Normoalbuminuric Group Research Articles

Association between Mannose‐Binding Lectin and Vascular Complications in Type 1 Diabetes

Complement activation and inflammation have been suggested in the pathogenesis of diabetic vascular lesions. We investigated serum mannose‐binding lectin (MBL) levels and polymorphisms in the MBL gene in type 1 diabetic (T1DM) patients with and without diabetic nephropathy and associated macrovascular complications. Polymorphisms in the MBL gene and serum MBL levels were determined in 199 T1DM patients with overt nephropathy and 192 T1DM patients with persistent normoalbuminuria matched for age, sex and duration of diabetes as well as in 100 healthy control subjects. The frequencies of high and low expression MBL genotypes were similar in patients with T1DM and healthy controls. High MBL genotypes were significantly more frequent in diabetic patients with nephropathy than in the normoalbuminuric group, and the risk of having nephropathy, given a high MBL genotype, assessed by odds ratio was 1.52 (1.02–2.27), P = 0.04. Median serum MBL concentrations were significantly higher in patients with nephropathy than in patients with normoalbuminuria [2306 µg/l (IQR 753–4867 µg/l) versus 1491 µg/l (IQR 577–2944), P = 0.0003], and even when comparing patients with identical genotypes, serum MBL levels were higher in the nephropathy group than in the normoalbuminuric group. Patients with a history of cardiovascular disease had significantly elevated MBL levels independently of nephropathy status [3178 µg/l (IQR 636–5231 µg/l) versus 1741 µg/l (IQR 656–3149 µg/l), P = 0.02]. The differences in MBL levels between patients with and without vascular complications were driven primarily by pronounced differences among carriers of high MBL genotypes (P < 0.0001). Our findings suggest that MBL may be involved in the pathogenesis of microvascular and macrovascular complications in type 1 diabetes and that determination of MBL status might be used to identify patients at increased risk of developing these complications.

Association Between Mannose-Binding Lectin and Vascular Complications in Type 1 Diabetes

Complement activation and inflammation have been suggested in the pathogenesis of diabetic vascular lesions. We investigated serum mannose-binding lectin (MBL) levels and polymorphisms in the MBL gene in type 1 diabetic patients with and without diabetic nephropathy and associated macrovascular complications. Polymorphisms in the MBL gene and serum MBL levels were determined in 199 type 1 diabetic patients with overt nephropathy and 192 type 1 diabetic patients with persistent normoalbuminuria matched for age, sex, and duration of diabetes, as well as in 100 healthy control subjects. The frequencies of high- and low-expression MBL genotypes were similar in patients with type 1 diabetic and healthy control subjects. High MBL genotypes were significantly more frequent in diabetic patients with nephropathy than in the normoalbuminuric group, and the risk of having nephropathy given a high MBL genotype assessed by odds ratio (OR) was 1.52 (1.02-2.27, P = 0.04). Median serum MBL concentrations were significantly higher in patients with nephropathy than in patients with normoalbuminuria: 2,306 microg/l (interquartile range [IQR] 753-4,867 microg/l) vs. 1,491 microg/l (577-2,944 microg/l), P = 0.0003. In addition, even when comparing patients with identical genotypes, serum MBL levels were higher in the nephropathy group than in the normoalbuminuric group. Patients with a history of cardiovascular disease had significantly elevated MBL levels independent of nephropathy status (3,178 microg/l [IQR 636-5,231 microg/l] vs. 1,741 microg/l [656-3,149 microg/l], P = 0.02). The differences in MBL levels between patients with and without vascular complications were driven primarily by pronounced differences among carriers of high MBL genotypes (P < 0.0001). Our findings suggest that MBL may be involved in the pathogenesis of micro- and macrovascular complications in type 1 diabetes, and that determination of MBL status might be used to identify patients at increased risk of developing these complications.

Incidence of overt proteinuria and coronary artery disease in patients with type 2 diabetes mellitus: the role of microalbuminuria and retinopathy

The 5-year incidence of coronary artery disease (CAD) and progression to overt proteinuria was investigated in patients with type 2 diabetes mellitus who had microalbuminuria with (MA+R group, n=93) or without (MA−R group, n=138) diabetic retinopathy. The rate of progression to overt proteinuria was higher in the MA+R group than in the MA−R group. The MA−R group had more components of metabolic syndrome than the MA+R and normoalbuminuric (NA, n=205) groups. The MA−R group had a higher 5-year incidence of CAD than the NA group. The incidence of CAD tended to be higher in the MA−R group than in the MA+R group, but statistical significance was not reached. The present study shows that patients with diabetic retinopathy and microalbuminuria represent a group with incipient diabetic nephropathy having higher risk for progression to overt proteinuria. On the other hand, patients with microalbuminuria and no retinopathy may represent a group with characteristics of metabolic syndrome.

