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Shiro Maeda,
Minako Imamura,
Mahiro Kurashige,
Shinichi Araki,
Daisuke Suzuki, Tetsuya Babazono,
Takashi Uzu,
Tomoya Umezono,
Masao Toyoda,
Koichi Kawai,
Masahito Imanishi,
Kazushige Hanaoka,
Hiroshi Maegawa,
Yasuko Uchigata,
Tatsuo Hosoya
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ABSTRACT: 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.
Clinical and Experimental Nephrology 03/2013; · 1.37 Impact Factor
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Mahiro Kurashige,
Minako Imamura,
Shin-Ichi Araki,
Daisuke Suzuki, Tetsuya Babazono,
Takashi Uzu,
Tomoya Umezono,
Masao Toyoda,
Koichi Kawai,
Masahito Imanishi,
Kazushige Hanaoka,
Hiroshi Maegawa,
Yasuko Uchigata,
Tatsuo Hosoya,
Shiro Maeda
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ABSTRACT: Several linkage analyses have mapped a susceptibility locus for diabetic nephropathy to chromosome 18q22-23, and polymorphisms within the carnosine dipeptidase 1 gene (CNDP1), located on 18q22.3, have been shown to be associated with diabetic nephropathy in European subjects with type 2 diabetes. However, the association of this locus with diabetic nephropathy has not been evaluated in the Japanese population. In this study, we examined the association of polymorphisms within the CNDP1/CNDP 2 locus with diabetic nephropathy in Japanese subjects with type 2 diabetes.
We genotyped a leucine repeat polymorphism (D18S880) that is within CNDP1 along with 29 single nucleotide polymorphisms (SNPs) in the CNDP1/CNDP2 locus for 2,740 Japanese subjects with type 2 diabetes (1,205 nephropathy cases with overt nephropathy or with end-stage renal disease [ESRD], and 1,535 controls with normoalbuminuria). The association of each polymorphism with diabetic nephropathy was analysed by performing logistic regression analysis. We did not observe any association between D18S880 and diabetic nephropathy in Japanese subjects with type 2 diabetes. None of the 29 SNPs within the CNDP1/CNDP2 locus were associated with diabetic nephropathy, but a subsequent sex-stratified analysis revealed that 1 SNP in CNDP1 was nominally associated with diabetic nephropathy in women (rs12604675-A; p = 0.005, odds ratio [OR] = 1.76, 95% confidence interval [CI], 1.19-2.61). Rs12604675 was associated with overt proteinuria (p = 0.002, OR = 2.18, 95% CI, 1.32-3.60), but not with ESRD in Japanese women with type 2 diabetes.
Rs12604675-A in CNDP1 may confer susceptibility to overt proteinuria in Japanese women with type 2 diabetes.
PLoS ONE 01/2013; 8(1):e54064. · 4.09 Impact Factor
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ABSTRACT: BackgroundAbdominal obesity has been implicated in the pathogenesis of microalbuminuria in patients with diabetes; however, the underlying
mechanisms remain unclear. Increased leptin secretion by adipocytes may be one of the factors responsible for the relationship
between abdominal obesity and microalbuminuria, because increased leptin secretion has been demonstrated to contribute to
renal impairment. We therefore conducted a cross-sectional study to clarify the relationship between increased serum leptin
levels associated with abdominal obesity and albuminuria in patients with type 2 diabetes mellitus (T2DM).
MethodsWe studied a total of 502 adult patients with T2DM, 220 women and 282 men, with a mean (±SD) age of 60±13years. Patients
with macroalbuminuria and those with an estimated glomerular filtration rate of <15ml/min/1.73m2 were excluded. Waist circumference was used as a surrogate marker of abdominal obesity. For statistical analyses, analysis
of covariance and multivariate linear regression analysis were conducted.
ResultsThe geometric mean (95% confidence interval) of serum leptin levels adjusted for conventional risk factors was significantly
higher in patients with microalbuminuria than in those with normoalbuminuria [5.6 (5.3–5.9) vs. 6.3 (5.8–6.8) ng/ml, p=0.030]. In the multiple regression analysis, waist circumference was significantly associated with urinary albumin excretion,
though statistical significance disappeared when serum leptin levels were incorporated into this model. Serum leptin levels
remained significantly associated with urinary albumin excretion.
