Article Association of Hyperuricemia with Renal Outcomes, Cardiovascular Disease, and Mortality Wan-Chun Liu,* † Chi-Chih Hung, † Szu-Chia Chen,* † Shih-Meng Yeh, † Ming-Yen Lin, † Yi-Wen Chiu, †‡ Mei-Chuan Kuo, † Jer-Ming Chang,* †‡ Shang-Jyh Hwang, †‡ and Hung-Chun Chen †‡ Background and objectives Hyperuricemia is an independent risk factor for mortality, cardiovascular disease, and renal disease in general population. However, the relationship between hyperuricemia with clinical outcomes in CKD remains controversial. Design, setting, participants, & measurements The study investigated the association between uric acid with all- cause mortality, cardiovascular events, renal replacement therapy, and rapid renal progression (the slope of estimated GFR was less than 26 ml/min per 1.73 m 2 /y) in 3303 stages 3–5 CKD patients that were in the integrated CKD care system in one medical center and one regional hospital in southern Taiwan. Results In all subjects, the mean uric acid level was 7.962.0 mg/dl. During a median 2.8-year follow-up, there were 471 (14.3%) deaths, 545 (16.5%) cardiovascular events, 1080 (32.3%) participants commencing renal re- placement therapy, and 841 (25.5%) participants with rapid renal progression. Hyperuricemia increased risks for all-cause mortality and cardiovascular events (the adjusted hazard ratios for quartile four versus quartile one of uric acid [95% confidence interval] were 1.85 [1.40–2.44] and 1.42 [1.08–1.86], respectively) but not risks for renal replacement therapy (0.96 [0.79–1.16]) and rapid renal progression (1.30 [0.98–1.73]). Conclusions In stages 3–5 CKD, hyperuricemia is a risk factor for all-cause mortality and cardiovascular events but not renal replacement therapy and rapid renal progression. Clin J Am Soc Nephrol 7: ccc–ccc, 2012. doi: 10.2215/CJN.09420911 Introduction A large number of epidemiologic studies have sug- gested the independent role of hyperuricemia on in- creased mortality, cardiovascular disease (CVD), and renal disease in the general population (1–6). How- ever, published data on CKD is limited and incon- sistent. Hyperuricema is highly prevalent in CKD, which might account for the decreased renal excretion of uric acid when renal function declines and the as- sociation of hyperuricemia with various risk factors for CKD, such as hypertension and diabetes melli- tus (DM) (1,7,8). In CKD, it is unclear whether uric acid is merely a marker that reflects the integration of comorbidities and renal damage or a true risk-causative factor for clinical outcomes. Previous epidemiologic studies in predialysis or dialysis patients suggested a J-shaped association between uric acid and mortality (9,10), whereas stud- ies in earlier-stage CKD found a linear relationship for all-cause and cardiovascular mortality (11). In studies regarding uric acid to renal outcome, one study found that hyperuricemia damaged residual renal function in peritoneal dialysis patients (12); one study suggested a weak association in CKD subjects (13), whereas an- other study repudiated this association (11). A recent small, randomized control trial showed that allopu- rinol treatment lowered uric acid level, slowed renal progression, and reduced cardiovascular and hospital- ization risk in moderate CKD (14). These published data were controversial and limited in sample sizes, population difference, data for calcium, phosphate, and proteinuria, and medication use. We investigated 3303 stages 3–5 patients from a CKD care system in southern Taiwan to answer the question of whether uric acid is an independent risk factor for mortality, cardiovascular events, and renal outcome. Materials and Methods Participants and Measurements Between November 11, 2002 and May 31, 2009, 3749 patients who joined the Integrated CKD Care Program Kaohsiung for Delaying Dialysis prospective obser- vation study from two affiliated hospitals (Kaohsiung Medical University Hospital and Kaohsiung Municipal Hsiao-Kang Hospital) of Kaohsiung Medical Univer- sity in southern Taiwan were included and followed until May 31, 2010. The definition of CKD by National Kidney Foundation Kidney Disease Outcomes Qual- ity Initiative Guidelines was used, and the CKD stage was classified using subjects’ baseline estimated GFR (eGFR). Most of the participants were referred from local medical units or other specialists in the two *Department of Internal Medicine, Kaohsiung Municipal Hsiao-Kang Hospital, Kaohsiung, Taiwan; † Division of Nephrology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan; and ‡ Department of Internal Medicine, Faculty of Renal Care, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan Correspondence: Dr. Shang-Jyh Hwang, Division of Nephrology, Department of Internal Medicine, Chung-Ho Memorial Hospital, Kaohsiung Medical University, 100 Tzyou First Road, Kaohsiung 807, Taiwan. Email: sjhwang@kmu.edu.tw www.cjasn.org Vol 7 April, 2012 Copyright © 2012 by the American Society of Nephrology 1 . Published on February 2, 2012 as doi: 10.2215/CJN.09420911 CJASN ePress