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.Patients with increased aortic stiffness and patients with chronic kidney disease (CKD) share many risk factors (1) and are at increased risk of incident cardiovascular disease (CVD) and cardiovascular mortality (2). A recent large cross-sectional population-based study revealed a significant association of CKD components, albuminuria and reduced glomerular filtration rate (GFR) with arterial stiffness (3). However, the association between arterial stiffness and decline in renal function is controversial in longitudinal studies. Aortic pulse wave velocity (PWV), the gold standard for measuring aortic stiffness, was reported to be independently associated with a decline in renal function in patients with CKD from the Arterial Compliance and Oxidant Stress as Predictors of Loss of Renal Function, Morbidity and Mortality in Chronic Kidney Disease study (ACADEMIC) (4) but not in those from the Framingham Heart Study (5).In type 2 diabetic patients, age and duration of diabetes were previously reported to be associated with aortic PWV (6). With regard to CKD components, albuminuria was recently reported to be associated with aortic PWV (7). However, a longitudinal analysis to reveal whether increased arterial stiffness predicts the progression of albuminuria and/or a rapid decline in renal function has never been determined in diabetic patients. We, therefore, conducted this observational cohort study to highlight the relationship between carotid-femoral PWV (cf-PWV) and change of albuminuria and GFR in type 2 diabetic patients.     

PC-1基因K121 Q变异与2型糖尿病的关系

目的探讨浆细胞膜糖蛋白(PC-1)基因4号外显子K121Q多态性与2型糖尿病及临床特征的相关性.方法用聚合酶链反应-限制性内切酶片段长度多态性分析(PCR-RFLP)、DNA测序等技术检测上海地区汉族人群中165例2型糖尿病患者和98名正常糖耐量对照者PC-1基因K121Q的多态性分布情况,同时采用PCR-单链构像多态性分析(PCR-SSCP)筛查该区域其他可能与2型糖尿病发生有关的多态性位点.结果糖尿病患者中KK基因型143例(86.67%),KQ基因型22例(13.33%),QQ基因型0例(0.00%),K、Q等位基因频率分别为93.33%和6.67%;正常对照组中KK基因型85例(86.73%),KQ基因型12例(12.25%),QQ基因型1例(1.02%),K、Q等位基因频率分别为92.86%和7.14%,2组人群的基因型和等位基因频率差异无显著性(P＞0.05);2型糖尿病患者中Q等位基因携带者的胰岛素抵抗指数(IR)、血糖、胰岛素、血脂等均略高于KK基因型的患者,但两者之间的差异均无显著性;中国上海地区汉族人群Q等位基因频率明显低于欧洲白种人.结论目前尚不能确定PC-1基因K121Q多态性与上海地区汉族人群胰岛素抵抗及2型糖尿病发病相关;PC-1基因的K121Q多态性具有明显的种族差异.     

PC-1基因K121Q变异与2型糖尿病的关系

目的探讨浆细胞膜糖蛋白(PC1)基因4号外显子K121Q多态性与2型糖尿病及临床特征的相关性。方法用聚合酶链反应限制性内切酶片段长度多态性分析(PCR RFLP)、DNA测序等技术检测上海地区汉族人群中165例2型糖尿病患者和98名正常糖耐量对照者PC1基因K121Q的多态性分布情况,同时采用PCR单链构像多态性分析(PCR SSCP)筛查该区域其他可能与2型糖尿病发生有关的多态性位点。结果糖尿病患者中KK基因型143例(86.67%),KQ基因型22例(13.33%),QQ基因型0例(0.00%),K、Q等位基因频率分别为93.33%和6.67%;正常对照组中KK基因型85例(86.73%),KQ基因型12例(12.25%),QQ基因型1例(1.02%),K、Q等位基因频率分别为92.86%和7.14%,2组人群的基因型和等位基因频率差异无显著性(P>0.05);2型糖尿病患者中Q等位基因携带者的胰岛素抵抗指数(IR)、血糖、胰岛素、血脂等均略高于KK基因型的患者,但两者之间的差异均无显著性;中国上海地区汉族人群Q等位基因频率明显低于欧洲白种人。结论目前尚不能确定PC1基因K121Q多态性与上海地区汉族人群胰岛素抵抗及2型糖尿病发病相关;PC1基因的K121Q多态性具有明显的种族差异。     

Urinary albumin excretion rate is associated with increased ambulatory blood pressure in normoalbuminuric type 2 diabetic patients