Relationship between transforming growth factor beta1 and progression of hypertensive renal disease.

In this study the role of circulating transforming growth factor beta1 (TGFbeta1) on progression of renal hypertensive disease has been investigated. Fifty consecutive outpatients with essential hypertension were enrolled and divided into three groups, according to their urinary albumin excretion (UAE). Group A comprised 10 hypertensives with UAE <or=20 mg/24 h (normoalbuminuric group); Group B included 21 hypertensives with UAE > 20 < 300 mg/24 h (microalbuminuric group); Group C encompassed 19 hypertensives with UAE >or= 300 mg/24 h (proteinuric group). In all patients UAE by immunonephelometric assay, circulating TGFbeta1 by a solid phase specific sandwich ELISA technique, BUN and creatinine by routine laboratory methods were determined. In addition, left ventricular telediastolic internal diameter, interventricular septum diastolic (IVSTd), posterior wall thickness, total and normalised to height(2.7) left ventricular mass, relative wall thickness and left ventricular ejection fraction by M-B Mode echocardiography were calculated. Our results indicated that TGFbeta1 levels were significantly (P < 0.05) higher in Group B and C than Group A and in Group C than Group B. In addition IVSTd values were significantly (P < 0.05) higher in both Group B and C than Group A. An evident, but not significant, higher prevalence of subjects with left ventricular hypertrophy were observed in Group C as compared with other groups. In all hypertensive subjects TGFbeta1 correlated directly with UAE (P < 0.0001) but not with BMI, LVM/h(2.7) and mean blood pressure. Our data indicated that TGFbeta1 might be considered a useful marker to evaluate the severity and progression of hypertensive renal disease. Additional long-term clinical data are needed to evaluate whether inhibition of TGFbeta1 system may prolong the time to the ESRD in hypertensive patients.

Insulin action and skeletal muscle blood flow in patients with Type 1 diabetes and microalbuminuria

Our objective was to determine whether Type 1 diabetic patients with microalbuminuria are less sensitive to the effects of insulin on glucose metabolism and skeletal muscle blood flow, compared to those with normal albumin excretion, after careful matching for confounding variables. We recruited 10 normotensive Type 1 diabetic patients with microalbuminuria and 11 with normoalbuminuria matched for age, sex, body mass index, duration of diabetes and HbA 1c. Peripheral and hepatic insulin action was assessed using a two-step euglycaemic hyperinsulinaemic clamp (2 h at 0.4 mU kg −1 min −1, 2 h at 2.0 mU kg −1 min −1) combined with isotope dilution methodology. Skeletal muscle blood flow was determined by venous occlusion plethysmography. During the clamps, glucose infusion rates required to maintain euglycaemia were similar in the microalbuminuric subjects and controls (step 1, 8.2±1.4 (SE) vs 9.2±1.3 μmol kg −1 min −1: step 2, 30.9±2.7 vs 32.0±3.8 μmol kg −1 min −1), as was hepatic glucose production basally and at steady state in step 1. In step 2, hepatic glucose production was lower in the microalbuminuric group (2.9±0.9 vs 6.4±0.7 μmol kg −1 min −1, P=0.005). During step 2, skeletal muscle blood flow increased significantly above baseline in the normoalbuminuric group (4.1±0.5 vs 3.2±0.4 ml 100-ml −1 min −1, P=0.01) but not in the microalbuminuric group (2.4±0.3 vs 2.3±0.4 ml 100-ml −1 min −1). In conclusion, microalbuminuria in Type 1 diabetes was found to be associated with impairment of insulin-mediated skeletal muscle blood flow, but not with insulin resistance.

