Albuminuria and reduced glomerular filtration rate for predicting the renal outcomes in type 2 diabetic patients.

AIM: The first clinical manifestation of diabetic kidney disease is usually the development of microalbuminuria. However, recent studies have focused on diabetic patients with reduced glomerular filtration rate (GFR) without albuminuria. To evaluate the association of albuminuria and GFR with renal outcomes, we performed an observational study. METHODS: A total of 3231 type 2 diabetic patients were included in this study between 2003 and 2005. There were 1249 women and the mean age was 59 ± 12 years. The renal endpoints were defined as the initiation of renal replacement therapy (RRT) or 50% reduction from the baseline of estimated GFR (eGFR). RESULTS: At baseline, 669 (20.7%) patients had eGFR <60 mL/min per 1.73 m(2) and 1134 (35.1%) had albuminuria. During the mean follow-up period of 5.9 ± 1.6 years, 107 patients initiated RRT. A 50% reduction of eGFR from the baseline value was found in 279 patients. None of the normoalbuminuric subjects with or without reduced eGFR required RRT during the observational period (P < 0.01). Compared to normoalbuminuria patients with eGFR ≥60 mL/min per 1.73 m(2) at baseline, the group of normoalbuminuria patients with reduced eGFR had a 2.5-fold risk of developing the renal endpoints, (95% confidence interval (CI): 1.0-6.3, P = 0.053). Patients with microalbuminuria with eGFR ≥60 mL/min per 1.73 m(2) at baseline had a 5.0-fold risk of developing the evaluated renal endpoints (95% CI: 2.8-8.8, P < 0.001). CONCLUSION: Albuminuria was a significant predictor for the evaluated renal endpoints, but the impact of eGFR is likely to be less than that of albuminuria.

Obesity as an effect modifier of the association between leptin and diabetic kidney disease.

AIMS/INTRODUCTION: Obesity has been shown to be a modifier of the association between leptin levels and cardiovascular events. We examined whether obesity modifies the association between serum leptin levels and the progression of diabetic kidney disease. MATERIALS AND METHODS: This was an observational longitudinal study on patients with type 2 diabetes. We enrolled 410 and 348 patients in the eGFR and ACR cohorts, respectively. Patients were classified into three groups by sex-specific tertile of leptin levels. Obesity was defined as body mass index ≥25 kg/m(2). Outcomes were the rate of change in estimated glomerular filtration rate (eGFR) and progression to a more advanced stage of albuminuria. RESULTS: In the eGFR cohort, the mean eGFR change during the median follow-up period of 4.7 years was -1.4 mL/min/1.73 m(2)/year. An interaction between leptin levels (low, medium or high) and obesity (present or absent) on the change in eGFR was detected (P interaction = 0.003). In the lean group, adjusted eGFR decline in patients with low leptin was steeper than that in patients with medium leptin (2.1 and 0.8 mL/min/1.73 m(2)/year, P = 0.023). In the obese group, patients with high leptin had a steeper adjusted eGFR decline than those with medium leptin (1.7 and 0.6 mL/min/1.73 m(2)/year, P = 0.044). In the ACR cohort, 29 patients showed progression of albuminuria during the median follow-up period of 3.9 years. There was no interaction between leptin levels and obesity on the outcome (P interaction = 0.094). CONCLUSIONS: Obesity might modify the effects of leptin on kidney function decline in patients with type 2 diabetes.

Association of serum bilirubin levels with development and progression of albuminuria, and decline in estimated glomerular filtration rate in patients with type 2 diabetes mellitus.

AIMS/INTRODUCTION: Recent observational studies suggest elevated levels of bilirubin, an endogenous anti-oxidant, might protect against kidney disease. We carried out an observational cohort study to assess whether higher baseline levels of bilirubin, within normal range, could predict the rate of development and progression of diabetic nephropathy in patients with type 2 diabetes. MATERIALS AND METHODS: Japanese type 2 diabetic patients with normo- or microalbuminuria and normal serum bilirubin (<1.2 mg/dL) were recruited from a single center, and categorized according to baseline serum bilirubin levels. Two independent end-points were specified: development or progression of diabetic nephropathy, based on transition to a more advanced stage of albuminuria (albuminuria cohort), and the rate of change in estimated glomerular filtration rate (eGFR cohort). RESULTS: Albuminuria and eGFR cohorts were constructed consisting of 1,915 patients and 1,898 patients, respectively, with 1,738 patients overlapping. Mean follow up was 4.4 and 5.4 years for the two cohorts, respectively. Within the albuminuria cohort, 132 (9%) of 1,418 patients with normoalbuminuria developed microalbuminuria, and 56 (11%) of 497 patients with microalbuminuria developed macroalbuminuria. Higher baseline bilirubin levels were associated with significantly lower risk of progression from microalbuminuria to macroalbuminuria in both the univariate and multivariate analyses. In normoalbuminuric patients, an inverse association was found when restricted to a subgroup with elevated hemoglobin A1c levels. There was no relationship between bilirubin levels and the rate of change in eGFR. CONCLUSIONS: Higher serum bilirubin levels, within normal range, might be predictive of a lower risk of progression of nephropathy in type 2 diabetic patients.

