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American Journal of Kidney Diseases

Management of Gout and Hyperuricemia in CKD

Published:April 26, 2017DOI:https://doi.org/10.1053/j.ajkd.2017.01.055
      Hyperuricemia and gout, the clinical manifestation of monosodium urate crystal deposition, are common in patients with chronic kidney disease (CKD). Although the presence of CKD poses additional challenges in gout management, effective urate lowering is possible for most patients with CKD. Initial doses of urate-lowering therapy are lower than in the non-CKD population, whereas incremental dose escalation is guided by regular monitoring of serum urate levels to reach the target level of < 6 mg/dL (or < 5 mg/dL for patients with tophi). Management of gout flares with presently available agents can be more challenging due to potential nephrotoxicity and/or contraindications in the setting of other common comorbid conditions. At present, asymptomatic hyperuricemia is not an indication for urate-lowering therapy, though emerging data may support a potential renoprotective effect.

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      References

        • Kuo C.F.
        • Grainge M.J.
        • Zhang W.
        • Doherty M.
        Global epidemiology of gout: prevalence, incidence and risk factors.
        Nat Rev Rheumatol. 2015; 11: 649-662
        • Zhu Y.
        • Pandya B.J.
        • Choi H.K.
        Prevalence of gout and hyperuricemia in the US general population: the National Health and Nutrition Examination Survey 2007-2008.
        Arthritis Rheum. 2011; 63: 3136-3141
        • Johnson R.J.
        Why focus on uric acid?.
        Curr Med Res Opin. 2015; 31: 3-7
        • Roughley M.J.
        • Belcher J.
        • Mallen C.D.
        • Roddy E.
        Gout and risk of chronic kidney disease and nephrolithiasis: meta-analysis of observational studies.
        Arthritis Res Ther. 2015; 17: 90
        • Krishnan E.
        Reduced glomerular function and prevalence of gout: NHANES 2009-10.
        PLoS One. 2012; 7: e50046
        • Zhu Y.
        • Pandya B.J.
        • Choi H.K.
        Comorbidities of gout and hyperuricemia in the US general population: NHANES 2007-2008.
        Am J Med. 2012; 125: 679-687 e1
        • Fraser S.D.
        • Roderick P.J.
        • May C.R.
        • et al.
        The burden of comorbidity in people with chronic kidney disease stage 3: a cohort study.
        BMC Nephrol. 2015; 16: 193
        • Dalbeth N.
        • Merriman T.R.
        • Stamp L.K.
        Gout.
        Lancet. 2016; 388: 2039-2052
        • Neogi T.
        Clinical practice. Gout.
        N Engl J Med. 2011; 364: 443-452
        • Hak A.E.
        • Curhan G.C.
        • Grodstein F.
        • Choi H.K.
        Menopause, postmenopausal hormone use and risk of incident gout.
        Ann Rheum Dis. 2010; 69: 1305-1309
        • Vargas-Santos A.B.
        • Zhang Y.
        • Lu N.
        • et al.
        Patterns of joint involvement in gout flares.
        Arthritis Rheumatol. 2016; 68 ([abstract]) (Accessed November 23, 2016)
        • De Souza A.
        • Fernandes V.
        • Ferrari A.J.
        Female gout: clinical and laboratory features.
        J Rheumatol. 2005; 32: 2186-2188
        • Forbess L.J.
        • Fields T.R.
        The broad spectrum of urate crystal deposition: unusual presentations of gouty tophi.
        Semin Arthritis Rheum. 2012; 42: 146-154
        • De Leonardis F.
        • Govoni M.
        • Colina M.
        • Bruschi M.
        • Trotta F.
        Elderly-onset gout: a review.
        Rheumatol Int. 2007; 28: 1-6
        • Abhishek A.
        Calcium pyrophosphate deposition disease: a review of epidemiologic findings.
        Curr Opin Rheumatol. 2016; 28: 133-139
        • Neogi T.
        • Jansen T.L.
        • Dalbeth N.
        • et al.
        2015 Gout classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative.
        Ann Rheum Dis. 2015; 74: 1789-1798
        • Neogi T.
        • Jansen T.L.
        • Dalbeth N.
        • et al.
        2015 Gout classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative.
        Arthritis Rheumatol. 2015; 67: 2557-2568
        • Khanna D.
        • Fitzgerald J.D.
        • Khanna P.P.
        • et al.
        2012 American College of Rheumatology guidelines for management of gout. Part 1: systematic nonpharmacologic and pharmacologic therapeutic approaches to hyperuricemia.
