Table 4.

Observational studies of urate-lowering therapy in gout and non-gout conditions, with reported results on kidney function.

Study	Study design	Setting & Participants	Exposure	Results
Whelton et al, 2011127	FOCUS study: open-label extension study	24 centers in US; 116 hyperuricemic gout pts with CrCl >50–79 mL/min at baseline	Febuxostat 40, 80 or 120 mg/day	The effects of SUA reduction were associated with maintenance or improvement in eGFR over a 5-year follow-up period
Pai et al, 2013128	Cohort study	Outpatient department of Nephrology at Nizam’s Institute of Medical Sciences, Hyderabad, India; 183 pts with hyperuricemia, with eGFR <90 mL/min (mean baseline eGFR: 35.4 mL/min among the exposed and 38.9 mL/min among the non-exposed)	Allopurinol 100 mg/day vs. usual treatment	eGFR remained stable in pts treated with allopurinol while the control group presented a significant decline in kidney function, resulting in a significant difference between groups at one and two years of follow-up
Whelton et al, 2013129	Report of kidney outcomes from the EXCEL study	174 centers in US and Canada; 551 pts with gout and serum creatinine ≤ 1.5 mg/dL56 or ≤ 2.0 mg/dL57	Only febuxostat, at any dosea	Greater reductions in SUA were associated with less decline in eGFR
Levy et al, 2014116	Cohort study	Kaiser Permanente Southern California Health Plan, US; 16,186 patients with hyperuricemia and CKD ≤ 3b	ULT (allopurinol, febuxostat, probenecid)	Individuals who achieved a SUA <6 mg/dL on ULT had 37% lower risk of kidney disease progression
Shibagaki et al, 2014130	Observational study	University hospitals, Japan; 70 patients with SUA ≥ 8 mg/dL and eGFR ≤ 45 mL/min	Febuxostat 10–60 mg/day, adjusted to a target SUA ≤ 6.0 mg/dL	Pts with CKD stage 3b presented a 7.4%-increase in eGFR from baseline, while those with CKD 4 and 5 showed decreased eGFR at 24 weeks; SUA level at week 24 as well as relative and absolute reduction in SUA were identified as independent variables for increase in eGFR in the multivariate analysis
Kim et al, 2015131	Cohort study	Dongguk University Ilsan Hospital (tertiary hospital), Goyang, Korea; 158 pts with asymptomatic hyperuricemic and CKD stage 3	ULT (allopurinol, febuxostat, benzbromarone)	Individuals on ULT had significantly less kidney disease progression, and those who achieved the target SUA with ULT dose adjustment had better kidney outcomes compared with those who were maintained on their initial dose
Singh et al, 2016132	Cohort study	Medicare claims data from 2006 to 2012 (5% random sample), US; 30,022 allopurinol treatment episodes with no diagnostic code for kidney failure in the previous 183 days	Allopurinol dose and duration	Higher allopurinol dose was independently protective against incident kidney failure in the elderly allopurinol users; a longer duration of allopurinol use may be associated with a decreased risk of incident kidney failure
Ma et al 2016133	Cohort study	Zhongshan Hospital (tertiary hospital), Shanghai, China; 106 primary gout pts with eGFR >60 mL/min and 51 healthy controls	ULT (allopurinol 300 mg/day, febuxostat 40 or 80 mg/day, benzbromarone 50 mg/day) used by 88 gout pts	CrCl showed a significant increase in the xanthine oxidase inhibitor group at six months of treatment

^aIn the EXCEL study, 1086 subjects from two prior phase 3 trials^56,57 were enrolled and randomized to either allopurinol 100–300mg, febuxostat 80mg, or febuxostat 120mg, and were permitted to switch between these three arms during the first 6 months to achieve and maintain the SUA target.⁵⁸

CrCl: creatinine clearance; SUA: serum urate; eGFR: estimated glomerular filtration rate; ULT: urate-lowering therapy; CKD: chronic kidney disease; FOCUS, ●●●; EXCEL●●●