Use of uric acid-lowering agents limits experimental cyclosporine nephropathy

Abstract

Background: Hyperuricemia frequently complicates cyclosporine (CsA) therapy. Previous studies have shown that hyperuricemia exacerbates interstitial and vascular lesions in the cyclosporine model. We tested the hypothesis that normalization of uric acid could prevent the development of cyclosporine toxicity.

Methods: CsA nephropathy was induced by administering CsA (15 mg/kg/day) for 7 weeks to rats on a low salt diet (CsA group). The effect of preventing hyperuricemia was determined by concomitant treatment with a xanthine oxidase inhibitor, allopurinol (CsAALP), or with a uricosuric, benzbromarone (CsABENZ), in drinking water. Control groups included vehicle-treated rats.

Results: CsA-treated rats developed mild hyperuricemia with arteriolar hyalinosis, tubular atrophy, striped interstitial fibrosis, increased cell proliferation and decreased VEGF expression. Treatment with allopurinol or benzbromarone limited renal disease, with reduced interstitial fibrosis, cell proliferation, macrophage infiltration, osteopontin expression and arteriolar hyalinosis, in association with restoration of VEGF expression. Both drugs provided comparable protection.

Conclusions: An increase in uric acid exacerbates CsA nephropathy in the rat. Concomitant treatment with allopurinol or benzbromarone reduced the severity of renal disease. The similar protection observed with both drugs suggests that the effect is associated more with lowering uric acid levels than the antioxidant effect of allopurinol.

Fig. 1

a Tubular atrophy was significantly increased in the cyclosporine group compared to control. Treatment with allopurinol or benzbromarone reduced tubular lesion to a greater extent than controls. b Interstitial fibrosis, analyzed by Sirius red staining (×200), showed a similar pattern in the control group (c), stripped fibrosis pattern in CsA-treated animals (d), allopurinol group (e) and benzbromarone group (f) showing lower interstitial fibrosis. Arteriolar hyalinosis (g) and ischemic glomerulosclerosis (h) were increased in CsA-treated animals and limited by uric acid-lowering agent treatment (CsAALP or CsABENZ). ^a p < 0.05 vs. control; ^b p < 0.05 vs. CsA; ^c p < 0.05 vs. CsAALP; ^d p < 0.05 vs. CsABENZ.

Fig. 2

Fibrosis correlates with uric acid levels. There was a positive correlation between uric acid levels and percent of interstitial fibrosis (Spearman correlation, R² = 0.49; p < 0.05).

Fig. 3

a OPN expression was significantly increased in the CsA group compared to controls. Allopurinol therapy was associated with a reduction in OPN expression, but a strong effect was observed with benzbromarone treatment. b OPN staining in different groups. ×200. c Interstitial macrophage infiltration (ED-1+ cells) significantly increased in the CsA group compared to control. Treatment with uric acid-lowering agents partially limited interstitial inflammation (d) and macrophage infiltration (ED1 staining) in different groups. ×200. e VEGF expression was reduced in the cortex and medulla in CsA-treated animals, compared to control. Treatment with uric acid-lowering agents partially restored VEGF expression. f VEGF staining in different groups. ×200. ^a p < 0.05 vs. control; ^b p < 0.05 vs. CsA; ^c p < 0.05 vs. CsAALP; ^d p < 0.05 vs. CsABENZ.