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Aims/Introduction: Diabetic kidney disease is characterized by increased albuminuria and/or a reduced glomerular filtration rate (GFR). We analyzed secular changes in the prevalence of albuminuria and reduced estimated GFR (eGFR) in Japanese patients with type 2 diabetes, and identified factors associated with these changes. Materials and Methods: Using 1996, 2001, 2006 and 2014 cohort data from the Japanese serial cross‐sectional studies conducted at Shiga University of Medical Science, secular changes in the prevalence of diabetic kidney disease (albuminuria and/or reduced eGFR), patient characteristics and their associations were analyzed. Results: The prevalence of microalbuminuria and macroalbuminuria decreased over time, whereas the prevalence of moderately reduced eGFR (30–60 mL/min/1.73 m2) and severely reduced eGFR (<30 mL/min/1.73 m2) increased. Severely reduced eGFR was observed mainly in the patients with macroalbuminuria, regardless of year. Conversely, the prevalence of moderately reduced eGFR increased in the patients without macroalbuminuria. Both macroalbuminuria and moderately reduced eGFR without macroalbuminuria in the 2014 cohort were refractory to the recently recommended intensive therapy. Finally, we showed that obesity accompanied by vascular dysfunction was a risk factor for the development of albuminuria, and that age‐dependent arterial stiffness was associated with reduced eGFR without macroalbuminuria in the 2014 cohort. Conclusions: During the past 20 years in Japan, the prevalence of albuminuria declined, whereas that of reduced eGFR increased. Additionally, obesity‐ and high age‐related vascular damage seems to be associated with macroalbuminuria and reduced eGFR without macroalbuminuria, respectively. [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]

OBJECTIVE -- Genetic factors have been considered to contribute to the development and progression of diabetic nephropathy. The KCNQ1 gene (potassium voltage-gated channel, KQT-like subfamily, member 1) was originally identified as a strong susceptibility gene for type 2 diabetes in two Japanese genome-wide association studies. In this study, we examined the association of single nucleotide polymorphisms (SNPs) within KCNQ1 with diabetic nephropathy in Japanese subjects with type 2 diabetes. RESEARCH DESIGN AND METHODS -- We genotyped 33 SNPs in KCNQ1 using 754 type 2 diabetic patients with overt nephropathy and 558 control subjects (an initial study), and we further examined the association of a candidate SNP using three other independent Japanese populations (replications 1-3). RESULTS -- We found that five SNPs were nominally associated with diabetic nephropathy, and the association of rs2237897 was the strongest. We also found that the T allele frequencies of rs2237897 were consistently higher in the nephropathy groups than in the control groups for all study populations (initial study: 0.33 vs. 0.27; replication 1:0.32 vs. 0.30; replication 2:0.33 vs. 0.28; and replication 3:0.32 vs. 0.28), although the individual associations did not reach statistically significant levels. Combined analysis by a meta-analysis revealed that the T allele of rs2237897 was significantly associated with susceptibility to diabetic nephropathy in Japanese subjects with type 2 diabetes (odds ratio 1.22 [95% CI 1.10-1.34], P = 3.1 x 10[sup -4], corrected P = 0.01). CONCLUSIONS -- These results suggest that KCNQ1 is a new candidate gene for conferring susceptibility to diabetic nephropathy. [ABSTRACT FROM AUTHOR]

