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Patterns, causes, and effects of hyperkalemia

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Introduction

Hyperkalemia is a relatively common transient acute electrolyte abnormality. Due to its propensity to cause malignant cardiac arrhythmias, severe hyperkalemia is regarded as a medical emergency that requires immediate therapeutic responses. Recent advances in hyperkalemia research have resulted in better understanding of the risk factors underlying the development of hyperkalemia, and of the outcomes associated with elevations in serum potassium, with the ultimate goal to design optimal interventional strategies aimed at preventing and treating life-threatening hyperkalemia. In this article we examine the incidence and the predisposing factors of hyperkalemia, and review the clinical outcomes associated with various elevated levels of serum potassium.

Incidence and risk factors of hyperkalemia

There are no general population-based studies examining the incidence or prevalence of hyperkalemia, which is regarded as a relatively rare and transient condition in patients without certain risk factors (see below). A Canadian study examining 129,076 unselected elderly patients in the province of Ontario reported hyperkalemia (diagnosed by ICD-10 codes) in 2.6% of emergency room visits and 3.5% of hospital admissions (see Table 1).¹ The major limitation of this study was its reliance on diagnostic codes, which are known to have a low sensitivity and thus miss many cases for most studied conditions. Indeed, in the Canadian study the specificity of the ICD-10 code for hyperkalemia was very high (99%) but its sensitivity was very low (14.6%), thus indicating that the true frequency of hyperkalemia may be significantly higher.

Nevertheless, in a large study examining hospitalized veterans treated in the United States, and using actual serum potassium values to examine the frequency of hyperkalemia, the incidence of elevated serum potassium levels was similarly low at 3.2% (Table 1).² While using serum potassium levels allows for better certainty in detecting hyperkalemia in administrative data sets, its numeric frequency will be affected by the serum level used to define hyperkalemia. In the above-referenced study a serum potassium of > 5.5 mEq/L was used for such purpose; using a lower level (eg, > 5.0 mEq/L) would have resulted in higher frequency, while using higher levels (eg, > 6.0 mEq/L) would have the opposite effect.

Hyperkalemia occurs much more frequently in populations that are predisposed to its development by virtue of certain comorbid conditions or other risk factors. The most important risk factor for hyperkalemia is decreased kidney function. Virtually all studies examining patients with kidney disease have reported significantly higher frequencies of hyperkalemia compared to the general population, and the frequency increases linearly with the increasing severity of chronic kidney disease (CKD). In a moderately large prospective cohort of patients with CKD, a lower measured glomerular filtration rate (GFR) was associated with a substantial increase in the frequency of hyperkalemia: 2% in patients whose GFR was 60–90 mL/min vs 42% in patients whose GFR was

< 20 mL/min.³ In a small study examining 238 patients with a mean estimated GFR (eGFR) of 14.6 mL/min/1.73m² who were enrolled in an advanced CKD clinic, the incidence of serum potassium levels > 5.0 and > 5.5 mEq/L was 54% and 40%, respectively.⁴ Another study of 1,277 male United States veterans with a mean eGFR of 37 mL/min/1.73m² found serum potassium levels of > 5.3 mEq/L in 7.7% of patients during a baseline evaluation.⁵

Underscoring the transitional nature of hyperkalemia and the difficulty of characterizing the risks associated with it based on single measurements in time, the same study reported a much higher incidence of 42% when examining all serum potassium measured over a median of 2.7 years.⁵ Not surprisingly, patients on renal replacement therapy—especially those on chronic, three-times-weekly hemodialysis (HD)—experience the highest incidence of hyperkalemia. In a study examining 74,219 HD patients, the frequency of a 3-month averaged serum potassium level of > 5.5 mEq/L was 12.5%.⁶ While patients with kidney transplants may have better kidney function compared to CKD or HD patients, they are also predisposed to hyperkalemia, with a reported incidence of elevated serum potassium levels in 44–73% of patients treated with calcineurin inhibitors.⁷

