Effect of Tolvaptan in Autosomal Dominant Polycystic Kidney Disease by CKD Stage: Results from the TEMPO 3:4 Trial

Background and objectives The Tolvaptan Efficacy and Safety in Management of Autosomal Dominant Poly cystic Kidney Disease and Its Outcomes 3:4 study demonstrated a significant beneficial effect of the vasopressin V2 receptor antagonist tolvaptan on rates of kidney growth and eGFR decline in autosomal dominant polycystic kidney disease (ADPKD). This post hoc analysis was performed to reassess the primary and secondary efficacy endpoints by CKD stage at baseline. Design, setting, participants, & measurements In a phase 3, multicenter, double-blind, placebo -controlled, 3 -year trial, 1445 patients with ADPKD (age 18-50 years), with total kidney volume (TKV).750 ml and estimated creatinine clearance ml/min, were randomly assigned 2:1 to split -dose tolvaptan (45/15, 60/30, or 90/30 mg daily as tolerated) or placebo. The primary endpoint was annualized rate of TKV change. Secondary endpoints included a composite endpoint of time to multiple composite ADPKD-related events (worsening kidney function, kidney pain, hypertension, and albuminuria) and rate of kidney function decline. Results Tolvaptan reduced annualized TKV growth by 1.99%, 3.12%, and 2.61% per year (all P<0.001; subgroup treatment interaction, P=0.17) and eGFR decline by 0.40 in CKD1 (P=0.23), 1.13 in CKD2 (P<0.001) and 1.66 ml/min per 1.73 m2 per year in CKD3 (P<0.001) with a trend for a positive subgroup -treatment interaction (P=0.07) across CKD1, CKD2 and CKD3. ADPKD-related events were less frequent in tolvaptan recipients than in placebo recipients among those with CKD1 (hazard ratio [HR], 0.83; 95% confidence interval [95% CI], 0.70-0.98; P=0.03) and those with CKD 3 (HR, 0.71; 95% CI, 0.57-0.89; P=0.003), but not among those with CKD2 (HR, 1.02; 95% CI, 0.85-1.21; P=0.86). Aquaresis-related adverse events (more frequent in the tolvaptan group) and ADPKD-related adverse events (more frequent in the placebo group) were not associated with CKD stage. Hypernatremia events in tolvaptan-treated patients with CKD3 and plasma aminotransferase elevations in tolvaptan-treated patients across CKD stages 1-3 occurred more frequently than in placebo recipients. Conclusions This post hoc analysis suggests clinically similar beneficial effects of tolvaptan in ADPKD across CKD stages 1-3.