Rapamycin for treatment of chronic allograft nephropathy in renal transplant patients.
Chronic allograft nephropathy (CAN) represents the main cause of renal allograft loss after 1 yr of transplantation. Calcineurin inhibitor (CNI) use is associated with increased graft expression of profibrotic cytokines, whereas rapamycin inhibits fibroblast proliferation. The aim of this randomized, prospective, open-label, single-center study was to evaluate the histologic and clinical effect of rapamycin on biopsy-proven CAN. Eighty-four consecutive patients who had biopsy-proven CAN and received a transplant were randomized to receive either a 40% CNI reduction plus mycophenolate mofetil (group 1; 50 patients) or immediate CNI withdrawal and rapamycin introduction with a loading dose of 0.1 mg/kg per d and a maintaining dose aiming at through levels of 6 to 10 ng/ml (group 2; 34 patients). The follow-up period was 24 mo. At the end of follow-up, 25 patients (group 1, 10 patients; group 2, 15 patients) underwent a second biopsy. CAN lesions were graded according to Banff criteria. alpha-Smooth muscle actin (alpha-SMA) protein expression was evaluated in all biopsies as a marker of fibroblast activation. Graft function and Banff grading were superimposable at randomization. Graft survival was significantly better in group 2 (P = 0.0376, chi2 = 4.323). CAN grading worsened significantly in group 1, whereas it remained stable in group 2. After 24 mo, all group 1 biopsies showed an increase of alpha-SMA expression at the interstitial and vascular levels (P < 0.001); on the contrary, alpha-SMA expression was dramatically reduced in group 2 biopsies (P = 0.005). This study demonstrates that rapamycin introduction/CNI withdrawal improves graft survival and reduces interstitial and vascular alpha-SMA expression, slowing down the progression of allograft injury in patients with CAN.
Stallone
Giovanni
G
Department of Biomedical Sciences, Division of Nephrology, University of Foggia, Foggia, Italy.
Infante
Barbara
B
Schena
Antonio
A
Battaglia
Michele
M
Ditonno
Pasquale
P
Loverre
Antonia
A
Gesualdo
Loreto
L
Schena
Francesco Paolo
FP
Grandaliano
Giuseppe
G
D001707:Biopsy, Needle; D002908:Chronic Disease; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D015433:Glomerulonephritis, Membranous / Q000188:drug therapy* / Q000473:pathology; D006084:Graft Rejection; D006085:Graft Survival; D006801:Humans; D007150:Immunohistochemistry; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D007676:Kidney Failure, Chronic / Q000175:diagnosis / Q000601:surgery; D016030:Kidney Transplantation / Q000009:adverse effects* / Q000473:pathology*; D008297:Male; D011336:Probability; D011379:Prognosis; D016016:Proportional Hazards Models; D011446:Prospective Studies; D016037:Single-Blind Method; D020123:Sirolimus / Q000627:therapeutic use*; D014181:Transplantation Immunology / Q000502:physiology; D014184:Transplantation, Homologous
D007166:Immunosuppressive Agents; D020123:Sirolimus