Hyperkalemia in Chronic Kidney Disease in the New Era of Kidney Protection Therapies

Abstract

Despite recent therapeutic advances, chronic kidney disease (CKD) is one of the fastest growing global causes of death. This illustrates limitations of current therapeutic approaches and, potentially, unidentified knowledge gaps. For decades, renin-angiotensin-aldosterone system blockers (RAAS) have been the mainstay of therapy for CKD. However, they favor the development of hyperkalemia that that is already common in CKD patients due to the CKDassociated decrease in urinary potassium (K + ) excretion and metabolic acidosis. Hyperkalemia may itself be life-threatening as it may trigger potentially lethal arrhythmia, and additionally may limit the prescription of RAAS blockers and lead to low K + diets associated to low dietary fiber intake. Indeed, hyperkalemia is associated with adverse kidney, cardiovascular and survival outcomes. Recently, novel kidney protective therapies, ranging from sodium/glucose cotransporter 2 (SGLT2) inhibitors to new mineralocorticoid receptor antagonists have shown efficacy in clinical trials. Herein, we review K + pathophysiology and the clinical impact and management of hyperkalemia considering these developments and the availability of the novel K + binders patiromer and sodium zirconium cyclosilicate, recent results from clinical trials targeting metabolic acidosis (sodium bicarbonate, veverimer) and an increasing understanding of the role of the gut microbiota in health and disease. Key points-Hyperkalemia is a potentially lethal consequence of CKD.-Some commonly used treatments in CKD patients, like inhibitors of the RAAS system, have a potential effect worsening hyperkalemia -New treatments available in the nephrologist's armamentarium can be used in order to maintain K levels in the safe range Declarations:

2023 ESH Guidelines for the management of arterial hypertension The Task Force for the management of arterial hypertension of the European Society of Hypertension

“…Novel potassium binders (patiromer and sodium zirconium cyclosilicate) were shown to normalize elevated serum potassium and chronically maintain normal serum potassium levels in CKD patients treated with ACEis, ARBs or spironolactone, with a good tolerability [1375,1376]. These agents can be used to maintain serum potassium <5.5 mmol/l in patients with CKD [1377,1378]. Most patients with CKD will not achieve target BP control with ACEi or ARB monotherapy, and a DHP-CCB or a diuretic should almost always be included in the treatment regimen, most often both drugs [1379,1380].…”

Renin–angiotensin–aldosterone pathway modulators in chronic kidney disease: A comparative review

“…Earlier pharmacological management of hyperkalemia used sodium polystyrene sulfonate (SPS) and calcium polystyrene sulfonate (CPS), cation-exchange resins, with no trials to ascertain their efficacy and safety. These older generation K + binders were contraindicated in CKD associated with hypercalcemia or vascular calcification, leading to poor adherence ( Valdivielso et al, 2021 ). Recently, two new K + -binding drugs have been approved by FDA for the treatment of hyperkalemia: sodium zirconium cyclosilicate (SZC) and patiromer.…”

“…Patients receiving RAAS inhibitor therapy and patients with severe hyperkalemia had consistent reductions in serum K + with SZC ( Pitt et al, 2011 ; Ash et al, 2015 ). In CKD patients with hyperkalemia or risk of developing hyperkalemia, patiromer significantly reduced serum K + concentrations, thereby facilitating the continuation of RAAS inhibitor therapy ( Valdivielso et al, 2021 ).…”

Use of angiotensin converting enzyme inhibitors in chronic kidney disease - a review of the literature

“…Podwyższone stężenie jonów K + jest czynnikiem ograniczającym stosowanie inhibitorów ACE, a częstość występowania hiperkaliemii wzrasta proporcjonalnie do stadium PChN, dlatego też leczenie ACEI szczególnie u osób z dysfunkcją nerek wymaga okresowej kontroli stężenia jonów potasu [9,11] Według publikacji włoskich naukowców wzrost stężenia fosforanów, będący konsekwencją obniżonej funkcji nerek w przebiegu PChN, przyczynia się do konieczności wcześniejszych dializ, dlatego stwierdzono, że fosforany osłabiają nefroprotekcyjne działanie ACEI [22].…”