topiroxostat and Renal-Insufficiency--Chronic

Chronic kidney disease (CKD) has become a global public health issue and uric acid (UA) remains a major risk factor of CKD. As the main organ for the elimination of UA, kidney owned a group of urate transporters in tubular epithelium. Kidney disease hampered the UA excretion, and the accumulation of serum UA in return harmed the renal function. Commercially, there are three kinds of agents targeting at urate-lowering, xanthine oxidoreductase inhibitor which prevents the production of UA, uricosuric which increases the concentration of UA in urine thus decreasing serum UA level, and uricase which converts UA to allantoin resulting in the dramatic decrement of serum UA. Of note, in patients with CKD, administration of above-mentioned agents, alone or combined, needs special attention. New evidence is emerging for the efficacy of several urate-lowering drugs for the treatment of hyperuricemia in patients with CKD. Besides, loads of novel and promising drug candidates and phytochemicals are in the different phases of research and development. As of today, there is insufficient evidence to recommend the widespread use of UA-lowering therapy to prevent or slow down the progression of CKD. The review summarized the evidence and perspectives about the treatment of hyperuricemia with CKD for medicinal chemist and nephrologist.

Topics: Biological Products; Drug Discovery; Flavonoids; Humans; Renal Insufficiency, Chronic; Uric Acid

Uric acid (UA) remains a risk factor for the progression of chronic kidney disease (CKD). Most observational studies showed a slight elevation in the serum UA level and this independently predicts the incidence and development of CKD. The recent meta-analysis, however, did not reach the conclusion that urate-lowering therapy with allopurinol retards the progression of CKD. The target level of serum UA if treated is another issue of debate. Our recent analysis by propensity score analysis has shown that the serum UA should be targeted below 6.0 mg/dL to inhibit the progression towards end-stage renal disease. Underlying mechanisms whereby an increase in serum UA induces kidney injury have been elucidated in animal models. Hyperuricemic models can lead to systemic hypertension, arteriolosclerosis including afferent arteriolopathy as well as albuminuria probably due to the activation of oxidative stress. Discoveries of urate transporters have elucidated the novel mechanism of UA transport in the kidney and intestine. The intestinal ABCG2 may play a compensatory role in light of decreased renal clearance of UA in CKD model rats, the trigger of which is not a uremic toxin but serum UA itself. Insulin directly upregulates URAT1 and downregulates ABCG2 in the kidney tubules, suggesting a possible link between UA and metabolic syndrome. This review summarizes the recent knowledge on the causal effect of serum UA on the kidney injury.

Topics: Allopurinol; Animals; Anion Transport Proteins; ATP Binding Cassette Transporter, Subfamily G, Member 2; Disease Progression; Enzyme Inhibitors; Febuxostat; Glucosides; Gout Suppressants; Humans; Hyperuricemia; Monosaccharide Transport Proteins; Nitriles; Oxidative Stress; Pyridines; Renal Insufficiency, Chronic; Risk Factors; Sodium-Glucose Transporter 2 Inhibitors; Thiophenes; Uric Acid; Xanthine Oxidase

Accruing evidence suggests that Xanthine Oxidase inhibitors (XOis) may bring direct renal benefits, besides those related to their hypo-uricemic effect. We hence aimed at performing a systematic review of randomized controlled trials (RCTs) to verify if treatment with XOis may improve renal outcomes in individuals with chronic kidney disease (CKD).. Ovid-MEDLINE, PubMed and CENTRAL databases were searched for RCTs comparing any XOi to standard therapy or placebo. The primary endpoint of interest was progression to End-Stage Kidney Disease (ESKD); secondary endpoints were changes in serum creatinine, glomerular filtration rate (eGFR), proteinuria and albuminuria.. XOis treatment significantly reduced the risk of ESKD compared to the control (3 studies, 204 pts; RR = 0.42; 95% CI, 0.22, 0.80) and also improved eGFR in data pooled from RCTs with long follow-up times (>3 mo.) (4 studies, 357 pts; mean difference (MD) 6.82 mL/min/1.73 m²; 95% CI, 3.50, 10.15) and high methodological quality (blind design) (3 studies, 400 pts; MD 2.61 mL/min/1.73 m²; 95% CI, 0.23, 4.99). Conversely, no definite effects were apparently noticed on serum creatinine, proteinuria and albuminuria.. XOis may represent a promising tool for retarding disease progression in CKD patients. Future trials are awaited to confirm the generalizability of these findings to the whole CKD population.

