Managing Hyperkalemia Caused by Inhibitors of The Renin-Angiotensin-Aldosterone System

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The new england journal of medicine

review article

current concepts

Managing Hyperkalemia Caused by Inhibitors


of the Renin–Angiotensin–Aldosterone System
Biff F. Palmer, M.D.

From the Department of Medicine, Divi-

a ngiotensin-converting–enzyme (ace) inhibitors and angio-


tensin-receptor blockers are used commonly in clinical practice to treat hy-
pertension and decrease cardiovascular events in high-risk patients. A side ef-
fect of such therapy is the development of hyperkalemia. Hyperkalemia has been
attributed to the use of ACE inhibitors in 10 to 38 percent of hospitalized patients with
sion of Nephrology, University of Texas
Southwestern Medical School, Dallas. Ad-
dress reprint requests to Dr. Palmer at the
Department of Medicine, University of Tex-
as Southwestern Medical School, 5323
Harry Hines Blvd., Dallas, TX 75390-8856,
this complication.1-4 Hyperkalemia develops in approximately 10 percent of outpa- or at [email protected].
tients within a year after these drugs are prescribed.5 Patients at greatest risk for hyper-
N Engl J Med 2004;351:585-92.
kalemia include those with diabetes and those with impaired renal function in whom a
Copyright © 2004 Massachusetts Medical Society.
defect in the excretion of renal potassium may already exist.
Hyperkalemia is an uncommon complication of therapy with ACE inhibitors or an-
giotensin-receptor blockers in patients without risk factors. The low incidence of hy-
perkalemia in controlled trials involving these drugs can be attributed to the enroll-
ment of patients at low risk, frequent follow-up, and intensive monitoring. As an
example, the mean serum creatinine concentration in major trials involving patients
with congestive heart failure ranged from 1.2 to 1.4 mg per deciliter (106 to 124 µmol
per liter).6 Since one third to one half of patients with congestive heart failure have re-
nal insufficiency, in actual practice a large proportion of patients being treated with
these drugs are at increased risk for hyperkalemia.6 Physicians are willing to prescribe
these drugs for such high-risk patients because chronic kidney disease is among the
strongest predictors of death in patients with congestive heart failure. The develop-
ment of hyperkalemia poses a therapeutic dilemma, since the patients at highest risk
for this complication are the same patients who derive the greatest cardiovascular ben-
efit from these drugs.
Hyperkalemia is likely to become an even more common clinical event, since ACE
inhibitors and angiotensin-receptor blockers are increasingly being used in higher
doses and in combination, in the belief that these measures provide additional cardio-
vascular protection.7-10 Further increasing the risk is the practice of adding an aldoste-
rone-receptor blocker to one of these drugs to improve outcomes in patients with con-
gestive heart failure.11,12 There is preliminary evidence that this combination of drugs
may also be of benefit in slowing the progression of chronic kidney disease.13 To the
extent that such treatment strategies improve cardiovascular outcomes, it will be of
considerable importance for physicians to identify patients at risk (Table 1) and to im-
plement measures designed to lessen the likelihood that hyperkalemia will develop.
Although close monitoring is required, such measures will allow the majority of pa-
tients to enjoy the cardiovascular benefits of these drugs instead of being considered to
have an intolerance to them as a result of hyperkalemia.

