Reviewing the evidence for de novo immunosuppression with sirolimus.
Calcineurin inhibitors (CNIs), introduced in the 1980s, have been the foundation of maintenance immunosuppression in solid organ transplantation because they substantially reduce the risk of acute rejection and improve short-term outcomes. However, CNIs (both tacrolimus and cyclosporine) are implicated in direct and indirect nephrotoxicity, leading to tubular atrophy, interstitial fibrosis, and glomerulosclerosis. Therefore, CNI reduction or minimization has been a longstanding goal, and reducing CNI drug doses at virtually any time posttransplantation will improve glomerular filtration rate (GFR) by 10%-20%. One approach to avoid these long-term changes is to use a CNI-free regimen for maintenance therapy based on sirolimus, which has a different mechanism of action. The use of a de novo regimen including an induction antibody followed by sirolimus, mycophenolate mofetil, and steroids has been used in several trials (>1000 patients), consistently demonstrating improved renal function at 1, 2, and now 5 years. Long-term analysis has confirmed significantly improved renal function (creatinine and estimated and measured GFR), preservation of kidney histology, and death censored graft survival compared with CNI-based regimens. This combination has a somewhat different side effect profile, and wider experience has revealed that the use of de novo sirolimus requires careful therapeutic drug level monitoring to optimize these results. In addition, the de novo introduction of sirolimus should be restricted in the obese, in the presence of dense oligoanuria, and among subjects at high immunologic risk for an acute rejection episode.
Flechner
S M
SM
Cleveland Clinic Lerner College of Medicine, Cleveland, Ohio 44195, USA. flechns@ccf.org
D065095:Calcineurin Inhibitors; D005919:Glomerular Filtration Rate / Q000187:drug effects; D006801:Humans; D007165:Immunosuppression Therapy / Q000379:methods*; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D016030:Kidney Transplantation / Q000276:immunology* / Q000502:physiology; D015337:Multicenter Studies as Topic; D016032:Randomized Controlled Trials as Topic; D020123:Sirolimus / Q000627:therapeutic use*
D065095:Calcineurin Inhibitors; D007166:Immunosuppressive Agents; D020123:Sirolimus