Cyclosporine renal dysfunction.
Cyclosporine (CsA), introduced as an immunosuppressive agent in the 1980s, quickly become the first-line treatment in organ transplantation. However, these improvements were associated with an increased incidence of renal dysfunction. CsA causes histopathological changes in renal transplants that are often difficult to distinguish from other processes, especially chronic allograft nephropathy. Enhanced angiotensin II, transforming growth factor-beta, and vascular endothelial growth factor expression together with down-regulation of nitric oxide synthesis may play roles in chronic CsA nephropathy. Efforts have recently focused upon protocols that minimize the risk of CsA nephrotoxicity while preserving low rates of acute rejection. Four types of CsA-sparing studies have emerged from recent clinical experience: (1) conversion studies in which a nonnephrotoxic drug is substituted to allow CsA reduction, (2) minimal CsA exposure studies in which reduced CsA doses are combined with nonnephrotoxic drugs, (3) withdrawal studies in which CsA is completely discontinued at some time after transplantation, and (4) CsA-free studies in which the drug is completely avoided from the time of transplantation. Monitoring of CsA immunosuppression according to C2 blood levels, which better correlate with the area under the time-concentration curve than trough concentrations, should reduce the risk for toxicity; however, the most appropriate target range has not yet been clearly established. Because of interindividual differences in CsA absorption and susceptibility to renal dysfunction, the current therapeutic drug monitoring should be supplemented with pharmacogenetic information on genetic variability of relevant genes for pharmacokinetic parameters and therapeutic targets. This approach may guide choices for immunosuppressants for particular patients, with low toxicity. Thus, despite of 20 years of its history, CsA renal dysfunction remains an important clinical challenge.
Vítko
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Transplant Center, Department of Nephrology, Institute for Clinical and Experimental Medicine, Prague, Czech Republic. stefan.vitko@medicon.cz
Viklický
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D065095:Calcineurin Inhibitors; D016572:Cyclosporine / Q000009:adverse effects* / Q000097:blood / Q000493:pharmacokinetics; D006801:Humans; D007166:Immunosuppressive Agents / Q000009:adverse effects; D007668:Kidney / Q000187:drug effects* / Q000473:pathology; D016030:Kidney Transplantation / Q000276:immunology* / Q000473:pathology
D065095:Calcineurin Inhibitors; D007166:Immunosuppressive Agents; D016572:Cyclosporine