Searching for the Risk-Benefit Profile of Higher Potassium Intake in CKD: Primum Non Nocere

Observational studies indicate that higher dietary potassium intake is associated with improved BP control, lower risk of cardiovascular disease, and slower CKD progression.¹ Similarly, randomized controlled trials (RCTs) of potassium supplementation and potassium-based salt substitutes demonstrate consistent reductions in BP and in hypertension-associated adverse outcomes in populations with a low risk of hyperkalemia.² However, the effect of potassium supplementation on clinical outcomes in patients with moderate to advanced CKD is unknown because these patients are typically excluded from such trials due to concerns of hyperkalemia. In fact, the belief that higher potassium intake increases the risk of hyperkalemia in CKD remains poorly investigated.² Alternatively, the risk of adverse outcomes resulting from mild or moderate chronic hyperkalemia in advanced CKD is still a matter of debate, notwithstanding the consistent associations between hyperkalemia and poor outcomes in nondialysis CKD.³ Unmet gaps thus ensue—many guidelines recommendlow-potassium diets (e.g., 2–4 g/d by the Kidney Disease Outcomes Quality Initiative [KDOQI]) without clear evidence from RCTs^2,4,5; concerns of hyperkalemia blunt plausible interventions, such as salt substitutes or potassium supplementation, in CKD.

The kidney has a prime role in regulating potassium homeostasis. Up to 90% of the filtered potassium is reabsorbed through the proximal tubule and ascending loop of Henle; urinary excretion stems mostly from apical potassium channels in the distal nephron, tightly regulated by aldosterone.² As glomerular filtration declines, hyperkalemia ensues, despite the increased fractional potassium excretion by the kidneys and higher colon potassium secretion due to greater aldosterone levels.³ CKD progression also impairs postprandial kaliuresis, a key mechanism to reduce postprandial hyperkalemia.⁵ In fact, postprandial hyperkalemia episodes may increase the risk of adverse events despite normal fasting plasma potassium levels.⁵ Higher mortality associated with hyperkalemia episodes is detected as early as 1 day after the index event among CKD patients.³

On the other hand, potassium inhibits the thiazide-sensitive Na/Cl cotransporter in the distal nephron, increasing sodium excretion.. Observational data support the hypothesis that lower potassium intake is associated with worse kidney outcomes in CKD; however, these studies have at least two key limitations: information and confounding biases. Urinary potassium is, at its best, a limited surrogate for potassium intake.² By itself, potassium intake can be a proxy for a diet rich in plants, a predictor of better outcomes irrespective of dietary potassium in patients with CKD.²

On the safety side, the effect of dietary potassium intake on serum potassium levels in nondialysis CKD is uncertain. In an RCT enrolling 47 patients with CKD in stage 3 or 4, a 0.2-mEq/L difference in serum potassium was achieved in 6 months by a low-potassium diet following KDOQI recommendations.⁶ However, almost half of the patients in the intervention arm used sodium polystyrene (versus 9.5% in the control arm), limiting interpretation. In another two small feasibility studies addressing the acceptability and safety of the potassium-rich Dietary Approaches to Stop Hypertension diet, no effect on serum potassium was detected after 2 and 5 weeks of the intervention in patients with stage 3 CKD.²

This is the ground where the clinical trial by Gritter et al.⁷ lands. The ongoing RCT is a multicenter, three-arm, double-blind, placebo-controlled study testing 40 mmol (1.5 g) of potassium (chloride or citrate) supplements per day in CKD stage 3b or 4. The study is powered to detect a slower decline in eGFR by 3 ml/min per 1.73 m² over 2 years among 399 participants, a smaller effect size compared with other metabolic interventions that may reduce CKD progression, such as sodium bicarbonate.⁷ The prespecified analysis⁷ of this RCT published in this issue of JASN represents a first yet vital step toward closing outstanding gaps in potassium supplementation among patients with nondialysis CKD.⁸ By analyzing data from 191 patients at the run-in phase of the trial, Gritter et al.⁷ demonstrate that 2 weeks of 40 mmol of potassium supplementation per day increases plasma potassium by 0.4 mEq/L, causing hyperkalemia (potassium ≥5.5 mEq/L) in 11% of the study population. As expected, older age and higher baseline plasma potassium were associated with a higher risk of hyperkalemia. Plasma potassium was normalized by the discontinuation of potassium supplementation in most patients; only a small group warranted additional interventions, with no reported serious adverse events.

The incidence of hyperkalemia in this analysis must be interpreted in the context of other interventions that can affect potassium balance. A renin-angiotensin inhibitor (RAASi) was used by 83% of the study population, and 43% were prescribed loop and/or thiazide diuretics at baseline; only 2% were using sodium-glucose cotransporter 2 inhibitors, an intervention that can decrease potassium levels. The high use of RAASi is reassuring; the African American Study of Kidney Disease and Hypertension post hoc analysis reported 7.2% hyperkalemia events among patients with CKD assigned to ramipril.⁹ However, new agents that reduce CKD progression, such as nonsteroidal mineralocorticoid antagonists (MRAs), are on the horizon. In the Finerenone in Reducing Kidney Failure and Disease Progression in Diabetic Kidney Disease (FIDELIO-DKD) trial, serum potassium increased by 0.23 mEq/L in the finerenone group compared with placebo, and hyperkalemia was detected in 21.7% of the intervention group.¹⁰

Altogether, the analysis by Gritter et al.⁷ indicates that potassium supplementation in patients with stage 3b or 4 CKD is safe in the short term, with comparable, if not lower, risk of acute hyperkalemia than other interventions affecting potassium excretion in CKD, such as RAASi and MRAs. The standard of care, however, is a moving target; the uptake of MRAs and sodium-glucose cotransporter 2 inhibitors is expected to increase globally, and their net effects on potassium balance remain unascertained. Nonetheless, the evidence of safety provided in this prespecified analysis is reassuring to the continuity of the main study. The full trial results will describe the long-term risk-benefit profile of potassium supplementation in a population with impaired kidney function. Safety assured, tackling the efficacy of potassium supplementation or potassium-based salt substitutes in nondialysis CKD can foster a paradigm shift for clinical trials and patient care alike.

Disclosures

M. Guedes reports a postdoctoral scholarship from Pontificia Universidade Católica do Paraná and research grants from AstraZeneca. R. Pecoits-Filho reports research grants from Fresenius Medical Care and the National Council for Scientific and Technological Development; honoraria (paid to employer) from Akebia, AstraZeneca, Bayer, Boehringer-Lilly, Fresenius Medical Care, GSK, and Novo Nordisk for participation in advisory boards and educational activities; consultancy for George Clinical; an advisory or leadership role with the Standardised Outcomes in Nephrology (SONG) Initiative Executive Committee; advisory or leadership roles with the editorial boards of American Journal of Kidney Diseases, Blood Purification, Hemodialysis International, International Society of Nephrology, Kidney Disease Improving Global Outcomes, Nephrology, and Peritoneal Dialysis International; and speakers bureaus for AstraZeneca, Bayer, and Boeringer. R. Pecoits-Filho is employed by the Arbor Research Collaborative for Health, which runs the Dialysis Outcomes and Practice Patterns Study (DOPPS). Global support for the ongoing DOPPS programs is provided without restriction on publications by a variety of funders. Funding is provided to the Arbor Research Collaborative for Health and not to R. Pecoits-Filho directly. Details are available at https://www.dopps.org/AboutUs/Support.aspx.

Funding

None.

Author Contributions

M. Guedes and R. Pecoits-Filho conceptualized the study, wrote the original draft, and reviewed and edited the manuscript.