REVIEWS Management of hyperkalaemia in chronic kidney disease Csaba P. Kovesdy Abstract | Hyperkalaemia is common in patients with chronic kidney disease (CKD), in part because of the effects of kidney dysfunction on potassium homeostasis and in part because of the cluster of comorbidities (and their associated treatments) that occur in patients with CKD. Owing to its electrophysiological effects, severe hyperkalaemia represents a medical emergency that usually requires prompt intervention, whereas the prevention of hazardous hyperkalaemic episodes in at-risk patients requires measures aimed at the longterm normalization of potassium homeostasis. The options for effective and safe medical interventions to restore chronic potassium balance are few, and long-term management of hyperkalaemia is primarily limited to the correction of modifiable exacerbating factors. This situation can result in a difficult trade-off in patients with CKD, because drugs that are beneficial to these patients (for example, renin–angiotensin–aldosteronesystem antagonists) are often the most prominent cause of their hyperkalaemia. Maintaining the use of these beneficial medications while implementing various strategies to control potassium balance is desirable; however, discontinuation rates remain high. The emergence of new medications that specifically target hyperkalaemia could lead to a therapeutic paradigm shift, emphasizing preventive management over ad hoc treatment of incidentally discovered elevations in serum potassium levels. Kovesdy, C. P. Nat. Rev. Nephrol. advance online publication 16 September 2014; doi:10.1038/nrneph.2014.168
Introduction
University of Tennessee Health Science Center, University of Tennessee, 956 Court Avenue, Memphis, TN 38163, USA. [email protected]
Hyperkalaemia is one of the clinically most important electrolyte abnormalities because it can cause severe electrophysiological disturbances, such as cardiac arrhyth mias. Hyperkalaemia is defined as a serum potassium level above the normal range, and various arbitrary cutoffs, such as >5.0, >5.5 or >6.0 mmol/l, are used to denote dif ferent levels of severity. Hyperkalaemia has been associ ated with increased mortality in patients with chronic kidney disease (CKD) and those undergoing haemo dialysis,1–4 highlighting the importance of maintaining serum potassium levels in the physiologically normal range. The mechanisms driving hyperkalaemia typically involve a combination of factors, such as increased dietary potassium intake, disordered distribution between intra cellular and extracellular compartments and abnormali ties in potassium excretion. In clinical practice, CKD is the most common predisposing condition for hyperkalaemia and, in combination with one or more exacerbating factors (discussed below), can induce recurrent episodes of abnormally elevated serum potassium levels. Hyperkalaemia occurs especially frequently in patients with CKD who are treated with certain classes of medi cations, such as angiotensin-converting-enzyme (ACE) inhibitors, angiotensin-receptor blockers (ARBs) or other inhibitors of the renin–angiotensin–aldosterone system (RAAS). These therapeutic agents are beneficial in patients with CKD and are also the standard of care Competing interests The author declares no competing interests.
for some common comorbidities of CKD, such as con gestive heart failure (CHF). Although treatment with RAAS inhibitors is desirable in patients with CKD, it is often difficult or impossible to continue this therapy over extended periods of time owing to the development of hyperkalaemia. Currently, no reliably effective and safe maintenance treatments can be given in combina tion with RAAS inhibitors to offset the hyperkalaemia caused by these otherwise beneficial therapeutic agents. Hence, the safe response to recurrent episodes of hyper kalaemia in patients with CKD who receive RAAS inhib itors is considered to be tapering or discontinuation of this medication. This Review summarizes the mechanisms under lying hyperkalaemia, its epidemiology and clinical consequences, with a focus on patients with CKD and endstage renal disease (ESRD). Currently available treatment regimens are discussed, highlighting areas of uncertainty, and emerging therapies that might enable the more-liberal use of RAAS inhibitors in various populations of patients at risk of hyperkalaemia are described.