It has been suggested that genetic susceptibility plays an important role in the pathogenesis of diabetic nephropathy. A large-scale genotyping analysis of gene-based single nucleotide polymorphisms (SNPs) in Japanese patients with type 2 diabetes identified the gene encoding acetyl-coenzyme A carboxylase beta (ACACB) as a candidate for a susceptibility to diabetic nephropathy; the landmark SNP was found in the intron 18 of ACACB (rs2268388: intron 18 +4139 C . T, p = 1.4x10-6, odds ratio = 1.61, 95% confidence interval [CI]: 1.33-1.96). The association of this SNP with diabetic nephropathy was examined in 9 independent studies (4 from Japan including the original study, one Singaporean, one Korean, and two European) with type 2 diabetes. One case-control study involving European patients with type 1 diabetes was included. The frequency of the T allele for SNP rs2268388 was consistently higher among patients with type 2 diabetes and proteinuria. A meta-analysis revealed that rs2268388 was significantly associated with proteinuria in Japanese patients with type 2 diabetes (p = 5.35x10-8, odds ratio = 1.61, 95% Cl: 1.35-1.91). Rs2268388 was also associated with type 2 diabetes-associated end-stage renal disease (ESRD) in European Americans (p = 6x10-4, odds ratio = 1.61, 95% Cl: 1.22- 2.13). Significant association was not detected between this SNP and nephropathy in those with type 1 diabetes. A subsequent in vitro functional analysis revealed that a 29-bp DNA fragment, including rs2268388, had significant enhancer activity in cultured human renal proximal tubular epithelial cells. Fragments corresponding to the disease susceptibility allele (T) had higher enhancer activity than those of the major allele. These results suggest that ACACB is a strong candidate for conferring susceptibility for proteinuria in patients with type 2 diabetes. [ABSTRACT FROM AUTHOR]

To elucidate the role of the renin–angiotensin system (RAS) in diabetic nephropathy, we examined the association between diabetic nephropathy in a large cohort of Japanese type 2 diabetic patients and polymorphisms within the genes that encode angiotensin-converting enzyme ( ACE), angiotensinogen ( AGT) and angiotensin II receptor type 1 ( AGTR1). Single nucleotide polymorphisms (SNPs) within these genes were genotyped using invader assay in 747 nephropathy cases and 557 control subjects. Eight SNPs within the ACE gene were significantly associated with diabetic nephropathy ( P<0.05), including five SNPs in almost complete linkage disequilibrium to the insertion/deletion polymorphism in the 16th intron ( P=0.01, odds ratio =1.34, 95% CI 1.07–1.69). Three SNPs within the AGT, including M235T and one SNP in the AGTR1, were also significantly associated with nephropathy (M235T P=0.01, odds ratio =0.74, 95% CI 0.59–0.94). In addition, we found that the allelic mRNA expression corresponding to the 235M allele was significantly higher than that for the 235T allele in normal kidney tissues. Furthermore, we found a significant additional effect of these three genes by a step-wise logistic regression analysis (final empirical P value =0.00005). We concluded that RAS gene polymorphisms may contribute to the susceptibility to diabetic nephropathy in type 2 diabetes. [ABSTRACT FROM AUTHOR]

A 34-year-old Japanese man presented with blurred vision, headache, nausea, anemia, thrombocytopenia, and severe renal dysfunction. Thrombotic microangiopathy was initially suspected to have been caused by malignant hypertension. Antihypertensive medications did not improve his thrombocytopenia or renal dysfunction, and other diseases causing thrombotic microangiopathy were ruled out. Therefore, the patient was diagnosed with atypical hemolytic uremic syndrome. A renal biopsy revealed an overlap of thrombotic microangiopathy and C3 glomerulopathy. Genetic testing revealed c.848A>G (p.Asp283Gly), a missense heterozygous variant in the gene encoding complement factor I. Overlapping atypical hemolytic uremic syndrome and C3 glomerulopathy with complement factor I mutation is very rare, especially in Japan.

