Hideaki Kaneshige

Detection of immune complexes in polymorphonuclear leukocytes by double immunofluorescence in patients with IgA nephropathy.

Abstract The amounts of cytoplasmic inclusion bodies in peripheral blood polymorphonuclear cells (PMN) were determined in patients with IgA nephropathy and other glomerular diseases to elucidate whether or not IgA-dominant immune complexes were phagocytized by PMN in these patients. Fifteen patients with IgA nephropathy, 8 patients with other glomerular diseases, and 10 healthy adults were examined. The amounts of cytoplasmic inclusion bodies were measured by a double immunofluorescence technique. It was demonstrated that the percentages of IgA with C3 and IgA without C3 cytoplasmic inclusion bodies were significantly increased in patients with IgA nephropathy compared with those obtained in other glomerular diseases and healthy adults. There was a significant correlation between the levels of serum IgA and the percentage of IgA with C3 cytoplasmic inclusion bodies in PMN from patients with IgA nephropathy. It was suggested that IgA-dominant immune complexes are phagocytized by peripheral blood PMN in patients with IgA nephropathy.

Pleiotropic Effects of Sitagliptin in the Treatment of Type 2 Diabetes Mellitus Patients

Background Sitagliptin is a DPP-4 inhibitor that became available for use in Japan three years ago. This study was conducted to identify the pleiotropic effects of sitagliptin other than blood glucose lowering in Japanese type 2 diabetes mellitus patients. Methods A retrospective, observational study of 940 type 2 diabetes mellitus patients was conducted. The primary outcome measures were HbA1c, blood pressure, and lipid profiles measured at 0, 4, and 12 weeks of sitagliptin therapy. Results After 12 weeks of sitagliptin treatment, compared with baseline, HbA1c decreased 0.64% ± 0.86%; systolic blood pressure (SBP) and diastolic blood pressure (DBP) decreased significantly; and serum creatinine (Cr) and uric acid (UA) levels were mildly but significantly elevated. A correlation analysis of the changes in systolic blood pressure, diastolic blood pressure, creatinine, and uric acid (ΔSBP, ΔDBP, ΔCr, ΔUA) from baseline to 12 weeks showed significant negative correlations between ΔSBP and ΔCr, ΔSBP and ΔUA, and ΔDBP and ΔCr. Total cholesterol and postprandial triglycerides were significantly decreased at both 4 and 12 weeks. Alkaline phosphatase (ALP) decreased significantly, and there was a significant positive correlation between changes in ALP and HbA1c. Conclusions Sitagliptin seems to be effective not only in lowering blood glucose but also in lowering blood pressure, lipid, and ALP levels. Sitagliptin appears to contribute to a Na-diuretic action due to GLP-1.

Efficacy and safety of sitagliptin monotherapy and combination therapy in Japanese type 2 diabetes patients

(J Diabetes Invest, doi: 10.1111/j.2040‐1124.2012.00221.x, 2012)

Impaired Solubilization of Glomerular Immune Deposits by Sera From Patients With IgA Nephropathy

A study of the solubilization of glomerular immune deposits by sera from patients with IgA nephropathy is described. Renal biopsy specimens were obtained from patients with IgA nephropathy and other glomerular diseases. These specimens were incubated with fresh and heated sera from the same patients and healthy adults at 37 degrees C for one hour in plastic tubes. The sections were stained with fluorescein isothiocyanate (FITC)-labeled heavy chain specific anti-human IgA antiserum and then examined with a fluorescent microscope. It was shown that the solubilization of glomerular immune deposits by sera from patients with IgA nephropathy was significantly less than that by sera from healthy adults. It is possible that impaired solubilization of immune complexes in vivo could lead to the accumulation of glomerular immune deposits in patients with IgA nephropathy.

Immunofluorescence staining of renal biopsy samples in patients with diabetic nephropathy in non-insulin-dependent diabetes mellitus using monoclonal antibody to reduced glycated lysine

This is the first report on immunofluorescence staining of renal biopsy samples in human diabetic nephropathy (DN) using monoclonal antibodies to reduced glycated lysine. In order to detect the localization of glycated lysine in the mesangial matrix and/or the glomerular basement membrane (GBM), we examined immunofluorescence staining using antibodies against reduced glycated lysine in the glomeruli of 16 patients with DN and ten age-matched patients with diffuse mesangial proliferative glomerulonephritis without IgA deposition (DPGN) as controls. In the early stage of DN, immunofluorescence microscopy revealed the presence of intense staining for reduced glycated lysine in the GBM as well as in part of the tubular basement membrane, but not in the mesangial area. In contrast, immunofluorescence microscopy revealed less staining for glycated lysine in the GBM in the advanced stage of DN, and no reaction with any part of the renal tissue in patients with DPGN. It was concluded that detection of reduced glycated lysine in GBM in the early stage of DN might be associated with the initial pathogenesis of this disease.

Increase of IgA in Pharyngeal Washings from Patients with IgA Nephropathy

The levels of IgA and total proteins in pharyngeal washings were examined in patients with IgA nephropathy and other glomerular diseases in order to determine whether secretory IgA, IgA1 and IgA2 were increased in these patients. Thirty patients with IgA nephropathy, 21 patients with other glomerular diseases and 15 healthy adults were examined. The levels of IgA were quantitated by radial immunodiffusion and laser nephelometry. The levels of total proteins in pharyngeal washings were quantitated by Tonein®-TR It was demonstrated that the levels of IgA in pharyngeal washings were significantly increased in patients with IgA nephropathy compared to those with other glomerular diseases and healthy adults. The levels of total proteins in pharyngeal washings were increased in patients with IgA nephropathy, and the ratio of IgA and total proteins in the washings from patients with IgA nephropathy was not significantly different from those healthy adults. There was a significant correlation between the levels of IgA in pharyngeal washings and those of IgA in sera from patients with IgA nephropathy. The IgA observed in pharyngeal washings contained secretory components, IgA1 and IgA2, in patients with IgA nephropathy. It is suggested that the increase of IgA in the pharyngeal washings in parallel with the increase of total proteins might be associated with local inflammation.[Am J Med Sci 1983; 286(2): 15–21.]