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normal handling Table 1. Risk Factors for Hyperkalemia with the Use
of potassium in the kidney of Drugs That Interfere with the Renin–Angiotensin–
Aldosterone System.
Potassium is freely filtered by the glomerulus. Most
filtered potassium is reabsorbed in the proximal tu- Chronic kidney disease*
Diabetes mellitus
bule and the loop of Henle, with only 10 percent of
Decompensated congestive heart failure
the filtered load reaching the distal nephron. Potas-
Volume depletion
sium is then secreted in the collecting duct. Potas-
Advanced age
sium secretion in this segment is regulated and var-
Drugs used concomitantly that interfere in renal
ies according to physiological needs. The two most potassium excretion
important physiological determinants of potassium Nonsteroidal antiinflammatory drugs
excretion are the serum aldosterone concentration Beta-blockers
Calcineurin inhibitors: cyclosporine, tacrolimus
and the delivery of sodium to the distal nephron. Heparin
Aldosterone secretion is influenced by the renin– Ketoconazole
angiotensin system and by the plasma potassium Potassium-sparing diuretics: spironolactone,
eplerenone, amiloride, triamterene
concentration. Renin is secreted by the juxtaglo- Trimethoprim
merular cells in the afferent arteriole when renal Pentamidine
perfusion pressure is low, as in states of low blood Potassium supplements, including salt substitutes and
volume or their functional equivalents such as con- certain herbs
gestive heart failure or cirrhosis. Renin acts on an-
* The risk is inversely related to the glomerular filtration
giotensinogen to form angiotensin I, which is then rate and increases substantially when the rate is less
converted to angiotensin II by angiotensin-con- than 30 ml per minute.
verting enzyme. Angiotensin II stimulates the re-
lease of aldosterone from the zona glomerulosa
cells in the adrenal gland. Plasma potassium also
has a direct stimulatory effect on aldosterone se- ron, aldosterone deficiency, and abnormal func-
cretion.14 The stimulatory effects of angiotensin II tioning of the cortical collecting tubule. These
and potassium on the release of aldosterone ap- abnormalities can result from the effects of other
pear to be synergistic, since the presence of one drugs, from underlying disease, or commonly from
factor increases the response to the other.14,15 This a combination of both.
interaction between angiotensin II and potassium
involves the activation of a local intra-adrenal re- decreased distal delivery of sodium
nin–angiotensin system.16 Under normal circumstances, there is an inverse
relationship between the plasma aldosterone con-
induction of hyperkalemia centration and the delivery of sodium to the distal
nephron so that potassium excretion remains in-
ACE inhibitors and angiotensin-receptor blockers dependent of changes in extracellular fluid volume.
impair urinary potassium excretion by interfering Under conditions of decreased renal perfusion, al-
with the stimulatory effect of angiotensin II on al- dosterone concentrations increase. At the same
dosterone secretion in the adrenal gland. ACE in- time, the proximal absorption of sodium and water
hibitors block the formation of angiotensin II, increases, and as a result, their distal delivery de-
whereas angiotensin-receptor blockers prevent an- creases. Renal potassium excretion remains fairly
giotensin II from binding to its adrenal receptor. In constant under these conditions, since the stimu-
addition to their effects on circulating angiotensin latory effect of increased aldosterone is counterbal-
II, these drugs may interfere with angiotensin II anced by the decreased delivery of filtrate to the dis-
that is generated locally within the adrenal zona tal nephron.
glomerulosa.16 Mild-to-moderate reductions in renal perfusion
Hyperkalemia may develop as a complication of typically do not cause the distal delivery of sodium
therapy with ACE inhibitors or angiotensin-recep- to fall to a level that impairs potassium secretion
tor blockers in patients with one or more of three sufficiently to result in clinically significant hyper-
disturbances that impair the excretion of potassi- kalemia. In most patients with untreated conges-
um: decreased delivery of sodium to the distal neph- tive heart failure, the serum potassium concentra-

