Comparing nephrotoxicity of the calcineurin inhibitors, cyclosporine A and tacrolimus, identifies their differential effects within the renal compartments, rat model

Chronic calcineurin inhibitor (CNI) nephrotoxicity is a major drawback in current immunosuppressive regimens. In the chronic setting, arteriolar hyalinosis, decreased glomerular filtration rate, interstitial fibrosis and tubular dedifferentiation are the major adverse side effects. Regimens with cyclosporine A (CsA) and tacrolimus (Tac) have been compared before the background of potentially more harmful effects of CsA. Conversely, CsA is still widely used in transplant recipients and has been considered for replacement of Tac in posttransplant diabetes.To identify regulatory mechanisms in CsA and Tac nephrotoxicity in rat, we used quantitative transcriptomics Overall design: Adult (10 to12 weeks) male Wistar rats were divided into groups receiving cyclosporine A (CsA; target trough plasma level 3 mg/ml) and the respective vehicle (saline), or tacrolimus (Tac; target trough plasma level 3.5 ng/ml) and the respective vehicle (25% DMSO/75% PEG500), via subcutaneously implanted osmotic minipumps (Alzet, 2ML4, Cupertino, California) for 28 days. Kidneys were harvested and bulk RNA-seq was performed.