Fibrinolysis in patients with diabetic nephropathy determined by plasmin-α2 plasmin inhibitor complexes in plasma

Activation of fibrinolysis in patients with diabetic nephropathy was determined by the plasma levels of plasmin-alpha 2 plasmin inhibitor complexes (alpha 2PIC) using a one-step sandwich enzyme immunoassay (EIA). Plasma levels of alpha 2PIC in diabetic patients with persistent proteinuria were significantly higher than those in diabetic patients without proteinuria, patients with chronic glomerulonephritis, and healthy adults. Plasma levels of alpha 2PIC in diabetic patients with intermittent proteinuria were also significantly higher than those of diabetic patients without proteinuria, patients with chronic glomerulonephritis, and healthy adults. Diabetic patients have been suggested to have a hypercoagulable state. The findings obtained from this study indicated that activation of fibrinolysis might counteract the hypercoagulable state in patients with diabetic nephropathy.

Safety and efficacy of adding sitagliptin to insulin in patients with type 2 diabetes: The ASSIST-K study

We retrospectively studied more than 1000 patients with type 2 diabetes attending 36 Japanese clinics to investigate the efficacy and safety of adding sitagliptin to various insulin regimens. We found that the treatment with add-on sitagliptin for 6-months was effective, irrespective of the type or dose of concomitant insulin.

Factors Influencing Changes in Hemoglobin A1c and Body Weight During Treatment of Type 2 Diabetes With Ipragliflozin: Interim Analysis of the ASSIGN-K Study

Background Ipragliflozin is a selective sodium glucose co-transporter 2 (SGLT2) inhibitor that blocks glucose reabsorption in the proximal tubules. SGLT2 inhibitors are expected to be effective in patients with insulin resistance and obesity, but it is important to select treatment according to patient background factors that minimizes the risk of adverse events. There have been a limited number of investigations into the relationship between the clinical efficacy (reducing hemoglobin A1c (HbA1c) and body weight (BW)) or safety of SGLT2 inhibitors and patient characteristics. Methods ASSIGN-K is an investigator-initiated, multicenter, prospective observational study examining the efficacy and safety of ipragliflozin (50 - 100 mg/day for 52 weeks) in Japanese patients with type 2 diabetes mellitus (T2DM) who had inadequate glycemic control with HbA1c ≥ 6.0% (National Glycohemoglobin Standardization Program) despite diet and exercise therapy or diet and exercise plus antidiabetic drug therapy. We conducted an interim analysis of the relationship between changes in HbA1c or BW and characteristics in patients who had been on treatment for more than 12 weeks. Results In 257 patients completing 12 weeks of treatment, HbA1c decreased significantly from 8.23% to 7.55% (-0.68%, P < 0.01). The change in HbA1c after 12 weeks was -0.17%, -0.33%, and -1.16% when baseline HbA1c was < 7%, 7% to < 8%, and ≥ 8%, respectively (P < 0.05, P < 0.01, and P < 0.01, respectively), and -1.30%, -0.62%, and -0.62% when baseline body mass index (BMI) was < 25, 25 to < 30, and ≥ 30, respectively (all P < 0.01). Stratified analysis showed that age, gender, or BMI did not have a significant influence on the improvement in HbA1c. Multiple regression analysis showed that reduction in HbA1c was greater as baseline HbA1c increased and the duration of diabetes decreased. A higher baseline HbA1c was associated with less weight loss. Conclusions Ipragliflozin significantly improved HbA1c in patients with T2DM. HbA1c improved more when baseline HbA1c was higher and the duration of diabetes was shorter, suggesting that current treatment policies for diabetes could be re-examined.

Is a Switch From Insulin Therapy to Liraglutide Possible in Japanese Type 2 Diabetes Mellitus Patients

Background To evaluate the efficacy of switching from insulin to the GLP-1 receptor agonist liraglutide in type 2 diabetes mellitus patients. Methods The subjects were 231 outpatients with type 2 diabetes mellitus being treated with liraglutide for the first time. For 161 patients, liraglutide was continued for 24 weeks (continuation group), and for 70 patients, liraglutide was discontinued before 24 weeks (discontinuation group). Fasting and postprandial blood glucose levels, HbA1c, body weight, and insulin dose were evaluated before the switch to liraglutide (baseline) and at 12 and 24 weeks of administration. Trends in HbA1c and weight were compared at 12 and 24 weeks of administration. Multiple regression analyses were conducted to identify clinical factors predicting a successful switch to liraglutide. Results Multiple regression analysis with ΔHbA1c as the dependent variable in the continuation group indicated that HbA1c at 12 weeks of administration decreased with higher baseline HbA1c and increased with higher baseline daily insulin doses. Multiple regression analysis with Δweight as the dependent variable indicated that Δweight at 24 weeks of liraglutide administration was higher with higher baseline daily insulin doses and longer duration of diabetes. Based on the area under the receiver operating characteristic curve, cut-off values of 19 units for daily insulin dose and nine years for duration of diabetes were identified. Conclusions Switching from insulin to liraglutide therapy is possible for carefully selected patients. Daily insulin dosage and duration of insulin therapy appear to be clinically useful indicators for the efficacy of liraglutide therapy.