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` new england journal
`The
`
`of
`
` medicine
`
`review article
`
`current concepts
`Managing Hyperkalemia Caused by Inhibitors
`of the Renin–Angiotensin–Aldosterone System
`
`Biff F. Palmer, M.D.
`
`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
`1-4
` Hyperkalemia develops in approximately 10 percent of outpa-
`this complication.
`5
` Patients at greatest risk for hyper-
`tients within a year after these drugs are prescribed.
`kalemia include those with diabetes and those with impaired renal function in whom a
`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
`6
` Since one third to one half of patients with congestive heart failure have re-
`per liter).
`nal insufficiency, in actual practice a large proportion of patients being treated with
`6
`these drugs are at increased risk for hyperkalemia.
` 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-
`7-10
` Further increasing the risk is the practice of adding an aldoste-
`vascular protection.
`rone-receptor blocker to one of these drugs to improve outcomes in patients with con-
`11,12
`gestive heart failure.
` There is preliminary evidence that this combination of drugs
`13
`may also be of benefit in slowing the progression of chronic kidney disease.
` 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.
`
`From the Department of Medicine, Divi-
`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,
`or at biff.palmer@utsouthwestern.edu.
`
`N Engl J Med 2004;351:585-92.
`Copyright © 2004 Massachusetts Medical Society.
`
`n engl j med
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`351;6
`
`www.nejm.org august
`
`5, 2004
`
`585
`
`The New England Journal of Medicine
`
`Downloaded from nejm.org at SIDLEY AUSTIN LLP on October 3, 2016. For personal use only. No other uses without permission.
`
` Copyright © 2004 Massachusetts Medical Society. All rights reserved.
`
`
`
`JANSSEN EXHIBIT 2067
`Wockhardt v. Janssen IPR2016-01582
`
`

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` new england journal
`The
`
` medicine
`of
`
`normal handling
`of potassium in the kidney
`
`Potassium is freely filtered by the glomerulus. Most
`filtered potassium is reabsorbed in the proximal tu-
`bule and the loop of Henle, with only 10 percent of
`the filtered load reaching the distal nephron. Potas-
`sium is then secreted in the collecting duct. Potas-
`sium secretion in this segment is regulated and var-
`ies according to physiological needs. The two most
`important physiological determinants of potassium
`excretion are the serum aldosterone concentration
`and the delivery of sodium to the distal nephron.
`Aldosterone secretion is influenced by the renin–
`angiotensin system and by the plasma potassium
`concentration. Renin is secreted by the juxtaglo-
`merular cells in the afferent arteriole when renal
`perfusion pressure is low, as in states of low blood
`volume or their functional equivalents such as con-
`gestive heart failure or cirrhosis. Renin acts on an-
`giotensinogen to form angiotensin I, which is then
`converted to angiotensin II by angiotensin-con-
`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-
`14
`cretion.
` The stimulatory effects of angiotensin II
`and potassium on the release of aldosterone ap-
`pear to be synergistic, since the presence of one
`14,15
`factor increases the response to the other.
` This
`interaction between angiotensin II and potassium
`involves the activation of a local intra-adrenal re-
`16
`nin–angiotensin system.
`
`induction of hyperkalemia
`
`ACE inhibitors and angiotensin-receptor blockers
`impair urinary potassium excretion by interfering
`with the stimulatory effect of angiotensin II on al-
`dosterone secretion in the adrenal gland. ACE in-
`hibitors block the formation of angiotensin II,
`whereas angiotensin-receptor blockers prevent an-
`giotensin II from binding to its adrenal receptor. In
`addition to their effects on circulating angiotensin
`II, these drugs may interfere with angiotensin II
`that is generated locally within the adrenal zona
`16
`glomerulosa.
`Hyperkalemia may develop as a complication of
`therapy with ACE inhibitors or angiotensin-recep-
`tor blockers in patients with one or more of three
`disturbances that impair the excretion of potassi-
`um: decreased delivery of sodium to the distal neph-
`
`Table 1. Risk Factors for Hyperkalemia with the Use
`of Drugs That Interfere with the Renin–Angiotensin–
`Aldosterone System.
