How Dangerous Is Hyperkalemia? : Journal of the American Society of Nephrology

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Up Front Matters: Brief Reviews

How Dangerous Is Hyperkalemia?

Montford, John R.*,†; Linas, Stuart*,‡

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Journal of the American Society of Nephrology 28(11):p 3155-3165, November 2017. | DOI: 10.1681/ASN.2016121344
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Integrated Discussion


Hyperkalemia is an electrolyte disturbance occurring with increased frequency among patients with CKD, diabetes, heart failure, and use of certain medications such as renin angiotensin aldosterone system (RAAS) inhibitors and nonsteroidal anti-inflammatory drugs.1–4 Extracellular potassium concentration is usually kept within a narrow physiologic range by redundant and highly efficient homeostatic mechanisms that simultaneously control internal potassium redistribution while regulating net potassium excretion. Hyperkalemia occurs when rises in extracellular potassium concentration are accompanied by one, or additive, defects in these two processes. Blunted potassium redistribution typically occurs through insulin deficiency, decreases in aldosterone biosynthesis or action, diminished adrenergic signaling, and osmolar disturbances including hyperglycemia. Renal failure, and/or failure to augment distal tubular potassium secretion, is largely responsible for the maintenance of hyperkalemia. Many studies reproducibly identify common clinical risk factors that are associated with the development of hyperkalemia regardless of the clinical setting (Table 1).

Table 1. - Risk factors for the development of hyperkalemia
Clinical Risk Factor Medication Exposure
Male sex Potassium supplements
Non-black Penicillin G
DM Digoxin
CKD β-adrenergic blockers
Acidosis Heparin
Urinary obstruction Amiloride, Triamterene
Trimethoprim, Pentamidine
DM, diabetes mellitus; CVD, cardiovascular disease; NSAIDs, nonsteroidal anti-inflammatory drugs; CHF, congestive heart failure; ACEi, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blockade.

The fatal consequences of rapid increases in extracellular potassium concentration have been demonstrated in the setting of acute intravenous potassium loading in animals.5,6 Early rises in extracellular potassium concentration lower the resting cardiac membrane potential. This decreases the threshold for rapid phase-0 Na+-dependent depolarization resulting in an increase in cardiac conduction velocity.7 By electrocardiogram (ECG), these changes are manifested by “peaked” or “tented” T waves most prominent in the precordial (V2–V4) leads. With larger acute rises in extracellular potassium concentration, conduction delay becomes prominent in the atrioventricular node and His–Purkinje system due to action potential shortening and prolongation of phase-4 diastolic depolarization.7,8 Indeed, prolongation of the PR interval, P-wave amplitude, and increased QRS complex width are ominous findings in patients with advanced hyperkalemia that can precede a classically described “sine-wave” pattern on ECG.9 Thus, hyperkalemia predisposes to both cardiac hyperexcitability (ventricular tachycardia, ventricular fibrillation) and depression (bradycardia, atrioventricular block, interventricular conduction delay, and asystole), both of which can be fatal.

Despite a wealth of animal data demonstrating cardiotoxicity from acute hyperkalemia, these presentations are overall uncommon in humans. Reports of acute hyperkalemia precipitating cardiac arrest typically involve intravenous potassium loading, massive cell turnover, or shift of potassium in the setting of surgical anesthesia or critical illness.10–14 In these cases, the measured potassium concentration was usually normal shortly before cardiopulmonary arrest; and only with rapid increases in serum potassium did the findings of tachy- and bradyarrhythmias associated with hyperkalemia become apparent. These extreme situations constitute a small minority of clinical hyperkalemia in humans which is often incidental, asymptomatic, and of unknown duration. Additionally, there are many published reports demonstrating a large disconnect between degree of hyperkalemia and expected ECG findings in humans.

The ECG was observed to be somewhat unreliable in older studies of patients with potassium levels <6.5 meq/L.9,15 Modern studies and case reports also support that extreme hyperkalemia is accompanied by inconsistent findings. For example, a prospective study examining treatment strategies for acute hyperkalemia revealed only 46% of all patients with a serum potassium >6.0 meq/L had ascribable ECG changes.16 In another study of hospitalized patients with serum potassium levels >6.0 meq/L, the ECG was noted to be completely insensitive at diagnosing mild-to-moderate degrees of hyperkalemia and only approached minimal predictive power with potassium levels of 7.2–9.4 meq/L.17 In patients on hemodialysis with hyperkalemia, ECG-diagnosed T wave “tenting” did not predict the serum potassium and substantially lost its sensitivity with increasing patient age and presence of diabetes.18 Specificity for hyperkalemia and sudden death at follow-up was improved with evaluation of the T:R wave amplitude in these patients, but sensitivity was also diminished.

Hyperkalemia has also been associated with a host of nontraditional ECG changes including T wave inversions19 and pseudonormalizations,20 bundle branch,21 bifascicular,22 sinoatrial exit,20 and atypic bundle branch blocks,8 and ST depressions and elevations.15,23,24 There are even reports of profound hyperkalemia with minimal or no discernable ECG changes.21,25,26 Additionally, metabolic acidosis,27 left ventricular hypertrophy,28 early benign repolarization,29 and acute coronary ischemia30 are known to induce T wave “tenting” in patients with normal serum potassium. Because there are currently inconsistent data supporting the utility of the ECG in predicting the degree of, and prognosis with, hyperkalemia, we must turn to published data that examines the relationship between hyperkalemia and cardiovascular outcomes.

Hyperkalemia in the Setting of Critical Illness

Compelling data link hyperkalemia with heightened adverse outcomes in the critically ill population. In a retrospective analysis of 932 hospitalized adults in two Korean medical centers, high rates of arrhythmia (in 35.2%) and cardiac arrest (in 43.3%) occurred in patients with serum potassium levels >6.5 meq/L.31 Nonsurvivors in this cohort had a higher prevalence of comorbidities which independently predicted death including multiorgan failure (odds ratio [OR], 7.64; 95% confidence interval [95% CI], 4.00 to 14.57), malignancy (OR, 2.88; 95% CI, 1.68 to 4.96), AKI (OR, 2.17; 95% CI, 1.27 to 3.71), and need for intensive care (OR, 3.62; 95% CI, 1.79 to 7.32). Furthermore, as compared with survivors with hyperkalemia, nonsurvivors had higher increases in serum potassium preceding death (1.1±1.3 versus 2.2±1.5 meq/L change in serum potassium from admission, respectively). Most cases of hyperkalemia developed during hospitalization (in 60% of the cohort) with a mean admission potassium level of 5.7±1.5 meq/L rising to 7.1±0.7 meq/L after an average of 17 days of follow-up.

In another retrospective review of >39,000 patients admitted to the intensive care unit at two teaching hospitals in Boston, Massachusetts between 1997 and 2007, incident hyperkalemia independently predicted mortality at the time of critical care initiation.32 This association was graded, with even minor elevations in serum potassium (to levels 4.5–5.0 meq/L) conferring an increased risk of death (OR for death within 30 days, 1.49; 95% CI, 1.38 to 1.59), and remained significant after adjusting for many potential confounders prevalent in the critical care setting (adjusted OR, 1.18; 95% CI, 1.09 to 1.27). Furthermore, failure of serum potassium to correct by >1.0 meq/L within 48 hours after initial measurement continued to predict death; whereas, this association was attenuated among patients achieving this degree of correction. Khanagavi et al.33 reported on hospitalized patients with serum potassium >5.1 meq/L, finding that duration of hyperkalemia and mortality increased substantially with concomitant tissue necrosis [hazard ratio (HR) for death, 4.55; 95% CI, 1.74 to 11.90], metabolic acidosis (HR, 4.84; 95% CI, 1.48 to 15.82), and AKI (HR, 3.89; 95% CI, 1.14 to 13.26). Total duration of hyperkalemia was also associated with death, although the association was less robust (HR, 1.06; 95% CI, 1.02 to 1.09).

