2010 - TTS International Congress


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Complications Cardiovascular

31.24 - Short-term treatment of Sirolimus to rat cardiac transplant recipients results in renal toxicity

Presenter: Ashwani, Khanna, Baltimore, United States
Authors: Khanna A.

SHORT-TERM TREATMENT OF SIROLIMUS TO RAT CARDIAC TRANSPLANT RECIPIENTS RESULTS IN RENAL TOXICITY

COMPLICATIONS - CARDIOVASCULAR

A.K. Khanna
Medicine (cardiology), University of Maryland, Baltimore/MD/UNITED STATES OF AMERICA

Body:
Background: It is apparent that the treatment of renal and non-renal transplant recipients with Sirolimus results in increased proteinuria and renal toxicity. In this experimental study, we examined the effect of Sirolimus on allograft rejection, renal histology and genomic mediators in a rat cardiac transplant model. Methods and Materials: Allogeneic histoincompatible heterotopic heart transplants were performed using Wistar Furth (WF) and Lewis (LEW) as donor and recipient rat strains. Treatment with SRL (0.25 mg/kg/day) was provided for 30 days. Recipients were monitored with heart palpation for rejection. One native kidney was used to isolate RNA samples for quantification of mRNA and the other kidney was used for histopathological analysis with hemotoxylin /eosin (H E), Periodic acid-Schiff (PAS) and Massons’ trichrome staining to assess histopathology, extracellular matrix and fibrosis.
Results: Histopathological analysis of renal tissues demonstrated frequent arterial hyalinosis, glomerusclerosis, almost complete glomerular collapse and prominence of visceral epithelial cells that contain blebs and vacuoles. We also observed tubular changes pertaining to renal toxicity such as tubular atrophy/vacuolization, epithelial blebs, hyalinization and extensive interstitial fibrosis. Additionally, increase in the number of intratubular proteinaceous casts, proteinaceous material swollen proximal tubular epithelial cells with increased intracytoplasmic protein droplets were seen in Sirolimus treated recipients. Staining with 4-HNE of renal tissue demonstrated increased oxidative stress in response to SRL treatment. Intrarenal mRNA expression (Mean SEM, expressed as relative fold expression) of CTGF (125 18), renin (175 45), p22phox (400 216) and TGF-b (85 12) was observed in rat cardiac transplant recipients treated with Sirolimus for 30 days.
Conclusions: These studies provide evidence that even a short-term course of Sirolimus exposure leads to arterial and glomerular hyalinosis protein droplets indicative of proteinuria. These changes occur in concert with activation of the oxidative stress and tissue repair and rennin angiotensin pathways.

Disclosure: All authors have declared no conflicts of interest.


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