Impaired glomerular and tubular function as a short-term effect of sirolimus treatment in the rat.
OBJECTIVE
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.


CONCLUSIONS
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.
Nielsen
Finn Thomsen
FT
Laboratory of Nephropathology, Department of Nephrology Y, Odense University Hospital, Denmark.
Starklint
Henrik
H
Dieperink
Hans
H
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects*; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007668:Kidney / Q000187:drug effects* / Q000473:pathology / Q000503:physiopathology; D007678:Kidney Glomerulus / Q000187:drug effects; D007684:Kidney Tubules / Q000187:drug effects; D008297:Male; D023421:Models, Animal; D051381:Rats; D017207:Rats, Sprague-Dawley; D020123:Sirolimus / Q000494:pharmacology*; D016038:Skin Transplantation; D014184:Transplantation, Homologous
D007166:Immunosuppressive Agents; D020123:Sirolimus