Background: Chronic kidney disease (CKD) and non-alcoholic steatohepatitis (NASH) are major health burdens closely related to metabolic syndrome. A link between CKD and NASH has been assumed; however, the underlying mechanism is still unknown. Ectopic lipid deposition (ELD) in the hepatocyte results in endoplasmic reticulum (ER) stress, which plays an important role in the development of steatohepatitis. ELD is also assumed to play a role in the development of kidney injury. We aimed to investigate the role of ELD and ER stress in the development of CKD, and evaluate the efficacy of a sodium glucose cotransporter-2 inhibitor, ipragliflozin. Methods: Male FLS-ob/ob mice that closely imitate the pathophysiology of NASH were treated with vehicle or ipragliflozin. Metabolic characteristics, histology of the kidney, ER stress, and apoptotic signals were evaluated. Results: The serum triglyceride was significantly lower in mice treated with ipragliflozin. Ipragliflozin reduced ELD in renal tubules. Ipragliflozin also reduced the expression levels of GRP78 and CHOP, apoptotic cells, and interstitial fibrosis. Conclusions: ELD induced kidney injury through ER stress. Ipragliflozin improved the pathogenesis of CKD by reducing ELD and ER stress in NASH-model mice. Our results suggest ipragliflozin has therapeutic effect on CKD in NASH.

Background: Knowledge of the natural history and management of hepatic hemangiomas is lacking. The aim of this study was to investigate the natural history of hemangiomas and to elucidate the factors that determine tumor growth and optimal management. Methods: A total of 211 adult patients were enrolled, with follow-up for more than three years. Follow-up was performed with repeated ultrasonography (US) and laboratory tests for liver function and coagulation factors (platelets, prothrombin time (PT), fibrinogen, thrombin–antithrombin III complex (TAT), D-dimer, and fibrin and fibrinogen degradation products (FDP)). Results: Tumor size decreased in 38.9% of patients, showed no change in 31.3%, and increased in 29.8%. The incidence of a size increase was very high in patients under 40 years of age and decreased gradually with age, whereas the incidence of a size decrease increased with age and increased markedly over 60 years of age. The incidence of an increase in size decreased gradually with size enlargement, whereas the incidence of a decrease in size increased markedly with tumor size and further increased rapidly when hemangiomas became larger than 60 mm. Values of TAT, D-dimer, FDP, and Mac-2 binding protein glycosylation isomer (M2BPGi) were closely related to the change in size of hemangiomas. Conclusions: Hemangiomas in older patients (>60 years of age) and larger tumors (>60 mm in size) had a tendency to decrease in size, resulting from the reduction in coagulation disorders and the progression of liver fibrosis. Therefore, the majority of patients with hemangiomas can be safely managed by clinical observation.

Background: Knowledge of the relationships between hepatic hemangiomas and coagulopathy and the risk factors for hemangiomas is lacking. The aim of this study was to investigate the prevalence and characteristics of hepatic hemangiomas associated with coagulopathy, elucidate the causes of coagulopathy, and identify the predictive factors for hemangioma-related complications. Methods: In 281 consecutive patients with hepatic hemangiomas, we performed ultrasonography and conducted serum laboratory tests for liver function and six coagulation factors, i.e., platelets, as well as five coagulation fibrinolytic markers (prothrombin time (PT), fibrinogen, thrombin-antithrombin III complex (TAT), d-dimer, and fibrin and fibrinogen degradation products (FDP)) as indicators of coagulation disorder. Results: Among 281 patients, 56 (19.9%) had abnormal coagulation factors. Abnormal values of d-dimer were most frequently found among the six coagulation factors. The number of abnormal coagulation factors was significantly correlated with tumor size, M2BPGi, and HDL cholesterol, among which tumor size was the most significant independent predictor of the number of abnormal coagulation factors. Conclusions: The prevalence of hepatic hemangiomas associated with coagulopathy was relatively high and became more frequent with increases in tumor size. Predictive factors of hemangioma-related complications were found to be a tumor size of >5 cm in diameter and coagulopathy, especially the elevation of d-dimer.

Little is known about the effect of hepatic hemangiomas on protein induced by vitamin K absence or antagonist II (PIVKA-II). The aim of this study was to clarify the correlation of PIVKA-II levels with hepatic hemangiomas. In 335 consecutive patients with hepatic hemangiomas, ultrasonography (US), laboratory tests for liver function, serum levels of PIVKA-II and α-fetoprotein (AFP), and coagulation factors (platelets, prothrombin time (PT), fibrinogen, thrombin–antithrombin III complex (TAT), D-dimer, and fibrin and fibrinogen degradation products (FDPs)) as indicators of coagulation disorders were examined. PIVKA-II levels were significantly higher in the hemangioma group than in the control group (p < 0.0001), and significantly higher in the large hemangioma group (p < 0.0001). PIVKA-II levels in the hemangioma increase group were higher with increases in tumor size and abnormal coagulation factors, and those in the hemangioma decrease group were lower with decreases in tumor size and abnormal coagulation factors. PIVKA-II levels were significantly correlated with tumor size (p < 0.0001) and all coagulation factors (p < 0.05) except prothrombin. Hepatic hemangiomas were associated with elevated serum PIVKA-II levels, showing significant correlations with tumor size and coagulation disorders. PIVKA-II elevation was attributed to the increased production of prothrombin precursors caused by accelerated coagulation–fibrinolysis within hemangiomas.