Managing Hyperkalemia Caused by Inhibitors of The Renin-Angiotensin-Aldosterone System
Managing Hyperkalemia Caused by Inhibitors of The Renin-Angiotensin-Aldosterone System
Managing Hyperkalemia Caused by Inhibitors of The Renin-Angiotensin-Aldosterone System
review article
current concepts
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-
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-
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.
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
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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