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current concepts

tion is normal or at the high end of the normal turbances can result from a disease state or from
range as long as the impairment in cardiac func- the effects of other drugs (Fig. 1).
tion and renal perfusion is not severe. When such Several conditions affect this system at its point
patients are treated with ACE inhibitors or angio- of origin and lead to the impaired release of renin
tensin-receptor blockers, the fall in the circulating with subsequent hypoaldosteronism — a syndrome
aldosterone concentration typically will be coun- commonly referred to as hyporeninemic hypoaldo-
terbalanced by increased distal delivery of sodium steronism. The normal aging process is accompa-
so that the serum potassium concentration remains nied by impaired release of renin, placing elderly pa-
stable. The increase in the distal delivery of sodium tients at slightly increased risk for hyperkalemia.18
is due to the afterload-reducing effects of these Diabetic nephropathy is the most common cause
drugs, which cause an improvement in cardiac out- of hyporeninemic hypoaldosteronism, accounting
put and renal perfusion. The reduction in angio- for 43 to 63 percent of cases.19,20 The risk of hyper-
tensin II concentration plays an important role in kalemia is further increased in diabetic patients as
decreasing proximal sodium reabsorption. In ad- a result of insulin deficiency, which in turn limits
dition, most patients are treated with loop diuret- the body’s ability to shift potassium into cells.
ics, which further enhance the delivery of sodium Several medications are known to interfere with
to the collecting duct. the release of renin. Nonsteroidal antiinflammatory
When renal perfusion becomes more severely drugs have been reported to cause hyperkalemia in
reduced, as in intractable congestive heart failure, up to 46 percent of hospitalized patients.21 These
proximal reabsorption can become so intense that drugs interfere with the stimulatory effect of prosta-
very little sodium escapes into the distal nephron. glandins on the release of renin.22 The subsequent
Despite increased concentrations of aldosterone, fall in aldosterone concentrations is exacerbated
the lack of availability of sodium can begin to im- when these drugs are used with inhibitors of the re-
pair renal potassium secretion. To the extent that nin–angiotensin system, since prostaglandins serve
cardiac output and renal perfusion become refrac- an intermediary role in the stimulatory effect of an-
tory to the afterload-reducing effects of ACE inhib- giotensin II on aldosterone secretion.23 The cyclo-
itors or angiotensin-receptor blockers, the risk of oxygenase-2–selective inhibitors should be used
hyperkalemia increases. In this setting, these drugs with the same caution that applies to the use of tra-
may also cause the serum creatinine concentration ditional nonsteroidal antiinflammatory drugs.24
to rise owing to reductions in intraglomerular pres- Hyperkalemia has been reported to develop in 44
sure that are no longer offset by increases in glo- to 73 percent of transplant recipients who receive
merular perfusion.17 Patients in whom this effect immunosuppressive therapy with cyclosporine or
occurs generally have a urinary sodium concen- tacrolimus.25 These drugs suppress the release of
tration of less than 10 mmol per liter and a relative- renin and directly interfere with the secretion of po-
ly high urinary potassium concentration, often ex- tassium in the collecting duct.26 The use of ACE
ceeding 40 mmol per liter. Despite the high urinary inhibitors and angiotensin-receptor blockers to
potassium concentration, total urinary potassium slow the progression of chronic allograft nephrop-
excretion is inadequate because of the low urinary athy can be expected to increase the risk of hyper-
volume. kalemia.27
Beta-adrenergic blocking agents can confer a
decreased aldosterone activity predisposition to the development of hyperkale-
The decline in serum aldosterone concentrations mia through two potential mechanisms.28 These
that occurs with the use of ACE inhibitors and angi- drugs block the stimulatory effect of the sympa-
otensin-receptor blockers is not sufficient to im- thetic nervous system on the release of renin. In ad-
pair the excretion of potassium in most patients. dition, they can interfere with the cellular uptake of
The development of hyperkalemia as a result of potassium through decreased activity of sodium–
decreased aldosterone concentrations is usually potassium ATPase.29
seen when aldosterone concentrations have already Heparin can cause hyperkalemia by blocking the
decreased before the administration of the drugs. biosynthesis of aldosterone in the adrenal gland.30
Decreased aldosterone concentrations can result This complication can develop irrespective of the
from disturbances that originate at any point in the dose used and may be seen after either intravenous
renin–angiotensin–aldosterone system. Such dis- or subcutaneous administration. The azole antifun-

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Figure 1. The Renin–Angiotensin–Aldosterone System and Regulation of Potassium Excretion in the Kidney.
Aldosterone binds to a cytosolic receptor in the principal cell and stimulates sodium reabsorption across the luminal membrane through
a well-defined sodium channel. As sodium is reabsorbed, the electronegativity of the lumen increases, thereby providing a more favorable
driving force for the secretion of potassium through an apically located potassium channel. The permeability of the anion that accompanies
sodium also influences the secretion of potassium, with less permeable anions having a greater stimulatory effect on this secretion. Disease
states or drugs that interfere at any point along this system can impair the secretion of potassium in the kidney and increase the risk of hyper-
kalemia when ACE inhibitors or angiotensin-receptor blockers are used. In many patients, this risk is magnified because of disturbances
at multiple points in this system. NSAIDs denotes nonsteroidal antiinflammatory drugs.