Data from these studies suggest that not only the absolute level, but the velocity and duration of hyperkalemia are associated with poor outcomes with critical illness. Although compelling, these studies are limited by their retrospective design and weighed down by the severity of illness in the subjects. Mortality was high (30.7%) in the cohort by An et al.31 and many patients needed cardiopulmonary resuscitation (32%), the majority for reasons unrelated to hyperkalemia. Although initial and sustained hyperkalemia predicted mortality in the study by McMahon et al.,32 there are no data regarding the disease-specific clinical improvement or lack of improvement in the patients who suffered in-hospital mortality. Furthermore, these studies were unable to adequately control for the severity of patient illness due to a lack of physiologic data.

Hyperkalemia during Acute Myocardial Infarction

Hyperkalemia was not originally identified as a potential risk factor for poor outcomes during evolution of acute myocardial infarction (AMI),34 despite the existence of strong biologic plausibility in animal models.35,36 However, modern approaches, including percutaneous coronary intervention (PCI) and more widespread adoption of RAAS inhibitors, β-adrenergic blockers, and mineralocorticoid receptor antagonists (MRAs), have drastically improved patient survival while also predisposing the post-AMI population to more frequent hyperkalemia. One widely cited retrospective trial of 38,689 hospitalized patients with AMI treated in the modern era demonstrated an independent increase in mortality among patients with potassium levels >5.1 meq/L (OR, 3.27; 95% CI, 2.52 to 4.24) which persisted in patients with serum potassium levels of 4.5–5.0 meq/L (OR, 1.99; 95% CI, 1.68 to 2.36).37 A subsequent analysis of this same cohort showed elevated in-hospital mortality with exposure to a higher number of hyperkalemic episodes (13.4%, 16.2%, and 19.8% increase in mortality with one, two, and three or more potassium measurements >5.0 meq/L, respectively) and maximum achieved serum potassium level (4.2%, 11.1%, 16.6%, 26.6%, and 31.7% increase in mortality with potassium levels <5.0, 5.0–5.5, 5.5–6.0, 6.0–6.5, and >6.5 meq/L, respectively).38 Another retrospective trial analyzing 90-day mortality in 2596 Danish patients with heart failure post-AMI also supports that a serum potassium >5.1 meq/L is associated with higher risk of death (HR, 2.3; 95% CI, 1.4 to 3.6).39

The studies by Goyal et al.37 and Grodzinsky et al.38 are strengthened by use of robust adjustment models that control for baseline risk, medications, PCI use, and other pertinent factors. Nevertheless, residual confounding in very ill patients is common in retrospective analyses, and outcomes in patients with serum potassium >4.5 meq/L in the study by Goyal et al.37 were ultimately driven by a small number of individuals (11%, 2%, and 0.6% of the entire cohort had potassium levels 4.5–5.0, 5.1–5.5, and >5.5 meq/L, respectively). These patients also had substantially higher comorbidities, and lower rates of PCI, aspirin, RAAS inhibitor, β-blocker, and statin usage. The analysis by Krogager et al.39 suffers a similar limitation, including very few patients with serum potassium levels >5.1 meq/L. In the study by Goyal et al.37 there was also a paradoxic dissociation between rates of malignant arrhythmias and rates of overall mortality in higher versus lower ranges of hyperkalemia and normokalaemia, in which both associations were more congruent. The authors hypothesized that poor coding of arrhythmias associated with extremes of hyperkalemia, such as sinus arrest and asystole, led to this discrepancy.

Hyperkalemia with CKD

One of the first studies to demonstrate an independent association of hyperkalemia and risk of subsequent death involved a large retrospective study of Japanese patients with advanced CKD presenting for dialysis initiation.40 An initial serum potassium level >5.5 meq/L at dialysis vintage was the strongest single independent predictor of mortality after an average of 15 years of follow-up. In patients on hemodialysis, potassium levels >5.641 and >5.742 meq/L have been associated with higher mortality. This is also reflected in patients on peritoneal dialysis, with one study suggesting hyperkalemia >5.5 meq/L is associated with a heightened risk of death.43 Potassium increases during longer intradialytic intervals, and many have attempted to link these fluctuations to the higher incidence of sudden cardiac death in patients with ESRD. In a 3-year study of community dwelling patients on hemodialysis, the presence of hyperkalemia (defined as three or more averaged serum potassium levels >6.0 meq/L over a 6-month period) was one of the strongest single predictors of sudden death (HR, 2.7; 95% CI, 1.3 to 5.9).44

A recently published retrospective observational trial of 52,734 patients on a Monday/Wednesday/Friday hemodialysis schedule revealed that serum potassium levels 5.5–6.0 meq/L were associated with higher risk for subsequent hospitalization, emergency department visits, and mortality within 4 days of measurement.45 Of note, the association between hyperkalemia and hospitalization was magnified among patients entering a longer intradialytic interval (adjusted OR for hospitalization, 1.12; 95% CI, 1.0 to 1.24; OR, 1.04; 95% CI, 0.94 to 1.16; and OR, 1.68; 95% CI, 1.22 to 2.30 for patients with potassium measurements performed on Monday, Wednesday, and Friday, respectively).

The association of mortality with hyperkalemia also appears to extend to patients with earlier stage CKD. Einhorn et al.2 conducted a retrospective analysis of 245,808 United States adult veterans with and without CKD, showing potassium levels of >5.5 meq/L predicted death just 1 day after measurement. In another study of 36,000 patients in the Cleveland Clinic system with an eGFR<60 ml/min per 1.73 m2, sustained hyperkalemia (defined as an average serum potassium level >5.5 meq/L over 2.3 years) was also associated with increased all-cause mortality.46

However, an interesting paradox is documented in these later studies regarding the relationship between CKD stage, hyperkalemia, and mortality. In the study by Einhorn et al.2 the strongest association between hyperkalemia and 1-day mortality involved patients with normal renal function (OR, 10.32 and 31.64 for serum potassium ranges ≥5.5 and <6.0 and ≥6.0 meq/L, respectively), and declined as CKD stage progressed; with stage 5 CKD associated with a much lower relative risk (OR, 2.31 and 8.02 for serum potassium ≥5.5 and <6.0 and ≥6.0 meq/L, respectively). Patients with ESRD in the study by Nakhoul et al.46 also seemed to be protected with hyperkalemia relative to the entire cohort (adjusted HR for death, 1.20; 95% CI, 0.91 to 1.58 versus 1.65; 95% CI, 1.48 to 1.84, respectively). Furthermore, An et al.31 showed a graded decrease in risk of death among patients with extreme levels of hyperkalemia (>6.5 meq/L) as CKD stage increased (OR for death with stage 2, 3, 4, and 5 CKD, 0.52; 95% CI, 0.35 to 0.78, 0.31; 95% CI, 0.21 to 0.46, 0.13; 95% CI, 0.06 to 0.26, and 0.17; 95% CI, 0.11 to 0.27). Similar results were observed among dialysis versus non-CKD patients with hyperkalemia and AMI in the studies performed by Goyal et al.37 and Grodzinsky et al.38 One prospective observational analysis of sustained hyperkalemia and outcomes in patients with creatinine clearance <50 ml/min demonstrated that hyperkalemia in the ranges of 5.0–6.0 meq/L (using an average of six measurements per patient) appeared to be well tolerated.47

Adaptive increases in circulating catecholamines, aldosterone, and augmentation of renal and gastrointestinal (GI) potassium elimination are thought to blunt hyperkalemia development in CKD and could partially explain this apparent disconnect in mortality relative to non-CKD patients.48–53 However, physiologic adaptation incompletely explains why mortality risk could be diminished once hyperkalemia has already been established. Furthermore, patients with CKD might be uniquely predisposed to more not less toxicity with hyperkalemia due to a higher prevalence of metabolic derangements (e.g., hypocalcemia, acidosis, and elevated uremic solutes) and structural heart disease. Left ventricular hypertrophy,54,55 atrial fibrillation,56,57 heart rate variability,58 heart failure,59 silent myocardial infarction,60 QT abnormalities,61 and pulmonary hypertension62,63 are all highly prevalent in the CKD population and could lower arrhythmogenic potential with concurrent hyperkalemia. All of these factors could be further compounded by changes in individual solutes, rapid osmolar shifts, high ultrafiltration rates, and myocardial stunning during dialysis treatments. Thus, persons with CKD might be uniquely predisposed or uniquely protected from cardiotoxicity with hyperkalemia relative to other populations, and further studies should be performed with these apparent inconsistencies in mind.