ConclusionsLeptin may be a factor mediating the relationship between abdominal obesity and microalbuminuria in patients with T2DM.
KeywordsLeptin-Abdominal obesity-Microalbuminuria-Diabetic nephropathy
04/2012; 1(1):42-48.
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ABSTRACT: Patients with peripheral artery disease (PAD), defined as having low ankle-brachial pressure index (ABI), have increased risk for incident stroke compared with those without PAD. We aimed to reveal whether ABI abnormality, especially high ABI is associated with prevalent silent cerebral infarction (SCI) in type 2 diabetic patients.
We studied 538 Japanese type 2 diabetic patients, 227 women and 311 men, with a mean [±SD] age of 64±11 years. All patients underwent cranial magnetic resonance imaging (MRI). Values of ABI were classified as low (<0.9), normal (0.9≤ and <1.3), and high (1.3≤). Logistic regression model was used to calculate odds ratio and 95% confidence interval (95% CI) for prevalent SCI.
The mean ABI among the overall 538 patients was 1.09±0.16. Low and high ABI values were found in 52 (9.7%) and 33 (6.1%) patients, respectively. SCI was detected in 297 (55.2%) patients. The prevalence in patients with low, normal, and high ABI values were 88.5%, 49.7%, and 78.8 (p<0.001), respectively. In the multivariate logistic regression analysis, both patients with high and low ABI were significantly increased risk of prevalent SCI (odds ratio 4.53, 95% CI 1.67-12.34, p=0.003 and odds ratio 3.50, 95% CI 1.50-10.29, p=0.005), independently of other traditional cardiovascular risk factors, than those with normal ABI.
Both high and low ABI may be strongly associated with prevalent SCI in Japanese patients with type 2 diabetes.
Atherosclerosis 02/2012; 222(2):490-4. · 3.79 Impact Factor
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Ryotaro Bouchi, Tetsuya Babazono,
Michino Mugishima,
Naoshi Yoshida,
Izumi Nyumura,
Kiwako Toya,
Ko Hanai,
Nobue Tanaka,
Akiko Ishii,
Yasuko Uchigata,
Yasuhiko Iwamoto
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ABSTRACT: To investigate the association between aortic stiffness and incident albuminuria and the decline in estimated glomerular filtration rate (eGFR) in patients with type 2 diabetes.
We investigated 461 Japanese type 2 diabetic patients, comprising 199 women and 262 men, with a mean age of 59 ± 11 years. Patients were divided into two groups according to the median value of carotid-femoral pulse wave velocity (cf-PWV), which was used to evaluate aortic stiffness. The end point was defined as the transition from normo- to microalbuminuria or micro- to macroalbuminuria. The Cox proportional hazard model was used to calculate the hazard ratio (HR) and 95% CI. The correlation between cf-PWV and rate of change in eGFR was also determined by linear regression analysis.
The baseline mean (± SD) cf-PWV was 9.6 ± 2.4 m/s. During a median follow-up period of 5.9 years (range 0.3-8.6), progression of albuminuria was observed in 85 patients. The 5-year cumulative incidence of the end point in patients with cf-PWV below and above the median was 8.5 and 19.4%, respectively (P = 0.002, log-rank test). cf-PWV was significantly associated with incident albuminuria (HR 1.23, 95% CI 1.13-1.33, P < 0.001) by multivariate Cox regression analysis. A significant association between cf-PWV and annual change in eGFR was also suggested by multiple linear regression analysis (standardized estimate -0.095, P = 0.031).
Aortic stiffness is associated with incident albuminuria and the rate of decline in glomerular filtration rate in type 2 diabetic patients.
Diabetes care 12/2011; 34(12):2570-5. · 8.09 Impact Factor
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ABSTRACT: To clarify the association of serum leptin levels with progression of diabetic kidney disease in patients with type 2 diabetes (T2D).
This was an observational cohort study of 668 patients with T2D. Patients were classified into three groups by sex-specific tertile of leptin levels. Outcome measurements were the rate of change in estimated glomerular filtration rate (eGFR) and progression to a more advanced stage of albuminuria.
