Acute kidney injury in gout: prevalence and risk factors through two decades

Abstract

Aim: To compare the rate of acute kidney injury (AKI) associated with non-steroidal anti-inflammatory drugs (NSAIDs) through two consecutive decades in patients with gout and to study factors associated with AKI events.

Methods: Retrospective analysis of data from Jan 1994 to Dec 2024. Data on AKI and upper gastrointestinal bleeding (UGB) were collected during the same period (2005–2024), along with general (age, gender, time from onset), gout-related (tophi, imaging, clinical distribution, number of flares), treatment-related (diuretic and urate-lowering medications, exposure to the triple whammy), and comorbidities-related variables (hypertension, hyperlipidemia, diabetes, chronic kidney disease). Analysis was made for the whole cohort and comparing decades with each other. Survival analysis was performed to evaluate those variables independently associated with a higher risk of AKI.

Results: 1,207 cases were available for analysis. The overall cumulated rate of AKI was 13.3%, showing an increase from 9.9% to 16.1% from the first to the second decades, respectively, but no change in the severity of AKI was observed. In contrast, there was no change in the rate of UGB through the two decades (close to 2%). There was an increase in the frequency of gout severity variables, triple whammy exposure, and comorbid conditions through the two decades. Age, tophaceous gout, chronic kidney disease, triple whammy exposure, were variables independently associated with a higher risk of AKI, while urate-lowering prescription was associated with a lower risk.

Conclusions: An increase in the rate of AKI was observed through the two decades studied, associated with an increase in gout severity, comorbidity, and exposure to triple whammy. Chronic kidney disease and exposure to triple whammy in older patients with severe (tophaceous) gout seem to define the combination for the highest risk, in whom the avoidance of NSAIDs should be carefully considered.

Keywords

gout / kidney injury / chronic kidney disease / NSAIDs / triple whammy

References

[1] Dalbeth N, Choi HK, Joosten LAB, Khanna PP, Matsuo H, Perez-Ruiz F, et al. Gout. Nat Rev Dis Primers. 2019; 5: 69.

[2] Quilis N, Sivera F, Seoane-Mato D, Pérez-Ruiz F, Sánchez-Piedra C, Díaz-González F, et al.; Working Group Proyecto EPISER2016. Prevalence of gout in the adult general population in Spain: Estimating the proportion of undiagnosed cases. Joint Bone Spine. 2022; 89: 105257.

[3] Richette P, Clerson P, Périssin L, Flipo RM, Bardin T. Revisiting comorbidities in gout: a cluster analysis. Ann Rheum Dis. 2015; 74: 142-7.

[4] Perez-Ruiz F, Carmona L, Yébenes MJG, Pascual E, de Miguel E, Ureña I, et al.; GEMA Study Group, Sociedad Española de Reumatología. An audit of the variability of diagnosis and management of gout in the rheumatology setting: the gout evaluation and management study. J Clin Rheumatol. 2011; 17: 349-55.

[5] LaForge JM, Urso K, Day JM, Bourgeois CW, Ross MM, Ahmadzadeh S, et al. Non-steroidal Anti-inflammatory Drugs: Clinical Implications, Renal Impairment Risks, and AKI. Adv Ther. 2023; 40: 2082-96.

[6] Harężlak T, Religioni U, Szymański FM, Hering D, Barańska A, Neumann-Podczaska A, et al. Drug Interactions Affecting Kidney Function: Beware of Health Threats from Triple Whammy. Adv Ther. 2022; 39: 140-7.

[7] Ragnarsdotttir TH, Kristjansdottir M, Gislason G, Sanchez-Brunete V, Tomasdottir MO, Samuelsson OH, et al. Prospective study of risk factors for community-acquired acute kidney injury. Eur J Intern Med. 2025; 131: 83-8.

[8] Bellomo R, Ronco C, Kellum JA, Mehta RL, Palevsky P; the ADQI workgroup. Acute renal failure - definition, outcome measures, animal models, fluid therapy and information technology needs: the Second International Consensus Conference of the Acute Dialysis Quality Initiative (ADQI) Group. Crit Care. 2004; 8: R204-12.

[9] Makris K, Spanou L. Acute Kidney Injury: Definition, Pathophysiology and Clinical Phenotypes. Clin Biochem Rev. 2016; 37: 85-98.

[10] Scope of Work: KDIGO Clinical Practice Guideline for Acute Kidney Injury (AKI) and Acute Kidney Disease (AKD) Update 2023 [Internet]. [cited 2025 May 21]. Available from: https://kdigo.org/wp-content/uploads/2023/10/KDIGO-AKI-Guideline_Scope-of-Work_25Oct2023_Final.pdf

[11] Garegnani L, Oltra G, Burgos MA, Ivaldi D, Varela LB, Díaz Menai S, et al. Proton pump inhibitors for the prevention of non-steroidal anti-inflammatory drug-induced ulcers and dyspepsia. Cochrane Database Syst Rev. 2025: CD014585.

[12] Gupta S, Mandal S, Banerjee K, Almarshood H, Pushpakumar SB, Sen U. Complex Pathophysiology of Acute Kidney Injury (AKI) in Aging: Epigenetic Regulation, Matrix Remodeling, and the Healing Effects of H₂S. Biomolecules. 2024; 14: 1165.

