#6950 FEBUXIOSTAT AND ALLOPURINOL VERSUS NON-TREATMENT IN HEMODIALYSIS PATIENTS WITH OUTCOMES
Authors: Ishii Takeo 
Published: June 2023

Abstract

Background and Aims
Uric acid is relatively low in hemodialysis because it is removed during dialysis. The therapeutic intervention for hyperuricemia is controversial. RCT of allopurinol and febuxostat has been performed in hyperuricemic patients to inhibit xanthine oxido reductase (XOR) and reduce uric acid levels further improve outcomes. Nonetheless, we reported preventive effect of XOR inhibitors for dialysis patients on Sci Rep 2017, but the difference in the protective effect for CVD events and mortality between XOR inhibitors is insufficient in dialysis patients. Furthermore, febuxostat is also known to be a potent ATP-binding cassette transporter subfamily G member 2 (ABCG2) inhibitor that promotes the accumulation of uremic toxins by excretion from the gut in dialysis patients and hyperuricemic patients. We investigated the preventative effect of XOR inhibitors on outcomes under three year observation for 6575 hemodialysis patients.

Method
6575 dialysis patients were divided into baseline 3 groups (ALLO group, FEB group, non-treatment group). Outcomes were all-cause mortality and CVD events, defined by ICD coding using longitudinal data. Causal associations for outcomes of allopurinol (ALLO) or febuxostat (FEB) were analized using 3 years of longitudinal data versus control at each visit, including concomitant drugs, marginal structural models (MSM) that examined the causal effect of ALLO or FEB versus control with weight for adjust covariate using multiple imputation for missing data.

Results
Over all all-cause death was 1167 / 6575 (17.74%) cases. In non-treated group 993 / 4827(20.57%), ALLO-treated group 98 / 778 (12.60%), and 136 / 970 (14.20%) in FEB-treated group. CVD events 14723,and number of cvd events for each treatment group non-treated 11229 events, ALLO 1377, FEB 2117 events. MSM indicated that ALLO estimated HR 0.35 for all cause mortality versus non-treated group (p&lt;0.001). MSM also indicated that FEB estimated HR 0.42 for all cause mortality versus un treatment (p&lt;0.001). There was no difference of preventive effect between ALLO and FEB for all cause mortality, but each drugs indicated preventive effect in each base line XOR treatment categories. In CVD events, ALLO indicated preventive effect of HR 0.81 versus control (p&lt;0.001). But FEB did not indicated preventive effect of HR 0.98 (95% CI: 0.91 -1.04). ALLO was estimated preventive effect for CVD events against FEB in HR 0.83 (95% CI 0.75-0.92).

Conclusion
ALLO and FEB had a prevent effect for all-cause mortality, further FEB was not inferior to ALLO in all-cause mortality in the realm of XOR inhibition. Nevertheless, FEB could not indicate preventive effect for CVD events compared with ALLO and control, which is assumed of ABCG2 inhibitory effect. But was not increase risk for all cause mortality or CVD events compared with ALLO and control. This study provide a new suggestion that it is important for CKD patients to apply extrarenal excretion pathway ABCG2 of uremic toxin and uric acid to prevent CV events because of impaired renal function. In humans 70% of uremic toxin is excreted from urine, and 30% from gut. It is required further investigation and treatment strategies of uric acid lowering therapy should be considered about excretion of uremic substances outside of the kidneys.