Patients with low or high leptin levels had a steeper eGFR decline (-2.07 and -2.14 mL/min/1.73 m(2)/year) than those with midrange leptin levels (-0.82 mL/min/1.73 m(2)/year; P < 0.01), whereas patients with low leptin levels had an elevated risk of progression of albuminuria as compared with those with high leptin levels (hazard ratio 3.125 [95% CI 1.302-7.499]).
Both low and high serum leptin levels were risk factors for kidney function decline. Meanwhile, lower serum leptin levels were associated with progression of albuminuria.
Diabetes care 12/2011; 34(12):2557-9. · 8.09 Impact Factor
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ABSTRACT: The impact of serum lipid abnormalities on the progression of diabetic kidney disease (DKD) remains conflicting. Furthermore, gender differences in the association between dyslipidaemia and outcome of DKD are largely unknown. We therefore conducted this single-centre observational cohort study to clarify gender differences in the association between serum lipid profiles and the progression of DKD.
Seven hundred and twenty-three Japanese type 2 diabetes mellitus (T2DM) patients with normoalbuminuria or microalbuminuria, 280 women and 443 men, with a mean (± SD) age of 63 ± 11 years were studied. The endpoint was the progression to a more advanced stage of albuminuria. For statistical analyses, Cox proportional hazard model analyses were conducted.
During the mean follow-up period of 4.3 years, 62 of 477 patients with normoalbuminuria and 69 of 246 patients with microalbuminuria reached the endpoint. A significant interaction between high-density lipoprotein (HDL) cholesterol and gender was detected (P(interaction) = 0.04); therefore, separate analyses were conducted for men and women. Overall, in men, the univariate Cox proportional hazard model revealed that higher triglycerides and lower HDL cholesterol levels were significantly associated with higher risk of reaching the endpoint. In the multivariate Cox proportional hazard model, only HDL cholesterol levels remained as an independent predictor of the endpoint (hazard ratio 0.391, P = 0.01). In women, no serum lipid parameters were associated with the endpoint.
Lower HDL cholesterol levels seem to be associated with the progression of DKD in men but not in women.
Nephrology Dialysis Transplantation 07/2011; 27(3):1070-5. · 3.40 Impact Factor
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Shiro Maeda,
Daisuke Koya,
Shin-ichi Araki, Tetsuya Babazono,
Tomoya Umezono,
Masao Toyoda,
Koichi Kawai,
Masahito Imanishi,
Takashi Uzu,
Daisuke Suzuki,
Hiroshi Maegawa,
Atsunori Kashiwagi,
Yasuhiko Iwamoto,
Yusuke Nakamura
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ABSTRACT: 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.
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.
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).
These results indicate that SIRT1 may play a role in susceptibility to diabetic nephropathy in Japanese subjects with type 2 diabetes.
Clinical and Experimental Nephrology 02/2011; 15(3):381-90. · 1.37 Impact Factor
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ABSTRACT: Chronic kidney disease (CKD) is an important risk factor for cardiovascular disease in patients with diabetes. The relationship between renal manifestations of CKD (albuminuria and decreased glomerular filtration rate) and silent cerebral infarction (SCI) has attracted attention; however, most studies examined the effects of components of CKD on prevalence of SCI. We sought to assess the relationship between SCI and the development and progression of nephropathy in type 2 diabetic patients. We studied 366 type 2 diabetic patients with normoalbuminuria (urinary albumin-to-creatinine ratio [ACR] <30 mg g(-1), N=246) or microalbuminuria (ACR=30-299 mg g(-1), N=120). SCI was defined by cranial MRI. The primary end point was progression from normo- to microalbuminuria or from micro- to macroalbuminuria. The cumulative incidence of the primary end point was estimated using the Kaplan-Meier method. Risk estimates for reaching the end point were calculated using Cox proportional hazard model analyses. During a median follow-up period of 3.9 years, 23 normoalbuminuric and 24 microalbuminuric patients reached the primary end point. Patients with SCI (N=171) had a greater incidence of reaching the end point than those without SCI (N=195, P=0.020 by the log-rank test), with a hazard ratio of 2.02 (95% confidence interval=1.09-3.72, P=0.025) in the multivariate Cox regression model. Although the common pathogenesis of SCI and albuminuria in diabetic patients is still unclear, SCI may be a predictor of progression of nephropathy in type 2 diabetic patients.
