Professional Documents
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Introduction
Hyperkalaemia is one of the clinically most important for some common comorbidities of CKD, such as con
electrolyte abnormalities because it can cause severe gestive heart failure (CHF). Although treatment with
electrophysiological disturbances, such as cardiac arrhyth RAAS inhibitors is desirable in patients with CKD, it
mias. Hyperkalaemia is defined as a serum potassium level is often difficult or impossible to continue this therapy
above the normal range, and various arbitrary cutoffs, over extended periods of time owing to the development
such as >5.0, >5.5 or >6.0 mmol/l, are used to denote dif of hyperkalaemia. Currently, no reliably effective and
ferent levels of severity. Hyperkalaemia has been associ safe maintenance treatments can be given in combina
ated with increased mortality in patients with chronic tion with RAAS inhibitors to offset the hyperkalaemia
kidney disease (CKD) and those undergoing haemo caused by these otherwise beneficial therapeutic agents.
dialysis,1–4 highlighting the importance of maintaining Hence, the safe response to recurrent episodes of hyper
serum potassium levels in the physiologically normal kalaemia in patients with CKD who receive RAAS inhib
range. The mechanisms driving hyperkalaemia typically itors is considered to be tapering or discontinuation of
involve a combination of factors, such as increased dietary this medication.
potassium intake, disordered distribution between intra This Review summarizes the mechanisms under
cellular and extracellular compartments and abnormali lying hyperkalaemia, its epidemiology and clinical
ties in potassium excretion. In clinical practice, CKD is the consequences, with a focus on patients with CKD and end-
most common predisposing condition for hyperkalaemia stage renal disease (ESRD). Currently available treatment
and, in combination with one or more exacerbating regimens are discussed, highlighting areas of uncertainty,
factors (discussed below), can induce recurrent episodes and emerging therapies that might enable the more-liberal
of abnormally elevated serum potassium levels. use of RAAS inhibitors in various populations of patients
Hyperkalaemia occurs especially frequently in patients at risk of hyperkalaemia are described.
with CKD who are treated with certain classes of medi
cations, such as angiotensin-converting-enzyme (ACE) Mechanisms of hyperkalaemia in CKD
inhibitors, angiotensin-receptor blockers (ARBs) or The principal mechanism through which the kidneys
other inhibitors of the renin–angiotensin–aldosterone maintain potassium homeostasis is the secretion of
University of Tennessee system (RAAS). These therapeutic agents are beneficial potassium into the distal convoluted tubule and the prox
Health Science Center,
University of Tennessee, in patients with CKD and are also the standard of care imal collecting duct. As glomerular filtration rate (GFR)
956 Court Avenue, decreases, the ability of the kidneys to maintain serum
Memphis, TN 38163,
USA. Competing interests potassium levels in a physiologically normal range is
csaba.kovesdy@va.gov The author declares no competing interests. increasingly jeopardized.5–9 Experimental studies suggest
Acute Chronic
kidney Decreased Tubulointerstitial Anaemia requiring kidney
injury GFR damage blood transfusion disease
Relative
insulin
deficiency
Inability to dispose Inhibition of Decreased renin
of K+ into the Na+/K+-ATPase: production:
intracellular space decreased ductal decreased
Decreased Block of β2-receptor
Hypertonicity production aldosterone K+ reabsorption ability to antagonists
of aldosterone: effects: and K+ redistribute
Inability to induce decreased decreased redistribution across K+ to the
tubular K+ secretion K+ secretion K+ secretion cell membranes intracellular space
Figure 1 | Mechanisms contributing to the development of hyperkalaemia in patients with chronic kidney disease and
associated comorbidities. Abbreviations: GFR, glomerular filtration rate; RAAS, renin–angiotensin–aldosterone system.
of hyperkalaemia—often as high as 40–50%—especially these agents in patients who would have been excluded
in diabetic patients, those with advanced stages of from these trials because of, for example, more-advanced
CKD,3,33,35 kidney transplant recipients17 and patients CKD or high baseline serum potassium levels. This situ
treated with RAAS inhibitors.36,37 The strong association ation might have contributed to the marked increase in
of RAAS inhibitor therapy with hyperkalaemia is further hyperkalaemia rates seen in everyday practice following
underscored by the results of clinical trials of these agents the publication of some influential RAAS inhibitor trials
in patients with CKD. Early clinical trials did not report and to a worrisome increase in hyperkalaemia-related
the incidence of hyperkalaemia, and discontinuation morbidity and mortality.51 Interestingly, in one study, the
rates related to this complication were very low (typically incidence of hyperkalaemia seemed to increase following
<1–2%).38–42 In subsequent trials, however, the incidence the initiation of RAAS inhibitors even in patients receiv
of hyperkalaemia ranged from 1.9% to 38.4%; hyper ing maintenance dialysis, although the lack of functioning
kalaemia was most common in patients with advanced kidneys in these patients should have rendered them
CKD and its incidence increased with the number of immune to hyperkalaemia caused by RAAS inhibitors.
RAAS inhibitors received (Table 1).38–48 Differences in These observations might be attributable to the inhibitory
reported rates of hyperkalaemia between clinical trials effects of these agents on both gastrointestinal and renal
could relate to different definitions of hyperkalaemia, dif tubular potassium excretion in patients with residual
ferent patient populations, or occur because some trials kidney function.52 Moreover, the results of small pub
required confirmation of hyperkalaemia by repeat meas lished53–58 and ongoing 59 clinical trials in the past 5 years
urements. As in the early clinical trials, treatment dis suggest that mineralocorticoid-receptor blockers, such
continuation rates due to hyperkalaemia remain very low as spironolactone or eplerenone, have beneficial effects
in contemporary studies. However, the strict enrolment in patients on dialysis. Use of these agents could, there
criteria and close follow-up of patients included in clinical fore, increase and result in a rise in hyperkalaemia rates
trials mean that these reported rates of hyperkalaemia and in patients on dialysis.
