Phosphorus Restriction Prevents Rapamycin-Induced Kidney Damage in Rats.

Abstract

Introduction: There are conflicting reports about the effect or rapamycin on the kidneys. Rapamycin is known to promote phosphaturia that may be associated to renal injury.

Methods: Detailed histopathological studies were performed on the kidneys of rats with normal (control) and reduced (Nx) renal mass that were treated with rapamycin (1.3 mg/kg for 22 days) or placebo. The effect of rapamycin was also evaluated in control and Nx rats fed different amounts of phosphorus: 0.6% P (NP), 1.2% P (HP), and 0.2% P (LP). Quantitative scores of kidney lesions were obtained for interstitial nephritis (IN), tubular damage (TD), and nephrocalcinosis (NC).

Results: When compared with placebo, rapamycin administration to Nx rats resulted in significant increases in IN (4.17 ± 0.74 vs. 1.51 ± 0.53%) and TD (14.45 ± 1.51 vs. 8.61 ± 1.83%). Rapamycin also increased NC both in control (0.86 ± 0.23 vs. 0.14 ± 0.06%) and Nx (0.86 ± 0.32 vs. 0.15 ± 0.14%) rats. In control rats receiving rapamycin, feeding HP aggravated IN (3.25 ± 0.48%), TD (22.47 ± 4.56%), and NC (3.66 ± 0.75%), while feeding LP prevented development of any renal lesions. In Nx rats treated with rapamycin, HP intake also increased IN (8.95 ± 1.94%), TD (26.86 ± 3.95%), and NC (2.77 ± 0.60%), whereas feeding LP reduced all lesions to lower levels than in rats fed NP. Rapamycin treatment increased fractional excretion of P (FEP), and an excellent correlation between scores for renal lesions and FEP was found.

Conclusion: Rapamycin has deleterious effects on kidney pathology causing lesions that are located mainly at tubular and tubulointerstitial level. Rapamycin-induced kidney damage is more evident in rats that already have decreased renal function and seems to be related to the phosphaturic effect of the drug. Dietary P restriction prevents kidney damage in rats treated with rapamycin.