The renoprotective effect of once-weekly GLP-1 receptor agonist dulaglutide on progression of nephropathy in Japanese patients with type 2 diabetes and moderate to severe chronic kidney disease (JDDM67).

AIMS/INTRODUCTION: Few studies have investigated the renoprotective effect of glucagon-like peptide-1 (GLP-1) receptor in patients with chronic kidney disease (CKD). This study evaluated the effect of dulaglutide 0.75 mg on renal function in Japanese patients with type 2 diabetes and CKD stage 3 to 4. MATERIALS AND METHODS: Dulaglutide (group A) and non-dulaglutide (group B) were compared using data collected from a computerized diabetes care database. For group B, propensity score weighting based on propensity scores was performed. Evaluation items were a change from baseline in hemoglobin A1c (HbA1c), body weight, urine albumin-to-creatinine ratio (UACR), and estimated glomerular filtration rate (eGFR), for 3 years. RESULTS: In total, the data obtained from 255 patients (125 and 130 patients for group A and B, respectively) were analyzed. Propensity score-adjusted patient background characteristics (group A vs B) were age 70.8 vs 69.4 years, body weight 70.2 vs 72.9 kg, body mass index 27.3 vs 28.1 kg/m2 , HbA1c 8.4 vs 8.5%, eGFR 47.9 vs 47.7 mL/min/1.73 m2 , and UACR 218 vs 251 mg/gCr. Although there were no statistically significant differences in the change from baseline between groups A and B at most time points in eGFR, a statistically significant eGFR decline in group B was observed in slope analysis for 3 years. This renoprotective effect was marked in patients with macro-albuminuria and/or concomitant SGLT2 inhibitor use. CONCLUSIONS: Dulaglutide slowed the eGFR decline in patients with type 2 diabetes and CKD stage 3 to 4.

Inclusion bodies of aggregated hemosiderins in liver macrophages.

Hemosiderin formation is a structural indication of iron overload. We investigated further adaptations of the liver to excess iron. Five patients with livers showing iron-rich inclusions larger than 2 µm were selected from our database. The clinical features of patients and structures of the inclusions were compared with those of 2 controls with mild iron overload. All patients had severe iron overload with more than 5000 ng/mL of serum ferritin. Etiologies were variable, from hemochromatosis to iatrogenic iron overload. Their histological stages were either portal fibrosis or cirrhosis. Inclusion bodies were ultra-structurally visualized as aggregated hemosiderins in the periportal macrophages. X-ray analysis always identified, in addition to a large amount of iron complexes including oxygen and phosphorus, a small amount of copper and sulfur in the mosaic matrixes of inclusions. There were no inclusions in the control livers. Inclusion bodies, when the liver is loaded with excess iron, may appear in the macrophages as isolated organella of aggregated hemosiderins. Trace amounts of copper-sulfur complexes were always identified in the mosaic matrices of the inclusions, suggesting cuproprotein induction against excess iron. In conclusion, inclusion formation in macrophages may be an adaptation of the liver loaded with excess iron.

Measurement of serum hepcidin-25 levels as a potential test for diagnosing hemochromatosis and related disorders.

BACKGROUND: Iron overload syndromes include a wide spectrum of genetic and acquired conditions. Recent studies suggest suppressed hepcidin synthesis in the liver to be the molecular basis of hemochromatosis. However, a liver with acquired iron overload synthesizes an adequate amount of hepcidin. Thus, hepcidin could function as a biochemical marker for differential diagnosis of iron overload syndromes. METHODS: We measured serum iron parameters and hepcidin-25 levels followed by sequencing HFE, HJV, HAMP, TFR2, and SLC40A1 genes in 13 Japanese patients with iron overload syndromes. In addition, we performed direct measurement of serum hepcidin-25 levels using liquid chromatography-tandem mass spectrometry in 3 Japanese patients with aceruloplasminemia and 4 Italians with HFE hemochromatosis. RESULTS: One patient with HJV hemochromatosis, 2 with TFR2 hemochromatosis, and 3 with ferroportin disease were found among the 13 Japanese patients. The remaining 7 Japanese patients showed no evidence for genetic basis of iron overload syndrome. As far as the serum hepcidin-25 was concerned, seven patients with hemochromatosis and 3 with aceruloplasminemia showed markedly decreased serum hepcidin-25 levels. In contrast, 3 patients with ferroportin disease and 7 with secondary iron overload syndromes showed serum hepcidin levels parallel to their hyperferritinemia. Patients with iron overload syndromes were divided into 2 phenotypes presenting as low and high hepcidinemia. These were then associated with their genotypes. CONCLUSION: Determining serum hepcidin-25 levels may aid differential diagnosis of iron overload syndromes prior to genetic analysis.

Role of Smad4 on TGF-beta-induced extracellular matrix stimulation in mesangial cells.

BACKGROUND: The best characterized signaling pathway employed by transforming growth factor-beta (TGF-beta) is the Smad pathway; however, its role in matrix production in mesangial cells is unclear. We focused on Smad4, as Smad4 is essential for the activation of Smad-dependent target genes. METHODS: To investigate the function of Smad4 in extracellular matrix (ECM) production, we generated several stably transfected mesangial cell lines (MMC) that have a deletion in the linker region (Smad4 Delta M4: Delta 275-322) or have a deletion in MH1 of Smad4 (Smad4N4: Delta 1-136). The ECM genes, alpha1 type I collagen (COL1A1), plasminogen activator inhibitor-1 (PAI-1) and fibronectin (FN) were assessed in wild-type mesangial cells and stably transfected Smad4-DN cell lines in the absence and presence of TGF-beta. RESULTS: As compared to wild-type MMC that had a 10.8-fold stimulation of TGF-beta-induced p3TP-Lux activity, MMC stably transfected with Smad4 Delta M4 and Smad4N4 had only a 2.0-fold and 1.3-fold stimulation, respectively, indicating that they had dominant-negative effects on TGF-beta signaling. Basal and TGF-beta-induced COL1A1 expression in Smad4 dominant-negative cells were dramatically reduced to very low levels. The early (2 hours) TGF-beta-induced PAI-1 mRNA expression was inhibited; however, the sustained (24 to 48 hours) TGF-beta-induced expression was not affected in Smad4 dominant-negative cells. For FN, TGF-beta-induced expression was maintained in Smad4-dominant negative cells. CONCLUSION: These results indicate that Smad4 is essential for basal and TGF-beta-induced COL1A1 expression, and contributes to the early, but not sustained TGF-beta-induced PAI-1 expression in mesangial cells. However, TGF-beta-induced FN expression is independent of Smad4. In conclusion, Smad4 has a discriminate effect in mediating specific ECM molecules stimulated by TGF-beta in mesangial cells.