Inducible myocardial ischaemia in asymptomatic Type 2 diabetic patients

Background: to define the prevalence of inducible myocardial ischaemia in asymptomatic Type 2 diabetic patients and its relation to urinary albumin excretion rate (AER). Methods: 98 Type 2 diabetic patients aged 56±7 years, and 20 non-diabetic volunteers were recruited. Dypiridamole plus exercise thallium-201 myocardial single photon emission computed tomography (SPECT) was performed in all participants. Exclusion criteria were: age <30 or >70 years, evidence of cardiovascular disease, anomalous ECG, autonomic neuropathy or serum creatinine level >177 μmol/l. Results: 36 out of 98 diabetic patients (37%) showed abnormal thallium SPECT (considered as inducible myocardial ischaemia), versus one out of 20 (5%) in control group (odds ratio 7.3 (95% CI 1.1–50.5), P<0.005). Among diabetic patients, prevalence of inducible ischaemia was greater in those with higher urinary AER (AER <30:30–300:> 300 mg/24 h: 26: 53: 88%, and greater in the normoalbuminuric group compared to the control group (26 vs. 5%; P<0.05). An AER >30 mg/24 h was the only independent factor associated with inducible myocardial ischaemia in the multivariate analysis ( P=0.009). Conclusions: raised urinary AER in asymptomatic diabetic patients is a risk factor for present myocardial ischaemia demonstrated by thallium dypiridamole tomography. The prevalence of inducible myocardial ischaemia in asymptomatic diabetic patients without known coronary disease is much higher than in non-diabetic population.

Diurnal blood pressure variations in incipient and end stage diabetic renal disease

Our aim was to compare the diurnal blood pressure patterns of people with Type 1 diabetes on continuous ambulatory peritoneal dialysis (CAPD, n=9) or haemodialysis ( n=10) to diabetic patients with normo-albuminuria ( n=12) or micro-albuminuria ( n=15). Blood pressure was measured with an ABPM02 Meditech oscillometric blood pressure monitor. The micro-albuminuric group had significantly higher nocturnal diastolic and mean arterial pressures than the normo-albuminuric group. CAPD and haemodialysis patients had significantly higher day time, nocturnal mean systolic, diastolic and mean arterial blood pressures. Micro-albuminuric and end-stage renal failure patients displayed a loss of the physiological drop of systolic blood pressure, which was only significant in the normo-albuminuric group. Nocturnal drop of blood pressure characterised by diurnal indices were 7.4% in the CAPD, 8.8% in the haemodialysis, 10.0% in the micro-albuminuric and 16.5% in the normo-albuminuric group. These results suggest, that pathological circadian blood pressure variation is common in diabetic patients on dialysis, and ambulatory blood pressure monitoring can be a useful tool both in its the detection and its adequate treatment.

Urinary albumin excretion and transcapillary escape rate of albumin in malignancies.

Transcapillary escape rate of albumin was determined in 22 patients with different malignancies. In addition, urinary albumin excretion rate was measured in 24-h urine samples using a sensitive immunoassay. Increased urinary albumin excretion was defined as >/=20 microg/min according to conventional standards. Renal glomerular filtration and tubular function was estimated by 51Cr-EDTA plasma clearance and urinary beta 2-microglobulin, respectively. Median urinary albumin excretion rate was 15.0 microg/min (range 6-510 microg/min) and the frequency of increased urinary albumin excretion was 41%. This agrees with other studies showing increased albuminuria in several types of malignant diseases. Patients with advanced disease (tumour, node, metastasis (TNM) stage II-IV) had a significantly higher urinary albumin excretion rate than patients with localized disease (TNM stage I). Serum creatinine, glomerular filtration rate and urinary beta 2-microglobulin were all within normal limits. Median transcapillary escape rate of albumin was 5.5 %/h (range 2-8 %/h) and this level is comparable with values in healthy subjects. There was no significant difference in transcapillary escape rate between patients with elevated urinary albumin excretion and the normoalbuminuric group. Median value of the absolut outflux of albumin was 10.6 g/h with similar levels in patients with increased urinary albumin excretion and patients with normoalbuminuria. Our results indicate a high prevalence of minor glomerular dysfunction with a slightly elevated urinary albumin excretion in patients with malignancies. The normal endothelial function, as estimated by the transcapillary escape rate of albumin, suggests an overall unaffected capillary permeability and increased urinary albumin loss appears to be an isolated renal phenomenon in cancer patients.