Mechanisms of hyperkalaemia in CKD
The principal mechanism through which the kidneys maintain potassium homeostasis is the secretion of potassium into the distal convoluted tubule and the prox imal collecting duct. As glomerular filtration rate (GFR) decreases, the ability of the kidneys to maintain serum potassium levels in a physiologically normal range is increasingly jeopardized.5–9 Experimental studies suggest
NATURE REVIEWS | NEPHROLOGY
ADVANCE ONLINE PUBLICATION | 1 © 2014 Macmillan Publishers Limited. All rights reserved
REVIEWS Key points ■■ Hyperkalaemia is common in patients with chronic kidney disease (CKD), especially when CKD is accompanied by exacerbating factors ■■ Hyperkalaemia is associated with adverse outcomes in patients with CKD, and can restrict the use of beneficial medications, such as renin–angiotensin– aldosterone-system (RAAS) inhibitors ■■ Current therapeutic paradigms for hyperkalaemia emphasize intermittent acute interventions and the elimination of exacerbating factors (including RAAS inhibitors) ■■ Proactive treatment strategies to prevent the development of hyperkalaemia could also benefit patients by enabling more liberal use of RAAS inhibitors ■■ The emergence of new potassium binders may result in more widespread implementation of strategies for hyperkalaemia prevention
that the kidneys can adjust to a decrease in the number of nephrons through increasing potassium secretion by the surviving nephrons, and remain able to maintain normokalaemia under steady state conditions. However, their ability to respond to an acute increase in potas sium load is hampered, resulting in the development of hyperkalaemic episodes.10 Patients with CKD often have other conditions that exacerbate hyperkalaemia, in addition to the decreased GFR and tubulointerstitial damage that prevent the kidneys from upregulating potassium excretion (Figure 1). Often, multiple precipitating factors are present in a single patient, which explains why hyper kalaemia is most commonly detected in patients with CKD in clinical practice. Dietary modifications in patients with CKD often involve an emphasis on sodium restric tion, and some patients switch to salt substitutes, not real izing that these can contain potassium salts. Furthermore, ‘heart-healthy’ diets are inherently rich in potassium— which is beneficial in most people (by virtue of improved blood pressure control and other mechanisms), but can also contribute to an increased risk of hyperkalaemia in susceptible patients. Other CKD-related conditions that contribute to hyperkalaemia are metabolic acidosis, which causes a shift of potassium from the intracellular to the extracellular space11 (the effect of which depends more on the aetiology of the acidosis rather than on the actual pH);12–15 anaemia requiring blood transfusion, which can result in a high acute potassium load (typically occurring with large transfusions and the use of outdated blood);16 and kidney transplantation, which can result in hyper kalaemia through various mechanisms (for example, development of renal tubular a cidosis or the effects of calcineurin inhibitors).17–19 In addition, some hyperkalaemia-inducing comorbid ities are not caused by CKD itself, but often occur in patients with CKD, and hence are instrumental to the high incidence of hyperkalaemia seen in these patients. Acute kidney injury results in a rapid decrease in both GFR and tubular flow, and is often accompanied by a hypercatabolic state, tissue injury and high acute potas sium loads (for example, secondary to gastrointestinal bleeding). These conditions all contribute to the develop ment of hyperkalaemia, which can be of life-threatening severity and is one of the most common indications for emergency haemodialysis. Diabetes mellitus and
