Management of Chronic Hyperkalemia in Patients With Chronic Kidney Disease: An Old Problem With News Options

Abstract

Hyperkalemia is one of the main electrolyte disorders in patients with chronic kidney disease (CKD). The prevalence of hyperkalemia increases as the Glomerular Filtration Rate (GFR) declines. Although chronic hyperkalemia is not a medical emergency, it can have negative consequences for the adequate cardio-renal management in the medium and long term. Hyperkalemia is common in patients on renin-angiotensin-aldosterone system inhibitors (RAASi) or Mineralocorticoid Receptor Antagonists (MRAs) and can affect treatment optimization for hypertension, diabetes mellitus, heart failure (HF), and CKD. Mortality rates are higher with suboptimal dosing among patients with CKD, diabetes or HF compared with full RAASi dosing, and are the highest among patients who discontinue RAASis. The treatment of chronic hyperkalemia is still challenging. Therefore, in the real world, discontinuation or reduction of RAASi therapy may lead to adverse cardiorenal outcomes, and current guidelines differ with regard to recommendations on RAASi therapy to enhance cardio and reno-protective effects. Treatment options for hyperkalemia have not changed much since the introduction of the cation exchange resin over 50 years ago. Nowadays, two new potassium binders, Patiromer Sorbitex Calcium, and Sodium Zirconium Cyclosilicate (SZC) already approved by FDA and by the European Medicines Agency, have demonstrated their clinical efficacy in reducing serum potassium with a good safety profile. The use of the newer potassium binders may allow continuing and optimizing RAASi therapy in patients with hyperkalemia keeping the cardio-renal protective effect in patients with CKD and cardiovascular disease. However, further research is needed to address some questions related to potassium disorders (definition of chronic hyperkalemia, monitoring strategies, prediction score for hyperkalemia or length for treatment).

Keywords: RAASi; chronic kidney disease; hyperkalemia; patiromer; potassium binders; zirconium.

Figure 1

Regulation of external and internal potassium balance. So-called feed-forward control refers to a potassium control pathway that responds to a pre-determined signal from the organism and is highly relevant to the mechanism of additional potassium regulation. The brain generates a regulatory circuit with the kidney and the colon that anticipates the presentation of food. Gastrointestinal-renal signals with a kaliuretic effect are generated, which will be able to mediate renal potassium elimination independent of changes in serum potassium and aldosterone concentration. Several co-transporters and ion channels are involved in the complex regulatory system of potassium reabsorption. The distal convoluted tubule mediates reabsorption of 5–10% of filtered potassium. Increased plasma K⁺ concentration depolarizes cells in the proximal portion of the distal convoluted tubule (DCT1) through effects dependent on the potassium. Increased Na⁺ delivery and flow to the downstream distal portion of the DCT where aldosterone sensitivity begins (DCT2, connecting tubule, and collecting duct) along with increased aldosterone levels drive potassium secretion.

Figure 2

Two compensatory mechanisms in the colon respond to elevated serum potassium levels in patients with CKD. Current studies highlight the existence of a feed-forward control in the regulation of potassium homeostasis, capable of causing rapid changes in renal potassium excretion. Among the different elements of this feed-forward control, the colon plays a fundamental role in the regulation of potassium. It is worth noting the different transport capacity of the potassium in the various segments of the colon or the different expression or activity of potassium channels on the membrane apical of the colon (BK channels). Although the role of the colon in excretion of potassium is not well-known yet, recent studies have found that in CKD the colon is responsible for a considerable increase in potassium removal, which is attributed to an increase in activity of the BK channels. There are two compensatory mechanisms in the colon in response to elevated serum potassium levels in patients with CKD: passive and active secretion.

Figure 3

Treatment algorithm for chronic hyperkalemia. Current recommendations regarding the management of chronic hyperkalemia (long-term elevated serum potassium) include the management of diuretics, modification of RAASi dose, treatment of metabolic acidosis with sodium bicarbonate, and removal of other hyperkalemia-causing medications. A team approach for chronic hyperkalemia, primary care physicians, nurses, pharmacists, or dietitians is optimal. The initiation of potassium binding agents should be considered in patients with chronic hyperkalemia despite optimized diuretic therapy and correction of metabolic acidosis. CKD, chronic kidney disease; DM, Diabetes Mellitus; HF, hearth failure; K, potassium; RAASi, renin-angiotensin-aldosterone system inhibitors.