Studies have demonstrated the presence of a strong association between serum uric acid (SUA) and acute kidney injury (AKI) consistently across several disease models. Exposure to SUA at different time periods and concentrations has reliably resulted in AKI whether assessed by conventional or novel biomarkers or by kinetic estimated glomerular filtration rate (KeGFR) engineered for non-steady dynamic states. In experimental models, moderate hyperuricemia was associated with an absence of intrarenal crystals, manifestation of tubular injury, macrophage infiltration, and increased expression of inflammatory mediators that were attenuated with uric acid lowering therapy with rasburicase, a recombinant urate oxidase. In a pilot clinical trial, treatment with rasburicase was associated with a decreased incidence of AKI and evidence for less renal structural injury. Lowering SUA also improved KeGFR and estimated glomerular filtration rate in 2 separate studies. SUA has also been linked to diabetic nephropathy, hypertension, cardiovascular disease, chronic kidney disease, metabolic syndrome, and their mechanisms of action share many common traits. In this article, we explore the evidence for the causal role of SUA in AKI using Bradford Hill criteria as a guideline with data integration from related fields.

Keywords:
Uric acid, Acute kidney injury, Causality
1.
Ames BN, Cathcart R, Schwiers E, Hochstein P. Uric acid provides an antioxidant defense in humans against oxidant- and radical-caused aging and cancer: a hypothesis.
Proc Natl Acad Sci USA
. 1981 Nov; 78(11): 6858–62.
2.
Johnson RJ, Bakris GL, Borghi C, Chonchol MB, Feldman D, Lanaspa MA, et al. Hyperuricemia, Acute and Chronic Kidney Disease, Hypertension, and Cardiovascular Disease: Report of a Scientific Workshop Organized by the National Kidney Foundation.
Am J Kidney Dis
. 2018 Jun; 71(6): 851–65.
3.
Hill AB. The environment and disease: association or causation?
Proc R Soc Med
. 1965 May; 58: 295–300.
4.
Fedak KM, Bernal A, Capshaw ZA, Gross S. Applying the Bradford Hill criteria in the 21st century: how data integration has changed causal inference in molecular epidemiology.
Emerg Themes Epidemiol
. 2015 Sep; 12(1): 14.
5.
Kjellstrand CM, Cambell DC 2nd, von Hartitzsch B, Buselmeier TJ. Hyperuricemic acute renal failure.
Arch Intern Med
. 1974 Mar; 133(3): 349–59.
6.
Ejaz AA, Mu W, Kang DH, Roncal C, Sautin YY, Henderson G, et al. Could uric acid have a role in acute renal failure?
Clin J Am Soc Nephrol
. 2007 Jan; 2(1): 16–21.
7.
Ejaz AA, Beaver TM, Shimada M, Sood P, Lingegowda V, Schold JD, et al. Uric acid: a novel risk factor for acute kidney injury in high-risk cardiac surgery patients?
Am J Nephrol
. 2009; 30(5): 425–9.
8.
Lapsia V, Johnson RJ, Dass B, Shimada M, Kambhampati G, Ejaz NI, et al. Elevated uric acid increases the risk for acute kidney injury.
Am J Med
. 2012 Mar; 125(3): 302.e9–17.
9.
Ejaz AA, Kambhampati G, Ejaz NI, Dass B, Lapsia V, Arif AA, et al. Post-operative serum uric acid and acute kidney injury.
J Nephrol
. 2012 Jul-Aug; 25(4): 497–505.
10.
Ejaz AA, Alquadan KF, Dass B, Shimada M, Kanbay M, Johnson RJ. Effects of serum uric acid on estimated GFR in CS patients: a pilot study.
Am J Nephrol
. 2015; 42(6): 402–9.
11.
Lee EH, Choi JH, Joung KW, Kim JY, Baek SH, Ji SM, et al. Relationship between Serum Uric Acid Concentration and Acute Kidney Injury after Coronary Artery Bypass Surgery.
J Korean Med Sci
. 2015 Oct; 30(10): 1509–16.
12.
Gaipov A, Solak Y, Turkmen K, Toker A, Baysal AN, Cicekler H, et al. Serum uric acid may predict development of progressive acute kidney injury after open heart surgery.
Ren Fail
. 2015 Feb; 37(1): 96–102.
13.
Koratala A, Singhania G, Alquadan KF, Shimada M, Johnson RJ, Ejaz AA. Serum uric acid exhibits inverse relationship with estimated glomerular filtration rate.
Nephron
. 2016; 134(4): 231–7.
14.
Ejaz AA, Pourafshar N, Mohandas R, Smallwood BA, Johnson RJ, Hsu JW. Uric acid and the prediction models of tumor lysis syndrome in AML.
PLoS One
. 2015 Mar; 10(3):e0119497.
15.
Joung KW, Jo JY, Kim WJ, Choi DK, Chin JH, Lee EH, et al. Association of preoperative uric acid and acute kidney injury following cardiovascular surgery.
