Tolvaptan suppresses monocyte chemotactic protein-1 excretion in autosomal-dominant polycystic kidney disease

Background: Autosomal-dominant polycystic kidney disease (ADPKD) is characterized by multitudes of expanding renal cysts associated with mononuclear interstitial infiltrates. Monocyte chemotactic protein-1 is produced in the kidneys and excreted in the urine (uMCP1) of these patients in increased amounts. In the TEMPO 3:4 trial, tolvaptan slowed the rate of increase in total kidney volume (TKV) and the rate of decline in estimated glomerular filtration rate (EGFR). In a sub-Analysis, we determined whether tolvaptan administration for up to 3 years changed the urinary excretion of MCP-1 referenced to creatinine in 869 treated subjects compared with 438 placebo subjects. Methods: Treatment group differences of uMCP1 at 0.75, 12, 24 and 36 months were evaluated by ANCOVA with factor of treatment and covariate baseline. Results: At baseline, mean uMCP1 was 4296 224 pg/mg in the tolvaptan and 434 6 233 pg/mg in the placebo groups, -4-fold greater than normal. Log uMCP1 associated positively with log TKV (r = 0.2645, P < 0.0001) and negatively with EGFR (r = -0.1555 P < 0.0001) and fasting urine osmolality (r = -0.1933, P < 0.0001). Tolvaptan reduced uMCP1 13.8 6 4.4% (P < 0.0001) below placebo-Treated subjects at 24 months and 14.4 6 3.7% (P < 0.0001) at 36 months, and to the same extent in females and males. The effect of tolvaptan on uMCP1 excretion at 36 months extended across CKD Stage 1 (11.16 6.4%, P = 0.0595), CKD 2 (13.9 6 5.4%, P = 0.0050) and CKD 3 (21.4 6 8.0%, P= 0.0020). Conclusion: Tolvaptan, administered for 3 years to patients with ADPKD, caused a sustained reduction in the urinary excretion ofMCP-1 relative to placebo.