OBJECTIVE: To evaluate the 24-h blood pressure profile in normoalbuminuric type 2 diabetic patients. RESEARCH DESIGN AND METHODS: A cross-sectional study was conducted in 90 type 2 diabetic patients with a urinary albumin excretion rate (UAER) <20 microg/min on two occasions, 6 months apart (immunoturbidimetry). Patients underwent clinical and laboratory evaluations. Ambulatory blood pressure monitoring and echocardiograms were also performed. RESULTS: UAER was found to correlate positively with systolic doctor's office blood pressure measurements (r = 0.243, P = 0.021) and ambulatory blood pressure (24 h: r = 0.280, P = 0.008) and left ventricular posterior wall thickness (r = 0.359, P = 0.010). Patients were divided into four groups according to UAER (<5, > or =5-10, > or =10-15, and > or =15-20 microg/min). Systolic blood pressure parameters for the 1st, 2nd, 3rd, and 4th groups, respectively, were 123.0 +/- 10.6, 132.5 +/- 15.0, 139.0 +/- 23.4, and 130.7 +/- 8.0 mmHg for 24-h blood pressure (ANOVA P = 0.004) and 48.4 +/- 6.0, 54.5 +/- 11.2, 58.8 +/- 15.6, and 57.6 +/- 8.0 mmHg for 24-h pulse pressure (ANOVA P = 0.003). A progressive increase in the prevalence of diabetic retinopathy was observed from the 1st to the 4th UAER group: 27.3, 43.8, 45.5, and 66.7% (P = 0.029 for trend). CONCLUSIONS: In type 2 diabetic patients, UAER in the normoalbuminuric range is positively associated with systolic ambulatory blood pressure indexes, left ventricular posterior wall thickness, and diabetic retinopathy, suggesting that intensive blood pressure treatment may prevent diabetes complications in these patients.     

Cigarette smoking is associated with low glomerular filtration rate in male patients with type 2 diabetes

OBJECTIVE: The relationship between cigarette smoking and renal dysfunction in diabetes has predominantly been documented in patients with type 1 diabetes. The aim of the present study was to explore the relationship between cigarette smoking and glomerular filtration rate (GFR) in a large cross-sectional study carried out in male subjects with type 2 diabetes. The role of metabolic syndrome in modulating this relationship was also investigated. RESEARCH DESIGN AND METHODS: One hundred fifty-eight current smokers and 158 never smokers with type 2 diabetes were consecutively recruited. Low GFR was defined as GFR <60 ml/min per 1.73 m(2). RESULTS: The proportion of patients affected by low GFR was significantly higher in current smokers (20.9 vs. 12.0%, P = 0.03). The adjusted risk (odds ratio [OR]) of low GFR in current smokers was 2.20 (95% CI 1.14-4.26, P = 0.02) and markedly higher in patients from the first tertile of disease duration (4.27 [1.26-14.40], P = 0.02). When metabolic syndrome was added to the statistical model exploring the relationship between smoking and low GFR, the risk of low GFR showed a small change, although it did not become any more significant (1.84 [0.98-3.45], P = 0.06). Current smokers showed even higher free oxygen radical test unit values (560.0 +/- 91.5 vs. 442.7 +/- 87.2, P < 0.0001). CONCLUSIONS: In a large population of male patients with type 2 diabetes, the risk of low GFR is markedly enhanced by smoking and is at least partially mediated by metabolic syndrome.     

Autonomic dysfunction and urinary albumin excretion rate are associated with an abnormal blood pressure pattern in normotensive normoalbuminuric type 1 diabetic patients

OBJECTIVE: To analyze the role of autonomic function and other possible factors associated with a blunted fall in nocturnal blood pressure. RESEARCH DESIGN AND METHODS: A total of 39 normotensive normnoalbuminuric type 1 diabetic patients were studied. Glomerular filtration rate (51Cr-EDTA technique), extracellular volume (51Cr-EDTA distribution volume), and urinary albumin excretion rate (UAER) (by radioimmunoassay) were measured. The subjects' 24-h ambulatory blood pressure and a 24-h electrocardiogram were recorded simultaneously Heart rate variability was calculated in the time domain for 24 h, in the frequency domain at night, at rest in the supine position, and during tilt. Patients were classified according to diastolic blood pressure (dBP) night/day ratio as dipper patients (< or =0.9) and nondipper patients (>0.9). RESULTS: Nondipper patients presented a higher low-frequency (LF) component (a sympathetic index) and higher LF/high-frequency (HF) ratio during sleep than dipper patients (0.29 +/- 0.12 vs. 0.19 +/- 0.10 normalized units [n.u.], P = 0.008; and 0.98 +/- 0.53 vs. 0.55 +/- 0.45 n.u., P = 0.007, respectively). At rest, the LF component in nondipper patients (0.38 +/- 0.13 n.u.) was higher than in dipper patients (0.27 +/- 0.12 n.u., P = 0.04). After the tilt, nondipper patients did not show an increase in the LF component (P = 0.32), but in dipper patients, the increase was significant (P = 0.001). In both groups, tilting promoted a decrease in the HF component (a parasympathetic index). In a stepwise multiple linear regression analysis, the LF component during sleep and the UAER accounted for 24% of the variability in the dBP night/day ratio. CONCLUSIONS: The predominance of sympathetic activity and increased levels of UAER, although within the normal range, are associated with a blunted fall in nocturnal dBP in normoalbuminuric normotensive type 1 diabetic patients.     