        Arthritis Care Res (Hoboken). 2012; 64: 1431-1446
        • Khanna D.
        • Khanna P.P.
        • Fitzgerald J.D.
        • et al.
        2012 American College of Rheumatology guidelines for management of gout. Part 2: therapy and antiinflammatory prophylaxis of acute gouty arthritis.
        Arthritis Care Res (Hoboken). 2012; 64: 1447-1461
        • Zhang W.
        • Doherty M.
        • Bardin T.
        • et al.
        EULAR evidence based recommendations for gout. Part II: management. Report of a task force of the EULAR Standing Committee for International Clinical Studies Including Therapeutics (ESCISIT).
        Ann Rheum Dis. 2006; 65: 1312-1324
        • Jordan K.M.
        • Cameron J.S.
        • Snaith M.
        • et al.
        British Society for Rheumatology and British Health Professionals in Rheumatology guideline for the management of gout.
        Rheumatology (Oxford). 2007; 46: 1372-1374
        • Sivera F.
        • Andres M.
        • Carmona L.
        • et al.
        Multinational evidence-based recommendations for the diagnosis and management of gout: integrating systematic literature review and expert opinion of a broad panel of rheumatologists in the 3e initiative.
        Ann Rheum Dis. 2014; 73: 328-335
        • Emmerson B.T.
        The management of gout.
        N Engl J Med. 1996; 334: 445-451
        • Lindsay K.
        • Gow P.
        • Vanderpyl J.
        • Logo P.
        • Dalbeth N.
        The experience and impact of living with gout: a study of men with chronic gout using a qualitative grounded theory approach.
        J Clin Rheumatol. 2011; 17: 1-6
        • Doherty M.
        • Jansen T.L.
        • Nuki G.
        • et al.
        Gout: why is this curable disease so seldom cured?.
        Ann Rheum Dis. 2012; 71: 1765-1770
        • Dalbeth N.
        • Stamp L.
        Allopurinol dosing in renal impairment: walking the tightrope between adequate urate lowering and adverse events.
        Semin Dial. 2007; 20: 391-395
        • Wright D.F.
        • Doogue M.P.
        • Barclay M.L.
        • et al.
        A population pharmacokinetic model to predict oxypurinol exposure in patients on haemodialysis.
        Eur J Clin Pharmacol. 2017; 73: 71-78
        • Horikoshi R.
        • Akimoto T.
        • Inoue M.
        • Morishita Y.
        • Kusano E.
        Febuxostat for hyperuricemia: experience with patients on chronic hemodialysis treatment.
        Clin Exp Nephrol. 2013; 17: 149-150
        • Akimoto T.
        • Morishita Y.
        • Ito C.
        • et al.
        Febuxostat for hyperuricemia in patients with advanced chronic kidney disease.
        Drug Target Insights. 2014; 8: 39-43
        • Mitsuboshi S.
        • Yamada H.
        • Nagai K.
        • Okajima H.
        Switching from allopurinol to febuxostat: efficacy and tolerability in hemodialysis patients.
        J Pharm Health Care Sci. 2015; 1: 28
        • Frassetto L.A.
        • Gibson S.
        Febuxostat and increased dialysis as a treatment for severe tophaceous gout in a hemodialysis patient.
        Case Rep Nephrol. 2016; 2016: 9106935
        • Lim D.H.
        • Oh J.S.
        • Ahn S.M.
        • et al.
        Febuxostat in hyperuricemic patients with advanced CKD.
        Am J Kidney Dis. 2016; 68: 819-821
        • Bleyer A.J.
        • Wright D.
        • Alcorn H.
        Pharmacokinetics and pharmacodynamics of pegloticase in patients with end-stage renal failure receiving hemodialysis.
        Clin Nephrol. 2015; 83: 286-292
        • Garg J.P.
        • Chasan-Taber S.
        • Blair A.
        • et al.
        Effects of sevelamer and calcium-based phosphate binders on uric acid concentrations in patients undergoing hemodialysis: a randomized clinical trial.
        Arthritis Rheum. 2005; 52: 290-295
        • Ohno I.
        • Yamaguchi Y.
        • Saikawa H.
        • et al.
        Sevelamer decreases serum uric acid concentration through adsorption of uric acid in maintenance hemodialysis patients.
        Intern Med. 2009; 48: 415-420
        • Ohno I.
        • Ichida K.
        • Okabe H.
        • et al.
        Frequency of gouty arthritis in patients with end-stage renal disease in Japan.