J Cardiothorac Vasc Anesth
. 2014 Dec; 28(6): 1440–7.
16.
Ben-Dov IZ, Kark JD. 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 Aug; 26(8): 2558–66.
17.
Otomo K, Horino T, Miki T, Kataoka H, Hatakeyama Y, Matsumoto T, et al. Serum uric acid level as a risk factor for acute kidney injury in hospitalized patients: a retrospective database analysis using the integrated medical information system at Kochi Medical School hospital.
Clin Exp Nephrol
. 2016 Apr; 20(2): 235–43.
18.
Nie S, Feng Z, Tang L, Wang X, He Y, Fang J, et al. Risk Factor Analysis for AKI Including Laboratory Indicators: a Nationwide Multicenter Study of Hospitalized Patients.
Kidney Blood Press Res
. 2017; 42(5): 761–73.
19.
Greenberg KI, McAdams-DeMarco MA, Köttgen A, Appel LJ, Coresh J, Grams ME. Plasma Urate and Risk of a Hospital Stay with AKI: The Atherosclerosis Risk in Communities Study.
Clin J Am Soc Nephrol
. 2015 May; 10(5): 776–83.
20.
Joung KW, Choi SS, Kong YG, Yu J, Lim J, Hwang JH, et al. Incidence and risk factors of acute kidney injury after radical cystectomy: importance of preoperative serum uric acid level.
Int J Med Sci
. 2015 Jul; 12(7): 599–604.
21.
Yu J, Park HK, Kwon HJ, Lee J, Hwang JH, Kim HY, et al. Risk factors for acute -kidney injury after percutaneous nephrolithotomy: implications of intraoperative hypotension.
Medicine (Baltimore)
. 2018 Jul; 97(30):e11580.
22.
Kanbay M, Solak Y, Afsar B, Nistor I, Aslan G, Çağlayan OH, et al. Serum Uric Acid and Risk for Acute Kidney Injury Following Contrast.
Angiology
. 2017 Feb; 68(2): 132–44.
23.
Liang J, Zhang P, Hu X, Zhi L. Elevated serum uric acid after injury correlates with the early acute kidney in severe burns.
Burns
. 2015 Dec; 41(8): 1724–31.
24.
Kanbay M, Jensen T, Solak Y, Le M, Roncal-Jimenez C, Rivard C, et al. Uric acid in metabolic syndrome: from an innocent bystander to a central player.
Eur J Intern Med
. 2016 Apr; 29: 3–8.
25.
Cicerchi C, Li N, Kratzer J, Garcia G, Roncal-Jimenez CA, Tanabe K, et al. Uric acid-dependent inhibition of AMP kinase induces hepatic glucose production in diabetes and starvation: evolutionary implications of the uricase loss in hominids.
FASEB J
. 2014 Aug; 28(8): 3339–50.
26.
Sautin YY, Nakagawa T, Zharikov S, Johnson RJ. Adverse effects of the classic antioxidant uric acid in adipocytes: NADPH oxidase-mediated oxidative/nitrosative stress.
Am J Physiol Cell Physiol
. 2007 Aug; 293(2):C584–96.
27.
Roncal-Jimenez CA. Lanaspa MA, Rivard CJ, Nakagawa T, Sanchez-Lozada LG, Jalal D, et al. Sucrose induces fatty liver and pancreatic inflammation in male breeder rats independent of excess energy intake.
Metabolism
. 2011 Sep; 60(9): 1259–70.
28.
Lanaspa MA. Sanchez-Lozada LG, Choi YJ, Cicerchi C, Kanbay M, Roncal-Jimenez CA, et al. Uric acid induces hepatic steatosis by generation of mitochondrial oxidative stress: potential role in fructose-dependent and -independent fatty liver.
J Biol Chem
. 2012 Nov; 287(48): 40732–44.
29.
Kaufeld T, Foerster KA, Schilling T, Kielstein JT, Kaufeld J, Shrestha M, et al. Preoperative serum uric acid predicts incident acute kidney injury following cardiac surgery.
BMC Nephrol
. 2018 Jul; 19(1): 161.
30.
Liu Y, Tan N, Chen J, Zhou Y, Chen L, Chen S, et al. The relationship between hyperuricemia and the risk of contrast-induced acute kidney injury after percutaneous coronary intervention in patients with relatively normal serum creatinine.
Clinics (São Paulo)
. 2013 Jan; 68(1): 19–25.
31.
Spencer HW, Yarger WE, Robinson RR. Alterations of renal function during dietary-induced hyperuricemia in the rat.
Kidney Int
. 1976 Jun; 9(6): 489–500.
32.
Mulay SR, Shi C, Ma X, Anders HJ. Novel Insights into Crystal-Induced Kidney Injury.
Kidney Dis (Basel)
. 2018 Jun; 4(2): 49–57.
33.