cardiovascular disease are two of the most common comorbidities in patients with CKD and both are linked to the development of hyperkalaemia through differ ent mechanisms. Insulin deficiency and hypertonicity caused by hyperglycaemia in patients with diabetes con tributes to an inability to disperse high acute potassium loads into the intracellular space.20 Furthermore, dia betes mellitus is associated with hyporeninaemic hypo aldosteronism and the resultant inability to upregulate tubular potassium secretion.21,22 Cardiovascular disease and other associated condi tions, such as acute myocardial ischaemia, left ventricular hypertrophy and CHF, require various medical treatments that have been linked to hyperkalaemia (Figure 1). Their importance in the aetiology of hyperkalaemia in patients with CKD is underscored by the fact that some of these medications are difficult or impossible to use in patients with CKD who are, therefore, deprived of their proven cardiovascular benefits. For example, β2-adrenergicreceptor blockers contribute to hyperkalaemia through inhibition of renin production and a decreased ability to redistribute potassium to the intracellular space.23 Heparin treatment has also been linked to hyperkalaemia through decreased production of aldosterone.24 Cardiac glycosides, such as digoxin, contribute to hyperkalaemia through inhibition of the Na+/K+-ATPase, which is neces sary for secretion of potassium into the collecting duct and for redistribution of potassium across cell membranes.25 However, the effects of these drugs on serum potassium levels are limited (increases of ~0.2–0.5 mmol/l) unless other predisposing factors are present.26,27 The medications linked to hyperkalaemia that are most relevant in clinical practice are RAAS inhibitors (ACE inhibitors, ARBs, direct renin inhibitors and mineralocorticoid-receptor blockers). In populations without CKD, the incidence of hyperkalaemia associated with RAAS inhibitor monotherapy is 5.1 mmol/l
5.2%
Not reported
Benazepril in advanced CKD48 (2006)
226 Chinese patients with advanced CKD Group 1: eGFR 37.10 ± 6.30 ml/min/1.73 m2* Group 2: eGFR 26.30 ± 5.30 ml/min/1.73 m2*
≥6.0 mmol/l
1.9% (group 1) 5.3% (group 2)
1.3% (3 patients from group 2)‡
AASK43 (2009)
417 African American patients with eGFR 46.30 ± 13.50 ml/min/1.73 m2*
>5.5 mmol/l
7.2%
Not reported
NEPHRON‑D46 (2013)
1,448 US veterans (99% men) with diabetic nephropathy and eGFR 30–90 ml/min/1.73 m2
>6.0 mmol/l, or need for emergency room visit, hospitalization or dialysis
4.4% (losartan + placebo) 9.9% (losartan + lisinopril)
Not reported
*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 a detailed description of which is beyond the scope of this Review. Studies in patients with non-dialysis-dependent CKD demonstrated a significant association between hyperkalaemia and increased long-term all-cause mor tality.3,62 Similar associations between hyperkalaemia and mortality were reported in patients receiving chronic haemodialysis,1,2,4 but assessment of the increased mor tality attributable to hyperkalaemia in this population is confounded by exposure to low-potassium dialysates, which are themselves a risk factor for sudden death.63,64 In patients receiving peritoneal dialysis, hyperkalaemia and variability in serum potassium levels were associated with increased mortality in the first year following the measurement of an abnormal potassium level, but not thereafter.65 This discrepancy between the short-term and long-term associations with mortality could be explained by the electrophysiological effects of hyperkalaemia, which present an acute danger primarily because they can cause cardiac arrhythmias.66–68 Indeed, studies that exam ined mortality associated with abnormal serum potassium levels during a short time-window have corroborated the existence of this s hort-term m ortality risk.33
Treatment of hyperkalaemia Acute management It is unclear what level of hyperkalaemia represents an imminent danger to the individual. In a large retrospec tive study, a serum potassium level >6 mmol/l was associ ated with a greater than 30-fold increase in the risk of 1‑day mortality,33 but long-term adverse effects of hyper kalaemia have been associated with levels >5 mmol/l.45 It is important to emphasize that, beside the absolute serum potassium level, numerous other factors determine when hyperkalaemia becomes hazardous in a given individual, such as the rate of change in serum potassium levels, the concurrent presence of low serum concentrations of