`
`Chronic kidney disease*
`Diabetes mellitus
`Decompensated congestive heart failure
`Volume depletion
`Advanced age
`Drugs used concomitantly that interfere in renal
`potassium excretion
`Nonsteroidal antiinflammatory drugs
`Beta-blockers
`Calcineurin inhibitors: cyclosporine, tacrolimus
`Heparin
`Ketoconazole
`Potassium-sparing diuretics: spironolactone,
`eplerenone, amiloride, triamterene
`Trimethoprim
`Pentamidine
`Potassium supplements, including salt substitutes and
`certain herbs
`
`* The risk is inversely related to the glomerular filtration
`rate and increases substantially when the rate is less
`than 30 ml per minute.
`
`ron, aldosterone deficiency, and abnormal func-
`tioning of the cortical collecting tubule. These
`abnormalities can result from the effects of other
`drugs, from underlying disease, or commonly from
`a combination of both.
`
`decreased distal delivery of sodium
`Under normal circumstances, there is an inverse
`relationship between the plasma aldosterone con-
`centration and the delivery of sodium to the distal
`nephron so that potassium excretion remains in-
`dependent of changes in extracellular fluid volume.
`Under conditions of decreased renal perfusion, al-
`dosterone concentrations increase. At the same
`time, the proximal absorption of sodium and water
`increases, and as a result, their distal delivery de-
`creases. Renal potassium excretion remains fairly
`constant under these conditions, since the stimu-
`latory effect of increased aldosterone is counterbal-
`anced by the decreased delivery of filtrate to the dis-
`tal nephron.
`Mild-to-moderate reductions in renal perfusion
`typically do not cause the distal delivery of sodium
`to fall to a level that impairs potassium secretion
`sufficiently to result in clinically significant hyper-
`kalemia. In most patients with untreated conges-
`tive heart failure, the serum potassium concentra-
`
`586
`
`n engl j med
`
`351;6
`
`www.nejm.org august
`
`,
`
`5
`
`2004
`
`The New England Journal of Medicine
`
`Downloaded from nejm.org at SIDLEY AUSTIN LLP on October 3, 2016. For personal use only. No other uses without permission.
`
` Copyright © 2004 Massachusetts Medical Society. All rights reserved.
`
`

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`current concepts
`
`tion is normal or at the high end of the normal
`range as long as the impairment in cardiac func-
`tion and renal perfusion is not severe. When such
`patients are treated with ACE inhibitors or angio-
`tensin-receptor blockers, the fall in the circulating
`aldosterone concentration typically will be coun-
`terbalanced by increased distal delivery of sodium
`so that the serum potassium concentration remains
`stable. The increase in the distal delivery of sodium
`is due to the afterload-reducing effects of these
`drugs, which cause an improvement in cardiac out-
`put and renal perfusion. The reduction in angio-
`tensin II concentration plays an important role in
`decreasing proximal sodium reabsorption. In ad-
`dition, most patients are treated with loop diuret-
`ics, which further enhance the delivery of sodium
`to the collecting duct.
`When renal perfusion becomes more severely
`reduced, as in intractable congestive heart failure,
`proximal reabsorption can become so intense that
`very little sodium escapes into the distal nephron.
`Despite increased concentrations of aldosterone,
`the lack of availability of sodium can begin to im-
`pair renal potassium secretion. To the extent that
`cardiac output and renal perfusion become refrac-
`tory to the afterload-reducing effects of ACE inhib-
`itors or angiotensin-receptor blockers, the risk of
`hyperkalemia increases. In this setting, these drugs
`may also cause the serum creatinine concentration
`to rise owing to reductions in intraglomerular pres-
`sure that are no longer offset by increases in glo-
`17
`merular perfusion.
` Patients in whom this effect
`occurs generally have a urinary sodium concen-
`tration of less than 10 mmol per liter and a relative-
`ly high urinary potassium concentration, often ex-
`ceeding 40 mmol per liter. Despite the high urinary
`potassium concentration, total urinary potassium
`excretion is inadequate because of the low urinary
`volume.
`
`decreased aldosterone activity
`The decline in serum aldosterone concentrations
`that occurs with the use of ACE inhibitors and angi-
`otensin-receptor blockers is not sufficient to im-
`pair the excretion of potassium in most patients.
`The development of hyperkalemia as a result of
`decreased aldosterone concentrations is usually
`seen when aldosterone concentrations have already
`decreased before the administration of the drugs.
`Decreased aldosterone concentrations can result
`from disturbances that originate at any point in the
`renin–angiotensin–aldosterone system. Such dis-
`
`turbances can result from a disease state or from
`the effects of other drugs (Fig. 1).
