title: 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.
authors: Division of Nephrology, School of Medical Sciences, State University of Campinas, UNICAMP, Campinas, Brazil.
authors: Fernanda Cristina
authors: FC
authors: Mazali
authors: Richard J
authors: RJ
authors: Johnson
authors: Marilda
authors: M
authors: Mazzali
mesh_terms: D000493:Allopurinol / Q000494:pharmacology*; D000818:Animals; D001553:Benzbromarone / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D016572:Cyclosporine / Q000633:toxicity*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005355:Fibrosis / Q000517:prevention & control; D033461:Hyperuricemia / Q000139:chemically induced / Q000517:prevention & control; D007150:Immunohistochemistry; D007668:Kidney / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D007674:Kidney Diseases / Q000139:chemically induced / Q000517:prevention & control*; D008297:Male; D053495:Osteopontin / Q000378:metabolism; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D014527:Uric Acid / Q000097:blood; D014528:Uricosuric Agents / Q000494:pharmacology; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D014969:Xanthine Oxidase / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D014528:Uricosuric Agents; D042461:Vascular Endothelial Growth Factor A; D053495:Osteopontin; D014527:Uric Acid; D001553:Benzbromarone; D000493:Allopurinol; D016572:Cyclosporine; D014969:Xanthine Oxidase