Clinical Diabetic Nephropathy Research Articles

Reduced glomerular filtration rate and cardiovascular damage in diabetes: a key role for abnormal albuminuria

There is general agreement that a fall rate in glomerular filtration rate (GFR) is the principal endpoint in diabetics with renal disease, and that abnormal albuminuria (including microalbuminuria) is an important intermediate end-point. The relative roles of blood pressure (BP) elevation and abnormal albuminuria in the prediction and genesis of renal disease are a matter of debate, and are further analysed in this paper. New studies show that neither genetic predisposition to hypertension (parental BP) nor parental abnormal albuminuria can be used to predict renal disease in patients with type 1 (insulin-dependent) diabetes. However, parental predisposition to proteinuria seems to be important to certain types of patients with type 2 (non-insulin-dependent) diabetes. Cross-sectional as well as follow-up studies document that GFR is generally well preserved in microalbuminuria (in both type 1 and type 2 patients), while the transition to clinical proteinuria is associated with a decline in GFR. Thus, prevention of overt proteinuria is important in clinical trials in microalbuminuric patients. In type 1 diabetes clear ultrastructural changes have been documented with microalbuminuria and a good correlation between abnormal albuminuria and structural damage is seen. Structural damage in normo- and microalbuminuric patients correlates poorly with BP. New studies in type 1 diabetes document that microalbuminuria (but not elevated BP) predicts not only clinical diabetic nephropathy but also end-stage renal failure and mortality. In type 2 diabetes microalbuminuria is the strongest predictor of mortality, whereas BP elevation is not a predictor. Several studies now document that antihypertensive treatment, especially with inhibitors of angiotensin converting enzyme, is able to reverse or reduce abnormal albuminuria, even in non-hypertensive type 1 patients, and possibly preserve GFR. Therefore, microalbuminuria may be the main indicator for starting antihypertensive treatment in these patients. With respect to organ damage in the retina, abnormal albuminuria is an important indicator of the risk of severe diabetic retinopathy. BP elevation seems not to be an initiating factor, but rather aggravates established retinopathy. Left ventricular hypertrophy has a stronger correlation with BP elevation than normoalbuminuria, suggesting that left ventricular hypertrophy is at least partially a phenomenon secondary to elevated BP in diabetic patients with abnormal albuminuria. Generally, abnormal albuminuria is a strong indicator of cardiovascular renal damage in diabetic patients and in most organs is a stronger factor than elevated BP.

Renoprotective action of angiotensin-converting enzyme inhibition in diabetes mellitus.

Roughly 40% of all diabetics, whether insulin dependent or not, develop persistent albuminuria, a decline in their glomerular filtration rate, and elevated blood pressure, i.e., diabetic nephropathy. Diabetic nephropathy is the single most important cause of end-stage renal disease in the Western world, accounting for over one-quarter of all end-stage renal disease. Systemic/glomerular hypertension plays a role in the initiation and progression of diabetic glomerulopathy. Angiotensin-converting enzyme (ACE) inhibitors are superior to conventional antihypertensive drugs in preventing the development of glomerular lesions in insulin-treated streptozotocin diabetic rats. Lowering of glomerular hypertension may be the crucial factor involved. Human studies suggest that ACE inhibitors postpone the progression to clinical overt diabetic nephropathy in normotensive diabetic patients with persistent microalbuminuria. ACE inhibitors combined with a diuretic reduce albuminuria and postpone renal insufficiency in hypertensive diabetics with overt nephropathy. No treatment modality other than antihypertensive treatment has yet been proven to be effective in protecting renal function in diabetic nephropathy. All previous reports dealing with the natural history of diabetic nephropathy have demonstrated a cumulative death rate between 50 and 77% 10 years after the onset of proteinuria. Effective antihypertensive treatment has reduced the cumulative death rate to 15-20% 10 years after the onset of nephropathy.

