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Aims/Introduction: We evaluated the efficacy of multifactorial intensive treatment (IT) on renal outcomes in patients with type 2 diabetes and advanced‐stage diabetic kidney disease (DKD). Materials and Methods: The Diabetic Nephropathy Remission and Regression Team Trial in Japan (DNETT‐Japan) is a multicenter, open‐label, randomized controlled trial with a 5‐year follow‐up period. We randomly assigned 164 patients with advanced‐stage diabetic kidney disease (urinary albumin‐to‐creatinine ratio ≥300 mg/g creatinine, serum creatinine level 1.2–2.5 mg/dL in men and 1.0–2.5 mg/dL in women) to receive either IT or conventional treatment. The primary composite outcome was end‐stage kidney failure, doubling of serum creatinine or death from any cause, which was assessed in the intention‐to‐treat population. Results: The IT tended to reduce the risk of primary end‐points as compared with conventional treatment, but the difference between treatment groups did not reach the statistically significant level (hazard ratio 0.69, 95% confidence interval 0.43–1.11; P = 0.13). Meanwhile, the decrease in serum low‐density lipoprotein cholesterol level and the use of statin were significantly associated with the decrease in primary outcome (hazard ratio 1.14; 95% confidence interval 1.05–1.23, P < 0.001 and hazard ratio 0.53, 95% confidence interval 0.28–0.998, P < 0.05, respectively). The incidence of adverse events was not different between treatment groups. Conclusions: The risk of kidney events tended to decrease by IT, although it was not statistically significant. Lipid control using statin was associated with a lower risk of adverse kidney events. Further follow‐up study might show the effect of IT in patients with advanced diabetic kidney disease. [ABSTRACT FROM AUTHOR]

Background: In patients with diabetes, albuminuria is a risk marker of end-stage renal disease and cardiovascular events. An increased renin-angiotensin system activity has been reported to play an important role in the pathological processes in these conditions. We compared the effect of aliskiren, a direct renin inhibitor (DRI), with that of angiotensin receptor blockers (ARBs) on albuminuria and urinary excretion of angiotensinogen, a marker of intrarenal renin-angiotensin system activity. Methods: We randomly assigned 237 type 2 diabetic patients with high-normal albuminuria (10 to <30 mg/g of albumin-to-creatinine ratio) or microalbuminuria (30 to <300 mg/g) to the DRI group or ARB group (any ARB) with a target blood pressure of <130/80 mmHg. The primary endpoint was a reduction in albuminuria. Results: Twelve patients dropped out during the observation period, and a total of 225 patients were analyzed. During the study period, the systolic and diastolic blood pressures were not different between the groups. The changes in the urinary albumin-to-creatinine ratio from baseline to the end of the treatment period in the DRI and ARB groups were similar (-5.5% and -6.7%, respectively). In contrast, a significant reduction in the urinary excretion of angiotensinogen was observed in the ARB group but not in the DRI group. In the subgroup analysis, a significant reduction in the albuminuria was observed in the ARB group but not in the DRI group among high-normal albuminuria patients. Conclusion: DRI and ARB reduced albuminuria in hypertensive patients with type 2 diabetes. In addition, ARB, but not DRI, reduced albuminuria even in patients with normal albuminuria. DRI is not superior to ARB in the reduction of urinary excretion of albumin and angiotensinogen. [ABSTRACT FROM AUTHOR]

