Sirolimus-based immunosuppression with reduce dose cyclosporine or tacrolimus after renal transplantation.
Sirolimus (SRL), a fermentation product of Streptomyces hygroscopicus, complexes with the FKBP12 to inhibit cyclin dependent kinase(s), collectively termed the target of rapamycin (TOR), causing G(1)-S phase cell cycle arrest. Safety and efficacy have been documented in clinical renal transplantation, but concerns were raised due to important biologically relevant side effects. Hyperlipidemia was identified, beginning with early clinical experiences, and the unexpected findings that SRL may exacerbate CsA associated nephrotoxicity was observed during the pivotal phase III studies. This report details results of our experience using SRL (target trough concentration, 10-15 ng/mL) with low dose CsA (target trough concentration, 50-100 ng/mL), seeking to determine whether this approach might provide effective immunosuppression while reducing associated nephrotoxicity. Among 121 renal transplant recipients, 62 received the SRL based regimen and 59 received MMF with all patients receiving CsA and prednisone. Similar to earlier clinical experiences, hematopoeitic abnormalities and hyperlipidemia were observed among patients who received SRL, and those abnormalities were readily controlled. However, unlike observations from the phase III SRL studies, renal function was not adversely affected. These findings support the growing body of evidence indicating that SRL based immunosuppression in combination low dose calcineurin inhibitors and corticosteroids is safe, efficacious, and without associated renal toxicity.
Section of Nephrology, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut, USA.
R N
RN
Formica
K M
KM
Lorber
A L
AL
Friedman
M J
MJ
Bia
F
F
Lakkis
J D
JD
Smith
M I
MI
Lorber
D001794:Blood Pressure; D003404:Creatinine / Q000097:blood; D016572:Cyclosporine / Q000008:administration & dosage / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D005500:Follow-Up Studies; D006084:Graft Rejection / Q000453:epidemiology; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000627:therapeutic use; D016030:Kidney Transplantation / Q000276:immunology / Q000502:physiology*; D011183:Postoperative Complications / Q000453:epidemiology; D012086:Reoperation / Q000706:statistics & numerical data; D020123:Sirolimus / Q000627:therapeutic use*; D016559:Tacrolimus / Q000008:administration & dosage / Q000627:therapeutic use*; D022021:Tacrolimus Binding Proteins / Q000378:metabolism; D013997:Time Factors
D007166:Immunosuppressive Agents; D016572:Cyclosporine; D003404:Creatinine; D022021:Tacrolimus Binding Proteins; D020123:Sirolimus; D016559:Tacrolimus