Predominantly Vegetarian Diet in Patients with Incipient and Early Clinical Diabetic Nephropathy: Effects on Albumin Excretion Rate and Nutritional Status

Several studies have suggested that dietary protein quality may be an important determinant in the natural history of renal disease. We have therefore studied the effects of a predominantly vegetarian diet in eight patients with Type 1 diabetes mellitus and an albumin excretion rate (AER) in excess of 30 micrograms min-1. The AER was measured after an 8-week run-in period on the patient's usual diet, and again after 8 weeks of a predominantly vegetarian diet in which the proportion of vegetable protein was supplemented in order to minimize the reduction in total dietary protein intake. The median fractional albumin clearance fell during the study from an initial value of 188 x 10(-+) (range 58-810 x 10(-4)) at the end of the run-in period to 87 x 10(-4) (23-829 x 10(-4)) at the end of the period on low animal protein diet (difference 79 x 10(-4) (95% Cl 9-149 x 10(-4)), p less than 0.05). The AER then returned to values similar to those obtained at the beginning of the study after a further 8 weeks in those patients returning to their usual diet. No significant changes in blood glucose control or in arterial pressure were observed. A predominantly vegetarian diet may therefore have important beneficial effects on diabetic nephropathy without the need for a heavily restricted total protein intake.

Efficacy of captopril in postponing nephropathy in normotensive insulin dependent diabetic patients with microalbuminuria.

To assess the effectiveness of angiotensin converting enzyme inhibition in preventing the development of diabetic nephropathy (albuminuria greater than 300 mg/24h).Open randomised controlled study of four years' duration.Outpatient diabetic clinic in tertiary referral centre.44 normotensive (mean blood pressure 127/78 (SD 12/10) mm Hg) insulin dependent diabetic patients with persistent microalbuminuria (30-300 mg/24h).The treatment group (n = 21) was initially given captopril (25 mg/24 h). The dose was increased to 100 mg/24 h during the first 16 months and thiazide was added after 30 months. The remaining 23 patients were left untreated.Albuminuria, kidney function, development of diabetic nephropathy (albuminuria greater than 300 mg/24 h), and arterial blood pressure.Clinical and laboratory variables were comparable at baseline. Urinary excretion of albumin was gradually reduced from 82 (66-106) to 57 (39-85) mg/24 h (geometric mean (95% confidence interval)) in the captopril treated group, whereas an increase from 105(77-153) to 166 (83-323) mg/24 h occurred in the control group (p less than 0.05). Seven of the untreated patients progressed to diabetic nephropathy, whereas none of the captopril treated patients developed clinical overt diabetic nephropathy (p less than 0.05). Systemic blood pressure, glomerular filtration rate, haemoglobin A1c concentration, and urinary excretion of sodium and urea remained practically unchanged in the two groups.The findings suggest that angiotensin converting enzyme inhibition postpones the development of clinical overt diabetic nephropathy in normotensive insulin dependent diabetic patients with persistent microalbuminuria.

Diurnal Variation in Urinary Protein Excretion in Diabetic Nephropathy

We examined the diurnal variation in urinary excretion rate of albumin, IgG and beta 2-Microglobulin (beta 2-M) in healthy volunteers (n = 24), and in patients with type I diabetes mellitus having normal albumin excretion rate (less than 20 micrograms/min; n = 16), incipient diabetic nephropathy (albumin excretion rate 20-200 micrograms/min; n = 12) and clinical diabetic nephropathy (albumin excretion rate greater than 200 micrograms/min; n = 12). Diurnal variation was defined as [(overnight minus daytime): daytime excretion rate] times 100%. Median diurnal variation in albumin excretion rate in the various groups varied from -32 to -57%, and in IgG excretion rate from -42 to -65%, being not significantly different between the proteins or between the groups. Diurnal variation in beta 2-M excretion rate was similar in healthy volunteers and in patients with normal albumin excretion rate or incipient diabetic nephropathy (median -36 to -43%), but significantly reduced in patients with clinical diabetic nephropathy (median 0%; P less than 0.005), nine of whom had elevated beta 2-M excretion rates, suggesting tubular dysfunction. Except for beta 2-M excretion rate in patients with clinical diabetic nephropathy, the diurnal variations in albumin excretion rate, IgG excretion rate and beta 2-M excretion rate were larger than the diurnal variation in creatinine excretion rate (median -7 to -11%, P less than 0.005). Diurnal variations in albumin excretion rate and IgG excretion rate were highly correlated (r = 0.89, P less than 0.00001). These data suggest that similar mechanisms may account for diurnal variations in albumin excretion rate and IgG excretion rate.(ABSTRACT TRUNCATED AT 250 WORDS)