treatment discontinuation due to hyperkalaemia probably
greatly underestimate the real frequency of these events Outcomes
in everyday clinical practice.49,50 The success of RAAS Hyperkalaemia is associated with increased mortality
inhibitors in achieving improved clinical outcomes and in patients with normal kidney function as well as in
the apparent absence of hyperkalaemia as an important patients along the entire spectrum of CKD severity. The
problem in clinical trials has resulted in increased use of effects of hyperkalaemia are mediated through complex
Table 1 | Hyperkalaemia associated with RAAS inhibitor use in selected clinical trials in patients with CKD
Study (year Patients receiving RAAS inhibitor Definition of Incidence Discontinuation due
main results hyperkalaemia to hyperkalaemia
published)
RENAAL45 675 patients with diabetic nephropathy ≥5.0 mmol/l and 38.4% (≥5.0 mmol/l) Not reported
(2001) and sCr 115–265 μmol/l ≥5.5 mmol/l 10.8% (≥5.5 mmol/l)
IDNT47 579 patients with diabetic nephropathy >6 mmol/l 18.6% 2.1% (irbesartan)
(2001) and sCr 88.40–265.00 μmol/l 0.4% (placebo)
J-LIGHT44 58 Japanese patients with sCr >5.1 mmol/l 5.2% Not reported
(2004) 180.34 ± 42.43 μmol/l*
Benazepril in 226 Chinese patients with advanced CKD ≥6.0 mmol/l 1.9% (group 1) 1.3% (3 patients
advanced CKD48 Group 1: eGFR 37.10 ± 6.30 ml/min/1.73 m2* 5.3% (group 2) from group 2)‡
(2006) Group 2: eGFR 26.30 ± 5.30 ml/min/1.73 m2*
AASK43 417 African American patients with eGFR >5.5 mmol/l 7.2% Not reported
(2009) 46.30 ± 13.50 ml/min/1.73 m2*
NEPHRON‑D46 1,448 US veterans (99% men) with diabetic >6.0 mmol/l, or need 4.4% Not reported
(2013) nephropathy and eGFR 30–90 ml/min/1.73 m2 for emergency room (losartan + placebo)
visit, hospitalization 9.9%
or dialysis (losartan + lisinopril)
*Values are ± 1 SD. ‡Unclear in which treatment arm. Abbreviations: AASK, African American Study of Kidney Disease and Hypertension; CKD, chronic kidney
disease; eGFR, estimated glomerular filtration rate; IDNT, Irbesartan Diabetic Nephropathy Trial; J‑LIGHT, Japanese Losartan Therapy Intended for the Global
Renal Protection in Hypertensive Patients; NEPHRON‑D, Veterans Affairs Nephropathy in Diabetes; RAAS, renin–angiotensin–aldosterone system; RENAAL,
Reduction of Endpoints in Noninsulin-Dependent Diabetes Mellitus with the Angiotensin II Antagonist Losartan; sCr, serum creatinine.
alterations in cell membrane electrophysiology, 60,61 calcium and magnesium (often exacerbated by the use
a detailed description of which is beyond the scope of this of diuretics and/or proton pump inhibitors) or abnormal
Review. Studies in patients with non-dialysis-dependent serum pH. To what extent the concomitant presence of
CKD demonstrated a significant association between such abnormalities might potentiate the electrophysio
hyperkalaemia and increased long-term all-cause mor logical effects of hyperkalaemia is not well established
tality.3,62 Similar associations between hyperkalaemia and needs further examination. Severe hyperkalae
and mortality were reported in patients receiving chronic mia (most often defined as serum levels >6 mmol/l)
haemodialysis,1,2,4 but assessment of the increased mor typically represents a clinical urgency or emergency,
tality attributable to hyperkalaemia in this population is which may warrant immediate attention in the form of
confounded by exposure to low-potassium dialysates, cardiac monitoring, acute medical i nterventions and,
which are themselves a risk factor for sudden death.63,64 occasionally, emergency dialysis.
In patients receiving peritoneal dialysis, hyperkalaemia
and variability in serum potassium levels were associated Diagnostic electrocardiography
with increased mortality in the first year following the In the acute management of hyperkalaemia, electro
measurement of an abnormal potassium level, but not cardiography (ECG) is often used to gauge the sever
thereafter.65 This discrepancy between the short-term and ity of its effect on cardiac function. However, individual
long-term associations with mortality could be explained variations in sensitivity to serum levels of potassium are
by the electrophysiological effects of hyperkalaemia, evident in the ECG changes typically associated with
which present an acute danger primarily because they can hyperkalaemia, such as peaked T waves, as well as pro
cause cardiac arrhythmias.66–68 Indeed, studies that exam longation of the PR interval and QRS complex duration.
ined mortality associated with abnormal serum potassium Although case reports in patients with serum potassium
levels during a short time-window have corroborated the levels >9 mmol/l highlight an association with marked
existence of this s hort-term m
ortality risk.33 ECG changes,69–71 the ability of ECG features to predict
hyperkalaemia of moderate severity is considered poor,
Treatment of hyperkalaemia since only half of patients with serum potassium levels
Acute management >6.5 mmol/l display typical ECG changes.72 In a retro
It is unclear what level of hyperkalaemia represents an spective study of 90 patients with hyperkalaemia (of
imminent danger to the individual. In a large retrospec whom >80% had serum potassium levels >7.2 mmol/l),
tive study, a serum potassium level >6 mmol/l was associ typical ECG changes associated with hyperkalaemia
ated with a greater than 30-fold increase in the risk of showed poor sensitivity and specificity for predicting
1‑day mortality,33 but long-term adverse effects of hyper patients’ actual serum potassium levels, 73 prompting
kalaemia have been associated with levels >5 mmol/l.45 It the authors to recommend that these ECG changes
is important to emphasize that, beside the absolute serum should not be used to guide treatment of hyperkalaemia.
potassium level, numerous other factors determine when In another study of 145 patients with ESRD, the ratio
hyperkalaemia becomes hazardous in a given individual, of T wave to R wave amplitude was more specific than
such as the rate of change in serum potassium levels, the T wave tenting for predicting a serum potassium level
concurrent presence of low serum concentrations of >6 mmol/l, but both features had poor sensitivity (33%
and 24%, respectively).74 Interestingly, patients in this minimally) affect serum potassium levels. Additional
study who had an abnormal T:R wave amplitude ratio pharmacologic agents that induce potassium trans
had an increased long-term risk of sudden death, sug port into the intracellular space include insulin,84,85
gesting that ECG changes might identify patients who β 2‑receptor agonists 84 and bicarbonate 86 (Table 2).
