Potassium and Its Discontents: New Insight, New Treatments

Abstract

Hyperkalemia is common in patients with impaired kidney function or who take drugs that inhibit the renin-angiotensin-aldosterone axis. During the past decade, substantial advances in understanding how the body controls potassium excretion have been made, which may lead to improved standard of care for these patients. Renal potassium disposition is primarily handled by a short segment of the nephron, comprising part of the distal convoluted tubule and the connecting tubule, and regulation results from the interplay between aldosterone and plasma potassium. When dietary potassium intake and plasma potassium are low, the electroneutral sodium chloride cotransporter is activated, leading to salt retention. This effect limits sodium delivery to potassium secretory segments, limiting potassium losses. In contrast, when dietary potassium intake is high, aldosterone is stimulated. Simultaneously, potassium inhibits the sodium chloride cotransporter. Because more sodium is then delivered to potassium secretory segments, primed by aldosterone, kaliuresis results. When these processes are disrupted, hyperkalemia results. Recently, new agents capable of removing potassium from the body and treating hyperkalemia have been tested in clinical trials. This development suggests that more effective and safer approaches to the prevention and treatment of hyperkalemia may be on the horizon.

Keywords: K channels; ion channel; ion transport.

Figure 1.

Changes in urinary K⁺ excretion associate with changes in plasma K⁺ concentration. Effect of a meal on plasma K⁺ concentration, plasma aldosterone concentration, and urinary K⁺ excretion in humans. The studies were conducted in six healthy volunteers who consumed a normal (25 mmol) and high (100 mmol) meal. Note the close correlation between rise in plasma K⁺, rise in aldosterone, and rise in urinary K⁺ excretion. Modified from Rabelink et al., with permission.

Figure 2.

Plasma K⁺ concentration varies throughout the day. Plasma measurements were conducted in 24 normal men under standardized conditions, with meals indicated by black bars. The whiskers indicate the lowest and highest results, and the central box spans the 25th to 75th percentiles. Reprinted from Sennels et al., with permission.

Figure 3.

Dietary K⁺ affects NaCl and K⁺ transport differently, via aldosterone and plasma K⁺ concentration. On a high-K⁺ diet, high–plasma K⁺ concentration inhibits NCC, although it stimulates aldosterone. Aldosterone stimulates ENaC (and ROMK), enhancing K⁺ secretion. On a low-K⁺ diet, NCC is stimulated by low plasma [K⁺], but aldosterone levels are low. Thus, Na⁺ and Cl⁻ are retained, raising BP.

Figure 4.

ZS-9 and SPS lower plasma K⁺ concentration. ZS-9 versus placebo indicates results of ZS-9 extracted from Figure 1. ZS-9 (10 g) is drawn from data in Kosiborod et al.. Effects of SPS and SPS + sorbitol are from Gruy-Kapral et al.. Note that the data are not necessarily comparable but shown for illustration. Modified from Kosiborod et al. and Gruy-Kapral et al., with permission.