Hyperkalemia with Selected Medication Exposure

Hyperkalemia that develops while exposed to certain medications could alter the threshold of cardiac toxicity. Cases of digoxin poisoning have illustrated quite dramatic rises in serum potassium with associated arrhythmias.64 In the studies performed by Khanagavi et al.33 and McMahon et al.32, but not An et al.,31 potassium supplementation with hyperkalemia was linked to heightened mortality. With regard to the risks of hyperkalemia while exposed to RAAS inhibitors and β-adrenergic blockers, patients in the study by An et al.31 had lower observed mortality. Conversely, critically ill patients in the study by McMahon et al.32 were not afforded similar protection with either agent. Unfortunately, there is no data on patient mortality stratified by exposure versus nonexposure to RAAS inhibitors and β blockers in the studies performed by Goyal et al.,37 Grodzinsky et al.,38 and Krogager et al.39 Patients with higher mortality in these studies were less likely to be exposed to either agent. Other data indicate that RAAS inhibitor use is linked with more profound hyperkalemia and death in the elderly65 and in patients with diabetic versus nondiabetic CKD.66 In the randomized controlled Hypertension in Hemodialysis Patients Treated with Atenolol or Lisinopril trial,67 lisinopril predisposed patients on dialysis to more hyperkalemia and higher cardiovascular morbidity than atenolol; although, the lack of a control group is a limitation to further generalizations that can be made from this study.

There is conflicting data regarding the outcome of patients with hyperkalemia exposed to MRAs. Post hoc data68 from the Eplerenone Post–Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS) trial indicates that eplerenone maintains a mortality benefit in patients with CKD and eGFR<60 ml/min per 1.73 m2 while simultaneously predisposing these patients to higher rates of hyperkalemia. Unfortunately, patients with more advanced CKD (serum creatinine >2.5 mg/dl) were excluded from both the original EPHESUS trial69 and the earlier Randomized Aldactone Evaluation Study.70 It is important to note that no hyperkalemia-associated deaths were reported in either of these trials. However, in an analysis of the Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure, patients with serum potassium levels >5.5 meq/L had a higher risk of all-cause mortality.71 MRA exposure was also associated with more hyperkalemia (>5.0 meq/L) and higher mortality in a study of 15,803 United States veterans with established cardiovascular disease (OR for death, 1.50; 95% CI, 0.40 to 5.64).72 Patients with eGFR<60 ml/min per 1.73 m2 in this study had even worse outcomes while on MRAs (OR for death, 1.74; 95% CI, 1.11 to 2.71). Another recent study examining spironolactone use in 27,213 predialysis patients in Taiwan demonstrated that exposure was independently associated with increases in hospitalizations for heart failure (adjusted HR, 1.35; 95% CI, 1.08 to 1.67), infection-related deaths (adjusted HR, 1.42; 95% CI, 1.16 to 1.73), and all-cause mortality (adjusted HR, 1.35; 95% CI, 1.24 to 1.46).73

Implications of Data Supporting an Association between Hyperkalemia and Mortality

To date, the published studies demonstrating an association of mortality with hyperkalemia are largely limited to retrospective analyses that do not provide evidence of causation. Much of the published data are also cross-sectional in nature, potentially raising more questions than answers. Furthermore, there are sparse data to suggest that treatment of hyperkalemia modifies risk. In the study of critically ill patients by McMahon et al.,32 the risk of mortality with hyperkalemia was attenuated in patients achieving a >1.0 meq/L decrease in serum potassium within 48 hours; although, it is unclear if this represented an actual treatment effect. Other studies suggesting that longer durations and failure to reverse hyperkalemia are associated with mortality suffer from similar limitations. Of note, An et al.31 attempted to control for the effect of treatment by giving individual therapies a weighted score which was plotted against patient survival. Although increasing number of targeted interventions for hyperkalemia was associated with improved patient survival, there was no control for other treatments that were directed at reversing the underlying illness. It is interesting to note that when hemodialysis or continuous renal replacement therapy were included as treatments for hyperkalemia in this study, the improvement in patient mortality was eliminated. Extracorporeal elimination of potassium is the most efficient and definitive therapy for life-threatening hyperkalemia. Therefore, it is surprising that these therapies were not associated with improvement in mortality whereas others (withdraw of offending medicines, intravenous calcium, insulin/dextrose, etc.) were, especially if hyperkalemia is presumed to be the proximate cause of mortality.

Abrupt incidence and more rapid velocity of hyperkalemia are salient features in studies such as those performed by An et al.,31 Goyal et al.,37 and Grodzinsky et al.38 More rapid development of hyperkalemia is potentially more cardiotoxic, and directed treatment might have more protective effects in this population compared with others. Nevertheless, we can find only one published attempt at protocolizing treatment of patients who develop hyperkalemia while hospitalized.16 This study demonstrated no significant changes in patient outcome with prescribed protocols, although clinician adherence was low. We conclude that prospectively designed randomized trials of treatment for hyperkalemia should be performed with valid endpoints (e.g., target potassium levels) and outcome measures (e.g., mortality, arrhythmia, and health care utilization) in mind. A well designed trial using accepted therapies to lower serum potassium in noncritically ill monitored hospitalized patients with hyperkalemia would be the safest initial study to perform. Presently, we will review the common treatments for hyperkalemia and the potential pitfalls in using these agents.

Treatment of Hyperkalemia

Many reviews have been published on this topic and we will only briefly highlight these strategies. Acute treatment of life-threatening hyperkalemia necessitates infusion of intravenous calcium to protect against malignant cardiac hyperexcitability followed by agents which have been proven in humans to rapidly and effectively shift potassium into the intracellular space. Insulin appears the most well studied treatment in this regard and its rapid action to shift potassium is not dependent on receptor-ligand signaling and downstream protein synthesis. Unlike β-adrenergic agonist and bicarbonate therapy, insulin does not lose its efficacy, and might be enhanced, in the presence of renal failure.49 Intravenous dextrose is usually given to prevent hypoglycemia and further stimulates endogenous insulin production. Studies suggest that oral glucose loading may also be an effective strategy to increase insulin and reduce serum potassium in patients on hemodialysis.74 There is conflicting data regarding the efficacy of β-adrenergic agonists and sodium bicarbonate to reliably shift potassium; however, we observe that these agents are often used in the acute management of hyperkalemia. Ultimately, acute hemodialysis may be necessary for the extracorporeal elimination of potassium in life-threatening situations.