are particularly sensitive to the electrophysiological However, the efficacy of intravenous bicarbonate for this
effects of hyperkalaemia.74 In response to the publica indication in patients on dialysis has been questioned.87,88
tion of this study, other researchers commented75 that The effects of interventions that alter the distribution of
intravenous infusion of calcium into hyperkalaemic potassium usually occur within a short period of time
patients with ECG changes linked to hyperkalaemia (<1 h), but they do not affect total body potassium levels.
could serve as a test to determine whether these changes Definitive therapy for hyperkalaemia in patients with
were incidental to or caused by the hyperkalaemia, and a net positive potassium balance necessitates the removal
whether treatment of hyperkalaemia could be expected of potassium from the body. Removal can be achieved
to reverse them.75 through enhanced renal excretion (for example, forced
diuresis with loop diuretics), but this approach might not
Interventions be effective in patients with limited GFR, such as those
Interventions used to treat acute hyperkalaemia include with advanced CKD and ESRD. Increasing gastrointes
the intravenous administration of either calcium salts tinal excretion of potassium, through the administra
or hypertonic saline (which is effective in patients with tion of potassium-binding resins (sodium polystyrene
underlying hyponatraemia).76,77 These agents restore sulphonate or calcium polystyrene sulphonate), has been
the electrophysiological properties of cell membranes widely used to control acute hyperkalaemia, not only in
through various mechanisms,78–83 but do not (or only patients with ESRD and CKD, but also in patients with
normal kidney function.72 The approval of sodium poly colon (of which 62% involved transmural necrosis) and
styrene sulphonate for the treatment of hyperkalaemia the mortality rate was 33%.101 Although case reports can
by the FDA was based on a clinical trial published in provide an important safety warning, only a few studies
1961, in which 32 hyperkalaemic patients with severe have attempted to systematically assess the frequency
azotaemia showed a decrease in serum potassium of of complications associated with sodium polystyrene
0.9 mmol/l in the first 24 h following the administration sulphonate. In a retrospective study of 752 hospitalized
of this drug.89 Subsequently, the addition of sorbitol to patients exposed to sodium polystyrene sulphonate in
sodium polystyrene sulphonate was advocated to allevi sorbitol the incidence of colonic necrosis was 0.3% overall,
ate the constipation associated with its use.90 In 2014, and all cases of this complication occurred in patients
a retrospective analysis of data from 154 hospitalized who received this treatment within 1 week after under
patients with hyperkalaemia (mean serum potassium going surgery (2 of 117 patients, 1.8%). By contrast, no
level 5.9 mmol/l) showed that administration of sodium colonic necrosis was identified in 862 control patients
polystyrene sulphonate resulted in dose-d ependent who had undergone haemodialysis or organ transplanta
reductions in serum potassium of 0.7–1.1 mmol/l. 72 tion but did not receive sodium polystyrene sulphonate.102
Administration of the highest doses of sodium poly However, in a subsequent, retrospective cohort study of
styrene sulphonate was associated with the best response 123,391 hospitalized patients, of whom 2,194 received
in patients treated with this agent alone. However, con sodium polystyrene sulphonate in sorbitol, episodes of
comitant administration of other antihyperkalaemic colonic necrosis occurred in 0.14% of patients receiving
therapies was associated with a greater decrease in serum sodium polystyrene sulphonate and 0.07% of those not
potassium levels than was observed in patients receiving exposed to this drug.103 To date it remains unclear whether
sodium polystyrene sulphonate alone, although only a gastrointestinal toxicity is a consequence of polystyrene
few patients received combination treatment.72 sulphonate alone or whether exacerbating factors need
Of note, dialysis was not yet available at the time when to be present. Experimental studies suggest that the sorbi
sodium polystyrene sulphonate was initially introduced tol added to sodium polystyrene sulphonate is the main
and few or no alternative therapies could be offered to exacerbating factor for colonic necrosis.104 However, some
hyperkalaemic patients, which perhaps contributed case reports suggest that polystyrene sulphonate deriva
to the widespread application of this treatment in clini tives administered without sorbitol can also cause gastro
cal practice. However, the utility and safety of sodium intestinal toxicity.99,100 Owing to these safety concerns, the
polystyrene sulphonate in the treatment of hyperkalae FDA issued a black box warning in 2009, recommending
mia is now being questioned. Serum potassium levels against mixing sodium polystyrene sulphonate with 70%
typically do not decline until several hours after the sorbitol.105 Nonetheless, utilization of this agent (with and
administration of oral sodium polystyrene sulphonate,91 without sorbitol at a 33% concentration) for the acute
which makes this agent inappropriate as an emergency treatment of hyperkalaemia remains widespread.72
intervention and might delay the initiation of definitive In summary, acute management of hyperkalaemia
therapies. Furthermore, several researchers have ques involves various interventions, including the intravenous
tioned the effectiveness of sodium polystyrene sulpho administration of calcium salts or drugs that affect the
nate in lowering serum potassium levels,92–94 and some cellular distribution of potassium, and definitive meas
have suggested that the effects of cathartics, such as ures to remove potassium from the body. Haemodialysis
sorbitol, mixed with the sodium polystyrene sulphonate is an effective acute therapy, but it is invasive and requires
might in fact be responsible for most of the potassium- specialized equipment and personnel. Forced diuresis
lowering effect seen after its administration.93 In normo could be an option in patients with adequate kidney
kalaemic individuals, careful measurements of faecal function, but data are lacking on its efficacy and safety.
potassium excretion after the administration of sodium In patients with impaired kidney function and when
polystyrene sulphonate combined with either a cathar acute dialysis is not available,106 potassium binding resins
tic (sorbitol or phenolphthalein) or placebo indicated no remain the only therapeutic option. Sodium polystyrene
significant increase in gastrointestinal excretion of potas sulphonate (which is currently the only potassium-
sium attributable to the resin.95 This lack of effect might be binding resin approved for lowering of serum potassium
explained by the low potassium concentration gradients levels in most countries, although calcium polystyrene
in normokalaemic patients, but also by the fact that the sulphonate is also used in some places) is still consid
capacity of sodium polystyrene sulphonate to exchange ered an effective treatment for acute hyperkalaemia.72
potassium for sodium is about 33%, such that only about However, questions about its safety profile remain.
