RESUMO
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.
Assuntos
Alopurinol/farmacologia , Benzobromarona/farmacologia , Ciclosporina/toxicidade , Nefropatias/prevenção & controle , Animais , Proliferação de Células/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Fibrose/prevenção & controle , Hiperuricemia/induzido quimicamente , Hiperuricemia/prevenção & controle , Imuno-Histoquímica , Rim/efeitos dos fármacos , Rim/metabolismo , Rim/patologia , Nefropatias/induzido quimicamente , Masculino , Osteopontina/metabolismo , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , Ácido Úrico/sangue , Uricosúricos/farmacologia , Fator A de Crescimento do Endotélio Vascular/metabolismo , Xantina Oxidase/antagonistas & inibidores , Xantina Oxidase/metabolismoRESUMO
Hyperuricemia is a common complication in organ transplant recipients, with a higher incidence in kidney and heart recipients. Risk factors for post-transplant hyperuricemia include reduced glomerular filtration rate, diuretic use, cyclosporine therapy, increasing age at transplant, obesity, and metabolic syndrome, as well as the presence of pretransplant hyperuricemia. The impact of hyperuricemia in patient and graft survival is unclear because uric acid only recently has been considered a risk factor for cardiovascular disease and graft survival. The effect of uric acid on graft function remains controversial, with studies suggesting that uric acid is an independent risk factor for chronic allograft dysfunction, contrasting with other studies suggesting that hyperuricemia is only a marker of reduced glomerular filtration rate. Strategies to reduce uric acid levels include reduction or avoidance of cyclosporine treatment, adequacy of antihypertension treatment, avoidance of diuretics, nutritional management, and use of uric acid-lowering agents. In this article, we review the incidence and risk factors for the development of post-transplant hyperuricemia, the effect of different immunosuppressive regimens in uric acid handling, and recent results from studies comparing uric acid levels and renal function in organ transplant recipients that try to identify which comes first: hyperuricemia or chronic allograft dysfunction?
Assuntos
Hiperuricemia/complicações , Nefropatias/etiologia , Transplante de Rim , Complicações Pós-Operatórias/etiologia , Ácido Úrico/metabolismo , Sobrevivência de Enxerto , Humanos , Hiperuricemia/epidemiologia , Taxa de SobrevidaRESUMO
A nefrotoxicidade por ciclosporina caracteriza-se, do ponto de vista histológico, por fibrose intersticial em faixa, atrofia tubular e hialinose de arteríolas aferentes glomerulares, ou seja, um quadro compatível com doença renal isquêmica. Esta isquemia provocada pela ciclosporina leva a redução da taxa de filtração glomerular, com consequente elevação dos níveis séricos de ácido úrico. Além disto, a ciclosporina altera o transporte tubular de urato, favorecendo o desenvolvimento de hiperuricemia. No modelo experimental de nefropatia pela ciclosporina, a elevação dos níveis de ácido úrico apresenta associação com lesão túbulo intersticial mais severa, além de maior frequência de hialinose de arteríola aferente. Em estudos anteriores demonstramos que a hiperuricemia agrava a nefrotoxicidade pela ciclosporina e também que, a administração concomitante de agentes hipouricemiantes previne a lesão renal pela CsA. Assim, consideramos a hipótese de que, em um modelo experimental de nefropatia crônica pela ciclosporina, instalada, a normalização dos níveis de ácido úrico com alopurinol ou benzbromarona poderia reverter a lesão renal estabelecida. Nefropatia pela ciclosporina foi induzida em ratos Sprague Dawley com injeções subcutâneas diárias de ciclosporina, em associação com dieta hipossódica, por 5 semanas. Ao final deste período, grupos experimentais foram divididos com interrupção da ciclosporina, tratamento com CsA isolada ou em associação com alopurinol ou benzbromarona por um período adicional de 4 semanas. Ao final de 9 semanas de estudo, foram realizadas avaliações funcionais e histológicas...
Chronic allograft nephropathy is characterized by stripped tubular atrophy and interstitial fibrosis, in presence of arteriolar hyalinosis, resembling an ischemic pattern of chronic kidney disease. Chronic ischemia is associated with reduced glomerular filtration rate, and increase in serum uric acid levels. Cyclosporine per se also has a direct effect on tubular urate handling that facilitates the development of hyperuricemia. Hyperuricemia exacerbates chronic cyclosporine nephropathy, with a more severe tubulointerstitial fibrosis and atrophy, as well as worsening of arteriolar hyalinosis. In a previous study we have shown that concomitant treatment with uric acid lowering agents limits the development of experimental CsA nephropathy. The hypothesis of the present study was that treatment with uric acid lowering agents, after the development of CsA nephropathy could reverse or reduce the severity of tubulointerstitial disease. Male Sprague Dawley rats received daily SC injections of cyclosporine in presence of low salt diet, during 5 weeks. At the end of this period, experimental groups were assigned for CsA withdrawal, maintenance of daily CsA alone or associated with allopurinol or benzbromarone in drinking water for an additional period of 4 weeks. At the end of 9 weeks of study, rats were sacrificed for functional and morphological analysis of kidneys...