Other risk factors of hyperkalemia

Besides decreased kidney function, there are numerous other conditions that predispose to the development of hyperkalemia. Often these conditions cluster along with CKD or acute kidney injury, explaining the much higher incidence of hyperkalemia in some of the reports examining select patient populations. The main conditions predicting hyperkalemia in cohort studies (along with low GFR) were diabetes mellitus, higher protein intake, metabolic acidosis, and white race.^5,6 The highest risk of hyperkalemia was observed in populations where there was a clustering of multiple risk factors.^8,9 A large observational cohort of 245,808 hospitalized United States veterans identified CKD and the use of renin-angiotensin-aldosterone system inhibitors (RAASi) as the main risk factors of hyperkalemia: the respective adjusted incidence rate of hyperkalemia in CKD patients with and without RAASi use was 8.22 and 1.77 per 100 patient-months, respectively.² RAASi therapy has been associated with hyperkalemia even in HD patients,¹⁰ possibly because of the effect of RAASi on gastrointestinal potassium secretion.

RAASi use has also been shown to play a major role in the development of hyperkalemia in the numerous randomized controlled clinical trials examining these agents for the treatment of blood pressure or various cardiovascular diseases.¹¹ Since these trials have been conducted in patients with various other risk factors which themselves predispose to hyperkalemia (such as the presence of CKD), and since the definition of hyperkalemia has varied from trial to trial, it is not surprising that the frequency of hyperkalemia varies substantially in the different trials. Illustrating this, the frequency of hyperkalemia has ranged from 1.9% to 38.4% in trials conducted among patients with CKD, with the highest incidence reported in patients who received dual RAASi therapy.^12–21 Summarizing the lessons learned about hyperkalemia from clinical trials are two meta-analyses of trials examining single vs dual RAASi therapy. The first meta-analysis identified 33 randomized controlled trials with 68,405 patients, and reported that dual RAASi therapy was associated with a 55% higher relative risk of hyperkalemia.²² The second meta-analysis focused on studies of patients with CKD and included 59 trials with 4,975 patients. In this second meta-analysis, dual RAASi therapy resulted in both higher serum potassium concentrations and a 3.4% higher absolute rate of hyperkalemia.²³ A noteworthy observation is that the frequency of hyperkalemia tends to be lower in clinical trials compared to the frequency that is reported in observational studies examining data from general clinical care. This is not surprising, as clinical trials typically recruit select patients who are more motivated and thus more likely to follow instructions, such as dietary restrictions used to control hyperkalemia.^24,25

Outcomes associated with hyperkalemia

Due to health care providers’ heightened awareness of the potential for malignant arrhythmias, it is not surprising that hyperkalemia has been linked to a high number of emergency room visits and hospitalizations: in 2011 there were 66,989 emergency room visits and 33,999 hospital admissions in the United States by patients with a primary diagnosis of hyperkalemia.²⁶ More importantly, abnormal serum potassium levels have also been associated with higher mortality in any studied patient population, including patients both with and without CKD. In a large study of hospitalized patients with acute myocardial infarction, serum potassium displayed a U-shaped association with mortality; the higher mortality associated with elevated serum potassium was apparent even for levels above 4.0 mEq/L.²⁷ This study also found an association of serum potassium with ventricular fibrillation, with higher risks noted for serum potassium levels > 5.0 mEq/L.²⁷ A large observational study of 245,808 hospitalized United States veterans also reported higher risk of 1-day mortality associated with serum potassium levels > 5.5 mEq/L,² supporting speculations that hyperkalemia may increase the risk of mortality by engendering malignant arrhythmias.^28,29