40 mmol of potassium can be bound and excreted by a
30 g dose of the drug.96 Questions about the effective Chronic management
ness of potassium-binding resins are compounded by The chronic management of hyperkalaemia presents
concerns about their safety, with several case reports a fundamentally different challenge compared to its
describing severe upper and lower gastrointestinal inju acute treatment. Contrary to acute potassium-lowering
ries following administration of these drugs.97–100 A litera interventions, which are intended to achieve immedi
ture review found 30 reports describing 58 patients with ate restoration of the cell membrane’s normal electro
a gastrointestinal injury following the administration of physiologic milieu to avert cardiac arrhythmias, chronic
sodium polystyrene sulphonate. Most were injuries to the management aims to prevent the development of
hyperkalaemia by c orrecting the underlying defects in These new agents will have to undergo rigorous clini
potassium homeostasis. cal trials before they can be approved for clinical use.
Chronic management of hyperkalaemia usually starts Hence, clinicians will hopefully have more certainty
by identifying and eliminating correctable causes, such as than is possible for sodium polystyrene sulphonate about
a high potassium intake, hyperkalaemia-inducing medi their expected benefits and risks. Two new agents are
cations or metabolic acidosis. Effective interventions currently in advanced stages of clinical development for
include dietary education and a review of prescribed, the management of chronic hyperkalaemia. Patiromer is
over-the-counter and herbal medications. In addition, an oral, non-absorbed, high-capacity potassium binder.
kaliuretic diuretics and sodium bicarbonate can be In a placebo-controlled trial involving 120 patients
administered (Table 2).17 Administration of aldosterone with heart failure who had discontinued RAAS inhibi
(in the form of oral fludrocortisone acetate) is effective tors because of hyperkalaemia and were starting treat
in patients with aldosterone deficiency,107 but high doses ment with an aldosterone antagonist, the patients who
might be needed, which can induce sodium retention, received patiromer experienced serum potassium levels
oedema and hypertension. that were 0.45 mmol/l lower than those in patients who
Unfortunately, some of the most strong hyperkalaemia- received placebo. The incidence of hyperkalaemia was
inducing medications are RAAS inhibitors, which are also lower in the patiromer group than in the placebo
administered to patients with CKD and other comorbidi group (7.3% versus 24.5%, respectively), and more
ties because of their beneficial effects on clinical outcomes, patients in the active drug group than in the placebo
as discussed earlier. However, in many patients, recurrent group were able to tolerate spironolactone at a daily dose
and/or severe hyperkalaemia makes the use of these medi of 50 mg.111,112
cations impossible, depriving patients of their beneficial Another new agent is ZS‑9, which is a highly selective,
effects. Although discontinuation of RAAS inhibitors oral sorbent designed to preferentially trap potassium
very often resolves hyperkalaemia in patients with CKD, ions throughout the gastrointestinal tract. In vitro studies
implementation of alternative measures that might enable showed that ZS‑9 has a potassium-binding capacity of
continuation of these medications would be desirable. ≤3.5 mmol/g, exceeding the capacity of existing polymer-
Dietary modifications, the addition of diuretics (which based resins.113 ZS‑9 consists of an inorganic crystal, zir
could have the added benefit of improved blood pressure conium silicate, rather than an organic polymer resin,
control) and correction of metabolic acidosis could be which could be important for differentiating its effects
beneficial and could occasionally allow continuation of from those of nonselective ion binders. The clinical
the RAAS inhibitors. development of this agent includes assessments of its
Another potential solution could be the use of novel role in the treatment of acute and chronic hyperkalaemia,
nonsteroidal mineralocorticoid-receptor antagonists. A regardless of the underlying cause. Publication of results
phase II clinical trial examining one such agent (finer from clinical trials assessing the efficacy and safety of
enone) in patients with chronic heart failure indicated ZS‑9 is pending.
a reduced incidence of hyperkalaemia compared with The use of potassium binders might be a realistic pos
spironolactone.108 A similar phase II trial of finerenone sibility for the treatment of patients with chronic hyper
(versus eplerenone) in patients with heart failure and kalaemia, but dedicated studies are required to prove a
either diabetes or moderate to advanced CKD is cur benefit over current practices.
rently underway.109 Phase III clinical trials are awaited to
confirm these early promising findings. Haemodialysis
Finally, chronic maintenance dialysis remains the princi
Potassium binders pal means to control potassium balance in patients with
If the above interventions do not resolve hyperkalaemia, ESRD, especially those without residual kidney function.
the addition of potassium-binding resins might be neces The current treatment paradigms for patients receiving
sary. However, the few studies that have evaluated the routine haemodialysis are, however, potentially hazard
efficacy of sodium polystyrene sulphonate for the treat ous for patients prone to hyperkalaemia. To avoid the
ment of hyperkalaemia were performed in patients with accumulation of potassium in patients with a normal or
acute hyperkalaemia,89,90 and very limited information is high potassium intake, low-potassium dialysates must
available on the efficacy and safety of this agent for the be used. This approach achieves a net even potassium
chronic management of hyperkalaemia. In a retrospec balance, but results in marked fluctuations in serum
tive study of 14 patients with RAAS-inhibitor-associated potassium levels: they gradually rise to high predialy
hyperkalaemia who were treated with daily sorbitol-free sis levels, only to fall to much lower levels in a short
sodium polystyrene sulphonate, serum potassium levels period of time during and after dialysis. Such very rapid
were adequately controlled and no patients developed changes in extracellular potassium concentration could
colonic necrosis.110 However, given the low frequency of be hazardously arrhythmogenic. Although formal clini
this complication, larger studies are needed to assess the cal trials are lacking, the available observational studies
efficacy, and especially the safety, of sodium polystyrene suggest that predialysis hyperkalaemia is associated
sulphonate in this setting. with increased mortality 4 and that use of low-potassium
Potassium-binding medications other than sodium dialysates is associated with an increased risk of sudden
polystyrene sulphonate could soon become available. cardiac death.63
1. Lowrie, E. G. & Lew, N. L. Death risk in 8. Kopple, J. D. & Coburn, J. W. Metabolic studies 16. Michael, J. M., Dorner, I., Bruns, D.,
hemodialysis patients: the predictive value of of low protein diets in uremia. I. Nitrogen and Ladenson, J. H. & Sherman, L. A. Potassium
commonly measured variables and an evaluation potassium. Medicine (Baltimore) 52, 583–595 load in CPD-preserved whole blood and two
of death rate differences between facilities. Am. (1973). types of packed red blood cells. Transfusion 15,