calcium and magnesium (often exacerbated by the use of diuretics and/or proton pump inhibitors) or abnormal serum pH. To what extent the concomitant presence of such abnormalities might potentiate the electrophysio logical effects of hyperkalaemia is not well established and needs further examination. Severe hyperkalae mia (most often defined as serum levels >6 mmol/l) typically represents a clinical urgency or emergency, which may warrant immediate attention in the form of cardiac monitoring, acute medical i nterventions and, occasionally, emergency dialysis. Diagnostic electrocardiography In the acute management of hyperkalaemia, electro cardiography (ECG) is often used to gauge the sever ity of its effect on cardiac function. However, individual variations in sensitivity to serum levels of potassium are evident in the ECG changes typically associated with hyperkalaemia, such as peaked T waves, as well as pro longation of the PR interval and QRS complex duration. Although case reports in patients with serum potassium levels >9 mmol/l highlight an association with marked ECG changes,69–71 the ability of ECG features to predict hyperkalaemia of moderate severity is considered poor, since only half of patients with serum potassium levels >6.5 mmol/l display typical ECG changes.72 In a retro spective study of 90 patients with hyperkalaemia (of whom >80% had serum potassium levels >7.2 mmol/l), typical ECG changes associated with hyperkalaemia showed poor sensitivity and specificity for predicting patients’ actual serum potassium levels, 73 prompting the authors to recommend that these ECG changes should not be used to guide treatment of hyperkalaemia. In another study of 145 patients with ESRD, the ratio of T wave to R wave amplitude was more specific than T wave tenting for predicting a serum potassium level >6 mmol/l, but both features had poor sensitivity (33%
4 | ADVANCE ONLINE PUBLICATION
www.nature.com/nrneph © 2014 Macmillan Publishers Limited. All rights reserved
REVIEWS Table 2 | Interventions used for acute or chronic treatment of hyperkalaemia Treatment
Route of administration
Onset of action, duration of effect
Mechanism
Comments
6.8 mmol of calcium, corresponding to 10 ml CaCl (10%)* or 30 ml calcium gluconate (10%) solutions
Intravenous (acute)
1–3 min 30–60 min
Membrane potential stabilization
Does not affect serum potassium level Effect measured by normalization of electrocardiographic changes Dose can be repeated if no effects noted Caution advised in patients receiving digoxin
50–250 ml hypertonic saline (3–5%)‡76,77
Intravenous (acute)
5–10 min ~2 h
Membrane potential stabilization
Efficacy only in hyponatraemic patients
50–100 mmol sodium bicarbonate
Intravenous (acute) or oral (chronic)
5–10 min ~2 h
Redistribution
Efficacy questioned for acute treatment of patients on dialysis
10 units of regular insulin
Intravenous (acute)
30 min 4–6 h
Redistribution
Administer with 50 g of glucose intravenously to prevent hypoglycaemia
β2‑receptor agonists: 10–20 mg aerosol (nebulized) or 0.5 mg in 100 ml of 5% dextrose in water (intravenous)
Intravenous or nebulized (both acute)
30 min 2–4 h
Redistribution
Effect independent of insulin and aldosterone Caution in patients with known coronary artery disease
40 mg furosemide or equivalent dose of other loop diuretic. Higher doses may be needed in patients with advanced CKD
Intravenous (acute) or oral (chronic)
Varies Until diuresis present or longer1
Excretion
Loop diuretics for acute intervention Loop or thiazide diuretics for chronic management
Fludrocortisone acetate ≥0.1 mg (up to 0.4– 1.0 mg daily)
Oral (chronic)
NA
Excretion
In patients with aldosterone deficiency Large doses might be needed to effectively lower potassium levels Sodium retention, oedema and hypertension might occur
Cation exchange resins 25–50 g
Oral or rectal (either acute or chronic), with or without sorbitol
1–2 h ≥4–6 h§
Excretion
Sodium polystyrene sulphonate is the only approved agent in most countries Calcium polystyrene sulphonate is approved in some countries New agents are in development
Dialysis
Haemodialysis (acute or chronic); peritoneal dialysis (chronic)
Within minutes Until end of dialysis or longer§
Removal
Effects of dialysis on serum sodium, bicarbonate, calcium and/or magnesium levels can affect results
*CaCl is caustic and could damage peripheral veins. ‡Limited data available from clinical studies. §Effects can last for an unspecified length of time depending on ongoing potassium intake or cellular redistribution. Abbreviations: CKD, chronic kidney disease; NA, not applicable.
