Therapeutic potential of vasopressin V2 receptor antagonist in a mouse model for autosomal dominant polycystic kidney disease: optimal timing and dosing of the drug

E. Meijer, R. T. Gansevoort*, P. E. de Jong, A. M. van der Wal, W. N. Leonhard, S. R. de Krey, J. van den Born, G. M. Mulder, H. van Goor, J. Struck, E. de Heer, D. J. M. Peters

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

62 Citations (Scopus)

Abstract

Background. The renoprotective effect of vasopressin V2 receptor antagonist (V2RA) is currently being tested in a clinical trial in early autosomal dominant polycystic kidney disease (ADPKD). If efficacious, this warrants life-long treatment with V2RA, however, with associated side effects as polydipsia and polyuria. We questioned whether we could reduce the side effects without influencing the renoprotective effect by starting the treatment later in the disease or by lowering drug dosage.

Methods. To investigate this, we administered V2RA OPC-31260 at a high (0.1%) and low (0.05%) dose to a tamoxifen-inducible kidney epithelium-specific Pkd1-deletion mouse model starting treatment at Day 21 (early) or 42 (advanced). After 3 and 6 weeks of treatment, we monitored physiologic and potential renoprotective effects.

Results. Initiation of V2RA treatment at advanced stage of the disease lacked renoprotective effects and had less pronounced physiologic effects than early initiation. After 3 weeks on a high dose, cyst ratio and kidney weight were reduced versus untreated controls (18 versus 25%, P - 0.05, and 0.33 versus 0.45 g, P = 0.03, respectively). After 6 weeks of treatment, however, this did not reach significance anymore, even at a high dose (cyst ratio 24 versus 27%, P - 0.12, and kidney weight 0.55 versus 0.66 g, P - 0.38).

Conclusions. Our results suggest that intervention with V2RA should be instituted early in ADPKD and that it might be necessary to further increase the dosage of this drug later in the disease to decrease cyst growth.

Original languageEnglish
Pages (from-to)2445-U39
Number of pages9
JournalNephrology Dialysis Transplantation
Volume26
Issue number8
DOIs
Publication statusPublished - Aug-2011

Keywords

  • ADPKD
  • disease stage
  • drug dose
  • PKD
  • vasopressin V2 receptor antagonist

Cite this