The unanswered Questions in Hyperuricemia: is it a cause of chronic kidney disease, a compensation mechanism, a coincidence, a consequence of disease or concurrent phenomenon?

Keywords: uric acid; hyperuricemia; renal insufficiency, chronic kidney disease; glomerular filtration rate; therapy


Chronic kidney disease (CKD) has become a global public health problem because of its high prevalence and the accompanying increase in the risk of end-stage renal disease, cardiovascular disease, and premature death. The role of uric acid (UA) in the pathogenesis and progression of CKD remains controversial. Although many evidence-based studies have suggested that UA itself may harm patients with CKD by increasing inflammation and CKD progression, the issue is still a matter of discussions. In this review we try to clarify what is hyperuricemia – cause of CKD, compensation, coincidence, consequence of CKD or it is only an epiphenomenon, and to evaluate current evidence of different types of targeted hypouricemic therapy effectiveness. So, to treat or not to treat?


Download data is not yet available.


Chung W, Kim AJ, Ro H, Chang JH, Lee HH, Jung JY. HUA is an independent risk factor for mortality only if chronic kidney disease is present. Am J Nephrol. 2013;37(5):452–461.  doi: 10.1159/000350534.

Trigka K, PatrasGreece KS, Fourtounas C. HUA and chronic kidney disease: an enigma yet to be solved. Renal failure. 2014;36(9):1351-1359. doi: 10.3109/0886022X.2014.947516

Bellomo G. UA and chronic kidney disease: A time to act? World J Nephrol. 2013;2(2):17–25.  doi:  10.5527/wjn.v2.i2.17

Eleftheriadis T, Golphinopoulos S, Pissas G, Stefanidis I. Asymptomatic HUA and chronic kidney disease: Narrative review of a treatment controversial. Journal of Advanced Research. 2017 Sep; 8(5):555. doi: 10.1016/j.jare.2017.05.001

Madero M, Sarnak MJ, Wang X, Greene T, Beck GJ, Kusek JW. UA and long-term outcomes in CKD. Am J Kidney Dis. 2009;53:796–803. doi:  10.1053/j.ajkd.2008.12.021

Prasad Sah OS, Qing YX. Associations Between HUA and Chronic Kidney Disease: A Review, Nephro-Urol Mon. 2015 ;7(3):e27233. doi: 10.5812/numonthly.7(3)2015.27233.

Singh JA. Racial and gender disparities among patients with gout. Curr Rheumatol Rep. 2013;15(2):307. doi: 10.1007/s11926-012-0307-x.

Bakan A, Oral A, Elcioglu OC, Takir M, Kostek O, Ozkok A. HUA is associated with progression of IgA nephropathy.  Int Urol Nephrol. 2015;47:673–678. doi: 10.1007/s11255-015-0939-7

Jalal DI, Rivard CJ, Johnson RJ, et al. Serum UA levels predict the development of albuminuria over 6 years in patients with type 1 diabetes: Findings from the coronary artery calcification in type 1 diabetes study. Nephrol Dial Transplant. 2010;25(6):1865–1869.  doi: 10.1093/ndt/gfp740

Johnson RJ, Nakagawa T, Jalal D, Sánchez-Lozada LG, Kang DH, Ritz E. UA and chronic kidney disease: Which is chasing which? Nephrol Dial Transplant. 2013;28(9):2221–2228.  doi: 10.1093/ndt/gft029

Kim WJ, Kim SS, Bae MJ, et al. High-normal serum UA predicts the development of chronic kidney disease in patients with type 2 diabetes mellitus and preserved kidney function. J Diabetes Complications. 2014;28(2):130–134. doi: 10.1016/j.jdiacomp.2013.11.006

Koratala A, Singhania G, Alquadan KF, Shimada M, Johnson RJ, Ejaz AA. Serum UA Exhibits Inverse Relationship with Estimated Glomerular Filtration Rate. Nephron. 2016;134:231-237.  doi: 10.1159/000448629

