Abstract
Hyperuricaemia is an independent risk factor for renal function decline. Evidence is emerging that urate-lowering therapy might be beneficial in subjects with renal impairment. We review the association between renal impairment and gout, some of the related pathogenic processes and the possible impact of gout treatment on the progression of renal impairment. Nevertheless, the management of gout is more complex in the presence of chronic kidney disease. The main aim of gout therapy is to fully dissolve the urate crystals, thus curing the disease. Avoidance of attacks—prophylaxis—and their prompt treatment if they occur, along with accurate information to patients, completes the treatment strategy. This article provides a practical guide to managing gout in older patients and in those with renal impairment. We highlight the shortcomings in our current treatment options and strategies.
Similar content being viewed by others
References
Pascual E, Addadi L, Andrés M, et al. Mechanisms of crystal formation in gout: a structural approach. Nat Rev Rheumatol. 2015;11:725–30.
Martinon F, Petrilli V, Mayor A, et al. Gout associated uric acid crystals activate the NALP3 inflammasome. Nature. 2006;440:237–41.
Pascual E. Persistence of monosodium urate crystals and low grade inflammation in the synovial fluid of patients with untreated gout. Arthritis Rheum. 1991;34:141–5.
Pascual E, Castellano JA. Treatment with colchicine decreases the white cell counts in the synovial fluid of asymp-tomatic knees that contain monosodium urate crystals. J Rheuma-tol. 1992;19:600–3.
Dalbeth N, Pool B, Gamble GD, et al. Cellular characterization of the gouty tophus: a quantitative analysis. Arthritis Rheum. 2010;62:1549–56.
Yu TF, Gutmann AB. Mobilization of gouty tophi by protracted use of uricosuric agents. Am J Med. 1951;11:765–9.
Pascual E, Sivera F. The time required for disappearance of urate crystals from synovial fluid after successful hypouricemic treatment relates to the duration of gout. Ann Rheum Dis. 2007;66:1056–8.
Richette P, Doherty M, Pascual E, et al. 2016 updated EULAR evidence-based recommendations for the management of gout. Ann Rheum Dis. 2017;76:29–42.
Khanna D, Fitzgerald JD, Khanna PP, American College of Rheumatology, 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(10):1431–46.
Khanna D, Khanna PP, Fitzgerald JD, American College of Rheumatology, 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;64:1447–61.
Wallace KL, Riedel AA, Joseph-Ridge N, Wortmann R. Increasing prevalence of gout and hyperuricemia over 10 years among older adults in a managed care population. J Rheumatol. 2004;31:1582–7.
Bieber JD, Terkeltaub RA. Gout: on the brink of novel therapeutic options for an ancient disease. Arthritis Rheum. 2004;50:2400–14.
Lawrence RC, Felson DT, Helmick CG, et al. Estimates of the prevalence of arthritis and other rheumatic conditions in the United States. Arthritis Rheum. 2008;58:26–35.
Terkeltaub RA. Gout: epidemiology, pathology, and pathogenesis. In: Klippel JH, Crofford LJ, Stone JH, et al., editors. Primer on the rheumatic diseases. 12th ed. Atlanta: Arthritis Foundation; 2001. p. 307–12.
Roughley MJ, Belcher J, Mallen CD, et al. Gout and risk of chronic kidney disease and nephrolithiasis: meta-analysis of observational studies. Arthritis Res Ther. 2015;1(17):90.
Jing J, Kielstein JT, Schultheiss UT, et al. Prevalence and correlates of gout in a large cohort of patients with chronic kidney disease: the German Chronic Kidney Disease (GCKD) study. Nephrol Dial Transpl. 2015;30:613–21.
Yu KH, Kuo CF, Luo SF, et al. Risk of end stage renal disease associated with gout: a nationwide population study. Arthritis Res Ther. 2012;14:R83.
Tsai CW, Lin SY, Kuo CC, et al. Serum uric acid and progression of kidney disease: a longitudinal analysis and mini-review. PLoS One. 2017;12:e0170393.
Bose B, Badve SV, Hiremath SS, et al. Effects of uric acid-lowering therapy on renal outcomes: a systematic review and meta-analysis. Nephrol Dial Transpl. 2014;29:406–13.
