Tolvaptan suppresses monocyte chemotactic protein-1 excretion in autosomal-dominant polycystic kidney disease
(2016) Nephrology Dialysis Transplantation — Vol. 32, n° 969-975, p. gfw060 (2016)
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- Abstract 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 429 ± 224 pg/mg in the tolvaptan and 434 ± 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 ± 4.4% (P < 0.0001) below placebo-treated subjects at 24 months and 14.4 ± 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 (11.1 ± 6.4%, P = 0.0595), CKD 2 (13.9 ± 5.4%, P = 0.0050) and CKD 3 (21.4 ± 8.0%, P = 0.0020). Conclusion: Tolvaptan, administered for 3 years to patients with ADPKD, caused a sustained reduction in the urinary excretion of MCP-1 relative to placebo.
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Grantham, J. J., Chapman, A. B., Blais, J., Czerwiec, F. S., Devuyst, O., Gansevoort, R. T., Higashihara, E., Krasa, H., Zhou, W., Ouyang, J., Perrone, R. D., & Torres, V. E. (2016). Tolvaptan suppresses monocyte chemotactic protein-1 excretion in autosomal-dominant polycystic kidney disease. Nephrology Dialysis Transplantation, 32(969-975), gfw060. https://doi.org/10.1093/ndt/gfw060 (Original work published 2016)