J. Kidney Dis. 15, 458–482 (1990). 9. Schrier, R. W. & Regal, E. M. Influence of 144–149 (1975).
2. Iseki, K. et al. Impact of the initial levels of aldosterone on sodium, water and potassium 17. Palmer, B. F. Managing hyperkalemia caused by
laboratory variables on survival in chronic dialysis metabolism in chronic renal disease. Kidney Int. inhibitors of the renin‑angiotensin‑aldosterone
patients. Am. J. Kidney Dis. 28, 541–548 (1996). 1, 156–168 (1972). system. N. Engl. J. Med. 351, 585–592 (2004).
3. Hayes, J. et al. Association of hypo- and 10. Bourgoignie, J. J., Kaplan, M., Pincus, J., 18. Heering, P. J. et al. Aldosterone resistance in
hyperkalemia with disease progression and Gavellas, G. & Rabinovitch, A. Renal handling kidney transplantation is in part induced by a
mortality in males with chronic kidney disease: of potassium in dogs with chronic renal down-regulation of mineralocorticoid receptor
the role of race. Nephron Clin. Pract. 120, insufficiency. Kidney Int. 20, 482–490 (1981). expression. Clin. Transplant. 18, 186–192
c8–c16 (2012). 11. Simmons, D. H. & Avedon, M. Acid-base (2004).
4. Kovesdy, C. P. et al. Serum and dialysate alterations and plasma potassium concentration. 19. Laine, J. & Holmberg, C. Renal and adrenal
potassium concentrations and survival in Am. J. Physiol. 197, 319–326 (1959). mechanisms in cyclosporine-induced
hemodialysis patients. Clin. J. Am. Soc. Nephrol. 12. Adrogué, H. J. & Madias, N. E. Changes in plasma hyperkalaemia after renal transplantation. Eur. J.
2, 999–1007 (2007). potassium concentration during acute acid-base Clin. Invest. 25, 670–676 (1995).
5. Gonick, H. C., Kleeman, C. R., Rubini, M. E. & disturbances. Am. J. Med. 71, 456–467 (1981). 20. DeFronzo, R. A., Sherwin, R. S., Felig, P. & Bia, M.
Maxwell, M. H. Functional impairment in chronic 13. Graber, M. A model of the hyperkalemia Nonuremic diabetic hyperkalemia. Possible role
renal disease. III. Studies of potassium produced by metabolic acidosis. Am. J. Kidney of insulin deficiency. Arch. Intern. Med. 137,
excretion. Am. J. Med. Sci. 261, 281–290 (1971). Dis. 22, 436–444 (1993). 842–843 (1977).
6. Hayes, C. P. Jr & Robinson, R. R. Fecal 14. Magner, P. O., Robinson, L., Halperin, R. M., 21. Glassock, R. J., Goldstein, D. A., Goldstone, R. &
potassium excretion in patients on chronic Zettle, R. & Halperin, M. L. The plasma Hsueh, W. A. Diabetes mellitus, moderate renal
intermittent hemodialysis. Trans. Am. Soc. Artif. potassium concentration in metabolic acidosis: insufficiency and hyperkalemia. Am. J. Nephrol.
Intern. Organs 11, 242–246 (1965). a re-evaluation. Am. J. Kidney Dis. 11, 220–224 3, 233–240 (1983).
7. Hayes, C. P. Jr, McLeod, M. E. & Robinson, R. R. (1988). 22. Tuck, M. L., Sambhi, M. P. & Levin, L.
An extrarenal mechanism for the maintenance 15. Oster, J. R., Perez, G. O. & Vaamonde, C. A. Hyporeninemic hypoaldosteronism in diabetes
of potassium balance in severe chronic renal Relationship between blood pH and potassium mellitus. Studies of the autonomic nervous
failure. Trans. Assoc. Am. Physicians 80, 207–216 and phosphorus during acute metabolic acidosis. system’s control of renin release. Diabetes 28,
(1967). Am. J. Physiol. 235, F345–F351 (1978). 237–241 (1979).
23. Arrizabalaga, P. et al. Increase in serum 40. [No authors listed] Randomised placebo- oligo-anuric chronic hemodialysis patients
potassium caused by β‑2 adrenergic blockade in controlled trial of effect of ramipril on decline —a pilot study. Clin. Nephrol. 76, 388–395
terminal renal failure: absence of mediation by in glomerular filtration rate and risk of terminal (2011).
insulin or aldosterone. Proc. Eur. Dial. Transplant renal failure in proteinuric, non-diabetic 58. Vukusich, A. et al. A randomized, double-blind,
Assoc. 20, 572–576 (1983). nephropathy. The GISEN Group (Gruppo Italiano placebo-controlled trial of spironolactone on
24. Edes, T. E. & Sunderrajan, E. V. Heparin-induced di Studi Epidemiologici in Nefrologia). Lancet carotid intima–media thickness in nondiabetic
hyperkalemia. Arch. Intern. Med. 145, 349, 1857–1863 (1997). hemodialysis patients. Clin. J. Am. Soc. Nephrol.
1070–1072 (1985). 41. Ruggenenti, P. et al. Blood-pressure control for 5, 1380–1387 (2010).
25. Bismuth, C., Gaultier, M., Conso, F. & renoprotection in patients with non-diabetic 59. Hammer, F. et al. Rationale and design of the
Efthymiou, M. L. Hyperkalemia in acute digitalis chronic renal disease (REIN‑2): multicentre, Mineralocorticoid Receptor Antagonists in End-
poisoning: prognostic significance and randomised controlled trial. Lancet 365, Stage Renal Disease Study (MiREnDa). Nephrol.
therapeutic implications. Clin. Toxicol. 6, 939–946 (2005). Dial. Transplant. 29, 400–405 (2014).
