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Currently, neither the American Diabetes Association nor the Kidney Foundation consider the results of a positive dipstick urine test for protein, a semi-quantitative measurement, in the final evaluation of diabetic nephropathy. Instead, they require a quantitative test. The object of this study was to assess whether a positive semi-quantitative test could accurately substitute for a quantitative one to evaluate renal disease. We determined the proportion of urine samples dipstick positive for protein that had an albumin:creatinine ratio of 30 microg/mg or more, the recommended value for the diagnosis of microalbuminuria (incipient nephropathy). Albumin:creatinine ratios were measured in urine samples from 19 diabetic and 51 nondiabetic patients in which the dipstick test for protein was positive. Twelve of 24 (50%) urine samples trace positive for protein by a dipstick method had albumin:creatinine ratios of 30 microg/mg or more, whereas 42 of 46 (91%) urine samples greater than or equal to 1+ for protein exceeded that ratio. The results were similar in the two groups of patients. The positive predictive value for a test result more than or equal to 1+ for protein was 91%. We conclude that in contrast to the recommendations of the American Diabetes Association and the National Kidney Foundation, dipstick positive proteinuria of more than or equal to 1+ can substitute for an albumin:creatinine ratio. An algorithm for this more cost-effective approach to the diagnosis of diabetic nephropathy is suggested.
J Diabetes Complications
PMID:Relationship between dipstick positive proteinuria and albumin:creatinine ratios. 1023 10

1. Treatment with heparin has beneficial effects in diabetic nephropathy. The occurrence of increased urinary albumin excretion in diabetic patients reflects general vascular dysfunction, including increased transcapillary permeability of macromolecules. The aim of the present study was to evaluate the effects of heparin on vascular dysfunction in diabetic rats. 2. Male Sprague-Dawley rats were used in two studies. Diabetes was induced by 65 mg/kg, i.v., streptozotocin. In one study, diabetic rats were dosed subcutaneously with different heparin fractions for 8 months and the transcapillary escape rate of albumin (TERalb) was measured in anaesthetized animals. In the other study, heparin was given for 6 weeks, followed by tissue albumin clearance measurements in awake rats. Normal and diabetic rats receiving saline served as controls. 3. Blood glucose did not differ among the diabetic groups and ranged from 22 to 26 mmol/L. The mean (+/- SD) TERalb was increased by diabetes compared with values in normal rats (17.5 +/- 3 vs 14.1 +/- 3.3%/h, respectively). Neither unfractionated nor low molecular weight heparin significantly affected this increase. [131I]-Albumin clearance was significantly increased in diabetic rats in the eye, skin and skeletal muscle tissues compared with normal rats (0.17-0.40 vs 0.1-0.23 microL plasma/g per min). Low molecular weight heparin treatment did not affect the increased organ albumin clearance. 4. In conclusion, heparin treatment does not affect diabetes-induced vascular dysfunction as expressed by increased TERalb and clearance of albumin in rats.
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PMID:Effects of heparin on vascular dysfunction in diabetic rats. 1038 30

Results are presented of diabetes complication screening in children and adolescents aged 6-20 years. Their diabetes duration was 0.02-18.4 yr and median HbA1c over the preceding 36 months was 8.4% [IQR 7.8-9.3]. Gradable retinal photographs were obtained in 937: 110 less than 11 years (< 11 yr Gp). Albumin excretion rate (AER) was obtained from 3 timed overnight urine collections in 691: 100 in < 11 yr Gp. Early retinopathy was found in 27% (9% in < 11 yr Gp). Microalbuminuria (AER > or = 20 micrograms/min) was found in 4%. Significant individual risk factors for both complications were higher blood pressure, cholesterol, HbA1c, pubertal staging, older age and longer diabetes duration. Using multiple logistic regression, significant risk factors for retinopathy were longer duration and older age and in addition higher HbA1c. Diabetes complication screening detected early subclinical disease in children and adolescents who may benefit from lowering blood pressure and improving metabolic control. Screening should commence after five years of duration in young children, and after two years of duration in adolescents.
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PMID:Diabetes complication screening in 937 children and adolescents. 1039 65