Hypertension Research 10/2010; 33(10):1000-3. · 2.58 Impact Factor
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ABSTRACT: It is unclear whether albuminuria and reduced glomerular filtration rate (GFR) independently increase the risk of incident stroke and coronary artery disease (CAD) in Japanese patients with diabetes. We investigated the independent effects of albuminuria and estimated GFR (eGFR) on the first occurrence of stroke and CAD in patients with type 2 diabetes mellitus (T2DM). We studied 1002 T2DM patients with eGFR (ml min⁻¹ per 1.73 m²) ≥15 and had no previous cardiovascular disease (CVD) history. GFR was estimated using the modified three-variable equation for the Japanese. Patients were divided into four eGFR categories: ≥90, 60-89, 30-59 and 15-29. The end point was an incident stroke and CAD events. The Cox proportional hazard model was used to calculate hazard ratio and 95% confidence interval. During a mean follow-up period of 5.2±2.1 years, 72 episodes of stroke and 90 of CAD were observed. Multivariate Cox analysis revealed no significant association between the eGFR category and incident stroke. The stroke hazard ratio (95% confidence interval) in reference to patients with an eGFR ≥90 was 0.78 (0.40-1.56) for patients with an eGFR of 60-89, 1.47 (0.70-3.10) for patients with an eGFR of 30-59 and 1.14 (0.39-3.35) for patients with an eGFR of 15-29. Reduced eGFR was a significant risk factor for CAD, with hazard ratios (95% confidence interval) for patients with an eGFRs of 60-89, 30-59 and 15-29 at 1.81 (1.01-3.57), 2.03 (1.04-4.40) and 3.01 (1.13-8.02), respectively. Reduced eGFR is independently associated with incident CAD but not stroke in Japanese patients with T2DM.
Hypertension Research 09/2010; 33(12):1298-304. · 2.58 Impact Factor
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Shiro Maeda,
Shin-Ichi Araki, Tetsuya Babazono,
Masao Toyoda,
Tomoya Umezono,
Koichi Kawai,
Masahito Imanishi,
Takashi Uzu,
Hirotaka Watada,
Daisuke Suzuki,
Atsunori Kashiwagi,
Yasuhiko Iwamoto,
Kohei Kaku,
Ryuzo Kawamori,
Yusuke Nakamura
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ABSTRACT: 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.
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.
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]).
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.
Diabetes 05/2010; 59(8):2075-9. · 8.29 Impact Factor
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ABSTRACT: Visceral obesity has been implicated in the pathogenesis of diabetic nephropathy. Waist circumference has been used as a surrogate measure of visceral fat mass; however, subcutaneous fat mass is also correlated with waist circumference. We therefore conducted this cross-sectional study to clarify the relationship between directly measured sizes of visceral and subcutaneous fat and microalbuminuria in patients with type 2 diabetes (T2DM).
We studied a total of 208 adult Japanese individuals with T2DM, 99 women and 109 men, with a mean +/- standard deviation (SD) age of 56 +/- 13 years. Patients with macroalbuminuria, defined as a urinary albumin-to-creatinine ratio (ACR) >or=300 mg/g creatinine, and those with an estimated glomerular filtration rate <15 ml/min/1.73 m(2) were excluded. Visceral and subcutaneous fat areas were measured by abdominal computed tomography.
In the univariate correlational analysis, logarithmically transformed urinary ACR was significantly associated with visceral fat area (r = 0.14, p = 0.047) but not with subcutaneous fat area (r = 0.08, p = 0.237). In the multiple regression analysis with stepwise selection procedure, visceral fat area but not subcutaneous fat area was selected as an independent variable that was statistically associated with urinary ACR.
This cross-sectional study suggests that increased visceral but not subcutaneous fat is independently associated with microalbuminuria in Japanese adult patients with T2DM.
Clinical and Experimental Nephrology 04/2010; 14(2):132-6. · 1.37 Impact Factor
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Toshihiko Ohshige,
Yasushi Tanaka,
Shin-ichi Araki, Tetsuya Babazono,
Masao Toyoda,
Tomoya Umezono,
Hirotaka Watada,
Daisuke Suzuki,
Yasuhiko Iwamoto,
Ryuzo Kawamori,
Yusuke Nakamura,
Shiro Maeda
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ABSTRACT: 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.
