Calcineurin inhibitor-sparing regimens in solid organ transplantation: focus on improving renal function and nephrotoxicity.
BACKGROUND
The calcineurin inhibitors (CNIs), cyclosporine and tacrolimus, have had a revolutionary effect on the overall success of renal transplantation through reduction in early immunologic injury and acute rejection rates. However, the CNIs have a significant adverse impact on renal function and cardiovascular disease, and extended long-term graft survival has not been achieved. The recognition of these effects sparked interest in CNI-sparing strategies. Strategies to limit CNI exposure include CNI minimization, avoidance, and withdrawal. We sought to review the impact of CNI-sparing strategies in kidney, liver, and heart transplantation.


METHODS
A PubMed search 1966 to August 2006 was conducted to identify relevant research articles, and the references of these articles as well as the authors' personal files were reviewed.


RESULTS
Calcineurin inhibitor minimization using mycophenolate mofetil or sirolimus may be associated with a modest increase in creatinine clearance (CrCl) and a decrease in serum creatinine (SCr) in the short term. Despite improvement in CrCl or SCr, CNI nephrotoxicity and chronic allograft nephrotoxicity are progressive over time when CNI exposure is maintained. In kidney transplantation, the tubulo-interstitial and glomerular damage are irreversible. Mycophenolate mofetil may improve renal outcomes during CNI minimization more than sirolimus, and antibody induction may be effective to limit CNI exposure, but longer-term follow-up data are required. Use of sirolimus with mycophenolate mofetil or azathioprine to avoid CNI exposure de novo has improved glomerular filtration rate for at least two yr in most studies in kidney transplantation; however, experience is limited in liver and heart transplantation, and reports of delayed graft function and wound healing with sirolimus may have dampened enthusiasm for de novo use. Late CNI withdrawal has achieved variable results, possibly because withdrawal was attempted after the kidney damage was too extensive. Early CNI withdrawal, prior to significant graft damage, has generally improved CrCl and markers of fibrosis and decreased chronic allograft lesions, a finding also observed with sirolimus in most CNI avoidance studies. Successful withdrawal appears to be more effective than CNI minimization.


CONCLUSIONS
Calcineurin inhibitors are associated with significant nephrotoxicity and chronic kidney damage. Minimization is associated with a modest increase in renal function, but persistent damage is observed on biopsies as long as the CNIs are continued. Avoidance is hampered by lack of experience and possible sirolimus-induced side effects. CNI withdrawal may be the best option by delivering CNIs during the early period of immunologic graft injury and then converting them to less nephrotoxic agents before significant renal damage occurs.
Flechner
Stuart M
SM
Transplant Center, Cleveland Clinic, Cleveland, OH 44195, USA. flechns@ccf.org
Kobashigawa
Jon
J
Klintmalm
Goran
G
D003404:Creatinine / Q000378:metabolism; D016572:Cyclosporine / Q000627:therapeutic use; D005919:Glomerular Filtration Rate; D006085:Graft Survival; D016027:Heart Transplantation / Q000276:immunology*; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D007668:Kidney / Q000187:drug effects*; D007676:Kidney Failure, Chronic / Q000453:epidemiology / Q000517:prevention & control; D016030:Kidney Transplantation / Q000276:immunology*; D016031:Liver Transplantation / Q000276:immunology*; D009173:Mycophenolic Acid / Q000031:analogs & derivatives* / Q000627:therapeutic use; D011183:Postoperative Complications / Q000453:epidemiology / Q000517:prevention & control; D020123:Sirolimus / Q000627:therapeutic use*; D016559:Tacrolimus / Q000627:therapeutic use; D014184:Transplantation, Homologous
D007166:Immunosuppressive Agents; D016572:Cyclosporine; D003404:Creatinine; D009173:Mycophenolic Acid; D020123:Sirolimus; D016559:Tacrolimus