Mende C. Management of chronic kidney disease: the relationship between serum UA and development of nephropathy. Adv Ther. 2015;32:1177–1191.  doi: 10.1007/s12325-015-0272-7

Shi Y, Chen W, Jalal D, Li Z, Chen W, Mao H. Clinical outcome of HUA in IgA nephropathy: a retrospective cohort study and randomized controlled trial. Kidney Blood Press Res. 2012;35:153–160. doi: 10.1159/000331453  

Treviño-Becerra A, Iseki K (eds). UA in Chronic Kidney Disease. Contrib Nephrol. Basel, Karger. 2018;192:135-146. doi: 10.1159/000484279.

Tsai CW, Lin SY, Kuo CC, Huang CC. Serum UA and Progression of Kidney Disease: A Longitudinal Analysis and Mini-Review. PLoS ONE. 2017;12(1): e0170393. doi: 10.1371/journal.pone.0170393.  

Zoppini G, Targher G, Chonchol M, et al. Serum UA levels and incident chronic kidney disease in patients with type 2 diabetes and preserved kidney function. Diabetes Care. 2012;35(1):99–104. doi: 10.2337/dc11-1346

Wang Y, Bao X. Effects of UA on endothelial dysfunction in early chronic kidney disease and its mechanisms. Eur J Med Res. 2013;18(1):26.  4. doi: 10.1186/2047-783X-18-26

Kohagura K, Kochi M, Miyagi T, Kinjyo T, Maehara Y, Nagahama K. An association between UA levels and renal arteriolopathy in chronic kidney disease: a biopsy-based study. Hypertens Res. 2013;36:43–49. 4. doi: 10.1038/hr.2012.135  

Whelton A, Macdonald PA, Zhao L, Hunt B, Gunawardhana L. Renal function in gout: long term treatment effects of Febuxostat. J Clin Rheumatol. 2011;17(1):7–13.  doi: 10.1097/RHU.0b013e318204aab4.

Chuengsamarn S, Rattanamongkolgul S, Jirawatnotai S. Association between serum UA level and microalbuminuria to chronic vascular complications in Thai patients with type 2 diabetes. J Diabetes Complications. 2014;28(2):124–129 doi: 10.1016/j.jdiacomp.2013.12.002

Zhang Y, Yamamoto T, Hisatome I, et al. UA induces oxidative stress and growth inhibition by activating adenosine monophosphate-activated protein kinase and extracellular signal-regulated kinase signal pathways in pancreatic β cells. Mol Cell Endocrinol. 2013;375(1-2):89–96. doi: 10.1016/j.mce.2013.04.027.

Dogan A, Yarlioglues M, Kaya MG, et al. Effect of long-term and high-dose allopurinol therapy on endothelial function in normotensive diabetic patients. Blood Press. 2011;20(3):182–187.  doi: 10.3109/08037051.2010.538977.

Puddu P, Puddu GM, Cravero E, Vizioli L, Muscari A. Relationships among HUA, endothelial dysfunction and cardiovascular disease: Molecular mechanisms and clinical implications. J Cardiol. 2012;59(3):235–242. doi: 10.1016/j.jjcc.2012.01.013.

Kanellis J, Kang DH. UA as a mediator of endothelial dysfunction, inflammation, and vascular disease. Semin Nephrol. 2005;25(1):39–42 doi: 10.1016/j.semnephrol.2004.09.007

Boban M, Kocic G, Radenkovic S, et al. Circulating purine compounds, UA, and XO/dehydrogenase relationship in essential hypertension and end stage renal disease. Ren Fail. 2014;36(4):613-618. doi: 10.3109/0886022X.2014.882240

Ling Y, Li XM, Gao X. Cross-sectional association of serum C-reactive protein and UA with albuminuria in Chinese type 2 diabetic patients. Chin Med J (Engl). 2013;126(21):4023–4029.  doi: 10.3760/cma.j.issn.0366-6999.20131485

Terawaki H, Nakayama M, Miyazawa E, et al. Effect of allopurinol on cardiovascular incidence among hypertensive nephropathy patients: The Gonryo study. Clin Exp Nephrol. 2013;17(4):549–553. doi: 10.1007/s10157-012-0742-z.

