Rationale and Design of a Randomized Placebo-Controlled Clinical Trial Assessing the Renoprotective Effects of Potassium Supplementation in Chronic Kidney Disease

Abstract

Background/Aims: Dietary potassium (K⁺) has beneficial effects on blood pressure and cardiovascular (CV) outcomes. Recently, several epidemiological studies have revealed an association between urinary K⁺ excretion (as proxy for dietary intake) and better renal outcomes in subjects with chronic kidney disease (CKD). To address causality, we designed the “K⁺ in CKD” study. Methods: The K⁺ in CKD study is a multicenter, randomized, double blind, placebo-controlled clinical trial aiming to include 399 patients with hypertension, CKD stage 3b or 4 (estimated glomerular filtration rate [eGFR] 15–44 mL/min/1.73 m²), and an average eGFR decline > 2 mL/min/1.73 m²/year. As safety measure, all included subjects will start with a 2-week open-label phase of 40 mmol potassium chloride daily. Patients who do not subsequently develop hyperkalemia (defined as serum K⁺ >5.5 mmol/L) will be randomized to receive potassium chloride, potassium citrate (both K⁺ 40 mmol/day), or placebo for 2 years. The primary end point is the difference in eGFR after 2 years of treatment. Secondary end points include other renal outcomes (> 30% decrease in eGFR, doubling of serum creatinine, end-stage renal disease, albuminuria), ambulatory blood pressure, CV events, all-cause mortality, and incidence of hyperkalemia. Several measurements will be performed to analyze the effects of potassium supplementation, including body composition monitoring, pulse wave velocity, plasma renin and aldosterone concentrations, urinary ammonium, and intracellular K⁺ concentrations. Conclusion: The K⁺ in CKD study will demonstrate if K⁺ sup­plementation has a renoprotective effect in progressive CKD, and whether alkali therapy has additional beneficial effects.

Potassium homeostasis and management of dyskalemia in kidney diseases: conclusions from a Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference

“…102 Whether potassium supplementation results in renoprotection is also currently being examined in the "K þ in CKD" study. 72 Direct evidence in support of the current recommendation for restricting dietary potassium in patients with CKD was lacking; however, we did not find evidence that increased potassium intake, or liberalization of potassium restrictions, in patients with advanced CKD is safe. While we acknowledge that dietary potassium restriction is a valid strategy to treat acute hyperkalemia, we hypothesize that potassium restriction as a general strategy to prevent hyperkalemia in persons with CKD may deprive patients of the beneficial effects associated with potassium-rich diets.…”

“…This practice is widespread, and studies evaluating adherence to dietary recommendations in patients undergoing hemodialysis consistently report low potassium intake with corresponding low intake of fruits, vegetables, and other plant-derived compounds (e.g., fiber, vitamin C, and carotenoids). 67,68 However, observational studies in persons with CKD or ESKD report weak associations between dietary potassium intake and potassium concentration, [69][70][71][72] challenging the belief that the amount of potassium consumed strongly influences potassium concentration.…”

Effects of Potassium or Sodium Supplementation on Mineral Homeostasis: A Controlled Dietary Intervention Study

“…We postulate that bone may serve as a buffer for an increase in dietary potassium intake, to which osteocytes may respond by reducing FGF23 production. Future studies should address the impact of dietary potassium supplementation on both FGF23 and plasma phosphate in osteocytes, animal models, and in specific patient groups such as CKD patients ( 40 ). CKD patients are at risk for mineral bone disorders, which is linked to the derangements of 1,25[OH]-vitamin D 3 , PTH, and FGF23 ( 41 ).…”

Dyskalemia in Chronic Kidney Disease: How Concerned Should We Be?

“…While we often focus on hyperkalemia in CKD, other studies indicate that low potassium intake is associated with adverse outcomes [25][26][27]. To address this question, a multicenter randomized placebo-controlled trial is being conducted by Gritte et al [28], in which 399 CKD G3b or 4 patients are being enrolled in a 1: 1: 1 study design to receive placebo, potassium chloride, or potassium citrate. The results of this study will address, for the first time in a randomized controlled trial, the effect of potassium suppleThere were several salient differences between these 2 studies.…”

“…Analyzing these articles in light of the Bradford Hill criteria, it is notable that hyperkalemia was associated mentation (with or without alkali) on renal and cardiovascular outcomes including all-cause mortality (NCT03253172) [28].…”