Diuretics are often underappreciated as an effective treatment of hyperkalemia owing to misconceptions regarding the efficacy of these drugs in patients with lower renal function. Indeed, absence of diuretic usage is associated with the development of hyperkalemia in at-risk patients.47 Patients with CKD and patients who experience diuretic braking, in which response to a diuretic becomes blunted over time, are known to need higher diuretic doses, diuretic rotation, or combination diuretics to maintain a therapeutic effect.75 Therapies directed at augmenting GI potassium excretion have been in use for many years, principally with sodium polystyrene sulfate (SPS). Generally, SPS has been shown to be unreliable in the acute setting although data on chronic management might support its use.76 Newer agents, such as sodium zirconium cyclosilicate (ZS-9; AstraZeneca) and the recently Food and Drug Administration (FDA)–approved patiromer (Veltassa; Relypsa), have been demonstrated to effectively lower serum potassium when administered in patients with chronic hyperkalemia at levels <6.5 meq/L.77–80 Furthermore, serum potassium may be rapidly lowered within hours by both ZS-979 and patiromer,81 suggesting a previously unrecognized role of the upper GI tract in potassium regulation.

Correction of hypoaldosteronism by mineralocorticoid administration may be an effective therapy to reverse hyperkalemia. Data indicate that urinary losses of potassium only partially explain the treatment effect, suggesting a role for enhanced intracellular redistribution or augmented GI excretion.82,83 This therapy has enjoyed some recent resurgence, with several reports demonstrating successful treatment of hyperkalemia due to a range of causes.84–86 However, small randomized placebo-controlled trials using oral fludrocortisone in patients on hemodialysis with hyperkalemia have demonstrated poor efficacy87 or modest efficacy88 at lowering serum potassium. It is important to note that the doses used in these trials were relatively low (0.1 mg fludrocortisone daily), and older data indicate that patients with renal disease require much higher doses (up to 1.0 mg daily) to effectively reverse hyperkalemia.82

Perhaps the most underused of all therapies to combat hyperkalemia involves reduction of dietary potassium intake. Careful screening of the diet for potassium-rich foods is not often performed due to time-crunched clinician visits and poor dietary education given to health care providers. A careful review of potassium intake and directed counseling might prevent incident hyperkalemia and serve as an important adjunct with other therapies in the treatment of hyperkalemia. However, we can find no human data that dietary counseling is an effective strategy in the prevention or treatment of hyperkalemia. Data on the effectiveness of dietary potassium reduction in hyperkalemic individuals with advanced CKD (who often have relatively fixed levels of urinary and GI potassium excretion) is particularly needed.

Adverse Events Linked to Potassium-Lowering Therapies

Clinicians employ these therapies to patients with hyperkalemia, but to what target level? And at what cost to the patient and the health care system? It is important to highlight that many of the treatments used in management of hyperkalemia may have untoward or even unrecognized side effects. Acute infusions of elemental calcium can induce heart block in patients with digoxin-induced hyperkalemia89 and precipitate acute dermal calcifications.90,91 Given the higher prevalence of hyperphosphatemia in patients with CKD, intravenous calcium infusion carries the theoretic risk of creating or worsening existing metastatic vascular calcifications.

Hypoglycemia and tachycardia can accompany insulin and albuterol administration, respectively. Large intravenous infusions of sodium bicarbonate may precipitate acute hyperosmolarity,92 including case reports of central pontine myelinolysis.93 Sodium bicarbonate infusions also risk development of acute pulmonary edema,94 ionized hypocalcemia,94,95 and worsening of AKI and mortality in patients undergoing cardiac surgery.96

Diuretics can induce volume contraction, dysnatremias, hypomagnesemia, nephrolithiasis, and gout flares. SPS has been linked with numerous cases of intestinal necrosis,97–99 which has given this drug a warning label by the FDA and limited its modern appeal. Newer potassium exchange resins are not without potential side effects and have been shown to induce hypomagnesemia,78 hypercalciuria,100 and even edema80 at high doses. Long-term effects from these drugs are unknown and neither of these newer agents have been shown to be efficacious in patients on dialysis. Exogenous mineralocorticoids are not commonly used for hyperkalemia given concerns for precipitating volume overload and significant cardiopulmonary complications.82

Central line insertion for acute dialysis access can predispose to a host of periprocedural complications and trauma to the central veins that vitally feed future dialysis access creation. Very low potassium–containing dialysate solutions (<2.0 meq/L) are sometimes employed for severe cases of hyperkalemia but the consequences of achieving a rapid (within minutes) reduction in extracellular potassium concentration are unknown. Data suggest that lower potassium–containing dialysates are associated with significant morbidity and mortality101–103; which has largely led to abandoning this practice. Finally, unnecessary hospitalizations and clinician hypervigilance may predispose an already frail patient population to a cascade of unpredictable iatrogenic effects.

Who Is Most Likely to Benefit from the Correction of Hyperkalemia and How to Achieve It? An Opinion-Based Set of Recommendations

Despite decades of knowledge regarding the potential risks of hyperkalemia, the high incidence and prevalence of hyperkalemia in patients with certain comorbidities and medication exposures, and the availability of effective potassium-lowering therapies, there are no guidelines to advise who should be treated. Neither the Kidney Disease: Improving Global Outcomes nor the Kidney Disease Outcomes Quality Initiative have published guidelines in the treatment of hyperkalemia. The Investigator Network Initiative Cardiovascular and Renal Clinical Trialists recently published guidelines104 on workup of hyperkalemia and treatment strategies in patients with serum potassium >5.1 meq/L, but doesn’t stipulate exactly who should be treated.

On the basis of the published data demonstrating disparate risks of hyperkalemia in different patient populations, the safety profile and reliability of agents to reduce serum potassium, and our own experience, we propose a step-wise strategy for the prevention and treatment of hyperkalemia in the following sections which is applicable in a range of clinical settings. We propose treatment on the basis of clinical presentation of the patient rather than degree of hyperkalemia, which poorly predicts cardiotoxicity in humans. Although we support a threshold for initiating therapy in certain patients, we do not support that any upper limit of hyperkalemia constitutes an “emergency” on the basis of the serum potassium concentration alone. Furthermore, we do not recommend guiding therapies on the basis of ECG findings given their inherent variability. We have found that relying on the ECG without extensive knowledge of the patient’s prior cardiac history, velocity of hyperkalemia development, and baseline ECG (all are almost never present) can distract from addressing the underlying cause and interfere with appropriate targeted therapy.

Prevention and Supportive Treatment of Hyperkalemia

To reduce the incidence of hyperkalemia, at risk patients, as defined in Table 1, should be identified and managed in an anticipatory fashion, with dietary modifications, avoidance of medications which might worsen risk for hyperkalemia, and surveillance for common clinical scenarios that create additive risk. We advise all patients with existing hyperkalemia (>5.0 meq/L) to reduce potassium intake to <40 meq/d. Similar dietary reductions are advised in patients with eGFR<30 ml/min per 1.73 m2 and in patients with eGFR>30 ml/min per 1.73 m2 but prone to hyperkalemia. In at-risk patients with high-to-normal levels of serum potassium (4.5–5.0 meq/L), proactive dietary screening is advised to identify and mitigate large potassium loads. We readily admit these dietary recommendations are not based on evidence supporting efficacy, and they could have the adverse effect of steering patients with CKD away from more nutrient-rich foods.

Providers should seek to limit or abstain from exposing higher-risk patients to medications listed in Table 1. In cases where avoidance of these agents is not possible, close monitoring and frequent laboratory checks are advised. The data on avoidance of β-adrenergic blockers in patients prone to hyperkalemia is controversial, because β blocker usage is one of the few established therapies in CKD and non-CKD patients which is associated with lower risk of cardiovascular events. Our own practice, depending on the degree of hyperkalemia and clinical presentation, is to maintain these drugs unless other supportive measures fail to correct the hyperkalemia.

We advise cautious administration of higher RAAS inhibitor doses and MRAs in patients with diabetic CKD, advanced CKD, and those with a prior history of hyperkalemia. Combination RAAS inhibitor regimens should be avoided because these therapies place patients at special risk for hyperkalemia without proven benefit. Hyperkalemia which develops on a diuretic should prompt an investigation for factors which might cause diuretic braking and limit distal nephron sodium delivery, and thus potassium secretion.

