American Journal of Kidney Diseases

Uric Acid and the Risks of Kidney Failure and Death in Individuals With CKD

  • Anand Srivastava
    Address for Correspondence: Anand Srivastava, MD, MPH, Center for Translational Metabolism and Health, Institute for Public Health and Medicine, Division of Nephrology and Hypertension, Northwestern University Feinberg School of Medicine, 633 N St Clair St, Ste 18-083, Chicago, IL 60611.
    Renal Division, Brigham & Women’s Hospital, Boston, MA

    Division of Nephrology and Hypertension, Center for Translational Metabolism and Health, Institute for Public Health and Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL
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  • Arnaud D. Kaze
    Renal Division, Brigham & Women’s Hospital, Boston, MA
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  • Ciaran J. McMullan
    Renal Division, Brigham & Women’s Hospital, Boston, MA
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  • Tamara Isakova
    Division of Nephrology and Hypertension, Center for Translational Metabolism and Health, Institute for Public Health and Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL
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  • Sushrut S. Waikar
    Renal Division, Brigham & Women’s Hospital, Boston, MA
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Published:November 10, 2017DOI:


      Serum uric acid concentrations increase in chronic kidney disease (CKD) and may lead to tubular injury, endothelial dysfunction, oxidative stress, and intrarenal inflammation. Whether uric acid concentrations are associated with kidney failure and death in CKD is unknown.

      Study Design

      Prospective observational cohort study.

      Settings & Participants

      3,885 individuals with CKD stages 2 to 4 enrolled in the Chronic Renal Insufficiency Cohort (CRIC) between June 2003 and September 2008 and followed up through March 2013.


      Baseline uric acid concentrations.


      Kidney failure (initiation of dialysis therapy or transplantation) and all-cause mortality.


      During a median follow-up of 7.9 years, 885 participants progressed to kidney failure and 789 participants died. After adjustment for demographic, cardiovascular, and kidney-specific covariates, higher uric acid concentrations were independently associated with risk for kidney failure in participants with estimated glomerular filtration rates (eGFRs) ≥ 45 mL/min/1.73 m2 (adjusted HR per 1−standard deviation greater baseline uric acid, 1.40; 95% CI, 1.12-1.75), but not in those with eGFRs < 30 mL/min/1.73 m2. There was a nominally higher HR in participants with eGFRs of 30 to 44 mL/min/1.73 m2 (adjusted HR, 1.13; 95% CI, 0.99-1.29), but this did not reach statistical significance. The relationship between uric acid concentration and all-cause mortality was J-shaped (P = 0.007).


      Potential residual confounding through unavailable confounders; lack of follow-up measurements to adjust for changes in uric acid concentrations over time.


      Uric acid concentration is an independent risk factor for kidney failure in earlier stages of CKD and has a J-shaped relationship with all-cause mortality in CKD. Adequately powered randomized placebo-controlled trials in CKD are needed to test whether urate lowering may prove to be an effective approach to prevent complications and progression of CKD.

