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

Ida Fernandes1, Ye Zhang, Yuhua Qi

  • 1Division of Immunology and Organ Transplantation, Department of Surgery, The University of Texas Medical School, Houston, TX, USA.

Transplantation
|December 24, 2009
PubMed
Abstract

Insights

Reduced kidney mass significantly worsens drug-induced kidney injury from cyclosporine A and/or sirolimus. This nephrotoxicity correlates with increased kidney injury molecule-1 (KIM-1) and decreased sodium/phosphate cotransporter 2 (NaPi-2) expression.

Area of Science:

  • Nephrology
  • Pharmacology
  • Toxicology

Background:

  • Cyclosporine A (CsA) and sirolimus (SRL) are immunosuppressants with known nephrotoxic potential.
  • The impact of reduced nephron mass on CsA and/or SRL-induced nephrotoxicity is not fully understood.

Purpose of the Study:

  • To evaluate the effect of reduced nephron mass on cyclosporine A (CsA) and/or sirolimus (SRL) nephrotoxicity.
  • To investigate the expression of key renal transporters and injury markers in response to reduced nephron mass and drug treatment.

Main Methods:

  • Salt-depleted rats with two kidneys (2K), one kidney (1K), or half a kidney (1/2K) were treated with CsA and/or SRL for 7 or 28 days.
  • Renal function was assessed by serum creatinine clearance (CrCl).
  • Expression of aquaporin-2, sodium/phosphate cotransporter (NaPi)-2, paracellin-1, and kidney injury molecule (KIM)-1 was measured using real-time polymerase chain reaction.

Main Results:

  • Reduced nephron mass exacerbated CsA/SRL-induced nephrotoxicity, evidenced by significantly decreased CrCl, particularly in the 1/2K group.
  • Twenty-eight-day treatment worsened CrCl in all 1/2K groups.
  • While aquaporin-2, NaPi-2, and paracellin-1 mRNA levels generally increased with reduced nephron mass, NaPi-2 mRNA decreased in 1/2K rats treated with CsA/SRL for 28 days.
  • KIM-1 mRNA expression significantly increased in untreated 1/2K rats and was markedly elevated (50- to 200-fold) in CsA/SRL-treated 1/2K rats.

Conclusions:

  • Reduced nephron mass significantly potentiates nephrotoxicity induced by CsA and/or SRL.
  • Increased KIM-1 expression and inhibited NaPi-2 expression are key molecular correlates of this enhanced nephrotoxicity.

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