'Metabolic acidosis'
above.)

Increasing potassium intake is not a major cause of hyperkalemia in individuals without

another risk factor such as reduced aldosterone secretion or responsiveness or acute or
chronic kidney disease. In healthy adults, raising potassium intake from a normal value of
100 mEq/day to a much higher value of 400 mEq/day only produces a modest elevation in
serum potassium from 3.8 mEq/L at baseline to 4.8 mEq/L at the end of day 2 and 4.2 mEq/L
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at day 20 ( figure 3) [10]. Urinary potassium excretion increases to the level of intake by the
end of the second day, an effect that is mediated by both the elevation in plasma potassium
and increased secretion of aldosterone. (See 'Potassium adaptation' above.)

Persistent hyperkalemia — Given the ability of healthy individuals to handle large

potassium loads with only a small rise in serum potassium ( figure 3) [10], the most
common causes of persistent hyperkalemia are associated with impaired urinary potassium
excretion due to reduced secretion of or response to aldosterone, acute or chronic kidney
disease, and/or effective arterial blood volume depletion. Effective arterial blood volume
depletion may be due to true volume depletion or to heart failure or cirrhosis, in which
decreased tissue perfusion is due to a reduced cardiac output and vasodilation, respectively
( table 1). (See 'Reduced urinary potassium excretion' above.)

Administration of angiotensin inhibitors and aldosterone antagonists in patients with heart

failure can contribute to the development of hyperkalemia but can also improve patient
outcomes [104]. Limiting potassium intake and the use of loop diuretics may minimize the
degree of hyperkalemia and allow these potentially life-saving therapies to be continued.
(See "Treatment and prevention of hyperkalemia in adults", section on 'Prevention' and
"Primary pharmacologic therapy for heart failure with reduced ejection fraction", section on
'Mineralocorticoid receptor antagonist' and "Primary pharmacologic therapy for heart failure
with reduced ejection fraction", section on 'Hyperkalemia'.)

Urinary potassium excretion — Measurement of 24-hour urinary potassium excretion is of

limited utility in patients with persistent stable hyperkalemia because urinary potassium
excretion is primarily determined by and roughly equal to potassium intake. These patients
have an impairment in urinary potassium excretion since a higher-than-normal plasma
potassium concentration is required to excrete the daily potassium load.

Although uncommon, 24-hour urinary potassium excretion above 80 to 100 mEq/day

(normal potassium intake) suggests that increased potassium intake (as with ingestion of a
salt substitute) may be contributing to the hyperkalemia. However, as noted above,
increasing potassium intake alone is not sufficient in healthy adults. In this setting, raising
potassium intake from 100 to 400 mEq/day only increases the serum potassium from 3.8
mEq/L at baseline to 4.8 mEq/L at the end of day 2 and 4.2 mEq/L by day 20, a time at which
intake and output are again equal ( figure 3) [10]. (See 'Potassium adaptation' above.)

Transtubular potassium gradient — It would be desirable to assess the degree of

aldosterone activity in patients with hyperkalemia by estimating the tubular fluid potassium
concentration at the most distal site of potassium secretion in the cortical collecting tubule.
Although this measurement cannot be made in humans, it was proposed that the potassium
concentration at this site could be estimated clinically from calculation of the transtubular
potassium gradient (TTKG) [105-107].
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However, in a later publication, the authors of the original studies suggested that the
assumptions underlying the TTKG were not valid [108], suggested that the equation did not
consider the effects of distal tubular urea reabsorption on potassium excretion, and
concluded that the TTKG was not a reliable test for the diagnosis of hyperkalemia. However,
these criticisms are theoretical and not supported by animal experiments [109]. Thus, it is
unclear whether use of the TTKG is appropriate for assessment of the renal response to
hyperkalemia. An alternative is the potassium:creatinine ratio; however, this calculation has
not been extensively validated in hyperkalemia.

