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

Hidekatsu Yanai¹, Hisayuki Katsuyama¹, Mariko Hakoshima¹

¹Department of Diabetes, Endocrinology and Metabolism, National Center for Global Health and Medicine Kohnodai Hospital, Chiba 272-8516, Japan.

|February 25, 2023

Insights

Dotinurad, a novel hyperuricemia treatment, effectively lowers serum uric acid (UA) and improves metabolic parameters in chronic kidney disease (CKD) patients. It also increases urinary UA excretion, showing potential benefits for CKD progression.

Area of Science:

Nephrology
Pharmacology
Metabolic Diseases

Background:

Chronic kidney disease (CKD) is a global health issue with limited curative treatments.
Hyperuricemia is a recognized risk factor for CKD progression.
Existing uric acid (UA)-lowering treatments have shown limited evidence for impacting CKD progression, with uricosuric agents previously avoided due to safety concerns.

Purpose of the Study:

To evaluate the effects of dotinurad, a selective URAT1 inhibitor, on metabolic parameters and kidney function in patients with hyperuricemia, particularly those with CKD.
To assess dotinurad's efficacy in reducing serum UA levels and increasing urinary UA excretion.
To explore the relationship between urinary UA excretion and renal function markers.

Main Methods:

Retrospective analysis of 84 patients treated with dotinurad from June 2018 to August 2021.
Comparison of metabolic parameters at baseline and at 3 and 6 months post-treatment initiation.
Assessment of serum UA levels, urinary UA excretion, serum lipids, blood pressure, body weight, albuminuria, and serum creatinine.

Main Results:

Dotinurad treatment led to significant reductions in serum UA levels.
Improvements were observed in serum lipids, systolic blood pressure, body weight, and albuminuria.
Increased urinary UA excretion was noted, with efficacy in both UA underexcretion and renal UA overload types.
Urinary UA excretion was negatively correlated with serum creatinine levels, suggesting a potential renoprotective effect.

Conclusions:

Dotinurad is effective in lowering serum UA and improving metabolic parameters in patients with hyperuricemia, including those with CKD.
The selective inhibition of URAT1 by dotinurad may offer beneficial effects on CKD pathology.
URAT1 inhibition presents a promising therapeutic target for managing CKD and diabetic kidney disease (DKD).

Read full analysis

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.

Keywords:

chronic kidney disease dotinurad estimated glomerular filtration rate serum creatinine urate transporter 1 urinary uric acid excretion

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