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A biomarker, by which we can predict alterations of renal function in normoalbuminuric diabetic patients, is not available. Here, we report that endogenous anti-fibrotic peptide N-acetyl-seryl-aspartyl-lysyl-proline (AcSDKP) represents a potential biomarker to predict alterations in eGFR in normoalbuminuric diabetic patients. We analyzed 21 normoalbuminuric diabetic patients with eGFR ≥ 30 ml/min/1.73 m2 and measured AcSDKP levels in first morning void urine. We divided patients into two groups based on the median values: low or high urinary AcSDKP groups (uAcSDKP/Crlow or uAcSDKP/Crhigh). At baseline, no significant differences in sex, age, HbA1c, BMI, serum creatinine levels, etc., were observed between the two groups. During ~ 4 years, the alteration in eGFR [ΔeGFRop (ΔeGFR observational periods)] was significantly stable in uAcSDKP/Crhigh group compared with uAcSDKP/Crlow group over time (P = 0.003, χ2 = 8.58). We also evaluated urine kidney injury molecule-1 (uKim-1) levels and found that ΔeGFRop was also stable in low uKim-1 group compared with high uKim-1 group over time (P = 0.004, χ2 = 8.38). Patients who fulfilled the criteria for both uAcSDKP/Crhigh and uKim-1low exhibited stable ΔeGFRop (P

A biomarker, by which we can predict alterations of renal function in normoalbuminuric diabetic patients, is not available. Here, we report that endogenous anti-fibrotic peptide N-acetyl-seryl-aspartyl-lysyl-proline (AcSDKP) represents a potential biomarker to predict alterations in eGFR in normoalbuminuric diabetic patients.We analyzed 21 normoalbuminuric diabetic patients with eGFR ≥ 30 ml/min/1.73 mDuring ~ 4 years, the alteration in eGFR [ΔeGFRAcSDKP represents a potentially useful biomarker to predict alterations in the renal function of patients with diabetes presenting normoalbuminuria.

Background: The number of patients suffering from diabetic nephropathy resulting in end-stage kidney disease is increasing worldwide. In clinical settings, there are limited data regarding the impact of the urinary albumin-to-creatinine ratio (UACR) and reduced estimated glomerular filtration rate (eGFR) on renal and cardiovascular outcomes and all-cause mortality. Methods: We performed a historical cohort study of 4328 Japanese participants with type 2 diabetes from 10 centers. Risks for renal events (requirement for dialysis or transplantation, or half reduction in eGFR), cardiovascular events (cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke), and all-cause mortality were assessed according to UACR and eGFR levels. Results: During follow-up (median 7.0years, interquartile range 3.0-8.0years), 419 renal events, 605 cardiovascular events and 236 deaths occurred. The UACR levels increased the risk and the adjusted hazard ratios for these three events. In addition to the effects of UACR levels, eGFR stages significantly increased the adjusted hazard ratios for renal events and all-cause mortality, especially in patients with macroalbuminuria. Diabetic nephropathy score, based on the prognostic factors, well predicted incidence rates per 1000 patient/year for each event. Conclusions: Increased UACR levels were closely related to the increase in risks for renal, cardiovascular events and all-cause mortality in Japanese patients with type 2 diabetes, whereas the association between high levels of UACR and reduced eGFR was a strong predictor for renal events. © 2013 Japanese Society of Nephrology.

Diabetic nephropathy, leading to end-stage renal disease, has a considerable impact on public health and the social economy. However, there are few national registries of diabetic nephropathy in Japan. The aims of this prospective cohort study are to obtain clinical data and urine samples for revising the clinical staging of diabetic nephropathy, and developing new diagnostic markers for early diabetic nephropathy.The Japanese Society of Nephrology established a nationwide, web-based, and prospective registry system. On the system, there are two basic registries; the Japan Renal Biopsy Registry (JRBR), and the Japan Kidney Disease Registry (JKDR). In addition to the two basic registries, we established a new prospective registry to the system; the Japan Diabetic Nephropathy Cohort Study (JDNCS), which collected physical and laboratory data.We analyzed the data of 321 participants (106 female, 215 male; average age 65 years) in the JDNCS. Systolic and diastolic blood pressure was 130.1 and 72.3 mmHg, respectively. Median estimated glomerular filtration rate (eGFR) was 33.3 ml/min/1.73 m(2). Proteinuria was 1.8 g/gCr, and serum levels of albumin were 3.6 g/dl. The majority of the JDNCS patients presented with preserved eGFR and low albuminuria or low eGFR and advanced proteinuria. In the JRBR and JKDR registries, 484 and 125 participants, respectively, were enrolled as having diabetes mellitus. In comparison with the JRBR and JKDR registries, the JDNCS was characterized by diabetic patients presenting with low proteinuria with moderately preserved eGFR.There are few national registries of diabetic nephropathy to evaluate prognosis in Japan. Future analysis of the JDNCS will provide clinical insights into the epidemiology and renal and cardiovascular outcomes of type 2 diabetic patients in Japan.

Background. Glomerular mesangial cells were found to have a considerable number of receptors for insulin-like growth factor I (IGF-I) and to proliferate in response to IGF-I. However, the mechanism of the metabolic actions of IGF-I in mesangial cells has not yet been fully elucidated. Methods. In order to clarify the effect of IGF-I on glucose metabolism in mesangial cells, we performed a kinetic analysis of 2-deoxyglucose (2-DOG) uptake, the first step of glucose metabolism, and examined the gene and protein expression of glucose transporter 1 (GLUT 1), a major facilitative glucose transporter in mesangial cells. Results. IGF-I was able to increase 2-DOG uptake significantly after 12 h, and the kinetic analysis of 2-DOG uptake revealed that IGF-I increased maximum velocity (Vmax) without changing Michaelis constant (Km). The expression of GLUT 1 mRNA was increased after the exposure to IGF-I and reached the maximal level at 6 h, followed by an increase in its protein expression. Conclusions. These results suggest that IGF-I plays an important role in glucose metabolism in glomerular mesangial cells by enhancing glucose transport through an increase in the expression of GLUT 1.

