Efficacy and Safety of Esaxerenone in Hypertensive Patients with Diabetic Kidney Disease: A Multicenter, Open-Label, Prospective Study.

INTRODUCTION: Clinical data of esaxerenone in hypertensive patients with diabetic kidney disease (DKD) are lacking. We evaluated the efficacy and safety of esaxerenone in patients with DKD and an inadequate response to blood pressure (BP)-lowering treatment. METHODS: In this multicenter, open-label, prospective study, patients were divided into urinary albumin-to-creatinine ratio subcohorts (UACR < 30, 30 to < 300, and 300 to < 1000 mg/gCr). Esaxerenone was initiated at 1.25 mg/day and followed by incremental dose escalation based on BP and serum potassium level monitoring. The treatment period was 12 weeks. The primary endpoint was change in morning home systolic BP/diastolic BP (SBP/DBP) from baseline to end of treatment (EOT). Secondary endpoints included achievement rate of target BP, change in UACR from baseline, and safety. RESULTS: In total, 113 patients were enrolled. Morning home SBP/DBP significantly decreased from baseline to EOT in the total population (- 11.6/- 5.2 mmHg, both p < 0.001) and in all UACR subcohorts (all p < 0.001). The target BP achievement rate was 38.5%. Significant reductions in bedtime home and office BPs were also shown in the total population and all UACR subcohorts. UACR significantly improved from baseline to EOT in the total (- 50.9%, p < 0.001) and all UACR subcohorts (all p < 0.001). Incidence of serum potassium elevation as drug-related treatment emergent adverse events was 2.7%. The change from baseline in estimated glomerular filtration rate (eGFR) was - 4.8 mL/min/1.73 m2. CONCLUSION: Esaxerenone demonstrated a BP-lowering effect and improved albuminuria. The effects were consistent regardless of the severity of albuminuria without clinically relevant serum potassium elevation and eGFR reduction. CLINICAL TRIAL REGISTRATION: jRCTs06119002.

Beneficial impact of Gpnmb and its significance as a biomarker in nonalcoholic steatohepatitis.

Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease worldwide. Gpnmb is classified as a type 1 membrane protein and its soluble form is secreted by ADAM10-mediated cleavage. Gpnmb mRNA was found in the Kupffer cells and white adipose tissues (WATs) and its upregulation in obesity was recently found. Here, we generated aP2 promoter-driven Gpnmb transgenic (Tg) mice and the overexpression of Gpnmb ameliorated the fat accumulation and fibrosis of the liver in diet-induced obesity model. Soluble form of Gpnmb in sera was elevated in Gpnmb Tg mice and Gpnmb concentrated in hepatic macrophages and stellate cells interacted with calnexin, which resulted in the reduction of oxidative stress. In the patients with non-alcoholic steatohepatitis, serum soluble GPNMB concentrations were higher compared with the patients with simple steatosis. The GPNMB is a promising biomarker and therapeutic target for the development and progression of NAFLD in obesity.

Translocase of inner mitochondrial membrane 44 alters the mitochondrial fusion and fission dynamics and protects from type 2 diabetes.

OBJECTIVE: In obesity and type 2 diabetes, the impairment of mitochondrial function in white adipose tissue (WAT) is linked to a reduction in whole body insulin sensitivity. Timm44 is upregulated in the kidneys of streptozotocin-induced diabetic mice. In the inner mitochondrial membrane, Timm44 anchors mitochondrial heat-shock protein 70 (mtHsp70) to the translocase of inner mitochondrial membrane 23 (TIM23) complex and facilitates the import of mitochondria-targeted preproteins into the mitochondrial matrix dependent on the inner membrane potential and ATP hydrolysis on ATPase domain of mtHsp70. METHODS: We generated the aP2-promoter driven Timm44 transgenic (Tg) mouse model and investigated whether Timm44 Tg mice fed high-fat/high-sucrose (HFHS) chow are protected from type 2 diabetes and obesity. RESULTS: The body weight of aP2-promoter driven Timm44 Tg mice was lower than that of wild type mice, and insulin sensitivity was greater in Timm44 Tg mice than in wild type mice. Although WAT weight was not altered in Timm44 Tg mice fed HFHS chow, adipocyte size was reduced, and mitochondrial fusion associated with decreased expression of fission genes, such as Dnm1l and Fis1, was observed. In addition, when fed standard (STD) chow, the expressions of the fusion genes Opa1, Mfn1 and Mfn2, and Mfn1 were significantly increased in Timm44 Tg mice compared to wild type mice, and fused mitochondria were also observed in Timm44 Tg mice fed STD chow. CONCLUSIONS: The Timm44 gene may be a new target for the treatment of type 2 diabetes.