        Intern Med. 2005; 44: 706-709
        • Ifudu O.
        • Tan C.C.
        • Dulin A.L.
        • Delano B.G.
        • Friedman E.A.
        Gouty arthritis in end-stage renal disease: clinical course and rarity of new cases.
        Am J Kidney Dis. 1994; 23: 347-351
        • Hill E.M.
        • Sky K.
        • Sit M.
        • Collamer A.
        • Higgs J.
        Does starting allopurinol prolong acute treated gout? A randomized clinical trial.
        J Clin Rheumatol. 2015; 21: 120-125
        • Taylor T.H.
        • Mecchella J.N.
        • Larson R.J.
        • Kerin K.D.
        • Mackenzie T.A.
        Initiation of allopurinol at first medical contact for acute attacks of gout: a randomized clinical trial.
        Am J Med. 2012; 125: 1126-1134 e7
        • Hande K.R.
        • Noone R.M.
        • Stone W.J.
        Severe allopurinol toxicity. Description and guidelines for prevention in patients with renal insufficiency.
        Am J Med. 1984; 76: 47-56
        • Rees F.
        • Hui M.
        • Doherty M.
        Optimizing current treatment of gout.
        Nat Rev Rheumatol. 2014; 10: 271-283
        • Rees F.
        • Jenkins W.
        • Doherty M.
        Patients with gout adhere to curative treatment if informed appropriately: proof-of-concept observational study.
        Ann Rheum Dis. 2013; 72: 826-830
        • Dalbeth N.
        • Kumar S.
        • Stamp L.
        • Gow P.
        Dose adjustment of allopurinol according to creatinine clearance does not provide adequate control of hyperuricemia in patients with gout.
        J Rheumatol. 2006; 33: 1646-1650
        • Reinders M.K.
        • Haagsma C.
        • Jansen T.L.
        • et al.
        A randomised controlled trial on the efficacy and tolerability with dose escalation of allopurinol 300-600 mg/day versus benzbromarone 100-200 mg/day in patients with gout.
        Ann Rheum Dis. 2009; 68: 892-897
        • Stamp L.K.
        • O'Donnell J.L.
        • Zhang M.
        • et al.
        Using allopurinol above the dose based on creatinine clearance is effective and safe in patients with chronic gout, including those with renal impairment.
        Arthritis Rheum. 2011; 63: 412-421
        • Stamp L.K.
        • Day R.O.
        • Yun J.
        Allopurinol hypersensitivity: investigating the cause and minimizing the risk.
        Nat Rev Rheumatol. 2016; 12: 235-242
        • Paisansinsup T.
        • Breitenstein M.K.
        • Schousboe J.T.
        Association between adverse reactions to allopurinol and exposures to high maintenance doses: implications for management of patients using allopurinol.
        J Clin Rheumatol. 2013; 19: 180-186
        • Stamp L.K.
        • Taylor W.J.
        • Jones P.B.
        • et al.
        Starting dose is a risk factor for allopurinol hypersensitivity syndrome: a proposed safe starting dose of allopurinol.
        Arthritis Rheum. 2012; 64: 2529-2536
        • Yun J.
        • Mattsson J.
        • Schnyder K.
        • et al.
        Allopurinol hypersensitivity is primarily mediated by dose-dependent oxypurinol-specific T cell response.
        Clin Exp Allergy. 2013; 43: 1246-1255
        • Somkrua R.
        • Eickman E.E.
        • Saokaew S.
        • Lohitnavy M.
        • Chaiyakunapruk N.
        Association of HLA-B*5801 allele and allopurinol-induced Stevens Johnson syndrome and toxic epidermal necrolysis: a systematic review and meta-analysis.
        BMC Med Genet. 2011; 12: 118
        • Kim S.C.
        • Newcomb C.
        • Margolis D.
        • Roy J.
        • Hennessy S.
        Severe cutaneous reactions requiring hospitalization in allopurinol initiators: a population-based cohort study.
        Arthritis Care Res (Hoboken). 2013; 65: 578-584
        • Rundles R.W.
        Allopurinol in gouty nephropathy and renal dialysis.
        Ann Rheum Dis. 1966; 25: 694-696
        • Hayes Jr., C.P.
        • Metz E.N.
        • Robinson R.R.
        • Rundles R.W.
        The use of allopurinol (HPP) to control hyperuricemia in patients on chronic intermittent hemodialysis.
        Trans Am Soc Artif Intern Organs. 1965; 11: 247-254
        • Day R.O.