The American Diabetes Association emphasizes fasting plasma glucose (FPG) levels, rather than the oral glucose tolerance test (OGTT), to diagnose diabetes mellitus. The diagnostic cutoff for FPG is 126 mg/dL (7.0 mmol/L). A 2-hour plasma glucose level of 200 mg/dL (11.1 mmol/L) or more during an OGTT or a random plasma glucose level of 200 mg/dL (11.1 mmol/L) or more also is diagnostic of diabetes. The 100-g, 3-hour OGTT remains the "gold standard" for gestational diabetes mellitus (GDM). Two of 4 samples exceeding cutoffs (fasting, > or = 105 mg/dL [5.8 mmol/L]; 1 hour, > or = 190 mg/dL [10.5 mmol/L]; 2 hours, > or = 165 mg/dL [9.2 mmol/L]; 3 hours, > or = 145 mg/dL [8.0 mmol/L]) indicate GDM. An effective GDM screening test is plasma glucose 1 hour after a 50-g oral glucose load. Tight control, which requires self-monitoring of blood glucose, reduces microvascular complications for patients with type 1 or type 2 diabetes. Patients with well-controlled diabetes have glycohemoglobin concentrations of 7% AIc (0.07 AIc/A) or less. Microalbuminuria indicates early, reversible, diabetic nephropathy. The random urine albumin-creatinine ratio is a convenient effective screening test. Albumin-creatinine ratios in the 0.03 to 0.30 (g/g) range indicate microalbuminuria.
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PMID:Laboratory diagnosis and monitoring of diabetes mellitus. 1054 54

Hypoalbuminemia predicts death in dialysis patients. Although hypoalbuminemia has been attributed to malnutrition, evidence of inflammation (C-reactive protein [CRP] and cytokine levels) has recently been recognized to predict albumin concentration in dialysis patients. We measured CRP and albumin levels in October 1995 in 91 hemodialysis (HD) patients. During a 34-month follow-up period, we determined the incidence and cause of death. Patients were divided into four groups based on serum albumin levels (<3.5 [lowest quartile], 3.5 to 3.8, 3.9 to 4.0, and >4.0 g/dL [highest quartile]). Survival differed among the four groups (P = 0.0063). Patients with albumin levels greater than 4.0 g/dL had the greatest survival. Kaplan-Meier survival estimates of patients from varying CRP quartiles (<2.6, 2.6 to 5.2, 5.3 to 11.5, and >11.5 microg/mL) differed among the four groups (P < 0.0001). The group with the greatest CRP level (>11.5 microg/mL) had the lowest survival. Multivariate analysis using the Cox proportional hazards model showed that only CRP level (chi-square = 21.11; P < 0.0001) and age (chi-square = 5.44; P = 0.020) predicted death. Albumin level (chi-square = 0.16; P = 0.69) was not predictive. Only when CRP was excluded from the model did low serum albumin level (chi-square = 12. 04; P = 0.0004) predict death. CRP level (chi-square = 16.79; P < 0. 0001) and age (chi-square = 6.38; P = 0.012) also superceded albumin level (chi-square = 0.45; P = 0.51) in predicting cardiovascular mortality. Although values for blood urea nitrogen, creatinine, and normalized protein catabolic rate were significantly less among patients who died, these parameters, as well as cholesterol level and diabetes, were not important predictors of death in multivariate analysis. The acute-phase response or the cause of the acute-phase response is largely responsible for the effect of hypoalbuminemia on mortality in HD patients.
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PMID:C-Reactive protein predicts all-cause and cardiovascular mortality in hemodialysis patients. 1069 73