Hyperkalemia out of proportion to changes in eGFR should prompt a rigorous investigation for urinary obstruction, insulinopenia, acidosis, and disorders which predispose to hypoladosteronism, such as adrenal insufficiency. Patients with advanced CKD, including those on dialysis, who newly develop hyperkalemia should be evaluated for new constipation or bowel obstruction. In hospitalized patients, the clinician should be attentive to the risk of incident hyperkalemia with blood product administration, sepsis, multiorgan failure, myonecrosis, and rewarming of a cooled patient. Patients on dialysis should have access interventions and other operations scheduled away from long dialytic intervals to minimize the periprocedural risk of hyperkalemia. Furthermore, monitoring postprocedural serum potassium in patients on dialysis with higher prevalent hyperkalemia is advised.

Emergency Treatment of Hyperkalemia

A “Hyperkalemia Emergency,” which we define as a serum potassium >6.0 meq/L or a sudden increase in serum potassium 1.0 meq/L above 4.5 meq/L within 24 hours associated with cardiopulmonary arrest, evolving critical illness, AMI, or signs and symptoms of neuromuscular weakness, should be treated with agents that rapidly and reliably shift serum potassium into the intracellular space while preparations are made for elimination of total body potassium (TBK+). Infusion of intravenous calcium, insulin, and dextrose, and lastly inhaled or intravenous β-adrenergic agonist therapy should be administered only in these extreme circumstances. Consideration for sodium bicarbonate administration should be given in cases of hyperkalemia accompanying severe metabolic acidosis. Arrangements for emergent hemodialysis should be made early and proactively unless a rapidly reversible cause is identified and therapy is expedited. Our practice might require instituting hemodialysis in patients who might otherwise recover from hyperkalemia with directed treatment, yet in this demographic the failure to rapidly stabilize or reverse hyperkalemia might have fatal consequences.

Urgent Treatment for Hyperkalemia

We propose a more guarded strategy to treat hyperkalemia in less dire circumstances, which constitutes the majority of hyperkalemia cases in practice. In patients with hyperkalemia, but outside extremis, we propose adopting a four-step system aimed at maximizing elimination of TBK+ in a prompt but safe manner: (1) Increase urinary potassium clearance, (2) augment potassium excretion through the GI tract, (3) administer exogenous mineralocorticoids in selected patients, and (4) initiate dialysis or optimize dialysis delivery (Table 2). We propose executing this strategy in patients with normal renal function with serum potassium >5.0 meq/L, patients with non-ESRD CKD and serum potassium >5.5 meq/L, and patients with ESRD on maintenance dialysis and serum potassium >6.0 meq/L who have failed supportive measures to reverse the hyperkalemia (or are deemed more at risk to fail with supportive measures alone). Utilizing one of these strategies along with supportive measures should be sufficient to reverse most cases of hyperkalemia; although, several strategies in combination can be used to maximize efficacy in patients with suspicion of multifactorial hyperkalemia.

Table 2. - Strategies to urgently treat hyperkalemia
Steps Clinical Question Strategy
1. Increase urinary potassium losses Is the patient volume contracted or euvolemic? Yes, administer trial of volume expansion with or without loop diuretic
Is the patient volume overloaded or hypertensive? Yes, stratify and treat:
a. eGFR>60 ml/min per 1.73 m2 and diuretic-naïve  Start low dose loop or thiazide-like diuretic
b. eGFR<60 ml/min per 1.73 m2 and diuretic-naïve  Start moderate dose loop diuretic
c. currently taking diuretics  Double existing diuretic dose and/or add  loop diuretic, thiazide-like diuretic, or carbonic  anhydrase inhibitor
2. Increase gastrointestinal potassium elimination Does the patient have a contraindication (recent abdominal surgery, ileus, obstipation, history of ischemic bowel) to cathartics? No, consider a limited trial of patiromer, ZS-9, or SPS
3. Mineralocorticoid replacement Does the patient have a contraindication (greater than stage 1 HTN, volume overload, history of heart failure) to mineralocorticoid administration? No, consider a trial of fludrocortisone 0.1 mg daily × 3–5 d (In patients with moderately advanced CKD consider maintaining or increasing diuretics in tandem)
4. Dialysis optimization or initiation Is the patient currently on maintenance dialysis? Yes, optimize dialysis delivery:
 Assess delivered dialysis dose, duration, and frequency
 Screen for patient noncompliance with dialysis and  patient/caregiver burnout
 Address any access dysfunction including poor blood  flows, recirculation
 Assess dialysate K+ and HCO3 concentrations
No, revisit steps 1–3 and consider hospitalization and urgent dialysis initiation if hyperkalemia persists
SPS, sodium polystyrene sulfate; HTN, hypertension.

The goals of this treatment strategy are to stabilize and gradually reduce serum potassium in low-risk patients, and more rapidly reduce serum potassium in higher-risk patients without the need to employ intravenous calcium, insulin, dextrose, β-adrenergic agonists, and bicarbonate that have little use outside emergencies and are wholly ineffective at removing TBK+. The inclusion of mineralocorticoid administration is likely a controversial position. In our own practice, we have observed that this strategy is safe and very effective in a time-limited fashion in appropriately selected patients. Although we include dialysis initiation in cases of refractory hyperkalemia, outside patients with oligoanuric renal failure and critical illness we have found there are very few circumstances that will require the initiation of dialysis for hyperkalemia alone. We propose that a close follow-up plan should be implemented for every patient with hyperkalemia, particularly in the outpatient setting. Adopting this strategy might potentially spare patients from unnecessary emergency department visits and hospitalizations. Furthermore, employing a strategy such as this might better integrate knowledge of potassium homeostasis by the treating clinician and steer both low- and higher-risk patients with hyperkalemia into appropriate, effective, and safe treatment plans.


S.L. reports serving on an advisory board for ZS Pharma. No financial support was received in the preparation of this manuscript.