        • Kannangara D.R.
        • Hayes J.M.
        • Furlong T.J.
        Successful use of allopurinol in a patient on dialysis.
        BMJ Case Rep. 2012; : 2012
        • Jalalzadeh M.
        • Nurcheshmeh Z.
        • Mohammadi R.
        • Mousavinasab N.
        • Ghadiani M.H.
        The effect of allopurinol on lowering blood pressure in hemodialysis patients with hyperuricemia.
        J Res Med Sci. 2012; 17: 1039-1046
        • Becker M.A.
        • Schumacher Jr., H.R.
        • Wortmann R.L.
        • et al.
        Febuxostat compared with allopurinol in patients with hyperuricemia and gout.
        N Engl J Med. 2005; 353: 2450-2461
        • Schumacher Jr., H.R.
        • Becker M.A.
        • Wortmann R.L.
        • et al.
        Effects of febuxostat versus allopurinol and placebo in reducing serum urate in subjects with hyperuricemia and gout: a 28-week, phase III, randomized, double-blind, parallel-group trial.
        Arthritis Rheum. 2008; 59: 1540-1548
        • Becker M.A.
        • Schumacher H.R.
        • MacDonald P.A.
        • Lloyd E.
        • Lademacher C.
        Clinical efficacy and safety of successful longterm urate lowering with febuxostat or allopurinol in subjects with gout.
        J Rheumatol. 2009; 36: 1273-1282
        • Becker M.A.
        • Schumacher H.R.
        • Espinoza L.R.
        • et al.
        The urate-lowering efficacy and safety of febuxostat in the treatment of the hyperuricemia of gout: the CONFIRMS trial.
        Arthritis Res Ther. 2010; 12: R63
        • Saag K.G.
        • Whelton A.
        • Becker M.A.
        • MacDonald P.
        • Hunt B.
        • Gunawardhana L.
        Impact of febuxostat on renal function in gout patients with moderate-to-severe renal impairment.
        Arthritis Rheumatol. 2016; 68: 2035-2043
        • Sofue T.
        • Inui M.
        • Hara T.
        • et al.
        Efficacy and safety of febuxostat in the treatment of hyperuricemia in stable kidney transplant recipients.
        Drug Des Devel Ther. 2014; 8: 245-253
        • Tojimbara T.
        • Nakajima I.
        • Yashima J.
        • Fuchinoue S.
        • Teraoka S.
        Efficacy and safety of febuxostat, a novel nonpurine selective inhibitor of xanthine oxidase for the treatment of hyperuricemia in kidney transplant recipients.
        Transplant Proc. 2014; 46: 511-513
        • Chou H.Y.
        • Chen C.B.
        • Cheng C.Y.
        • et al.
        Febuxostat-associated drug reaction with eosinophilia and systemic symptoms (DRESS).
        J Clin Pharm Ther. 2015; 40: 689-692
        • Febuxostat (Adenuric)
        Toxic epidermal necrolysis and severe hypersensitivity reactions added to the EU SPC.
        Prescrire Int. 2015; 24: 153
      1. Health Canada. Summary safety review - ULORIC (febuxostat) - assessing a possible risk of drug reaction/rash with eosinophilia and systemic symptoms (DRESS). http://www.hc-sc.gc.ca/dhp-mps/medeff/reviews-examens/uloric3-eng.php. Accessed August 4, 2016.

      2. European Medicines Agency. Adenuric: EPAR - product information (last updated: February 5, 2016). http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/000777/WC500021812.pdf. Accessed August 04, 2016.

        • Paschou E.
        • Gavriilaki E.
        • Papaioannou G.
        • Tsompanakou A.
        • Kalaitzoglou A.
        • Sabanis N.
        Febuxostat hypersensitivity: another cause of DRESS syndrome in chronic kidney disease?.
        Eur Ann Allergy Clin Immunol. 2016; 48: 251-255
        • Gandhi P.K.
        • Gentry W.M.
        • Bottorff M.B.
        Cardiovascular thromboembolic events associated with febuxostat: investigation of cases from the FDA adverse event reporting system database.
        Semin Arthritis Rheum. 2013; 42: 562-566
      3. Health Canada. Summary safety review - ULORIC (febuxostat) - assessing the potential risk of heart failure. http://www.hc-sc.gc.ca/dhp-mps/medeff/reviews-examens/uloric2-eng.php. Accessed August 4, 2016.

        • White W.B.
        • Chohan S.
        • Dabholkar A.
        • Hunt B.
        • Jackson R.
