Impact of reduced nephron mass on cyclosporine-and/or sirolimus-induced nephrotoxicity

Ida Fernandes, Ye Zhang, Yuhua Qi, Mo Er Wang, Hemongshu Podder, Wojciech Lisik, Richard Knight, Barry D. Kahan, Stanislaw M. Stepkowski

Research output: Contribution to journalArticle

9 Scopus citations

Abstract

BACKGROUND: We evaluated the impact of reduced nephron mass on nephrotoxicity by cyclosporine A (CsA) and/or sirolimus (SRL). METHODS: Renal function was tested in salt-depleted rats bearing two kidneys (2K), one kidney, or half a kidney (1/2K) and treated for 7 or 28 days with CsA (5 mg/kg) and/or SRL (0.8 mg/kg). We also measured the expression of aquaporin-2, sodium/phosphate cotransporter (NaPi)-2, paracellin-1, and kidney injury molecule (KIM)-1 by real-time polymerase chain reaction. RESULTS: At 7 days in 2K, serum creatinine clearance (CrCl) was decreased only in CsA/SRL-treated group (P<0.05) compared with controls; in 1/2K, CrCl was decreased in all groups, but most dramatically in CsA/SRL group (P<0.05). Extended 28-day therapy worsened CrCl in all 1/2K groups (P<0.01). Although the expression of aquaporin-2, NaPi-2, and paracellin-1 mRNAs tended to increase in kidneys with a reduced nephron mass, NaPi-2 mRNA levels decreased in 1/2K rats exposed to CsA/SRL for 28 days (P<0.05). In contrast, low KIM-1 mRNA expression in control 2K rats increased fourfold in untreated 1/2K (P<0.05), and 50-to 200-fold in CsA/SRL-treated 1/2K (P=0.01). CONCLUSIONS: Nephrotoxicity is significantly worsened by reduced nephron mass, which correlates with increased expression of KIM-1 and inhibited expression of NaPi-2.

Original languageEnglish (US)
Pages (from-to)1323-1331
Number of pages9
JournalTransplantation
Volume88
Issue number12
DOIs
StatePublished - Dec 2009

Keywords

  • Cyclosporine
  • Drug toxicity
  • Sirolimus

ASJC Scopus subject areas

  • Transplantation

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