and 24%, respectively).74 Interestingly, patients in this study who had an abnormal T:R wave amplitude ratio had an increased long-term risk of sudden death, sug gesting that ECG changes might identify patients who are particularly sensitive to the electrophysiological effects of hyperkalaemia.74 In response to the publica tion of this study, other researchers commented75 that intravenous infusion of calcium into hyperkalaemic patients with ECG changes linked to hyperkalaemia could serve as a test to determine whether these changes were incidental to or caused by the hyperkalaemia, and whether treatment of hyperkalaemia could be expected to reverse them.75 Interventions Interventions used to treat acute hyperkalaemia include the intravenous administration of either calcium salts or hypertonic saline (which is effective in patients with underlying hyponatraemia).76,77 These agents restore the electrophysiological properties of cell membranes through various mechanisms,78–83 but do not (or only
minimally) affect serum potassium levels. Additional pharmacologic agents that induce potassium trans port into the intracellular space include insulin,84,85 β 2‑receptor agonists 84 and bicarbonate 86 (Table 2). However, the efficacy of intravenous bicarbonate for this indication in patients on dialysis has been questioned.87,88 The effects of interventions that alter the distribution of potassium usually occur within a short period of time (
Introduction
University of Tennessee Health Science Center, University of Tennessee, 956 Court Avenue, Memphis, TN 38163, USA. [email protected]
Hyperkalaemia is one of the clinically most important electrolyte abnormalities because it can cause severe electrophysiological disturbances, such as cardiac arrhyth mias. Hyperkalaemia is defined as a serum potassium level above the normal range, and various arbitrary cutoffs, such as >5.0, >5.5 or >6.0 mmol/l, are used to denote dif ferent levels of severity. Hyperkalaemia has been associ ated with increased mortality in patients with chronic kidney disease (CKD) and those undergoing haemo dialysis,1–4 highlighting the importance of maintaining serum potassium levels in the physiologically normal range. The mechanisms driving hyperkalaemia typically involve a combination of factors, such as increased dietary potassium intake, disordered distribution between intra cellular and extracellular compartments and abnormali ties in potassium excretion. In clinical practice, CKD is the most common predisposing condition for hyperkalaemia and, in combination with one or more exacerbating factors (discussed below), can induce recurrent episodes of abnormally elevated serum potassium levels. Hyperkalaemia occurs especially frequently in patients with CKD who are treated with certain classes of medi cations, such as angiotensin-converting-enzyme (ACE) inhibitors, angiotensin-receptor blockers (ARBs) or other inhibitors of the renin–angiotensin–aldosterone system (RAAS). These therapeutic agents are beneficial in patients with CKD and are also the standard of care Competing interests The author declares no competing interests.
for some common comorbidities of CKD, such as con gestive heart failure (CHF). Although treatment with RAAS inhibitors is desirable in patients with CKD, it is often difficult or impossible to continue this therapy over extended periods of time owing to the development of hyperkalaemia. Currently, no reliably effective and safe maintenance treatments can be given in combina tion with RAAS inhibitors to offset the hyperkalaemia caused by these otherwise beneficial therapeutic agents. Hence, the safe response to recurrent episodes of hyper kalaemia in patients with CKD who receive RAAS inhib itors is considered to be tapering or discontinuation of this medication. This Review summarizes the mechanisms under lying hyperkalaemia, its epidemiology and clinical consequences, with a focus on patients with CKD and endstage renal disease (ESRD). Currently available treatment regimens are discussed, highlighting areas of uncertainty, and emerging therapies that might enable the more-liberal use of RAAS inhibitors in various populations of patients at risk of hyperkalaemia are described.