Aims/Introduction In Japan, liraglutide was recently approved for patients with type 2 diabetes. To our knowledge, there are no markers predicting successful switching from insulin therapy to liraglutide monotherapy in Japanese patients with type 2 diabetes and renal impairment. We therefore assessed clinical characteristics predicting successful switching. Materials and Methods We analyzed 21 patients with type 2 diabetes and estimated glomerular filtration rates <60 mL/min/1.73 m2 receiving long-term insulin in Shiga University of Medical Science Hospital, Otsu, Shiga, Japan. Their β-cell function was assessed by measuring urinary C-peptide and C-peptide immunoreactivity ( CPR) index, along with glucagon loading and oral glucose tolerance tests. Blood glucose concentration and blood pressure were measured daily before and after switching from insulin to liraglutide, and glycated hemoglobin ( Hb A1c; National Glycohemoglobin Standardization Program) was assessed 12 weeks after switching to liraglutide. Results Baseline Hb A1c was significantly lower in successfully switched than in unsuccessfully switched patients. CPR index, urinary C-peptide concentration and 6-min post-glucagon increment in CPR (Δ CPR) did not differ significantly in the two groups. Δ CPR 120 min after 75 g oral glucose was significantly higher in successfully than unsuccessfully switched patients. Mean blood glucose concentrations before breakfast, after breakfast, before lunch and after dinner were significantly lower in successfully switched patients. Hb A1c did not change significantly in either group. Conclusions Measurement of oral glucose-stimulated Δ CPR120 min is recommended when considering switching Japanese type 2 diabetes patients with renal impairment from insulin to liraglutide monotherapy. [ABSTRACT FROM AUTHOR]

Prevention of cardiovascular disease (CVD) is an important therapeutic object of diabetes care. This study assessed whether an index based on plasma free amino acid (PFAA) profiles could predict the onset of CVD in diabetic patients. The baseline concentrations of 31 PFAAs were measured with high-performance liquid chromatography-electrospray ionization-mass spectrometry in 385 Japanese patients with type 2 diabetes registered in 2001 for our prospective observational follow-up study. During 10 years of follow-up, 63 patients developed cardiovascular composite endpoints (myocardial infarction, angina pectoris, worsening of heart failure and stroke). Using the PFAA profiles and clinical information, an index (CVD-AI) consisting of six amino acids to predict the onset of any endpoints was retrospectively constructed. CVD-AI levels were significantly higher in patients who did than did not develop CVD. The area under the receiver-operator characteristic curve of CVD-AI (0.72 [95% confidence interval (CI): 0.64–0.79]) showed equal or slightly better discriminatory capacity than urinary albumin excretion rate (0.69 [95% CI: 0.62–0.77]) on predicting endpoints. A multivariate Cox proportional hazards regression analysis showed that the high level of CVD-AI was identified as an independent risk factor for CVD (adjusted hazard ratio: 2.86 [95% CI: 1.57–5.19]). This predictive effect of CVD-AI was observed even in patients with normoalbuminuria, as well as those with albuminuria. In conclusion, these results suggest that CVD-AI based on PFAA profiles is useful for identifying diabetic patients at risk for CVD regardless of the degree of albuminuria, or for improving the discriminative capability by combining it with albuminuria. [ABSTRACT FROM AUTHOR]

Background: A recent genome-wide association study for diabetic nephropathy in European type 1 diabetes identified 3 candidate loci for diabetic nephropathy. In this study, we examined the association of the 3 single nucleotide polymorphism (SNP) loci with susceptibility to diabetic nephropathy in Japanese subjects with type 2 diabetes. Methods: We genotyped 3 SNPs, rs7583877 in AFF3, rs12437854 in the RGMA- MCTP2 locus and rs7588550 in ERBB4, for 2,300 Japanese patients with type 2 diabetes [initial study, 1,055 nephropathy cases with overt proteinuria or with end-stage renal disease (ESRD) and 1,245 control patients with normoalbuminuria]. The association of these SNPs with diabetic nephropathy was examined by using a logistic regression analysis. Results: We observed a significant association of rs7588550 in ERBB4 with diabetic nephropathy in the Japanese patients with type 2 diabetes, although the effect direction was not consistent with that in the European study [ p = 0.0126, odds ratio (OR) = 0.79, 95 % confidence interval (CI): 0.65–0.95]. We further examined the association of rs7588550 with diabetic nephropathy in an independent Japanese cohort (596 nephropathy cases and 311 controls) and observed the same trend of the association with the initial study. We did not observe any association of the remaining 2 SNP loci with diabetic nephropathy in the present Japanese sample. Conclusion: The association of SNP loci derived from GWAS in European type 1 diabetes with diabetic nephropathy was not replicated in the Japanese patients with type 2 diabetes, although the ERBB4 locus may have some effect also in Japanese type 2 diabetes. [ABSTRACT FROM AUTHOR]