PC-1基因K121Q变异与2型糖尿病肾病的关系

目的探讨浆细胞膜糖蛋白(PC-1)基因第4外显子K121Q多态性与2型糖尿病肾病的相关性。方法应用多聚酶链反应(PCR)结合限制性酶切技术检测青岛地区50例2型糖尿病患者和48例正常人PC-1基因K121Q的多态性分布情况。结果正常对照组中KK基因型38例(79.2%),KQ基因型10例(20.8%),QQ基因型0例(0.00%),K、Q等位基因频率分别为89.6%和10.4%。糖尿病患者中KK基因型41例(82%),KQ基因型9例(18%),QQ基因型0例(0.00%),K、Q等位基因频率分别为91%和9%,2组人群的基因型和等位基因频率无显著性差异(P>0.05)。结论PC-1基因多态性与2型糖尿病及2型糖尿病肾病无明显相关性,QQ基因型不是2型糖尿病及2型糖尿病肾病发病的危险因子。     

Glycated albumin is independently associated with estimated glomerular filtration rate in nondiabetic patients with chronic kidney disease

BackgroundGlycated albumin (GA) may contribute to diabetic nephropathy, but the clinical significance of GA in patients with chronic kidney disease (CKD) is unknown.MethodsPatients were classified with the NKF/DOQI classification system as mild (stage I, II), moderate (stage III), or advanced CKD (stage IV). Those undergoing dialysis or with CKD stage V were excluded. GA was measured using the Lucica TM GA-L assay kit. The relationship between GA and renal dysfunction was analyzed in patients with or without diabetes.ResultsA total of 187 subjects were enrolled. GA values in those with normal, mild, moderate and advanced CKD were 18.4 ± 1.4%, 18.4 ± 3.1%, 19.0 ± 3.8%, 20.4 ± 6.4%, respectively, in diabetic patients (N = 67, p = 0.5), and were 14.1 ± 1.9%, 14.2 ± 2.2%, 15.9 ± 1.9%, 15.0 ± 1.7%, respectively, in nondiabetic patients (N = 120, p = 0.004). GA value was negatively correlated to eGFR in nondiabetic patients (r = ?0.35, p < 0.001) but not in diabetic patients (r = ?0.11, p = 0.39). In the adjusted model, GA is independently correlated to eGFR only in nondiabetic subjects.ConclusionsIncreased GA concentrations are independently associated with renal dysfunction in nondiabetic patients with CKD.     

Angiotensin converting enzyme gene polymorphism and glomerular filtration rate changes in type 2 diabetic patients

It has been suggested that an insertion/deletion (I/D) polymorphism in intron 16 of the angiotensin-converting enzyme (ACE) gene may be associated with diabetic nephropathy The aim of this study was to investigate whether an association exists between ACE I/D polymorphism and glomerular filtration rate (GFR) in type 2 diabetes mellitus. A total of 128 type 2 diabetic patients were included in the study with the following ACE genotype distribution: DD 40, ID 58,11 30. I/D polymorphism was determined by polymerase chain reaction (PCR). Mean GFR was not statistically different according to ACE genotype (DD: 89.9 +/- 28.1 ml/min, ID: 99.5 +/- 25.1 ml/min, II: 96.6 +/- 19.6 ml/min). There was no significant difference in genotype distribution in normo-, micro- and macroalbuminuric patients (DD:ID:II [%], normo- 35:46:19, micro-28:55:17, macro- 31:55:14). ACE I/D polymorphism does not seem to be associated with GFR in type 2 diabetic patients.     