Elevated vascular endothelial growth factor in type 1 diabetic patients with diabetic nephropathy

Growth factors have been suggested to play a role in the development and progression of diabetic nephropathy. Vascular endothelial growth factor (VEGF) is a potent cytokine family that induces angiogenesis and markedly increases endothelial permeability. The aim of the present study was to investigate plasma levels of VEGF in a large cohort of type 1 diabetic patients with diabetic nephropathy and in long-standing type 1 diabetic patients with persistent normoalbuminuria, and to evaluate VEGF as a predictor of nephropathy progression. We measured VEGF with an enzyme-linked immunosorbent assay (ELISA) technique in 199 type 1 diabetic patients with diabetic nephropathy (122 males, age 41 +/- 10 years, diabetes duration 28 +/- 8 years), glomerular filtration rate (GFR) (median [range]) 75 [10-143] mL/min/1.73 m2, and in 188 long-standing type 1 diabetic patients with persistent normoalbuminuria (115 males, age 43 +/- 10 years, diabetes duration 27 +/- 9 years). One hundred fifty-five of the proteinuric patients were followed for at least 3 years after baseline examination with yearly GFR measurements. Plasma levels of VEGF were significantly increased in patients with nephropathy as compared to the normoalbuminuric group; (median [range]): 45.7 [22.0-410] versus 27.1 [22.0-355] ng/L, respectively, P < 0.001. This difference was ascribed to elevated VEGF levels in nephropathic men: 51.8 [22.0-410] versus 22.0 [22.0-308] ng/L, P < 0. 001. No differences were found between women with and without nephropathy: 37.8 [22.0-325] versus 36.6 [22.0-335] ng/L, NS. In proteinuric patients with GFR above and below the median value, there was no difference in the level of VEGF, NS. Plasma VEGF was below the detection limit (22.0 ng/L) in 60 patients with nephropathy and 93 patients with normoalbuminuria, P < 0.001. The mean rate of GFR decline was 3.5 (SE: 0.4) mL/min/year, and the following baseline variables acted as predictors of progression: albuminuria, mean arterial blood pressure and male gender. Hemoglobin A1c and plasma VEGF did not act as predictors. No significant differences between patients with and without proliferative retinopathy were detected. Our data suggest that VEGF is elevated early in the course of diabetic nephropathy in men with type 1 diabetes mellitus. Baseline albuminuria, arterial blood pressure and male gender was predictors of diabetic nephropathy progression, while plasma VEGF and Hemoglobin A1c did not contribute. The importance of VEGF in the initiation of diabetic nephropathy remains to be established.

Increased Urinary Albumin Excretion Rate in Breast Cancer Patients

A high frequency of slightly increased urinary albumin excretion (UAE) has been reported in patients with malignancies. Earlier studies have indicated a prognostic significance of UAE in some malignant diseases. We measured urinary albumin in 24-h urine samples in 44 patients with newly diagnosed early breast cancer and in 22 patients with relapse of metastatic breast cancer disease. The prevalence of microalbuminuria ( > or = 20 microg/min) was 20.5% in patients with early breast cancer and 54.5% in patients with metastatic disease. Median UAE was significantly higher in patients with metastatic breast cancer compared with the early breast cancer group (20.5 microg/min vs. 9.2 microg/min; p < 0.01). In patients with metastatic breast cancer, univariate survival analysis revealed a significantly lower survival rate in patients with microalbuminuria compared with the normoalbuminuric group (p <0.001). The present study demonstrates a high frequency of microalbuminuria in patients with breast cancer. Increased UAE was most prevalent in patients with metastatic disease. Our results also suggest that UAE may be a prognostic marker in metastatic breast cancer. Further prospective studies with a larger number of patients and controls are needed to test the validity of these observations.

Cardiovascular morbidity and early mortality cluster in parents of type 1 diabetic patients with diabetic nephropathy.

