Nephrotoxicity of immunosuppressive drugs: new insight and preventive strategies.
Cyclosporine and tacrolimus reduce allograft rejection, improve allograft half-life and patient survival. Ironically, the nephrotoxicity of these agents may adversely affect allograft survival in renal transplant recipients or cause end-stage renal diseases in other solid organ and bone marrow transplant recipients. Acute dose-dependent and chronic non-dose-dependent nephrotoxicity has been reported in both transplant recipients and patients with autoimmune disorders. Preliminary evidence suggests that drug therapeutic monitoring has little value in the diagnosis or management of nephrotoxicity associated with calcineurin inhibitors. Although the exact mechanism of nephrotoxicity is not fully understood, several factors have been implicated in the pathogenesis of immunosuppressive-induced nephrotoxicity. Renal and systemic vasoconstriction, increased release of endothelin-1, decreased production of nitric acid and increased expression of TGF-beta are the major adverse pathophysiologic abnormalities of these agents. Reducing the dose of a calcineurin inhibitor, or using protocols without calcineurin inhibition may ultimately minimize the risk of drug toxicity and improve allograft and patient survival. New experiences with non-nephrotoxic agents and protocols including mycophenolate and sirolimus allow for early calcineurin inhibitor reduction or elimination without increasing the risk of allograft rejection.
Olyaei
A J
AJ
Division of Nephrology, Hypertension and Clinical Pharmacology, Oregon Health Sciences University and Solid Organ and Cellular Transplantation, Legacy Good Samaritan Hospital, Portland, Oregon 97201, USA. olyaeia@ohsu.edu
de Mattos
A M
AM
Bennett
W M
WM
D065095:Calcineurin Inhibitors; D016572:Cyclosporine / Q000009:adverse effects; D019332:Endothelin-1 / Q000096:biosynthesis; D006084:Graft Rejection / Q000188:drug therapy; D007166:Immunosuppressive Agents / Q000009:adverse effects* / Q000494:pharmacology / Q000627:therapeutic use; D007668:Kidney / Q000098:blood supply / Q000187:drug effects* / Q000378:metabolism; D007674:Kidney Diseases / Q000139:chemically induced* / Q000517:prevention & control; D009173:Mycophenolic Acid / Q000031:analogs & derivatives* / Q000627:therapeutic use; D009569:Nitric Oxide / Q000378:metabolism; D020123:Sirolimus / Q000009:adverse effects* / Q000627:therapeutic use; D016559:Tacrolimus / Q000009:adverse effects; D016212:Transforming Growth Factor beta / Q000096:biosynthesis; D053773:Transforming Growth Factor beta1; D014661:Vasoconstriction / Q000187:drug effects
D065095:Calcineurin Inhibitors; D019332:Endothelin-1; D007166:Immunosuppressive Agents; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D009569:Nitric Oxide; D016572:Cyclosporine; D009173:Mycophenolic Acid; D020123:Sirolimus; D016559:Tacrolimus