Albuminuria and associated medical risk factors: A cross-sectional study in 451 type II (noninsulin-dependent) diabetic patients. Part 2

The association between urinary albumin concentration (UAC) in a morning urine sample and medical risk factors was evaluated in a cross-sectional study of 451 type II (noninsulin-dependent) diabetic patients. The following four groups of patients were created according to their urinary albumin levels: A) normal (<12.5 mg/L); B) high normal (12.5–30 mg/L); C) microalbuminuria, ie, incipient nephropathy (31–299 mg/L); and D) clinical nephropathy (≥300 mg/L). The patients with high normal levels had higher HbA 1c and systolic blood pressure levels than patients with values within normal limits. The prevalence of incipient and clinical diabetic nephropathy was 20 and 7%, respectively. Incipient nephropathy was associated with higher blood pressures and body weights. Patients with clinical nephropathy had even further increases in these parameters, were older, and had longer duration of diabetes. In both groups of nephropathy, men were preponderant. Thirty six percent of all patients and 73% of patients with clinical nephropathy were treated for hypertension; 55% were treated with insulin. The insulin-treated patients had poorer metabolic control, but there were no differences in blood pressure or serum creatinine levels as compared with those of patients not receiving insulin treatment. The proportion of patients with severe retinopathy increased with the degree of albuminuria, although 22% of the patients with clinical nephropathy continued to be nonretinopathic.

Impaired left-ventricular function in insulin-dependent diabetic patients with increased urinary albumin excretion

Cardiac function was studied in 30 patients with insulin-dependent diabetes mellitus. Three groups, matched for age and diabetes duration, were defined as: group I (n = 10), normal urinary albumin excretion less than 30 mg 24 h-1; group II (n = 10), incipient diabetic nephropathy (urinary albumin excretion in the range of 30-300 mg 24 h-1); and group III (n = 10), clinical diabetic nephropathy (urinary albumin excretion greater than 300 mg 24 h-1). Ten non-diabetic subjects matched for sex and age served as controls. The left-ventricular end-diastolic volume measured by radionuclide cardiography was, at rest and during exercise, lower in group II and III compared with controls (p less than 0.05), while intermediate values were found in group I. The cardiac output was similar in the control group and group I; it was reduced, but not significantly so (p = 0.10), in group III and was significantly lower in group II (p less than 0.05). Stroke volume was also lower in group II and III than in controls (p less than 0.05), but not so in group I. These differences could not be explained by differences in metabolic control, blood pressure, blood volume status, degree of autonomic neuropathy or frequency of coronary heart disease. Our results might suggest that insulin-dependent diabetic patients with slightly but persistently elevated urinary albumin excretion have reduced diastolic compliance of the left-ventricle leading to impaired cardiac performance.(ABSTRACT TRUNCATED AT 250 WORDS)

Albuminuria and associated medical risk factors: A cross-sectional study in 476 type I (insulin-dependent) diabetic patients. Part 1