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current concepts

gals, such as ketoconazole, interfere with the bio- deciliter (159 µmol per liter), and the estimated glo-
synthesis of adrenal steroids and therefore can pre- merular filtration rate is 31 ml per minute. Such
dispose patients to aldosterone deficiency. a patient is likely to have hyporeninemic hypoal-
dosteronism and abnormal functioning of the col-
abnormal functioning of the cortical lecting duct. Depending on the severity of the heart
collecting tubule failure, there may also be decreased distal delivery
The risk of hyperkalemia increases when ACE in- of sodium. This patient is clearly at increased risk
hibitors and angiotensin-receptor blockers are used for the development of hyperkalemia. At the same
with drugs or in disease states that interfere with time, drugs that interfere in the renin–angioten-
the function of the cortical collecting tubule. Acute sin system can provide this patient with consider-
or chronic tubulointerstitial renal disease is char- able cardiovascular benefit. An ACE inhibitor or
acterized by the early onset of impaired renal po- an angiotensin-receptor blocker would be useful
tassium secretion, even though renal function may to slow the progression of renal disease, to treat
be only mildly depressed. These disorders cause the underlying heart failure, to reduce the risk of a
early damage of the tubules, which results in end- future cardiovascular event, and to reduce the risk
organ resistance to the effects of aldosterone such of death.34-37 Given the presence of heart failure,
that even a small decline in the circulating aldoste- an aldosterone-receptor blocker might be added to
rone concentration can limit renal potassium ex- reduce the chance of death further.11
cretion. Many of the diseases that affect tubular The initial approach to such a patient is to deter-
function also impair the release of renin; as a re- mine the specific risk of hyperkalemia by accurate-
sult, hyporeninemic hypoaldosteronism and im- ly assessing the level of renal function (Table 2).38
paired tubular function may coexist. Patients who In general, the risk will increase as renal function
may have these coexisting conditions include those declines; however, an estimated glomerular filtra-
with diabetic nephropathy, renal transplants, sys- tion rate of 30 ml per minute should be considered
temic lupus erythematosus, amyloidosis, sickle cell a threshold below which the likelihood that hy-
disease, or obstruction of the urinary tract. perkalemia will develop substantially increases.
The potassium-sparing diuretics impair the abil- Patients with diabetic nephropathy who have only
ity of the cortical collecting tubule to secrete potas- mild-to-moderate reductions in the glomerular
sium. In an analysis of elderly subjects who were filtration rate (30 to 90 ml per minute) should be
treated with ACE inhibitors, those admitted to the considered at higher risk because of the frequent
hospital because of hyperkalemia were 27 times as presence of hyporeninemic hypoaldosteronism.
likely to have received a prescription for a potassi- In patients with chronic kidney disease, the level of
um-sparing diuretic during the previous week as renal function should not be the sole criterion for
were those taking ACE inhibitors who were not ad- deciding whether use of these drugs should be ini-
mitted to the hospital.31 Amiloride and triam- tiated or continued. When they are used in patients
terene block the epithelial sodium channel in the with severe reductions in the glomerular filtration
collecting duct. Blockade of sodium reabsorption rate (i.e., those with rates below 30 ml per minute),
through this channel abolishes the negative poten- close monitoring is required. Withholding these
tial of the lumen and therefore removes a major drugs solely on the basis of the level of renal func-
driving force for the secretion of potassium. A sim- tion will unnecessarily deprive many patients of the
ilar effect can be seen with trimethoprim and pent- cardiovascular benefit that they otherwise would
amidine.32,33 Spironolactone and eplerenone are have received, particularly since numerous steps
potassium-sparing diuretics that block the interac- can be taken to minimize the risk of hyperkalemia
tion of aldosterone with the aldosterone receptor. (Table 2).
One should review the patient’s medication pro-
file and, whenever possible, discontinue drugs that
minimizing the risk
of hyperkalemia can impair the excretion of potassium in the kid-
ney. Patients should be asked specifically about the
Consider the hypothetical case of a 58-year-old use of over-the-counter nonsteroidal antiinflam-
white woman with type 2 diabetes mellitus, con- matory drugs as well as herbal remedies, since
gestive heart failure, and diabetic nephropathy. herbs may be a hidden source of dietary potassi-
The serum creatinine concentration is 1.8 mg per um. An example of such foods is noni juice, which

