Moritsugu Kimura

Expression of transcription factor Snai1 and tubulointerstitial fibrosis in progressive nephropathy.

BACKGROUND Tubulointerstitial fibrosis (TIF) is seen as the final stage of progressive nephropathy, and the degree of TIF is reported to be a major determinant in renal outcomes. In recent years, epithelial-mesenchymal transition (EMT) and the zinc-finger transcription factor snail homolog 1 (Snai1) have each been implicated in the mechanism of TIF. The relationship between EMT and these transcription factors is unclear, however, so in this study we attempted to elucidate the correlation between the expression of Snai1 and clinical markers. METHODS We performed immunohistochemical staining on human renal tissue obtained from patients with diabetic nephropathy (DN), IgA nephropathy (IgAN), minimal change disease (MCD) and minor glomerular abnormality (MGA) using anti-Snai1 and anti-vimentin antibodies. We counted Snai1-positive and Snai1/vimentin double positive tubular epithelial cells. RESULTS Snai1 protein was mainly observed in the nuclei of flattened, damaged tubular epithelial cells, especially in IgAN and DN, and positive cell numbers were significantly higher in IgAN than in MGA, MCD or DN. Snai1/vimentin double staining showed that some vimentin-positive tubular epithelial cells also contained Snai1-positive nuclei, and double positive cell numbers were increased in IgAN and DN. Statistical analysis revealed positive correlations between Snai1/vimentin double positive cell numbers and proteinuria and creatinine in IgAN. Positive correlations were also seen between Snai1/vimentin double positive cell numbers and the severity of proteinuria in DN. CONCLUSIONS The results of this study indicate that Snai1 plays an important role in TIF in patients with progressive nephropathy.

Insulin glargine improves glycemic control and quality of life in type 2 diabetic patients on hemodialysis

BACKGROUND Diabetic patients on hemodialysis often experience severe hypoglycemia during intensive insulin therapy using conventional neutral protamine hagedorn (NPH) or nonintensive therapy with premixed insulin. Insulin glargine can simulate normal basal insulin secretion. We investigated the efficacy and safety of switching from NPH to glargine in type 2 diabetes patients on hemodialysis. METHODS Hemodialysis patients who were being treated with NPH-based basal-bolus insulin therapy, regular insulin, NPH insulin or premixed insulin were switched to glargine. The target early morning fasting blood glucose (FBG) level was 110 mg/dL. Any increase in glargine dose was coupled with a reduction in the dose of any regular or rapid-acting insulin analogue as far as possible while maintaining a constant daily insulin dose. FBG, HbA(1c), daily insulin dosage, percentage of basal insulin dose in total daily insulin dose, body weight and incidence of hypoglycemic events were evaluated during the study period. Quality of life (QOL) was measured with a short questionnaire. RESULTS HbA(1c) improved significantly during the observation period after switching. The daily insulin dose was reduced from 20.1 ± 15.2 to 18.1 ± 15.1 U/day, although the change was not statistically significant. FBG decreased significantly from 174.4 ± 58.7 to 126.2 ± 27.7 mg/dL. Body weight measured after dialysis did not change, and there were no changes in hemoglobin or hematocrit. The frequency of hypoglycemic episodes decreased significantly. QOL reports with switching to glargine were improved compared with those before switching. CONCLUSION The results suggest that glargine is useful, can improve QOL of diabetic patients on hemodialysis, and achieve better glycemic control than NPH.

Upregulation of α3β1-Integrin in Podocytes in Early-Stage Diabetic Nephropathy

Background. Podocyte injury plays an important role in the onset and progression of diabetic nephropathy (DN). Downregulation of α3β1-integrin expression in podocytes is thought to be associated with podocyte detachment from the glomerular basement membrane, although the mechanisms remain obscure. To determine the mechanism of podocyte detachment, we analyzed the expression levels of α3β1-integrin in podocytes in early and advanced stages of DN. Methods. Surgical specimens from DN patients were examined by in situ hybridization, and the expression levels of α3- and β1-integrin subunits in glomeruli of early (n = 6) and advanced (n = 8) stages were compared with those of normal glomeruli (n = 5). Heat-sensitive mouse podocytes (HSMP) were cultured with TGF-β1 to reproduce the microenvironment of glomeruli of DN, and the expression levels of integrin subunits and the properties of migration and attachment were examined. Results. Podocytes of early-stage DN showed upregulation of α3- and β1-integrin expression while those of advanced stage showed downregulation. Real-time PCR indicated a tendency for upregulation of α3- and β1-integrin in HSMP cultured with TGF-β1. TGF-β1-stimulated HSMP also showed enhanced in vitro migration and attachment on collagen substrate. Conclusions. The results suggested that podocyte detachment during early stage of DN is mediated through upregulation of α3β1-integrin.