对2型糖尿病患者肾小球滤过功能的评价

目的评价临床上常用的测定肾小球滤过率（GFR）的指标在2型糖尿病患者的适用性。方法2型糖尿病患者60例，以体表面积标准化的双血浆法^99Tc^m-DTPA血浆清除率测定值（rGFR）作为测定GFR的参考指标，比较血肌酐（Scr）、肌酐清除率（Ccr）、^99Tc^m-DTPA肾动态显像法（gGFR）、基于Scr的GFR评估方程7（MDRD 7）以及血清半胱氨酸蛋白酶抑制剂C（cystatin C，Cys C）等多种方法与rGFR的相关性，测定上述方法在反映2型糖尿病患者肾功能减退的特异性和敏感性，用受试者工作特征曲线（ROC）评价上述指标检测肾小球滤过功能的准确性。结果2型糖尿病患者60例，其中男35例，女25例，年龄（62．4±11．7）岁，病史（10．66±9．35）年，Scr、Ccr、gGFR、MDRD 7及Cys C测定结果均与gGFR呈显著相关（r分别为-0．500、0．675、0．367、0．428及-0．588，P均〈0．001），其中Ccr与rGFR值相关性最好，其次为Cys C。Ccr、MDRD方程7及Cys C在判断GFR下降时的敏感度较高（分别为82．1％、85．7％及85．7％），显著高于Scr及gGFR方法（10．7％及46．6％，P〈0．01）；Scr在判断GFR下降时的特异度为100％，显著高于MDRD方程7的特异度（25．0％，P〈0．01）。Cys C和Ccr的受试者工作特征曲线（ROC）下面积显著高于Scr，MDRD方程7和gGFR。Cys C的最佳判定域值为1．18mg／L，该域值的敏感度和特异度分别为80％和57．5％；Ccr的最佳判定域值为62ml／min，该域值的敏感度和特异度分别为90％和67．9％。结论Ccr和Cystatin C能够较理想地反映2型糖尿病患者GFR的变化。     

Biological variability of albumin excretion rate and albumin-to-creatinine ratio in hypertensive type 2 diabetic patients.

The importance of measuring microalbuminuria is well established. However, only scanty data are available concerning the biological variability of albumin excretion in type 2 diabetic subjects. We report our experience from a large clinical trial of a new antihypertensive drug (Lercanidipine) designed to reduce albumin excretion and blood pressure in type 2 diabetic patients with hypertension and microalbuminuria. Eighty seven patients with persistent microalbuminuria were studied within 1 year of the clinical trial. The measurements were performed on blood and timed urine samples frozen at -80 degrees C and shipped to a central laboratory unit. Preliminary experiments were performed to assess albumin stability in urine under various conditions (4 degrees C, -20 degrees C and -80 degrees C), particularly with regard to the albumin/creatinine ratio. Urine samples can be stored up to 3 weeks at 4 degrees C or up to 2 months at -80 degrees C. The biological variability of the albumin excretion rate was 25.7%, while that of the albumin/creatinine ratio was 13.4%. These data are useful in defining the analytical goals of imprecision for microalbuminuria (CV = 13% for albumin, and CV = 6% for albumin/creatinine ratio). No correlation between albumin/creatinine ratio and HbA1c was found in the cohort of 61 microalbuminuric patients who completed the trial. The results of this study confirm that the albumin/ creatinine ratio is much more suitable for monitoring albumin excretion in longitudinal studies than the albumin excretion rate.     

Autoregulation of glomerular filtration rate in patients with type 2 diabetes during isradipine therapy

OBJECTIVE: Calcium-channel blockade impairs renal autoregulation in animals. Impaired renal autoregulation leads to transmission of the systemic blood pressure (BP) into the glomerulus, resulting in capillary hypertension. Information on the impact of calcium antagonist treatment on renal autoregulation in humans is lacking. This study examines the effect of isradipine treatment on the autoregulation of the glomerular filtration rate (GFR). RESEARCH DESIGN AND METHODS: We performed a randomized double-blind crossover study with 5 mg o.d. isradipine retard and matching placebo in 16 hypertensive patients with type 2 diabetes. Each treatment arm lasted 4 weeks. On the last day of each treatment period, GFR (single-shot 51Cr-EDTA plasma clearance technique for 4 h) was measured twice between 8:00 A.M. and 5:00 P.M., first without clonidine and then after intravenous injection of 75 micro g clonidine. BP was measured every 10 min (Takeda TM2420; A&D, Tokyo). RESULTS: Clonidine reduced mean arterial BP (MABP) by 15 +/- 1 vs. 11 +/- 1 mmHg (means +/- SE) during placebo and isradipine treatment, respectively (P < 0.05). GFR was reduced from 102 +/- 4 to 99 +/- 4 ml. min(-1). 1.73 m(-2) with placebo (P < 0.01) and from 106 +/- 5 to 98 +/- 5 ml. min(-1). 1.73 m(-2) during treatment with isradipine (P < 0.01). Mean difference (95% CI) between changes in GFR with placebo and isradipine was -4.6 ml. min(-1). 1.73 m(-2) (-10.0 to 0.6) (P = 0.08). Six patients had a reduction in GFR >13% (exceeding the normal limit of autoregulation) combined with a complete pressure-passive vasculature (defined as DeltaMABP% < or = DeltaGFR%) during isradipine treatment versus none during the placebo treatment (P < 0.05). CONCLUSIONS: Isradipine impairs GFR autoregulation in a sizeable proportion of hypertensive type 2 diabetic patients.     