Yoshimura A, Adachi H, Hirai Y, et al. Serum UA is associated with the left ventricular mass index in males of a general population. Int Heart J. 2014;55(1):65–70.   doi: 10.1536/ihj.13-170

Jalal DI, Chonchol M, Chen W, Targher G. UA as a target of therapy in CKD. Am J Kidney Dis. 2013;61(1):134–146. doi:  10.1016/j.jare.2017.04.007

Li L, Yang C, Zhao Y, Zeng X, Liu F, Fu P. Is HUA an independent risk factor for new-onset chronic kidney disease? A systematic review and meta-analysis based on observational cohort studies. BMC Nephrol. 2014;15:122. doi: 10.1186/1471-2369-15-122.

Uchida S, Chang WX, Ota T, Tamura Y, Shiraishi T, Kumagai T. Targeting UA and the inhibition of progression to end-stage renal disease–a propensity score analysis. PLoS One. 2015;10:e0145506.  doi: 10.1371/journal.pone.0145506

Sturm G, Kollerits B, Neyer U, Ritz E, Kronenberg F. MMKD Study Group. UA as a risk factor for progression of non-diabetic chronic kidney disease? The Mild to Moderate Kidney Disease (MMKD) Study. Exp Gerontol. 2008;43(4):347–352.  doi: 10.1016/j.exger.2008.01.006

Goicoechea M, Garcia dV., Verdalles U, Verde E, Macias N, Santos A. 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.  doi: 10.1053/j.ajkd.2014.11.016

Ramirez MEG.,  Bargman J.M. Treatment of asymptomatic HUA in chronic kidney disease: A new target in an old enemy – A review. J Adv Res. 2017 Sep; 8(5): 551–554.  doi: 10.1016/j.jare.2017.04.006

Waring WS, McKnight JA, Webb DJ, Maxwell SR. Lowering serum urate does not improve endothelial function in patients with type 2 diabetes. Diabetologia. 2007;50(12):2572–2579.  doi:10.1007/s00125-007-0817-7

Sowers JR. Diabetes mellitus and vascular disease. Hypertension. 2013;61(5):943–947. doi: 10.1161/HYPERTENSIONAHA.111.00612 .

Altemtam N, Russell J, El Nahas M. A study of the natural history of diabetic kidney disease. (DKD) Nephrol Dial Transplant. 2012;27:1847–1854. doi: 10.1093/ndt/gfr561.

Ito H, Abe M, Mifune M, et al. HUA is independently associated with coronary heart disease and renal dysfunction in patients with type 2 diabetes mellitus. PLoS One. 2011;6(11):e27817. doi: 10.1371/journal.pone.0027817.

Miao Y, Ottenbros SA, Laverman GD, et al. Effect of a reduction in UA on renal outcomes during losartan treatment: A post hoc analysis of the reduction of endpoints in non-insulin-dependent diabetes mellitus with the Angiotensin II Antagonist Losartan Trial. Hypertension. 2011;58(1):2–7. doi: 10.1161/HYPERTENSIONAHA.111.171488.

Nitta K, Iimuro S, Imai E, et al. Risk factors for increased left ventricular hypertrophy in patients with chronic kidney disease. Clin Exp Nephrol. 2013;17(5):730–742.  doi: 10.1007/s10157-012-0758-4.