      Index Words

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        • Masuo K.
        • Kawaguchi H.
        • Mikami H.
        • Ogihara T.
        • Tuck M.L.
        Serum uric acid and plasma norepinephrine concentrations predict subsequent weight gain and blood pressure elevation.
        Hypertension. 2003; 42: 474-480
        • Cirillo P.
        • Sato W.
        • Reungjui S.
        • et al.
        Uric acid, the metabolic syndrome, and renal disease.
        J Am Soc Nephrol. 2006; 17: S165-S168
        • Nakanishi N.
        • Okamoto M.
        • Yoshida H.
        • Matsuo Y.
        • Suzuki K.
        • Tatara K.
        Serum uric acid and risk for development of hypertension and impaired fasting glucose or type II diabetes in Japanese male office workers.
        Eur J Epidemiol. 2003; 18: 523-530
        • Bos M.J.
        • Koudstaal P.J.
        • Hofman A.
        • Witteman J.C.
        • Breteler M.M.
        Uric acid is a risk factor for myocardial infarction and stroke: the Rotterdam study.
        Stroke. 2006; 37: 1503-1507
        • Feig D.I.
        • Kang D.H.
        • Johnson R.J.
        Uric acid and cardiovascular risk.
        N Engl J Med. 2008; 359: 1811-1821
        • Silbernagel G.
        • Hoffmann M.M.
        • Grammer T.B.
        • Boehm B.O.
        • Marz W.
        Uric acid is predictive of cardiovascular mortality and sudden cardiac death in subjects referred for coronary angiography.
        Nutr Metab Cardiovasc Dis. 2013; 23: 46-52
        • Howard S.
        • Jones D.
        • Ching-Hon P.
        The tumor lysis syndrome.
        N Engl J Med. 2011; 364: 1844-1854
        • Mazzali M.
        • Hughes J.
        • Kim Y.
        • et al.
        Elevated uric acid increases blood pressure in the rat by a novel crystal-independent mechanism.
        Hypertension. 2001; 38: 1101-1106
        • Sanchez-Lozada L.G.
        • Lanaspa M.A.
        • Cristobal-Garcia M.
        • et al.
        Uric acid-induced endothelial dysfunction is associated with mitochondrial alterations and decreased intracellular ATP concentrations.
        Nephron Exp Nephrol. 2012; 121: e71-e78
        • Rabadi M.M.
        • Kuo M.C.
        • Ghaly T.
        • et al.
        Interaction between uric acid and HMGB1 translocation and release from endothelial cells.
        Am J Physiol Renal Physiol. 2012; 302: F730-F741
        • Zoccali C.
        • Maio R.
        • Mallamaci F.
        • Sesti G.
        • Perticone F.
        Uric acid and endothelial dysfunction in essential hypertension.
        J Am Soc Nephrol. 2006; 17: 1466-1471
        • Sanchez-Lozada L.
        • Tapia E.
        • Santamaria J.
        • et al.
        Mild hyperuricemia induces vasoconstriction and maintains glomerular hypertension in normal and remnant kidney rats.
        Kidney Int. 2005; 67: 237-247
        • Zhou Y.
        • Fang L.
        • Jiang L.
        • et al.
        Uric acid induces renal inflammation via activating tubular NF-kappaB signaling pathway.
        PLoS One. 2012; 7: e39738
        • Kurts C.
        A crystal-clear mechanism of chronic kidney disease.
        Kidney Int. 2013; 84: 859-861
        • Corry D.B.
        • Eslami P.
        • Yamamoto K.
        • Nyby M.D.
        • Makino H.
        • Tuck M.L.
        Uric acid stimulates vascular smooth muscle cell proliferation and oxidative stress via the vascular renin-angiotensin system.
        J Hypertens. 2008; 26: 269-275
        • Yu M.A.
        • Sanchez-Lozada L.G.
        • Johnson R.J.
        • Kang D.H.
        Oxidative stress with an activation of the renin-angiotensin system in human vascular endothelial cells as a novel mechanism of uric acid-induced endothelial dysfunction.
        J Hypertens. 2010; 28: 1234-1242
        • Weiner D.E.
        • Tighiouart H.
        • Elsayed E.F.
        • Griffith J.L.
        • Salem D.N.
        • Levey A.S.
        Uric acid and incident kidney disease in the community.
        J Am Soc Nephrol. 2008; 19: 1204-1211
        • Hsu C.Y.
        • Iribarren C.
        • McCulloch C.E.
        • Darbinian J.
        • Go A.
