Hyperuricemia Exacerbates Chronic Cyclosporine Nephropathy1

BACKGROUND: Hyperuricemia frequently complicates cyclosporine (CSA) therapy. The observation that longstanding hyperuricemia is associated with chronic tubulointerstitial disease and intrarenal vasoconstriction raised the hypothesis that hyperuricemia might contribute to chronic CSA nephropathy. METHODS: CSA nephropathy was induced by the administration of CSA (15 mg/kg/day) for 5 and 7 weeks to rats on a low salt diet (CSA group). The effect of hyperuricemia on CSA nephropathy was determined by blocking the hepatic enzyme uricase with oxonic acid (CSA-OA). Control groups included rats treated with vehicle (VEH) and oxonic acid alone (OA). Histological and functional studies were determined at sacrifice. RESULTS: CSA treated rats developed mild hyperuricemia with arteriolar hyalinosis, tubular injury and striped interstitial fibrosis. CSA-OA treated rats had higher uric acid levels in association with more severe arteriolar hyalinosis and tubulointerstitial damage. Intrarenal urate crystal deposition was absent in all groups. Both CSA and CSA-OA treated rats had increased renin and decreased NOS1 and NOS3 in their kidneys, and these changes are more evident in CSA-OA treated rats. CONCLUSION: An increase in uric acid exacerbates CSA nephropathy in the rat. The mechanism does not involve intrarenal uric acid crystal deposition and appears to involve activation of the renin angiotensin system and inhibition of intrarenal nitric oxide production.