Abstract
Cyclosporin A (CsA), a calcineurin inhibitor, remain the cornerstone of immunosuppressive regimens, regardless of nephrotoxicity, which depends on the duration of drug exposure. The mechanisms and biomarkers underlying the transition from CsA-induced renal dysfunction to nephrotoxicity deserve better elucidation, and would help clinical decisions. This study aimed to clarify these issues, using a rat model of short- and long-term CsA (5 mg/kg bw/day) treatments (3 and 9 weeks, respectively). Renal function was assessed on serum and urine; kidney tissue was used for histopathological characterization and gene and/or protein expression of markers of proliferation, fibrosis and inflammation. In the short-term, creatinine and blood urea nitrogen (BUN) levels increased and clearances decreased, accompanied by glomerular filtration rate (GFR) reduction, but without kidney lesions; at that stage, CsA exposure induced proliferating cell nuclear antigen (PCNA), transforming growth factor beta 1 (TGF-β1), factor nuclear kappa B (NF-κβ) and Tumor Protein P53 (TP53) kidney mRNA up-regulation. In the long-term treatment, renal dysfunction data was accompanied by glomerular and tubulointerstitial lesions, with remarkable kidney mRNA up-regulation of the mammalian target of rapamycin (mTOR) and the antigen identified by monoclonal antibody Ki-67 (Mki67), accompanied by mTOR protein overexpression. Transition from CsA-induced renal dysfunction to nephrotoxicity is accompanied by modification of molecular mechanisms and biomarkers, being mTOR one of the key players for kidney lesion evolution, thus suggesting, by mean of molecular evidences, that early CsA replacement by mTOR inhibitors is indeed the better therapeutic choice to prevent chronic allograft nephropathy.
Highlights
Calcineurin inhibitors (CNIs), such as Cyclosporine A (CsA), remain pivotal immunosuppressive drugs to prevent allograft rejection and its introduction in clinical practice led to a significant improvement in post-transplant survival [1,2]
Exposure, both kidney MDA levels and MDA clearance significantly increased (Figure 1). Both Cyclosporin A (CsA)-treated groups (3 and 9 weeks) showed statistically significant differences when compared with the corresponding controls, the AUC values do not differ (p = 0.6111) between the two treatments, which might be due to the reversal of MDA clearance profile between 3 and 9 weeks (Figure 1F)
We found that serum markers of renal dysfunction were already significantly increased after 3 weeks of CsA
Summary
Calcineurin inhibitors (CNIs), such as Cyclosporine A (CsA), remain pivotal immunosuppressive drugs to prevent allograft rejection and its introduction in clinical practice led to a significant improvement in post-transplant survival [1,2]. Renal dysfunction is an independent risk factor for graft loss and mortality after kidney transplantation (KTx) and cardiovascular/cardiorenal disease is the main cause of dead post-KTx [7,8,9]; extended long-term graft survival has not been completely achieved The recognition of these serious adverse effects sparked interest in CsA-sparing strategies [10]: CsA avoidance is associated with high acute rejection rates and is not an option; dose reduction is associated with a modest improvement in renal function, but CsA-induced nephropathy is progressive over time when exposure is maintained; minimization protocols are the current preferred therapy, including the conversion from CsA to other drugs, specially to Sirolimus (SRL), an inhibitor of the mammalian target of rapamycin (mTOR) [11,12]. The major question nowadays concerning the protocols of immunotherapy is to find the most adequate duration for
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