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at risk include milkweed, lily of the valley, Siberian


Table 2. Approach to Patients at Risk for Hyperkalemia Caused by Inhibitors
of the Renin–Angiotensin–Aldosterone System.
ginseng, and hawthorn berries.41,44
Patients should follow a low-potassium diet
Estimate glomerular filtration rate to assess specific risk of hyperkalemia* with specific counseling against the use of salt sub-
Glomerular filtration rate (in ml/min/1.73 m2) = 186 ¬ serum creatinine stitutes that contain potassium.45 Foods rich in po-
(in mg/dl)¡1.154 ¬ age (in yr)¡0.203 ¬ 0.742 (if female) ¬ 1.210 (if black) tassium include orange juice, melons, and bananas.
Creatinine clearance (in ml/min) = [140 ¡ age (in yr) ¬ weight (in kg) ÷ 72 ¬ Diuretics are particularly effective in minimizing
serum creatinine (in mg/dl)] ¬ 0.85 (if female)
hyperkalemia. Diuretics enhance the excretion of
Whenever possible, discontinue drugs that interfere in renal potassium secre-
tion, inquire about use of herbal preparations, and discontinue non-
potassium in the kidney by increasing the delivery
steroidal antiinflammatory drugs, including selective cyclooxygenase-2 of sodium to the collecting duct. In patients with
inhibitors an estimated glomerular filtration rate that is 30 ml
Prescribe low-potassium diet; inquire about use of salt substitutes that con- per minute or higher, thiazide diuretics can be used,
tain potassium but in patients with more severe renal insufficiency,
Prescribe thiazide or loop diuretics (loop diuretics necessary when estimated loop diuretics are required.
glomerular filtration rate is <30 ml/min)
If a potassium-sparing diuretic is added to an
Prescribe sodium bicarbonate to correct metabolic acidosis in patients with
chronic kidney disease: 1 or 2 650-mg tablets twice a day (each tablet
ACE inhibitor or to an angiotensin-receptor block-
contains 8 mEq of sodium bicarbonate) or 1/2 –1 tsp of baking soda er, as in the treatment of congestive heart failure,
daily (25–50 mEq of sodium bicarbonate) close monitoring is required. The incidence of seri-
Initiate therapy with low-dose ACE inhibitor or angiotensin-receptor blocker ous hyperkalemia in the Randomized Aldactone
Measure potassium 1 wk after initiating therapy or after increasing dose Evaluation Study was only 2 percent.11 The average
of drug serum creatinine concentration in this study was
If potassium increases to ≤5.5 mmol/liter, decrease dose of drug; if patient is 1.2 mg per deciliter (106 µmol per liter), and the
taking some combination of an ACE inhibitor, an angiotensin-receptor
blocker, and an aldosterone-receptor blocker, discontinue one and re-
dose of spironolactone that was prescribed did
check potassium not exceed 25 mg daily. Subsequent reports have
The dose of spironolactone should not exceed 25 mg daily when used with described a higher frequency of hyperkalemia in
an ACE inhibitor or angiotensin-receptor blocker; this combination actual practice.46 The reports have included pa-
of drugs should be avoided when the glomerular filtration rate is tients with more severe renal dysfunction (creati-
<30 ml/min
nine concentration, 1.8 to 2.0 mg per deciliter
If potassium is >5.5 mmol/liter despite steps described above, discontinue
drugs [159 to 176 µmol per liter]) who were given high-
er doses of this aldosterone-receptor blocker.47-50
* Use of the serum creatinine concentration alone is inadequate for this pur- The patients were more likely than those in the
pose, since substantial losses in renal function are required before there is a clinical trial to be taking potassium supplements
measurable increase in the serum creatinine concentration. The recent clinical
practice guidelines of the National Kidney Foundation recommend the use of
or some other drug known to impair the excretion
predictive equations based on the serum creatinine concentration, age, sex, of renal potassium. The clinical and laboratory fol-
race, and body size to estimate the glomerular filtration rate as the preferred low-up also was less vigorous than that in the clin-
method of clinically assessing renal function.38 The formula for the glomerular
filtration rate is an abbreviated version of the equation used in the Modification
ical trial.
of Diet in Renal Disease Study.39 An easy method of estimating the glomerular In patients with chronic kidney disease and met-
filtration rate can be found at www.kidney.org/professionals/kdoqi/gfr_page. abolic acidosis, the administration of sodium bi-
cfm. The formula for the creatinine clearance is the Cockcroft–Gault equation.
carbonate is an effective strategy to minimize in-
creases in the serum potassium concentration.51
This drug will increase the excretion of potassium
is derived from the fruit of the noni tree (Morinda in the kidney as a result of increased distal delivery
citrifolia) and contains 56 mmol of potassium per of sodium and will shift potassium into cells as the
liter40; substantial quantities of potassium are also acidosis is corrected. Ensuring that the patient is
found in alfalfa (Medicago sativa), dandelion (Tarax- first receiving effective diuretic therapy will lessen
acum officinale), horsetail (Equisetum arvense), and the likelihood of the development of volume over-
nettle (Urtica dioica).41,42 Chan su is an herb mar- load as a complication of the administration of so-
keted as a topical aphrodisiac.43 This substance dium bicarbonate.
contains an extract of toad skin that mimics the If treatment with an ACE inhibitor or an angio-
toxicity of digitalis, which can result in hyperkale- tensin-receptor blocker is to be initiated, it is best
mia. Other herbs containing digoxin-like substanc- to begin with low doses. The serum potassium con-
es that may precipitate hyperkalemia in patients centration should be checked within one week af-