Albumin concentration in a morning urine sample was analyzed in a cross-sectional study in 476 insulin-dependent diabetic patients. The following groups of patients were defined: A) normal urinary albumin (urine albumin <12.5 mg/L); B) high normal albuminuria (12.5–30 mg/L); C) microalbuminuria, ie, incipient nephropathy (31–299 mg/L); and D) clinical nephropathy (≥300 mg/L). The prevalences of incipient and clinical diabetic nephropathy were 24.8 and 14.4%, respectively. There were no differences in clinical parameters such as age, age at onset or duration of diabetes, blood pressure, serum creatinine, or HbA 1c levels between groups A and B. The frequency of retinopathy in these groups was 55 and 50%, respectively. In group C, there were increases in age, duration of diabetes, blood pressure, serum creatinine, and HbA 1c levels. The frequency of retinopathy was higher (80%), and more patients had severe forms (47%). In group D, there were further increases in all parameters and, in addition, younger age at onset of diabetes. The frequency of retinopathy was 97%, and severe forms of retinopathy were more common (86%). Seventeen percent of the patients were treated for hypertension. These patients were older, had longer duration of diabetes, and had higher levels of blood pressure, serum creatinine, and urinary albumin, as well as a younger age at onset of diabetes than patients not requiring antihypertensive treatment.

Kidney volume in type 1 (insulin-dependent) diabetic patients with normal or increased urinary albumin excretion: effect of long-term improved metabolic control

Forty-seven patients with type 1 (insulin-dependent) diabetes mellitus and 14 normal subjects had renal volume determined by an ultrasonic technique. Renal volume of 299 +/- 49 ml/1.73 m2 (mean +/- SD) in type 1 diabetic patients with normal urinary albumin excretion exceeded that in the normal subjects (245 +/- 53 ml/1.73 m2, p less than 0.05). Compared with diabetic patients with normal urinary albumin excretion, renal volume was significantly higher in patients with microalbuminuria (372 +/- 24 ml/1.73 m2, p less than 0.05) and patients with clinical nephropathy (352 +/- 48 ml/1.73 m2, p less than 0.05). In a multiple linear regression with HbA1c, urinary albumin excretion, age, diabetes duration and mean blood pressure as independent variables, variations in HbA1c could account for 33% of the variations in kidney volume (n = 47, r = 0.57, p less than 0.01). The other variables played no role. When only patients without clinical nephropathy were included, HbA1c and kidney volume remained significantly correlated (n = 34, r = 0.60, p less than 0.01). In those patients a strong correlation between kidney volume and function, i.e. the glomerular filtration rate was found (n = 34, r = 0.70, p less than 0.01); metabolic control and function were also correlated (n = 34, r = 0.62, p less than 0.01). The urinary albumin excretion accounted for only 6% of the variation of the kidney volume (NS). In nine patients with microalbuminuria the kidney volume could be reduced during 2 years of improved metabolic control by means of insulin infusion pumps.(ABSTRACT TRUNCATED AT 250 WORDS)

Should There Be an Expanded Role for Kidney Biopsy in the Management of Patients With Type I Diabetes?

Diabetic nephropathy is the single most important cause of end-stage renal disease (ESRD) in the United States. Further, the increased risk of mortality from type I diabetes is almost entirely confined to patients developing clinical diabetic nephropathy. Nonetheless, kidney biopsy has had little role in the clinical assessment of diabetic patients or in the design of clinical research in diabetic nephropathy. The development of dipstick-positive proteinuria in patients with type I diabetes of more than 10 years' duration is regularly associated with advanced structural changes of diabetic nephropathology; in these patients, clinical parameters, especially the rate of decline of glomerular filtration rate (GFR), are accurate monitors of disease progression. Microalbuminuria indicates a very high risk of overt proteinuria and thus ESRD. This increased risk is associated with levels of urinary albumin excretion (UAE; greater than 30 micrograms/min [45 mg/24 h]), which are frequently accompanied by hypertension and reduced or decreasing GFR. At this stage, lesions of diabetic nephropathy are usually already well established. Thus, microalbuminuria is more a marker of early nephropathy than a predictor of later renal injury. Before these clinical stages of nephropathy, there are no accurate predictors of renal risk. Renal biopsy may serve this role by indicating those patients who are developing significant lesions during the "silent" phase of the disease. In large measure, this value of the biopsy derives from evidence that the lesions tend to develop linearly over time and can be measured by techniques that are relatively easily established in standard surgical pathology environments. Renal biopsies can serve to assure the majority of diabetic patients that they are developing serious lesions slowly, if at all.(ABSTRACT TRUNCATED AT 250 WORDS)