A familial predisposition was proposed to be a determinant of the increased morbidity and mortality from cardiovascular disease in type 1 diabetic patients with diabetic nephropathy. The insertion allele of an insertion/deletion polymorphism in the ACE (ACE/ID) gene seems to protect against coronary heart disease in nondiabetic and diabetic subjects. The aim of the present study was to evaluate these hypotheses in parents of a large group of type 1 diabetic patients with and without diabetic nephropathy. We investigated cardiovascular morbidity and mortality of parents of 163 type 1 diabetic patients with nephropathy and parents of 163 sex- and age-matched normoalbuminuric patients with type 1 diabetes. Kaplan-Meier curves showed that total parental mortality was significantly increased in parents of type 1 diabetic patients with nephropathy (121 of 244 [ approximately 50%] ) as compared with parents of normoalbuminuric type 1 diabetic patients (119 of 269 [approximately 44%]) (P = 0.008 [log-rank test]) partially due to an increase in cardiovascular deaths (48 of 244 [approximately 20%] vs. 42 of 269 [approximately 16%], P<0.05). In addition, more patients with nephropathy, as compared with the normoalbuminuric group, had at least one parent with fatal/nonfatal cardiovascular disease (46% [95% CI 38-54] vs. 36% [28-44], P = 0.05). Fathers of patients homozygous for the I-allele of the ACE/ID polymorphism had significantly less myocardial infarction as compared with other genotypes (P = 0.03), regardless of the nephropathic state of the offspring. Cardiovascular morbidity and early mortality clusters in parents of type 1 diabetic patients with diabetic nephropathy The ACE/ID polymorphism helps explain the increased morbidity from cardiovascular disease.

Elevated Urinary Albumin Excretion is not Linked to the Angiotensin I-converting Enzyme Gene Polymorphism in Clinically Healthy Subjects

An elevated urinary albumin excretion (UAE) in non-diabetic subjects without renal or cardiovascular disease has been shown to be predictive of ischaemic heart disease. An insertion (I)/deletion (D) polymorphism in the angiotensin I-converting enzyme (ACE) gene has been identified and the D allele may be associated with cardiovascular disease. The aim of this study was to find a potential linkage between this polymorphism and elevated UAE. For studies of UAE and cardiovascular pathophysiology, a highly selected population sample has been identified comprising all clinically healthy subjects aged 40-65 years with elevated UAE in a dipstick negative urinary sample (n = 27) from The Copenhagen City Heart Study. Neither the ACE genotype distribution (p = 0.12) nor the D and I allele frequencies (p = 0.69) differed significantly between subjects with elevated UAE and a matched normoalbuminuric control group (n = 46). Elevated UAE in clinically healthy subjects is not linked to the ACE gene polymorphism.

Endothelial dysfunction in Type 2 diabetic subjects with and without microalbuminuria.

The primary aim of this study was to determine whether microalbuminuria is associated with endothelial dysfunction in Type 1 diabetes mellitus. The secondary aim was to determine whether any reported biochemical markers of cardiovascular risk are associated with endothelial dysfunction in this group. Measurements were made of the vasodilatory responses of the brachial artery to post-ischaemic hyperaemia and to sublingual glyceryl trinitrate (GTN) (causing endothelium-dependent and endothelium-independent dilation, respectively) using a high-resolution ultrasound technique in 18 Type 1 diabetic patients with microalbuminuria, 18 age and sex-matched normoalbuminuric Type 1 diabetic patients and 18 non-diabetic control subjects. There was a significant reduction in flow-mediated dilation (FMD) in microalbuminuric and normoalbuminuric diabetic patients compared with control subjects (2.4% (95% confidence interval (CI) 1.0-3.8%) and 2.3% (95% CI 0.7-3.9%) respectively vs. 6.3% (95% CI 5.1-7.5%), P<0.0001) but no difference in GTN-mediated dilation (14.7% (95% CI 10.7-18.7%) and 15.2% (95% CI 11.2-19.2%) vs. 18.7% (95% CI 16.1-21.3%), P = 0.09). There was no significant difference in FMD, however, between the microalbuminuric group and normoalbuminuric group (P=0.45). FMD was not significantly associated with urinary albumin-creatinine ratio, glycosylated haemoglobin, plasma glucose, lipid or lipoprotein concentrations in diabetic patients. There was a positive correlation between active transforming growth factor (TGF)-beta concentration, a novel biochemical marker of macrovascular disease, and FMD in diabetic patients (r=0.36, P<0.05). GTN-mediated dilation was positively associated with HDL-cholesterol concentration (r = 0.49, P = 0.002) but not with other biochemical variables (including active TGF-beta concentration). Active TGF-beta concentration was not associated with degree of microalbuminuria or other biochemical parameters. These data suggest that endothelial dysfunction occurs in Type 1 diabetic patients regardless of urine albumin status. Endothelial dysfunction appears therefore to predate the development of microalbuminuria as a marker for the development of coronary artery disease. It is also concluded that low plasma levels of active TGF-beta are associated with an impaired endothelial response and this may provide a useful tool for identifying Type 1 diabetic patients at a greater risk of coronary artery disease.