Sheikhbahaei S, Fotouhi A, Hafezi-Nejad N, Nakhjavani M, Esteghamati A. Serum UA, the metabolic syndrome, and the risk of chronic kidney disease in patients with type 2 diabetes. Metab Syndr Relat Disord. 2014;12(2):102–109. doi: 10.2215/CJN.03140315

Pai BH, Swarnalatha G, Ram R, Dakshinamurty KV. Allopurinol for prevention of progression of kidney disease with HUA. Indian J Nephrol. 2013;23(4):280–286.  doi: 10.4103/0971-4065.114499

Sedaghat S, Hoorn EJ, van Rooij FJ, et al. Serum UA and chronic kidney disease: The role of hypertension. PLoS One. 2013;8(11):e76827. doi: 10.1371/journal.pone.0076827

Sezai A, Soma M, Nakata K, et al. Comparison of febuxostat and allopurinol for HUA in cardiac surgery patients (NU-FLASH Trial). Circ J. 2013;77(8):2043–2049. doi:10.1253/circj.CJ-13-0082

Gois PH, Souza ER. Pharmacotherapy for HUA in hypertensive patients. Cochrane Database Syst Rev. 2013;1:CD008652. doi: 10.1002/14651858.

Sezer S, Karakan S, Atesagaoglu B, Acar FN. Allopurinol reduces cardiovascular risks and improves renal function in pre-dialysis chronic kidney disease patients with HUA. Saudi J Kidney Dis Transpl. 2014;25(2):316–320. doi: 10.4103/1319-2442.128520

Gibson T, Rodgers V, Potter C, HA Simmonds. Allopurinol treatment and its effect on renal function in gout: a controlled study. Ann Rheum Dise. 1982;41(1):59–65. doi: 10.1136/ard.41.1.59

Chanard J, Toupance O, Lavaud S, Hurault de Ligny B, Bernaud C, Moulin B. Amlodipine reduces cyclosporine-induced HUA in hypertensive renal transplant recipients. Nephrol Dial Transplant. 2003;18(10):2147–2153. doi:10.1093/ndt/gfg341

Siu YP, Leung KT, Tong MK, Kwan TH. Use of allopurinol in slowing the progression of renal disease through its ability to lower serum UA level. Am J Kidney Dis. 2006;47:51–59.  doi: 10.1053/j.ajkd.2005.10.006

Liu WC, Hung CC, Chen SC, et al. Association of HUA with renal outcomes, cardiovascular disease, and mortality. Clin J Am Soc Nephrol. 2012;7(4):541–548. doi: 10.2215/CJN.09420911

Kanbay M, Yilmaz MI, Sonmez A, et al. Serum UA independently predicts cardiovascular events in advanced nephropathy. Am J Nephrol. 2012;36(4):324–331.  doi: 10.1159/000342390

Malaguarnera M, Vacante M, Russo C, Dipasquale G, Gargante MP, Motta M. A single dose of rasburicase in elderly patients with HUA reduces serum UA levels and improves renal function. Expert Opn Pharmacother. 2009;10(5):737–742. doi: 10.1517/14656560902781972

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(2):128–132

Sircar D, Chatterjee S, Waikhom R, Golay V, Raychaudhury A, Chatterjee S. Efficacy of febuxostat for slowing the GFR decline in patients with CKD and asymptomatic HUA: a 6-month, double-blind, randomized, placebo-controlled trial. Am J Kidney Dis. 2015;66:945–950.  doi: 10.1053/j.ajkd.2015.05.017

Dong J, Han QF, Zhu TY, et al. The associations of UA, cardiovascular and all-cause mortality in peritoneal dialysispatients. PLoS One. 2014;9(1):e82342 doi: 10.1371/journal.pone.0082342

Wang H, Wei Y, Kong X, Xu D. Effects of urate-lowering therapy in HUA on slowing the progression of renal function: A meta-analysis. J Ren Nutr. 2013;23(5):389–396.  doi: 10.1053/j.jrn.2012.08.005. 