`Several conditions affect this system at its point
`of origin and lead to the impaired release of renin
`with subsequent hypoaldosteronism — a syndrome
`commonly referred to as hyporeninemic hypoaldo-
`steronism. The normal aging process is accompa-
`nied by impaired release of renin, placing elderly pa-
`18
`tients at slightly increased risk for hyperkalemia.
`Diabetic nephropathy is the most common cause
`of hyporeninemic hypoaldosteronism, accounting
`19,20
` The risk of hyper-
`for 43 to 63 percent of cases.
`kalemia is further increased in diabetic patients as
`a result of insulin deficiency, which in turn limits
`the body’s ability to shift potassium into cells.
`Several medications are known to interfere with
`the release of renin. Nonsteroidal antiinflammatory
`drugs have been reported to cause hyperkalemia in
`21
`up to 46 percent of hospitalized patients.
` These
`drugs interfere with the stimulatory effect of prosta-
`22
`glandins on the release of renin.
` The subsequent
`fall in aldosterone concentrations is exacerbated
`when these drugs are used with inhibitors of the re-
`nin–angiotensin system, since prostaglandins serve
`an intermediary role in the stimulatory effect of an-
`23
` The cyclo-
`giotensin II on aldosterone secretion.
`oxygenase-2–selective inhibitors should be used
`with the same caution that applies to the use of tra-
`24
`ditional nonsteroidal antiinflammatory drugs.
`Hyperkalemia has been reported to develop in 44
`to 73 percent of transplant recipients who receive
`immunosuppressive therapy with cyclosporine or
`25
`tacrolimus.
` These drugs suppress the release of
`renin and directly interfere with the secretion of po-
`26
` The use of ACE
`tassium in the collecting duct.
`inhibitors and angiotensin-receptor blockers to
`slow the progression of chronic allograft nephrop-
`athy can be expected to increase the risk of hyper-
`27
`kalemia.
`Beta-adrenergic blocking agents can confer a
`predisposition to the development of hyperkale-
`28
` These
`mia through two potential mechanisms.
`drugs block the stimulatory effect of the sympa-
`thetic nervous system on the release of renin. In ad-
`dition, they can interfere with the cellular uptake of
`potassium through decreased activity of sodium–
`29
`potassium ATPase.
`Heparin can cause hyperkalemia by blocking the
`30
`biosynthesis of aldosterone in the adrenal gland.
`This complication can develop irrespective of the
`dose used and may be seen after either intravenous
`or subcutaneous administration. The azole antifun-
`
`n engl j med
`
`351;6
`
`www.nejm.org august
`
`5, 2004
`
`587
`
`The New England Journal of Medicine
`
`Downloaded from nejm.org at SIDLEY AUSTIN LLP on October 3, 2016. For personal use only. No other uses without permission.
`
` Copyright © 2004 Massachusetts Medical Society. All rights reserved.
`
`

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`
` new england journal
`The
`
` medicine
`of
`
`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.
`
`588
`
`n engl j med
`
`351;6
`
`www.nejm.org august
`
`,
`
`5
`
`2004
`
`The New England Journal of Medicine
`
`Downloaded from nejm.org at SIDLEY AUSTIN LLP on October 3, 2016. For personal use only. No other uses without permission.
`
` Copyright © 2004 Massachusetts Medical Society. All rights reserved.
`
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`current concepts
`
`gals, such as ketoconazole, interfere with the bio-
`synthesis of adrenal steroids and therefore can pre-
`dispose patients to aldosterone deficiency.
`
`abnormal functioning of the cortical
`collecting tubule
`The risk of hyperkalemia increases when ACE in-
`hibitors and angiotensin-receptor blockers are used
`with drugs or in disease states that interfere with
`the function of the cortical collecting tubule. Acute
`or chronic tubulointerstitial renal disease is char-
`acterized by the early onset of impaired renal po-
`tassium secretion, even though renal function may
`be only mildly depressed. These disorders cause
`early damage of the tubules, which results in end-
`organ resistance to the effects of aldosterone such
`that even a small decline in the circulating aldoste-
`rone concentration can limit renal potassium ex-
`cretion. Many of the diseases that affect tubular
`function also impair the release of renin; as a re-
`sult, hyporeninemic hypoaldosteronism and im-
`paired tubular function may coexist. Patients who
`may have these coexisting conditions include those
`with diabetic nephropathy, renal transplants, sys-
`temic lupus erythematosus, amyloidosis, sickle cell
`disease, or obstruction of the urinary tract.