Plasma renin and prorenin and renin gene variation in patients with insulin-dependent diabetes mellitus and nephropathy.

The most striking abnormality in the renin angiotensin system in diabetic nephropathy (DN) is increased plasma prorenin. Renin is thought to be low or normal in DN. In spite of altered (pro)renin regulation the renin gene has not been studied for contribution to the development of DN. We studied plasma renin, prorenin, and four polymorphic markers of the renin gene in 199 patients with IDDM and DN, and in 192 normoalbuminuric IDDM controls matched for age, sex, and duration of diabetes. Plasma renin and total renin were measured by immunoradiometric assays. Genotyping was PCR-based. Plasma renin was increased in patients with nephropathy (median (range), 26.3 (5.2-243.3) vs 18.3 (4.2-373.5) microU/ml in the normoalbuminuric group, P<0.0001). Prorenin levels were elevated out of proportion to renin levels in nephropathic patients (789 (88-5481) vs 302 (36-2226) microU/ml, P<0.0001). Proliferative retinopathy had an additive effect on plasma prorenin, but not on renin. DN was associated with a BglI RFLP in the first intron of the renin gene (bb-genotype: n=106 vs 82 in DN and normoalbuminuric patients respectively, P=0.037), but not with three other polymorphisms in the renin gene. A trend for association of higher prorenin levels with the DN-associated allele of this renin polymorphism was observed in a subgroup of patients with DN (bb vs Bb+BB, P=0.07). The results indicate that in DN there is an increase in both renin and prorenin levels. A renin gene polymorphism may contribute weakly to DN. Although speculative, one of the renin gene alleles could lead to increased renin gene expression, leading to higher renin and prorenin levels. These may play a role in the pathogenesis of DN.

Autonomic nerve function in adolescents with Type 1 diabetes mellitus: relationship to microalbuminuria.

Thirty adolescent patients with Type 1 diabetes mellitus and microalbuminuria were studied for evidence of early autonomic neuropathy. Using tests involving cardiovascular and pupillary reflexes, the adolescents were compared with a normoalbuminuric group of patients with diabetes, who were matched for age, sex, puberty and duration of diabetes. There was an increased prevalence of autonomic nerve dysfunction in the patients with microalbuminuria. These patients had higher resting heart rates (86 beats/min in the microalbuminuric group vs. 77 beats/min in normoalbuminuric controls, P = 0.002), and impaired pupillary dilatation in darkness (pupillary diameter % 56.5% vs. 62.5%, P = 0.003). Patients with microalbuminuria also had poorer long term glycaemic control (mean HbA1C 8.7% vs. 7.8%, P = 0.002) and higher blood pressures (systolic 125 vs. 116 mmHg, P = 0.001; diastolic 69 vs. 62 mmHg, P = 0.0001; mean arterial pressure 90 vs. 83 mmHg, P = 0.002) than those with normal urinary albumin excretion. Microalbuminuria and autonomic nerve dysfunction co-exist in patients with Type 1 DM. Longitudinal studies will determine whether these findings have implications for the identification of patients at higher risk of progression of early renal complications.

Prevalence of left ventricular hypertrophy in Type I diabetic patients with diabetic nephropathy.