Sánchez-Lozada LG, Tapia E, Santamaría J, Avila-Casado C, Soto V, Nepomuceno T, et al. Mild hyperuricemia induces vasoconstriction and maintains glomerular hypertension in normal and remnant kidney rats.
Kidney Int
. 2005 Jan; 67(1): 237–47.
34.
Kang DH, Park SK, Lee IK, Johnson RJ. Uric acid-induced C-reactive protein expression: implication on cell proliferation and nitric oxide production of human vascular cells.
J Am Soc Nephrol
. 2005 Dec; 16(12): 3553–62.
35.
Kang DH, Han L, Ouyang X, Kahn AM, Kanellis J, Li P, et al. Uric acid causes vascular smooth muscle cell proliferation by entering cells via a functional urate transporter.
Am J Nephrol
. 2005 Sep-Oct; 25(5): 425–33.
36.
Kanellis J, Watanabe S, Li JH, Kang DH, Li P, Nakagawa T, et al. Uric acid stimulates monocyte chemoattractant protein-1 production in vascular smooth muscle cells via mitogen-activated protein kinase and cyclooxygenase-2.
Hypertension
. 2003 Jun; 41(6): 1287–93.
37.
Khosla UM, Zharikov S, Finch JL, Nakagawa T, Roncal C, Mu W, et al. Hyperuricemia induces endothelial dysfunction.
Kidney Int
. 2005 May; 67(5): 1739–42.
38.
Nakagawa T, Hu H, Zharikov S, Tuttle KR, Short RA, Glushakova O, et al. A causal role for uric acid in fructose-induced metabolic syndrome.
Am J Physiol Renal Physiol
. 2006 Mar; 290(3):F625–31.
39.
Kanbay M, Siriopol D, Nistor I, Elcioglu OC, Telci O, Takir M, et al. Effects of allopurinol on endothelial dysfunction: a meta-analysis.
Am J Nephrol
. 2014; 39(4): 348–56.
40.
Agarwal A, Dong Z, Harris R, Murray P, Parikh SM, Rosner MH, et al.; Acute Dialysis Quality Initiative XIII Working Group. Cellular and Molecular Mechanisms of AKI.
J Am Soc Nephrol
. 2016 May; 27(5): 1288–99.
41.
Shimada M, Johnson RJ, May WS Jr, Lingegowda V, Sood P, Nakagawa T, et al. A novel role for uric acid in acute kidney injury associated with tumour lysis syndrome.
Nephrol Dial Transplant
. 2009 Oct; 24(10): 2960–4.
42.
Shimada M, Dass B, Ejaz AA. Paradigm shift in the role of uric acid in acute kidney injury.
Semin Nephrol
. 2011 Sep; 31(5): 453–8.
43.
Roncal CA, Mu W, Croker B, Reungjui S, Ouyang X, Tabah-Fisch I, et al. Effect of elevated serum uric acid on cisplatin-induced acute renal failure.
Am J Physiol Renal Physiol
. 2007 Jan; 292(1):F116–22.
44.
Ejaz AA, Dass B, Lingegowda V, Shimada M, Beaver TM, Ejaz NI, et al. Effect of uric acid lowering therapy on the prevention of acute kidney injury in cardiovascular surgery.
Int Urol Nephrol
. 2013 Apr; 45(2): 449–58.
45.
Galardy PJ, Hochberg J, Perkins SL, Harrison L, Goldman S, Cairo MS. Rasburicase in the prevention of laboratory/clinical tumour lysis syndrome in children with advanced mature B-NHL: a Children’s Oncology Group Report.
Br J Haematol
. 2013 Nov; 163(3): 365–72.
46.
Kanbay M, Huddam B, Azak A, Solak Y, Kadioglu GK, Kirbas I, 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 Aug; 6(8): 1887–94.
47.
Erol T, Tekin A, Katırcıbaşı MT, Sezgin N, Bilgi M, Tekin G, et al. Efficacy of allopurinol pretreatment for prevention of contrast-induced nephropathy: a randomized controlled trial.
Int J Cardiol
. 2013 Aug; 167(4): 1396–9.
48.
Kumar A, Bhawani G, Kumari N, Murthy KS, Lalwani V, Raju CN. Comparative study of renal protective effects of allopurinol and N-acetyl-cysteine on contrast induced nephropathy in patients undergoing cardiac catheterization.
J Clin Diagn Res
. 2014 Dec; 8(12):HC03–07.
49.
Roncal Jimenez CA, Ishimoto T, Lanaspa MA, Rivard CJ, Nakagawa T, Ejaz AA, et al. Fructokinase activity mediates dehydration-induced renal injury.
Kidney Int
. 2014 Aug; 86(2): 294–302.
50.
Kim JH, Gil HW, Yang JO, Lee EY, Hong SY. Serum uric acid level as a marker for mortality and acute kidney injury in patients with acute paraquat intoxication.
Nephrol Dial Transplant
. 2011 Jun; 26(6): 1846–52.
© 2019 S. Karger AG, Basel
2019
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.