`The potassium-sparing diuretics impair the abil-
`ity of the cortical collecting tubule to secrete potas-
`sium. In an analysis of elderly subjects who were
`treated with ACE inhibitors, those admitted to the
`hospital because of hyperkalemia were 27 times as
`likely to have received a prescription for a potassi-
`um-sparing diuretic during the previous week as
`were those taking ACE inhibitors who were not ad-
`31
` Amiloride and triam-
`mitted to the hospital.
`terene block the epithelial sodium channel in the
`collecting duct. Blockade of sodium reabsorption
`through this channel abolishes the negative poten-
`tial of the lumen and therefore removes a major
`driving force for the secretion of potassium. A sim-
`ilar effect can be seen with trimethoprim and pent-
`32,33
` Spironolactone and eplerenone are
`amidine.
`potassium-sparing diuretics that block the interac-
`tion of aldosterone with the aldosterone receptor.
`
`minimizing the risk
`of hyperkalemia
`
`Consider the hypothetical case of a 58-year-old
`white woman with type 2 diabetes mellitus, con-
`gestive heart failure, and diabetic nephropathy.
`The serum creatinine concentration is 1.8 mg per
`
`deciliter (159 µmol per liter), and the estimated glo-
`merular filtration rate is 31 ml per minute. Such
`a patient is likely to have hyporeninemic hypoal-
`dosteronism and abnormal functioning of the col-
`lecting duct. Depending on the severity of the heart
`failure, there may also be decreased distal delivery
`of sodium. This patient is clearly at increased risk
`for the development of hyperkalemia. At the same
`time, drugs that interfere in the renin–angioten-
`sin system can provide this patient with consider-
`able cardiovascular benefit. An ACE inhibitor or
`an angiotensin-receptor blocker would be useful
`to slow the progression of renal disease, to treat
`the underlying heart failure, to reduce the risk of a
`future cardiovascular event, and to reduce the risk
`34-37
` Given the presence of heart failure,
`of death.
`an aldosterone-receptor blocker might be added to
`11
`reduce the chance of death further.
`The initial approach to such a patient is to deter-
`mine the specific risk of hyperkalemia by accurate-
`38
`ly assessing the level of renal function (Table 2).
`In general, the risk will increase as renal function
`declines; however, an estimated glomerular filtra-
`tion rate of 30 ml per minute should be considered
`a threshold below which the likelihood that hy-
`perkalemia will develop substantially increases.
`Patients with diabetic nephropathy who have only
`mild-to-moderate reductions in the glomerular
`filtration rate (30 to 90 ml per minute) should be
`considered at higher risk because of the frequent
`presence of hyporeninemic hypoaldosteronism.
`In patients with chronic kidney disease, the level of
`renal function should not be the sole criterion for
`deciding whether use of these drugs should be ini-
`tiated or continued. When they are used in patients
`with severe reductions in the glomerular filtration
`rate (i.e., those with rates below 30 ml per minute),
`close monitoring is required. Withholding these
`drugs solely on the basis of the level of renal func-
`tion will unnecessarily deprive many patients of the
`cardiovascular benefit that they otherwise would
`have received, particularly since numerous steps
`can be taken to minimize the risk of hyperkalemia
`(Table 2).
`One should review the patient’s medication pro-
`file and, whenever possible, discontinue drugs that
`can impair the excretion of potassium in the kid-
`ney. Patients should be asked specifically about the
`use of over-the-counter nonsteroidal antiinflam-
`matory drugs as well as herbal remedies, since
`herbs may be a hidden source of dietary potassi-
`um. An example of such foods is noni juice, which
`
`n engl j med
`
`351;6
`
`www.nejm.org august
`
`5, 2004
`
`589
`
`The New England Journal of Medicine
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`Downloaded from nejm.org at SIDLEY AUSTIN LLP on October 3, 2016. For personal use only. No other uses without permission.
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` Copyright © 2004 Massachusetts Medical Society. All rights reserved.
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` new england journal
`The
`
` medicine
`of
`
`Table 2. Approach to Patients at Risk for Hyperkalemia Caused by Inhibitors
`of the Renin–Angiotensin–Aldosterone System.
