A Janus‐headed electrolyte and ‘RALES' disease’

In ancient Roman mythology, Janus is the god of beginnings and transitions. Janus has two faces, one looking back into the past and one looking ahead into the future (Figure 1). According to Ovid, having two faces also enabled him to never turn his back on his adored Cardea. In the figurative sense, something that is Janus‐headed is ambivalent and must be seen in context. In this regard, potassium is the Janus among electrolytes in heart failure. Potassium is abundant in cells and sparse in the extracellular space. This concentration gradient helps to build up the transmembrane potential that is indispensable for electrical signal conduction in the heart and in other organs. A decrease in extracellular potassium concentration augments, and an increase dampens excitability. Both conditions can severely impair normal physiological function. Serum potassium levels are largely determined by urinary potassium excretion. By acting on the expression of sodium and potassium transporters in the collecting tubules, the renin–angiotensin–aldosterone system (RAAS) causes sodium retention and potassium excretion. In patients with heart failure (HF), low levels of serum potassium are associated with increased mortality. Potassium depletion may result from neurohumoral RAAS activation in these patients, as well as from diuretic treatment, a mainstay in the management of heart failure. In the SOLVD trial cohort, the use of non‐potassium‐sparing diuretics was an independent risk factor for sudden cardiac death. The RALES, EPHESUS, and EMPHASIS‐HF trials have firmly established the role of potassium‐sparing mineralocorticoid receptor antagonists (MRA) in the treatment of heart failure. Aldosterone and eplerenone retain potassium and have direct effects on the myocardium. Because aldosterone levels are often increased despite RAAS blockade, simultaneous application of MRA has an additive effect over ACE inhibitors and angiotensin receptor blockers. On the other hand, the concomitant use of MRA and other RAAS blocking agents may put patients at risk of fatal arrhythmias due to hyperkalaemia—Janus’ second face. This is most commonly seen in those that exhibit reduced aldosterone levels in the first place, e.g. due to hyporeninaemic hypoaldosteronism. Elderly patients and those with diabetes mellitus or/and kidney disease are at highest risk. In the wake of the landmark MRA trials, the prescription rates for MRA have sharply increased. A concomitant increase in the rates of hyperkalaemia has been reported in one study (Figure 2), but not in another. However, the coincidence of hospital admissions due to very severe hyperkalaemia and the dual use of MRA and other RAAS blocking medications is now such a commonplace clinical experience that the term ‘RALES’ disease’ (Morbus RALES) has gained currency among emergency physicians. To assess the actual risk of patients on dual MRA and other RAAS blocking treatment, we queried Würzburg University Hospital’s Clinical Data Warehouse (Table 1). The Data Warehouse is a clinical registry that includes every inpatient and outpatient case managed by any department at this tertiary care centre. Out of ~5 million cases, we identified 118 691 cases (2.4%) between 2003 and January 2017 with at least one RAAS blocking agent (including an MRA). Dual ED ITOR IAL