The role of hypertension in the development of nephropathy in type 1 (insulin-dependent) diabetes mellitus

Which comes first when developing clinical diabetic nephropathy, the blood pressure rise or the increasing urinary albumin excretion? This issue is discussed based on recent literature of studies in humans with Type 1 (insulin-dependent) diabetes mellitus. We conclude that hypertension has a central role in the progression of diabetic nephropathy and has deleterious effects on the life expectancy of patients who already have signs of diabetic renal disease in terms of elevated urinary albumin excretion. However, blood pressure is preceded by small increments of urinary albumin excretion rates, an indicator of universally increased vascular leakiness, and thus does not seem to be the cause of diabetic nephropathy.

Natural history of hypertension and kidney disease in diabetes

Diabetic nephropathy is the most severe complication of insulin-dependent diabetes mellitus. Epidemiological studies have shown that 30-40% of the patients develop this complication, which is associated with an increase in mortality. Haemodynamic factors, in particular, hyperfiltration, increased flow, and capillary hypertension have been suggested to be of pathogenetic importance, but this is still controversial. Of clinical importance is the close association between clinical diabetic nephropathy and increased blood pressure. Several studies have demonstrated a beneficial effect of early antihypertensive therapy. Most encouraging, however, is the recent finding of a reduced mortality in patients with diabetic nephropathy in whom early antihypertensive therapy has been carried out.

A new enzyme-linked immunosorbent assay for urine and serum concentrations of the carboxyterminal domain (NCI) of collagen IV. Application in type I (insulin-dependent) diabetes

The major collagenous component of glomerular basement membrane (GBM) is collagen IV. Serum concentrations of the carboxyterminal end (NCI) of collagen IV have been proposed to be related to GBM turnover, which has been suspected to increase in diabetes mellitus. For the quantification of serum and urinary concentrations of NCI, a specific, sensitive enzyme-linked immunosorbent assay (ELISA) with monoclonal antibodies was developed. The detection limit of the assay was 30 ug/1 at the 50% intercept of the standard curve. The intra- and interassay coefficients of variation were 6.2% and 13.9% for serum, respectively, and 11.9% and 39.7% for urine, respectively. The levels of NCI in serum and urine in 67 insulin-dependent diabetics and in 90 sex- and age-matched controls were compared. There were no differences in the serum concentrations of NCI between the diabetics and healthy controls. As a group, the diabetics had a higher urinary excretion of NCI than the controls (20.1 vs 12.5 ng/min, 2p<0.05). Furthermore, the results showed that the excretion of NCI in the urine was normal when the urinary albumin excretion rate (AER) was normal (<6.5 μg/min). The excretion was increased during the early stage of incipient diabetic nephropathy (AER 6.5-30 μg/min) and decreased to normal values with progression to clinical diabetic nephropathy (AER above 500 μg/min). Thus, it is suggested that an increased urinary excretion of NCI may be an early marker for incipient diabetic nephropathy.

Assessment of AlbuSure and its usefulness in identifying IDDM subjects at increased risk for developing clinical diabetic nephropathy.

