Therapeutic mTOR inhibition in autosomal dominant polycystic kidney disease: What is the appropriate serum level?

G. Canaud, B. Knebelmann, P. C. Harris, F. Vrtovsnik, J. M. Correas, N. Pallet, C. M. Heyer, E. Letavernier, F. Bienaimé, E. Thervet, F. Martinez, F. Terzi, C. Legendre

Research output: Contribution to journalArticlepeer-review

46 Scopus citations

Abstract

Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited renal disease, and sirolimus, a mammalian target of rapamycin (mTOR) inhibitor, has been shown to significantly retard cyst expansion in animal models. The optimal therapeutic dose of sirolimus is not yet defined. Here, we report the history of a previously unknown ADPKD deceased donor whose kidneys were engrafted in two different recipients. One of the two received an immunosuppressive regimen based on sirolimus for 5 years while the other did not. After transplantation, both patients developed severe transplant cystic disease. Donor DNA sequence identified a new hypomorphic mutation in PKD1. The rate of cyst growth was identical in the two patients regardless of the treatment. While sirolimus treatment reduced the activation of mTOR in peripheral blood mononuclear cells, it failed to prevent mTOR activation in kidney tubular cells, this could account for the inefficiency of treatment on cyst growth. Together, our results suggest that the dose of sirolimus required to inhibit mTOR varies according to the tissue.

Original languageEnglish (US)
Pages (from-to)1701-1706
Number of pages6
JournalAmerican Journal of Transplantation
Volume10
Issue number7
DOIs
StatePublished - Jul 2010

Keywords

  • DNA sequencing
  • Disease transmission
  • Donor risk
  • Peripheral blood
  • Polycystic kidney disease
  • Renal allograft biopsies
  • Renalmedicine
  • Sirolimus
  • mTOR inhibitor

ASJC Scopus subject areas

  • Immunology and Allergy
  • Transplantation
  • Pharmacology (medical)

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