The increased mortality of patients with diabetic nephropathy is mainly due to cardiovascular disease and end stage renal failure. Left ventricular hypertrophy is an independent risk factor for myocardial ischaemia and sudden death. The aim of our cross-sectional study was to evaluate left ventricular structure and function in Type I (insulin-dependent) diabetic patients with diabetic nephropathy. M-mode and Doppler echocardiography were done on 105 Type I diabetic patients with diabetic nephropathy [61 men, age (means +/- SD) 44+/-9 years, and albuminuria [median(range)] 567(10-8188) mg/24 h, serum creatinine 109 (53-558) micromol/l], and 140 Type I diabetic patients with persistent normoalbuminuria [79 men, 47+/-10 years, urinary albumin excretion rate 8 (0-30) mg/24 h, and serum creatinine 81 (55-121) micromol/l]. Patients with and without nephropathy were comparable with respect to sex, body mass index, and duration of diabetes. Arterial blood pressure was slightly higher in patients with nephropathy: 140/79 +/- 17/9 mm Hg vs 134/78 +/- 15/8 mm Hg, p < 0.01, and the majority of proteinuric patients received antihypertensive drugs, 84 vs 17 %, respectively, p < 0.001. Left ventricular mass index was increased in the nephropathic group (means +/- SD) 100.6+/-23.9 g/m2 compared with the normoalbuminuric group 91.4+/-21.9 g/m2, p = 0.002. Left ventricular hypertrophy was found more often in patients with nephropathy 23 (14-31)% compared with patients with normoalbuminuria 9 (5-14)%, p < 0.005. Diastolic function, assessed by the ratio between the peak diastolic velocity and the peak atrial systolic velocity (E/A ratio) and isovolumic relaxation time, was reduced in patients with vs without nephropathy: 1.17+/-0.29 vs 1.34+/-0.32, and 81.7+/-16.5 vs 74.6+/-14.5, p < 0.001 and p = 0.002, respectively. Systolic function was about the same and normal in both groups. Our study suggests that an increase in left ventricular mass index and a decrease in diastolic function occurs early in the course of diabetic nephropathy.

Increased left ventricular mass in normotensive type 1 diabetic patients with diabetic nephropathy.

Diabetic nephropathy increases the risk of premature cardiovascular disease and sudden death, particularly in type 1 diabetic patients. One possible mechanism for this risk may be left ventricular hypertrophy. In our study, we aimed to evaluate left ventricular structure and function in normotensive type 1 diabetic patients with and without nephropathy. M-mode and Doppler echocardiography was performed in 17 type 1 diabetic patients with nephropathy (albuminuria [median (range)], 345 (135-2,846) mg/24 h) and compared with 34 normotensive, normoalbuminuric (10 [3-30] mg/24 h) type 1 diabetic patients matched for arterial blood pressure (mean +/- SD) ([134/77] +/- [13/7] vs. [129/78] +/- [12/7] mmHg), age (40 +/- 11 vs. 42 +/- 10 years), duration of diabetes (28 +/- 7 vs. 28 +/- 6 years), and BMI (24.2 +/- 4.2 vs. 24.6 +/- 2.4 kg/m2). Left ventricular mass (LVM) index was significantly higher in patients with nephropathy compared with patients with normoalbuminuria (100.8 +/- 10.3 vs. 88.2 +/- 21.0 g/m2, respectively; P = 0.02). Greater ventricular septum width was demonstrated in the nephropathic group compared with the control group (9.4 +/- 1.0 vs. 8.2 +/- 1.3 mm, respectively; P = 0.002). No significant difference in posterior wall thickness was apparent. The nephropathic group tended to have reduced diastolic function (E/A ratio, 1.2 +/- 0.3 vs. 1.4 +/- 0.4; P = 0.09). Fractional shortening was normal and about the same in the two groups. The groups did not differ with respect to serum creatinine or hemoglobin, while metabolic control (assessed by HbA1c) and plasma renin and prorenin levels were elevated in the nephropathic group compared with the normoalbuminuric group. A blood pressure-independent increase in LVM may contribute to the increased cardiac morbidity and mortality in normotensive type 1 diabetic patients with diabetic nephropathy. Glycemic abnormalities and activation of the renin-angiotensin system may lead to the ventricular enlargement.

Diurnal blood pressure variation and albuminuria in normotensive patients with insulin-dependent diabetes mellitus.

Abnormalities of the systemic blood pressure are closely associated with the development of diabetic nephropathy. Our aim was to examine the relationship between diurnal blood pressure pattern and albuminuria in insulin-dependent normotensive diabetic patients before the development of overt nephropathy. Urinary albumin excretion rates were determined by radioimmunoassay, and 24-h ambulatory blood pressure monitoring was performed. Means and diurnal index was calculated for systolic, diastolic and mean arterial blood pressure, for day-time, night-time, and the whole day. The results of the normoalbuminuric (n = 39) and microalbuminuric (n = 29) groups are compared, and correlation of the blood pressure parameters with albuminuria is analysed. Twenty-four hours and night-time mean blood pressures were significantly higher, diurnal indices characterizing the night-time blood pressure drop were smaller in the microalbuminuric group. With multiple regression analysis a significant positive correlation was found between albumin excretion rates and 24-h mean systolic blood pressure and a significant negative correlation between albumin excretion rates and the diurnal index of mean arterial pressure (r2= 0.40, P<0.0001). In the normoalbuminuric group 1 (2.6%) patient, in the microalbuminuric group 7 (24.1%/) were 'non-dippers'. We conclude that in normotensive insulin-dependent diabetic patients the night-time decrease of blood pressure is smaller if microalbuminuria is present. Higher nocturnal blood pressure load is associated with the increase of albuminuria, even before the onset of overt diabetic nephropathy or hypertension.

