Cisplatin-induced renal inflammation is ameliorated by cilastatin nephroprotection

Nephrol Dial Transplant. 2017 Oct 1;32(10):1645-1655. doi: 10.1093/ndt/gfx005.


Background: Cisplatin is a potent chemotherapeutic drug whose nephrotoxic effect is a major complication and a dose-limiting factor for antitumoral therapy. There is much evidence that inflammation contributes to the pathogenesis of cisplatin-induced nephrotoxicity. We found that cilastatin, a renal dehydropeptidase-I inhibitor, has protective effects in vitro and in vivo against cisplatin-induced renal damage by inhibiting apoptosis and oxidation. Here, we investigated the potential use of cilastatin to protect against cisplatin-induced kidney injury and inflammation in rats.

Methods: Male Wistar rats were divided into four groups: control, cilastatin-control, cisplatin and cilastatin-cisplatin. Nephrotoxicity was assessed 5 days after administration of cisplatin based on blood urea nitrogen, creatinine, glomerular filtration rate (GFR), kidney injury molecule (KIM)-1 and renal morphology. Inflammation was measured using the electrophoretic mobility shift assay, immunohistochemical studies and evaluation of inflammatory mediators.

Results: Compared with the control rats, cisplatin-administered rats were affected by significant proximal tubule damage, decreased GFR, increased production of inflammatory mediators and elevations in urea, creatinine and tissue KIM-1 levels. Cilastatin prevented these changes in renal function and ameliorated histological damage in cisplatin-administered animals. Cilastatin also reduced pro-inflammatory cytokine levels, activation of nuclear factor-κB and CD68-positive cell concentrations.

Conclusions: Cilastatin reduces cisplatin-induced nephrotoxicity, which is associated with decreased inflammation in vivo. Although the exact role of decreased inflammation in nephroprotection has not been fully elucidated, treatment with cilastatin could be a novel strategy for the prevention of cisplatin-induced acute kidney injury.

Keywords: acute kidney injury; cilastatin; cisplatin; inflammation; nephroprotection.

MeSH terms

  • Acute Kidney Injury / pathology
  • Animals
  • Antineoplastic Agents / toxicity*
  • Apoptosis / drug effects
  • Blood Urea Nitrogen
  • Cilastatin / pharmacology*
  • Cilastatin / therapeutic use
  • Cisplatin / toxicity*
  • Creatinine / blood
  • Cytokines / blood
  • Cytokines / urine
  • Drug Evaluation, Preclinical
  • Glomerular Filtration Rate / drug effects
  • Kidney Tubules, Proximal / drug effects
  • Kidney Tubules, Proximal / pathology
  • Male
  • NF-kappa B / metabolism
  • Nephritis / chemically induced
  • Nephritis / metabolism
  • Nephritis / prevention & control*
  • Protease Inhibitors / pharmacology*
  • Protease Inhibitors / therapeutic use
  • Rats
  • Rats, Wistar


  • Antineoplastic Agents
  • Cytokines
  • NF-kappa B
  • Protease Inhibitors
  • Cilastatin
  • Creatinine
  • Cisplatin