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;66:945–50.
Singh JA, Cleveland JD. Comparative effectiveness of allopurinol versus febuxostat for preventing incident renal disease in older adults: an analysis of medicare claims data. Ann Rheum Dis. 2017;76(10):1669–78.
Shi Y, Evans JE, Rock KL. Molecular identification of a danger signal that alerts the immune system to dying cells. Nature. 2003;425:516–21.
Ghaemi-Oskouie F, Shi Y. The role of uric acid as an endogenous danger signal in immunity and inflammation. Curr Rheumatol Rep. 2011;13:160–6.
Crişan TO, Cleophas MC, Oosting M, et al. Soluble uric acid primes TLR-induced proinflammatory cytokine production by human primary cells via inhibition of IL-1Ra. Ann Rheum Dis. 2016;75:755–62.
Andrés M, Francés R, Pascual E. Uric acid enhances monosodium urate induced pro-inflammatory response in gouty patients: a basic and translational research study. Ann Rheum Dis. 2015;74(Suppl. 2):777.
De Miguel E, Puig JG, Castillo C, et al. Diagnosis of gout in patients with asymptomatic hyperuricaemia: a pilot ultrasound study. Ann Rheum Dis. 2012;71:157–8.
Pineda C, Amezcua-Guerra LM, Solano C, et al. Joint and tendon subclinical involvement suggestive of gouty arthritis in asymptomatic hyperuricemia: an ultrasound controlled study. Arthritis Res Ther. 2011;17(13):R4.
Dalbeth N, House ME, Aati O, et al. Urate crystal deposition in asymptomatic hyperuricaemia and symptomatic gout: a dual energy CT study. Ann Rheum Dis. 2015;74:908–11.
Talbott JH, Terplan KL. The kidney in gout. Medicine (Baltimore). 1960;39:405–67.
Verger D, Leroux-Robert C, Ganter P, et al. Gouty tophi in the renal medulla in chronic uremia: study of 17 cases discovered from among 62 autopsies. Nephron. 1967;4(6):356–70.
Linnane JW, Burry AF, Emmerson BT. Urate deposits in the renal medulla: prevalence and associations. Nephron. 1981;29:216–22.
Ayoub I, Almaani S, Brodsky S, et al. Revisiting medullary tophi: a link between uric acid and progressive chronic kidney disease? Clin Nephrol. 2016;85:109–13.
Carr A, Doyle AJ, Dalbeth N, et al. Dual-energy CT of urate deposits in costal cartilage and intervertebral disks of patients with tophaceous gout and age-matched controls. Am J Roentgenol. 2016;206:1063–7.
Baer AN, Kurano T, Thakur UJ, et al. Dual-energy computed tomography has limited sensitivity for non-tophaceous gout: a comparison study with tophaceous gout. BMC Musculoskelet Disord. 2016;18(17):91.
Simkin PA, Bassett JE, Lee QP. Not water, but formalin, dissolves urate crystals in tophaceous tissue samples. J Rheumatol. 1994;21:2320–1.
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;72:826–30.
Abhishek A, Jenkins W, La-Crette J, et al. Long-term persistence and adherence on urate-lowering treatment can be maintained in primary care-5-year follow-up of a proof-of-concept study. Rheumatology (Oxford). 2017;56:529–33.
Araujo EG, Bayat S, Petsch C, et al. Tophus resolution with pegloticase: a prospective dual-energy CT study. RMD Open. 2015;1:1–e000075.
Perez-Ruiz F, Calabozo M, Pijoan JI, et al. Effect of urate-lowering therapy on the velocity of size reduction of tophi in chronic gout. Arthritis Rheum. 2002;47:356–60.
Pascual E, Andrés M, Vázquez-Mellado J, et al. Severe gout: strategies and innovations for effective management. Jt Bone Spine. 2017;84:541–6.
Perez-Ruiz F, Calabozo M, Herrero-Beites AM, et al. Improvement of renal function in patients with chronic gout after proper control of hyperuricemia and gouty bouts. Nephron. 2000;86:287–91.
Perez-Ruiz F, Herrero-Beites AM, Carmona L. A two-stage approach to the treatment of hyperuricemia in gout: the “dirty dish” hypothesis. Arthritis Rheum. 2011;63:4002–6.