Introduction: We investigated trends in the proportion of diabetes treatment and glycemic control, which may be altered by recent advances in insulin and non-insulin drugs, in Japanese patients with type 2 diabetes., Research Design and Methods: A serial cross-sectional study was performed using a multicenter large-population database from the Japan Diabetes Clinical Data Management study group. Patients with type 2 diabetes who attended clinics belonging to the study group between 2002 and 2018 were included to examine trends in glycated hemoglobin A1c (HbA1c) by treatment group using multivariable non-linear regression model., Results: The proportion of patients with insulin only decreased from 15.0% to 3.6%, patients with insulin+non-insulin drugs increased from 8.1% to 15.1%, patients with non-insulin drugs increased from 50.8% to 67.0%, and those with no drugs decreased from 26.1% to 14.4% from 2002 to 2018, respectively. The HbA1c levels of each group, except for no drugs, continued to decrease until 2014 (unadjusted mean HbA1c (%) from 2002 to 2014: from 7.89 to 7.45 for insulin only, from 8.09 to 7.63 for insulin+non-insulin, and from 7.51 to 6.98 for non-insulin) and remained unchanged thereafter. Among insulin-treated patients, use of human insulin decreased, use of long-acting analog insulin increased, and concomitant use of non-insulin drugs increased (from 35.1% in 2002 to 80.9% in 2018), which included increased use of dipeptidyl peptidase 4 inhibitors, sodium-glucose cotransporter 2 inhibitors, and glucagon-like peptide 1 receptor agonists, and the persistently high use of metformin., Conclusions: During the past two decades, combined use of insulin and non-insulin drugs increased and glycemic control improved and leveled off after 2014 in Japanese patients with type 2 diabetes. Further studies of the trend in association with age and factors related to metabolic syndrome are necessary to investigate strategies aiming at personalized medicine in diabetes care., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Several reports have suggested that genetic susceptibility contributes to the development and progression of diabetic retinopathy. We aimed to identify genetic loci that confer susceptibility to diabetic retinopathy in Japanese patients with type 2 diabetes. We analysed 5 790 508 single nucleotide polymorphisms (SNPs) in 8880 Japanese patients with type 2 diabetes, 4839 retinopathy cases and 4041 controls, as well as 2217 independent Japanese patients with type 2 diabetes, 693 retinopathy cases and 1524 controls. The results of these two genome-wide association studies (GWAS) were combined with an inverse variance meta-analysis (Stage-1), followed by de novo genotyping for the candidate SNP loci (P < 1.0 × 10-4) in an independent case-control study (Stage-2, 2260 cases and 723 controls). After combining the association data (Stages 1 and 2) using meta-analysis, the associations of two loci reached a genome-wide significance level: rs12630354 near STT3B on chromosome 3, P = 1.62 × 10-9, odds ratio (OR) = 1.17, 95% confidence interval (CI) 1.11-1.23, and rs140508424 within PALM2 on chromosome 9, P = 4.19 × 10-8, OR = 1.61, 95% CI 1.36-1.91. However, the association of these two loci was not replicated in Korean, European or African American populations. Gene-based analysis using Stage-1 GWAS data identified a gene-level association of EHD3 with susceptibility to diabetic retinopathy (P = 2.17 × 10-6). In conclusion, we identified two novel SNP loci, STT3B and PALM2, and a novel gene, EHD3, that confers susceptibility to diabetic retinopathy; however, further replication studies are required to validate these associations., (© The Author(s) 2021. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Objective: Nonalbuminuric diabetic kidney disease (DKD) has become the prevailing phenotype in patients with type 2 diabetes. However, it remains unclear whether its prognosis is poorer than that of other DKD phenotypes., Research Design and Methods: A total of 2,953 Japanese patients with type 2 diabetes and estimated glomerular filtration rate (eGFR) ≥30 mL/min/1.73 m 2 , enrolled in an observational cohort study in 2004, were followed until 2015. On the basis of albuminuria (>30 mg/g creatinine) and reduced eGFR (<60 mL/min/1.73 m 2 ) at baseline, participants were classified into the four DKD phenotypes-no-DKD, albuminuric DKD without reduced eGFR, nonalbuminuric DKD with reduced eGFR, and albuminuric DKD with reduced eGFR-to assess the risks of mortality, cardiovascular disease (CVD), and renal function decline., Results: During the mean follow-up of 9.7 years, 113 patients died and 263 developed CVD. In nonalbuminuric DKD, the risks of death or CVD were not higher than those in no-DKD (adjusted hazard ratio 1.02 [95% CI 0.66, 1.60]) and the annual decline in eGFR was slower than in other DKD phenotypes. The risks of death or CVD in nonalbuminuric DKD without prior CVD were similar to those in no-DKD without prior CVD, whereas the risks in nonalbuminuric DKD with prior CVD as well as other DKD phenotypes were higher., Conclusions: Nonalbuminuric DKD did not have a higher risk of mortality, CVD events, or renal function decline than the other DKD phenotypes. In nonalbuminuric DKD, the presence of macrovascular complications may be a main determinant of prognosis rather than the renal phenotype., (© 2020 by the American Diabetes Association.)

