Impaired Glomerular and Tubular Function as a Short-Term Effect of Sirolimus Treatment in the Rat

Aims: To investigate acute and short-term effects of sirolimus (SRL) on glomerulo-tubular function, blood pressure (BP), and renal morphology in the rat. Methods: Male Sprague-Dawley rats, weighing initially 140–180 g were treated with SRL in three series: SRL 0.2, 0.4, or 0.8 mg/kg/day intraperitoneally for up to 28 days after skin allo-transplantation from Lewis donors (to establish a dosage with significant immunosuppressive effect). SRL 0.4 mg/kg intravenously (acute effects). SRL 0.4 mg/kg/day intraperitoneally for 7 days (short-term effects). Inulin, lithium (C Li ) and sodium clearance, and intra-arterial BP were measured in conscious catheterized rats. Morphological kidney studies were completed after post-mortem fixation. Results: Maximum immunosuppressive effect was achieved with SRL 0.4 mg/kg/day. SRL acutely increased GFR and C Li , whereas fractional proximal reabsorption (PFR) declined. In the short-term study SRL had opposite effects on GFR and C Li , unaffected proximal tubular reabsorption and PFR, raised BP, diminished food consumption, and slower increase in body weight. Morphological changes were non-specific. Conclusion: In a dosage giving maximum immunosuppressive effect, SRL revealed acute effects on glomerular and proximal tubular function thus indicating increased outflow from the proximal tubules whereas one week of SRL treatment produced a change resembling the known nephrotoxic effects of the calcineurine inhibitors.