Yanai Hidekatsu, Adachi Hiroki, Hakoshima Mariko, Katsuyama Hisayuki
Department of Diabetes, Endocrinology and Metabolism, National Kohnodai Medical Center, Japan Institute for Health Security, Chiba, Japan.
J Clin Med Res. 2025 Jun 9;17(6):320-333. doi: 10.14740/jocmr6250. eCollection 2025 Jun.
Epidemiological studies have reported that hyperuricemia is associated with the development of metabolic syndrome, hypertension, dyslipidemia, type 2 diabetes, and chronic kidney disease (CKD). Renal uric acid (UA) reabsorption is mainly mediated by urate transporter 1 (URAT1) in renal proximal tubule epithelial cells. Recently, URAT1 was found to be expressed in the liver and adipose tissue in addition to the kidney. UA enters such organs via URAT1 and induces inflammation and oxidative stress, which may lead to metabolic disorders. We investigated the effects of long-term treatment with the novel uricosuric drug, a highly selective inhibitor of URAT1, dotinurad, on metabolic parameters and renal function.
We retrospectively picked up patients who had taken dotinurad for the treatment of asymptomatic hyperuricemia for more than 2 years. We compared metabolic parameters and renal function at baseline with the data at 6, 12, 18, and 24 months after starting dotinurad.
Pharmacologically, dotinurad decreases serum UA, by selectively inhibiting URAT1 and decreasing renal reabsorption of UA, which was supported by our result that dotinurad significantly increased urine UA and reduced serum UA. In addition to UA-lowering, dotinurad was associated with improvements in body weight, liver function, hepatic steatosis index as the marker for metabolic dysfunction-associated steatotic liver disease (MASLD), serum lipids, and albuminuria. The ATP-binding cassette transporter G2 (ABCG2) regulates renal and intestinal excretion of UA and uremic toxins and strongly affects renal function. Our study also indicates that switching from xanthine oxidase inhibitors, which inhibit ABCG2, to dotinurad, which does not inhibit ABCG2, was beneficial for albuminuria and maintaining the estimated glomerular filtration rate.
Dotinurad may improve obesity, MASLD, serum lipids, and CKD by blocking the entry of UA via URAT1 to the adipose tissue, liver, and kidney.
流行病学研究报告称，高尿酸血症与代谢综合征、高血压、血脂异常、2型糖尿病和慢性肾脏病（CKD）的发生有关。肾脏尿酸（UA）重吸收主要由肾近端小管上皮细胞中的尿酸转运蛋白1（URAT1）介导。最近，发现URAT1除了在肾脏表达外，在肝脏和脂肪组织中也有表达。UA通过URAT1进入这些器官并诱导炎症和氧化应激，这可能导致代谢紊乱。我们研究了新型促尿酸排泄药物、URAT1的高选择性抑制剂多可那度长期治疗对代谢参数和肾功能的影响。
我们回顾性选取了服用多可那度治疗无症状高尿酸血症超过2年的患者。我们将基线时的代谢参数和肾功能与开始服用多可那度后6、12、18和24个月的数据进行了比较。
从药理学角度来看，多可那度通过选择性抑制URAT1并减少肾脏对UA的重吸收来降低血清UA，我们的结果支持了这一点，即多可那度显著增加尿UA并降低血清UA。除了降低UA外，多可那度还与体重、肝功能、作为代谢功能障碍相关脂肪性肝病（MASLD）标志物的肝脂肪变指数、血脂和蛋白尿的改善有关。ATP结合盒转运蛋白G2（ABCG2）调节肾脏和肠道对UA和尿毒症毒素的排泄，并强烈影响肾功能。我们的研究还表明，从抑制ABCG2的黄嘌呤氧化酶抑制剂转换为不抑制ABCG2的多可那度，对蛋白尿和维持估计肾小球滤过率有益。
多可那度可能通过阻断UA经URAT1进入脂肪组织、肝脏和肾脏来改善肥胖、MASLD、血脂和CKD。