To explore novel genetic loci for diabetic nephropathy, we performed genome-wide association studies (GWAS) for diabetic nephropathy in Japanese patients with type 2 diabetes. We analyzed the association of 5,768,242 single nucleotide polymorphisms (SNPs) in Japanese patients with type 2 diabetes, 2,380 nephropathy cases and 5,234 controls. We further performed GWAS for diabetic nephropathy using independent Japanese patients with type 2 diabetes, 429 cases and 358 controls and the results of these two GWAS were combined with an inverse variance meta-analysis (stage-1), followed by a de novo genotyping for the candidate SNP loci (p < 1.0 × 10(-4)) in an independent case-control study (Stage-2; 1,213 cases and 1,298 controls). After integrating stage-1 and stage-2 data, we identified one SNP locus, significantly associated with diabetic nephropathy; rs56094641 in FTO, P = 7.74 × 10(-10). We further examined the association of rs56094641 with diabetic nephropathy in independent Japanese patients with type 2 diabetes (902 cases and 1,221 controls), and found that the association of this locus with diabetic nephropathy remained significant after integrating all association data (P = 7.62 × 10(-10)). We have identified FTO locus as a novel locus for conferring susceptibility to diabetic nephropathy in Japanese patients with type 2 diabetes., Competing Interests: The authors have declared that no competing interests exist.

Aims/introduction: Diabetes and obesity are important health and economic concerns. We investigated the influence of obesity on diabetes control, the annual medical expenditures and medications in Japanese patients with type 2 diabetes who were relatively lean in comparison with those in Western countries., Materials and Methods: A total of 402 Japanese patients with type 2 diabetes were enrolled and their annual medical expenditures investigated. Obesity was defined as body mass index ≥25 kg/m 2 , according to the obesity classifications from the Japan Society for the Study of Obesity., Results: A total of 165 patients (41.0%) were classified as obese. The obese group was younger, had poor glycemic control and higher frequency of hypertension than the non-obese group. The median total annual medical expenditures for all participants was ¥269,333 (interquartile range ¥169,664-437,437), which was equivalent to approximately $US2,450. The annual medical expenditure was significantly higher in patients with obesity than in non-obese patients (P < 0.001). This difference was mainly attributed to the annual expenditures for medication and hospitalization. In particular, the medication expenditures and the average number of drug classes for hyperglycemia and hypertension were significantly higher in the obese group., Conclusions: Japanese patients with type 2 diabetes and obesity had higher annual medical expenditures and a larger number of medications, but their diabetes control care was insufficient in comparison with those without obesity. Further studies are required to assess the effect of reducing bodyweight on diabetes control and costs., (© 2017 The Authors. Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd.)

Background and Objectives: We investigated the association of urinary potassium and sodium excretion with the incidence of renal failure and cardiovascular disease in patients with type 2 diabetes., Design, Setting, Participants, & Measurements: A total of 623 Japanese type 2 diabetic patients with eGFR≥60 ml/min per 1.73 m(2) were enrolled in this observational follow-up study between 1996 and 2003 and followed-up until 2013. At baseline, a 24-hour urine sample was collected to estimate urinary potassium and sodium excretion. The primary end point was renal and cardiovascular events (RRT, myocardial infarction, angina pectoris, stroke, and peripheral vascular disease). The secondary renal end points were the incidence of a 50% decline in eGFR, progression to CKD stage 4 (eGFR<30 ml/min per 1.73 m(2)), and the annual decline rate in eGFR., Results: During the 11-year median follow-up period, 134 primary end points occurred. Higher urinary potassium excretion was associated with lower risk of the primary end point, whereas urinary sodium excretion was not. The adjusted hazard ratios for the primary end point in Cox proportional hazards analysis were 0.56 (95% confidence interval [95% CI], 0.33 to 0.95) in the third quartile of urinary potassium excretion (2.33-2.90 g/d) and 0.33 (95% CI, 0.18 to 0.62) in the fourth quartile (>2.90 g/d) compared with the lowest quartile (<1.72 g/d). Similar associations were observed for the secondary renal end points. The annual decline rate in eGFR in the fourth quartile of urinary potassium excretion (-1.3 ml/min per 1.73 m(2)/y; 95% CI, -1.5 to -1.0) was significantly slower than those in the first quartile (-2.2; 95% CI, -2.4 to -1.8)., Conclusions: Higher urinary potassium excretion was associated with the slower decline of renal function and the lower incidence of cardiovascular complications in type 2 diabetic patients with normal renal function. Interventional trials are necessary to determine whether increasing dietary potassium is beneficial., (Copyright © 2015 by the American Society of Nephrology.)

