Horses for Courses: What is the Best Oral Potassium Supplementation Strategy?

Physicians are familiar with potassium supplementation in hypokalemia. In that context, the accompanying anion modifies the therapeutic effect. Potassium is delivered as the chloride salt, with bicarbonate (or the bicarbonate precursor, citrate) or, less commonly, with phosphate. The optimal formulation is determined by acid–base status, primarily because hypokalemia is commonly associated with an acid–base disturbance that the supplemented anion can help to correct. In alkalosis (e.g., after vomiting or in Gitelman or Bartter syndromes), KCl is the rational choice; in acidosis (e.g., with diarrhea or renal tubular acidosis), KHCO₃ or K citrate is preferred.¹

The anion affects both how K⁺ is shifted into cells and excreted through urine. This was first demonstrated in 1965 in balance studies of human subjects given sodium nitrate infusions to induce hypokalemic alkalosis.² Attempts to correct hypokalemia with KHCO₃ supplementation failed because of persisting urinary K⁺ losses, whereas KCl supplementation rapidly restored body K⁺ balance. These differential effects reflect opposing effects on extracellular and urinary pH of chloride (which will lower pH) and bicarbonate (which will raise it). A lower pH tends to shift potassium out of intracellular stores. A lower urinary pH will, at least acutely, oppose K⁺ excretion by the kidneys. If increasing total body K⁺ content is the goal, then KCl is more efficacious than KHCO₃ because less K⁺ is lost through urine. Therefore, guidelines favor KCl for correcting acute hypokalemia.³

More recently, researchers have explored a further indication for potassium supplementation: use in normokalemic patients to improve cardiovascular health. The impetus came from observational evidence that K⁺ intake is associated with lower BP, albuminuria, cardiovascular events, and mortality.⁴ Estimates suggest that dietary potassium intake is habitually below the recommended adequate intake of 90–120 mmol/d,⁵ and interventional studies show that K⁺ supplementation or substitution of regular table salt (100% NaCl) with low salt (75% NaCl and 25% KCl) can lower BP and reduce cardiovascular events.⁴ However, people with CKD or taking renin–angiotensin blockers or mineralocorticoid antagonists have an impaired capacity to excrete potassium. For these individuals, hyperkalemia is a safety concern that cautions against using K⁺ supplementation to improve cardiovascular outcomes.⁶ In this context, a recent study in patients with CKD stage G3b–4 used oral KCl supplements (40 mmol K⁺ per day) to increase potassium intake to recommended levels.⁷ Plasma [K⁺] increased by approximately 0.4 mmol/L over baseline, but 89% of participants remained normokalemic over the 14-day study period. Those developing hyperkalemia were older or had a higher baseline plasma potassium concentration.

Whether the accompanying anion modifies the safety or efficacy of K⁺ supplementation for cardiovascular protection is unknown, and a study by Wouda and colleagues, published in this issue of CJASN,⁸ begins to address this important question. The investigators performed a randomized crossover study in healthy adults to establish whether a single oral dose of K citrate or KCl had different effects on the primary end point of plasma potassium concentration. The potassium content of red blood cells, urinary potassium excretion, and plasma aldosterone were secondary outcome measures. An interesting feature of the study design was inclusion of an arm in which participants received the angiotensin-converting enzyme inhibitor lisinopril once daily over the 7-week period of investigation.

The K supplement (40 mmol) was taken after an overnight fast and caused plasma K⁺ concentration to rise by approximately 0.7 mmol/L over baseline at the 1-hour peak, with recovery to baseline after 4 hours. The accompanying anion had no effect on the extent or duration of the rise in plasma [K⁺]. Importantly, the peak rise in plasma [K⁺] after taking the oral supplement was not exaggerated by therapeutic RAS inhibition, although in this situation, plasma [K⁺] remained significantly above baseline 4 hours after ingestion of the KCl supplement. Plasma aldosterone was significantly increased by both KCl and K citrate, peaking 60 minutes after delivery; this effect was attenuated by lisinopril, but was not influenced by the anion.

To gain insight into the intracellular uptake of K⁺, Wouda et al. estimated potassium content of red blood cells.⁸ To do this, whole blood was collected in a lithium heparin tube and frozen. On thawing, the [K⁺] in the now hemolyzed blood was measured, plasma [K⁺] subtracted, and the resulting value multiplied by mean corpuscular volume. KCl supplementation had no effect on K⁺ content of red blood cells. By contrast, K citrate induced a significant increase in K⁺ content, 90 minutes after ingestion. The anion also modified the response by the kidney, with K citrate inducing greater kaliuresis than the equimolar KCl supplement. Overall, this study shows that accompanying K⁺ with citrate stimulates a greater cellular uptake and more pronounced urinary K⁺ excretion than delivery with chloride.