Topics: Aged; Allopurinol; Enzyme Inhibitors; Febuxostat; Female; Humans; Male; Middle Aged; Nitriles; Pyridines; Randomized Controlled Trials as Topic; Renal Insufficiency, Chronic; Xanthine Oxidase

Hyperuricemia would be a risk factor for the development/progression of CKD. However, several studies showed U-shape association between serum uric acid level and renal impairment, suggesting that hypouricemia was rather associated with renal dysfunction. Perhaps, there is the optimal target level of serum UA for renal function.. This is the first study, to the best of our knowledge, to determine the optimal target level of serum UA for renal protection and is expected to lead to progress in CKD treatment.. (UMIN000026741 and jRCTs051180146).

Topics: Humans; Nitriles; Pyridines; Randomized Controlled Trials as Topic; Renal Insufficiency, Chronic; Xanthine Oxidase

The TROFEO trial demonstrated that febuxostat causes greater and more rapid reduction of serum uric acid (s-UA) than topiroxostat. We compared these drugs in patients with chronic kidney disease (CKD) by sub-analysis of the TROFEO trial.. There was no significant difference of s-UA between the two groups either before or after treatment. However, s-UA did not exceed 6.0 mg/dL in febuxostat group during the study period, but it exceeded this level in seven patients from topiroxostat group, with the number being significantly higher in topiroxostat group. Serum creatinine (s-Cr) and eGFR were significantly better after 6 months of febuxostat treatment compared with topiroxostat Cystatin-C was significantly lower after 6 months of febuxostat treatment compared with topiroxostat. The Ox-LDL was significantly lower after 3 and 6 months of febuxostat treatment compared with topiroxostat.. Febuxostat had stronger renoprotective and antioxidant effects than topiroxostat in patients with hyperuricemia and CKD.

Topics: Aged; Antioxidants; Biomarkers; Cross-Over Studies; Down-Regulation; Enzyme Inhibitors; Febuxostat; Female; Glomerular Filtration Rate; Gout Suppressants; Humans; Hyperuricemia; Kidney; Male; Middle Aged; Nitriles; Pyridines; Renal Insufficiency, Chronic; Time Factors; Treatment Outcome; Uric Acid; Xanthine Oxidase

Topiroxostat, a selective xanthine oxidase inhibitor, shows effective reduction in the serum urate level in hyperuricemic patients with or without gout. The objective of this study was to evaluate the efficacy and safety of topiroxostat in hyperuricemic stage 3 chronic kidney disease patients with or without gout.. The study design was a 22-week, randomized, multicenter, double-blind study. The enrolled patients were randomly assigned to treatment with topiroxostat 160 mg/day (n = 62) or to the placebo (n = 61). The endpoints were the percent change in the serum urate level, change in the estimated glomerular filtration rate, the urinary albumin-to-creatinine ratio, the proportion of patients with serum urate levels of 356.88 μmol/L or less, blood pressure, and serum adiponectin.. After 22 weeks, although the changes in the estimated glomerular filtration rate and blood pressure were not significant, the percent change in the serum urate level (-45.38 vs. -0.08 %, P < 0.0001) and the percent change in urinary albumin-to-creatinine ratio (-33.0 vs. -6.0 %, P = 0.0092) were found to have decreased in the topiroxostat as compared with the placebo. Although the incidence of 'alanine aminotransferase increased' was higher in the topiroxostat, serious adverse event rates were similar in the two groups.. Topiroxostat 160 mg effectively reduced the serum urate level in the hyperuricemic stage 3 chronic kidney disease patients with or without gout.

