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.
Flechner
Stuart M
SM
Section of Renal Transplantation, Transplant Center, and Allogen Laboratories, The Cleveland Clinic Foundation, Cleveland, Ohio, USA. flechns@ccf.org
Kurian
Sunil M
SM
Solez
Kim
K
Cook
Daniel J
DJ
Burke
James T
JT
Rollin
Hank
H
Hammond
Jennifer A
JA
Whisenant
Thomas
T
Lanigan
Caroline M
CM
Head
Steven R
SR
Salomon
Daniel R
DR
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