A Role for Uric Acid in the Progression of Renal Disease DUK-HEE KANG,* †‡ TAKAHIKO NAKAGAWA,* LILI FENG,* SUSUMU WATANABE,* LIN HAN,* MARILDA MAZZALI,* LUAN TRUONG, § RAYMOND HARRIS, ¶ and RICHARD J JOHNSON* † *Division of Nephrology, Baylor College of Medicine, Houston, Texas; † Division of Nephrology, University of Washington, Seattle, Washington; ‡ Division of Nephrology, Ewha Women’s University College of Medicine, Ewha Medical Research Center, Seoul, Korea; § Division of Pathology, Baylor College of Medicine, Houston, Texas; and ¶ Division of Nephrology, Vanderbilt School of Medicine, Nashville, Tennessee. Abstract. Hyperuricemia is associated with renal disease, but it is usually considered a marker of renal dysfunction rather than a risk factor for progression. Recent studies have reported that mild hyperuricemia in normal rats induced by the uricase inhibitor, oxonic acid (OA), results in hypertension, intrarenal vascular disease, and renal injury. This led to the hypothesis that uric acid may contribute to progressive renal disease. To examine the effect of hyperuricemia on renal disease progres- sion, rats were fed 2% OA for 6 wk after 5/6 remnant kidney (RK) surgery with or without the xanthine oxidase inhibitor, allopurinol, or the uricosuric agent, benziodarone. Renal func- tion and histologic studies were performed at 6 wk. Given observations that uric acid induces vascular disease, the effect of uric acid on vascular smooth muscle cells in culture was also examined. RK rats developed transient hyperuricemia (2.7 mg/dl at week 2), but then levels returned to baseline by week 6 (1.4 mg/dl). In contrast, RK+OA rats developed higher and more persistent hyperuricemia (6 wk, 3.2 mg/dl). Hyperurice- mic rats demonstrated higher BP, greater proteinuria, and higher serum creatinine than RK rats. Hyperuricemic RK rats had more renal hypertrophy and greater glomerulosclerosis (24.2  2.5 versus 17.5  3.4%; P  0.05) and interstitial fibrosis (1.89  0.45 versus 1.52  0.47; P  0.05). Hyper- uricemic rats developed vascular disease consisting of thick- ening of the preglomerular arteries with smooth muscle cell proliferation; these changes were significantly more severe than a historical RK group with similar BP. Allopurinol sig- nificantly reduced uric acid levels and blocked the renal func- tional and histologic changes. Benziodarone reduced uric acid levels less effectively and only partially improved BP and renal function, with minimal effect on the vascular changes. To better understand the mechanism for the vascular disease, the expression of COX-2 and renin were examined. Hyperuricemic rats showed increased renal renin and COX-2 expression, the latter especially in preglomerular arterial vessels. In in vitro studies, cultured vascular smooth muscle cells incubated with uric acid also generated COX-2 with time-dependent prolifer- ation, which was prevented by either a COX-2 or TXA-2 receptor inhihbitor. Hyperuricemia accelerates renal progres- sion in the RK model via a mechanism linked to high systemic BP and COX-2–mediated, thromboxane-induced vascular dis- ease. These studies provide direct evidence that uric acid may be a true mediator of renal disease and progression. Hyperuricemia has long been associated with renal disease. Approximately 20 to 60% of patients with gout have mild or moderate renal dysfunction (1); before the availability of uric acid lowering agents, as many as 10 to 25% of patients with gout developed end-stage renal disease (2). The histologic lesion termed “gouty nephropathy” consists of glomeruloscle- rosis, interstitial fibrosis, and renal arteriolosclerosis, often with focal interstitial urate crystal deposition (2,3). These his- tologic findings have been observed in autopsies of 79 to 99% of patients with gout (3). Despite the association of gout with renal disease, contro- versy exists as to whether uric acid has an etiologic role (4 – 6). First, it has been difficult to ascribe the generalized renal injury in gout to the deposition of urate crystals, for they are often only focally present. Second, many patients with gout have hypertension or are elderly, and the renal lesions might simply reflect hypertensive or aging-associated renal damage (1). Third, results of the studies are mixed as to whether lowering uric acid will slow renal progression in patients with gout (7,8). The inability to resolve this issue has emphasized the need for additional studies (6). To investigate the role of uric acid in renal disease, we recently developed a model of hyperuricemia in rats (9). Most mammals have a low serum uric acid due to the presence of uricase; in humans and the Great Apes, the uricase gene was mutated and rendered nonfunctional. We therefore induced hyperuricemia in rats by providing low doses of oxonic acid, which is a uricase inhibitor. Unlike previous models of uricase Received May 31, 2002. Accepted August 1, 2002. Dr. Jared Grantham served as guest editor and supervised the review and final disposition of this manuscript. Correspondence to Dr. Duk-Hee Kang, Division of Nephrology, Ewha Wom- en’s University Hospital, 70 Chongno 6-ka Chongno-ku Seoul 110-126, Korea. Phone: 82-2-760-5121; Fax: 82-2-760-5008; E-mail: dhkang@ewha.ac.kr 1046-6673/1312-2888 Journal of the American Society of Nephrology Copyright © 2002 by the American Society of Nephrology DOI: 10.1097/01.ASN.0000034910.58454.FD J Am Soc Nephrol 13: 2888–2897, 2002