CHRONIC NEPHROPATHY/ CHRONIC REJECTION Experimental The Buffalo/Mna Rat, An Animal Model of FSGS Recurrence After Renal Transplantation L. Le Berre, Y. Godfrin, S. Perretto, H. Smit, F. Buzelin, D. Kerjaschki, C. Usal, C. Cuturi, J.P. Soulillou and J. Dantal B UFFALO/MNA rats, which were first described as presenting a spontaneous thymoma and a myopathy, also spontaneously develop a nephrotic syndrome with selective proteinuria, hypoalbuminemia, and hyperlipid- emia associated with glomerular lesions similar to the human focal and segmental glomerulosclerosis (FSGS). 1,2 The etiology and the mechanisms involved in this human disease remain unknown. 3 However, the recurrence of proteinuria and glomerular dammages of FSGS after renal transplantation in 30% to 50% of these patients strongly suggest the presence of an albuminuric plasmatic factor. 4 In the absence of a reliable biological test allowing its detec- tion, this proteinuric factor could not be characterized. Therefore, there is an urgent need of an animal model for a better understanding of FSGS mechanisms. In this study, to demonstrate the relevance of the Buffalo/ Mna rat as a spontaneous model of idiopathic nephrotic syndrome (INS), we have investigated (1) the effect of immunosuppressive drugs classically used in human FSGS/ INS and two novel treatments on Buffalo/Mna proteinuria, (2) the potential of recurrence of the Buffalo/Mna initial disease after transplantation of normal kidneys into Buffa- lo/Mna, and (3) the potential of the regression of the proteinuria of Buffalo/Mna kidneys after transplantation in normal recipients. METHODS Corticosteroids (CS) were administrated at 1 mg/kg/d, cyclosporine A (CsA) at 10 mg/kg/d, and cyclophosphamide (Cy) at 50 mg/kg/wk for 61 days. Control groups were injected with the same volume of NaCl 0.9% for CS group and olive oil for CsA group. Other groups received Mitoxantrone at 0.5 mg/kg/d for 14 days and every other day for 14 days or R7.3 Ab (anti–T-cell receptor) at 50 g/d alone for 9 days or simultaneously with CsA at 10 mg/kg/d for 20 days. Peripheral leukocyte population were monitored via cytometric analysis. Kidneys from healthy LEW.1W (RT1 u ) were grafted into proteinuric 6-month-old Buffalo/Mna (RT1 u ) using a protocol of tolerance induction by donor-specific transfusion (DST). 5 To dem- onstrate the efficiency of DST protocol in these strains, we realized an abdominal cardiac transplantation of LEW.1W hearts into Buffalo/Mna recipients with DST. The survival of the graft was monitored daily by abdominal palpation and estimation of the graft beating. The inverse combination was done to analyze if a protein- uric Buffalo/Mna kidney can recover its permselectivity in a normal environment. As control group, LEW.1W kidneys were grafted into Wistar Furth recipients (RT1 u ). In all experiments, proteinuria From INSERM U437 (L.L.B., Y.G., S.P., H.S., C.U., C.C., J.P.S., J.D.), Service d’Anatomopathologie, CHU Hotel Dieu (F.B.), Nantes, France, and the Institut fu ¨ r Klinische Pathologie (D.K.), Vienna, Austria. Address reprint requests to Dr J.P. Soulillou, ITERT CHR, Nantes 30 Bd, Jean Monnet, 44093 Nantes Cedexol, France. 0041-1345/01/$–see front matter © 2001 by Elsevier Science Inc. PII S0041-1345(01)02437-X 655 Avenue of the Americas, New York, NY 10010 3338 Transplantation Proceedings, 33, 3338–3340 (2001)