Effects of SZC on Hyperkalemia, Metabolic Acidosis in CKD

Hyperkalemia, or elevated serum potassium (sK+), and metabolic acidosis, or low serum bicarbonate (sHCO₃−), are common among patients with chronic kidney disease (CKD). The two conditions have a complex relationship wherein hyperkalemia may cause, and be caused by, metabolic acidosis.

The potassium binder sodium zirconium cyclosilicate (SZC) is an oral therapy for hyperkalemia that may also have benefits for metabolic acidosis. The NEUTRALIZE study by Stephen R. Ash, MD, and other researchers examined this potential dual effect of SZC on sK+ and sHCO₃− in patients with hyperkalemia and metabolic acidosis associated with CKD. The findings appeared in Kidney360.

NEUTRALIZE focused on nondialysis patients with stage 3-5 CKD, hyperkalemia (sK+ >5.0 to ≤5.9 mmol/L), and metabolic acidosis (sHCO₃− 16-20 mmol/L). Participants received open-label SZC 10 g three times daily for ≤48 hours; those who achieved normokalemia (sK+ 3.5-5.0mmol/L) were then randomized 1:1 to SZC 10 g or daily placebo for 4 weeks.

The primary end point of the study was the percentage of patients who maintained normokalemia at the end of treatment (EOT), which was day 29, without requiring rescue treatment for hyperkalemia. Secondary end points included mean change in sHCO₃− at EOT and percentage of patients with normokalemia with a ≥3 mmol/L increase in sHCO₃− without rescue.

A total of 229 patients were screened across 30 sites. Due to a high screen failure rate (83%; n=190), which was unrelated to safety concerns, just 39 patients were enrolled and entered the open-label phase of the study. At the end of the open-label phase, 37 patients were randomized to receive treatment in the double-blind maintenance phase. There were 17 patients in the SZC group and 20 in the placebo group. Mean age was 63.3 years, and most patients were male (67.6%) and White (86.5%).

Mean (SD) sK+ at baseline was 5.4 (0.4) mmol/L for the SZC group and 5.5 (0.4) mmol/L for the placebo group; these values were 16.1 (2.0) and 15.6 (2.6) mmol/L, respectively, for sHCO₃−. At EOT, more patients in the SZC group (88.2%) maintained normokalemia compared with the placebo group (20.0%) (odds ratio, 56.2; P=.001).

Secondary end point P values were not significant due to the low enrollment. Starting at day 15, treatment with SZC was associated with nominally significant increases in sHCO₃− compared with placebo. The percentage of patients maintaining normokalemia with a ≥3 mmol/L increase in sHCO₃− without requiring rescue treatment was 35.3% for the SZC group and 5.0% for the placebo group (P<.05).

Overall, the study met its primary end point of achieving and maintaining normokalemia and demonstrated nominally significant increases in sHCO₃− observed for SZC versus placebo. However, the data analysis was affected by the high screen failure rate, which led to a small sample size and early termination of the study.

“In summary,” the authors wrote, “SZC effectively lowers sK+ and maintains normokalemia with continued treatment for up to 4 weeks in patients with CKD with concomitant hyperkalemia and metabolic acidosis. In addition, SZC was associated with nominally significant increases in sHCO₃− compared with placebo. Further studies, on the basis of appropriate cohort size, may help validate the trend observed in sHCO₃− levels, supporting these clinically relevant findings.”

Source: Kidney360