Background--Long-term treatment of cardiac transplant recipients with cyclosporine results in a progressive decline in kidney function in a large number of patients. This complication is one of the most important prognostic parameters that determine the outcome of cardiac transplantation. Transforming growth factor- (TGF-) is one of the most potent mediators of the fibrogenic effects of cyclosporine.

Methods and Results--With the use of an experimental rodent model, heterotopic heart transplantation was performed, creating histocompatibility-disparate allografts. Because TGF- in part mediates both the immunosuppressive and nephrotoxic effects of cyclosporine, recipients were treated with cyclosporine with and without anti-TGF- antibody to determine whether anti-TGF- antibody could reduce the nephrotoxic effects of cyclosporine. Intrarenal expression of TGF-, collagen, fibronectin, matrix metalloproteinase-2, and tissue inhibitor of metalloproteinase-2 was studied with the use of reverse transcription-polymerase chain reaction. Intrarenal expression of TGF- protein was studied by immunohistochemistry and with the use of ELISA to quantify circulating levels of TGF- protein in plasma. Cyclosporine-induced graft survival (immunosuppressive effect) was abrogated with a higher concentration (2.5 mg/kg) of anti-TGF- antibody, whereas a lower concentration (1 mg/kg) inhibited both cyclosporine-induced expression of fibrogenic molecules and renal toxicity.

Conclusions--These results provide credence to the pivotal role of TGF- in immunosuppression-associated renal toxicity in recipients of cardiac transplantation. Furthermore, these findings support a potentially significant therapeutic use of optimal concentration of anti-TGF- antibody to ameliorate cyclosporine-associated nephrotoxicity in cardiac transplant recipients.