Comparison of acute rapamycin nephrotoxicity with cyclosporine and FK506

Abstract

Acute cyclosporine (CsA) nephrotoxicity is characterized by a reduction of glomerular filtration rate (GFR), hypomagnesemia and tubular injury. The mechanisms of CsA's immunosuppressive action and presumably its nephrotoxicity are mediated through inhibition of the renal phosphatase, calcineurin. FK506 (FK), which has a different chemical structure and binding immunophilin, also inhibits calcineurin. We compared the renal effects of these drugs to those of rapamycin (RAPA), which although similar in structure and intracellular binding to FK, does not work by changing calcineurin activity. Rats were given CsA (15 mg/kg/s.c.), FK (6 mg/kg/p.o.), RAPA (3 mg/kg/p.o.) or vehicle (V) for two weeks on a low salt diet. CsA and FK strikingly decreased urinary excretion of nitric oxide, renal blood flow and GFR, whereas RAPA did not. In contrast, all these three drugs caused significant hypomagnesemia associated with inappropriately high fractional excretion of magnesium, suggesting renal magnesium wasting. In addition, with all three drugs there were lesions in the rat kidneys consisting of tubular collapse, vacuolization and nephrocalcinosis. We thus showed that only the calcineurin inhibitors produced glomerular dysfunction in an acute experimental model of nephrotoxicity. The mechanism of hypomagnesemia and tubular injury induced by all three immunosuppressive drugs is unclear but may be independent of calcineurin. The mechanism of renal vasoconstriction on the other hand may be related to inhibition of calcineurin.

Tacrolimus (FK506) and methotrexate as prophylaxis for acute graft-versus-host disease in pediatric allogeneic stem cell transplantation

“…25 The major adverse effects previously reported with tacrolimus have included nephrotoxicity, neurotoxicity, hyperglycemia, and hypertension. [29][30][31][32] Other commonly reported side-effects include microangiopathic hemolytic anemias, 33 hyperkalemia, 34 hypomagnesemia, 35 and hypercholesterolemia. 36 Unlike cyclosporine, tacrolimus rarely causes gingival hyperplasia or hirsutism.…”

mTOR inhibitors: An overview

“…When renal blood flow and glomerular filtration rate were compared in rats treated with sirolimus (3 mg/kg/d orally), cyclosporine A (15 mg/kg/d subcutaneously), or tacrolimus (5 mg/kg/d orally), significantly better renal function was found in the sirolimus group compared with the cyclosporine A and tacrolimus groups. 74 In another study 75 of spontaneously hypertensive rats, creatinine clearance was not altered by continuous infusion of sirolimus (0.01 mg/kg), but was reduced by 20% after infusion of cyclosporine A (5 mg/kg).…”

Effects of sirolimus alone or in combination with cyclosporine A on renal ischemia/reperfusion injury

“…Burdmann et al (27) demonstrated that there was an increase in enzymuria 14 days after CsA or FK506 administration, which did not occur with SRL. Whiting et al (28) showed that SRL and CsA together caused a significant increase in enzymuria and a reduction of GFR, both effects attributable to additive renal toxicity (29,30). Lieberthal et al (15) demonstrated that recovery of renal function was delayed in rats treated with SRL on days 3 and 4 after 40-min ischemia.…”