The association between serum potassium levels and all-cause mortality was also U-shaped in numerous studies of patients with non-dialysis dependent CKD^5,30,31 (see Figure 1), chronic HD,^6,32,33 and peritoneal dialysis.³⁴ In most studies examining patients with CKD or on renal replacement therapy, the serum potassium levels associated with the lowest mortality were approximately 4.0–5.0 mEq/L.^5,6,30 It is unclear why the ideal potassium level was slightly higher in these studies compared to the above-mentioned study in non-CKD patients.²⁷ One could speculate that patients with decreased kidney function may develop a certain adaptation to hyperkalemia and may be able to withstand relatively higher serum potassium levels compared to patients in whom hyperkalemia is a much less common event. This hypothesis is indirectly supported by the findings of the above-mentioned large VA study.² This study also compared the relative risk of 1-day mortality associated with hyperkalemia in patients with and without CKD and found that the risk associated with similar levels of hyperkalemia was substantially higher in patients with normal kidney function and decreased proportionally with increasingly severe CKD: the respective odds ratios for serum potassium > 6.0 vs < 5.5 mEq/L in those with normal eGFR and in those with CKD stages 3, 4, and 5 were 31.64, 19.52, 11.56, and 8.02.

Multivariable adjusted log-hazard ratios and 95% confidence intervals of all-cause mortality associated with serum potassium levels in 1,277 male US veterans with a mean eGFR of 37 mL/min/1.73m.2 Adapted from Hayes J, et al. Nephron Clin Pract. 2012; 120: c8–16.5

Of the above patient populations in whom hyperkalemia is associated with adverse outcomes, including the potential for malignant arrhythmias and mortality, patients on three-times-a-week maintenance hemodialysis represent an especially vulnerable group. Because these patients often have no residual kidney function, dietary intake and cellular distribution of potassium can result in especially rapid rises in serum potassium. Mass potassium balance in these patients is achieved by intermittent rapid removal via hemodialysis, which typically results in a very rapid decline in serum potassium levels and thus further increases the risk for development of arrhythmias. To make matters worse, the changes in serum potassium are frequently accompanied by other arrhythmogenic factors such as hypocalcemia, hypomagnesemia, and metabolic alkalosis;^35,36 and these factors occur on a background of pre-existing cardiovascular disease and left ventricular hypertrophy in a large proportion of patients,³⁷ creating a hotbed for malignant arrhythmias.^38,39 Although studies have shown that pre-dialysis hyperkalemia,⁶ hypocalcemia,⁴⁰ hypomagnesemia,⁴¹ and low potassium dialysates^42,43 are individually associated with higher risk of mortality or sudden cardiac death, there is a conspicuous lack of detailed, large observational studies examining the combined effects of these abnormalities on arrhythmogenicity in HD patients.

Conclusions

Hyperkalemia is a common and important acute electrolyte abnormality that is detected most often in patients with CKD, especially if they are also exposed to exacerbating factors such as diabetes mellitus and treatment with RAASi. Hyperkalemia is associated with higher mortality and with higher incidence of malignant arrhythmias such as ventricular fibrillation. The serum potassium levels that are associated with the lowest risk for adverse clinical outcomes are likely around 4 mEq/L, although this may vary from study to study and may be higher in patients who are exposed to hyperkalemia more frequently, such as those with CKD or end-stage renal disease. There is a need for clinical trials to examine the impact on clinical outcomes of the therapeutic lowering of serum potassium vis-à-vis the prevention of hyperkalemia altogether in high-risk populations. Such interventions could have multiple benefits, including the prevention of malignant arrhythmias and the more widespread utilization of beneficial treatments such as the use of RAASi. -by Csaba P. Kovesdy, MD

Disclosure: Dr. Kovesdy served as a consultant to Relypsa, Inc., sanofi aventis U.S. LLC., and ZS Pharma Inc., and has received research support from AbbVie, Amgen, Janssen Pharmaceutical Companies of Johnson & Johnson, OPKO Health, Inc., and Shire. He is the recipient of honorarium from Abbott Nutrition, Relypsa, Inc., sanofi aventis U.S. LLC., and ZS Pharma Inc.

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