Diabetic nephropathy is one of the most serious complications among patients with long-standing diabetes mellitus. In recent years, nearly one third of the patients newly admitted to dialysis therapy in Japan suffer from diabetic nephropathy. Hyperglycemia appears to play a major role in the pathogenesis of this disease, probably via glomerular hemodynamic changes, as well as via metabolic alterations in glomerular cells, although both pathways may interact with each other. Recently, an activation of protein kinase C has been advocated to be a critical mediator between hyperglycemia and diabetic nephropathy. Protein kinase C is known to induce the production of various extracellular matrix proteins, which may cause the expansion of glomerular mesangium. Administration of a specific inhibitor of the β isoform of protein kinase C corrected glomerular hyperfiltration in diabetic rats. In addition, genetic factors may be involved in the progression of diabetic nephropathy, since various clinical studies have indicated the familial clustering of this complication in diabetes mellitus. Although the association with gene polymorphism of angiotensin-converting enzyme has been extensively studied by several individual research groups, a decisive conclusion has not been obtained. Further research using multicenter studies enrolling large numbers of patients may be needed to detect nephropathic gene(s).

The aim of his study was to compare the efficacy of pioglitazone with metformin on the reduction of albuminuria in type 2 diabetic patients with hypertension and microalbuminuria treated with renin-angiotensin system inhibitors (RAS-Is).The open-label, randomized trial was performed in type 2 diabetic patients with hypertension and microalbuminuria. On the basis of the treatment with RAS-Is, 68 patients with microalbuminuria received either pioglitazone (15-30 mg/day; n = 32) or metformin (500-750 mg/day; n = 31) for 52 weeks. Urinary albumin-to-creatinine ratio (UACR) was measured every 12 weeks.After 52 weeks of treatment, the changes in the log-UACR from baseline were -8.3% in the pioglitazone group and +4.2% in the metformin group (p = 0.01), with similar glycemic and blood pressure changes.The combination of pioglitazone and RAS-Is showed therapeutic benefit in the reduction of urinary albumin excretion for type 2 diabetic patients with hypertension and microalbuminuria.

Interleukin-18 (IL-18), a pro-inflammatory cytokine, is a predictor of cardiovascular and renal disease in diabetic patients. Postprandial hyperglycemia is one of the important factors contributing to an increase in the circulating pro-inflammatory cytokine levels. This study investigated the effect of miglitol, an α-glucosidase inhibitor, on postprandial hyperglycemia and IL-18 levels in diabetic patients with nephropathy. Fifteen Japanese diabetic patients with persistent proteinuria and preserved renal function were recruited. The patients received 50 mg miglitol thrice daily after the baseline examinations and were followed up for 12 weeks. A meal tolerance test was performed on eight patients at baseline and week 12. The fasting miglitol concentration was measured in seven patients just before the meal tolerance test. There were no changes in the body weight, blood pressure, liver and renal function, and proteinuria from baseline to week 12. However, the levels of glycated hemoglobin and interleukin 18 significantly decreased from baseline to week 12. During the meal tolerance test, plasma glucose was significantly decreased 60 min after treatment with miglitol, whereas the serum concentration of insulin was not changed. Fasting and postprandial levels of IL-18 were significantly decreased from baseline to week 12. Serum miglitol concentrations showed a significantly negative correlation with eGFR (r = −0.82, p = 0.02). However, the serum miglitol concentrations did not changed during the course of this study. Miglitol improved postprandial hyperglycemia and reduced serum IL-18 levels in patients with stage 3 diabetic nephropathy. Miglitol may therefore prevent atherosclerotic diseases and diabetic micro-vascular complications through decreasing glucose swings and/or the circulating IL-18 level.

The inhibition of the renin-angiotensin system in the diabetic condition was reported to enhance the sodium sensitivity of blood pressure. In patients with sodium-sensitive hypertension, high sodium intake reduces the nocturnal fall in blood pressure. Therefore, we examined the effects of the amount of sodium intake or diuretics in patients with diabetes treated with an angiotensin receptor blocker. We recruited 32 Japanese type 2 diabetic patients with base line blood pressure ≥130/80 mmHg and treated with valsartan (80 mg daily). At baseline, 24-h ambulatory blood pressure and 24-h urinary excretion of sodium were measured. The patients were then randomly assigned to take either combination therapy with 50 mg of losartan plus 12.5 mg of hydrochlorothiazide or monotherapy with 160 mg of valsartan for 24 weeks. At baseline, 22 of 32 (69%) patients were classified as non-dippers, and the night/day ratio of mean arterial pressure was significantly correlated with 24-h urinary sodium excretion. The combination therapy resulted in a significantly higher fall than the monotherapy in 24-h mean, daytime, night-time and morning blood pressures. The night/day ratio of mean arterial pressure was significantly reduced from the baseline at the end of the study in the combination therapy group, but not in the monotherapy group. In non-dipper patients, the diminished nocturnal fall in blood pressure was restored by the combination therapy. Excessive intake of salt causes non-dipping and diuretics restored nocturnal BP fall in type 2 diabetic patients treated with angiotensin 2 receptor blockers.