Table 5.

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

Trial	Study design	Participants	Intervention	Results
Gibson et al. 1982134	Randomized trial	59 patients with gout and normal kidney function	Allopurinol 200 mg/day + colchicine 0.5 mg twice a day vs. colchicine 0.5 mg twice a day	Allopurinol-treated patients did not present change in kidney function while those receiving only colchicine had a significant decrease in eGFR at two years of follow-up
Dahlöf et al. 2002135	Double-blind, randomized trial	9193 patients aged 55–80 years with essential hypertension and left ventricular hypertrophy	Losartan vs. atenolol for at least 4 years	There was no significant difference in serum creatinine between groups at the end of the trial, although the rise in SUA was lower in the losartan group
Siu et al. 2006136	Randomized trial	54 patients with CKD (proteinuria >0.5 g/24h and/or serum creatinine >1.35mg/dL) of varying etiologies and asymptomatic hyperuricemia	Allopurinol (100–300 mg/day) vs. conventional therapy	While SUA levels were significantly reduced in the treatment arm, there was only a non-significant trend toward a lower serum creatinine in the allopurinol group at 12 months; nonetheless, the combined end points of significant deterioration in kidney function and dialysis dependence occurred in 16% in the allopurinol group compared with 46% in the control group (P = 0.02), suggesting a renoprotective role for allopurinol
Momeni et al. 2010137	Double blind, placebo-controlled, randomized trial	40 patients with type 2 diabetes mellitus and diabetic nephropathy (proteinuria ≥ 500 mg/24 h and serum creatinine <3 mg/dL)	Allopurinol 100 mg/day vs. placebo	At four months, allopurinol-treated patients showed a significantly lower 24-hour urine protein compared to the control group, while serum creatinine remained stable in both groups
Kanbay et al. 2011138	Randomized study	105 subjects with normal kidney function: 72 with hyperuricemia + 33 normouricemic controls	Allopurinol 300 mg/day (in hyperuricemic) vs. no treatment (hyperuricemic patients and normouricemic controls)	Allopurinol use was associated with significant increase in eGFR at four months in comparison with baseline, while hyperuricemic and normouricemic controls had no significant change in the same period
Kao et al. 2011139	Double-blind, placebo-controlled, randomized trial	67 patients with CKD stage 3 and left ventricular hypertrophy	Allopurinol 300 mg/day vs. placebo	eGFR remained stable in both groups, with no significant difference in the change in eGFR between groups at nine months
Shi et al. 2012140	Open label, controlled, randomized trial	40 patients with IgA nephropathy, with proteinuria 0.15–2.0 g/24 h, albumin >3.5 g/dL, creatinine <3 mg/dL, and SUA >6 mg/dL in women and >7 mg/dL in men	Allopurinol 100–300 mg/day vs. usual care	At six months, there was no significant difference in the eGFR nor in the change in eGFR between groups
Goicoechea et al. 2010141 and Goicoechea et al. 2015142	Open label randomized trial	113 patients with eGFR <60 mL/min	Allopurinol 100 mg/day (n=57) vs. and continuation of usual therapy (n=56)	After 2 years, the allopurinol arm had significantly reduced SUA, indicating adherence to therapy, with 47% lower risk of kidney disease progression compared with the control group; of the original 113 patients, 107 participants were followed-up again 5 years later, during which time 12 of 56 allopurinol users stopped treatment and 10 of 51 controls started allopurinol; while the results were consistent with the original report, these data must be interpreted with caution given the post-hoc nature, small sample size, and the non-randomized (observational) nature of the data
Kim et al. 2014143	Post-hoc analysis on the data derived from a phase-III, double blind, randomized trial	Patients with gout and creatinine ≤ 1.5 mg/dL	Febuxostat (40, 80 or 120 mg/day) vs. allopurinol (300 mg/day) vs. placebo	At four weeks, patients on ULT presented a significant decrease in serum creatinine levels compared to the control group; in the adjusted model, SUA changes were significantly correlated with changes in serum creatinine
Liu et al. 2015144	Open label randomized trial	176 individuals with type 2 diabetes mellitus, normoalbuminuria and asymptomatic hyperuricemia with normal baseline kidney function (mean eGFR of 90 mL/min)	Allopurinol dose-adjusted according to SUA vs. conventional therapy	After 3 years of follow-up, the allopurinol-treated group had significantly lower urinary albumin excretion rate and serum creatinine, along with significantly higher eGFR in comparison with the group under conventional therapy
Sircar et al. 2015145	Double blind, placebo-controlled, randomized trial	108 patients with CKD stages 3 and 4 with asymptomatic hyperuricemia	Febuxostat 40 mg/day vs. placebo	Patients on febuxostat experienced less eGFR decline than the placebo group at 6 months
Tanaka et al. 2015146	Open label, controlled, randomized trial	45 patients with CKD stage 3 and asymptomatic hyperuricemia (22 of them were on allopurinol 50–100 mg/day)	Febuxostat 10–40 mg/day, adjusted with a SUA target of <6 mg/dL vs. conventional therapy; subjects on allopurinol at baseline could either continue allopurinol or switch to febuxostat	There was no significant difference in eGFR between febuxostat and control groups at 12 weeks
Sezai et el. 2015147	Single blind, controlled, randomized trial	109 patients with eGFR ≤60 mL/min and SUA ≥8 mg/dL, not on ULT, undergoing cardiac surgery	Febuxostat up to 60 mg/day (up to 40 mg/day if eGFR ≤30 mL/min) vs. allopurinol up to 300 mg/day (up to 200 mg/day if eGFR ≤30 mL/min) – doses adjusted to a target SUA ≤6.0 mg/dL	There was no significant difference in eGFR between treatment groups at 1, 3 or 6 months, despite SUA being significantly lower in the febuxostat group at these time points
Saag et al. 201660	Placebo- controlled blinded pilot randomized trial	96 gout subjects with moderate-to-severe kidney impairment (eGFR 15–50 mL/min/1.73m2)	Febuxostat vs. placebo	Primary endpoint: change in serum creatinine from baseline to month 12; there were no significant differences in serum creatinine or eGFR between the febuxostat arms vs. placebo at 6 or 12 months of follow-up
Bose et al. 2014148	Systematic review and meta- analysis of 5 RCTs evaluating eGFR134,138–141 and 3 RCTs evaluating change in serum creatinine136,137,149	Varying clinical conditions and kidney function stages	Allopurinol vs. placebo or conventional treatment	Change in serum creatinine from baseline favored allopurinol compared to the control arms, although the change in eGFR was not significantly different between groups; allopurinol may slow CKD progression, but adequately powered randomized trials are necessary to provide a more definitive conclusion
Kanji et al. 2015150	Systematic review and meta-analysis of 5 RCTs136,137,139–141	Varying clinical conditions in patients with CKD stages 3–5	Allopurinol vs. placebo or conventional treatment	There was a small but significant improvement in eGFR favoring allopurinol, though when limited to 3 RCTs in which the eGFR was not calculated by the meta-analysis’ authors from serum creatinine data, this finding was no longer significant; this meta-analysis highlights the paucity of large, well-conducted RCTs of allopurinol’s effects on kidney endpoints

eGFR: estimated glomerular filtration rate; CKD: chronic kidney disease; SUA: serum urate; ULT: urate-lowering therapy; RCT: randomized controlled trial; IgA, immuglobulin A; RCT, randomized controlled trial