Andrés M, Soriano R, Oliveira E, et al. Serum uric acid lowering treatment appears unnecessary during hemodialysis [abstract]. Ann Rheum Dis. 2017;76(Suppl. 2):361.
Duncan H, Elliott W, Horn DB, et al. Haemodialysis in the treatment of gout. Lancet. 1962;1(7241):1209–11.
Johnson WJ, O’Duffy JD. Chronic gouty nephropathy treated by long-term hemodialysis and allopurinol. Mayo Clin Proc. 1979;54:618–20.
Ifudu O, Tan CC, Dulin AL, et al. Gouty arthritis in end-stage renal disease: clinical course and rarity of new cases. Am J Kidney Dis. 1994;23(3):347–51.
Rundles R. Allopurinol in gouty nephropathy and renal dialysis. Ann Rheum Dis. 1966;25:694–6.
Hayes C, Metz E, Robinson R, et al. The use of allopurinol to control hyperuricaemia in patients on chronic intermittent hemodialysis. Trans Am Soc Artif Intern Organs. 1965;11:247–54.
Day R, Kannangara D, Hayes J, et al. Successful use of allopurinol in a patient on dialysis. BMJ Case Rep. 2012. https://doi.org/10.1136/bcr.02.2012.5814.
Stamp LK, Chapman PT, Palmer SC. Allopurinol and kidney function: an update. Jt Bone Spine. 2016;83:19–24.
Murrell G, Rapeport W. Clinical pharmacokinetics of allopurinol. Clin Pharmacokinet. 1986;11:343–53.
Hande KR. NooneRM, Stone WJ. Severe allopurinol toxicity: description and guidelines for prevention in patients with renal insufficiency. Am J Med. 1984;76:47–56.
Becker MA, Schumacher HR Jr, Wortmann RL, et al. Febuxostat compared with allopurinol in patients with hyperuricemia and gout. N Engl J Med. 2005;353:2450–61.
Perez-Ruiz F, Alonso-Ruiz A, Calabozo M, et al. Efficacy of allopurinol and benzbromarone for the control of hyperuricaemia: a pathogenic approach to the treatment of primary chronic gout. Ann Rheum Dis. 1998;57:545–9.
Reinders MK, Haagsma C, Jansen TL, 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;68:892–7.
Chao J, Terkeltaub RA. Critical reappraisal of allopurinol dosing, safety, and efficacy for hyperuricemia in gout. Curr Rheumatol Rep. 2009;11:135–40.
Dalbeth N, Kumar S, Stamp L, et al. Dose adjustment of allopurinol according to creatinine clearance does not provide adequate control of hyperuricemia in patients with gout. J Rheumatol. 2006;33:1646–50.
Stamp LK, Chapman PT, Barclay M, et al. Allopurinol dose escalation to achieve serum urate below 6 mg/dL: an open-label extension study. Ann Rheum Dis. 2017;76(12):2065–70.
Vázquez-Mellado J, Morales EM, Pacheco-Tena C, et al. Relation between adverse events associated with allopurinol and renal function in patients with gout. Ann Rheum Dis. 2001;60:981–3.
Dalbeth N, Stamp L. Allopurinol dosing in renal impairment: walking the tightrope between adequate urate lowering and adverse events. Semin Dial. 2007;20:391–5.
Schumacher HR Jr, Becker MA, Wortmann RL, 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;59:1540–8.
Quilis N, Andrés M, Gil S, Ranieri L, Vela P, Pascual E. E, et al. Febuxostat for patients with gout and severe chronic kidney disease: which is the appropriate dosage? Comment on the Article by Saag et al. Arthritis Rheumatol. 2016;68:2563–4.
Juge PA, Truchetet ME, Pillebout E, et al. Efficacy and safety of febuxostat in 73 gouty patients with stage 4/5 chronic kidney disease: a retrospective study of 10 centers. Jt Bone Spine. 2017;84:595–8.
Saag KG, Whelton A, Becker MA, et al. Impact of febuxostat on renal function in gout patients with moderate-to-severe renal impairment. Arthritis Rheumatol. 2016;68:2035–43.