        Cardiovascular safety of febuxostat and allopurinol in patients with gout and cardiovascular comorbidities.
        Am Heart J. 2012; 164: 14-20
        • MacDonald T.M.
        • Ford I.
        • Nuki G.
        • et al.
        Protocol of the Febuxostat versus Allopurinol Streamlined Trial (FAST): a large prospective, randomised, open, blinded endpoint study comparing the cardiovascular safety of allopurinol and febuxostat in the management of symptomatic hyperuricaemia.
        BMJ Open. 2014; 4: e005354
        • Mitri G.
        • Wittbrodt E.T.
        • Turpin R.S.
        • Tidwell B.A.
        • Schulman K.L.
        Cost comparison of urate-lowering therapies in patients with gout and moderate-to-severe chronic kidney disease.
        J Manag Care Spec Pharm. 2016; 22: 326-336
        • Smolen L.J.
        • Gahn J.C.
        • Mitri G.
        • Shiozawa A.
        Febuxostat in the management of gout: a cost-effectiveness analysis.
        J Med Econ. 2016; 19: 265-276
        • Beard S.M.
        • von Scheele B.G.
        • Nuki G.
        • Pearson I.V.
        Cost-effectiveness of febuxostat in chronic gout.
        Eur J Health Econ. 2014; 15: 453-463
        • Gandhi P.K.
        • Gentry W.M.
        • Ma Q.
        • Bottorff M.B.
        Cost-effectiveness analysis of allopurinol versus febuxostat in chronic gout patients: a U.S. payer perspective.
        J Manag Care Spec Pharm. 2015; 21: 165-175
        • Faruque L.I.
        • Ehteshami-Afshar A.
        • Wiebe N.
        • Tjosvold L.
        • Homik J.
        • Tonelli M.
        A systematic review and meta-analysis on the safety and efficacy of febuxostat versus allopurinol in chronic gout.
        Semin Arthritis Rheum. 2013; 43: 367-375
        • Kydd A.S.
        • Seth R.
        • Buchbinder R.
        • Edwards C.J.
        • Bombardier C.
        Uricosuric medications for chronic gout.
        Cochrane Database Syst Rev. 2014; : CD010457
        • Sundy J.S.
        • Baraf H.S.
        • Yood R.A.
        • et al.
        Efficacy and tolerability of pegloticase for the treatment of chronic gout in patients refractory to conventional treatment: two randomized controlled trials.
        JAMA. 2011; 306: 711-720
        • Becker M.A.
        • Baraf H.S.
        • Yood R.A.
        • et al.
        Long-term safety of pegloticase in chronic gout refractory to conventional treatment.
        Ann Rheum Dis. 2013; 72: 1469-1474
      4. Food and Drug Adminitration. Colcrys full prescribing information. http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/022352s022lbl.pdf. Accessed November 27, 2016.

        • Joosten L.A.
        • Netea M.G.
        • Mylona E.
        • et al.
        Engagement of fatty acids with Toll-like receptor 2 drives interleukin-1beta production via the ASC/caspase 1 pathway in monosodium urate monohydrate crystal-induced gouty arthritis.
        Arthritis Rheum. 2010; 62: 3237-3248
        • Neogi T.
        Gout.
        Ann Intern Med. 2016; 165: ITC1-ITC16
        • Dumusc A.
        • So A.
        Interleukin-1 as a therapeutic target in gout.
        Curr Opin Rheumatol. 2015; 27: 156-163
        • Schlesinger N.
        Anti-interleukin-1 therapy in the management of gout.
        Curr Rheumatol Rep. 2014; 16: 398
        • Tran T.H.
        • Pham J.T.
        • Shafeeq H.
        • Manigault K.R.
        • Arya V.
        Role of interleukin-1 inhibitors in the management of gout.
        Pharmacotherapy. 2013; 33: 744-753
        • Schlesinger N.
        • Detry M.A.
        • Holland B.K.
        • et al.
        Local ice therapy during bouts of acute gouty arthritis.
        J Rheumatol. 2002; 29: 331-334
        • Niel E.
        • Scherrmann J.M.
        Colchicine today.
        Joint Bone Spine. 2006; 73: 672-678
        • Terkeltaub R.A.
        • Furst D.E.
        • Bennett K.
        • Kook K.A.
        • Crockett R.S.
        • Davis M.W.
        High versus low dosing of oral colchicine for early acute gout flare: twenty-four-hour outcome of the first multicenter, randomized, double-blind, placebo-controlled, parallel-group, dose-comparison colchicine study.