Sakai Y, Otsuka T, Ohno D, Murasawa T, Sato N, Tsuruoka S. Febuxostat for treating allopurinol-resistant HUA in patients with chronic kidney disease. Ren Fail. 2014;36(2):225–231. doi: 10.3109/0886022X.2013.844622

Pasina L, Brucato AL, Djade CD, Di Corato P, Ghidoni S, Tettamanti M. Inappropriate prescription of allopurinol and febuxostat and risk of adverse events in the elderly: results from the REPOSI registry. Eur J Clin Pharmacol. 2014;70:1495–1503 doi: 10.1007/s00228-014-1752-4

Feng S, Jiang L, Shi Y, et al. UA levels and all-cause mortality in peritoneal dialysis patients. Kidney Blood Press Res. 2013;37(2-3):181–189. doi: 10.1159/000350143

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. doi: 10.1186/s12882-015-0047-z.

Bose B, Badve SV, Hiremath SS, et al. Effects of UA-lowering therapy on renal outcomes: A systematic review and meta-analysis. Nephrol Dial Transplant. 2014;29(2):406–413. doi: 10.1093/ndt/gft378

Hosoya T, Ohno I, Nomura S, Hisatome I, Uchida S, Fujimori S. Effects of topiroxostat on the serum urate levels and urinary albumin excretion in hyperuricemic stage 3 chronic kidney disease patients with or without gout. Clin Exp Nephrol. 2014;18:876–884.  doi: 10.1007/s10157-014-0935-8

Hosoya T, Kimura K, Itoh S, Inaba M, Uchida S, Tomino Y. The effect of febuxostat to prevent a further reduction in renal function of patients with HUA who have never had gout and are complicated by chronic kidney disease stage 3: study protocol for a multicenter randomized controlled study. Trials. 2014;15:26.  doi: 10.1186/1745-6215-15-26

Davies MJ., Trujillo A, Vijapurkar U, Damaraju CV, Meininger G. Effect of canagliflozin on serum UA in patients with type 2 diabetes mellitus. Diabetes Obes Metab. 2015;17:426–429. doi: 10.1111/dom.12439

Wanner C, Inzucchi SE, Lachin JM, Fitchett D, von Eynatten M, Mattheus M. Empagliflozin and progression of kidney disease in type 2 diabetes. N Engl J Med 2016;375:323–334. doi: 10.1056/NEJMc1611290.

 Cheung AK, Sarnak MJ, Yan G, et al. Cardiac diseases in maintenance hemodialysis patients: Results of the HEMO Study. Kidney Int. 2004;65(6):2380–2389. doi:10.1111/j.1523-1755.2004.00657.x

Lee CT, Chua S, Hsu CY, et al. Biomarkers associated with vascular and valvular calcification in chronic hemodialysis patients. Dis Markers. 2013;34(4):229–235.  doi: 10.3233/DMA-130965

Antunovic T, Stefanovic A, Ratkovic M, et al. High UA and low superoxide dismutase as possible predictors of all-cause and cardiovascular mortality in hemodialysis patients. Int Urol Nephrol. 2013;45(4):1111–1119 doi: 10.1681/ASN.2018010086

Lobo JC, Stockler-Pinto MB, da Nóbrega AC, Carraro-Eduardo JC, Mafra D. Is there association between UA and inflammation in hemodialysis patients? Ren Fail. 2013;35(3):361–366. doi: 10.3109/0886022X.2013.764274

Latif W, Karaboyas A, Tong L, et al. UA levels and all-cause and cardiovascular mortality in the hemodialysis population. Clin J Am Soc Nephrol. 2011;6(10):2470–2477. doi: 10.2215/CJN.00670111

Xia X, He F, Wu X, Peng F, Huang F, Yu X. Relationship between serum UA and all-cause and cardiovascular mortality in patients treated with peritoneal dialysis. Am J Kidney Dis. 2014;64(2):257–264. doi: 10.1053/j.ajkd.2013.08.027

How to Cite
Kolesnyk, M. (2018). The unanswered Questions in Hyperuricemia: is it a cause of chronic kidney disease, a compensation mechanism, a coincidence, a consequence of disease or concurrent phenomenon?. Ukrainian Journal of Nephrology and Dialysis, (4(60), 48-61.