Hyperkalemia: pathophysiology, risk factors and consequences

Abstract

There have been significant recent advances in our understanding of the mechanisms that maintain potassium homoeostasis and the clinical consequences of hyperkalemia. In this article we discuss these advances within a concise review of the pathophysiology, risk factors and consequences of hyperkalemia. We highlight aspects that are of particular relevance for clinical practice. Hyperkalemia occurs when renal potassium excretion is limited by reductions in glomerular filtration rate, tubular flow, distal sodium delivery or the expression of aldosterone-sensitive ion transporters in the distal nephron. Accordingly, the major risk factors for hyperkalemia are renal failure, diabetes mellitus, adrenal disease and the use of angiotensin-converting enzyme inhibitors, angiotensin receptor blockers or potassium-sparing diuretics. Hyperkalemia is associated with an increased risk of death, and this is only in part explicable by hyperkalemia-induced cardiac arrhythmia. In addition to its well-established effects on cardiac excitability, hyperkalemia could also contribute to peripheral neuropathy and cause renal tubular acidosis. Hyperkalemia-or the fear of hyperkalemia-contributes to the underprescription of potentially beneficial medications, particularly in heart failure. The newer potassium binders could play a role in attempts to minimize reduced prescribing of renin-angiotensin inhibitors and mineraolocorticoid antagonists in this context.

Keywords: aldosterone; arrhythmia; hyperkalemia; potassium; renin–angiotensin.

FIGURE 1

Pathogenesis of hyperkalemia: mechanisms in the distal nephron. Factors that can cause hyperkalemia are in red text. These perturb one or more of five key variables: glomerular filtration, urine flow, sodium delivery to the distal nephron, expression of aldosterone-sensitive ion channels and transporters and urinary pH. PHAI, type I pseudohypoaldosteronism; CNI, calcineurin inhibitor.

FIGURE 2

Mechanism of cardiac arrhythmia in hyperkalemia. In normokalemia, the cell membrane of the cardiomyocyte is polarized (resting potential around −90 mV). In moderate hyperkalemia, the cell membrane becomes partially depolarized, bringing the resting potential closer to the threshold potential for AP initiation. Therefore fast sodium channels (Na_v1.5) are activated more readily, increasing excitability and conduction velocity. This manifests as T wave peaking on the ECG as a mass of ventricular cardiomyocytes undergo (synchronous) early repolarization. In severe hyperkalemia, voltage-dependent inactivation of Na_v1.5 channels and activation of inwardly rectifying potassium channels (K_ir) lead to reductions in conduction velocity and can render cells refractory to excitation. This manifests as broadening of ECG complexes and/or conduction blocks. This figure represents an idealized model, as there is poor correlation between ECG features and the degree of hyperkalemia.