        Arthritis Rheum. 2010; 62: 1060-1068
        • Kesselheim A.S.
        • Solomon D.H.
        Incentives for drug development–the curious case of colchicine.
        N Engl J Med. 2010; 362: 2045-2047
        • Hung I.F.
        • Wu A.K.
        • Cheng V.C.
        • et al.
        Fatal interaction between clarithromycin and colchicine in patients with renal insufficiency: a retrospective study.
        Clin Infect Dis. 2005; 41: 291-300
        • Tufan A.
        • Dede D.S.
        • Cavus S.
        • Altintas N.D.
        • Iskit A.B.
        • Topeli A.
        Rhabdomyolysis in a patient treated with colchicine and atorvastatin.
        Ann Pharmacother. 2006; 40: 1466-1469
      5. PL Detail-Document, Clinically Significant Statin Drug Interactions. Pharmacist’s Letter/Prescriber’s Letter. March 2016. http://pharmacistsletter.therapeuticresearch.com/pl/ArticleDD.aspx?nidchk=1&cs=&s=PL&pt=2&fpt=31&dd=280606&pb=PL&cat=4803&segment=4421.

        • Neogi T.
        • George J.
        • Rekhraj S.
        • Struthers A.D.
        • Choi H.
        • Terkeltaub R.A.
        Are either or both hyperuricemia and xanthine oxidase directly toxic to the vasculature? A critical appraisal.
        Arthritis Rheum. 2012; 64: 327-338
        • Khosla U.M.
        • Zharikov S.
        • Finch J.L.
        • et al.
        Hyperuricemia induces endothelial dysfunction.
        Kidney Int. 2005; 67: 1739-1742
        • 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
        • Mazzali M.
        • Hughes J.
        • Kim Y.G.
        • et al.
        Elevated uric acid increases blood pressure in the rat by a novel crystal-independent mechanism.
        Hypertension. 2001; 38: 1101-1106
        • Mazzali M.
        • Kanellis J.
        • Han L.
        • et al.
        Hyperuricemia induces a primary renal arteriolopathy in rats by a blood pressure-independent mechanism.
        Am J Physiol Renal Physiol. 2002; 282: F991-F997
        • Sanchez-Lozada L.G.
        • Tapia E.
        • Avila-Casado C.
        • et al.
        Mild hyperuricemia induces glomerular hypertension in normal rats.
        Am J Physiol Renal Physiol. 2002; 283: F1105-F1110
        • Nakagawa T.
        • Mazzali M.
        • Kang D.H.
        • et al.
        Hyperuricemia causes glomerular hypertrophy in the rat.
        Am J Nephrol. 2003; 23: 2-7
        • Sanchez-Lozada L.G.
        • 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
        • Sanchez-Lozada L.G.
        • Tapia E.
        • Soto V.
        • et al.
        Treatment with the xanthine oxidase inhibitor febuxostat lowers uric acid and alleviates systemic and glomerular hypertension in experimental hyperuricaemia.
        Nephrol Dial Transplant. 2008; 23: 1179-1185
        • Mazali F.C.
        • Johnson R.J.
        • Mazzali M.
        Use of uric acid-lowering agents limits experimental cyclosporine nephropathy.
        Nephron Exp Nephrol. 2012; 120: e12-e19
        • Iseki K.
        • Oshiro S.
        • Tozawa M.
        • Iseki C.
        • Ikemiya Y.
        • Takishita S.
        Significance of hyperuricemia on the early detection of renal failure in a cohort of screened subjects.
        Hypertens Res. 2001; 24: 691-697
        • Iseki K.
        • Ikemiya Y.
        • Inoue T.
        • Iseki C.
        • Kinjo K.
        • Takishita S.
        Significance of hyperuricemia as a risk factor for developing ESRD in a screened cohort.
        Am J Kidney Dis. 2004; 44: 642-650
        • Domrongkitchaiporn S.
        • Sritara P.
        • Kitiyakara C.
        • et al.
        Risk factors for development of decreased kidney function in a southeast Asian population: a 12-year cohort study.
        J Am Soc Nephrol. 2005; 16: 791-799
        • 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
        • Obermayr R.P.
        • Temml C.
        • Gutjahr G.
        • Knechtelsdorfer M.
        • Oberbauer R.
        • Klauser-Braun R.
        Elevated uric acid increases the risk for kidney disease.
        J Am Soc Nephrol. 2008; 19: 2407-2413
        • 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.S.
        Risk factors for end-stage renal disease: 25-year follow-up.