Increased familial history of arterial hypertension, coronary heart disease, and renal disease in Brazilian type 2 diabetic patients with diabetic nephropathy.

To evaluate whether there is a familial association of arterial hypertension, coronary heart disease, renal disease, and stroke with diabetic nephropathy There were 115 outpatients and 34 patients with end-stage renal disease treated by hemodialysis (61 men, age range 41-81 years) and having at least one sibling with type 2 diabetes studied. The positive or negative history of siblings (n = 765) was assessed by a standard questionnaire. The urinary albumin excretion rate (UAER) was measured by radioimmunoassay in 24-h sterile urine (three samples). The subjects were grouped as normoalbuminuric (UAER <20 microg/min, n = 59), microalbuminuric (UAER 20-200 microg/min, n = 35), macroalbuminuric (UAER >200 microg/min, n = 21), and end-stage renal disease (n = 34). Patients with microalbuminuria, macroalbuminuria, or end-stage renal disease had an increased prevalence of sibling history of arterial hypertension (33.2, 37.3, and 33.8 vs. 23.4%, P < 0.001) and coronary heart disease (15.2, 17.0, and 19.4 vs. 10.2%, P = 0.044) compared with the normoalbuminuric group. The renal disease history was increased only in the siblings of patients with macroalbuminuria or end-stage renal disease (12.8 and 15.6 vs. 7.6 and 6.1%, P = 0.005). The presence of sibling arterial hypertension strongly increases the prevalence of sibling renal and coronary heart disease independent of patient renal status. There is an association of diabetic nephropathy and sibling history of arterial hypertension and renal and coronary heart disease in type 2 diabetic patients. These associations are not independent, and arterial hypertension may be their main determining factor.

Relationship of elevated urinary albumin excretion to components of the metabolic syndrome in non-insulin-dependent diabetes mellitus

Microalbuminuria is associated with increased morbidity and early mortality in non-insulin-dependent diabetes mellitus (NIDDM), mostly due to cardiovascular disease. This association may be due to a higher prevalence of known cardiovascular risk factors in those with microalbuminuria. We examined the relationship of microalbuminuria to components of the metabolic syndrome in 98 NIDDM patients with elevated urinary albumin excretion rate (UAER) (>10.5 μg/min) (high UAER) and 102 normoalbuminuric NIDDM patients. Patients with high UAER were older than normoalbuminuric patients ( P<0.05), but they did not differ with respect to duration of diabetes, total cholesterol, body mass index (BMI) or the prevalence of smoking. A total of 58 (60%) patients with elevated UAER had two or more of hypertension, ischaemic heart disease (IHD), hypertriglyceridaemia and obesity compared with 41 (40%) in the normoalbuminuric group, ( P<0.05). Only nine (9.2%) high UAER patients had none of the above risk factors compared with 26 (25.5%) in the normoalbuminuric group ( P<0.01). The prevalence of hypertension (blood pressure (BP)>160/95) was significantly higher in high UAER patients; 61/98 (62%) versus 39/102 (38%) in normoalbuminuric group, ( P<0.05). Elevated UAER was also associated with a higher risk of macrovascular disease ( P<0.01). The high UAER group included 50 Caucasian, 30 Asian and 18 Afro-Caribbean. The three groups did not differ with respect to total cholesterol, glycosylated haemoglobin (HbA 1c) or prevalence of smoking. Asians had a lower BMI, a lower BP and a lower prevalence of peripheral vascular disease (PVD), but had a higher serum triglyceride ( P<0.01 for all) compared with Caucasian. Patients of Afro-Caribbean origin had a lower prevalence of IHD (0%) compared with both Asians (16%) and Caucasians (22%). Elevated UAER in NIDDM is closely associated with components of the metabolic syndrome and an increased risk of IHD and PVD. There are however, significant ethnic differences in this association.