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Conversion to sirolimus ameliorates cyclosporine-induced nephropathy in the rat–focus on serum, urine, gene and protein renal expression biomarkers
Update time:2014-04-21 18:58:00   【 Font: Large  Medium Small

Abstract
Protocols of conversion from Cyclosporin A (CsA) to Sirolimus (SRL) have been widely used in immunotherapy post-transplantation, in particular to prevent CsA-induced nephropathy. However, the molecular mechanisms underlying these protocols remain to be elucidated, as well as the best biomarkers of nephropathy evolution. This study aimed to identify the molecular pathways andcharacterize the renal lesions, as well as, putative best biomarker of CsA to SRL conversion in a rat model. Four animal groups (n=6) were tested during 9 weeks: Control (vehicle); CsA (5 mg/kg bw/day); SRL (1 mg/kg bw/day); Conversion (CsA for 3 weeks followed by SRL for 6 weeks). Classical and emergent serum, urinary and kidney tissue (gene and protein expression) markers
were assessed. Renal lesions were analyzed in hematoxylin & eosin, periodic acid-schiff and masson’s trichrome stains. SRL-treated rats presented proteinuria and NGAL (serum and urinary) as best marker of renal impairment, which is of low-grade. After just 3 week of CsA treatment, when glomerular and tubulointerstitial lesions are yet slight or even absent, renal tissue (mRNA and/or protein expression) markers, including TGF-β, NF-Kβ, mTOR, PCNA, TP53, KIM-1 and CTGF are better indicator of renal disease initiation then the traditional serum and urine creatinine and BNU contents and clearances, which showed minor changes. Prolonged CsA exposure (9 weeks), aggravated renal damage, without clear changes on the traditional markers, but with changes on other non-classical markers, including serum TGF-β and IL-7, TBARs clearance and kidney TGF-β and mTOR. Conversion to SRL prevented CsA-induced renal damage evolution, viewed by the former non-classical measures, while NGAL (serum vs urine) seem to be a feasible biomarker of substitution to the mTOR inhibitor. In conclusion, our data suggest that some nontraditional emergent factors/mediators could be viewed as interesting biomarkers for CsA-induced nephrotoxicity evolution as well for conversion to sirolimus.

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Source:      by J Sereno, S Nunes, P Rodrigues-Santos, et al.
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