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.

Management of Gout and Hyperuricemia in CKD

“…96–101 In another rat model, allopurinol and benzbromarone limited the kidney damage caused by cyclosporine. 102 The effects of uricosurics (benziodarone, benzbromarone) in these experiments support the direct effects of UA rather than these effects being simply due to xanthine oxidase.…”

The Role of Uric Acid in Kidney Fibrosis: Experimental Evidences for the Causal Relationship

“…Thereafter, the research was performed using animal models of various kidney disease conditions, such as CsA nephropathy [36], diabetic nephropathy [38, 51], obstructive nephropathy [61], ischemia-reperfusion injury [62], and 5/6 nephrectomy rat model [34]. Further research using diverse animal models of CKD [79, 80] is essential not only for gaining a better understanding of molecular mechanisms of kidney fibrosis but also for designing more appropriate clinical studies.…”

Comorbidities in Patients with Crystal Diseases and Hyperuricemia

“…21,90 In a model of cyclosporine nephropathy, increasing urate worsened renal disease and ULT ameliorated renal damage. 91,92 An animal model of diabetic mice also showed that reducing SU improved diabetic nephropathy by reducing tubulointerstitial injury with no effect on glomerular damage. 93 …”