Diagnosis of hypoaldosteronism — Patients with persistent hyperkalemia in whom the

etiology has not been identified should be evaluated for the presence and cause of
hypoaldosteronism. This disorder can result from reduced aldosterone secretion or from
aldosterone resistance, which most often occurs in patients treated with potassium-sparing
diuretics and can be one of several factors that can contribute to hyperkalemia in acute and
chronic kidney disease. (See 'Reduced aldosterone secretion' above and 'Reduced response
to aldosterone' above.)

The approach to the diagnosis of hypoaldosteronism is discussed in detail elsewhere. (See

"Etiology, diagnosis, and treatment of hypoaldosteronism (type 4 RTA)", section on 'Diagnosis
of hypoaldosteronism'.)

SOCIETY GUIDELINE LINKS

Links to society and government-sponsored guidelines from selected countries and regions
around the world are provided separately. (See "Society guideline links: Fluid and electrolyte
disorders in adults".)

INFORMATION FOR PATIENTS

UpToDate offers two types of patient education materials, "The Basics" and "Beyond the
Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th
grade reading level, and they answer the four or five key questions a patient might have
about a given condition. These articles are best for patients who want a general overview
and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are
longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th
grade reading level and are best for patients who want in-depth information and are
comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to
print or e-mail these topics to your patients. (You can also locate patient education articles

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on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

● Basics topics (see "Patient education: Hyperkalemia (The Basics)")

SUMMARY

● Pathogenesis – Ingestion of a potassium load leads initially to the uptake of most of

the excess potassium by cells in muscle and the liver, a process that is facilitated by
insulin and the beta-2-adrenergic receptors, both of which increase the activity of Na-K-
ATPase pumps in the cell membrane. Some of the ingested potassium remains in the
extracellular fluid, producing a mild elevation in the plasma potassium concentration.
The increase in plasma potassium stimulates the secretion of aldosterone, which
enhances both sodium reabsorption and potassium secretion by principal cells
( figure 1). (See 'Brief review of potassium physiology' above.)

Increasing potassium intake alone is not a common cause of hyperkalemia unless it

occurs acutely. The net release of potassium from the cells (due to enhanced release or
decreased entry) can, if large enough (eg, increased tissue breakdown), cause a
transient elevation in the serum potassium concentration. Persistent hyperkalemia
requires impaired urinary potassium excretion. This is generally associated with a
reduction in aldosterone secretion or responsiveness, acute or chronic kidney disease,
and/or diminished delivery of sodium and water to the distal potassium secretory sites
( table 1). (See 'Brief review of potassium physiology' above.)

● Increased potassium release from cells – The following are causes of hyperkalemia
due to increased potassium release from cells (see 'Increased potassium release from
cells' above):

• Pseudohyperkalemia – Pseudohyperkalemia includes those conditions in which the

elevation in the measured serum potassium concentration is due to potassium
movement out of the cells during or after the blood specimen has been drawn. The
most common is mechanical trauma during venipuncture, which can result in the
release of potassium from red cells and a characteristic reddish tint of the serum
due to the concomitant release of hemoglobin. (See 'Pseudohyperkalemia' above.)

• Metabolic acidosis – In patients with metabolic acidosis other than organic acidosis
due to lactic acidosis or ketoacidosis, buffering of excess hydrogen ions in the cells
leads to potassium movement into the extracellular fluid, a transcellular shift that is
obligated in part by the need to maintain electroneutrality ( figure 4). (See
'Metabolic acidosis' above.)

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• Insulin deficiency, hyperglycemia, and hyperosmolality – Insulin promotes

potassium entry into cells, minimizing the rise in the serum potassium
concentration induced by concurrent potassium intake ( figure 5). In uncontrolled
diabetes mellitus, the combination of insulin deficiency/resistance and
hyperosmolality induced by hyperglycemia frequently leads to hyperkalemia even
though there may be marked potassium depletion due to urinary losses caused by
the osmotic diuresis ( figure 6). (See 'Insulin deficiency, hyperglycemia, and
hyperosmolality' above.)