153–162 (1973). 42. Mann, J. F., Gerstein, H. C., Pogue, J., Bosch, J. 60. Dittrich, K. L. & Walls, R. M. Hyperkalemia: ECG
26. Bühler, F. R. et al. Antihypertensive β blocking & Yusuf, S. Renal insufficiency as a predictor manifestations and clinical considerations.
action as related to renin and age: a of cardiovascular outcomes and the impact of J. Emerg. Med. 4, 449–455 (1986).
pharmacologic tool to identify pathogenetic ramipril: the HOPE randomized trial. Ann. Intern. 61. Parham, W. A., Mehdirad, A. A., Biermann, K. M.
mechanisms in essential hypertension. Am. J. Med. 134, 629–636 (2001). & Fredman, C. S. Hyperkalemia revisited. Tex.
Cardiol. 36, 653–669 (1975). 43. Weinberg, J. M. et al. Risk of hyperkalemia in Heart Inst. J. 33, 40–47 (2006).
27. Pedersen, E. B. & Kornerup, H. J. Relationship nondiabetic patients with chronic kidney disease 62. Korgaonkar, S. et al. Serum potassium and
between plasma aldosterone concentration and receiving antihypertensive therapy. Arch. Intern. outcomes in CKD: insights from the RRI-CKD
plasma potassium in patients with essential Med. 169, 1587–1594 (2009). cohort study. Clin. J. Am. Soc. Nephrol. 5,
hypertension during alprenolol treatment. Acta 44. Iino, Y. et al. Renoprotective effect of losartan 762–769 (2010).
Med. Scand. 200, 263–267 (1976). in comparison to amlodipine in patients with 63. Pun, P. H., Lehrich, R. W., Honeycutt, E. F.,
28. Bakris, G. L. et al. ACE inhibition or angiotensin chronic kidney disease and hypertension Herzog, C. A. & Middleton, J. P. Modifiable risk
receptor blockade: impact on potassium in renal —a report of the Japanese Losartan Therapy factors associated with sudden cardiac arrest
failure. VAL‑K Study Group. Kidney Int. 58, Intended for the Global Renal Protection in within hemodialysis clinics. Kidney Int. 79,
2084–2092 (2000). Hypertensive Patients (JLIGHT) study. Hypertens. 218–227 (2011).
29. Weir, M. R. & Rolfe, M. Potassium homeostasis Res. 27, 21–30 (2004). 64. Jadoul, M. et al. Modifiable practices associated
and renin‑angiotensin‑aldosterone system 45. Miao, Y. et al. Increased serum potassium with sudden death among hemodialysis patients
inhibitors. Clin. J. Am. Soc. Nephrol. 5, 531–548 affects renal outcomes: a post hoc analysis of in the Dialysis Outcomes and Practice Patterns
(2010). the Reduction of Endpoints in NIDDM with the Study. Clin. J. Am. Soc. Nephrol. 7, 765–774
30. Molnar, M. Z. et al. Angiotensin-converting enzyme Angiotensin II Antagonist Losartan (RENAAL) (2012).
inhibitor and angiotensin receptor blocker use trial. Diabetologia 54, 44–50 (2011). 65. Xu, Q. et al. Serum potassium levels and its
and mortality in patients with chronic kidney 46. Fried, L. F. et al. Combined angiotensin inhibition variability in incident peritoneal dialysis patients:
disease. J. Am. Coll. Cardiol. 63, 650–658 (2014). for the treatment of diabetic nephropathy. associations with mortality. PLoS ONE 9,
31. Pun, P. H., Lehrich, R. W., Smith, S. R. & N. Engl. J Med. 369, 1892–1903 (2013). e86750 (2014).
Middleton, J. P. Predictors of survival after 47. Sanofi Aventis US. Avapro© package insert 66. Epstein, F. H. Signs and symptoms of electrolyte
cardiac arrest in outpatient hemodialysis clinics. [online], http://products.sanofi.us/Avapro/ disorders. In Clinical disorders of fluid and
Clin. J. Am. Soc. Nephrol. 2, 491–500 (2007). Avapro.pdf (2014). electrolyte metabolism (eds Maxwell, M. H. &
32. Fleet, J. L. et al. Validity of the International 48. Hou, F. F. et al. Efficacy and safety of benazepril Kleeman, C. R.) 499–516 (McGraw-Hill, 1980).
Classification of Diseases 10th revision code for advanced chronic renal insufficiency. N. Engl. 67. Fisch, C. Electrolytes and the heart. In The Heart
for hyperkalaemia in elderly patients at J. Med. 354, 131–140 (2006). (ed. Hurst, J. W.) 1466–1479 (McGraw-Hill,
presentation to an emergency department and 49. Bozkurt, B., Agoston, I. & Knowlton, A. A. 1986).
at hospital admission. BMJ Open 2, e002011 Complications of inappropriate use of 68. Kleeman, K. & Singh, B. N. Serum electrolytes
(2012). spironolactone in heart failure: when an old and the heart. In Clinical disorders of fluid and
33. Einhorn, L. M. et al. The frequency of medicine spirals out of new guidelines. J. Am. electrolyte metabolism (eds Maxwell, M. H. &
hyperkalemia and its significance in chronic Coll. Cardiol. 41, 211–214 (2003). Kleeman, C. R.) 145–180 (McGraw-Hill, 1980).
kidney disease. Arch. Intern. Med. 169, 50. Shah, K. B., Rao, K., Sawyer, R. & Gottlieb, S. S. 69. Marques, J. S. & Diogo, A. N. Dead man walking:
1156–1162 (2009). The adequacy of laboratory monitoring in an extreme case of sinusoidal wave pattern in
34. Drawz, P. E., Babineau, D. C. & Rahman, M. patients treated with spironolactone for severe hyperkalemia. J. Am. Coll. Cardiol. 59,
Metabolic complications in elderly adults with congestive heart failure. J. Am. Coll. Cardiol. 46, 2118 (2012).
chronic kidney disease. J. Am. Geriatr. Soc. 60, 845–849 (2005). 70. Petrov, D. B. Images in clinical medicine. An
310–315 (2012). 51. Juurlink, D. N. et al. Rates of hyperkalemia electrocardiographic sine wave in hyperkalemia.
