Exploration of Musculoskeletal Diseases

Table 6. Differences in variables associated with AKI through the two decades studied.

Variables	D1	D2	p
Age (years)	62.2 ± 13.3	67.3 ± 14.0	< 0.001
Time from onset (years)	7.0 ± 7.7	6.1 ± 6.9	0.016
Serum urate at baseline (mg/dL)	9.0 ± 1.4	9.3 ± 1.5	< 0.001
Previous ULT prescription	245/544 (45.0%)	323/663 (48.7%)	0.202
Subcutaneous tophi	199/544 (36.6%)	200/663 (30.2%)	0.018
Polyarticular involvement (> 4 joints ever)	169/544 (31.1%)	248/663 (37.4%)	0.021
Joint damage in plain X-ray	248/544 (45.6%)	436/663 (65.8%)	0.001
Ultrasonographic tophi	324/460 (70.4%)	448/660 (67.9%)	0.363
Ethanol intake (> 15 g/day)	191/544 (35.1%)	178/663 (26.8%)	0.002
Arterial hypertension	309/544 (56.8%)	506/663 (76.3%)	< 0.001
Diuretic prescription	193/544 (35.5%)	303/663 (45.7%)	< 0.001
Triple whammy	183/544 (33.6%)	294/663 (44.3%)	< 0.001
Hyperlipidemia	281/544 (51.7%)	438/663 (66.1%)	< 0.001
Diabetes	129/544 (23.7%)	204/663 (30.8%)	0.006
Previous vascular event	171/544 (31.4%)	233/663 (35.1%)	0.174
CKD (eGFR < 60 mL/min)	197/544 (36.2%)	283/663 (42.7%)	0.022

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Variables statistically significant are shown in bold. AKI: acute kidney injury; D1: decade 1 from 2005 to 2014; D2: decade 2 from 2015 to 2024; ULT: urate-lowering therapy; CKD: chronic kidney disease; eGFR: estimated glomerular filtration rate.

Declarations

Acknowledgments

We thank patients for sharing their clinical data through all these years.

Author contributions

NPH: Conceptualization, Formal analysis, Validation, Writing—original draft, Writing—review & editing. JMUG: Validation, Writing—original draft, Writing—review & editing. FPR: Funding acquisition, Conceptualization, Investigation, Formal analysis, Validation, Writing—original draft, Writing—review & editing. All authors read and approved the submitted version.

Conflicts of interest

Fernando Perez-Ruiz, who is the Editor-in-Chief and Guest Editor of Exploration of Musculoskeletal Diseases, had no involvement in the decision-making or the review process of this manuscript. Other conflicts of interest related to the topic of the paper: Fernando Perez-Ruiz: advisor for Amgen, Arthrosi, Crystalyx, Protalix, Shanton, SNIPR, and SOBI; speaker for Menarini, EULAR, and Spanish Foundation for Rheumatology; grants from Cruces Rheumatology Association. Educational work for Spanish Foundation for Rheumatology; editorial work for Wolters-Kluwer. The other authors declare no conflicts of interest.

Ethical approval

The present cohort recruitment was approved by the OSI EEC Clinical Investigation Ethics Committee with approval reference code E03/45.

Consent to participate

Informed consent to participation in the study was obtained from all participants.

Consent to publication

Not applicable.

Availability of data and materials

The datasets generated for this study can be shared on request to the corresponding author, provided CEIC OSI EEC approval.

Funding

FPR was partially funded by Cruces Rheumatology Association, grant code [ARC-2024/1]. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Copyright

Publisher’s note

Open Exploration maintains a neutral stance on jurisdictional claims in published institutional affiliations and maps. All opinions expressed in this article are the personal views of the author(s) and do not represent the stance of the editorial team or the publisher.

References

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

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. [DOI] [PubMed]

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

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. [DOI] [PubMed]

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. [DOI] [PubMed]

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. [DOI] [PubMed] [PMC]

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. [DOI] [PubMed]

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. [DOI] [PubMed] [PMC]

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

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. [DOI] [PubMed] [PMC]

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. [DOI] [PubMed] [PMC]

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. [DOI] [PubMed]

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. [DOI] [PubMed]

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. [DOI] [PubMed] [PMC]

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. [DOI] [PubMed]

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. [DOI] [PubMed]

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. [DOI] [PubMed]

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. [DOI] [PubMed]

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]. [DOI] [PubMed]

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. [DOI] [PubMed]

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. [DOI] [PubMed]

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. [DOI] [PubMed] [PMC]

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. [DOI] [PubMed]

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. [DOI] [PubMed]

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. [DOI] [PubMed] [PMC]

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. [DOI]

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. [DOI] [PubMed]

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. [DOI] [PubMed]

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. [DOI] [PubMed]