Higher Albumin Excretion Rate Research Articles

Hyperhomocyst(e)inemia and endothelial dysfunction in IDDM.

Considering that elevated blood levels of homocyst(e)ine represent a known independent risk factor for macrovascular disease, we assessed the link between hyperhomocyst(e)inemia and diabetic microvascular complications. Homocyst(e)ine and thrombomodulin plasma levels, a marker of endothelial cell damage, were measured before and 3 h after oral methionine loading in 75 patients with stable, well-controlled IDDM and 40 healthy control subjects matched for sex and age. Exclusion criteria were hyperlipidemia, hypertension, smoking, or positive family history for cardiovascular disease. IDDM patients had higher pre- and postload homocyst(e)ine plasma levels than did healthy control subjects (12.0 vs. 7.7 mumol/l and 27.6 vs. 16.0 mumol/l; P < 0.001). Of 75 IDDM patients, 26 had homocyst(e)ine plasma levels above the normal range (defined as mean +2 SD of values obtained in the control group). The IDDM patients with hyperhomocyst(e)inemia had higher thrombomodulin plasma levels (62.2 vs. 38.2 ng/ml; P < 0.001), higher albumin excretion rates (485 vs. 115 mg/l; P < 0.005), and a higher prevalence of late diabetic complications (nephropathy, 76 vs. 33%; retinopathy, 69 vs. 51%; neuropathy, 57 vs. 41%; macroangiopathy, 57 vs. 33%) compared with IDDM patients with normal plasma homocyst(e)ine. In vitro experiments with human umbilical vein cells show an increased release of thrombomodulin into the culture supernatant only when endothelial cells were pretreated with advanced glycation end product (AGE)-albumin before L-homocystine was added. A synergistic action of homocyst(e)ine and AGEs might contribute to vascular complications of patients with diabetes. Hyperhomocyst(e)inemia is common in nephropathic diabetic patients and may contribute to the enhanced morbidity and mortality from cardiovascular diseases characteristically observed in IDDM patients with diabetic nephropathy.

Risk factors for kidney damage in the adult population of Wadena, Minnesota. A prospective study.

An increased albumin excretion rate (AER) is associated with impaired glucose tolerance and diabetes mellitus in some populations, but data on Americans of Northern European origin are lacking. In 1986-1987, AER and creatinine clearance were measured in 455 adults in a survey of the population of Wadena, Minnesota. Thirty-five subjects (8%) had an AER > or = 15 micrograms/minute, and eight of these had overt proteinuria (AER > or = 175 micrograms/minute). AER and creatinine clearance were uncorrelated except when AER was increased. Unadjusted mean AER in a stratified random sample of adults (n = 374) was 3.6 micrograms/minute. Adjusted values for 277 subjects with normal glucose tolerance and for 80 subjects with impaired glucose tolerance were very similar (3.8 and 3.7 micrograms/minute, respectively), whereas mean AER was 5.4 micrograms/minute for persons with non-insulin-dependent diabetes mellitus (NIDDM) who were not taking insulin and 9.4 micrograms/minute for persons with NIDDM who were taking insulin (p < 0.0001). After adjustment for age, mean creatinine clearance was unrelated to glucose tolerance. Systolic blood pressure was a major determinant of increased AER (p < 0.0001) and lowered creatinine clearance (p = 0.0011), independently of diabetes. AER was stable over 5 years among the 321 cases who were not taking insulin and were not severely hypertensive. The decrease in creatinine clearance was greater in ex-smokers and current smokers than in nonsmokers. The authors conclude that hypertension and NIDDM were independently associated with the risk of kidney damage in this population, as indicated by a higher AER. High-normal blood pressure, but not impaired glucose tolerance, was associated with microalbuminuria. These relatively mild changes may reflect an ethnically based resistance to the damaging effects of hyperglycemia on the kidney. Smoking may accelerate the aging-related decline in glomerular filtration rate.

Albumin excretion rate, serum insulin-like growth factor-I and glomerular filtration rate in type I diabetes mellitus at puberty.

