Circulating tumor necrosis factor-related biomarkers predict kidney function decline in Japanese patients with diabetes: An observational cohort study.

AIMS: Tumor necrosis factor (TNF) receptors (TNFRs: TNFR1 and, TNFR2) are reportedly associated with chronic kidney disease (CKD) progression chiefly in Caucasian patients with diabetes. We assessed the prognostic value of TNF-related biomarkers for CKD progression in Japanese patients with diabetes. METHODS: We estimated TNF-related biomarkers using an enzyme-linked immunosorbent assay in 640 patients with diabetes. Cox proportional hazards analysis was performed to estimate hazard ratios (HRs) per one standard deviation (SD) increase in a log-transformed biomarker. The kidney and the composite outcome were defined as a 30% reduction in estimated glomerular filtration rate (eGFR) from baseline, and kidney outcome plus death before kidney outcome, respectively. RESULTS: During the median follow-up of 5.4 years, 75 (11.7%) patients reached the kidney outcome and 37 (5.8%) died before reaching the kidney outcome. Each SD increase in baseline circulating TNFR1, TNFR2, and ephrin type-A receptor 2 (EphA2) was associated with a higher risk of the kidney outcome independently from baseline eGFR and urine albumin-to-creatinine ratio. However, circulating osteoprotegerin was associated with the composite outcome only. CONCLUSIONS: Elevated TNFR1, TNFR2, and EphA2 were associated with both kidney and composite outcomes in Japanese patients with diabetes.

Novel [ 111 In]In-BnDTPA-EphA2-230-1 Antibody for Single-Photon Emission Computed Tomography Imaging Tracer Targeting of EphA2.

Erythropoietin-producing hepatocellular receptor A2 (EphA2) is overexpressed in cancer cells and causes abnormal cell proliferation. Therefore, it has attracted attention as a target for diagnostic agents. In this study, the EphA2-230-1 monoclonal antibody (EphA2-230-1) was labeled with [111In]In and evaluated as an imaging tracer for single-photon emission computed tomography (SPECT) of EphA2. EphA2-230-1 was conjugated with 2-(4-isothiocyanatobenzyl)-diethylenetriaminepentaacetic acid (p-SCN-BnDTPA) and then labeled with [111In]In. [111In]In-BnDTPA-EphA2-230-1 was evaluated in cell-binding, biodistribution, and SPECT/computed tomography (CT) studies. The cellular uptake ratio of [111In]In-BnDTPA-EphA2-230-1 was 14.0 ± 2.1%/mg protein at 4 h in the cell-binding study. In the biodistribution study, a high uptake of [111In]In-BnDTPA-EphA2-230-1 was observed in tumor tissue (14.6 ± 3.2% injected dose/g at 72 h). The superior accumulation of [111In]In-BnDTPA-EphA2-230-1 in tumors was also confirmed using SPECT/CT. Therefore, [111In]In-BnDTPA-EphA2-230-1 has potential as a SPECT imaging tracer for EphA2.

Development of an In-House EphA2 ELISA for Human Serum and Measurement of Circulating Levels of EphA2 in Hypertensive Patients with Renal Dysfunction.

Identifying novel biomarkers of kidney function in patients with chronic kidney disease (CKD) has strong clinical value as current measures have limitations. This study aims to develop and validate a sensitive and specific ephrin type-A receptor 2 (EphA2) enzyme-linked immunosorbent assay (ELISA) for human serum, and determine whether its results correlate with traditional renal measures in patients with hypertension. The novel ELISA of the current study was validated and used to measure circulating EphA2 levels in 80 hypertensive patients with and without kidney function decline (eGFR less than 60 mL/min/1.73 m2). Validation of the EphA2 ELISA showed good recovery (87%) and linearity (103%) and no cross-reactivity with other Eph receptors. Patients with kidney function decline had lower diastolic blood pressure, and higher UPCR and EphA2 than those without kidney function decline. The association of age and eGFR with EphA2 was maintained in the stepwise multiple regression analysis. In a multivariate logistic model, EphA2 was associated with a lower eGFR (<60 mL/min/1.73 m2) after adjustment for age, sex, and UPCR. High circulating EphA2 levels have potential application as a clinical biomarker for the presence of CKD in patients with hypertension.

Immunotactoid Glomerulopathy with Nontuberculous Mycobacterial Infection: A Novel Association.

A 70-year-old woman underwent a renal biopsy due to nephrotic syndrome. She had suffered from nontuberculous mycobacterial infection (NTM) for 14 years. The patient was diagnosed as having membranoproliferative glomerulonephritis (MPGN) type 3 and immunoglobulin (Ig)-associated MPGN based upon LM/erythromycin and IF findings, respectively. In high-magnification imaging, electron-dense deposits showed immunotactoid glomerulopathy (ITG). There was no evidence of hematological cancer, and the patient improved after receiving treatments for NTM. To the best of our knowledge, this patient is the first to show an association between ITG and NTM. Although ITG is generally considered as related to lymphoproliferative disease, it is suggested that ITG is driven by bacterial infection and is a potential outcome of Ig-associated MPGN.

Novel Ridaifen-B Structure Analog Induces Apoptosis and Autophagy Depending on Pyrrolidine Side Chain.

Ridaifen (RID)-B is an analog derived from tamoxifen (TAM). TAM has an antitumor effect by acting as an antagonist to estrogen receptor (ER). However, TAM is known to also induces apoptosis in cancer cells that do not have ER. We clarified that RID-B induces cell death at a lower concentration than TAM, and causes ER-independent apoptosis and autophagy. Based on the results of previous studies, we assumed that RID-B had a unique target different from ER and examined structural activity correlation to determine what kinds of structural features are related to RID-B activity. As a result, we found there was activity even without one of phenyl groups (Ar3) in RID-B and revealed that two pyrrolidine side chains peculiar to RID-B are related to the action. Furthermore, analogs with shorter alkyl side chains induced autophagy, but analogs with certain length of alkyl side chains induced apoptosis. Also, although there is no doubt that RID-B induces apoptosis by causing mitochondrial injury, our results suggested that such injury induced mitochondria-selective autophagy. We revealed that RID-B induce mitophagy and that this mitophagy is a defense mechanism against RID-B. Our results suggest that autophagy was induced against apoptosis caused by mitochondrial dysfunction in RID-B, so the combination of autophagy inhibitor and anticancer-drug can be effective for cancer treatment.