Although the role of multiple humoral agents (such as plasma albumin, glucose, hormones etc.) are implicated in lipoprotein metabolism, the mechanism of action of these agents on various steps of the synthesis and secretion of lipoproteins and apolipoproteins (protein moieties of lipoproteins) are not completely understood. Specifically, the hepatocellular mechanisms of the effect of albumin and fatty acids on apolipoprotein (apo) AI and AII [major proteins of high density lipoproteins (HDL)] synthesis and secretion are not known. Using human hepatoblastoma cells (Hep G2) as an in vitro model system, this study examined the effect of albumin and fatty acids on the synthesis, secretion, and the steady-state mRNA expression of apo AI and AII. The data indicated that the incubation of Hep G2 cells with albumin, dose-dependently, inhibited apo AI and AII accumulation (secretion) in the media, de novo synthesis, and the steady-state mRNA expression. Albumin did not alter total protein synthesis; thus the effect of albumin appeared to be specific for the synthesis and secretion of apo AI and apo AII. Free fatty acids (FFA) are transported by albumin and diseases characterized by enhanced FFA mobilization (e.g. diabetes mellitus) are associated with low HDL levels. Studies were therefore performed to examine the effect of albumin-bound-oleic acid on apo AI and apo AII production. The results showed that the albumin-oleate complex further increased the inhibitory effects of albumin on apo AI and apo AII production. These data suggest how HDL metabolism may be affected at the hepatocellular level by alterations in plasma albumin concentrations and/or fatty acid mobilization in clinical situations characterized by altered HDL levels.
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PMID:Albumin inhibits apolipoprotein AI and AII production in human hepatoblastoma cell line (Hep G2): additive effects of oleate-albumin complex. 1070 13

Albumin excretion in urine is positively correlated with the presence of ischemic heart disease and atherosclerotic risk factors. We studied prospectively whether a slight increase of urinary albumin excretion, ie, microalbuminuria, adds to the increased risk of ischemic heart disease among hypertensive subjects. In 1983 and 1984, blood pressure, urinary albumin/creatinine concentration ratio, plasma total and HDL cholesterol levels, body mass index, and smoking status were obtained in a population-based sample of 2085 subjects, aged 30 to 60 years, who were free from ischemic heart disease, diabetes mellitus, and renal or urinary tract disease. Untreated arterial hypertension or borderline hypertension was present in 204 subjects, who were followed until 1993 by the National Hospital and Death Certificate Registers with respect to development of ischemic heart disease. During 1978 person-years, 18 (9%) of the hypertensive subjects developed ischemic heart disease. Microalbuminuria, defined as a urinary albumin/creatinine ratio above the upper decile (1.07 mg/mmol), was the strongest predictor of ischemic heart disease, with an unadjusted relative risk of 4.2 (95% CI 1.5 to 11.9, P=0.006) and a relative risk of 3.5 (95% CI 1.0 to 12.1, P=0.05) when adjusted for all other atherosclerotic risk factors, including age and gender. In conclusion, microalbuminuria confers a 4-fold increased risk of ischemic heart disease among hypertensive or borderline hypertensive subjects. Urinary albumin excretion should be measured regularly in a hypertension clinic, and a rigorous control of blood pressure and of other atherosclerotic risk factors is recommended in hypertensive patients with microalbuminuria.
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PMID:Arterial hypertension, microalbuminuria, and risk of ischemic heart disease. 1077 58

Albumin modified by Amadori glucose adducts stimulates the expression of extracellular matrix proteins by glomerular mesangial and endothelial cells, and has been mechanistically linked to the pathogenesis of diabetic nephropathy. To test the hypothesis that inhibiting the formation of glycated albumin might beneficially influence the development of kidney disease in diabetes, we treated diabetic db/db mice for 12 weeks with a low-molecular-weight compound (EXO-226) that impedes the condensation of free glucose with lysine epsilon-amino groups in albumin. Administration of EXO-226 (3 mg/kg) twice daily by gavage normalized the plasma concentration of glycated albumin within days after initiation of treatment and maintained glycated albumin within the normal range throughout the study, despite persistent and severe hyperglycemia. Urine albumin excretion, which was markedly increased at the start of the study (age 12 weeks), was significantly reduced in treated diabetic animals compared with their untreated diabetic littermates. The fall in creatinine clearance that was observed in untreated diabetic animals was prevented in diabetic littermates that received treatment. Compared with the nondiabetic controls, the amount of glomerular mesangial matrix was threefold greater in untreated diabetic mice; in contrast, the mesangial matrix fraction was only 1. 5 times that of nondiabetic controls in the treated diabetic animals, representing a reduction in mesangial matrix accumulation of more than 50%. EXO-226 also reduced the overexpression of mRNA encoding for alpha1 (IV) collagen in renal cortex of db/db mice. We conclude that normalization of plasma glycated albumin concentrations with the glycation inhibitor EXO-226 ameliorates the glomerular structural and functional abnormalities associated with diabetic nephropathy in the db/db mouse.
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PMID:Inhibiting albumin glycation ameliorates diabetic nephropathy in the db/db mouse. 1081 Feb 30