The albumin excretion rate (AER), insulin-like growth factor-I (IGF-I) levels, glomerular filtration rate (GFR) and glycosylated hemoglobin (HbA1c) levels were studied in 49 diabetic children and 49 controls. The duration of diabetes varied from newly diagnosed to 17.5 years. Diabetics exhibited a wide range of AER values and had significantly higher AER and IGF-I levels compared to controls. At puberty elevated circulating growth hormone (GH) concentrations were found with a parallel increase in the levels of IGF-I. High IGF-I levels were found in 10-12 year-old girls and 15-16 year-old boys in both diabetic and control groups. Positive correlations were found between IGF-I and GFR in girls of both groups (p < 0.05) and in control girls between IGF-I, GFR and microalbuminuria (p < 0.05). The diabetic boys also showed microalbuminuria with respect to controls at high HbA1c levels and when their testis volume exceeded 8 ml (p < 0.05). We concluded that the prominent change in GH release at puberty, reflected by IGF-I, is in pulse amplitude, and that this is increased in diabetes but it is not a very important factor when determining the abnormal levels of urinary albumin excretion.

Familial hypertension and albuminuria in normotensive type I diabetic patients.

An inherited predisposition to hypertension may increase susceptibility to nephropathy in type I diabetes. We evaluated the influence of a family history of essential hypertension on albuminuria in normotensive, normoalbuminuric type I diabetic patients. Forty-two diabetics (12.9 +/- 2.04 years) were divided into three groups according to tertiles of albumin excretion rate (group 1, 1.27 +/- 0.35; group 2, 2.43 +/- 0.49; group 3, 6.37 +/- 3.43 micrograms/min; P < .001). Familial hypertension was considered to be present if the patient had one parent or grandparent on antihypertensive therapy. The three groups did not differ concerning age, diabetes duration, insulin requirement, body mass index, blood pressure, and urinary glucose excretion. Albumin excretion rate did not correlate with any parameter studied. The frequency of hypertension was significantly lower among the relatives of the patients from group 1 compared with those from groups 2 and 3 (28.6% versus 64.3% versus 78.6%, P < .03). Our data suggest that a familial antecedent of hypertension in normoalbuminuric type I diabetic patients is associated with a high normal albumin excretion rate not related to increases in blood pressure. Early changes in renal hemodynamics, seen in patients with a predisposition to hypertension, may contribute to increments in albuminuria even within the normal range.

Poor metabolic control and predisposition to hypertension, rather than hypertension itself, are risk factors for nephropathy in type 2 diabetes

Sodium-lithium countertransport (Na+/ Li+ CT) activity in erythrocytes has been shown to be high in a subset of patients with essential but not secondary hypertension and in type 1 (insulin-dependent) diabetic patients with nephropathy. More recently it has been shown that the presence of a major gene for Na+/Li+ CT, or another closely linked gene, rather than the actual level of Na+/Li+ CT, increases the risk of hypertension onset. The aim of the present study was to investigate whether Na+/Li+ CT activity is associated with hypertension and nephropathy in type 2 (non-insulin-dependent) diabetes. We studied 18 type 2 diabetic patients with normal blood pressure levels (systolic ≤140 and diastolic ≤85 mmHg) and albumin excretion rate (≤15 μg/min), 19 type 2 diabetic patients with hypertension (systolic ≥145 and diastolic ≥90 mmHg) and a normal albumin excretion rate (≤15 μg/min) and 19 type 2 diabetic patients with an increased albumin excretion rate (≤20 μg/min), irrespective of blood pressure levels. Eighteen normal subjects, matched for sex and age, served as controls. Na+/Li+ CT activity in erythrocytes was higher in type 2 diabetics with a high albumin excretion rate (486±148 μmol/l erythrocytes per hour,P<0.01) and in hypertensive diabetics (410±129,P<0.05), but not in normotensive diabetics (340±141), than in controls (282±96) (mean±SD). Body mass index was higher in diabetics with hypertension and in those with an abnormal albumin excretion rate than in normotensive diabetics and controls. Blood pressure levels were higher in diabetic patients with an increased albumin excretion rate than in normotensive diabetics and controls. Of diabetic patients with a high albumin excretion rate 26% had normal diastolic blood pressure levels. Diabetics with a high albumin excretion rate had higher glycated haemoglobin, cholesterol and triglyceride levels and a longer duration of diabetes than hypertensive diabetics with a normal albumin excretion rate. The association of these clinical features in type 2 diabetes closely resembles that previously reported in type 1 diabetes. A novel finding of the present study is that predisposition to hypertension, as indicated by high Na+/Li+ CT, seems to confer a susceptibility to the development of renal damage in type 2 diabetes, partially independent of blood pressure levels per se, and that diabetic patients with high Na+/Li+ CT and hypertension are, to some extent, protected against the development of nephropathy when the metabolic control is tighter and the duration of the disease shorter.