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).
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(-4), corrected P = 0.01).
These results suggest that KCNQ1 is a new candidate gene for conferring susceptibility to diabetic nephropathy.
Diabetes care 04/2010; 33(4):842-6. · 8.09 Impact Factor
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Shiro Maeda,
Masa-aki Kobayashi,
Shin-ichi Araki, Tetsuya Babazono,
Barry I Freedman,
Meredith A Bostrom,
Jessica N Cooke,
Masao Toyoda,
Tomoya Umezono,
Lise Tarnow, [......],
Hyoung Doo Shin,
Kyong Soo Park,
Atsunori Kashiwagi,
Yasuhiko Iwamoto,
Kohei Kaku,
Ryuzo Kawamori,
Hans-Henrik Parving,
Donald W Bowden,
Oluf Pedersen,
Yusuke Nakamura
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ABSTRACT: 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 = 5.35 x 10(-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 = 6 x 10(-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.
PLoS Genetics 01/2010; 6(2):e1000842. · 8.69 Impact Factor
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ABSTRACT: We report a case of type 1 diabetes mellitus who was successfully treated with simultaneous pancreas and kidney (SPK) transplantation and both grafts survived for 16 yr. A 30-yr-old woman underwent SPK transplantation from a non-heart-beating donor in January 1992. She was treated with combined immunosuppressive therapy consisting of cyclosporine, azathioprine, methylprednisolone, and anti-lymphocyte globulin. Allograft kidney biopsy was performed 10 yr after transplantation to determine the cause of proteinuria, which revealed no recurrence of diabetic nephropathy, suggesting that long-term normalization of glycemic control achieved by successful pancreas transplantation can prevent recurrence of diabetic nephropathy in the kidney allograft.
Clinical Transplantation 09/2009; 23 Suppl 20:54-7. · 1.67 Impact Factor
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ABSTRACT: OBJECTIVE To assess the relationship between albuminuria, including elevation within the normal range, and decline in glomerular filtration rate (GFR) in diabetic patients. RESEARCH DESIGN AND METHODS A total of 5,449 Japanese diabetic patients were categorized according to sex and urinary albumin-to-creatinine ratio (ACR; <5, 5-9, 10-29, 30-99, 100-299, 300-999, 1,000-2,999, and > or =3,000 mg/g) and followed for at least 5 years. The rate of change in estimated GFR (eGFR) adjusted for age and baseline eGFR was compared among ACR categories. RESULTS A higher baseline ACR predicted a faster decline in eGFR for both sexes. Even within the normal range (<30 mg/g), ACR > or =10 mg/g in women and > or =5 mg/g in men was associated with a significantly greater rate of decline in eGFR relative to subjects with ACR <5 mg/g. CONCLUSIONS Elevated ACR, even within the normal range, is associated with a faster decline in eGFR in diabetic patients.
Diabetes care 05/2009; 32(8):1518-20. · 8.09 Impact Factor
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Diabetes care 04/2009; 32(3):e31. · 8.09 Impact Factor
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ABSTRACT: Diabetic patients with chronic kidney disease (CKD) frequently develop cardiac events within several years of the initiation of haemodialysis. The present study assesses the prognostic significance of stress myocardial ECG-gated perfusion imaging (MPI) in patients with diabetic CKD requiring haemodialysis.
Fifty-five asymptomatic patients with diabetic stage V CKD and no history of heart disease scheduled to start haemodialysis were enrolled in this study (56 +/- 11 years old; 49 with type 2 diabetes mellitus). All patients underwent (201)Tl stress ECG-gated MPI 1 month before or after the initiation of haemodialysis to assess myocardial involvement. We evaluated SPECT images using 17-segment defect scores graded on a 5-point scale, summed stress score (SSS) and summed difference scores (SDS). The patients were followed up for at least 2 years (42 +/- 15 months) to determine coronary intervention (CI) and heart failure (HF) as soft events and acute myocardial infarction (AMI) and all causes of deaths as hard events.