• Increased tissue catabolism – Any cause of increased tissue breakdown leads to

the release of intracellular potassium into the extracellular fluid. Hyperkalemia can
occur in this setting, particularly if kidney failure is also present. (See 'Increased
tissue catabolism' above.)

• Beta blockers – Beta blockers interfere with the beta-2-adrenergic facilitation of

potassium uptake by the cells, particularly after a potassium load ( figure 7). An
increase in serum potassium is primarily seen with nonselective beta blockers (such
as propranolol and labetalol).

• Other – Other causes of hyperkalemia due to increased potassium release from

cells include exercise, hyperkalemic periodic paralysis, red cell transfusion, and
various drugs including digitalis. (See 'Exercise' above and 'Hyperkalemic periodic
paralysis' above and 'Other' above.)

● Reduced urinary potassium secretion – The four major causes of hyperkalemia due
to reduced urinary potassium secretion are ( table 1) (see 'Reduced urinary
potassium excretion' above):

• Reduced aldosterone secretion – Any cause of decreased aldosterone release,

such as that induced by hyporeninemic hypoaldosteronism or certain drugs, can
diminish the efficiency of potassium secretion and lead to hyperkalemia and
metabolic acidosis (called type 4 renal tubular acidosis [RTA]) ( table 2). (See
'Reduced aldosterone secretion' above.)

• Reduced response to aldosterone (aldosterone resistance) – There are a number

of causes of hyperkalemia that are due to a reduced response to aldosterone, also
called aldosterone or mineralocorticoid resistance. The most common are the
administration of potassium-sparing diuretics and acute and chronic kidney disease.
(See 'Reduced response to aldosterone' above.)

• Reduced distal sodium and water delivery – Potassium secretion can be impaired
if there is a substantial reduction in sodium and water delivery to the potassium
secretory sites in the distal nephron (connecting segment and cortical collecting
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tubule). The most common cause is reduced effective arterial blood volume,
including any cause of true volume depletion (eg, gastrointestinal or renal losses) as
well as heart failure and cirrhosis in which decreased tissue perfusion is due to a
reduced cardiac output and vasodilation, respectively. (See 'Reduced distal sodium
and water delivery' above.)

• Acute and chronic kidney disease – In patients with acute kidney injury,
hyperkalemia is most prevalent in oliguric patients who also have increased
potassium release from cells due, for example, to rhabdomyolysis or tumor lysis
syndrome. In patients with chronic kidney disease, the ability to excrete dietary
potassium without the development of hyperkalemia generally persists as long as
both the secretion of and responsiveness to aldosterone are intact and distal
delivery of sodium and water are maintained. However, moderate increases in
potassium intake can be an important contributor to the development of
hyperkalemia in patients with impaired potassium excretion due to kidney function
impairment, particularly in combination with other predisposing factors
(hyporeninemic hypoaldosteronism, angiotensin-converting enzyme [ACE] inhibitor
therapy, etc). (See 'Acute and chronic kidney disease' above.)

• Other – Other causes of impaired urinary potassium excretion include Gordon's

syndrome and ureterojejunostomy. (See 'Other mechanisms of impaired potassium
secretion' above.)

● Evaluation – Evaluation of the patient with hyperkalemia usually begins with a careful
history, evaluation for clinical manifestations of hyperkalemia such as muscle weakness
and characteristic changes on the electrocardiogram, and laboratory testing for the
causes of hyperkalemia ( algorithm 1). (See 'Evaluation' above.)

Pseudohyperkalemia should be suspected when there is no apparent cause for the

hyperkalemia in an asymptomatic patient who has no clinical or electrocardiographic
manifestations of hyperkalemia. (See 'Exclude pseudohyperkalemia' above.)

In the absence of pseudohyperkalemia or recent potassium administration, an acute

rise in serum potassium is often due to increased release of potassium from the cells,
and the cause is identified from the history and laboratory data. (See 'Acute rise in
serum potassium' above.)