Aim: Diabetic nephropathy is a serious complication in patients with type 2 diabetes. The aim of this study was to explore the factors associated with the progression of this complication in elderly patients with type 2 diabetes. Methods: This retrospective study of a subgroup of patients registered with the Japanese Elderly Diabetes Intervention Trial included 621 Japanese patients with type 2 diabetes mellitus (age ≥65 years, 346 with normoalbuminuria, 190 with microalbuminuria and 85 with overt proteinuria). Multivariate Cox proportional hazard regression model with a backward stepwise procedure was applied to select factors with significant effects on worsening of nephropathy stage and the doubling of serum creatinine. Results: During the follow up (median 52 months), 21% of patients progressed from normoalbuminuria and microalbuminuria to a worse nephropathy stage. Aging, female sex and high-density lipoprotein cholesterol were identified as independent and significant factors that worsen nephropathy stage. Also, 6.1% of patients showed doubling of serum creatinine during follow up. A positive history of cardiovascular disease, hyperuricemia and conventional therapy were identified as significant factors involved in the doubling of serum creatinine. The cumulative incidence of the doubling of serum creatinine was significantly lower in the intensive therapy group than the conventional therapy group ( P = 0.016), although that of progression of nephropathy stage was similar in the two groups. Conclusions: We identified several factors associated with the progression of diabetic nephropathy in elderly patients with type 2 diabetes. The results suggest that multiple risk factor intervention seems important in preventing deterioration of renal dysfunction. Geriatr Gerontol Int 2012; 12 (Suppl. 1): 127-133. [ABSTRACT FROM AUTHOR]

Background: Sirtuin is a member of the nicotinamide adenine dinucleotide (NAD)-dependent deacetylases, and has been reported to play a pivotal role in energy expenditure, mitochondrial function and pathogenesis of metabolic diseases, including aging kidneys. In this study, we focused on the genes encoding sirtuin families, and examined the association between single nucleotide polymorphisms (SNPs) within genes encoding sirtuin families and diabetic nephropathy. Methods: We examined 52 SNPs within the SIRT genes (11 in SIRT1, 7 in SIRT2, 14 in SIRT3, 7 in SIRT4, 9 in SIRT5, and 4 in SIRT6) in 3 independent Japanese populations with type 2 diabetes (study 1: 747 cases (overt proteinuria), 557 controls; study 2: 455 cases (overt proteinuria) and 965 controls; study 3: 300 cases (end-stage renal disease) and 218 controls). The associations between these SNPs were analyzed by the Cochran-Armitage trend test, and results of the 3 studies were combined with a meta-analysis. We further examined an independent cohort (195 proteinuria cases and 264 controls) for validation of the original association. Results: We identified 4 SNPs in SIRT1 that were nominally associated with diabetic nephropathy ( P < 0.05), and subsequent haplotype analysis revealed that a haplotype consisting of the 11 SNPs within SIRT1 locus had a stronger association ( P = 0.0028). Conclusion: These results indicate that SIRT1 may play a role in susceptibility to diabetic nephropathy in Japanese subjects with type 2 diabetes. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Abstract: The prevalence of end-stage renal disease (ESRD) is uprising in the paralleled with the increase of chronic kidney disease (CKD) patients. Diabetic nephropathy (DN) is the most important underlying disease of CKD and a leading cause of ESRD in Japan. Intensified multifactorial intervention in patients with type 2 diabetes with microalbuminuria slows the progression to nephropathy, and progression of retinopathy and autonomic neuropathy. However, further studies are needed to establish the effect of intensified multifactorial treatment on DN with overt proteinuria. In this trial, doctors and co-medicals collaborate to treat the DN patients to prevent the deterioration of DN by multifactorial intensive therapy. Diabetic Nephropathy Remission and Regression Team Trial in Japan (DNETT-Japan) is an open, randomized controlled trial to evaluate the efficacy of renal protection of multifactorial intensive therapy in type 2 diabetes patients with overt proteinuria (urinary albumin-to-creatinine ratio ≥300mg/g creatinine). The study has a targeted enrollment of 600 Japanese patients, and divided into two protocols by renal insufficiency (protocol A: serum creatinine: <1.2mg/dl in male and <1.0mg/dl in female, and protocol B: serum creatinine: 1.2–2.5mg/dl in male and 1.0–2.5mg/dl in female). The patients were allocated standard treatment or intensive multifactorial treatment. Intensive treatment was a stepwise implementation of behavior modification, pharmacological therapy targeting hyperglycaemia, hypertension, dyslipidaemia, and proteinuria. The primary outcome is the proteinuria in protocol A and the composite endpoint of time to the first occurrence of doubling of serum creatinine, ESRD (the need for chronic dialysis, or renal transplantation) or death in protocol B. The follow-up period is 5 years and the study ends in 2014. [Copyright &y& Elsevier]

