Dataset Information

A Non-purine Xanthine Oxidoreductase Inhibitor Reduces Albuminuria in Patients with DKD: A Randomized Controlled Trial.

ABSTRACT:

Background

Diabetic kidney disease (DKD) is characterized by albuminuria and reduced renal function. Whether xanthine oxidoreductase inhibitors (XORIs) have a renoprotective effect in DKD patients with type 2 diabetes remains controversial. We conducted a proof-of-concept study to investigate the renal effects of a novel XORI, TMX-049, in patients with DKD and type 2 diabetes.

Methods

This is a multicenter, 12-week, randomized, double-blind, placebo-controlled phase 2a trial conducted at 49 centers across the United States between April 2018 and June 2019. In total, 130 patients with type 2 diabetes, urine albumin-creatinine ratio (UACR) 200 - 3000 mg/g, eGFR ≥30 ml/min per 1.73 m², and serum uric acid (sUA) 4 - 10 mg/dl were randomized 1:1:1 to TMX-049 200 mg (n=44) or 40 mg (n=44), or placebo (n=42). The primary end point was change in log-transformed UACR at week 12 from baseline. The secondary end points included changes in UACR, eGFR, and sUA from baseline.

Results

The least squares mean differences for changes in log-transformed UACR from baseline to week 12 compared with placebo were -0.43 (95% confidence interval [95% CI], -0.82 to -0.04, P=0.03) for TMX-049 200 mg and -0.05 (95% CI, -0.44 to 0.34, P=0.80) for 40 mg; a 35% reduction in UACR was observed with TMX-049 200 mg (ratio versus placebo, 0.65; 95% CI, 0.44 to 0.96) but not 40 mg (0.95; 95% CI, 0.64 to 1.41). Throughout the treatment period, marked reductions in sUA levels but no changes in eGFR were observed with both TMX-049 doses. TMX-049 was generally well tolerated, although two patients with TMX-049 200 mg developed gout.

Conclusions

TMX-049 200 mg reduced albuminuria at 12 weeks in patients with DKD and type 2 diabetes. TMX-049 may exert a renoprotective effect independent of its sUA-lowering effect.

SUBMITTER: Bakris GL

PROVIDER: S-EPMC8676384 | biostudies-literature | 2021 Aug

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

A Non-purine Xanthine Oxidoreductase Inhibitor Reduces Albuminuria in Patients with DKD: A Randomized Controlled Trial.

Bakris George L GL Mikami Hidetaka H Hirata Masayuki M Nakajima Akihiro A Cressman Michael D MD

Kidney360 20210630 8

<h4>Background</h4>Diabetic kidney disease (DKD) is characterized by albuminuria and reduced renal function. Whether xanthine oxidoreductase inhibitors (XORIs) have a renoprotective effect in DKD patients with type 2 diabetes remains controversial. We conducted a proof-of-concept study to investigate the renal effects of a novel XORI, TMX-049, in patients with DKD and type 2 diabetes.<h4>Methods</h4>This is a multicenter, 12-week, randomized, double-blind, placebo-controlled phase 2a trial condu ...[more]