Successful treatment by mycophenolate mofetil in a patient with focal segmental glomerulosclerosis associated with posterior reversible encephalopathy syndrome.

It has been reported that cyclosporine A (CsA) treatment may be associated with posterior reversible encephalopathy syndrome. We report a 16-year-old man who exhibited nephrotic syndrome and posterior reversible encephalopathy syndrome. Intensive antihypertensive therapy restored him to consciousness. Renal biopsy revealed that he suffered from focal segmental glomerulosclerosis. Although he was treated with prednisolone and low-density lipoprotein apheresis therapy, his proteinuria remained at high level. Then, mycophenolate mofetil (MMF) with less influence on vessel endothelium compared with CsA and tacrolimus was administered. Soon after, he reached remission of nephrotic syndrome without recurrence of posterior reversible encephalopathy syndrome. This is the first case that a young patient of focal segmental glomerulosclerosis with posterior reversible encephalopathy syndrome achieved a complete remission by MMF treatment without recurrence of posterior reversible encephalopathy syndrome. MMF may be effective for young patients of focal segmental glomerulosclerosis especially with clinical condition of vascular endothelial damage such as posterior reversible encephalopathy syndrome.

A Randomized Trial of Monopolar Soft-mode Coagulation Versus Heater Probe Thermocoagulation for Peptic Ulcer Bleeding.

BACKGROUND AND AIM: Endoscopic therapy has been demonstrated to be effective in achieving hemostasis for bleeding peptic ulcers. Thermal coagulation is one of the most commonly used methods, with a high success rate. Recently, endoscopic submucosal dissection for early gastric carcinoma was developed and hemostasis with soft coagulation using hemostatic forceps was introduced. The aim of this study was to compare the hemostatic efficacy of soft coagulation with heater probe thermocoagulation for peptic ulcer bleeding. METHODS: Patients who visited our hospital with hematemesis or melena underwent emergency endoscopy. Inclusion criteria were presentation with an actively bleeding ulcer, a nonbleeding visible vessel, or an adherent clot. Patients were excluded if they were unwilling to give written informed consent or had a bleeding gastric malignancy. Patients were randomized to receive endoscopic hemostasis with soft coagulation (Group S) or heater probe thermocoagulation (Group H). The primary endpoint was the primary hemostasis rate and secondary endpoints were rebleeding rate, complications, and the procedure time. RESULTS: Between May 2010 and February 2012, a total of 111 patients (89 gastric ulcers and 22 duodenal ulcers) were enrolled. Primary hemostasis was achieved in 54 patients (96%) in Group S and 37 (67%) in Group H (P<0.0001). Rebleeding occurred in 7 patients in Group H and none in Group S. Of these 7 patients, urgent surgery was performed in 1. Perforation occurred in 2 patients in Group H, which was managed conservatively. CONCLUSIONS: For patients with gastroduodenal ulcer bleeding, soft coagulation using monopolar hemostatic forceps is more effective than heater probe thermocoagulation for achieving hemostasis.

Monopolar soft-mode coagulation using hemostatic forceps for peptic ulcer bleeding.

BACKGROUND/AIMS: Upper gastrointestinal hemorrhage from bleeding peptic ulcer is sometimes difficult to treat by conventional endoscopic methods. Recently, monopolar electrocoagulation using a soft-coagulation system and hemostatic forceps (soft coagulation) has been used to prevent bleeding during endoscopic submucosal dissection. The aim of this study was to assess the safety and efficacy of soft coagulation in the treatment of bleeding peptic ulcer. METHODOLOGY: A total of 39 patients with peptic ulcers were treated using soft coagulation at our hospital between January 2005 and March 2010. Emergency treatment employed an ERBE soft-mode coagulation system using hemostatic forceps. Second-look endoscopy was performed to evaluate the efficacy of prior therapy. Initial hemostasis was defined as accomplished by soft coagulation, with or without other endoscopic therapy prior to soft coagulation. The rate of initial hemostasis, rebleeding, and ultimate hemostasis were retrospectively analyzed. RESULTS: The study subjects were 31 men and 8 women with a mean age of 68.3±13.7 years, with 29 gastric ulcers and 10 duodenal ulcers. Initial hemostasis was achieved in 37 patients (95%). During follow-up, bleeding recurred in two patients, who were retreated with soft coagulation. CONCLUSIONS: The monopolar soft coagulation is feasible and safe for treating bleeding peptic ulcers.