Nephrolithiasis associated with uricosuric therapies for the treatment of gout: a systematic review

Background/Aims Uric acid nephrolithiasis is a recognised side-effect of uricosuric therapies and a contraindication to their use. The objective of this systematic review was to assess the incidence and risk of nephrolithiasis in people with gout receiving uricosuric therapy. Methods A systematic review was undertaken using MEDLINE, Embase, Cochrane Library, Web of Science and Clinical Trials electronic databases from inception to 16th May 2023. Pre-specified search terms relating to 'gout', 'uricosuric drugs' and 'nephrolithiasis' and their synonyms were used. Title/abstract and full-text screening and data extraction were undertaken independently by two reviewers. Randomised controlled trials (RCTs) and observational cohort studies assessing the incidence and risk of nephrolithiasis in adults with gout treated with uricosuric therapies were included (with or without a non-uricosuric urate-lowering therapy (ULT) comparator group). The Cochrane Risk of Bias (RoB)-2 for randomised trials and the Risk Of Bias In Non-randomised Studies of Interventions (ROBINS-I) tools were used to assess the quality of included RCTs and cohort studies respectively. Results 507 articles were identified, of which 22 studies (8 RCTs, 14 cohort studies) were eligible for inclusion. The mean age of participants ranged from 51.2 years (standard deviation (SD) 10.9) to 66.8 years (SD 9.1). Participants were predominantly male (range 69-100%). Length of follow-up ranged from three months to 10 years. Eleven studies included participants with a prior history of nephrolithiasis. Ten studies assessed Benzbromarone monotherapy, five Lesinurad plus xanthine oxidase inhibitor (XOI), four Probenecid, three Sulfinpyrazone and one Lesinurad monotherapy (total 3091 participants). Ten studies included a non-uricosuric comparator group(s) (five placebo plus XOI, four XOI only, and one placebo only (total 1386 participants)), whereas 12 had no comparator group. Most studies assessed nephrolithiasis through clinical adverse event reporting rather than systematic assessment. The incidence of nephrolithiasis ranged from 0.0% to 11.8% in people receiving uricosuric therapy (four studies reported no stone events; incidence 0.1%-5% in seven studies, 5.1-10% in 9, and >10% in two). The incidence of nephrolithiasis ranged from 0.0% to 4.2% in those not receiving uricosurics. No studies calculated the risk of nephrolithiasis between uricosuric-treated and untreated groups. Few studies documented renal stone composition or reported the severity of clinical presentation of nephrolithiasis events. Conclusion Nephrolithiasis is a common side-effect of uricosuric therapy for gout. Future studies should provide risk estimates between uricosuric-treated and untreated groups, describe clinical presentation of stone events and, where possible, assess stone composition. Disclosure C. Dahanayake: None. R. Bajpai: Other; Dr Bajpai is a member of the Versus Arthritis College of Experts. K.M. Jordan: Other; Dr Jordan is a Trustee of the UK Gout Society. M. Lambie: Honoraria; Dr Lambie has received speakers honoraria from Baxter Healthcare and Fresenius Medical Care. Grants/research support; Dr Lambie has received an unrestricted research grant from Baxter Healthcare. E. Roddy: None.