        Risk factors for end-stage renal disease: 25 year follow-up.
        Arch Intern Med. 2009; 169: 342-350
        • Krishnan E.
        • Akhras K.S.
        • Sharma H.
        • et al.
        Serum urate and incidence of kidney disease among veterans with gout.
        J Rheumatol. 2013; 40: 1166-1172
        • Chonchol M.
        • Shlipak M.G.
        • Katz R.
        • et al.
        Relationship of uric acid with progression of kidney disease.
        Am J Kidney Dis. 2007; 50: 239-247
        • Madero M.
        • Sarnak M.J.
        • Wang X.
        • et al.
        Uric acid and long-term outcomes in CKD.
        Am J Kidney Dis. 2009; 53: 796-803
        • Ficociello L.H.
        • Rosolowsky E.T.
        • Niewczas M.A.
        • et al.
        High-normal serum uric acid increases risk of early progressive renal function loss in type 1 diabetes: results of a 6-year follow-up.
        Diabetes Care. 2010; 33: 1337-1343
        • Ishani A.
        • Grandits G.A.
        • Grimm R.H.
        • et al.
        Association of single measurements of dipstick proteinuria, estimated glomerular filtration rate, and hematocrit with 25-year incidence of end-stage renal disease in the Multiple Risk Factor Intervention trial.
        J Am Soc Nephrol. 2006; 17: 1444-1452
        • Goicoechea M.
        • de Vinuesa S.G.
        • Verdalles U.
        • et al.
        Effect of allopurinol in chronic kidney disease progression and cardiovascular risk.
        Clin J Am Soc Nephrol. 2010; 5: 1388-1393
        • Siu Y.P.
        • Leung K.T.
        • Tong M.K.
        • Kwan T.H.
        Use of allopurinol in slowing the progression of renal disease through its ability to lower serum uric acid level.
        Am J Kidney Dis. 2006; 47: 51-59
        • Sircar D.
        • Chatterjee S.
        • Waikhom R.
        • et al.
        Efficacy of febuxostat for slowing the GFR decline in patients with CKD and asymptomatic hyperuricemia: a 6-month, double-blind, randomized, placebo-controlled trial.
        Am J Kidney Dis. 2015; 66: 945-950
        • Levy G.
        • Rashid N.
        • Fang N.
        • Cheetham C.
        Effect of urate-lowering therapies on renal disease progression in patients with hyperuricemia.
        J Rheumatol. 2014; 41: 955-962
        • Feldman H.
        • Appel L.
        • Chertow G.
        • et al.
        The Chronic Renal Insufficiency Cohort (CRIC) Study: design and methods.
        J Am Soc Nephrol. 2003; 14: 148S-153S
        • Denker M.
        • Boyle S.
        • Anderson A.H.
        • et al.
        Chronic Renal Insufficiency Cohort Study (CRIC): overview and summary of selected findings.
        Clin J Am Soc Nephrol. 2015; 10: 2073-2083
        • Lash J.P.
        • Go A.S.
        • Appel L.J.
        • et al.
        Chronic Renal Insufficiency Cohort (CRIC) Study: baseline characteristics and associations with kidney function.
        Clin J Am Soc Nephrol. 2009; 4: 1302-1311
        • Bhatnagar V.
        • Richard E.L.
        • Wu W.
        • et al.
        Analysis of ABCG2 and other urate transporters in uric acid homeostasis in chronic kidney disease: potential role of remote sensing and signaling.
        Clin Kidney J. 2016; 9: 444-453
        • Levey A.
        • Stevens L.
        • Schmid C.
        • et al.
        A new equation to estimate glomerular filtration rate.
        Ann Intern Med. 2009; 150: 604-612
        • Govindarajulu U.
        • Malloy E.
        • Ganguli B.
        • Spiegelman D.
        • Eisen E.
        The comparison of alternative smoothing methods for fitting non-linear exposure-response relationships with Cox models in a simulation study.
        Int J Biostat. 2009; 5: 1557-4679
        • Fine J.
        • Gray R.
        A proportional hazards model for the subdistribution of a competing risk.
        J Am Stat Assoc. 1999; 94: 496-509
        • Ames B.
        • Cathcart R.
        • Schwiers E.
        • Hocstein P.
        Uric acid provides an antioxidant defense in humans against oxidant- and radical-cause aging and cancer: a hypothesis.
        Proc Natl Acad Sci U S A. 1981; 11: 6858-6862
