Neutrophil Elastase Inhibition by Sivelestat (ONO-5046) Attenuates AngII-Induced Abdominal Aortic Aneurysms in Apolipoprotein E-Deficient Mice.

BACKGROUND: Abdominal aortic aneurysm (AAA) is an arterial disease characterized by dilatation of the aortic wall. It has been suggested that neutrophil counts and neutrophil elastase activity are associated with AAA. We investigated whether a neutrophil elastase (NE) inhibitor, sivelestat (Siv), had a protective effect against angiotensin II (AngII)-induced AAAs. METHODS: Male apolipoprotein E-deficient mice were assigned into three groups: Vehicle + saline, AngII + saline, and AngII + Siv. All mice were administered intraperitoneally with either Siv or vehicle twice daily after AngII infusion. RESULTS: In the 4-week AngII infusion study, plasma NE concentration (P = 0.041) and its activity (P = 0.011) were elevated by AngII. These increases were attenuated by Siv (concentration:P = 0.010, activity:P = 0.027). Further, plasma elastase activity was closely correlated with aortic width (R = 0.6976, P < 0.001). In the 1-week AngII infusion study, plasma and tissue elastase activity increased by AngII (plasma:P = 0.034, tissue:P < 0.001), but were reduced by Siv (plasma:P = 0.014, tissue:P = 0.024). AngII increased aortic width (P = 0.011) but was attenuated by co-administration of Siv (P = 0.022). Moreover, Siv decreased the incidence of AAAs (P = 0.009). Elastin fragmentation induced by AngII was reduced by Siv. Many inflammatory cells that were either CD68 or Gr-1 positive were observed in the AngII + saline group, whereas few inflammatory cells were accumulated in the AngII + Siv group. MMP-2 and MMP-9 were enhanced by AngII, but were reduced by Siv. In vitro, MMP-2 activity was induced by human NE (medium:P < 0.001, cells:P = 0.001), which was attenuated by co-incubation of Siv in medium (P < 0.001) and protein of human aortic smooth muscle cells (P = 0.001). CONCLUSIONS: Siv attenuated AngII-induced AAA through the inhibition of NE.

The Beneficial Effect of Personalized Lifestyle Intervention in Chronic Kidney Disease Follow-Up Project for National Health Insurance Specific Health Checkup: A Five-Year Community-Based Cohort Study.

Background and Objectives: Mimasaka city is a relatively small city with a population of 28,381, and an aging rate (≥65 years old) of 38.9%, where only one nephrology clinic is available. Since 2013, the city has conducted its own unique lifestyle intervention for the participants of the National Health Insurance specific medical health checkup, aiming to prevent the progression of chronic kidney disease (CKD) severity. Materials and Methods: The persons in National Health Insurance specific medical health checkup (40−74 years old) conducted in Mimasaka city in 2013, with eGFR less than 50 mL/min/1.73 m² or 50−90 mL/min/1.73 m² with urine dipstick protein 1+ or more, were registered for the CKD follow-up project, as high-risk subjects for advanced renal dysfunction. Municipal workers directly visited the subjects' homes to provide individual health guidance and encourage medical consultation. We aimed to examine the effect of home-visit intervention on the changes of renal function and related factors until 2017. Results: The number of the high-risk subjects who continuously received the health checkup until 2017 was 63, and only 23 (36.5%) visited a medical institution in the first year. The eGFR decreased by only 0.4 mL/min/1.73 m²/year, and the subjects with urinary protein 1+ or higher decreased significantly from 20 (31.7%) to 9 (14.3%) (p = 0.034) in the high-risk subjects. The changes in eGFR and urinary protein was almost in the same fashion regardless of their medical institution visits. Next, we examined the effects of various factors on ΔeGFR, the changes of eGFR from 2013 to 2017, by multivariate linear regression analysis. The effects of medical institution visit were not significant, and the degree of urinary protein (coefficient B: 4.503, ß: 0.705, p < 0.001), age (coefficient B: 4.753, ß: 0.341, p = 0.004), and smoking (coefficient B: 5.878, ß: 0.295, p = 0.031) had independent significant effects, indicating that they were the factors exacerbating the decrease in eGFR from the baseline. Conclusions: The personalized lifestyle intervention by home-visit in CKD follow-up project showed the possibility of beneficial effects on the deterioration of renal function. This may be an efficient method to change behavior in a small community with limited medical resources.

The Association of Postprandial Triglyceride Variability with Renal Dysfunction and Microalbuminuria in Patients with Type 2 Diabetic Mellitus: A Retrospective and Observational Study.

OBJECTIVE: We examined whether or not day-to-day variations in lipid profiles, especially triglyceride (TG) variability, were associated with the exacerbation of diabetic kidney disease. METHODS: We conducted a retrospective and observational study. First, 527 patients with type 2 diabetes mellitus (DM) who had had their estimated glomerular filtration rate (eGFR) checked every 6 months since 2012 for over 5 years were registered. Variability in postprandial TG was determined using the standard deviation (SD), SD adjusted (Adj-SD) for the number of measurements, and maximum minus minimum difference (MMD) during the first three years of follow-up. The endpoint was a ≥40% decline from baseline in the eGFR, initiation of dialysis or death. Next, 181 patients who had no micro- or macroalbuminuria in February 2013 were selected from among the 527 patients for an analysis. The endpoint was the incidence of microalbuminuria, initiation of dialysis, or death. RESULTS: Among the 527 participants, 110 reached a ≥40% decline from baseline in the eGFR or death. The renal survival was lower in the higher-SD, higher-Adj-SD, and higher-MMD groups than in the lower-SD, lower-Adj-SD, and lower-MMD groups, respectively (log-rank test p = 0.0073, 0.0059, and 0.0195, respectively). A lower SD, lower Adj-SD, and lower MMD were significantly associated with the renal survival in the adjusted model (hazard ratio, 1.62, 1.66, 1.59; 95% confidence intervals, 1.05-2.53, 1.08-2.58, 1.04-2.47, respectively). Next, among 181 participants, 108 developed microalbuminuria or death. The nonincidence of microalbuminuria was lower in the higher-SD, higher-Adj-SD, and higher-MMD groups than in the lower-SD, lower-Adj-SD, and lower-MMD groups, respectively (log-rank test p = 0.0241, 0.0352, and 0.0474, respectively). CONCLUSIONS: Postprandial TG variability is a novel risk factor for eGFR decline and the incidence of microalbuminuria in patients with type 2 DM.

A case of fatal osteolytic hypercalcemia complicated with IgG4-related ophthalmic disease leading to renal failure.

A 40-year-old male was hospitalized with renal impairment and severe hypercalcemia. His concentration of serum IgG4 was high, but serum whole PTH, 1-25(OH)2 vitamin D3 and PTHrP were not elevated. Computed tomography showed swelling of the bilateral lacrimal glands and systemic lymphadenopathy. The histological findings of lacrimal gland biopsy fulfilled the diagnostic criteria of IgG4-related ophthalmic disease (IgG4ROD). Bone scintigraphy showed increased ectopic uptake in the stomach, heart, lungs, and kidneys. He died on day 16 of admission, although the therapies for hypercalcemia were continued. Autopsy results showed an increase of osteoclasts in the bone marrow and metastatic calcification in multiple organs, and excluded from the differential diagnosis other disorders which present lymph-node swelling and hypercalcemia such as cancer, lymphoma, Castleman's disease, and sarcoidosis. He was given a diagnosis of IgG4ROD with osteolytic hypercalcemia.