This study, which included 154 participants in a 10-yr follow-up study of diabetes complications, was conducted to evaluate AlbuSure (a qualitative test designed to detect urinary albumin concentrations greater than 0.03 g/L) for its ability to discriminate between albumin concentrations above and below the manufacturer's concentration threshold and to identify individuals at increased risk for developing diabetic nephropathy (i.e., those with albumin excretion rate [AER] greater than 0.0288 g/24 h). The reproducibility of AlbuSure results was also evaluated. The results of these evaluations were examined by three different types of urine collections (24 h, overnight, and timed postclinic) and overall. AlbuSure's validity was examined by comparing its results to immunonephelometrically measured concentrations and AER. When compared to albumin concentration, AlbuSure had an overall sensitivity of 81.8%, specificity of 94.8%, and positive predictive value of 90.6%. AlbuSure's sensitivity was lower (71.4%) when compared with AER; however, this was higher than the sensitivity achieved by dipsticks against AER (50.7%). On testing urine samples stored for 3 days at 4 degrees C, AlbuSure results were 100% reproducible after 1 day and had an overall reproducibility of 92% after 3 days. When urine was retested after 3 and 15 mo of storage at -70 degrees C, AlbuSure was greater than or equal to 90% reproducible, with some of the differing results attributable to corresponding changes in albumin concentration. The overnight sample appeared to be the sample of choice for testing with AlbuSure in that it showed excellent reproducibility and the highest sensitivity (compared to both albumin concentration and AER).

Diabetic nephropathy: hemodynamic basis and implications for disease management.

New evidence shows that systemic and intrarenal hemodynamic abnormalities are major factors in the initiation and progression of diabetic nephropathy. Genetic predisposition to elevated systemic blood pressure may contribute to its development. Glomerular vasodilation and hyperfiltration, mediated in part by prostaglandins, may play a role in glomerular damage early in the course of diabetes, but clinical studies are limited. The development of more sensitive assays for albuminuria now allows early diagnosis of incipient nephropathy in the "microalbuminuria" phase. Treatment during this phase with antihypertensive agents, including angiotensin-converting enzyme inhibitors, or with dietary protein restriction, can decrease the degree of albuminuria, but data on their long-term effects on disease progression are limited. In hypertensive patients with established clinical diabetic nephropathy characterized by proteinuria in excess of 0.3 to 0.5 g/d, antihypertensive therapy has a major impact on delaying renal failure. Modalities that lower both systemic and intraglomerular pressure may be more beneficial in preserving renal function than those that primarily lower systemic pressure. Any therapeutic intervention should be monitored meticulously to establish its efficacy and safety in the individual patient. Therapy specifically directed against hemodynamic abnormalities throughout the course of diabetic renal disease may significantly delay and decrease the negative impact of this diabetic complication on survival and quality of life.

FEATURES OF ENDOTHELIAL DYSFUNCTION IN EARLY DIABETIC NEPHROPATHY

The release of tissue plasminogen activator (tPA) by vascular endothelial cells during exercise was studied in forty men with insulin-dependent diabetes. Three groups, matched for age and diabetes duration, were defined as: group I (n = 19), normal urinary albumin excretion (less than 30 mg/24 h); group II (n = 11), incipient diabetic nephropathy (30-300 mg albumin excreted per 24 h); and group III (n = 10), clinical diabetic nephropathy (more than 300 mg albumin excreted per 24 h). Nine non-diabetic men served as controls. The rise in tPA antigen with exercise was similar in the controls and group I but significantly smaller in groups II and III (p <0·01). The albumin transcapillary escape rate was significantly higher in groups II and III than in group I and normal controls (p<0·01). The basal plasma level of von Willebrand factor was higher in groups III (p<0·01) and II (difference not significant, p = 0·06) than in group I and normal controls. These findings suggest that insulin-dependent diabetic patients with only slightly raised urinary albumin excretion have general endothelial cell dysfunction or damage. It is not yet clear whether these changes are important in the pathogenesis of thrombosis and atherosclerosis in these patients.