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1. Sarafidis PA, Blacklock R, Wood E, Rumjon A, Simmonds S, Fletcher-Rogers J, Ariyanayagam R, Al-Yassin A, Sharpe C, Vinen K: Prevalence and factors associated with hyperkalemia in predialysis patients followed in a low-clearance clinic. Clin J Am Soc Nephrol 7: 1234–1241, 201222595825
2. Einhorn LM, Zhan M, Hsu VD, Walker LD, Moen MF, Seliger SL, Weir MR, Fink JC: The frequency of hyperkalemia and its significance in chronic kidney disease. Arch Intern Med 169: 1156–1162, 200919546417
3. Weir MR, Rolfe M: Potassium homeostasis and renin-angiotensin-aldosterone system inhibitors. Clin J Am Soc Nephrol 5: 531–548, 201020150448
4. Lafrance JP, Miller DR: Dispensed selective and nonselective nonsteroidal anti-inflammatory drugs and the risk of moderate to severe hyperkalemia: A nested case-control study. Am J Kidney Dis 60: 82–89, 201222503390
5. Hiatt N, Katayanagi T, Miller A: Cardiac sensitivity to hyperkalemia in adrenalectomized dogs. Proc Soc Exp Biol Med 149: 168–171, 19751144421
6. Coulter DB, Swenson MJ: Effects of potassium intoxication on porcine electrocardiograms. Am J Vet Res 31: 2001–2011, 19705490631
7. Fisch C: Relation of electrolyte disturbances to cardiac arrhythmias. Circulation 47: 408–419, 19734567871
8. El-Sherif N, Turitto G: Electrolyte disorders and arrhythmogenesis. Cardiol J 18: 233–245, 201121660912
9. Surawicz B: Relationship between electrocardiogram and electrolytes. Am Heart J 73: 814–834, 19675338052
10. Lee SH, Kim KJ, Chang CH, Heo SB: Cardiac arrest from acute hyperkalemia during liver surgery -A case report-. Korean J Anesthesiol 59[Suppl]: S124–S127, 201021286420
11. Mercer CW, Logic JR: Cardiac arrest due to hyperkalemia following intravenous penicillin administration. Chest 64: 358–359, 19734749385
12. Wiltrout C: Hyperkalemia, bradycardia, and cardiac arrest during percutaneous declotting of an arteriovenous graft. Semin Intervent Radiol 27: 241–244, 201021629412
13. Huggins RM, Kennedy WK, Melroy MJ, Tollerton DG: Cardiac arrest from succinylcholine-induced hyperkalemia. Am J Health Syst Pharm 60: 694–697, 200312701553
14. Wilson D, Stewart A, Szwed J, Einhorn LH: Cardiac arrest due to hyperkalemia following therapy for acute lymphoblastic leukemia. Cancer 39: 2290–2293, 1977265752
15. Tarail R: Relation of abnormalities in concentration of serum potassium to electrocardiographic disturbances. Am J Med 5: 828–837, 194818100392
16. Acker CG, Johnson JP, Palevsky PM, Greenberg A: Hyperkalemia in hospitalized patients: Causes, adequacy of treatment, and results of an attempt to improve physician compliance with published therapy guidelines. Arch Intern Med 158: 917–924, 19989570179
17. Montague BT, Ouellette JR, Buller GK: Retrospective review of the frequency of ECG changes in hyperkalemia. Clin J Am Soc Nephrol 3: 324–330, 200818235147
18. Green D, Green HD, New DI, Kalra PA: The clinical significance of hyperkalaemia-associated repolarization abnormalities in end-stage renal disease. Nephrol Dial Transplant 28: 99–105, 201322610985
19. Khattak HK, Khalid S, Manzoor K, Stein PK: Recurrent life-threatening hyperkalemia without typical electrocardiographic changes. J Electrocardiol 47: 95–97, 201423973093
20. Yu AS: Atypical electrocardiographic changes in severe hyperkalemia. Am J Cardiol 77: 906–908, 19968623755
21. Martinez-Vea A, Bardají A, Garcia C, Oliver JA: Severe hyperkalemia with minimal electrocardiographic manifestations: A report of seven cases. J Electrocardiol 32: 45–49, 199910037088
22. O’Neil JP, Chung EK: Unusual electrocardiographic finding--bifascicular block due to hyperkalemia. Am J Med 61: 537–540, 1976973647
23. Simon BC: Pseudomyocardial infarction and hyperkalemia: A case report and subject review. J Emerg Med 6: 511–515, 19883146597
24. Pothiawala SE: Hyperkalemia induced pseudo-myocardial infarction in septic shock. J Postgrad Med 60: 338–340, 201425121383
25. Szerlip HM, Weiss J, Singer I: Profound hyperkalemia without electrocardiographic manifestations. Am J Kidney Dis 7: 461–465, 19863717152
26. Fordjour KN, Walton T, Doran JJ: Management of hyperkalemia in hospitalized patients. Am J Med Sci 347: 93–100, 201423255245
27. Dreyfuss D, Jondeau G, Couturier R, Rahmani J, Assayag P, Coste F: Tall T waves during metabolic acidosis without hyperkalemia: A prospective study. Crit Care Med 17: 404–408, 19892707009
28. Huwez FU, Pringle SD, Macfarlane PW: Variable patterns of ST-T abnormalities in patients with left ventricular hypertrophy and normal coronary arteries. Br Heart J 67: 304–307, 19921389704
29. Brady WJ, Chan TC: Electrocardiographic manifestations: Benign early repolarization. J Emerg Med 17: 473–478, 199910338242
30. Somers MP, Brady WJ, Perron AD, Mattu A: The prominent T wave: Electrocardiographic differential diagnosis. Am J Emerg Med 20: 243–251, 200211992348
31. An JN, Lee JP, Jeon HJ, Kim DH, Oh YK, Kim YS, Lim CS: Severe hyperkalemia requiring hospitalization: Predictors of mortality. Crit Care 16: R225, 201223171442
32. McMahon GM, Mendu ML, Gibbons FK, Christopher KB: Association between hyperkalemia at critical care initiation and mortality. Intensive Care Med 38: 1834–1842, 201222806439
33. Khanagavi J, Gupta T, Aronow WS, Shah T, Garg J, Ahn C, Sule S, Peterson S: Hyperkalemia among hospitalized patients and association between duration of hyperkalemia and outcomes. Arch Med Sci 10: 251–257, 201424904657
34. Friedensohn A, Faibel HE, Bairey O, Goldbourt U, Schlesinger Z: Malignant arrhythmias in relation to values of serum potassium in patients with acute myocardial infarction. Int J Cardiol 32: 331–338, 19911686433
35. Hill JL, Gettes LS: Effect of acute coronary artery occlusion on local myocardial extracellular K+ activity in swine. Circulation 61: 768–778, 19807357719
36. Coronel R, Fiolet JW, Wilms-Schopman FJ, Schaapherder AF, Johnson TA, Gettes LS, Janse MJ: Distribution of extracellular potassium and its relation to electrophysiologic changes during acute myocardial ischemia in the isolated perfused porcine heart. Circulation 77: 1125–1138, 19883359590
37. Goyal A, Spertus JA, Gosch K, Venkitachalam L, Jones PG, Van den Berghe G, Kosiborod M: Serum potassium levels and mortality in acute myocardial infarction. JAMA 307: 157–164, 201222235086
38. Grodzinsky A, Goyal A, Gosch K, McCullough PA, Fonarow GC, Mebazaa A, Masoudi FA, Spertus JA, Palmer BF, Kosiborod M: Prevalence and prognosis of hyperkalemia in patients with acute myocardial Infarction. Am J Med 129: 858–865, 201627060233
39. Krogager ML, Eggers-Kaas L, Aasbjerg K, Mortensen RN, Køber L, Gislason G, Torp-Pedersen C, Søgaard P: Short-term mortality risk of serum potassium levels in acute heart failure following myocardial infarction. Eur Heart J Cardiovasc Pharmacother 1: 245–251, 201527418967
40. Iseki K, Uehara H, Nishime K, Tokuyama K, Yoshihara K, Kinjo K, Shiohira Y, Fukiyama K: Impact of the initial levels of laboratory variables on survival in chronic dialysis patients. Am J Kidney Dis 28: 541–548, 19968840944