Echocardiographic assessment of cardiovascular function was performed in 47 type 1 diabetic patients and 30 healthy control subjects of comparable age, height, weight, and heart rate. Indexed left ventricular mass, stroke volume, cardiac output, cardiac index, shortening fraction, indexed diastolic dimension, and indexed diastolic volume were calculated and compared between patient and control groups. Left ventricular mass and performance were slightly elevated in type 1 diabetic patients compared with 30 healthy control individuals. However, only cardiac output had borderline statistical significance (p = 0.06). The reason might be short duration (mean, 4.02 +/- 4.07 years) of diabetes in our patients group. In 18 of 47 patients the duration of type 1 diabetes was even less than two years. Relation of left ventricular mass to independent variables showed that, left ventricular mass was significantly correlated with stroke volume (p = 0.008), cardiac index (p = 0.0005), indexed systolic blood pressure (p = 0.0000199), indexed diastolic blood pressure (p = 0.0000172) and left ventricular contractility (p = 0.000273) in diabetic patients. Left ventricular contractility was also independently associated in diabetic patients with the indexed systolic and diastolic blood pressure (p = 0.0000755 and 0.000678 respectively). Albumin excretion, duration of diabetes, glycosylated hemoglobin (HbAlc), serum creatinine, and left ventricular preload did not have significant univariate correlation with left ventricular contractility.
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PMID:Cardiovascular function in young patients with type 1 diabetes mellitus. 1091 Jun 22

Initial studies showing an approximately 80% rate of progression from microalbuminuria (MA) to proteinuria in type 1 diabetic patients led to the broad acceptance of MA as a useful clinical predictor of increased diabetic nephropathy (DN) risk. Some MA patients, however, have quite advanced renal structural changes, and MA may, in these cases, be a marker rather than a predictor of DN. More recent studies have observed only about a 30-45% risk of progression of MA to proteinuria over 10 years, while about 30% of type 1 diabetic patients with MA became normoalbuminuric and the rest remained microalbuminuric. The finding that some MA patients have only mild diabetic renal lesions is consistent with the lower than originally estimated risk of progression from MA to proteinuria and with the notion that some MA patients revert to normoalbuminuria. To increase the complexity of the scenario, some normoalbuminuric long-standing type 1 diabetic patients have well-established DN lesions and approximately 40% of all patients destined to progress to proteinuria are normoalbuminuric at initial screening, despite many years of diabetes. A similar picture is emerging in type 2 diabetic patients, although fewer studies have been conducted. Thus, the predictive precision for MA to progress to overt nephropathy over the subsequent decade or so is considerably less than originally described. It is unclear whether this is due to changes in the natural history of DN resulting from improved glycemia and blood pressure control, or whether there were overestimates of risk in the original studies due to the small sample sizes, post hoc analyses, and variable MA definitions. Albumin excretion rate (AER) remains the best available noninvasive predictor of DN risk and should be regularly measured according to established guidelines. However, AER may be unable to define patients who are safe from or at risk of DN with an accuracy that is adequate for optimal clinical decision making or for the design of certain clinical trials. Investigations into new risk markers or into the combined use of several currently available predictive parameters are needed.
Diabetes 2000 Sep
PMID:The need for early predictors of diabetic nephropathy risk: is albumin excretion rate sufficient? 1096 21


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