Voltage dependence of photocurrent in metal–semiconductor–metal structures under front-illuminated conditions

Abstract Bias dependence of the photocurrent in planar metal–semiconductor–metal systems under dc and ac optical illumination conditions has been examined experimentally. Making use of molybdenum–silicon–molybdenum structures with a long undepleted neutral region, we measured their dc and low frequency (100 Hz to 100 kHz) photoresponse properties. It was confirmed that, in addition to opto-electronic conversion function, these structures showed an appreciable voltage controllability of the photocurrent in the device.

The Prevalence of 25-hydroxyvitamin D Deficiency in Japanese Patients with Diabetic Nephropathy.

Objective The purpose of this study was to measure serum 25-hydroxyvitamin D [25(OH)D] levels in Japanese patients with diabetic nephropathy and determine the relationship between 25(OH)D concentrations and various factors. Methods The study subjects included 442 patients with type 2 diabetes. Their serum levels of creatinine, HbA1c, intact-parathyroid hormone, urinary albumin, 25(OH)D, and 1,25-dihydroxyvitamin D [1,25(OH)2D] were measured and their estimated glomerular filtration rate (eGFR) was determined. The patients were divided into four groups based on the risk for progression to chronic kidney disease (CKD): low, moderate, high, very high, based on their eGFR and their level of albuminuria. Results The median 25(OH)D level was 14.6 ng/mL; 11% of the patients had 25(OH)D deficiency (<10 ng/mL), and 2% of patients had active vitamin D deficiency, as defined by a 1,25(OH)2D level of <22 pg/mL. The serum 25(OH)D level was correlated with the serum 1,25(OH)2D level in patients with a very high risk for CKD, but not in those with a moderate or high risk for CKD. Conclusion Although the vitamin D levels of the Japanese patients with diabetic nephropathy and CKD were low, the prevalence of vitamin D deficiency, as defined by the 1,25(OH)2D level, was low. Albuminuria, younger age, and female gender were associated with a low 25(OH)D level. The serum level of 25(OH)D should be monitored to assess the vitamin D status of patients with nephropathy and CKD.

Exercise Therapy for Management of Type 2 Diabetes Mellitus: Superior Efficacy of Activity Monitors over Pedometers

We compared the efficacy of activity monitor (which displays exercise intensity and number of steps) versus that of pedometer in exercise therapy for patients with type 2 diabetes. The study subjects were divided into the activity monitor group (n = 92) and pedometer group (n = 95). The primary goal was improvement in hemoglobin A1c (HbA1c). The exercise target was set at 8,000 steps/day and 20 minutes of moderate-intensity exercise (≥3.5 metabolic equivalents). The activity monitor is equipped with a triple-axis accelerometer sensor capable of measuring medium-intensity walking duration, number of steps, walking distance, calorie consumption, and total calorie consumption. The pedometer counts the number of steps. Blood samples for laboratory tests were obtained during the visits. The first examination was conducted at the start of the study and repeated at 2 and 6 months. A significant difference in the decrease in HbA1c level was observed between the two groups at 2 months. The results suggest that the use of activity level monitor that displays information on exercise intensity, in addition to the number of steps, is useful in exercise therapy as it enhances the concept of exercise therapy and promotes lowering of HbA1c in diabetic patients.

Retrospective analysis of effects of sodium-glucose co-transporter 2 inhibitor in Japanese type 2 diabetes mellitus patients with chronic kidney disease

Aim: The aim of this study was to assess the renal effects of the glucose-lowering SGLT2 inhibitors in Japanese type 2 diabetes mellitus patients with chronic kidney disease. Methods: The Kanagawa Physicians Association maintains a registry of patients who visit their 31 clinics. Clinical data of type 2 diabetes mellitus patients with chronic kidney disease, who were prescribed SGLT2 inhibitors in addition to other treatments, were collected and analysed. Results: SGLT2i was associated with a fall in HbA1c from 64.1 ± 16.7 mmol/mol (8.0 ± 1.5%) to 56.5 ± 12.9 mmol/mol (7.3 ± 1.2%) (p < 0.01) in 869 analysed cases, a decrease in urine albumin-creatinine ratio from a median of 47.1 to 41.1 mg/gCr, and decrease in estimated glomerular filtration rate from 77.7 ± 23.9 to 75.0 ± 23.9 mL/min/1.73 m2 (p < 0.01). The effect on albumin-creatinine ratio was independent of age or stage of estimated glomerular filtration; however, there was a significant negative correlation between albumin-creatinine ratio at the initiation of SGLT2 inhibitor and change in ACR. Multiple linear regression analysis identified use of empagliflozin, β-blockers, and sulphonylureas, Δsystolic blood pressure at office, serum Cr and albumin-creatinine ratio value at initiation of SGLT2 inhibitor as independent and significant determinants of change in ACR. Conclusions: This study confirmed that the beneficial renal effects of SGLT2 inhibitor in Japanese type 2 diabetes mellitus patients with chronic kidney disease, similar to those reported in large-scale clinical trials conducted in Western countries.