41. Kovesdy CP, Regidor DL, Mehrotra R, Jing J, McAllister CJ, Greenland S, Kopple JD, Kalantar-Zadeh K: Serum and dialysate potassium concentrations and survival in hemodialysis patients. Clin J Am Soc Nephrol 2: 999–1007, 200717702709
42. Yusuf AA, Hu Y, Singh B, Menoyo JA, Wetmore JB: Serum potassium levels and mortality in hemodialysis patients: A Retrospective Cohort study. Am J Nephrol 44: 179–186, 201627592170
43. Torlén K, Kalantar-Zadeh K, Molnar MZ, Vashistha T, Mehrotra R: Serum potassium and cause-specific mortality in a large peritoneal dialysis cohort. Clin J Am Soc Nephrol 7: 1272–1284, 201222626960
44. Genovesi S, Valsecchi MG, Rossi E, Pogliani D, Acquistapace I, De Cristofaro V, Stella A, Vincenti A: Sudden death and associated factors in a historical cohort of chronic haemodialysis patients. Nephrol Dial Transplant 24: 2529–2536, 200919293137
45. Brunelli SM, Du Mond C, Oestreicher N, Rakov V, Spiegel DM: Serum potassium and short-term clinical outcomes among hemodialysis patients: Impact of the long interdialytic interval. Am J Kidney Dis 70: 21–29, 201728111027
46. Nakhoul GN, Huang H, Arrigain S, Jolly SE, Schold JD, Nally JV Jr ., Navaneethan SD: Serum potassium, end-stage renal disease and mortality in chronic kidney disease. Am J Nephrol 41: 456–463, 201526228532
47. Korgaonkar S, Tilea A, Gillespie BW, Kiser M, Eisele G, Finkelstein F, Kotanko P, Pitt B, Saran R: Serum potassium and outcomes in CKD: Insights from the RRI-CKD cohort study. Clin J Am Soc Nephrol 5: 762–769, 201020203167
48. Gennari FJ, Segal AS: Hyperkalemia: An adaptive response in chronic renal insufficiency. Kidney Int 62: 1–9, 200212081558
49. Salem MM, Rosa RM, Batlle DC: Extrarenal potassium tolerance in chronic renal failure: Implications for the treatment of acute hyperkalemia. Am J Kidney Dis 18: 421–440, 19911928061
50. Sandle GI, Gaiger E, Tapster S, Goodship TH: Evidence for large intestinal control of potassium homoeostasis in uraemic patients undergoing long-term dialysis. Clin Sci (Lond) 73: 247–252, 19873652631
51. Grimm PR, Sansom SC: BK channels in the kidney. Curr Opin Nephrol Hypertens 16: 430–436, 200717693758
52. Foster ES, Jones WJ, Hayslett JP, Binder HJ: Role of aldosterone and dietary potassium in potassium adaptation in the distal colon of the rat. Gastroenterology 88: 41–46, 19853964771
53. Butterfield I, Warhurst G, Jones MN, Sandle GI: Characterization of apical potassium channels induced in rat distal colon during potassium adaptation. J Physiol 501: 537–547, 19979218214
54. Foley RN, Curtis BM, Randell EW, Parfrey PS: Left ventricular hypertrophy in new hemodialysis patients without symptomatic cardiac disease. Clin J Am Soc Nephrol 5: 805–813, 201020378644
55. Bansal N, Keane M, Delafontaine P, Dries D, Foster E, Gadegbeku CA, Go AS, Hamm LL, Kusek JW, Ojo AO, Rahman M, Tao K, Wright JT, Xie D, Hsu CY; CRIC Study Investigators: A longitudinal study of left ventricular function and structure from CKD to ESRD: The CRIC study. Clin J Am Soc Nephrol 8: 355–362, 201323411431
56. Bansal N, Fan D, Hsu CY, Ordonez JD, Go AS: Incident atrial fibrillation and risk of death in adults with chronic kidney disease. J Am Heart Assoc 3: e001303, 201425332181
57. Soliman EZ, Prineas RJ, Go AS, Xie D, Lash JP, Rahman M, Ojo A, Teal VL, Jensvold NG, Robinson NL, Dries DL, Bazzano L, Mohler ER, Wright JT, Feldman HI; Chronic Renal Insufficiency Cohort (CRIC) Study Group: Chronic kidney disease and prevalent atrial fibrillation: The Chronic Renal Insufficiency Cohort (CRIC). Am Heart J 159: 1102–1107, 201020569726
58. Drawz PE, Babineau DC, Brecklin C, He J, Kallem RR, Soliman EZ, Xie D, Appleby D, Anderson AH, Rahman M; CRIC Study Investigators: Heart rate variability is a predictor of mortality in chronic kidney disease: A report from the CRIC Study. Am J Nephrol 38: 517–528, 201324356377
59. Harnett JD, Foley RN, Kent GM, Barre PE, Murray D, Parfrey PS: Congestive heart failure in dialysis patients: Prevalence, incidence, prognosis and risk factors. Kidney Int 47: 884–890, 19957752588
60. Rizk DV, Gutierrez O, Levitan EB, McClellan WM, Safford M, Soliman EZ, Warnock DG, Muntner P: Prevalence and prognosis of unrecognized myocardial infarctions in chronic kidney disease. Nephrol Dial Transplant 27: 3482–3488, 201222167594
61. Lorincz I, Mátyus J, Zilahi Z, Kun C, Karányi Z, Kakuk G: QT dispersion in patients with end-stage renal failure and during hemodialysis. J Am Soc Nephrol 10: 1297–1302, 199910361868
62. Sise ME, Courtwright AM, Channick RN: Pulmonary hypertension in patients with chronic and end-stage kidney disease. Kidney Int 84: 682–692, 201323739239
63. Kim SC, Chang HJ, Kim MG, Jo SK, Cho WY, Kim HK: Relationship between pulmonary hypertension, peripheral vascular calcification, and major cardiovascular events in dialysis patients. Kidney Res Clin Pract 34: 28–34, 201526484016
64. Fenton F, Smally AJ, Laut J: Hyperkalemia and digoxin toxicity in a patient with kidney failure. Ann Emerg Med 28: 440–441, 19968839532
65. Turgutalp K, Bardak S, Helvacı I, İşgüzar G, Payas E, Demir S, Kıykım A: Community-acquired hyperkalemia in elderly patients: Risk factors and clinical outcomes. Ren Fail 38: 1405–1412, 201627494301
66. Loutradis C, Tolika P, Skodra A, Avdelidou A, Sarafidis PA: Prevalence of hyperkalemia in diabetic and non-diabetic patients with chronic kidney disease: A Nested Case-Control study. Am J Nephrol 42: 351–360, 201526599956
67. Agarwal R, Sinha AD, Pappas MK, Abraham TN, Tegegne GG: Hypertension in hemodialysis patients treated with atenolol or lisinopril: A randomized controlled trial. Nephrol Dial Transplant 29: 672–681, 201424398888
68. Pitt B, Bakris G, Ruilope LM, DiCarlo L, Mukherjee R; EPHESUS Investigators: Serum potassium and clinical outcomes in the Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS). Circulation 118: 1643–1650, 200818824643
69. Pitt B, Remme W, Zannad F, Neaton J, Martinez F, Roniker B, Bittman R, Hurley S, Kleiman J, Gatlin M; Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study Investigators: Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction. N Engl J Med 348: 1309–1321, 200312668699
70. Pitt B, Zannad F, Remme WJ, Cody R, Castaigne A, Perez A, Palensky J, Wittes J; Randomized Aldactone Evaluation Study Investigators: The effect of spironolactone on morbidity and mortality in patients with severe heart failure. N Engl J Med 341: 709–717, 199910471456
71. Rossignol P, Dobre D, McMurray JJ, Swedberg K, Krum H, van Veldhuisen DJ, Shi H, Messig M, Vincent J, Girerd N, Bakris G, Pitt B, Zannad F: Incidence, determinants, and prognostic significance of hyperkalemia and worsening renal function in patients with heart failure receiving the mineralocorticoid receptor antagonist eplerenone or placebo in addition to optimal medical therapy: Results from the Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure (EMPHASIS-HF). Circ Heart Fail 7: 51–58, 201424297687
72. Jain N, Kotla S, Little BB, Weideman RA, Brilakis ES, Reilly RF, Banerjee S: Predictors of hyperkalemia and death in patients with cardiac and renal disease. Am J Cardiol 109: 1510–1513, 201222342847
