Renoprotective effects of topiroxostat for Hyperuricaemic patients with overt diabetic nephropathy study (ETUDE study): A prospective, randomized, multicentre clinical trial.

AIM: We aimed to evaluate the anti-albuminuric effects of topiroxostat in Japanese hyperuricaemic patients with diabetic nephropathy. METHODS: In this 24-week, multicentre, open-label, randomized (1 : 1) trial, we assigned hyperuricaemic patients with diabetic nephropathy (estimated glomerular filtration rate ≥ 20 mL/min per 1.73m2 ) and overt proteinuria (0.3 ≤ urine protein to creatinine ratio (UPCR) <3.5 g/g Cr) to either high dose (160 mg daily) or low dose (40 mg daily) topiroxostat. The primary endpoint was the change in albuminuria indicated by urine albumin-to-creatinine ratio (UACR) from the baseline at the final time point. RESULTS: A total of 80 patients underwent randomization. The changes in UACR after 24 weeks of treatment (or at the final time point if patients failed to reach 24 weeks) relative to the baseline were -122 mg/gCr (95% CI: -5.1 to -240.1, P = 0.041) in patients treated with high dose, while treatment with low dose topiroxostat could not show significant reduction (P = 0.067). In the linear mixed model including baseline albuminuria, eGFR, age, and sex as covariates, the decreases in UACR were still significant from baseline to 12 weeks by 228.7 ± 83.2 mg/gCr (P = 0.0075) in the high dose group. The adverse-event profile during this study was not different between the groups. CONCLUSION: Topiroxostat 160 mg daily reduced albuminuria in patients with diabetic nephropathy. (Funded by Sanwa Kagaku Kenkyusho; Trial registration, UMIN000015403).

Randomized control trial for the assessment of the anti-albuminuric effects of topiroxostat in hyperuricemic patients with diabetic nephropathy (the ETUDE study).

Proteinuria is an established risk factor for diabetic nephropathy. Recent studies indicate that some xanthine oxidase inhibitors have a renoprotective effect. The aim of this study was to assess whether topiroxostat reduces albuminuria in hyperuricemic patients with diabetic nephropathy and overt proteinuria. The ETUDE study is an ongoing 24-week, multicenter, open-label, randomized (1:1), parallel group study involving hyperuricemic patients with diabetic nephropathy (estimated glomerular filtration rate [eGFR] ≥ 20 mL/min/1.73 m(2)) and overt proteinuria (0.3 ≤ urine protein to creatinine ratio (UPCR) < 3.5 g/g Cr). Patients are randomly assigned to high dose (topiroxostat 160 mg daily) or low dose (topiroxostat 40 mg daily) on top of standard of care. The primary endpoint is the change in albuminuria indicated by urine albumin-to-creatinine ratio after 24 treated weeks relative to the baseline values. This trial was registered at the Japanese University Hospital Medical Information Network Clinical Trials Registry (UMIN-CTR: UMIN 000015403). The background, rationale, and study design of this trial are presented here. Seventy-six patients from four registered facilities have already been enrolled and received at least one dose of topiroxostat. This trial will end in 2017. The ETUDE trial is the first randomized controlled study of topiroxostat in hyperuricemic patients with diabetic nephropathy and overt proteinuria. We will clarify the pleiotropic function of topiroxostat including an anti-albumiuric effect as well as its effects on safely decreasing serum uric acid levels.

Association of Estimated Glomerular Filtration Rate and Proteinuria With Lipid-Rich Plaque in Coronary Artery Disease.

BACKGROUND: Estimated glomerular filtration rate (eGFR) and proteinuria are both important determinants of the risk of cardiovascular disease and mortality. The aim of the present study was to investigate the independent and combined effects of eGFR and proteinuria on tissue characterization of the coronary plaques of culprit lesions. METHODS AND RESULTS: Conventional intravascular ultrasound and 3-D integrated backscatter intravascular ultrasound (IB-IVUS) were performed in 555 patients undergoing elective percutaneous coronary intervention. They were divided into 2 groups according to the absence or presence of proteinuria (dipstick result ≥1+). Patients with proteinuria had coronary plaque with significantly greater percentage lipid volume compared with those without (43.6±14.8% vs. 48.6±16.1%, P=0.005). Combined analysis was done using eGFR and absence or presence of proteinuria. Subjects with eGFR 45-59 ml/min/1.73 m2 and proteinuria were significantly more likely to have higher percent lipid volume compared with those with eGFR >60 ml/min/1.73 m2 without proteinuria. After multivariate adjustment for confounders, the presence of proteinuria proved to be an independent predictor for lipid-rich plaque (OR, 1.85; 95% CI: 1.12-3.06, P=0.016). CONCLUSIONS: The addition of proteinuria to eGFR level may be of value in the risk stratification of patients with coronary artery disease.

Fulminant type 1 diabetes mellitus associated with a reactivation of Epstein-Barr virus that developed in the course of chemotherapy of multiple myeloma.

A 70-year-old woman who was diagnosed with multiple myeloma underwent chemotherapy. Three months after beginning chemotherapy, she was readmitted to the hospital because of fever and hepatopathy. Her elevated Epstein-Barr virus (EBV) antibody levels showed that the hepatopathy was caused by reactivation of EBV. On the 18th hospital day, the levels of fasting plasma glucose (FPG; 451 mg/dL) and pancreatic enzymes were suddenly elevated. Elevation of HbA1c level (6.4%) was slight, as compared with that of the FPG level. Arterial blood gas analysis showed metabolic acidosis and diabetic ketoacidosis was suspected. The serum C-peptide level was below the detectable limit both before and after glucagon load, thereby suggesting an insulin-dependent state. These features were identical to the features for fulminant type 1 diabetes mellitus. The levels of EBV anti-viral capsid antigen immunoglobulin M decreased, and the clinical course was identical to that associated with reactivation of EBV infection. (J Diabetes Invest, doi: 10.1111/j.2040.1124.2010.00061.x, 2010).