Ghosh D, McGann PM, Furlong TJ, et al. Febuxostat-associated rhabdomyolysis in chronic renal failure. Med J Aust. 2015;203:107–8.
Liu CT, Chen CY, Hsu CY, et al. Risk of febuxostat-associated myopathy in patients with CKD. Clin J Am Soc Nephrol. 2017;12:744–50.
Chohan S. Safety and efficacy of febuxostat treatment in subjects with gout and severe allopurinol adverse reactions. J Rheumatol. 2011;38:1957–9.
Chinchilla SP, Urionaguena I, Perez-Ruiz F. Febuxostat for the chronic management of hyperuricemia in patients with gout. Expert Rev Clin Pharmacol. 2016;9:665–73.
Bardin T, Chalès G, Pascart T, et al. Risk of cutaneous adverse events with febuxostat treatment in patients with skin reaction to allopurinol: a retrospective, hospital-based study of 101 patients with consecutive allopurinol and febuxostat treatment. Jt Bone Spine. 2016;83:314–7.
Quilis N, Andrés M, Muñoz C, et al. Skin events with febuxostat in gout patients and previous skin reactions to allopurinol: a retrospective review [abstract]. Arthritis Rheumatol. 2016;68(Suppl. 10):273–4.
Becker MA, MacDonald PA, Hunt B, et al. Treating hyperuricemia of gout: safety and efficacy of febuxostat and allopurinol in older versus younger subjects. Nucleosides Nucleotides Nucleic Acids. 2011;30:1011–7.
Miner JN, Tan PK, Hyndman D, et al. Lesinurad, a novel, oral compound for gout, acts to decrease serum uric acid through inhibition of urate transporters in the kidney. Arthritis Res Ther. 2016;18:214.
Perez-Ruiz F, Calabozo M, Fernandez-Lopez JM, et al. Treatment of chronic gout in patients with renal function impairment: an open, randomized, actively controlled study. J Clin Rheumatol. 1999;5:49–55.
Reinders MK, van Roon EN, Jansen TL, et al. Efficacy and tolerability of urate-lowering drugs in gout: a randomized controlled trial of benzbromarone versus probenecid after failure of allopurinol. Ann Rheum Dis. 2009;68:51–6.
Terkeltaub RA. Clinical practice. Gout N Engl J Med. 2003;349:1647–55.
Gillen M, Valdez S, Zhou D, et al. Effects of renal function on pharmacokinetics and pharmacodynamics of lesinurad in adult volunteers. Drug Des Dev Ther. 2016;10:3555–62.
Dalbeth N, Jones G, Terkeltaub R, et al. Lesinurad, a selective uric acid reabsorption inhibitor, in combination with febuxostat in patients with tophaceous gout: findings of a phase III clinical trial. Arthritis Rheumatol. 2017;69:1903–13.
Bardin T, Keenan RT, Khanna PP, et al. Lesinurad in combination with allopurinol: a randomised, double-blind, placebo-controlled study in patients with gout with inadequate response to standard of care (the multinational CLEAR 2 study). Ann Rheum Dis. 2017;76:811–20.
Tausche AK, Alten R, Dalbeth N, et al. Lesinurad monotherapy in gout patients intolerant to a xanthine oxidase inhibitor: a 6 month phase 3 clinical trial and extension study. Rheumatology (Oxford). 2017;56(12):2170–8.
Reinders M, van Roon E, Houtman P, et al. Biochemical effectiveness of allopurinol and allopurinol-probenecid in previously benzbromarone-treated gout patients. Clin Rheumatol. 2007;26:1459–65.
Mejía-Chew C, Torres RJ, de Miguel E, et al. Resolution of massive tophaceous gout with three urate-lowering drugs. Am J Med. 2013;126(11):e9–10.
Shoji A, Yamanaka H, Kamatani N. A retrospective study of the relationship between serum urate level and recurrent attacks of gouty arthritis: evidence for reduction of recurrent gouty arthritis with antihyperuricemic therapy. Arthritis Rheum. 2004;51:321–5.
Borstad GC, Bryant LR, Abel MP, et al. Colchicine for prophylaxis of acute flares when initiating allopurinol for chronic gouty arthritis. J Rheumatol. 2004;31:2429–32.