Topics: Adiponectin; Aged; Albuminuria; Blood Pressure; Comorbidity; Creatinine; Double-Blind Method; Enzyme Inhibitors; Female; Glomerular Filtration Rate; Gout; Humans; Hyperuricemia; Male; Middle Aged; Nitriles; Prevalence; Pyridines; Renal Insufficiency, Chronic; Treatment Outcome; Uric Acid; Xanthine Oxidase

Hyperuricemia is associated with chronic kidney disease (CKD). Although topiroxostat, a novel, non-purine, selective xanthine oxidase inhibitor, has a strong effect against hyperuricemia, limited data are available on its renoprotective effect against CKD.. This study was conducted between October 2014 and May 2016. Thirty patients (20 male, 10 female) were administered 40 mg/day of topiroxostat twice daily. All patients were followed for a year. To elucidate the effects of topiroxostat, we evaluated the clinically documented primary indication of progression, viz. laboratory evidence of kidney function decline (reference indicator), uric acid, and hypertension in different patient groups, separated according to their baseline uProt levels and baseline eGFR.. Topiroxostat treatment resulted in significant reduction in SUA (-1.53 mg/dL), systolic blood pressure (-8.9 mmHg), diastolic blood pressure (-5.0 mmHg), and urinary protein excretion (-795.5 mg/gCr) compared with baseline values. However, serum creatinine and urinary NAG levels, and estimated glomerular filtration rate did not change significantly.. Topiroxostat reduced SUA levels effectively and may exhibit renoprotective effect in hyperuricemic patients with CKD. Further studies are required to clarify whether topiroxostat prevents the progression of renal disease and improves the prognosis of CKD patients.

Topics: Aged; Biomarkers; Blood Pressure; Enzyme Inhibitors; Female; Humans; Hypertension; Hyperuricemia; Incidence; Japan; Kidney; Male; Middle Aged; Nitriles; Proteinuria; Pyridines; Renal Insufficiency, Chronic; Retrospective Studies; Time Factors; Treatment Outcome; Uric Acid; Xanthine Dehydrogenase; Xanthine Oxidase

Hyperuricemia is associated with the progression of chronic kidney disease (CKD) and cardiovascular diseases. Topiroxostat, a selective xanthine oxidase inhibitor, effectively reduces serum uric acid (UA) levels and urinary albumin excretion (UAE) in CKD patients. A 50-year-old Japanese man was referred to our hospital due to albuminuria and hyperuricemia, and renal biopsy showed a typical hyperuricemic arteriolopathy. Treatment with topiroxostat decreased serum UA levels (9.2 mg/dL at baseline to 6.4 mg/dL after 6 months), UAE (388 to 88 mg/g.cr), and urinary level of liver-type fatty acid-binding protein (28.8 to 19.8 µg/g.cr). Interestingly, topiroxostat treatment was associated with a trend towards improved flow-mediated dilation (5.4 to 5.8%). These results suggested that topiroxostat in CKD patients with hyperuricemia is potentially effective, not only for ameliorating renal damages but also for improving endothelial function beyond its UA-lowering action.

Topics: Humans; Hyperuricemia; Male; Middle Aged; Nitriles; Pyridines; Renal Insufficiency, Chronic

Topics: Aged; Aged, 80 and over; Drug Substitution; Enzyme Inhibitors; Febuxostat; Female; Gout Suppressants; Humans; Hyperuricemia; Kidney; Male; Middle Aged; Nitriles; Proteinuria; Pyridines; Renal Insufficiency, Chronic; Treatment Outcome; Xanthine Dehydrogenase; Xanthine Oxidase

Topics: Enzyme Inhibitors; Febuxostat; Humans; Hyperuricemia; Nitriles; Pyridines; Renal Insufficiency, Chronic; Thiazoles; Treatment Outcome; Uric Acid; Xanthine Oxidase