`
`
`
`Estimate glomerular filtration rate to assess specific risk of hyperkalemia*
`2
`Glomerular filtration rate (in ml/min/1.73 m
`) = 186 ¬ serum creatinine
`1
`154
`0
`203
`¡
`.
`¡
`.
`(in mg/dl)
` ¬ age (in yr)
` ¬ 0.742 (if female) ¬ 1.210 (if black)
`Creatinine clearance (in ml/min) = [140 ¡ age (in yr) ¬ weight (in kg) ÷ 72 ¬
`serum creatinine (in mg/dl)] ¬ 0.85 (if female)
`Whenever possible, discontinue drugs that interfere in renal potassium secre-
`tion, inquire about use of herbal preparations, and discontinue non-
`steroidal antiinflammatory drugs, including selective cyclooxygenase-2
`inhibitors
`Prescribe low-potassium diet; inquire about use of salt substitutes that con-
`tain potassium
`Prescribe thiazide or loop diuretics (loop diuretics necessary when estimated
`glomerular filtration rate is <30 ml/min)
`Prescribe sodium bicarbonate to correct metabolic acidosis in patients with
`chronic kidney disease: 1 or 2 650-mg tablets twice a day (each tablet
`1
`/
`contains 8 mEq of sodium bicarbonate) or
`–1 tsp of baking soda
`2
`daily (25–50 mEq of sodium bicarbonate)
`Initiate therapy with low-dose ACE inhibitor or angiotensin-receptor blocker
`Measure potassium 1 wk after initiating therapy or after increasing dose
`of drug
`If potassium increases to ≤5.5 mmol/liter, decrease dose of drug; if patient is
`taking some combination of an ACE inhibitor, an angiotensin-receptor
`blocker, and an aldosterone-receptor blocker, discontinue one and re-
`check potassium
`The dose of spironolactone should not exceed 25 mg daily when used with
`an ACE inhibitor or angiotensin-receptor blocker; this combination
`of drugs should be avoided when the glomerular filtration rate is
`<30 ml/min
`If potassium is >5.5 mmol/liter despite steps described above, discontinue
`drugs
`
`* Use of the serum creatinine concentration alone is inadequate for this pur-
`pose, since substantial losses in renal function are required before there is a
`measurable increase in the serum creatinine concentration. The recent clinical
`practice guidelines of the National Kidney Foundation recommend the use of
`predictive equations based on the serum creatinine concentration, age, sex,
`race, and body size to estimate the glomerular filtration rate as the preferred
`38
`method of clinically assessing renal function.
` The formula for the glomerular
`filtration rate is an abbreviated version of the equation used in the Modification
`39
`of Diet in Renal Disease Study.
` An easy method of estimating the glomerular
`filtration rate can be found at www.kidney.org/professionals/kdoqi/gfr_page.
`cfm. The formula for the creatinine clearance is the Cockcroft–Gault equation.
`
`Morinda
`is derived from the fruit of the noni tree (
`citrifolia
`) and contains 56 mmol of potassium per
`40
`liter
`; substantial quantities of potassium are also
`Medicago sativa
`Tarax-
`found in alfalfa (
`), dandelion (
`acum officinale
`Equisetum arvense
`), horsetail (
`), and
`41,42
`Urtica dioica
`nettle (
`).
` Chan su is an herb mar-
`43
`keted as a topical aphrodisiac.
` This substance
`contains an extract of toad skin that mimics the
`toxicity of digitalis, which can result in hyperkale-
`mia. Other herbs containing digoxin-like substanc-
`es that may precipitate hyperkalemia in patients
`
`at risk include milkweed, lily of the valley, Siberian
`41,44
`ginseng, and hawthorn berries.
`Patients should follow a low-potassium diet
`with specific counseling against the use of salt sub-
`45
`stitutes that contain potassium.
` Foods rich in po-
`tassium include orange juice, melons, and bananas.
`Diuretics are particularly effective in minimizing
`hyperkalemia. Diuretics enhance the excretion of
`potassium in the kidney by increasing the delivery
`of sodium to the collecting duct. In patients with
`an estimated glomerular filtration rate that is 30 ml
`per minute or higher, thiazide diuretics can be used,
`but in patients with more severe renal insufficiency,
`loop diuretics are required.
