POTENTIAL NEPHROPROTECTION WITH NOVEL URAT1 INHIBITOR DOTINURAD: A SYSTEMATIC REVIEW OF KIDNEY FUNCTION CHANGES

Dotinurad, a selective URAT1 inhibitor approved in Japan (2020) and other East Asian countries, represents a new generation of urate-lowering therapy. Unlike traditional agents such as allopurinol or febuxostat, preliminary clinical observations suggest dotinurad may offer unique renoprotective properties beyond urate reduction. Small-scale studies have reported unexpected improvements in estimated glomerular filtration rate (eGFR), contrasting with the typically neutral or negative renal effects of conventional urate-lowering drugs. However, no randomized controlled trials have specifically targeted kidney function as a primary endpoint. This systematic review aimed to explore the emerging evidence regarding dotinurad's effects on kidney function across diverse clinical settings.

We systematically searched PubMed, Embase, Cochrane CENTRAL, Ichushi-Web, and J-STAGE from inception to January 2025 for studies reporting eGFR changes with dotinurad. Given the exploratory nature of this novel therapeutic area, we adopted inclusive criteria: any study design (RCTs, observational studies, single-arm trials) with ≥10 participants receiving dotinurad (0.5-4 mg/day) for ≥8 weeks. We excluded treatment durations >52 weeks to minimize confounding from disease progression. When studies reported outcomes by kidney function subgroups, we extracted data at the most granular level available. For studies reporting only baseline and final values, we calculated change scores using Cochrane-recommended methods (r=0.5). Due to heterogeneous study designs, we performed descriptive synthesis rather than formal meta-analysis.

Fourteen studies met inclusion criteria, all conducted in Japan between 2019-2025, comprising 841 participants. Study designs included: 2 RCTs, 8 open-label single-arm trials, and 4 retrospective cohorts. When stratified by baseline kidney function subgroups, these yielded 20 distinct analyses. Follow-up ranged from 11 to 48 weeks. Baseline eGFR ranged from 19.5±5.2 to 101.0±12.0 mL/min/1.73m².

eGFR changes showed considerable heterogeneity, ranging from -1.8 (95%CI: -11.4, 7.8) to +12.0 (95%CI: 8.9, 15.1) mL/min/1.73m². Among analyses with baseline eGFR <60 mL/min/1.73m² (n=13), the majority (9/13) showed positive point estimates, with the most pronounced improvements reaching +12.0 and +7.4 mL/min/1.73m². Analyses with baseline eGFR ≥60 mL/min/1.73m² (n=7) showed more modest changes (-0.3 to +8.0 mL/min/1.73m²).

Importantly, 9 of 20 analyses (45%) demonstrated statistically significant improvements (confidence intervals excluding zero), all showing positive effects on eGFR. No analysis showed statistically significant deterioration. The remaining 11 analyses (55%) had confidence intervals crossing zero, reflecting uncertainty rather than harm. Dosing strategies included up-titration (14/20) and fixed dosing (6/20), with no clear differential pattern.

This first systematic review of dotinurad's renal effects reveals an encouraging signal not observed with traditional urate-lowering therapies. Nearly half of all analyses demonstrated statistically significant eGFR improvements, with none showing significant deterioration. The potential for kidney function improvement or stabilization, particularly in moderate-to-severe CKD (eGFR <60 mL/min/1.73m²), suggests mechanisms beyond simple urate reduction—possibly direct effects on glomerular hemodynamics through URAT1 inhibition, reduction in tubulointerstitial inflammation, or prevention of urate crystal-induced nephropathy.

However, interpretation requires caution. First, 85% of analyses came from uncontrolled single-arm studies, limiting causal inference. Second, the 55% of analyses with confidence intervals crossing zero indicate substantial variability in response. Third, all studies were conducted in East Asia, particularly Japan, leaving generalizability unknown.

Nevertheless, this review provides important hypothesis-generating evidence. The consistent absence of renal harm and frequent observation of benefit suggest dotinurad may offer added value—potential renoprotection—in CKD patients. Dedicated randomized controlled trials with eGFR as the primary endpoint are urgently needed, particularly with CKD stage-stratified analyses, long-term outcomes (>1 year), and establishment of optimal patient selection criteria. This review provides crucial preliminary evidence to inform such trial designs.