Given the ability of healthy individuals to handle large potassium loads with only a
small rise in serum potassium ( figure 3), the most common causes of persistent
hyperkalemia are associated with impaired urinary potassium excretion due to reduced
secretion of or response to aldosterone, acute or chronic kidney disease, and/or
effective arterial blood volume depletion. Measurement of 24-hour urinary potassium

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excretion is of limited utility in patients with persistent stable hyperkalemia. The

transtubular potassium gradient (TTKG) may be used for the diagnosis of hyperkalemia,
in combination with assessment of urine sodium. Patients with persistent hyperkalemia
in whom the etiology has not been identified should be evaluated for the presence and
cause of hypoaldosteronism. (See 'Persistent hyperkalemia' above.)

Use of UpToDate is subject to the Terms of Use.

REFERENCES

1. Boddy K, King PC, Hume R, Weyers E. The relation of total body potassium to height,
weight, and age in normal adults. J Clin Pathol 1972; 25:512.
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an analysis of 25 cases. Am J Med 2001; 110:438.

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GRAPHICS

Major causes of hyperkalemia

Increased potassium release from cells

Pseudohyperkalemia

Metabolic acidosis

Insulin deficiency, hyperglycemia, and hyperosmolality

Increased tissue catabolism

Beta blockers

Exercise

Hyperkalemic periodic paralysis

Other

Overdose of digitalis or related digitalis glycosides

Red cell transfusion

Succinylcholine

Arginine hydrochloride

Activators of ATP-dependent potassium channels (eg, calcineurin inhibitors, diazoxide, minoxidil, and
some volatile anesthetics)

Reduced urinary potassium excretion

Reduced aldosterone secretion

Reduced response to aldosterone

Reduced distal sodium and water delivery

Effective arterial blood volume depletion

Acute and chronic kidney disease

Other

Selective impairment in potassium secretion

Gordon's syndrome

Ureterojejunostomy

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Ion transport in collecting tubule principal cells

Schematic representation of sodium (Na) and potassium (K) transport in the sodium-reabsorbing
principal cells in the collecting tubules. The entry of filtered sodium into these cells is mediated by
selective sodium channels in the apical (luminal) membrane (ENaC); the energy for this process is
provided by the favorable electrochemical gradient for sodium (cell interior electronegative and low
cell sodium concentration). Reabsorbed sodium is pumped out of the cell by the Na-K-ATPase pump in
the basolateral (peritubular) membrane. The reabsorption of cationic sodium makes the lumen
electronegative, thereby creating a favorable gradient for the secretion of potassium into the lumen
via potassium channels (ROMK and BK) in the apical membrane. Aldosterone (Aldo), after combining
with the cytosolic mineralocorticoid receptor (Aldo-R), leads to enhanced sodium reabsorption and
potassium secretion by increasing both the number of open sodium channels and the number of Na-
K-ATPase pumps. The potassium-sparing diuretics (amiloride and triamterene) act by directly
inhibiting the epithelial sodium channel; spironolactone acts by competing with aldosterone for
binding to the mineralocorticoid receptor.

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Increased potassium secretion in potassium adaptation

Relationship between the plasma potassium concentration (which is raised by potassium chloride
infusion) and distal potassium secretion in normal animals (dashed line) and those treated with a
high-potassium diet for four weeks (solid line). A high-potassium diet leads to potassium adaptation:
at any plasma potassium concentration, distal potassium secretion is two to four times higher in
adapted animals compared to normals.

Data from: Stanton BA. Am J Physiol 1989; 257:R989.

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Response to potassium load

Response to increasing potassium intake from 100 to 400 meq/day in normal subjects. Urinary
potassium excretion rises to over 300 meq/day within two days, a response that is driven by increases
in both aldosterone release and the plasma potassium concentration. By day 20, potassium excretion
is almost 400 meq/day, the plasma aldosterone level is near normal, and there is only a small rise in
the plasma potassium concentration to 4.2 meq/L.

