Mycophenolate mofetil prevents the progressive renal failure induced by 5/6 renal ablation in rats

Background. Extensive renal ablation is associated with progressive scleros is of the remnant kidney. Because lymphocytes and monocytes accumulate in t he remnant kidney, it is likely that they play a role in the renal scarring . Therefore, we treated rats with 5/6 nephrectomy (5/6Nx) with mycophenolat e mofetil (MMF), a drug that has an antiproliferative effect and that suppr esses the expression of intercellular adhesion molecules. Methods. Sprague-Dawley rats with 5/6Nx received MMF (30 mg.kg(-1).day(-1) by daily gastric gavage, N = 15) or vehicle (N = 16). Ten additional rats w ere sham operated. All rats were fed a 30% protein diet. Body weight, serum creatinine, and urinary protein excretion were determined weekly. Lipid pe roxidation, as a measure of oxidative stress observed by urinary malondiald ehyde determinations, was performed every two weeks. Histologic studies wer e done in the remnant kidney four weeks (9 rats from the vehicle-treated gr oup, 7 rats from the MMF group, and 5 sham-operated rats) and eight weeks a fter surgery (the remaining rats). Glomerular volume, sclerosis in glomerul i (segmental and global) and interstitium (semi-quantitative scale), infilt rating lymphocytes and macrophages (CD43- and ED1-positive cells), and expr ession of adhesion molecules (CD54, CD18, and CD11b) were analyzed. Results. MMF treatment prevented the progressive increment in serum creatin ine and the proteinuria observed in the 5/6 nephrectomized rats during the eight weeks of observation (P < 0.01). Weight gain was comparable in the MM F-treated and sham-operated rats, whereas weight gain was decreased in untr eated 5/6 nephrectomized rats. Excretion of malondialdehyde increased after surgery but returned sooner to control levels in the MMF-treated rats. Inc rements in glomerular size and mean arterial blood pressure induced by rena l ablation were not modified by MMF treatment. Eight weeks after surgery, s egmental sclerosis was present in 48.4 +/- 8.35% (+/- SD) glomeruli in the vehicle-treated group versus 25 +/- 10.5% in the MMF-treated group (P < 0.0 01). Interstitial fibrosis was reduced significantly with MMF treatment (P < 0.001). Infiltration with CD43- and ED1-positive cells in glomeruli and i nterstitium was two to five times lower in MMF-treated rats (P < 0.01). Exp ression of adhesion molecules CD18 and CD11b was similarly reduced. Conclusion. MMF ameliorates the progressive renal damage in the remnant kid ney after 5/6Nx. This effect is associated with a reduction in the infiltra tion of lymphocytes and monocytes, whereas glomerular hypertrophy and syste mic hypertension are unchanged.