Vitamin D levels and asymptomatic coronary artery disease in type 2 diabetic patients with elevated urinary albumin excretion rate

OBJECTIVE

Coronary artery disease (CAD) is the major cause of morbidity and mortality in type 2 diabetic patients. Severe vitamin D deficiency has been shown to predict cardiovascular mortality in type 2 diabetic patients.

RESEARCH DESIGN AND METHODS

We investigated the association among severe vitamin D deficiency, coronary calcium score (CCS), and asymptomatic CAD in type 2 diabetic patients with elevated urinary albumin excretion rate (UAER) >30 mg/24 h. This was a cross-sectional study including 200 type 2 diabetic patients without a history of CAD. Severe vitamin D deficiency was defined as plasma 25-hydroxyvitamin D (p-25[OH]D3) <12.5 nmol/L. Patients with plasma N-terminal pro-brain natriuretic peptide >45.2 ng/L or CCS ≥400 were stratified as being high risk for CAD (n= 133). High-risk patients were examined by myocardial perfusion imaging (MPI; n = 109), computed tomography angiography (n = 20), or coronary angiography (CAG; n = 86). Patients’ p-25(OH)D3 levels were determined by high-performance liquid chromatography/tandem mass spectrometry.

RESULTS

The median (range) vitamin D level was 36.9 (3.8–118.6) nmol/L. The prevalence of severe vitamin D deficiency was 9.5% (19/200). MPI or CAG demonstrated significant CAD in 70 patients (35%). The prevalence of CCS ≥400 was 34% (68/200). Severe vitamin D deficiency was associated with CCS ≥400 (odds ratio [OR] 4.3, 95% CI [1.5–12.1], P = 0.005). This association persisted after adjusting for risk factors (4.6, 1.5–13.9, P = 0.007). Furthermore, severe vitamin D deficiency was associated with asymptomatic CAD (adjusted OR 2.9, 1.02–7.66, P = 0.047).

CONCLUSIONS

In high-risk type 2 diabetic patients with elevated UAER, low levels of vitamin D are associated with asymptomatic CAD.Coronary artery disease (CAD) is the major cause of morbidity and mortality in patients with type 2 diabetes. Diabetic patients have been shown to have an increased prevalence of subclinical CAD (1). Coronary calcium score (CCS), a noninvasive screening method quantifying the extent of coronary artery calcification (CAC), is generally accepted as a marker of increased cardiovascular risk. CCS has been shown to correlate strongly with histopathologic CAD (2,3) and the development of adverse coronary events (4,5).Results from cross-sectional studies examining the relation between low vitamin D levels and presence of CAD in the general population are conflicting (6,7). In type 1 diabetic patients, vitamin D deficiency has been shown to independently predict both prevalence and development of CAC (8). However, a study in type 2 diabetic patients with a history of cardiovascular disease (CVD) found a strong inverse association between low vitamin D levels and prevalent coronary, cerebrovascular, or peripheral CVD (9). Furthermore, low vitamin D levels have been associated with increased cardiovascular morbidity and mortality in the general population (10) and in patients with type 1 (8) and 2 (11) diabetes.To expand our knowledge on the increased all-cause and cardiovascular mortality seen in type 2 diabetic patients with low vitamin D levels, the current study investigated the association between severe vitamin D (plasma 25-hydroxyvitamin D [p-25(OH)D3]) deficiency and the presence of elevated CAC and asymptomatic CAD in type 2 diabetic patients with elevated urinary albumin excretion rate (UAER) >30 mg/24 h.