Effects of mycophenolate mofetil on acute ischaemia-reperfusion injury in rats and its consequences in the long term.

Background: Renal ischaemia-reperfusion injury (IRI) acutely decreases glomerular filtration rate (GFR) and impairs kidney function in the long term. Pre-treatment with chaetomellic acid (KM), an inhibitor of membrane-bound Ha-Ras, has demonstrated beneficial effects on acute renal ischaemia.

Methods: We tested whether mycophenolate mofetil (MMF, 20 mg/day for 4 days before IRI), an immunosuppressor with anti-inflammatory properties, improved renal outcome in uninephrectomized rats after IRI (45 min of renal ischaemia), alone or in combination with KM.

Results: One day after ischaemia, GFR was markedly depressed in untreated rats (-75% vs. normal rats, P < 0.001), and pre-treatment with MMF did not modify this fall (-75%, P < 0.001 vs. normal). KM (0.23 microg/kg before IRI) greatly prevented GFR loss (-39% vs. normal, P < 0.05), but its action was not further improved by the combined administration with MMF (GFR, -45% vs. normal, P < 0.05). MMF significantly reduced ICAM-1 expression and monocyte recruitment (P < 0.05 vs. untreated rats); nevertheless, renal histology of MMF rats was similar to that of untreated rats. Additional rats were examined 6 months after IRI: untreated rats with IRI showed reduced renal function (-42% vs. normal, P < 0.01) and proteinuria (P < 0.001 vs. normal); rats pre-treated with MMF showed a similar pattern, whereas rats treated with KM before IRI presented a better GFR (-20% vs. normal, not significant) and near-normal values of proteinuria. The combination of KM + MMF gained the same results.

Conclusions: Pre-treatment with MMF before IRI does not confer functional or morphological protection to the kidney, despite the reduced expression of some inflammatory markers. The combination of MMF + KM does not offer additional advantages to solitary KM treatment.