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 7.0 years, interquartile range 3.0-8.0 years), 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.

Background: Knowledge regarding the association between dietary sodium intake and the incidence of masked hypertension is limited., Methods: A total of 193 Japanese type 2 diabetic outpatients who had been treated with antihypertensive agents and with office blood pressures <140/90 mm Hg were recruited. Masked hypertension was defined as having office blood pressure <140/90 mm Hg and 24-h mean ambulatory blood pressure ≥130/80 mm Hg. The dietary sodium intake was estimated by measuring the 24-h urinary sodium excretion., Results: Masked hypertension was found in 128 (66.3%) patients. An age- and sex-adjusted univariate logistic regression analysis showed that urinary albumin excretion, renin-angiotensin system inhibitor use, office systolic blood pressure, and amount of dietary sodium intake were significantly associated with masked hypertension. A multivariate logistic regression analysis also identified an older age, renin-angiotensin system inhibitor use, an office elevated systolic blood pressure, and high dietary sodium intake to be independently associated with masked hypertension. When compared with those who consumed a low salt diet (sodium <120 mEq/day), the odds ratio for the risk of exhibiting masked hypertension in patients who consumed a medium salt diet (sodium 120 to <200 mEq/day) or a high salt diet (sodium ≥200 mEq/day) were 5.3 (P < 0.001) and 12.6 (P < 0.001), respectively., Conclusions: Masked hypertension is a common feature in type 2 diabetic patients being treated for hypertension. The observed association with sodium intake raised the hypothesis that excessive sodium intake may play a part in the genesis of masked hypertension in these patients.

Objective: Genetic factors are believed to contribute to the development and progression of diabetic nephropathy. Recently, a genome-wide association study for diabetic nephropathy revealed four novel candidate loci in European American subjects with type 1 diabetes. In this study, we determined the association of the four loci with diabetic nephropathy in Japanese subjects with type 2 diabetes., Research Design and Methods: We genotyped 11 singlenucleotide polymorphisms (SNPs) in four distinct loci (rs39059 and rs39075 in the CPVL/CHN2, rs1888747 and rs10868025 in FRMD3, rs739401 and rs451041 in CARS, and rs1041466, rs1411766, rs6492208, rs7989848, and rs9521445 in a chromosome 13q locus) in four independent Japanese populations., Results: Six SNPs were nominally associated with diabetic nephropathy in one of the four Japanese populations (P < 0.05; rs451041 in study 1; rs39059 and rs1888747 in study 3; rs1411766 in studies 1 and 4; and rs7989848 and rs9521445 in study 4); however, no significant association was observed for any SNP after correction for multiple testing errors in the individual populations. Nevertheless, a meta-analysis performed for the data obtained from all four populations revealed that one SNP (rs1411766) in chromosome 13q was significantly associated with diabetic nephropathy in the Japanese populations (nominal P = 0.004, corrected P = 0.04, odds ratio 1.26 [95% CI = 1.07-1.47])., Conclusions: Our results suggest that the rs1411766 locus may be commonly involved in conferring susceptibility to diabetic nephropathy among subjects with type 1 or type 2 diabetes across different ethnic groups.

Background: 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., Methods: We recruited 32 Japanese type 2 diabetic patients with base line blood pressure > or =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., Results: 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., Conclusions: Excessive intake of salt causes non-dipping and diuretics restored nocturnal BP fall in type 2 diabetic patients treated with angiotensin 2 receptor blockers.