Non-linear association between ankle-brachial pressure index and prevalence of silent cerebral infarction in Japanese patients with type 2 diabetes.

OBJECTIVE: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: Both high and low ABI may be strongly associated with prevalent SCI in Japanese patients with type 2 diabetes.

Gender differences in the association between HDL cholesterol and the progression of diabetic kidney disease in type 2 diabetic patients.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: Lower HDL cholesterol levels seem to be associated with the progression of DKD in men but not in women.

Fluctuations in HbA1c are associated with a higher incidence of cardiovascular disease in Japanese patients with type 2 diabetes.

UNLABELLED: Aims/Introduction: To reveal whether visit-to-visit variability in HbA1c is associated with higher risk of cardiovascular disease (CVD) in patients with type 2 diabetes. MATERIALS AND METHODS: The study was conducted on 689 Japanese patients with type 2 diabetes [295 women, 394 men; mean (±standard deviations (SD)) age 65 ± 11 years]. Variability in HbA1c was evaluated as the intrapersonal SD of serial measurements of HbA1c during the follow-up period for at least 12 months. Patients were divided into quartiles according to the SD of HbA1c, and the primary endpoint was defined as incident CVD. Cox's proportional hazards model was used to calculate hazard ratios (HR) and 95% confidence intervals (CI). RESULTS: During a median follow-up period of 3.3 years (range 1.0-6.3 years), 26 ± 14 measurements of HbA1c were obtained per patient and 61 episodes of incident CVD were recorded. The 5-year cumulative incidence of CVD in patients across the first, second, third, and fourth quartiles of SD in HbA1c was 4.9, 8.7, 17.1, and 26.2%, respectively (P < 0.001, log-rank test). Multivariate Cox regression analysis revealed that the incidence of CVD was significantly higher in patients in the fourth quartile of SD in HbA1c compared with those in the first quartile (HR 3.38; 95% CI 1.07-10.63; P = 0.039), independent of mean HbA1c and other traditional cardiovascular risk factors. CONCLUSIONS: Variability of HbA1c may be a potent predictor of incident CVD in Japanese patients with type 2 diabetes. (J Diabetes Invest, doi: 10.1111/j.2040-1124.2011.00155.x, 2011).

Arterial stiffness is associated with incident albuminuria and decreased glomerular filtration rate in type 2 diabetic patients.

OBJECTIVE: 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. RESEARCH DESIGN AND METHODS: 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. RESULTS: 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). CONCLUSIONS: Aortic stiffness is associated with incident albuminuria and the rate of decline in glomerular filtration rate in type 2 diabetic patients.

Association of serum leptin levels with progression of diabetic kidney disease in patients with type 2 diabetes.

OBJECTIVE: To clarify the association of serum leptin levels with progression of diabetic kidney disease in patients with type 2 diabetes (T2D). RESEARCH DESIGN AND METHODS: 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. RESULTS: 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]). CONCLUSIONS: 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.

Association of albuminuria and reduced estimated glomerular filtration rate with incident stroke and coronary artery disease in patients with type 2 diabetes.

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.

Silent cerebral infarction is associated with the development and progression of nephropathy in patients with type 2 diabetes.

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.

Involvement of visceral fat in the pathogenesis of albuminuria in patients with type 2 diabetes with early stage of nephropathy.

BACKGROUND: 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). METHODS: 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. RESULTS: 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. CONCLUSION: This cross-sectional study suggests that increased visceral but not subcutaneous fat is independently associated with microalbuminuria in Japanese adult patients with T2DM.

Higher levels of urinary albumin excretion within the normal range predict faster decline in glomerular filtration rate in diabetic patients.

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.

Is a reduced estimated glomerular filtration rate a risk factor for stroke in patients with type 2 diabetes?

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.

Asymmetric dimethylarginine is closely associated with the development and progression of nephropathy in patients with type 2 diabetes.

BACKGROUND: 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. METHODS: 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. RESULTS: 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). CONCLUSIONS: Higher plasma levels of ADMA may be a novel and potent predictor of the progression of nephropathy in adult Japanese type 2 diabetic patients.