        Arch Intern Med. 2009; 169: 342-350
        • See L.C.
        • Kuo C.F.
        • Chuang F.H.
        • et al.
        Serum uric acid is independently associated with metabolic syndrome in subjects with and without a low estimated glomerular filtration rate.
        J Rheumatol. 2009; 36: 1691-1698
        • Bellomo G.
        • Venanzi S.
        • Verdura C.
        • Saronio P.
        • Esposito A.
        • Timio M.
        Association of uric acid with change in kidney function in healthy normotensive individuals.
        Am J Kidney Dis. 2010; 56: 264-272
        • Ben-Dov I.Z.
        • Kark J.D.
        Serum uric acid is a GFR-independent long-term predictor of acute and chronic renal insufficiency: the Jerusalem Lipid Research Clinic cohort study.
        Nephrol Dial Transplant. 2011; 26: 2558-2566
        • Yamada T.
        • Fukatsu M.
        • Suzuki S.
        • Wada T.
        • Joh T.
        Elevated serum uric acid predicts chronic kidney disease.
        Am J Med Sci. 2011; 342: 461-466
        • Dawson J.
        • Jeemon P.
        • Hetherington L.
        • et al.
        Serum uric acid level, longitudinal blood pressure, renal function, and long-term mortality in treated hypertensive patients.
        Hypertension. 2013; 62: 105-111
        • Iseki K.
        • Iseki C.
        • Kinjo K.
        Changes in serum uric acid have a reciprocal effect on eGFR change: a 10-year follow-up study of community-based screening in Okinawa.
        Japan. Hypertens Res. 2013; 36: 650-654
        • Levy G.D.
        • Rashid N.
        • Niu F.
        • Cheetham T.C.
        Effect of urate-lowering therapies on renal disease progression in patients with hyperuricemia.
        J Rheumatol. 2014; 41: 955-962
        • Rodenbach K.E.
        • Schneider M.F.
        • Furth S.L.
        • et al.
        Hyperuricemia and progression of CKD in children and adolescents: the Chronic Kidney Disease in Children (CKiD) Cohort Study.
        Am J Kidney Dis. 2015; 66: 984-992
        • Uchida S.
        • Chang W.X.
        • Ota T.
        • et al.
        Targeting uric acid and the inhibition of progression to end-stage renal disease–a propensity score analysis.
        PLoS One. 2015; 10: e0145506
        • Yan D.
        • Tu Y.
        • Jiang F.
        • et al.
        Uric acid is independently associated with diabetic kidney disease: a cross-sectional study in a Chinese population.
        PLoS One. 2015; 10: e0129797
        • Chang Y.H.
        • Lei C.C.
        • Lin K.C.
        • Chang D.M.
        • Hsieh C.H.
        • Lee Y.J.
        Serum uric acid level as an indicator for CKD regression and progression in patients with type 2 diabetes mellitus-a 4.6-year cohort study.
        Diabetes Metab Res Rev. 2016; 32: 557-564
        • Hunsicker L.G.
        • Adler S.
        • Caggiula A.
        • et al.
        Predictors of the progression of renal disease in the Modification of Diet in Renal Disease Study.
        Kidney Int. 1997; 51: 1908-1919
        • Weiner D.E.
        • Tighiouart H.
        • Elsayed E.F.
        • et al.
        The relationship between nontraditional risk factors and outcomes in individuals with stage 3 to 4 CKD.
        Am J Kidney Dis. 2008; 51: 212-223
        • Sturm G.
        • Kollerits B.
        • Neyer U.
        • Ritz E.
        • Kronenberg F.
        • The 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
        • 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
        • Chang W.X.
        • Asakawa S.
        • Toyoki D.
        • et al.
        Predictors and the subsequent risk of end-stage renal disease - usefulness of 30% decline in estimated GFR over 2 years.
        PLoS One. 2015; 10: e0132927
        • Kuriyama S.
        • Maruyama Y.
        • Nishio S.
        • et al.
        Serum uric acid and the incidence of CKD and hypertension.
        Clin Exp Nephrol. 2015; 19: 1127-1134
        • Whelton A.
        • Macdonald P.A.
        • Zhao L.
        • Hunt B.
        • Gunawardhana L.
        Renal function in gout: long-term treatment effects of febuxostat.
        J Clin Rheumatol. 2011; 17: 7-13
        • Pai B.H.
        • Swarnalatha G.
        • Ram R.
        • Dakshinamurty K.V.
        Allopurinol for prevention of progression of kidney disease with hyperuricemia.
