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Kidney Week

Abstract: TH-PO112

Cilastatin in the Prevention and Treatment of Rhabdomyolysis-Induced Acute Renal Failure

Session Information

  • AKI: Mechanisms - I
    November 03, 2022 | Location: Exhibit Hall, Orange County Convention Center‚ West Building
    Abstract Time: 10:00 AM - 12:00 PM

Category: Acute Kidney Injury

  • 103 AKI: Mechanisms

Authors

  • Gonzalez-Nicolas Gonzalez, Maria Angeles, Instituto de Investigacion Sanitaria Gregorio Maranon, Madrid, Comunidad de Madrid, Spain
  • Humanes Sanchez, Blanca, Instituto de Investigacion Sanitaria Gregorio Maranon, Madrid, Comunidad de Madrid, Spain
  • Lazaro Fernandez, Alberto, Universidad Complutense de Madrid, Madrid, Comunidad de Madrid, Spain
Background

Rhabdomyolysis (RM) is a clinical and biochemical syndrome characterized by skeletal muscle rupture and massive release of cellular components including myoglobin (MG). MG directly damages the kidneys by activation of apoptotic, oxidative and inflammatory pathways in addition to tubular obstruction due to precipitation causing acute renal failure (ARF), one of its most serious complications. In fact, 50% of patients with RM will develop ARF with mortality rate can reach to 60%. Cilastatin, a renal dehydropeptidase-I inhibitor, has demonstrated its usefulness in the protection of ARF induced by nephrotoxic drugs due to interference with lipid rafts. Here, we evaluate the utility of cilastatin as a protector against RM-induced ARF.

Methods

RM was induced in Wistar rats by administering in the hind legs with 50% glycerol (or vehicle to the control group). Cilastatin (150 mg/kg) or its vehicle, was administered immediately and every 24 hours after RM induction. Renal damage was assessed 48h after glycerol/vehicle administration by measuring serum creatinine, blood urea nitrogen (BUN), glomerular filtration rate (GFR), renal damage biomarker KIM-1, renal tissue morphology and iron accumulation, as well as apoptotic, oxidative and inflammatory parameters such as caspase 3, CD68, 4-HNE and TGFβ among others.

Results

RM increased serum creatinine, BUN and decreased GFR compared to the control group. These renal effects were confirmed by an increase in the KIM-1 and the presence of severe morphological changes. Iron accumulation in tubular cells was observed, as well as a statistically significant increase in apoptotic, inflammatory and oxidative biomarkers. Cilastatin treatment completely prevented renal dysfunction and restored significantly all other parameters to levels found in the control groups. It also reduced many of the histological symptoms of renal damage.

Conclusion

Our findings support the potential use of cilastatin as a useful drug in the prevention and treatment of RM, ameliorating RM-induced ARF. Therefore, cilastatin may be a very beneficial therapeutic strategy in clinical practice for patients with some type of trauma or susceptible to renal damage due to RM.