The frequencies of myocardial ischaemia, resting perfusion defects, low ejection fraction and left ventricular (LV) dilatation were 24, 20, 29 and 49%, respectively. Ten events (18%) developed during the follow-up period including four CI, one HF, one AMI and four sudden deaths. Multivariate Cox analysis selected SDS (p = 0.0011) and haemoglobin A(1c) (HbA(1c)) (p = 0.0076) as independent prognostic indicators for all events.
Myocardial ischaemia, in addition to glycaemic control, is a strong prognostic marker for asymptomatic patients with diabetic CKD who are scheduled to start haemodialysis. Stress MPI is highly recommended for the management and therapeutic stratification of such patients.
European Journal of Nuclear Medicine 04/2009; 36(8):1315-21. · 4.53 Impact Factor
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ABSTRACT: Although chronic kidney disease is a risk factor for cardiovascular disease it is unclear whether diabetic patients with a reduced glomerular filtration rate (GFR), independent of (micro)albuminuria, carry an increased risk of stroke. We therefore investigated the independent effect of estimated GFR (eGFR) on stroke events in patients with type 2 diabetes mellitus (T2DM). We studied T2DM patients with an eGFR >or=15 ml min(-1) per 1.73 m(2), who had no history of stroke. Patients were divided into four categories by the eGFR at baseline for comparison: >or=90, 60-89, 30-59 and 15-29 ml min(-1) per 1.73 m(2). The end point was an incident stroke event. The Cox proportional hazard model was used to calculate the hazard ratio (HR) and 95% confidence interval (CI). The study included a total of 1300 T2DM patients (546 women and 754 men) with a mean (+/-s.d.) age of 63+/-13 years. During a mean follow-up period of 3.7+/-1.4 years, 91 patients experienced an incident stroke event. Although a lower eGFR was associated with an increased stroke risk using a univariate model, statistical significance disappeared after adjusting for other risk factors including albuminuria. The HR (95% CI) was 0.75 (0.40-1.41, P=0.373), 0.99 (0.50-1.95, P=0.964) and 0.91 (0.36-2.28, P=0.844) for patients with eGFRs of 60-89, 30-59 and 15-29 ml min(-1) per 1.73 m(2), respectively, compared with patients with an eGFR >or=90. Clinical albuminuria remained a significant risk factor for stroke, and the adjusted HR compared with normoalbuminuria was 2.40 (1.46-3.95, P=0.001). In conclusion, the association between reduced GFR and stroke events in patients with T2DM is likely to be mediated by albuminuria.
Hypertension Research 04/2009; 32(5):381-6. · 2.58 Impact Factor
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ABSTRACT: Nitric oxide (NO) is thought to play an important role in the pathogenesis of diabetic nephropathy. We conducted a prospective, observational cohort study to explore the relationship between plasma levels of asymmetric dimethylarginine (ADMA), an endogenous inhibitor of NO synthase, and the development and progression of nephropathy in patients with type 2 diabetes.
This was a hospital-based observational cohort study in Japanese type 2 diabetic patients with normoalbuminuria [urinary albumin-to-creatinine ratio (ACR) <30 mg/g creatinine] or microalbuminuria (30 < or = ACR <300 mg/g creatinine). The primary endpoint was the development or progression of diabetic nephropathy, based on transition from any given stage to a more advanced stage of albuminuria.
We studied 225 diabetic patients, 81 women and 144 men, with a mean (+/-SD) age of 64 +/- 10 years. The majority (183) of patients were normoalbuminuric, with the remainder microalbuminuric (42). During the median follow-up period of 5.2 years, 27 normoalbuminuric and 10 microalbuminuric patients reached the primary endpoint. When patients were separated according to the median ADMA level (0.46 mumol/l), patients with higher ADMA levels had a greater incidence of reaching the endpoint (P = 0.014 by the log-rank test). In the multivariate Cox proportional hazard model, the hazard ratio for reaching the endpoint for patients with higher versus lower ADMA levels was 2.72 (95% confidence interval 1.25-5.95; P = 0.012).
Higher plasma levels of ADMA may be a novel and potent predictor of the progression of nephropathy in adult Japanese type 2 diabetic patients.
Nephrology Dialysis Transplantation 02/2009; 24(6):1884-8. · 3.40 Impact Factor