35. Sarafidis, P. A. et al. Prevalence and factors after publication of the Randomized Aldactone N. Engl. J. Med. 366, 1824 (2012).
associated with hyperkalemia in predialysis Evaluation Study. N. Engl. J. Med. 351, 543–551 71. Siniorakis, E. et al. Hyperkalaemia,
patients followed in a low-clearance clinic. Clin. J. (2004). pseudohyperkalaemia and electrocardiographic
Am. Soc. Nephrol. 7, 1234–1241 (2012). 52. Knoll, G. A. et al. Renin–angiotensin system correlates. Int. J. Cardiol. 148, 242–243 (2011).
36. Makani, H., Bangalore, S., Desouza, K. A., blockade and the risk of hyperkalemia in 72. Fordjour, K. N., Walton, T. & Doran, J. J.
Shah, A. & Messerli, F. H. Efficacy and safety of chronic hemodialysis patients. Am. J. Med. 112, Management of hyperkalemia in hospitalized
dual blockade of the renin–angiotensin system: 110–114 (2002). patients. Am. J. Med. Sci. 347, 93–100 (2014).
meta-analysis of randomised trials. BMJ 346, 53. Ito, Y. et al. Long-Term effects of spironolactone 73. Montague, B. T., Ouellette, J. R. & Buller, G. K.
f360 (2013). in peritoneal dialysis patients. J. Am. Soc. Retrospective review of the frequency of ECG
37. Susantitaphong, P. et al. Efficacy and safety Nephrol. 25, 1094–1102 (2014). changes in hyperkalemia. Clin. J. Am. Soc.
of combined vs. single renin‑angiotensin‑ 54. Vazquez-Rangel, A. et al. Spironolactone to Nephrol. 3, 324–330 (2008).
aldosterone system blockade in chronic kidney prevent peritoneal fibrosis in peritoneal dialysis 74. Green, D., Green, H. D., New, D. I. & Kalra, P. A.
disease: a meta-analysis. Am. J. Hypertens. 26, patients: a randomized controlled trial. Am. J. The clinical significance of hyperkalaemia-
424–441 (2013). Kidney Dis. 63, 1072–1074 (2014). associated repolarization abnormalities in end-
38. Lewis, E. J., Hunsicker, L. G., Bain, R. P. & 55. Matsumoto, Y. et al. Spironolactone reduces stage renal disease. Nephrol. Dial. Transplant.
Rohde, R. D. The effect of angiotensin‑ cardiovascular and cerebrovascular morbidity 28, 99–105 (2013).
converting‑enzyme inhibition on diabetic and mortality in hemodialysis patients. J. Am. 75. Welch, A., Maroz, N. & Wingo, C. S.
nephropathy. The Collaborative Study Group. Coll. Cardiol. 63, 528–536 (2014). Hyperkalemia: getting to the heart of the matter.
N. Engl. J. Med. 329, 1456–1462 (1993). 56. Flevari, P. et al. Spironolactone improves Nephrol. Dial. Transplant. 28, 15–16 (2013).
39. Maschio, G. et al. Effect of the endothelial and cardiac autonomic function 76. Garcia-Palmieri, M. R. Reversal of hyperkalemic
angiotensin‑converting‑enzyme inhibitor in non heart failure hemodialysis patients. cardiotoxicity with hypertonic saline. Am. Heart. J.
benazepril on the progression of chronic renal J. Hypertens. 31, 1239–1244 (2013). 64, 483–488 (1962).
insufficiency. The Angiotensin‑Converting‑Enzyme 57. Shavit, L., Neykin, D., Lifschitz, M. & Slotki, I. 77. Weisberg, L. S. Management of severe
Inhibition in Progressive Renal Insufficiency Study Effect of eplerenone on blood pressure and hyperkalemia. Crit. Care Med. 36, 3246–3251
Group. N. Engl. J. Med. 334, 939–945 (1996). the renin‑angiotensin‑aldosterone system in (2008).
78. Beeler, G. W. Jr & Reuter, H. Membrane calcium 91. Emmett, M. et al. Effect of three laxatives and 104. Lillemoe, K. D. et al. Intestinal necrosis due to
current in ventricular myocardial fibres. J. Physiol. a cation exchange resin on fecal sodium and sodium polystyrene (Kayexalate) in sorbitol
207, 191–209 (1970). potassium excretion. Gastroenterology 108, enemas: clinical and experimental support for
79. Chen, C. M., Gettes, L. S. & Katzung, B. G. 752–760 (1995). the hypothesis. Surgery 101, 267–272 (1987).
Effect of lidocaine and quinidine on steady-state 92. Kamel, K. S. & Wei, C. Controversial issues in 105. US Food and Drug Administration. Kayexalate
characteristics and recovery kinetics of (dV/dt)max the treatment of hyperkalaemia. Nephrol. Dial. (sodium polystyrene sulfonate) powder. Safety
in guinea pig ventricular myocardium. Circ. Res. Transplant. 18, 2215–2218 (2003). labeling changes approved by FDA Center for
37, 20–29 (1975). 93. Kamel, K. S. & Schreiber, M. Asking the question Drug Evaluation and Research (CDER) [online],
80. Winkler, A. W., Hoff, H. E. & Smith, P. K. Factors again: are cation exchange resins effective for http://www.fda.gov/Safety/MedWatch/
affecting the toxicity of potassium. Am. J. Physiol. the treatment of hyperkalemia? Nephrol. Dial. SafetyInformation/ucm186845.htm (2009).
127, 430–436 (1939). Transplant. 27, 4294–4297 (2012). 106. Watson, M., Abbott, K. C. & Yuan, C. M. Damned
81. Eliakim, M., Rosenberg, S. Z. & Braun, K. 94. Sterns, R. H., Rojas, M., Bernstein, P. & if you do, damned if you don’t: potassium
Electrocardiographic changes following the Chennupati, S. Ion-exchange resins for the binding resins in hyperkalemia. Clin. J. Am. Soc.
administration of hypertonic saline to dogs. treatment of hyperkalemia: are they safe and Nephrol. 5, 1723–1726 (2010).
