Urate Transporter 1 Can Be a Therapeutic Target Molecule for Chronic Kidney Disease and Diabetic Kidney Disease: A Retrospective Longitudinal Study

Abstract

Chronic kidney disease (CKD) is a major global health problem for which there are no curative drug treatments. Hyperuricemia is one of risk factors for CKD. The evidence on effects of uric acid (UA)-lowering treatments on the progression of CKD was very limited and previous meta-analyses used only trials which primarily used xanthin oxidase (XO) inhibitors because the reports on fulminant hepatitis due to benzbromarone kept us from using uricosuric agents for hyperuricemia patients. Dotinurad, a novel selective urate reabsorption inhibitor for the treatment of hyperuricemia, reduces serum UA levels by selectively inhibiting urate transporter 1 (URAT1). We retrospectively picked up patients who had taken dotinurad from June 2018 to August 2021 and compared metabolic parameters at baseline with the data at 3 and 6 months after the start of dotinurad. We found 84 patients, and approximately 74% of patients were complicated with CKD. After the start of dotinurad, improvements in serum lipids, systolic blood pressure, body weight, and albuminuria, in addition to reduction in serum UA, were observed. Dotinurad increased urinary UA excretion, and was effective to reduce serum UA in patients with both UA underexcretion type and renal UA overload type. Furthermore, urinary UA excretion was significantly and negatively correlated with serum creatine levels at baseline and at 6 months after the start of dotinurad, and the change in urinary UA excretion after 3 months was significantly and negatively correlated with change in serum creatine levels. The property of dotinurad, which selectively inhibits URAT1, but not other UA transporters, such as ATP-binding cassette, subfamily G, and 2 (ABCG2), which ABCG2 is a UA and uremic toxin exporter, may be beneficially associated with pathology of CKD. URAT1 can be a therapeutic target molecule for CKD and DKD.

URAT1 is expressed in cardiomyocytes and dotinurad attenuates the development of diet-induced metabolic heart disease

“…The beneficial in vivo effects of dotinurad in terms of ameliorating the cardiac remodeling and function could also be indirectly mediated by the action of dotinurad on other tissues, such as the kidney. 20 However, at least, plasma Cr levels were comparable between HFD and NFD, and dotinurad treatment did not affect them ( Figure S2 ), consistent with our previous study. 21 …”

A Possible Exquisite Crosstalk of Urate Transporter 1 With Other Urate Transporters for Chronic Kidney Disease and Cardiovascular Disease Induced by Dotinurad

“…This exquisite crosstalk between URAT1 and ABCG2 induced by dotinurad may be beneficially associated with the development and progression of CKD. Our recent study showed that dotinurad reduced urinary albumin creatinine ratio (UACR) and increased eGFR in patients with CKD [11], supporting our hypothesis. Dotinurad does not inhibit OAT1/3, and then does not increase plasma IS [7].…”

A Possible Therapeutic Application of the Selective Inhibitor of Urate Transporter 1, Dotinurad, for Metabolic Syndrome, Chronic Kidney Disease, and Cardiovascular Disease

“…In this case, an improvement in albuminuria after the start of dotinurad was also observed [ 79 ]. In our study, the 6-month dotinurad treatment improved albuminuria and eGFR in hyperuricemic patients [ 14 ]. In another study, although eGFR did not significantly change in patients whose eGFR was 30 or more, dotinurad significantly improved the eGFR in patients whose eGFR was less than 30 [ 80 ].…”

“…We found that dotinurad reduced body weight, blood pressure, HbA1c, serum low-density lipoprotein-cholesterol (LDL-C), triglyceride (TG), and non-high-density lipoprotein-cholesterol (non-HDL-C), as well as serum UA, in patients with CKD and DKD [ 14 ]. To our knowledge, our study is the first to report such metabolic effects of dotinurad.…”

“…A highly selective inhibitor of URAT1, dotinurad, was developed [ 13 ] and is available in Japan. Unexpectedly, we found that dotinurad improved serum lipids, blood pressure, body weight, albuminuria, and the estimated glomerular filtration rate (eGFR); in addition, it reduced serum UA in patients with hyperuricemia complicated by CKD and diabetic kidney disease (DKD) [ 14 ]. Furthermore, the 24 week-dotinurad treatment favorably affected arterial stiffness and oxidative stress, suggesting that dotinurad provides off-target vascular protection [ 15 ].…”