Mechanisms of hyperkalaemia in CKD
The principal mechanism through which the kidneys maintain potassium homeostasis is the secretion of potassium into the distal convoluted tubule and the prox imal collecting duct. As glomerular filtration rate (GFR) decreases, the ability of the kidneys to maintain serum potassium levels in a physiologically normal range is increasingly jeopardized.5–9 Experimental studies suggest
NATURE REVIEWS | NEPHROLOGY
ADVANCE ONLINE PUBLICATION | 1 © 2014 Macmillan Publishers Limited. All rights reserved
REVIEWS Key points ■■ Hyperkalaemia is common in patients with chronic kidney disease (CKD), especially when CKD is accompanied by exacerbating factors ■■ Hyperkalaemia is associated with adverse outcomes in patients with CKD, and can restrict the use of beneficial medications, such as renin–angiotensin– aldosterone-system (RAAS) inhibitors ■■ Current therapeutic paradigms for hyperkalaemia emphasize intermittent acute interventions and the elimination of exacerbating factors (including RAAS inhibitors) ■■ Proactive treatment strategies to prevent the development of hyperkalaemia could also benefit patients by enabling more liberal use of RAAS inhibitors ■■ The emergence of new potassium binders may result in more widespread implementation of strategies for hyperkalaemia prevention
that the kidneys can adjust to a decrease in the number of nephrons through increasing potassium secretion by the surviving nephrons, and remain able to maintain normokalaemia under steady state conditions. However, their ability to respond to an acute increase in potas sium load is hampered, resulting in the development of hyperkalaemic episodes.10 Patients with CKD often have other conditions that exacerbate hyperkalaemia, in addition to the decreased GFR and tubulointerstitial damage that prevent the kidneys from upregulating potassium excretion (Figure 1). Often, multiple precipitating factors are present in a single patient, which explains why hyper kalaemia is most commonly detected in patients with CKD in clinical practice. Dietary modifications in patients with CKD often involve an emphasis on sodium restric tion, and some patients switch to salt substitutes, not real izing that these can contain potassium salts. Furthermore, ‘heart-healthy’ diets are inherently rich in potassium— which is beneficial in most people (by virtue of improved blood pressure control and other mechanisms), but can also contribute to an increased risk of hyperkalaemia in susceptible patients. Other CKD-related conditions that contribute to hyperkalaemia are metabolic acidosis, which causes a shift of potassium from the intracellular to the extracellular space11 (the effect of which depends more on the aetiology of the acidosis rather than on the actual pH);12–15 anaemia requiring blood transfusion, which can result in a high acute potassium load (typically occurring with large transfusions and the use of outdated blood);16 and kidney transplantation, which can result in hyper kalaemia through various mechanisms (for example, development of renal tubular a cidosis or the effects of calcineurin inhibitors).17–19 In addition, some hyperkalaemia-inducing comorbid ities are not caused by CKD itself, but often occur in patients with CKD, and hence are instrumental to the high incidence of hyperkalaemia seen in these patients. Acute kidney injury results in a rapid decrease in both GFR and tubular flow, and is often accompanied by a hypercatabolic state, tissue injury and high acute potas sium loads (for example, secondary to gastrointestinal bleeding). These conditions all contribute to the develop ment of hyperkalaemia, which can be of life-threatening severity and is one of the most common indications for emergency haemodialysis. Diabetes mellitus and
cardiovascular disease are two of the most common comorbidities in patients with CKD and both are linked to the development of hyperkalaemia through differ ent mechanisms. Insulin deficiency and hypertonicity caused by hyperglycaemia in patients with diabetes con tributes to an inability to disperse high acute potassium loads into the intracellular space.20 Furthermore, dia betes mellitus is associated with hyporeninaemic hypo aldosteronism and the resultant inability to upregulate tubular potassium secretion.21,22 Cardiovascular disease and other associated condi tions, such as acute myocardial ischaemia, left ventricular hypertrophy and CHF, require various medical treatments that have been linked to hyperkalaemia (Figure 1). Their importance in the aetiology of hyperkalaemia in patients with CKD is underscored by the fact that some of these medications are difficult or impossible to use in patients with CKD who are, therefore, deprived of their proven cardiovascular benefits. For