        • Davies K.
        • Sevanian A.
        • Muakkassah-Kelly S.
        • Hochstein P.
        Uric acid-iron ion complexes: a new aspect of the antioxidant functions of uric acid.
        Biochem J. 1986; 235: 747-754
        • Schwarzschild M.A.
        • Ascherio A.
        • Beal M.F.
        • et al.
        • The Parkinson Study Group SURE-PD Investigators
        Inosine to increase serum and cerebrospinal fluid urate in Parkinson disease: a randomized clinical trial.
        JAMA Neurol. 2014; 71: 141-150
        • Johnson R.J.
        • Nakagawa T.
        • Jalal D.
        • Sanchez-Lozada L.G.
        • Kang D.H.
        • Ritz E.
        Uric acid and chronic kidney disease: which is chasing which?.
        Nephrol Dial Transplant. 2013; 28: 2221-2228
        • Kumagai T.
        • Ota T.
        • Tamura Y.
        • Chang W.X.
        • Shibata S.
        • Uchida S.
        Time to target uric acid to retard CKD progression.
        Clin Exp Nephrol. 2016; 21: 182-192
        • Sturm G.
        • Kollerits B.
        • Neyer U.
        • Ritz E.
        • Kronenberg F.
        • Mild to Moderate Kidney Disease Study Group
        Uric acid as a risk factor for progression of non-diabetic chronic kidney disease? The Mild to Moderate Kidney Disease (MMKD) Study.
        Exp Gerontol. 2008; 43: 347-352
        • Latif W.
        • Karaboyas A.
        • Tong L.
        • et al.
        Uric acid levels and all-cause and cardiovascular mortality in the hemodialysis population.
        Clin J Am Soc Nephrol. 2011; 6: 2470-2477
        • Testa A.
        • Mallamaci F.
        • Spoto B.
        • et al.
        Association of a polymorphism in a gene encoding a urate transporter with CKD progression.
        Clin J Am Soc Nephrol. 2014; 9: 1059-1065
        • Ahola A.J.
        • Sandholm N.
        • Forsblom C.
        • et al.
        The serum uric acid concentration is not causally linked to diabetic nephropathy in type 1 diabetes.
        Kidney Int. 2017; 91: 1178-1185
        • Navaneethan S.D.
        • Beddhu S.
        Associations of serum uric acid with cardiovascular events and mortality in moderate chronic kidney disease.
        Nephrol Dial Transplant. 2009; 24: 1260-1266
        • Suliman M.E.
        • Johnson R.J.
        • Garcia-Lopez E.
        • et al.
        J-shaped mortality relationship for uric acid in CKD.
        Am J Kidney Dis. 2006; 48: 761-771
        • Lee S.M.
        • Lee A.L.
        • Winters T.J.
        • et al.
        Low serum uric acid level is a risk factor for death in incident hemodialysis patients.
        Am J Nephrol. 2009; 29: 79-85
        • Matsukuma Y.
        • Masutani K.
        • Tanaka S.
        • et al.
        A J-shaped association between serum uric acid levels and poor renal survival in female patients with IgA nephropathy.
        Hypertens Res. 2017; 40: 291-297
        • Yelken B.
        • Caliskan Y.
        • Gorgulu N.
        • Altun I.
        • et al.
        Reduction of uric acid levels with allopurinol treatment improves endothelial function in patients with chronic kidney disease.
        Clin Nephrol. 2012; 77: 275-282
        • Kanbay M.
        • Huddam B.
        • Azak A.
        • et al.
        A randomized study of allopurinol on endothelial function and estimated glomular filtration rate in asymptomatic hyperuricemic subjects with normal renal function.
        Clin J Am Soc Nephrol. 2011; 6: 1887-1894
        • Kao M.P.
        • Ang D.S.
        • Gandy S.J.
        • et al.
        Allopurinol benefits left ventricular mass and endothelial dysfunction in chronic kidney disease.
        J Am Soc Nephrol. 2011; 22: 1382-1389
        • Jalal D.
        • Decker E.
        • Perrenoud L.
        • et al.
        Vascular function and uric acid-lowering in stage 3 CKD.
        J Am Soc Nephrol. 2016; 28: 943-952
        • Maahs D.M.
        • Caramori L.
        • Cherney D.Z.
        • et al.
        Uric acid lowering to prevent kidney function loss in diabetes: the preventing early renal function loss (PERL) allopurinol study.
        Curr Diab Rep. 2013; 13: 550-559