New Potassium Binders for the Treatment of Hyperkalemia

Abstract

H yperkalemia is a clinical problem with potential mechanisms ranging from increased cellular potassium release (eg, pseudohyperkalemia, metabolic acidosis) to reduced potassium excretion (eg, reduced responsiveness to aldosterone, reduced aldosterone secretion, reduced distal sodium, and water delivery).1,2 Patients with chronic kidney disease (CKD), defined as an estimated glomerular filtration rate (eGFR) <45 mL/min per 1.73 m 2 , are at increased risk of hyperkalemia, resulting from ≥1 of these mechanisms.3 Renin-angiotensinaldosterone system inhibitors (RAASis) are recommended by guidelines for lowering blood pressure, slowing CKD progression in patients with CKD, 4,5 and reducing cardiovascular mortality and heart failure hospitalizations in patients with heart failure and a reduced ejection fraction, 6,7 but these drugs compound the hyperkalemia risk. 1,[8][9][10] The risk is magnified when the drugs are used in combination (eg, aliskiren in combination with ACE inhibitors or angiotensin receptor blockers; 8,11 mineralocorticoid receptor antagonists in combination with ACE inhibitors or angiotensin receptor blockers). Moreover, the risk for hyperkalemia is magnified in diseases, such as diabetes mellitus and heart failure. 4,5,12,13 The occurrence or fear of inducing hyperkalemia has led to premature discontinuation, suboptimal dosing, and often failure to use an RAASi, thereby exposing patients to increased cardiovascular risk.Current treatment approaches for chronic hyperkalemia are limited. Options for the management of hyperkalemia include discontinuation or reduced doses of RAASi, administration of loop diuretics, dietary potassium restriction, or sodium polystyrene sulfonate.14 None of these approaches are optimal because they require withholding life-saving or kidney preserving therapy (ie, RAASi), have a low rate of patient adherence (eg, dietary restriction), or have an unfavorable adverse effect profile and low tolerability (ie, sodium polystyrene sulfonate). 15 New agents to treat hyperkalemia are in the late stages of development. Clinical trial data suggest that these new agents effectively lower serum potassium and are well tolerated. [16][17][18][19][20] Therefore, these agents offer promising advantages over existing management options. It is possible that these agents might also facilitate maintenance of RAASi across the broad spectrum of patients with RAASi intolerance because of hyperkalemia (eg, CKD and heart failure), 18 and testing this hypothesis in larger clinical trials is warranted. This article reviews the clinical problem of hyperkalemia and identifies predictors of hyperkalemia in patients with hypertension, CKD, diabetes mellitus, and heart failure. It also presents recent clinical trial evidence of the efficacy and safety of new treatments for hyperkalemia, and it discusses how these agents may be used clinically, if approved. Overview of HyperkalemiaThe rate of hyperkalemia is low in uncomplicated hypertension patients treated with RAASi, 21 but it rises in the setting o...

Basolateral Kir4.1 activity in the distal convoluted tubule regulates K secretion by determining NaCl cotransporter activity

“…Its incidence appears to have increased because the most effective cardio- and reno-protective agents that block the renin/angiotensin/aldosterone system (RAAS), all impair renal K disposition. To prevent hyperkalemia induced by using RAAS inhibitors has led to the development of new agents to treat hyperkalemia [1]. Although these agents appear to be effective, they do not address the fundamental cause of the hyperkalemia, which is inappropriate kidney K retention.…”

An Evaluation of the Pharmacodynamics, Safety, and Tolerability of the Potassium Binder RDX7675

“…Cation exchange resins that reduce potassium absorption from the gut have been used to treat hyperkalemia since the 1950s, with SPS being the most widely used of these medications. However, poor palatability and the potential for gastrointestinal side effects have limited the use of SPS as a long‐term treatment . In recent years new treatments for patients with hyperkalemia have been developed.…”

“…Hyperkalemia most commonly develops in patients older than 65 years and with comorbid conditions, such as chronic kidney disease (CKD), heart failure, or diabetes . In patients with CKD, hyperkalemia can occur through a decreased glomerular filtration rate and mild acidosis, which limit renal excretion of potassium .…”

“…However, RAAS inhibitors decrease kidney excretion of potassium through their inhibitory effect on aldosterone, which can exacerbate hyperkalemia risk in patients with CKD, diabetes, and/or heart failure because of certain physiological disturbances associated with these conditions, such as aldosterone deficiency, decreased delivery of sodium to the distal nephron, and abnormal functioning of the cortical collecting tubule . Concern over the development of hyperkalemia in patients with CKD and/or heart failure can lead to RAAS inhibitor dose reduction and discontinuation, which increases cardiovascular risk . There is, therefore, a need for agents that can help to manage or prevent hyperkalemia in the long term and thereby enable concomitant use of optimal RAAS inhibitor therapy.…”

The association between serum potassium and mortality in patients with hypertension: ‘a wake-up call’

“…10 The recent availability, at least in the USA, of the nonabsorbed potassium-lowering polymer Patiromer and the likely availability within the year of the potassium-binding agent ZS9 provide an opportunity to maintain a RAAS-I in patients with hypertension. 11 While both Patiromer and ZS9 have been shown to be effective in reducing K + to normal levels in patients with hyperkalaemia and to be relatively well tolerated, it will be necessary to evaluate their long-term efficacy on cardiovascular outcomes while maintaining a RAAS-I in comparison with switching to another class of antihypertensive agent. It will also be important to compare the long-term efficacy and safety of Patiromer with those of ZS9 since while Patiromer exchanges potassium for calcium ZS9 exchanges potassium for sodium, raising the possibility that similarly to SPS, ZS9 could lead to an increase in sodium absorption and volume overload.…”