example, β2-adrenergicreceptor blockers contribute to hyperkalaemia through inhibition of renin production and a decreased ability to redistribute potassium to the intracellular space.23 Heparin treatment has also been linked to hyperkalaemia through decreased production of aldosterone.24 Cardiac glycosides, such as digoxin, contribute to hyperkalaemia through inhibition of the Na+/K+-ATPase, which is neces sary for secretion of potassium into the collecting duct and for redistribution of potassium across cell membranes.25 However, the effects of these drugs on serum potassium levels are limited (increases of ~0.2–0.5 mmol/l) unless other predisposing factors are present.26,27 The medications linked to hyperkalaemia that are most relevant in clinical practice are RAAS inhibitors (ACE inhibitors, ARBs, direct renin inhibitors and mineralocorticoid-receptor blockers). In populations without CKD, the incidence of hyperkalaemia associated with RAAS inhibitor monotherapy is 5.1 mmol/l
5.2%
Not reported
Benazepril in advanced CKD48 (2006)
226 Chinese patients with advanced CKD Group 1: eGFR 37.10 ± 6.30 ml/min/1.73 m2* Group 2: eGFR 26.30 ± 5.30 ml/min/1.73 m2*
≥6.0 mmol/l
1.9% (group 1) 5.3% (group 2)
1.3% (3 patients from group 2)‡
AASK43 (2009)
417 African American patients with eGFR 46.30 ± 13.50 ml/min/1.73 m2*
>5.5 mmol/l
7.2%
Not reported
NEPHRON‑D46 (2013)
1,448 US veterans (99% men) with diabetic nephropathy and eGFR 30–90 ml/min/1.73 m2
>6.0 mmol/l, or need for emergency room visit, hospitalization or dialysis
4.4% (losartan + placebo) 9.9% (losartan + lisinopril)
Not reported
*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 a detailed description of which is beyond the scope of this Review. Studies in patients with non-dialysis-dependent CKD demonstrated a significant association between hyperkalaemia and increased long-term all-cause mor tality.3,62 Similar associations between hyperkalaemia and mortality were reported in patients receiving chronic haemodialysis,1,2,4 but assessment of the increased mor tality attributable to hyperkalaemia in this population is confounded by exposure to low-potassium dialysates, which are themselves a risk factor for sudden death.63,64 In patients receiving peritoneal dialysis, hyperkalaemia and variability in serum potassium levels were associated with increased mortality in the first year following the measurement of an abnormal potassium level, but not thereafter.65 This discrepancy between the short-term and long-term associations with mortality could be explained by the electrophysiological effects of hyperkalaemia, which present an acute danger primarily because they can cause cardiac arrhythmias.66–68 Indeed, studies that exam ined mortality associated with abnormal serum potassium levels during a short time-window have corroborated the existence of this s hort-term m ortality risk.33
Treatment of hyperkalaemia Acute management It is unclear what level of hyperkalaemia represents an imminent danger to the individual. In a large retrospec tive study, a serum potassium level >6 mmol/l was associ ated with a greater than 30-fold increase in the risk of 1‑day mortality,33 but long-term adverse effects of hyper kalaemia have been associated with levels >5 mmol/l.45 It is important to emphasize that, beside the absolute serum potassium level, numerous other factors determine when hyperkalaemia becomes hazardous in a given individual, such as the rate of change in serum potassium levels, the concurrent presence of low serum concentrations of
calcium and magnesium (often exacerbated by the use of diuretics and/or proton pump inhibitors) or abnormal serum pH. To what extent the concomitant presence of such abnormalities might potentiate the electrophysio logical effects of hyperkalaemia is not well established and needs further examination. Severe hyperkalae mia (most often defined as serum levels >6 mmol/l) typically represents a clinical urgency or emergency, which may warrant immediate attention in the form of cardiac monitoring, acute medical i nterventions and, occasionally, emergency dialysis. Diagnostic electrocardiography In the acute management of hyperkalaemia, electro cardiography (ECG) is often used to gauge the sever ity of its effect on cardiac function. However, individual variations in sensitivity to serum levels of potassium are evident in the ECG changes typically associated with hyperkalaemia, such as peaked T waves, as well as pro longation of the PR interval and QRS complex duration. Although case reports in patients with serum potassium levels >9 mmol/l highlight an association with marked ECG changes,69–71 the ability of ECG features to predict hyperkalaemia of moderate severity is considered poor, since only half of patients with serum potassium levels >6.5 mmol/l display typical ECG changes.72 In a retro spective study of 90 patients with hyperkalaemia (of whom >80% had serum potassium levels >7.2 mmol/l), typical ECG changes associated with hyperkalaemia showed poor sensitivity and specificity for predicting patients’ actual serum potassium levels, 73 prompting the authors to recommend that these ECG changes should not be used to guide treatment of hyperkalaemia. In another study of 145 patients with ESRD, the ratio of T wave to R wave amplitude was more specific than T wave tenting for predicting a serum potassium level >6 mmol/l, but both features had poor sensitivity (33%