Data from: Rabelink TJ, Koomans HA, Hené RJ, et al. Kidney Int 1990; 38:942.

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Ion redistribution after acid load

Effect of an HCl load on the distribution of Cl – , Na + , and K + . As H + enters the cells to be buffered,
intracellular Na + and K + leave the cells and move into the extracellular fluid, tending to raise the
plasma K + concentration. These ion shifts are reversed when H + are removed from the extracellular
fluid.

HCl: hydrogen chloride; H + : hydrogen; Cl – : chloride; Na + : sodium; K + : potassium.

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Effects of glucose and beta-blockade on response to potassium load in

normals and dialysis patients

Peak increase in the plasma potassium concentration in normals and dialysis patients following the
ingestion of 0.25 meq/kg of potassium alone (K) or with glucose (K+G), a beta blocker (K+β), or a beta
blocker and glucose (K+β+G). The degree of hyperkalemia was minimized by glucose (via enhanced
release of insulin), increased by a beta blocker, and made more prominent (by as much as 0.4 meq/L)
with all interventions in dialysis patients, indicating decreased cell uptake of potassium in renal
failure.

Data from: Allon M, Dansby L, Shanklin N. Am J Med 1993; 94:475.

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Glucose-induced hyperkalemia in diabetes

Effect of a glucose load on the plasma potassium concentration in diabetics (solid line) and
nondiabetics (dashed line). Glucose led to a fall in the plasma potassium concentration in
nondiabetics due to stimulation of insulin release but a rise in diabetics due to the elevation in plasma
osmolality.

Data from: Nicolis GL, Kahn T, Sanchez A, et al. Arch Intern Med 1981; 141:49.

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Beta blocker enhances kalemic response to a potassium load

Change in the plasma potassium concentration after a potassium chloride infusion in control subjects
(dashed line) and those treated with a beta blocker (solid line). The rise in the plasma potassium
concentration was signficantly greater in the presence of beta blockade.

Data from: Rosa RM, Silva P, Young JB, et al. N Engl J Med 1980; 302:431.

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Major causes of hypoaldosteronism

Reduced aldosterone production

Hyporeninemic hypoaldosteronism

Kidney disease, most often diabetic nephropathy

Nonsteroidal antiinflammatory drugs

Calcineurin inhibitors

Volume expansion, as in acute glomerulonephritis

Angiotensin inhibitors, such as ACE inhibitors, angiotensin II receptor blockers, and direct renin
inhibitors

Chronic heparin therapy (impairs aldosterone synthesis)

Primary adrenal insufficiency

Severe illness

Inherited disorders

Congenital hypoaldosteronism (21-hydroxylase deficiency and isolated hypoaldosteronism)

Pseudohypoaldosteronism type 2 (Gordon's syndrome)

Aldosterone resistance
Inhibition of the epithelial sodium channel

Potassium-sparing diuretics, such as spironolactone, eplerenone, amiloride, and triamterene

Antibiotics, trimethoprim, and pentamidine

Pseudohypoaldosteronism type 1

Voltage defects

Markedly reduced distal sodium delivery

Acquired or congenital defects in sodium reabsorption by the distal tubule principal cells
(obstructive uropathy), SLE, and sickle cell disease

ACE: angiotensin-converting enzyme; SLE: systemic lupus erythematosus.

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Treatment of hyperkalemia in adults

ESKD: end-stage kidney disease; ACE: angiotensin-converting enzyme; CKD: chronic kidney disease;
RAS: renin-angiotensin system; NSAIDs: nonsteroidal antiinflammatory drugs; IV: intravenous; ECG:
electrocardiogram.

* Cardiac manifestations of hyperkalemia are discussed in detail in the topic on clinical manifestations
of hyperkalemia.

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¶ Some experts given IV calcium only to patients with ECG changes. Details are presented in the topic
on treatment of hyperkalemia.

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