Abstract

In patients with chronic kidney disease (CKD), metabolic acidosis is common and is linked to mortality, hypercatabolism, bone disease, and hyperkalemia. Although serum bicarbonate should be below 22 mmol/L according to clinical guidelines, metabolic acidosis is frequently not diagnosed or treated. Hyperkalemia can be treated with sodium zirconium cyclosilicate (SZC), which binds potassium in the intestines. SZC treated metabolic acidosis associated with CKD by increasing serum bicarbonate in clinical trials with a primary endpoint of serum potassium. Patients with more severe pre-existing metabolic acidosis experienced a greater rise in serum bicarbonate, a decrease in serum urea, and this pattern persisted for more than a year after starting SZC therapy. After switching from a potassium-binding resin, SZC also decreased serum urea and increased serum bicarbonate in normokalemic individuals. These results are mechanistically consistent with SZC binding the ammonium ion (NH4+) produced by gut microbial urease from urea, preventing its absorption, preventing liver regeneration of urea, and encouraging H+ excretion from the feces. Benefits dependent on lower urea levels, such as decreased protein carbamylation, and dependent on corrected metabolic acidosis (such as improved well-being, decreased catabolism, improved CKD mineral bone disorder, improved serum phosphate control, and slower CKD progression) may result from this mechanism of action. Research into the mechanisms and clinical effects of SZC’s effect on serum bicarbonate and urate is guided by a road map.