Tubular secretion of Tamm-Horsfall protein in type 1 (insulin-dependent) diabetes mellitus using a simplified enzyme linked immunoassay

The relationship between glomerular and tubular dysfunction and metabolic control in type 1 diabetes was studied. To that end the urinary excretion rates of albumin and Tamm-Horsfall protein as well as HbA1c levels were measured in 58 patients with different degrees of diabetic nephropathy and in 76 apparently healthy subjects matched for sex and age. The urinary Tamm-Horsfall protein levels were measured by a simplified enzyme linked immunoassay. The intra- and interassay variations were 8.9% and 13.6%, respectively. The intraindividual variation was 41% and the sensitivity of the assay was 4 micrograms/l. The Tamm-Horsfall protein excretion rate was 42.1 x/2.0 micrograms/min (geometric mean x/tolerance factor) in the diabetic patients compared to 34 x/1.9 micrograms/min in the control subjects (NS). The diabetic patients had higher albumin excretion rate (38.5 x/7.3 micrograms/min) than the control subjects (4.7 x/2.3 micrograms/min; P less than 0.001). By using multivariate analysis of variance, HbA1c level was found to be the only independent variable associated with Tamm-Horsfall protein excretion rate in diabetic patients (r = -0.28; P = 0.04), while no relationship was found between Tamm-Horsfall protein excretion rate and age, age at onset and duration of diabetes, gender, serum creatinine, diuresis, urinary albumin excretion rate, systolic and diastolic blood pressure levels and antihypertensive treatment. The urinary albumin excretion rate was associated with diastolic blood pressure (r = 0.34; P = 0.02) but not with HbA1c levels when testing the above variables by multivariate analysis of variance. In conclusion, these results may indicate a lack of relationship between glomerular and tubular dysfunction. The former was influenced only by diastolic blood pressure levels and the latter only by the degree of metabolic control. However, the correlations were weak and do not provide any insight into what is actually responsible for glomerular and tubular dysfunction.

Clinical significance of microalbuminuria in Japanese subjects with non-insulin-dependent diabetes

In order to elucidate the clinical significance of microalbuminuria in non-insulin-dependent diabetes mellitus (NIDDM), 62 Japanese subjects with NIDDM and without proteinuria were followed for three years. After the three-year follow up, four (19%) of 21 microalbuminuric patients—albumin excretion rates (AER) greater than 15 μg/min—developed overt proteinuria, while none of the 42 normoalbuminuric patients did. Among these normoalbuminuric patients, eight patients (19.5%) developed microalbuminuria. The microalbuminuric patients who developed overt proteinuria had higher AER at the beginning of the study than the patients who stayed microalbuminuric. The patients who developed microalbuminuria showed a significantly higher systolic blood pressure in the final year than the patients who stayed normoalbuminuric. These results indicate that microalbuminuria precedes overt proteinuria in Japanese NIDDM, and progression of diabetic nephropathy is rapid and associated with a rise in blood pressure.

A Study of Exercise-Induced Microalbuminuria in Type I (Insulin-Dependent) Diabetes Mellitus

Microalbuminuria is thought to be an important prognostic factor in diabetes mellitus. To study the influence of changes in blood pressure on the development of microalbuminuria during exercise, two exercise tests were carried out. A total of 32 insulin dependent diabetic men whose age at onset was less than 30 years, mean duration of diabetes 14 years (range 7 to 21) and mean age 29 years (range 21 to 40), and who did not have albuminuria (N-labstix negative) were studied. The diabetic patients were compared with a total of 29 age-matched male control subjects. Urinary albumin excretion was measured during two exercise tests: at a standardised workload (150 W) for 30 min, and at a standardised heart rate for 25 min. The diabetic patients had higher albumin excretion rates during both exercise tests compared with the control subjects. Blood pressure and heart rate during exercise were significantly higher in diabetic patients compared with control subjects in the standardised workload test. If the test was individualised to achieve the same standardised heart rate there was no significant difference in blood pressure between the diabetic patients and the control subjects. These results indicate that the diabetic kidneys were more sensitive than the healthy kidneys to similar degrees of haemodynamic stress induced by exercise.