Terkeltaub RA, Furst DE, Digiacinto JL, et al. Novel evidence-based colchicine dose-reduction algorithm to predict and prevent colchicine toxicity in the presence of cytochrome P450 3A4/P-glycoprotein inhibitors. Arthritis Rheum. 2011;63:2226–37.
Schlesinger N, Mysler E, Lin HY, et al. Canakinumab reduces the risk of acute gouty arthritis flares during initiation of allopurinol treatment: results of a double-blind, randomised study. Ann Rheum Dis. 2011;70:1264–71.
Lyseng-Williamson KA. Canakinumab: a guide to its use in acute gouty arthritis flares. BioDrugs. 2013;27:401–6.
Yagnik DR, Hillyer P, Marshall D, et al. Non inflammatory phagocytosis of monosodium urate monohydrate crystals by mouse macrophages: implications for the control of joint inflammation in gout. Arthritis Rheum. 2000;43:1779–89.
Scanu A, Oliviero F, Ramonda R, et al. Cytokine levels in human synovial fluid during the different stages of acute gout: role of transforming growth factor β1 in the resolution phase. Ann Rheum Dis. 2012;71:621–4.
Terkeltaub RA, Furst DE, Bennett K, et al. 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;62:1060–8.
Medani S, Wall C. Colchicine toxicity in renal patients: are we paying attention? Clin Nephrol. 2016;86:100–5.
Van Echteld I, Wechalekar MD, Schlesinger N, et al. Colchicine for acute gout. Cochrane Database Syst Rev. 2014; (8):CD006190. https://doi.org/10.1002/14651858.cd006190.
Bardin T, Richette P. Impact of comorbidities on gout and hyperuricaemia: an update on prevalence and treatment options. BMC Med. 2017;15:123.
Janssens HJ, Lucassen PL, Van de Laar FA, Janssen M, Van de Lisdonk EH. Systemic corticosteroids for acute gout. Cochrane Database Syst Rev. 2008;16(2):CD005521
Fernández C, Noguera R, González JA, et al. Treatment of acute gouty attacks with a small dose of intra-articular triamcinolone acetonide. J Rheumatol. 1999;26:2285–6.
Andrés M, Begazo A, Sivera F. Intraarticular triamcinolone plus mepivacaine provides a rapid and sustained relief for acute gouty arthritis. Ann Rheum Dis. 2016;75(Suppl. 2):1182.
Bardin T. Canakinumab for the patient with difficult-to-treat gouty arthritis: review of the clinical evidence. Jt Bone Spine. 2015;82(Suppl. 1):eS9–16.
Thueringer JT, Doll NK, Gertner E. Anakinra for the treatment of acute severe gout in critically ill patients. Semin Arthritis Rheum. 2015;45(1):81–5.
Aouba A, Deshayes S, Frenzel L, et al. Efficacy of anakinra for various types of crystal-induced arthritis in complex hospitalized patients: a case series and review of the literature. Mediators Inflamm. 2015;2015:792173.
Petite SE. Effectiveness of anakinra in acute gout: a retrospective review of initial and refractory therapy. Am J Ther. 2017;24:e633–4.
Pascual E, Sivera F. Why should be gout so poorly treated? Ann Rheum Dis. 2007;66:1269–70.
Funding
No funding was received for the preparation of this article.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
Eliseo Pascual has participated in the boards of Astra Zeneca, Menarini, Grunenthal and Pegloticase (unrelated to this article), and has received speaking fees from Astra Zeneca and Grunenthal (unrelated to this article). Mariano Andrés has received fees for participation in review activities such as data monitoring boards from Grunenthal and Astra-Zeneca, and has received support for travel from Menarini, Grunenthal and Astra-Zeneca. Francisca Sivera has received speaking fees from Menarini.
Rights and permissions
About this article
Cite this article
Pascual, E., Sivera, F. & Andrés, M. Managing Gout in the Patient with Renal Impairment. Drugs Aging 35, 263–273 (2018). https://doi.org/10.1007/s40266-018-0517-7
Published:
Issue Date:
DOI: https://doi.org/10.1007/s40266-018-0517-7