Hyperkalemia in Hypertension

1

Why is hyperkalemia important to understand in the management of individuals with hypertension?

Hyperkalemia is one of the most common electrolyte disorders encountered and affects a disproportionate number of individuals with chronic hypertension. The incidence of hyperkalemia ranges from 1.9% to 38% among participants of prospectively conducted trials examining the effects of renin-angiotensin-aldosterone system (RAAS) inhibitors on blood pressure reduction. In many studies, higher rates of hyperkalemia accompany patients with lower estimated glomerular filtration rate (eGFR), older age, and presence of comorbid diabetes mellitus and cardiovascular disease (CVD). Rates of hyperkalemia are particularly high among participants of trials combining angiotensin-converting enzyme inhibitors/angiotensin receptor blockers (ACEis/ARBs) with mineralocorticoid receptor antagonists (MRAs) for the treatment of heart failure.

The development of hyperkalemia is associated with higher rates of hospitalization and mortality in virtually every patient population studied. Hyperkalemia is known to confer direct cardiotoxicity (see following sections), as well as being a major cause of RAAS inhibitor de-escalation; which, in turn, is linked to increased rates of health care utilization, poor control of blood pressure, and worse survival. In general, most professional societies recommend heightened awareness when plasma potassium levels exceed 5.0 mEq/L and de-escalation or discontinuation of RAAS inhibitors with levels greater than 5.5 mEq/L. Practitioners should be aware that underlying patient characteristics such as the presence of heart failure, acute kidney injury (AKI), critical illness, and rapid hyperkalemia development appear to be at least as important as the degree of hyperkalemia at conferring poor patient outcomes.

2

How does the body normally manage potassium?

Potassium is the predominant intracellular cation with only a small percentage (1%–2%) remaining in the extracellular space. The Na ⁺ K ⁺ -ATPase pump, which is located in the plasma membrane of most nucleated cells in the body, is responsible for maintaining the high intracellular/low extracellular potassium concentration. The Na ⁺ K ⁺ -ATPase exchanges intracellular sodium for extracellular potassium and is under the influence of many physiological stimuli that serve in a coordinated fashion to buffer acute potassium loads:

• The pancreas releases insulin in response to nutritional glucose intake, which signals for cellular glucose uptake. This upregulates the Na ⁺ K ⁺ -ATPase in glucose responsive tissues like skeletal muscle.

• Catecholamine release and β ₂ -adrenergic receptor activation increases the activity of the Na ⁺ K ⁺ -ATPase.

• Elevated plasma potassium concentrations directly stimulate aldosterone release from the zona glomerulosa of the adrenal gland, which activates mineralocorticoid receptors to upregulate Na ⁺ K ⁺ -ATPase activity.

While the Na ⁺ K ⁺ -ATPase limits a rapid rise in extracellular potassium concentration after loading, the kidney maintains long-term balance by accomplishing net potassium excretion with only a small contribution occurring via gastrointestinal (GI) excretion (∼5%–10% of daily intake). The primary site of potassium handling in the kidney occurs in the principal cells of the collecting duct of the distal nephron. Potassium excretion by this nephron segment requires adequate distal nephron sodium delivery, a high tubular flow rate, and the presence (and signaling activity) of aldosterone. A feedback loop also exists between these principal cells and the distal convoluted tubule, whereby elevated plasma potassium concentrations directly inhibit the thiazide-sensitive sodium chloride cotransporter (NCC), thus augmenting distal sodium delivery and facilitating Na ⁺ -K ⁺ exchange in the more distal nephron. Consequently, any dysregulation in one or more of these processes can contribute significantly to the development of hyperkalemia.