Continuous Glucose Monitoring Effects on Blood Glucose Management in Diabetic Patients on Hemodialysis-Results in the Patients from Single Hospital

Objective: Diabetic patients on hemodialysis (HD) are prone to develop treatment-related serious hypoglycemia due to poor renal clearance of insulin and augmented drug efficacy, often resulting in withdrawal of insulin. Consequently, many patients are erroneously switched to oral glucose-lowering agents or diet therapy alone, without self-monitoring of blood glucose (SMBG). Therefore, we hypothesized that continuous glucose monitoring (CGM) may be useful for optimizing glycemic control and clinical management in diabetic patients on HD. Methods: In this study, 8 type 2 diabetic patients on HD who did not use SMBG after withdrawal of insulin and start of oral glucose-lowering agents, were recruited to measure and evaluate blood glucose with CGM. These patients thought to be controlled within glycemic control target proposed by the Japanese Society for Dialysis Therapy. Predialysis casual plasma glucose level (or 2-h postprandial plasma glucose level) of 200 mg/dl) after HD. Conclusions: Diabetic patients on HD require careful monitoring with SMBG, CGM, and direct measurement of postprandial blood glucose level during HD before any decision is made regarding withdrawal of insulin and cessation of SMBG.

Addition of Metformin to Liraglutide, A GLP-1 Receptor Agonist, Improves Glycemic Control in Patients with Type 2 Diabetes Mellitus

Background: The maximum permissible dose of liraglutide, a GLP-1 receptor agonist, under the Japanese Heath Insurance system is 0.9 mg/day. We determined the effects of adding metformin to liraglutide therapy in Japanese patients with type 2 diabetes. Material and Methods: This observational retrospective study included 47 patients with type 2 diabetes who were treated with liraglutide alone or in combination with sulfonylureas. Metformin was added at a dose ranging from 250 to 500 mg/day based on inadequate glycemic control. Liraglutide and metformin doses were converted from mg/day to mg/kg body weight/day before analysis of the correlation between the dose and changes in glycated hemoglobin (HbA1c) and body mass index (BMI). Results: Both HbA1c and BMI decreased significantly after 24 weeks of the combination treatment. Mild gastrointestinal adverse events were reported by 21% of the patients. Only the dose of metformin, but not that of liraglutide, expressed in mg/kg body weight was correlated significantly with decrease in HbA1c and BMI. Conclusions: The addition of metformin to the maximum permissible dose of liraglutide helps secure glycemic control and reduce BMI in Japanese patients with type 2 diabetes who exhibit inadequate response to liraglutide. *Corresponding author: Masao Toyoda, M.D., Ph.D., Division of Nephrology and Metabolism, Department of Internal Medicine, Tokai University School of Medicine, Isehara, Kanagawa 259-1193, Japan, Tel: +81-463-93-1121(ext. 2490); Fax: +81-46391-3350; E-mail: m-toyoda@is.icc.u-tokai.ac.jp

937 EFFICACY OF A DIRECT RENIN INHIBITOR COMBINED WITH ANGIOTENSIN II RECEPTOR BLOCKERS FOR HYPERTENSION IN PATIENTS WITH TYPE 2 DIABETES MELLITUS

Objectives: Aliskiren is a new oral direct renin inhibitor (DRI) that reduces plasma renin activity (PRA), resulting in more complete suppression of the renin-angiotensin system (RAS). The aim of this study was to evaluate the effect on blood pressure (BP) of this DRI and its potential renoprotective effect in patients with hypertensive diabetic nephropathy who were already receiving angiotensin II receptor blockers (ARBs). Design and Methods: Thirty-four type 2 diabetic patients with albminuria in whom the urinary albumin-to-creatinine ratio (ACR) was >30 mg/g·Cr despite ARB therapy were recruited for additional DRI treatment. They were followed prospectively for 3 months to assess changes of the office BP, ACR and estimated glomerular filtration rate (eGFR). In 10 patients, changes of the 24-hour home BP were also assessed by ambulatory BP monitoring (ABPM). Results: Administration of aliskiren significantly decreased both systolic and diastolic office BP (p<0.005). A small difference of nighttime systolic BP was also seen (p=0.01). Treatment with aliskiren for 3 months did not significantly reduce the mean ACR. However, there was significant reduction of both PRA (P < 0.005) and eGFR (P < 0.05) compared with baseline values. Conclusions: This study showed that aliskiren lowers the BP, especially the nighttime BP, in combination with ARB therapy. However, the present short-term results did not reveal a renoprotective effect. Therefore, a long-term observation study is warranted to assess the renoprotective potential of aliskirin. We will report the results of observation for 6 months at the presentation.