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

Jared J. Grantham, Arlene B. Chapman, Jaime Blais, Frank S. Czerwiec, Olivier Devuyst, Ron T. Gansevoort, Eiji Higashihara, Holly Krasa, Wen Zhou, John Ouyang, Ronald D. Perrone, Vicente Torres

Research output: Contribution to journalArticle

8 Scopus citations

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 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.

Original languageEnglish (US)
Pages (from-to)969-975
Number of pages7
JournalNephrology Dialysis Transplantation
Volume32
Issue number6
DOIs
StatePublished - Jan 1 2017

Keywords

  • Chemokine
  • Chronic renal disease
  • Disease progression
  • Interstitial inflammation
  • Renal biomarker

ASJC Scopus subject areas

  • Nephrology
  • Transplantation

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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. (2017). Tolvaptan suppresses monocyte chemotactic protein-1 excretion in autosomal-dominant polycystic kidney disease. Nephrology Dialysis Transplantation, 32(6), 969-975. https://doi.org/10.1093/ndt/gfw060