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Serum Potassium Levels And Mortality Risk in CKD

Serum Potassium Levels And Mortality Risk in CKD

Overview

The study delved into the impact of serum potassium levels on the health of elderly individuals with chronic kidney disease (CKD) stage 4-5. Hypokalemia and hyperkalemia were recognized as contributors to kidney function decline and sudden cardiac death. However, limited knowledge exists about the connection between serum potassium levels and mortality or the need for kidney replacement therapy (KRT). The researchers conducted an 8-year prospective observational cohort study on 1,714 patients aged 65 or older from the European Quality (EQUAL) study, starting when their estimated glomerular filtration rate (eGFR) fell below 20 mL/min/1.73 m². 

Serum potassium was measured every 3 to 6 months and grouped into various categories. The primary combined outcome was death before KRT initiation or the start of KRT. Statistical analyses, accounting for variables like age, gender, diabetes, cardiovascular disease, eGFR, and subjective global assessment (SGA), were employed to explore the relationship between different potassium levels and the risk of death or KRT initiation. 

The study population consisted of 66% men, with an average age of 76 years, mean eGFR of 17 mL/min/1.73 m², and mean SGA of 6.0. Over the 8-year period, 24% of participants passed away before starting KRT, and 35% initiated KRT. The analysis revealed adjusted hazard ratios for death or KRT initiation, with the lowest risk observed at a serum potassium level of approximately 4.9 mmol/L. The co-relation between serum potassium and the risk of death or KRT initiation followed a U-shaped pattern.

The study emphasized the importance of maintaining optimal serum potassium levels for patients with CKD stages 4-5. Both excessively high and low levels were associated with elevated risks of adverse outcomes. The findings highlighted a potential threshold around 4.9 mmol/L that seemed to confer the least risk, although the precision of estimations could have been enhanced with more frequent potassium measurements. Overall, the research underscored the significance of managing serum potassium within a specific range to mitigate risks in this patient population.

Introduction

Individuals grappling with chronic kidney disease (CKD) stages 4-5 confront the vulnerability of imbalanced serum potassium levels. These patients encounter a twofold challenge: the potential for hyperkalemia, stemming from compromised urinary potassium elimination and the utilization of renin-angiotensin-aldosterone system (RAAS) inhibitors for cardio-renal protection; and the risk of hypokalemia, attributed to non-potassium-sparing diuretic treatment or malnourishment. Both high and low potassium levels can trigger severe muscle paralysis and, in worst cases, life-threatening cardiac rhythm irregularities. 

The pivotal role of potassium in reinstating the resting membrane potential across cellular boundaries is essential for generating fresh action potentials. This function is crucial for neural and muscular operations within the human body. Furthermore, hypokalemia is linked to a swifter decline in kidney function among CKD patients, often through a condition called hypokalemic nephropathy involving chronic interstitial nephritis and fibrosis. Consequently, disturbances in serum potassium levels might correlate with both progression to kidney failure necessitating kidney replacement therapy (KRT) and heightened mortality risk. 

Understanding the extent of these modifiable risks within the CKD stages 4-5 population and identifying an optimal serum potassium level are paramount. This knowledge holds particular significance for older CKD stages 4-5 patients, who face elevated susceptibility to kidney failure and mortality. Due to factors such as comorbidities and complex medication regimens in the elderly, the interplay between serum potassium and the combined outcome of death or KRT commencement might diverge from that observed in younger counterparts.

Given the constraints of prior investigations in this domain, the present study investigates the correlation between serum potassium levels and the composite endpoint of death or initiation of KRT in older CKD stages 4-5 patients. By delving into this uncharted territory, the research aims to shed light on the intricate relationship between serum potassium and adverse outcomes in a demographic that demands focused attention.

Method

The ongoing European Quality (EQUAL) study focuses on advanced chronic kidney disease (CKD) treatment and is a prospective multi-center cohort investigation. Launched in April 2012 across six European countries—Germany, Italy, Poland, Sweden, the Netherlands, and the United Kingdom—the study targets patients aged ≥65 with CKD stages 4-5 under nephrology clinic care. Inclusion criteria involve the initial drop in estimated glomerular filtration rate (eGFR) to or below 20 mL/min/1.73 m² within the past six months, excluding cases of acute eGFR decline or prior kidney replacement therapy (KRT). 

Patient evaluations occur every 3 to 6 months, adhering to their routine care regimen, encompassing kidney transplantation, mortality, refusal of further involvement, center transfers, or end of the study, culminating in December 2021. All patients provided informed consent, and the study earned approval from local medical ethics committees or corresponding review boards. Data were consistently gathered and documented using a specially designed web-based clinical record form, further standardized to account for varying local laboratory practices. The eGFR was calculated using the CKD-EPI equation. The study aimed to explore the intricate link between serum potassium levels and the composite outcome of death or KRT start in older CKD stages 4-5 patients.

