Kidney and Cardiac Outcomes in Hyperkalemia

Best practice guidelines outline the emergency management of hyperkalemia. However, according to Andrew Mclean, MCChB, and colleagues at the University of Aberdeen, United Kingdom, the “true population burden remains unclear.” Previous studies have focused on selected subsets of patients or have not completely captured the population and laboratory tests, limiting the generalizability for health policy and planning.

In addition, thresholds for defining hyperkalemia are inconsistent and are not included in the Kidney Disease: Improving Global Outcomes guidelines. Guidelines from the UK Renal Association (2020) and the European Resuscitation Council define hyperkalemia as serum potassium level ≥5.5 mmol/L (mild), ≥6.0 mmol/L (moderate), and ≥6.5 mmol/L (severe). Current guidelines define severe hyperkalemia as a clinical emergency.

Hyperkalemia is associated with both chronic kidney disease (CKD) and acute kidney disease (AKD). Acute kidney injury (AKI) was once considered an urgent transient problem with few long-term effects. However, AKI is now known to be associated with serious long-term poor health within the umbrella of AKD. An episode of hyperkalemia may worsen kidney and cardiac outcomes independent of AKI and CKD, representing an additional risk stratification tool for the evaluation of kidney reserve, need for monitoring, and long-term decision making.

Dr. McLean et al conducted a long-term population study designed to assess the full population burdens of hyperkalemia, including how often it occurs, where it occurs, and the long-term implications for mortality and cardiac and kidney  health. The researchers hypothesized that, controlling for AKI and CKD, mild episodes of hyperkalemia may be a complementary marker of diminished kidney or physiological reserve even when standard metrics of kidney function are otherwise normal. Results of the study were reported in the American Journal of Kidney Diseases [2022;79(4):527-538].

The study was conducted among the 468,594 adult residents (2012-2014) in Grampian, United Kingdom. Of those, 302,630 had at least one blood test and were followed until 2019. Hyperkalemia was defined as serum potassium ≥5.5 mmol/L. Prior to measurement of potassium, adjustments for comorbidities, demographics, measures of acute and chronic kidney function, and medications prescribed were made. The exposure of interest was the first instance of hyperkalemia for Grampian residents within each year of interest (2012, 2013, and 2014).

The primary outcome of interest was all-cause mortality followed up for at least 5 years to the end of 2019. Secondary outcomes included cardiac events (fatal or nonfatal myocardial infarction, heart failure, or stroke) and kidney failure.

Over the 3-year study period, 13,482 people experienced a first hyperkalemia event (threshold ≥5.5 mmol/L). There were 59,571 first hyperkalemia events at ≥5.0 mmol/L, 4491 at ≥6.0 mmol/L, and 2016 at ≥6.5 mmol/L. Those definitions corresponded to respective annual incidence rates per 100 person-years of 0.96 (95% CI, 0.94-0.98) at ≥5.5 mmol/L versus 4.24 (95% CI, 4.20-4.27) at ≥5.0 mmol/L, 0.32 (95% CI, 0.31-0.33) at ≥6.0 mmol/L, and 0.14 (95% CI, 0.14-0.15) at ≥6.5 mmol/L.

Expressing hyperkalemia as a proportion of the 302,630 people with blood tests, hyperkalemia represented 4099 of 182,135 (2.3%), 4044 of 188,539 (2.1%), and 3769 of 193,407 (1.9%) of those with at least one blood test in 2012, 2013, and 2014, respectively.

Most of those with hyperkalemia presented in the community and did not require hospitalization. The proportion admitted to the hospital increased when restricted to only the most severe episodes of hyperkalemia (≥6.5 mmol/L). More than half of the group with hyperkalemia had a baseline estimated glomerular filtration rate (eGFR) of ≥60 mL/min/1.73 m² and fewer than 20% had concurrent AKI, even among those with severe hyperkalemia.

Compared with people without hyperkalemia, in unadjusted analysis those whose blood tests did indicate hyperkalemia were 20 times more likely to have had concurrent AKI or a baseline eGFR <30 mL/min/1.73 m². Those with hyperkalemia were also more likely to have diabetes, heart failure, and peripheral arterial disease. Prior use of renin angiotensin aldosterone system blockers, aldosterone antagonists, and trimethoprim-containing antibiotics was greater in those with hyperkalemia. Use of thiazide diuretics was less in those with hyperkalemia.

In analysis of the primary outcome of all-cause mortality, there was an association between even a mild threshold for hyperkalemia (potassium ≥5.5 mmol/L) and substantial increased long-term mortality; excess mortality was less pronounced for hyperkalemia threshold 5.0 mmol/L.

Whereas AKI was associated with substantial short-term mortality, hyperkalemia was associated with greater long-term mortality. Following exclusion of outcomes before 90 days, a persistent long-term excess risk independent of AKI was evident up to 5 years, a finding that remained even after restricting the cohort to people who remained in the community. Regardless of AKI status, there was an excess of both cardiac and noncardiac outcomes for those with hyperkalemia.

Following adjustment for age and sex, and then all listed covariates, and controlling for baseline eGFR, outcomes for all models demonstrated an association between hyperkalemia and long-term excess mortality and both cardiac events and noncardiac death. Excess event rates after hyperkalemia also extended to the kidney failure outcome. There was a particular association between hyperkalemia and an increased relative hazard of future kidney failure among those with otherwise preserved baseline eGFR (the researchers highlighted the wide confidence intervals due to the small number of events among those without hyperkalemia [hazard ratio, 16.99; 95% CI, 9.29-31.07]).

In citing limitations to the study findings, the researchers noted the observational design that limited evaluation of causal relationship between hyperkalemia and adverse outcomes.

In conclusion, the authors said, “This analysis reports a greater incidence of hyperkalemia than has been possible to determine in previous studies. The analysis also demonstrates poorer long-term health outcomes after hyperkalemia, especially kidney outcomes, that are complementary to and not explained by existing metrics of acute and chronic kidney excretory function. Clinicians should note that even minor episodes of hyperkalemia are prognostically relevant, important to communicate, and worthy of consideration in the planning of ongoing care, monitoring, and expectations for future health.”

Takeaway Points

1. Researchers reported results of a population-based cohort study of the incidence of hyperkalemia and its association with mortality and long-term cardiac and kidney health.
2. There was a substantial burden associated with hyperkalemia in the general population.
3. There were associations between hyperkalemia and poorer long-term health, particularly kidney outcomes, that were independent of other established risk factors.