        Indian J Nephrol. 2013; 23: 280-286
        • Whelton A.
        • MacDonald P.A.
        • Chefo S.
        • Gunawardhana L.
        Preservation of renal function during gout treatment with febuxostat: a quantitative study.
        Postgrad Med. 2013; 125: 106-114
        • Shibagaki Y.
        • Ohno I.
        • Hosoya T.
        • Kimura K.
        Safety, efficacy and renal effect of febuxostat in patients with moderate-to-severe kidney dysfunction.
        Hypertens Res. 2014; 37: 919-925
        • Kim Y.
        • Shin S.
        • Kim K.
        • Choi S.
        • Lee K.
        Effect of urate lowering therapy on renal disease progression in hyperuricemic patients with chronic kidney disease.
        J Rheumatol. 2015; 42: 2143-2148
        • Singh J.A.
        • Yu S.
        Are allopurinol dose and duration of use nephroprotective in the elderly? A Medicare claims study of allopurinol use and incident renal failure.
        Ann Rheum Dis. 2017; 76: 133-139
        • Ma L.
        • Wei L.
        • Chen H.
        • et al.
        Influence of urate-lowering therapies on renal handling of uric acid.
        Clin Rheumatol. 2016; 35: 133-141
        • Gibson T.
        • Rodgers V.
        • Potter C.
        • Simmonds H.A.
        Allopurinol treatment and its effect on renal function in gout: a controlled study.
        Ann Rheum Dis. 1982; 41: 59-65
        • Dahlof B.
        • Devereux R.B.
        • Kjeldsen S.E.
        • et al.
        Cardiovascular morbidity and mortality in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): a randomised trial against atenolol.
        Lancet. 2002; 359: 995-1003
        • 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
        • Momeni A.
        • Shahidi S.
        • Seirafian S.
        • Taheri S.
        • Kheiri S.
        Effect of allopurinol in decreasing proteinuria in type 2 diabetic patients.
        Iran J Kidney Dis. 2010; 4: 128-132
        • 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
        • Shi Y.
        • Chen W.
        • Jalal D.
        • et al.
        Clinical outcome of hyperuricemia in IgA nephropathy: a retrospective cohort study and randomized controlled trial.
        Kidney Blood Press Res. 2012; 35: 153-160
        • 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
        • Goicoechea M.
        • Garcia de Vinuesa S.
        • Verdalles U.
        • et al.
        Allopurinol and progression of CKD and cardiovascular events: long-term follow-up of a randomized clinical trial.
        Am J Kidney Dis. 2015; 65: 543-549
        • Kim H.A.
        • Seo Y.I.
        • Song Y.W.
        Four-week effects of allopurinol and febuxostat treatments on blood pressure and serum creatinine level in gouty men.
        J Korean Med Sci. 2014; 29: 1077-1081
        • Liu P.
        • Chen Y.
        • Wang B.
        • Zhang F.
        • Wang D.
        • Wang Y.
        Allopurinol treatment improves renal function in patients with type 2 diabetes and asymptomatic hyperuricemia: 3-year randomized parallel-controlled study.
        Clin Endocrinol (Oxf). 2015; 83: 475-482
        • 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
        • Tanaka K.
        • Nakayama M.
        • Kanno M.
        • et al.
        Renoprotective effects of febuxostat in hyperuricemic patients with chronic kidney disease: a parallel-group, randomized, controlled trial.
        Clin Exp Nephrol. 2015; 19: 1044-1053
        • Sezai A.
        • Soma M.
        • Nakata K.
        • et al.
        Comparison of febuxostat and allopurinol for hyperuricemia in cardiac surgery patients with chronic kidney disease (NU-FLASH trial for CKD).
        J Cardiol. 2015; 66: 298-303
        • Bose B.
        • Badve S.V.
        • Hiremath S.S.
        • et al.
        Effects of uric acid-lowering therapy on renal outcomes: a systematic review and meta-analysis.
        Nephrol Dial Transplant. 2014; 29: 406-413
        • Sarris E.
        • Bagiatudi G.
        • Stavrianaki D.
        • et al.
        Use of allopurinol in slowing the progression of chronic renal disease [abstract].
        Nephrol Dial Transplant. 2007; 22: vi61
        • Kanji T.
        • Gandhi M.
        • Clase C.M.
        • Yang R.
        Urate lowering therapy to improve renal outcomes in patients with chronic kidney disease: systematic review and meta-analysis.
        BMC Nephrol. 2015; 16: 58