Microalbuminuria in Adolescents With Insulin-Dependent Diabetes Mellitus

Two hundred ten adolescents aged 12 to 18 years with insulin-dependent diabetes mellitus were screened for microalbuminuria (albumin excretion rate of 15 to 300 micrograms/min). Sixteen (7.6%) showed persistent microalbuminuria (mean albumin excretion rate of 70.9 +/- 56.2 micrograms/min). There were no significant differences between those with and without microalbuminuria with respect to age, sex, disease duration, and blood pressure over the previous 9 months and hemoglobin A1c level measured over the preceding 3 years. Within the group with microalbuminuria, there was no correlation between albumin excretion rate and blood pressure. However, there was a significant positive correlation between log albumin excretion rate and mean hemoglobin A1c values measured over the preceding 3 years. Our findings suggest that when microalbuminuria has developed, poorer metabolic control is associated with a higher albumin excretion rate. An actual rise in systemic blood pressure may not always precede the development of microalbuminuria.

MICROALBUMINURIA AS PREDICTOR OF VASCULAR DISEASE IN NON-DIABETIC SUBJECTS: Islington Diabetes Survey

The relation between urinary albumin excretion rate (AER) and vascular disease was studied in 187 subjects aged over 40 selected from 1084 cases attending a diabetic screening project. AER exceeded 20 μg/min in 3 of 13 newly diagnosed diabetic subjects (23%) and 16 of 171 non-diabetic subjects (9·4%). There was a weak relation between AER and both systolic and diastolic blood pressures. Coronary heart disease was found in 54 of 164 (32·9%) subjects with AER of 20 μg/min or less and in 14 of 19 (74%) with AER above this. Peripheral vascular disease was present in 16 of 165 (9·7%) subjects with AER of 20 μg/min or less and 8 of 18 (44%) with a high AER. Logistic regression, including diabetes, impaired glucose tolerance, systolic and diastolic blood pressures, smoking, age, sex, ethnic origin, and body mass index, demonstrated the independence of this relation between AER above 20 μg/min and coronary heart disease (odds ratio [OR] 6·38, 95% confidence interval 1·91-21·4) and peripheral vascular disease (OR 7·72, 2·14-27·8). After a mean of 3·6 (SD 0·19) years, 167 subjects (89·3%) were traced. There had been 9 deaths, 3 (2·0%) among 149 subjects with normal AER and 6 (33%) among 18 microalbuminuric subjects (OR 24·33, 5·40-109·7).

MICROALBUMINURIA AS A PREDICTOR OF CLINICAL NEPHROPATHY IN INSULIN-DEPENDENT DIABETES MELLITUS

The overnight urinary albumin excretion rate (AER) of 87 patients with insulin-dependent diabetes mellitus was measured in 1966-67. 14 years later information was obtained on 63 of the original cohort; those alive were restudied, and for those who had died relevant clinical information and cause of death were recorded. The development of clinical diabetic nephropathy ('Albustix'-positive proteinuria) was related to the 1966-67 AER values. Clinical proteinuria developed in only 2 of 55 patients with AER below 30 μg/min but in 7 of 8 with AER between 30 and 140 μg/min. The risk of clinical diabetic nephropathy in the latter group was twenty-four times higher than in the former. 9·1% of patients with AER below 30 μg/min had died, compared with 37·5% with higher AER. The two groups did not differ significantly in age, sex composition, and initial blood pressure. Mean duration of diabetes was longer, but not significantly so, in those with AER above 30 μg/min. Thus, elevated levels of microalbuminuria strongly predict the development of clinical diabetic nephropathy. These levels of AER are potentially reversible, and their detection and treatment may prevent diabetic renal disease.