The research encompasses various statistical methods, such as Cox-proportional hazard models and restricted cubic spline analyses. Serum potassium is treated as a time-dependent variable, updated at 3–6-month intervals, and various confounders like age, sex, smoking status, medical history, and more were adjusted for in the analyses. Sensitivity analyses were performed, and potential confounders related to nutritional status were accounted for. The study’s analytical approach adhered to proportionality assumptions and was executed using R version 4.0.3.

In conclusion, the EQUAL study examines the intricate dynamics between serum potassium levels and the combined outcome of death or KRT start among elderly CKD stages 4-5 patients. The study employs robust statistical methods to navigate the complex interplay of variables while maintaining rigorous standards in data collection, analysis, and reporting.

Result

From a total of 1,736 participants in the EQUAL study, we examined 1,714 individuals (99%) with available serum potassium measurements. At baseline, the average age was 76 years with 66% being men. Notably, 42% had diabetes, 47% exhibited cardiovascular disease, and 54% used RAAS inhibitors. The mean eGFR was 17 mL/min/1.73 m², mean SGA was 6.0, and mean serum potassium level was 4.6 mmol/L. The prevalence of serum potassium categories varied: 2% had ≤3.5 mmol/L, 13% >3.5 to ≤4.0 mmol/L, 28% >4.0 to ≤4.5 mmol/L, 33% >4.5 to ≤5.0 mmol/L (reference), 17% >5.0 to ≤5.5 mmol/L, 5% >5.5 to ≤6.0 mmol/L, and 2% >6.0 mmol/L.

Throughout the follow-up period, a total of 6,091 potassium measurements were conducted, averaging 3.6 measurements per participant. Serum potassium distributions remained consistent over time. During follow-up, 7% experienced serum potassium ≤3.5 mmol/L, while 13% and 3% experienced levels >5.5 to ≤6.0 mmol/L and >6.0 mmol/L, respectively. Lower or higher serum potassium levels tended to be less persistent for two or more consecutive visits compared to normal levels.

The median time until death or KRT start was 2.6 years. Over 8 years, 24% (414) experienced death, 1% (15) underwent pre-emptive kidney transplantation, and 34% (580) initiated dialysis. This resulted in an overall crude combined death or KRT start rate of 26.2 per 100 patient-years. Start of KRT was more common than death before KRT initiation. Of the 414 deaths before KRT initiation, 26% were due to cardiovascular disease.

The rates of combined death or KRT start differed among serum potassium categories: 40 per 100 person-years for ≤3.5 mmol/L, 22 per 100 person-years for the reference category, and 59 per 100 person-years for >6.0 mmol/L. Adjusted HRs for serum potassium ≤3.5 mmol/L and >6.0 mmol/L were 1.6 and 2.2, respectively. Comparable associations were observed for separate outcomes such as KRT start, all-cause death, and cardiovascular death before KRT initiation.

A U-shaped relationship was evident between time-dependent serum potassium levels and the combined outcome of death or KRT start over the 8-year follow-up, with the lowest risk observed around 4.9 mmol/L. HRs increased notably below ≤4.5 mmol/L and above >5.4 mmol/L. For instance, patients with 6.5 mmol/L serum potassium had a threefold increased hazard compared to the optimum level of 4.9 mmol/L.

Sensitivity analyses, including a complete case analysis and adjustments for nutritional markers, validated the robustness of the results. Accounting for the relationship between serum potassium category and long-term outcomes contributes to a comprehensive understanding of the health implications for CKD stages 4-5 patients.

Conclusion

This expansive prospective multi-center study encompassed over 1,700 individuals aged ≥65 with CKD stages 4-5 and incident eGFR < 20 mL/min/1.73 m². The investigation unveiled a U-shaped correlation between serum potassium and the combined outcome of death or KRT initiation. Over an 8-year monitoring period, the serum potassium level linked with the least risk of death or KRT onset hovered around 4.9 mmol/L. Contrastingly, serum potassium concentrations below (≤3.5 mmol/L) and above (>6.0 mmol/L) this optimal level were associated with 1.6- and 2.2-fold amplified hazards for death or KRT induction, respectively, following meticulous adjustment for multiple factors.

This study’s significance is magnified by addressing limitations found in prior research. Unlike retrospective registry-based studies that targeted specific groups, this prospective study collected routine serum potassium data, thus minimizing selection bias. Furthermore, the focus solely on incident CKD stages 4-5 subjects fortified the results by avoiding survivor bias and refining the understanding of potassium’s effect at this specific stage.

In addition to renal function, serum potassium concentrations can be influenced by various factors such as medication and dietary habits. The delicate balance between hypokalemia and hyperkalemia’s adverse effects emphasizes the importance of managing potassium levels in CKD patients. Older patients, burdened with comorbidities and polypharmacy, can particularly benefit from this insight, given their heightened vulnerability.

To ascertain the connection between potassium supplementation and CKD advancement, ongoing clinical trials are underway. In conclusion, this study underscores the intricate interplay of serum potassium levels and CKD progression. By identifying an optimal potassium range for older patients with CKD stages 4-5, the study contributes vital information for guiding clinical decisions and improving patient care.

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