Objective: To assess whether an association between sodium-sensitive hypertension and metabolic syndrome exists; and whether, in patients with metabolic syndrome, the nocturnal fall of blood pressure decreases and salt restriction affects the circadian blood pressure rhythm., Methods: Japanese patients with essential hypertension, who were treated without any antihypertensive agent, were maintained on a high-sodium diet and a low-sodium diet for 1 week each. On the last day of each diet, the 24-h blood pressures were measured. A diagnosis of metabolic syndrome was made according to the International Diabetes Foundation definition, Results: Among the 56 patients with essential hypertension, 15 patients were complicated with metabolic syndrome while 41 patients were not. The nocturnal blood pressure fall was significant in patients without metabolic syndrome, while it was not so in patients with metabolic syndrome. Only in patients with metabolic syndrome was the nocturnal blood pressure fall enhanced by sodium restriction. The prevalence of sodium-sensitive hypertension in patients with metabolic syndrome was significantly higher than in those without metabolic syndrome (70.6 versus 36.0%, respectively; P = 0.017). A multiple logistic regression analysis revealed central obesity to be an independent risk factor for sodium-sensitive hypertension (odds ratio, 1.41; 95% confidence interval, 1.04-1.91)., Conclusions: In patients with essential hypertension, an inter-relationship exists among metabolic syndrome, enhanced sodium sensitivity of the blood pressure and non-dipping. The elevated risk of cardiovascular diseases in patients with metabolic syndrome may be related to sodium-sensitive hypertension and non-dipping.

Objective: We investigated the contribution of PKC-beta gene (PRKCB1) polymorphisms to diabetic kidney disease in a prospective observational follow-up study., Research Design and Methods: A total of 364 Japanese subjects with type 2 diabetes without overt proteinuria were enrolled during 1996-1998 and followed until 2004. Five single nucleotide polymorphisms (-1504C/T, -546C/G, -348A/G, -278C/T, and -238C/G) in the promoter region of PRKCB1 were genotyped. The end points were transition from stage to stage of diabetic nephropathy as a time-to-event outcome and the annual decline rate of estimated glomerular filtration rate (eGFR) as a slope-based outcome., Results: During the study (median 6 years), 34 of 364 subjects (9.3%) progressed. Kaplan-Meier estimation revealed that subjects with both T allele at -1054 C/T and G allele at -546 C/G polymorphisms frequently showed transition to advanced stages of diabetic nephropathy (P = 0.015). The annual change rate in eGFR in the subjects with both alleles was also significantly higher than in others (-2.96 +/- 0.62 vs. -1.63 +/- 0.15 ml/min per 1.73 m(2)/year, P = 0.02). The estimated frequency of this risk T-G haplotype was significantly higher in the progressors who showed transition to advanced nephropathy stages (12%) than in the nonprogressors (5%) (odds ratio 2.3 [95% CI 1.0-5.2]), and it was also higher in those with accelerated decline of the Delta eGFR (> or =3 ml/min per 1.73 m(2)/year) than in those without (2.1 [1.1-3.9])., Conclusions: Our study indicates that PRKCB1 is a predictor for worsening of kidney disease in Japanese subjects with type 2 diabetes.

Objective: The aim of this study is to clarify the conflicting results of the epsilon2/epsilon3/epsilon4 APOE polymorphism as a risk factor on diabetic nephropathy by a cohort study., Research Design and Methods: A total of 429 Japanese subjects with type 2 diabetes and with normoalbuminuria (n = 299) or with microalbuminuria (n = 130) were enrolled in a prospective observational follow-up study during 1995-1998 and followed until 2001 (for at least 3 years). The endpoint was the occurrence of a renal event defined as the progression to a higher stage of diabetic nephropathy., Results: During the study (the mean follow-up period: 4.4 +/- 1.0 years), 31 of 429 subjects progressed: 21 from normoalbuminuria to microalbuminuria and 10 from microalbuminuria to overt proteinuria. The allele frequency of the APOE polymorphism was significantly different between the progressors and the nonprogressors. Eight of 42 epsilon2 carriers (19%) progressed, whereas 23 of 387 noncarriers (6%) progressed with a relative risk of 3.2 (95% CI 1.5-6.7). When subjects were stratified by renal status at baseline, each relative risk for the progression in the epsilon2 carriers was 2.7 (0.99-7.4) in those with normoalbuminuria and 4.2 (1.3-13.3) in those with microalbuminuria. Furthermore, when analyzed only in subjects with normoalbuminuria and short duration of diabetes (<15 years) at baseline, the risk in the epsilon2 carriers became higher to 3.2 (1.2-8.8)., Conclusions: Our follow-up study indicates that the epsilon2 allele of the APOE polymorphism is a prognostic risk factor for both the onset and the progression of diabetic nephropathy in Japanese type 2 diabetes.