Abstract: The improvement of salt-sensitive hypertension is a therapeutic target for various vascular diseases. Glucagon-like peptide 1 (GLP-1), an incretin peptide, has been reported to have natriuretic effect as well as blood glucose lowering effect, although its exact mechanism and clinical usefulness remain unclear. Here, we examined anti-hypertensive effect of exendin-4, a GLP-1 analog, in salt-sensitive obese db/db mice and angiotensin II (angII)-infused C57BLK6/J mice. The treatment of exendin-4 for 12 weeks inhibited the development of hypertension in db/db mice. In db/db mice, the urinary sodium excretion was delayed and blood pressure was elevated in response to a high-salt load, whereas these were attenuated by exendin-4. In db/db mice, intra-renal angII concentration was increased. Furthermore, exendin-4 prevented angII-induced hypertension in non-diabetic mice and inhibited angII-induced phosphorylation of ERK1/2 in cultured renal cells. Considered together, our results indicate that exendin-4 has anti-hypertensive effects through the attenuation of angII-induced high-salt sensitivity. [Copyright &y& Elsevier]

Abstract: Diabetic nephropathy is a major cause of lower-limb amputation. We enrolled 250 type 2 diabetic patients without apparent occlusive peripheral arterial disease (ankle–brachial indices >0.9) and 40 age-matched nondiabetic subjects consecutively admitted to our hospital. Flow volume and resistive index (RI), an index of vascular resistance, at the popliteal artery were evaluated using gated two-dimensional cine-mode phase-contrast magnetic resonance imaging. Brachial–ankle pulse wave velocity (baPWV) was measured as an index of arterial distensibility. Flow volume was negatively correlated with both baPWV (p =0.0009) and RI (p <0.0001) among the patients. When the patients were grouped into four subgroups with or without albuminuria and renal insufficiency according to the levels of urinary albumin excretion rate (≥20 or <20μg/min) and estimated glomerular filtration rate (eGFR) (<60 or ≥60ml/min/1.73m2), albuminuric patients with renal insufficiency (n =30) showed the lowest flow volume (p =0.0078) and the highest baPWV (p =0.0006) and RI (p =0.0274) among the groups. Simple linear regression analyses demonstrated that eGFR correlated positively with flow volume (p =0.0020) and negatively with baPWV (p =0.0258) and RI (p =0.0029) in patients with albuminuria (n =92), but not with normoalbuminuria (n =158). Impaired peripheral circulation in lower-leg arteries associates with nephropathy in diabetic patients even though they have normal ankle–brachial indices. [Copyright &y& Elsevier]