`If a potassium-sparing diuretic is added to an
`ACE inhibitor or to an angiotensin-receptor block-
`er, as in the treatment of congestive heart failure,
`close monitoring is required. The incidence of seri-
`ous hyperkalemia in the Randomized Aldactone
`11
` The average
`Evaluation Study was only 2 percent.
`serum creatinine concentration in this study was
`1.2 mg per deciliter (106 µmol per liter), and the
`dose of spironolactone that was prescribed did
`not exceed 25 mg daily. Subsequent reports have
`described a higher frequency of hyperkalemia in
`46
` The reports have included pa-
`actual practice.
`tients with more severe renal dysfunction (creati-
`nine concentration, 1.8 to 2.0 mg per deciliter
`[159 to 176 µmol per liter]) who were given high-
`47-50
`er doses of this aldosterone-receptor blocker.
`The patients were more likely than those in the
`clinical trial to be taking potassium supplements
`or some other drug known to impair the excretion
`of renal potassium. The clinical and laboratory fol-
`low-up also was less vigorous than that in the clin-
`ical trial.
`In patients with chronic kidney disease and met-
`abolic acidosis, the administration of sodium bi-
`carbonate is an effective strategy to minimize in-
`51
`creases in the serum potassium concentration.
`This drug will increase the excretion of potassium
`in the kidney as a result of increased distal delivery
`of sodium and will shift potassium into cells as the
`acidosis is corrected. Ensuring that the patient is
`first receiving effective diuretic therapy will lessen
`the likelihood of the development of volume over-
`load as a complication of the administration of so-
`dium bicarbonate.
`If treatment with an ACE inhibitor or an angio-
`tensin-receptor blocker is to be initiated, it is best
`to begin with low doses. The serum potassium con-
`centration should be checked within one week af-
`
`590
`
`n engl j med
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`351;6
`
`www.nejm.org august
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`,
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`5
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`2004
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`The New England Journal of Medicine
`
`Downloaded from nejm.org at SIDLEY AUSTIN LLP on October 3, 2016. For personal use only. No other uses without permission.
`
` Copyright © 2004 Massachusetts Medical Society. All rights reserved.
`
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`current concepts
`
`ter the drug has been started. If the potassium con-
`centration is normal, then the dose of the drug can
`be titrated upward. With each increase in the dose,
`the serum potassium concentration should be mea-
`sured again one week later. For increased serum
`potassium concentrations of up to 5.5 mmol per li-
`ter, the dose can be lowered; in some cases, the po-
`tassium concentration will decline, and treatment
`with the renin-angiotensin blocker can be contin-
`3,4,52
`ued, albeit at a lower dose.
` In patients at risk
`for hyperkalemia, angiotensin-receptor blockers
`should be used with the same caution as are ACE
`inhibitors. In patients receiving some combination
`of an ACE inhibitor, an angiotensin-receptor block-
`er, and an aldosterone-receptor blocker, discontin-
`uation of one drug may also be effective in lowering
`the serum potassium concentration. If the serum
`
`potassium concentration is 5.6 mmol per liter or
`higher despite the precautions described above,
`then such drugs may need to be avoided. Particular
`attention should be given to patients with underly-
`ing disturbances of cardiac conduction, since even
`mild degrees of hyperkalemia can precipitate heart
`block.
`Sodium polystyrene sulfonate (Kayexalate) is
`commonly used to treat acute hyperkalemia. How-
`ever, long-term use is poorly tolerated because the
`resin is usually given in a suspension with hyperton-
`ic sorbitol to promote osmotic diarrhea. In addi-
`tion, long-term use has been associated with muco-
`sal injury in the lower and upper gastrointestinal
`53,54
`tract.
`
`Dr. Palmer reports having received lecture fees from Biovail, No-
`vartis, and Merck.
`
`references
`
`Acker CG, Johnson JP, Palevsky PM,
`1.
`Greenberg A. Hyperkalemia in hospitalized
`patients: causes, adequacy of treatment, and
`results of an attempt to improve physician
`compliance with published therapy guide-
`lines. Arch Intern Med 1998;158:917-24.
`Rimmer JM, Horn JF, Gennari FJ. Hyper-
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`mia: old culprits and new offenders. Am J
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`Agraharkar M, Siddiqui M, Memon A. Pre-
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`Scott RE. Multiplicative interaction between
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`Pratt JH, Rothrock JK, Dominguez JH.
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`co-Saenz R, Mulrow PJ. Production of renin,
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