Am. Heart J. 58, 97–101 (1959). effective? J. Am. Soc. Nephrol. 21, 733–735 107. DeFronzo, R. A. Hyperkalemia and hyporeninemic
82. Kaplan, J. L. et al. Hypertonic saline treatment (2010). hypoaldosteronism. Kidney Int. 17, 118–134
of severe hyperkalemia in nonnephrectomized 95. Gruy-Kapral, C. et al. Effect of single dose resin- (1980).
dogs. Acad. Emerg. Med. 7, 965–973 (2000). cathartic therapy on serum potassium 108. Pitt, B. et al. Safety and tolerability of the novel
83. Ballantyne, F. 3rd, Davis, L. D. & Reynolds, E. W. Jr. concentration in patients with end-stage renal non-steroidal mineralocorticoid receptor
Cellular basis for reversal of hyperkalemic disease. J. Am. Soc. Nephrol. 9, 1924–1930 antagonist BAY 94–8862 in patients with chronic
electrocardiographic changes by sodium. Am. J. (1998). heart failure and mild or moderate chronic
Physiol. 229, 935–940 (1975). 96. Kayexalate®(sodium polystyrene sulfonate, USP kidney disease: a randomized, double-blind trial.
84. Lens, X. M., Montoliu, J., Cases, A., cation-exchange resin) FDA Drug Label [online], Eur. Heart J. 34, 2453–2463 (2013).
Campistol, J. M. & Revert, L. Treatment of http://www.accessdata.fda.gov/drugsatfda_ 109. US National Library of Medicine. ClinicalTrials.gov
hyperkalaemia in renal failure: salbutamol v. docs/label/2009/011287s021lbl.pdf (2009). [online], http://clinicaltrials.gov/show/
insulin. Nephrol. Dial. Transplant 4, 228–232 97. Chelcun, J. L., Sable, R. A. & Friedman, K. NCT01807221 (2014).
(1989). Colonic ulceration in a patient with renal disease 110. Chernin, G. et al. Secondary prevention of
85. Alvestrand, A., Wahren, J., Smith, D. & and hyperkalemia. JAAPA 25, 34, 37–38 (2012). hyperkalemia with sodium polystyrene
DeFronzo, R. A. Insulin-mediated potassium 98. Gorospe, E. C., Lewis, J. T. & Bruining, D. H. sulfonate in cardiac and kidney patients on
uptake is normal in uremic and healthy subjects. Kayexalate-induced esophageal ulcer in a renin‑angiotensin‑aldosterone system inhibition
Am. J. Physiol. 246, E174–E180 (1984). patient with gastroparesis. Clin. Gastroenterol. therapy. Clin. Cardiol. 35, 32–36 (2012).
86. Schwarz, K. C., Cohen, B. D., Lubash, G. D. Hepatol. 10, A28 (2012). 111. Pitt, B. et al. Evaluation of the efficacy and safety
& Rubin, A. L. Severe acidosis and 99. Joo, M., Bae, W. K., Kim, N. H. & Han, S. R. of RLY5016, a polymeric potassium binder, in a
hyperpotassemia treated with sodium Colonic mucosal necrosis following double-blind, placebo-controlled study in
bicarbonate infusion. Circulation 19, 215–220 administration of calcium polystryrene sulfonate patients with chronic heart failure (the
(1959). (Kalimate) in a uremic patient. J. Korean Med. PEARL-HF) trial. Eur. Heart J. 32, 820–828
87. Allon, M. & Shanklin, N. Effect of bicarbonate Sci. 24, 1207–1211 (2009). (2011).
administration on plasma potassium in dialysis 100. Takeuchi, N. et al. Development of colonic 112. Buysse, J. M., Huang, I. Z. & Pitt, B. PEARL-HF:
patients: interactions with insulin and albuterol. perforation during calcium polystyrene sulfonate prevention of hyperkalemia in patients with heart
Am. J. Kidney Dis. 28, 508–514 (1996). administration: a case report. Case Rep. Med. failure using a novel polymeric potassium binder,
88. Mahoney, B. A. et al. Emergency interventions 2013, 102614 (2013). RLY5016. Future Cardiol. 8, 17–28 (2012).
for hyperkalaemia. Cochrane Database of 101. Harel, Z. et al. Gastrointestinal adverse events 113. Yang, A., Leon, A., Nuttall, M., Low, J. J.,
Systematic Reviews, Issue 2. Art. No.: with sodium polystyrene sulfonate (Kayexalate) Rasmussen, H. S. In vitro ion exchange capacity
CD003235. http://dx.doi.org/10.1002/ use: a systematic review. Am. J. Med. 126, and selectivity of ZS‑9, a novel, selective cation
14651858.CD003235.pub2. 264.e9–264.e24 (2013). trap for the treatment of hyperkalemia. Am. J.
89. Scherr, L., Ogden, D. A., Mead, A. W., Spritz, N. 102. Gerstman, B. B., Kirkman, R. & Platt, R. Intestinal Kidney Dis. 63, B115 (2014).
& Rubin, A. L. Management of hyperkalemia with necrosis associated with postoperative orally
a cation-exchange resin. N. Engl. J. Med. 264, administered sodium polystyrene sulfonate in Acknowledgements
115–119 (1961). sorbitol. Am. J. Kidney Dis. 20, 159–161 (1992). C.P.K. is supported by grants RO1 DK096920 and
90. Flinn, R. B., Merrill, J. P. & Welzant, W. R. 103. Watson, M. A. et al. Association of prescription UO1DK102163 from the US NIH-NIDDK. He is an
Treatment of the oliguric patient with a new of oral sodium polystyrene sulfonate with employee of the US Department of Veterans Affairs.
sodium-exchange resin and sorbitol; sorbitol in an inpatient setting with colonic Opinions expressed in this paper are those of the
a preliminary report. N. Engl. J. Med. 264, necrosis: a retrospective cohort study. Am. J. author and do not necessarily represent those of
111–115 (1961). Kidney Dis. 60, 409–416 (2012). the Department of Veterans Affairs.