[13] McFadden EC, Hirst JA, Verbakel JY, McLellan JH, Hobbs FDR, Stevens RJ, et al. Systematic Review and Metaanalysis Comparing the Bias and Accuracy of the Modification of Diet in Renal Disease and Chronic Kidney Disease Epidemiology Collaboration Equations in Community-Based Populations. Clin Chem. 2018; 64: 475-85.

[14] Dreischulte T, Morales DR, Bell S, Guthrie B. Combined use of nonsteroidal anti-inflammatory drugs with diuretics and/or renin-angiotensin system inhibitors in the community increases the risk of acute kidney injury. Kidney Int. 2015; 88: 396-403.

[15] Hansen RN, Burghle A, Grünfeld SB, Jørgensen AM, Westergaard S, Hamid H, et al. Counselling customers at risk of the triple whammy effect at community pharmacies - A feasibility study. Explor Res Clin Soc Pharm. 2023; 12: 100339.

[16] Hatakeyama Y, Horino T, Yasui S, Terada Y, Okuhara Y. Differences in characteristics and risk factors for acute kidney injury between elderly and very elderly patients: a retrospective review. Clin Exp Nephrol. 2024; 28: 1097-110.

[17] Prieto-García L, Pericacho M, Sancho-Martínez SM, Sánchez Á, Martínez-Salgado C, López-Novoa JM, et al. Mechanisms of triple whammy acute kidney injury. Pharmacol Ther. 2016; 167: 132-45.

[18] Nochaiwong S, Ruengorn C, Awiphan R, Koyratkoson K, Chaisai C, Noppakun K, et al. The association between proton pump inhibitor use and the risk of adverse kidney outcomes: a systematic review and meta-analysis. Nephrol Dial Transplant. 2018; 33: 331-42.

[19] Mitsuboshi S, Hitoshi K, Ominato A, Kinoshita T, Sugimoto Y, Kajiwara-Morita A, et al. Association between sodium-glucose cotransporter-2 inhibitor and adverse events in patients with moderate to severe chronic kidney disease: a systematic review and meta-analysis of randomized controlled trials. Eur J Clin Pharmacol. 2025; 81: 217-25.

[20] Yu T, Xiao J, Li M, Cheng SQ, Cai R, Huang L, et al. Risk of acute renal failure associated with combined use of SGLT2 inhibitors and potentially nephrotoxic drugs: an epidemiological surveillance study based on the FDA adverse event reporting system (FAERS). Expert Opin Drug Saf. 2025;[Epub ahead of print].

[21] Badve SV, Pascoe EM, Tiku A, Boudville N, Brown FG, Cass A, et al.; CKD-FIX Study Investigators. Effects of Allopurinol on the Progression of Chronic Kidney Disease. N Engl J Med. 2020; 382: 2504-13.

[22] Seiberth S, Berner J, Hug MJ, Strobach D. ‘Double Whamm’ and ‘Triple Whamm’ combinations in hospitalized surgical patients - real life data from a tertiary teaching hospital. Pharmazie. 2022; 77: 38-43.

[23] Guan C, Li C, Xu L, Che L, Wang Y, Yang C, et al. Hospitalized patients received furosemide undergoing acute kidney injury: the risk and prediction tool. Eur J Med Res. 2023; 28: 312.

[24] Calvo DM, Saiz LC, Leache L, Celaya MC, Gutiérrez-Valencia M, Alonso A, et al. Effect of the combination of diuretics, renin-angiotensin-aldosterone system inhibitors, and non-steroidal anti-inflammatory drugs or metamizole (triple whammy) on hospitalisation due to acute kidney injury: A nested case-control study. Pharmacoepidemiol Drug Saf. 2023; 32: 898-909.

[25] Onuigbo MA, Agbasi N. “Quadruple whammy”- a preventable newly described syndrome of post-operative AKI in CKD II and CKD III patients on combination “Triple whammy” medications: A Mayo Clinic Health System, Eau Claire, Wisconsin experience. Niger J Clin Pract. 2014; 17: 649-54.

[26] Kunitsu Y, Hira D, Morikochi A, Ueda T, Isono T, Morita SY, et al. Time until onset of acute kidney injury by combination therapy with “Triple Whammy” drugs obtained from Japanese Adverse Drug Event Report database. PLoS One. 2022; 17: e0263682.

[27] Farquhar H, Gaffo A, Stamp LK. Safety and efficacy of gout treatments in people with renal impairment. Explor Musculoskeletal Dis. 2024; 2: 360-74.

[28] Perez-Ruiz F, Calabozo M, Herrero-Beites AM, García-Erauskin G, Pijoan JI. Improvement of renal function in patients with chronic gout after proper control of hyperuricemia and gouty bouts. Nephron. 2000; 86: 287-91.

[29] Qaseem A, Harris RP, Forciea MA; for the Clinical Guidelines Committee of the American College of Physicians. Management of Acute and Recurrent Gout: A Clinical Practice Guideline From the American College of Physicians. Ann Intern Med. 2017; 166: 58-68.

[30] Wechalekar MD, Vinik O, Moi JHY, Sivera F, van Echteld IA, van Durme C, et al. The efficacy and safety of treatments for acute gout: results from a series of systematic literature reviews including Cochrane reviews on intraarticular glucocorticoids, colchicine, nonsteroidal antiinflammatory drugs, and interleukin-1 inhibitors. J Rheumatol Suppl. 2014; 92: 15-25.