There were important limitations. Red blood cells are serving as a proxy for skeletal myocytes, which constitute the major intracellular K⁺ store and may differ in the way they respond to supplemental K⁺. The K⁺ supplements were given after overnight fast and the real-world situation, where K⁺ ingestion in the context of a meal and accompanied by a rise in insulin, may well be different. Intestinal absorption of the K supplements was not measured, and despite an apparent increase in cellular K⁺ uptake and K⁺ excretion by the kidneys with K citrate, there was no difference between the two supplements in the increase in plasma [K⁺]. This may reflect differences in GI absorption. The trial protocol had to be amended during the study to change the formulation of KCl supplements because of a high frequency of GI side effects. This is a salient reminder that one of the main difficulties with K⁺ supplementation in clinical practice is the prosaic problem of finding a supplement that the patient can tolerate. Arguably, this is the area in which clinical research could have the biggest effect.

Nevertheless, this study adds to our understanding of how the anion modifies the handling of supplemental K⁺. The likely mechanisms of the effect on K⁺ excretion by the kidneys are summarized in Figure 1. They include the direct activation of distal tubular BK channels in alkaline urine and a shift from electroneutral to electrogenic Na⁺ reabsorption when urinary chloride is limiting. There is also recent evidence that alkalosis can stimulate KHCO₃ secretion by intercalated cells, through the combined action of pendrin and the KCl cotransporter KCC3a.⁹

Figure 1.

Effect of K⁺ supplementation on cellular K⁺ shifts and K⁺ excretion by the kidneys. (A) KCl will promote a fall in extracellular pH, shifting K⁺ out of skeletal muscle cells. The additional chloride load to the distal renal tubule will favor electroneutral NaCl reabsorption over electrogenic Na⁺ reabsorption in the collecting duct, limiting K⁺ excretion by the kidneys. (B) K citrate (or KHCO₃) will raise extracellular pH and shift K⁺ into skeletal muscle cells. Alkalinization activates BK channels and stimulates KHCO₃ secretion through the coordinated action of pendrin and KCC3a in intercalated cells. The ability of lisinopril to abolish the effects of K citrate on cellular K⁺ uptake and urinary K⁺ excretion may relate to the stimulatory effects of aldosterone on the Na-K-ATPase and BK expression, respectively. BK, “Big Potassium” channel; DCT, distal convoluted tubule; ENaC, epithelial sodium channel; IC, intercalated cell; KCC3a, potassium-chloride co-transporter; NBCe1 and NBCe2, sodium-bicarbonate co-transporters; NCC, sodium chloride co-transporter; NDCBE, sodium-dependent chloride-bicarbonate exchanger; NHE, sodium-hydrogen exchanger; ROMK, renal outer medullary K1.

In hypokalemia, the goal of K⁺ supplementation is clear: to raise plasma [K⁺]. In a cardiovascular context, it is not known whether the increased cellular uptake and excretion by the kidneys with K citrate supplements are desirable. The clinical goals are not obvious regarding K⁺ distribution because we do not fully understand the mechanisms whereby K⁺ supplements improve cardiovascular health. These may relate to the diuretic effect of potassium salts, softening endothelial cell membrane stiffness or promoting nitric oxide release. So, is the increased excretion of K⁺ by the kidneys with K citrate counterproductive, limiting the total dose of cardioprotective K⁺, or beneficial, reducing the risk of hyperkalemia? Although there have been conflicting results, both KCl and K citrate have been shown to lower BP in trials of predominantly healthy individuals.¹⁰ If so, then the safety profile may dictate which formulation is preferable.

Ultimately, the optimal K⁺ supplementation strategy for cardioprotection can only be determined in large-scale interventional trials with hard clinical end points. In the meantime, studies like this one⁸ contribute to our understanding of the underlying physiology that allows us to choose the right horse for the right course: to tailor K⁺ supplementation to the individual, factoring in acid–base status and risk of hyperkalemia.

Disclosures

M.A. Bailey reports consultancy for River 2 Renal and research funding from the British Heart Foundation and Kidney Research UK. R.W. Hunter reports research funding from British Heart Foundation, Medical Research Scotland, and Wellcome Trust.

Funding

None.

Author Contributions

Conceptualization: Robert W. Hunter.

Writing – original draft: Matthew A. Bailey, Robert W. Hunter.

Writing – review & editing: Matthew A. Bailey, Robert W. Hunter.