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current concepts

ter the drug has been started. If the potassium con- potassium concentration is 5.6 mmol per liter or
centration is normal, then the dose of the drug can higher despite the precautions described above,
be titrated upward. With each increase in the dose, then such drugs may need to be avoided. Particular
the serum potassium concentration should be mea- attention should be given to patients with underly-
sured again one week later. For increased serum ing disturbances of cardiac conduction, since even
potassium concentrations of up to 5.5 mmol per li- mild degrees of hyperkalemia can precipitate heart
ter, the dose can be lowered; in some cases, the po- block.
tassium concentration will decline, and treatment Sodium polystyrene sulfonate (Kayexalate) is
with the renin-angiotensin blocker can be contin- commonly used to treat acute hyperkalemia. How-
ued, albeit at a lower dose.3,4,52 In patients at risk ever, long-term use is poorly tolerated because the
for hyperkalemia, angiotensin-receptor blockers resin is usually given in a suspension with hyperton-
should be used with the same caution as are ACE ic sorbitol to promote osmotic diarrhea. In addi-
inhibitors. In patients receiving some combination tion, long-term use has been associated with muco-
of an ACE inhibitor, an angiotensin-receptor block- sal injury in the lower and upper gastrointestinal
er, and an aldosterone-receptor blocker, discontin- tract.53,54
uation of one drug may also be effective in lowering Dr. Palmer reports having received lecture fees from Biovail, No-
the serum potassium concentration. If the serum vartis, and Merck.

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tor, ramipril, on cardiovascular events in 20. Copyright © 2004 Massachusetts Medical Society.

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