73. Tseng WC, Liu JS, Hung SC, Kuo KL, Chen YH, Tarng DC, Hsu CC: Effect of spironolactone on the risks of mortality and hospitalization for heart failure in pre-dialysis advanced chronic kidney disease: A nationwide population-based study. Int J Cardiol 238: 72–78, 201728363684
74. Muto S, Sebata K, Watanabe H, Shoji F, Yamamoto Y, Ohashi M, Yamada T, Matsumoto H, Mukouyama T, Yonekura T, Namiki S, Kusano E: Effect of oral glucose administration on serum potassium concentration in hemodialysis patients. Am J Kidney Dis 46: 697–705, 200516183425
75. Sica DA: Diuretic use in renal disease. Nat Rev Nephrol 8: 100–109, 201122183505
76. Lepage L, Dufour AC, Doiron J, Handfield K, Desforges K, Bell R, Vallée M, Savoie M, Perreault S, Laurin LP, Pichette V, Lafrance JP: Randomized clinical trial of sodium polystyrene sulfonate for the treatment of mild hyperkalemia in CKD. Clin J Am Soc Nephrol 10: 2136–2142, 201526576619
77. Weir MR, Bakris GL, Bushinsky DA, Mayo MR, Garza D, Stasiv Y, Wittes J, Christ-Schmidt H, Berman L, Pitt B; OPAL-HK Investigators: Patiromer in patients with kidney disease and hyperkalemia receiving RAAS inhibitors. N Engl J Med 372: 211–221, 201525415805
78. Bakris GL, Pitt B, Weir MR, Freeman MW, Mayo MR, Garza D, Stasiv Y, Zawadzki R, Berman L, Bushinsky DA; AMETHYST-DN Investigators: Effect of patiromer on serum potassium level in patients with hyperkalemia and diabetic kidney disease: The AMETHYST-DN randomized clinical trial. JAMA 314: 151–161, 201526172895
79. Packham DK, Rasmussen HS, Lavin PT, El-Shahawy MA, Roger SD, Block G, Qunibi W, Pergola P, Singh B: Sodium zirconium cyclosilicate in hyperkalemia. N Engl J Med 372: 222–231, 201525415807
80. Kosiborod M, Rasmussen HS, Lavin P, Qunibi WY, Spinowitz B, Packham D, Roger SD, Yang A, Lerma E, Singh B: Effect of sodium zirconium cyclosilicate on potassium lowering for 28 days among outpatients with hyperkalemia: The HARMONIZE randomized clinical trial. JAMA 312: 2223–2233, 201425402495
81. Bushinsky DA, Williams GH, Pitt B, Weir MR, Freeman MW, Garza D, Stasiv Y, Li E, Berman L, Bakris GL: Patiromer induces rapid and sustained potassium lowering in patients with chronic kidney disease and hyperkalemia. Kidney Int 88: 1427–1433, 201526376130
82. DeFronzo RA: Hyperkalemia and hyporeninemic hypoaldosteronism. Kidney Int 17: 118–134, 19806990088
83. Kamel KS, Ethier JH, Quaggin S, Levin A, Albert S, Carlisle EJ, Halperin ML: Studies to determine the basis for hyperkalemia in recipients of a renal transplant who are treated with cyclosporine. J Am Soc Nephrol 2: 1279–1284, 19921627752
84. Dobbin SJH, Petrie JR, Lean MEJ, McKay GA: Fludrocortisone therapy for persistent hyperkalaemia. Diabet Med 34: 1005–1008, 201728375568
85. Sivakumar V, Sriramnaveen P, Krishna C, Manjusha Y, Reddy YS, Sridhar N, Subramanian S: Role of fludrocortisone in the management of tacrolimus-induced hyperkalemia in a renal transplant recipient. Saudi J Kidney Dis Transpl 25: 149–151, 201424434399
86. Brown G: Fludrocortisone for heparin-induced hyperkalemia. Can J Hosp Pharm 64: 463–464, 201122479104
87. Kaisar MO, Wiggins KJ, Sturtevant JM, Hawley CM, Campbell SB, Isbel NM, Mudge DW, Bofinger A, Petrie JJ, Johnson DW: A randomized controlled trial of fludrocortisone for the treatment of hyperkalemia in hemodialysis patients. Am J Kidney Dis 47: 809–814, 200616632019
88. Kim DM, Chung JH, Yoon SH, Kim HL: Effect of fludrocortisone acetate on reducing serum potassium levels in patients with end-stage renal disease undergoing haemodialysis. Nephrol Dial Transplant 22: 3273–3276, 200717616536
89. Jabbar AA, Wase A: Worsening wenckebach after calcium gluconate injection: Not uncommon but frequently missed diagnosis. Am J Emerg Med 31(5): 893.e5–893.e6, 2013
90. Watanabe S, Shioda T, Kobayashi K, Ishizaki S, Ito F, Fujibayashi M, Tanaka M: Calcinosis cutis confined to the dermis after intravenous administration of a calcium preparation: A case report and review of the Japanese literature. Case Rep Dermatol 6: 85–90, 201424761140
91. Moss J, Syrengelas A, Antaya R, Lazova R: Calcinosis cutis: A complication of intravenous administration of calcium glucanate. J Cutan Pathol 33[Suppl 2]: 60–62, 200616972958
92. Conte G, Dal Canton A, Imperatore P, De Nicola L, Gigliotti G, Pisanti N, Memoli B, Fuiano G, Esposito C, Andreucci VE: Acute increase in plasma osmolality as a cause of hyperkalemia in patients with renal failure. Kidney Int 38: 301–307, 19902402122
93. Chang KY, Lee IH, Kim GJ, Cho K, Park HS, Kim HW: Plasma exchange successfully treats central pontine myelinolysis after acute hypernatremia from intravenous sodium bicarbonate therapy. BMC Nephrol 15: 56, 201424708786
94. Cooper DJ, Walley KR, Wiggs BR, Russell JA: Bicarbonate does not improve hemodynamics in critically ill patients who have lactic acidosis. A prospective, controlled clinical study. Ann Intern Med 112: 492–498, 19902156475
95. Fox GN: Hypocalcemia complicating bicarbonate therapy for salicylate poisoning. West J Med 141: 108–109, 19846089440
96. Schiffl H: Sodium bicarbonate infusion for prevention of acute kidney injury: No evidence for superior benefit, but risk for harm? Int Urol Nephrol 47: 321–326, 201525164590
97. Chou YH, Wang HY, Hsieh MS: Colonic necrosis in a young patient receiving oral kayexalate in sorbitol: Case report and literature review. Kaohsiung J Med Sci 27: 155–158, 201121463839
98. McGowan CE, Saha S, Chu G, Resnick MB, Moss SF: Intestinal necrosis due to sodium polystyrene sulfonate (Kayexalate) in sorbitol. South Med J 102: 493–497, 200919373153
99. Saginur M, Thiesen A, Lacson A, Bigam D, Yap J: Small intestinal transplant mucosal necrosis associated with enteral sodium polystyrene sulfonate administration. Am J Transplant 12: 3152–3154, 201222900907
100. Bushinsky DA, Spiegel DM, Gross C, Benton WW, Fogli J, Hill Gallant KM, Du Mond C, Block GA, Weir MR, Pitt B: Effect of patiromer on urinary ion excretion in healthy adults. Clin J Am Soc Nephrol 11: 1769–1776, 201627679518
101. Wiegand CF, Davin TD, Raij L, Kjellstrand CM: Severe hypokalemia induced by hemodialysis. Arch Intern Med 141: 167–170, 19817458512
102. Jadoul M, Thumma J, Fuller DS, Tentori F, Li Y, Morgenstern H, Mendelssohn D, Tomo T, Ethier J, Port F, Robinson BM: Modifiable practices associated with sudden death among hemodialysis patients in the Dialysis Outcomes and Practice Patterns study. Clin J Am Soc Nephrol 7: 765–774, 201222403271
103. Morrison G, Michelson EL, Brown S, Morganroth J: Mechanism and prevention of cardiac arrhythmias in chronic hemodialysis patients. Kidney Int 17: 811–819, 19806447822
104. Rossignol P, Legrand M, Kosiborod M, Hollenberg SM, Peacock WF, Emmett M, Epstein M, Kovesdy CP, Yilmaz MB, Stough WG, Gayat E, Pitt B, Zannad F, Mebazaa A: Emergency management of severe hyperkalemia: Guideline for best practice and opportunities for the future. Pharmacol Res 113[Pt A]: 585–591, 201627693804

hyperkalemia; chronic kidney disease; electrolytes

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