PMID: 35369650

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Project description:Rationale & objectiveAllopurinol and febuxostat, which are xanthine oxidoreductase inhibitors, have been widely used as uric acid-lowering medications. However, evidence regarding their cardiovascular effects in hemodialysis is insufficient. This study compared the effects of allopurinol and febuxostat on mortality and cardiovascular outcomes in patients receiving hemodialysis.Study designA retrospective observational cohort study.Setting & participantsData of 6,791 patients who had no history of topiroxostat usage and underwent maintenance hemodialysis between March 2016 and March 2019 at Yokohama Daiichi Hospital, Zenjinkai, and its affiliated dialysis clinics in Japan's Kanagawa and Tokyo metropolitan areas were collected.ExposureAllopurinol, febuxostat, and nontreatment.OutcomesAll-cause mortality, cardiovascular disease (CVD) events, heart failure (HF), acute myocardial infarction (AMI), and stroke.Analytical approachFor the main analyses, marginal structural Cox proportional hazards models were used to estimate HRs adjusted for time-varying confounding and selection bias because of censoring.ResultsAllopurinol and febuxostat showed significantly better survival than nontreatment for all-cause mortality (HR, 0.40; 95% CI, 0.30-0.54 and HR, 0.49; 95% CI, 0.38-0.63, respectively), without significant difference between allopurinol and febuxostat. Allopurinol showed significantly better survival than nontreatment, whereas febuxostat did not for CVD events (HR, 0.89; 95% CI, 0.84-0.95 and HR, 1.01; 95% CI, 0.96-1.07, respectively), HF (HR, 0.71; 95% CI, 0.56-0.90 and HR, 1.03; 95% CI, 0.87-1.21, respectively), and AMI (HR, 0.48; 95% CI, 0.25-0.91 and HR, 0.76; 95% CI, 0.49-1.19, respectively). No comparisons showed significant results for stroke.LimitationsThe ratio of renal or intestinal excretion of uric acid and uremic toxins could not be elucidated, and we could not investigate gene polymorphism because of the large number of cases.ConclusionsAllopurinol and febuxostat improved survival for all-cause mortality. Allopurinol and not febuxostat reduced the risk of CVD events, HF, and AMI.

Project description:The xanthine oxidoreductase (XOR) family are metal-containing enzymes that use the molybdenum cofactor (Moco), 2Fe-2S clusters, and flavin adenine dinucleotide (FAD) for their catalytic activity. This large molybdoenzyme family includes xanthine, aldehyde, and CO dehydrogenases. XORs are widely distributed from bacteria to humans due to their key roles in the catabolism of purines, aldehydes, drugs, and xenobiotics, as well as interconversions between CO and CO2. Assessing the effect of excess metals on the Rubrivivax gelatinosus bacterium, we found that exposure to copper (Cu) or cadmium (Cd) caused a dramatic decrease in the activity of a high-molecular-weight soluble complex exhibiting nitroblue tetrazolium reductase activity. Mass spectrometry and genetic analyses showed that the complex corresponds to a putative CO dehydrogenase (pCOD). Using mutants that accumulate either Cu+ or Cd2+ in the cytoplasm, we show that Cu+ or Cd2+ is a potent inhibitor of XORs (pCOD and the xanthine dehydrogenase [XDH]) in vivo. This is the first in vivo demonstration that Cu+ affects Moco-containing enzymes. The specific inhibitory effect of these compounds on the XOR activity is further supported in vitro by direct addition of competing metals to protein extracts. Moreover, emphasis is given on the inhibitory effect of Cu on bovine XOR, showing that the XOR family could be a common target of Cu. Given the conservation of XOR structure and function across the tree of life, we anticipate that our findings could be transferable to other XORs and organisms. IMPORTANCE The high toxicity of Cu, Cd, Pb, As, and other metals arises from their ability to cross membranes and target metalloenzymes in the cytoplasm. Identifying these targets provides insights into the toxicity mechanisms. The vulnerability of metalloenzymes arises from the accessibility of their cofactors to ions. Accordingly, many enzymes whose cofactors are solvent exposed are likely to be targets of competing metals. Here, we describe for the first time, with in vivo and in vitro experiments, a direct effect of excess Cu on the xanthine oxidoreductase family (XOR/XDH/pCOD). We show that toxic metal affects these Moco enzymes, and we suggest that access to the Moco center by Cu ions could explain the Cu inhibition of XORs in living organisms. Human XOR activity is associated with hyperuricemia, xanthinuria, gout arthritis, and other diseases. Our findings in vivo highlight XOR as a Cu target and thus support the potential use of Cu in metal-based therapeutics against these diseases.

Dataset Information

A Non-purine Xanthine Oxidoreductase Inhibitor Reduces Albuminuria in Patients with DKD: A Randomized Controlled Trial.

Background

Methods

Results

Conclusions

Publications

A Non-purine Xanthine Oxidoreductase Inhibitor Reduces Albuminuria in Patients with DKD: A Randomized Controlled Trial.

Similar Datasets

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