De novo kidney transplantation without use of calcineurin inhibitors preserves renal structure and function at two years.
We performed a randomized prospective trial comparing calcineurin inhibitor (CNI)-free to CNI-based immunosuppression to determine the impact on renal function, structure and gene expression. Sixty-one kidney recipients treated with basiliximab mycophenolate mofetil (MMF) and prednisone (P) were randomly assigned to concentration-controlled sirolimus or cyclosporine. Two years post-transplant 55 patients underwent renal function studies, 48 (87%) underwent transplant biopsies; all classified by Banff scoring and 41 by DNA microarrays. Comparing sirolimus/MMF/P to cyclosporine/MMF/P there was a significantly lower serum creatinine (1.35 vs. 1.81 mg/dL; p = 0.008), higher Cockroft-Gault glomerular filtration rate (GFR) (80.4 vs. 63.4 mL/min; p = 0.008), iothalamate GFR (60.6 vs. 49.2 mL/min; p = 0.018) and Banff 0 (normal) biopsies (66.6 vs. 20.8%; p = 0.013). Regression analysis of calculated GFRs from 1 to 36 months yielded a positive slope for sirolimus of 3.36 mL/min/year, and a negative slope for cyclosporine of -1.58 mL/min/year (p = 0.008). Gene expression profiles from kidneys with higher Banff chronic allograft nephropathy (CAN) scores confirmed significant up-regulation of genes responsible for immune/inflammation and fibrosis/tissue remodeling. At 2 years the sirolimus-treated recipients have better renal function, a diminished prevalence of CAN and down-regulated expression of genes responsible for progression of CAN. All may provide for an alternative natural history with improved graft survival.
Section of Renal Transplantation, Transplant Center, and Allogen Laboratories, The Cleveland Clinic Foundation, Cleveland, Ohio, USA. flechns@ccf.org
Stuart M
SM
Flechner
Sunil M
SM
Kurian
Kim
K
Solez
Daniel J
DJ
Cook
James T
JT
Burke
Hank
H
Rollin
Jennifer A
JA
Hammond
Thomas
T
Whisenant
Caroline M
CM
Lanigan
Steven R
SR
Head
Daniel R
DR
Salomon
D000328:Adult; D000368:Aged; D001706:Biopsy; D065095:Calcineurin Inhibitors; D016572:Cyclosporine / Q000627:therapeutic use*; D006085:Graft Survival / Q000502:physiology; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D007249:Inflammation; D007677:Kidney Function Tests; D016030:Kidney Transplantation / Q000473:pathology / Q000502:physiology*; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D011241:Prednisone / Q000627:therapeutic use; D020123:Sirolimus / Q000627:therapeutic use*; D013997:Time Factors; D014184:Transplantation, Homologous; D016896:Treatment Outcome
D065095:Calcineurin Inhibitors; D007166:Immunosuppressive Agents; D016572:Cyclosporine; D011241:Prednisone; D020123:Sirolimus