4 | ADVANCE ONLINE PUBLICATION
www.nature.com/nrneph © 2014 Macmillan Publishers Limited. All rights reserved
REVIEWS Table 2 | Interventions used for acute or chronic treatment of hyperkalaemia Treatment
Route of administration
Onset of action, duration of effect
Mechanism
Comments
6.8 mmol of calcium, corresponding to 10 ml CaCl (10%)* or 30 ml calcium gluconate (10%) solutions
Intravenous (acute)
1–3 min 30–60 min
Membrane potential stabilization
Does not affect serum potassium level Effect measured by normalization of electrocardiographic changes Dose can be repeated if no effects noted Caution advised in patients receiving digoxin
50–250 ml hypertonic saline (3–5%)‡76,77
Intravenous (acute)
5–10 min ~2 h
Membrane potential stabilization
Efficacy only in hyponatraemic patients
50–100 mmol sodium bicarbonate
Intravenous (acute) or oral (chronic)
5–10 min ~2 h
Redistribution
Efficacy questioned for acute treatment of patients on dialysis
10 units of regular insulin
Intravenous (acute)
30 min 4–6 h
Redistribution
Administer with 50 g of glucose intravenously to prevent hypoglycaemia
β2‑receptor agonists: 10–20 mg aerosol (nebulized) or 0.5 mg in 100 ml of 5% dextrose in water (intravenous)
Intravenous or nebulized (both acute)
30 min 2–4 h
Redistribution
Effect independent of insulin and aldosterone Caution in patients with known coronary artery disease
40 mg furosemide or equivalent dose of other loop diuretic. Higher doses may be needed in patients with advanced CKD
Intravenous (acute) or oral (chronic)
Varies Until diuresis present or longer1
Excretion
Loop diuretics for acute intervention Loop or thiazide diuretics for chronic management
Fludrocortisone acetate ≥0.1 mg (up to 0.4– 1.0 mg daily)
Oral (chronic)
NA
Excretion
In patients with aldosterone deficiency Large doses might be needed to effectively lower potassium levels Sodium retention, oedema and hypertension might occur
Cation exchange resins 25–50 g
Oral or rectal (either acute or chronic), with or without sorbitol
1–2 h ≥4–6 h§
Excretion
Sodium polystyrene sulphonate is the only approved agent in most countries Calcium polystyrene sulphonate is approved in some countries New agents are in development
Dialysis
Haemodialysis (acute or chronic); peritoneal dialysis (chronic)
Within minutes Until end of dialysis or longer§
Removal
Effects of dialysis on serum sodium, bicarbonate, calcium and/or magnesium levels can affect results
*CaCl is caustic and could damage peripheral veins. ‡Limited data available from clinical studies. §Effects can last for an unspecified length of time depending on ongoing potassium intake or cellular redistribution. Abbreviations: CKD, chronic kidney disease; NA, not applicable.
and 24%, respectively).74 Interestingly, patients in this study who had an abnormal T:R wave amplitude ratio had an increased long-term risk of sudden death, sug gesting that ECG changes might identify patients who are particularly sensitive to the electrophysiological effects of hyperkalaemia.74 In response to the publica tion of this study, other researchers commented75 that intravenous infusion of calcium into hyperkalaemic patients with ECG changes linked to hyperkalaemia could serve as a test to determine whether these changes were incidental to or caused by the hyperkalaemia, and whether treatment of hyperkalaemia could be expected to reverse them.75 Interventions Interventions used to treat acute hyperkalaemia include the intravenous administration of either calcium salts or hypertonic saline (which is effective in patients with underlying hyponatraemia).76,77 These agents restore the electrophysiological properties of cell membranes through various mechanisms,78–83 but do not (or only
minimally) affect serum potassium levels. Additional pharmacologic agents that induce potassium trans port into the intracellular space include insulin,84,85 β 2‑receptor agonists 84 and bicarbonate 86 (Table 2). However, the efficacy of intravenous bicarbonate for this indication in patients on dialysis has been questioned.87,88 The effects of interventions that alter the distribution of potassium usually occur within a short period of time (