‘Microalbuminuria’ and Diabetes: A Critique—Assessment of Urinary Albumin Excretion and Its Role in Screening for Diabetic Nephropathy

Abnormal albumin excretion in the range not previously detectable by routine clinical methods can now be readily quantified, and has been shown to predict the development of clinically significant nephropathy in insulin-dependent diabetes mellitus (IDDM) and to predict excess mortality in non-insulin-dependent diabetes mellitus (NIDDM). Albuminuria of this degree has been inappropriately called "microalbuminuria," a misleading term which should be abandoned. In IDDM, persistent minimal elevation of albumin excretion predicts the development of more severe proteinuria and clinical diabetic nephropathy, which frequently progresses to renal failure. In NIDDM, the predictive value for renal failure remains to be established, but excess mortality occurs in those with abnormal albumin excretion, suggesting that it is an indicator of generalized vascular disease. However, the normal range of albumin excretion in older subjects is not well established. The relationship of glomerular injury to mildly elevated albumin excretion is uncertain. Several means of reducing the excretion rate have been described, but whether these can halt or prevent progression of glomerular injury is unknown. Thus, at the present time detection of mildly elevated albumin excretion and intervention to reduce the incidence of diabetic nephropathy or other diabetes-related complications fail to meet generally accepted criteria for prescriptive screening. However, such measurements of albumin excretion provide an important tool for research into the natural history and pathogenesis of diabetic nephropathy.

The predictive value of microalbuminuria.

An elevated urinary albumin excretion (termed microalbuminuria) has been proposed as a predictor for later development of clinical diabetic nephropathy (hypertension, falling glomerular filtration rate [GFR], and urinary albumin excretion greater than 300 mg/24 h). However, review of the original reports on the predictability of microalbuminuria revealed a concomitant presence of elevated BP and a propensity to falling GFR. Thus, the predictability of microalbuminuria rests on the added evaluation of BP and GFR. Additional investigation is needed to address the possibility that microalbuminuria and either a rising BP or a falling GFR or both indicates established diabetic nephropathy rather than predicting its development.

Comparison of the Prevalence and Associated Features of Abnormal Albumin Excretion in Insulin-dependent and Non-insulin-dependent Diabetes

Overnight albumin excretion rates were measured in 940 diabetic patients, 416 with insulin dependent and 524 with non-insulin dependent diabetes, and in 106 healthy volunteers. A significantly higher number of non-insulin dependent diabetic patients had abnormal albumin excretion compared with the insulin-dependent group (X2 = 15.2, p less than 0.002). Ten per cent of non-insulin-dependent and 7 per cent of insulin-dependent diabetic patients had albumin excretion rates in the range 30-150 micrograms/min and thus were at risk of the cardiovascular and renal complications of diabetes. Six per cent of non-insulin-dependent and 5 per cent of insulin-dependent diabetic patients had albumin excretion rates above 150 micrograms/min and thus were entering the phase of clinical diabetic nephropathy. Multivariate analysis revealed that male sex and retinopathy in insulin-dependent diabetes, and systolic blood pressure and retinopathy and peripheral vascular disease in non-insulin-dependent diabetes, were significantly related to albumin excretion. Only one patient with insulin-dependent diabetes of less than 5 years known duration had an albumin excretion rate in the range 30-150 micrograms/min, whereas such an excretion rate indicating patients at risk was observed at all durations of non-insulin-dependent diabetes. It is possible that during the long silent phase of non-insulin-dependent diabetes, before diagnosis, significant renal damage occurred.

A new enzyme-linked immunosorbent assay for urine and serum concentrations of the carboxyterminal domain (NCl) of collagen. IV. Application in type I (insulin-dependent) diabetes.

The major collagenous component of glomerular basement membrane (GBM) is collagen IV. Serum concentrations of the carboxyterminal end (NCl) of collagen IV have been proposed to be related to GBM turnover, which has been suspected to increase in diabetes mellitus. For the quantification of serum and urinary concentrations of NCl, a specific, sensitive enzyme-linked immunosorbent assay (ELISA) with monoclonal antibodies was developed. The detection limit of the assay was 30 micrograms/l at the 50% intercept of the standard curve. The intra- and interassay coefficients of variation were 6.2% and 13.9% for serum, respectively, and 11.9% and 39.7% for urine, respectively. The levels of NCl in serum and urine in 67 insulin-dependent diabetics and in 90 sex- and age-matched controls were compared. There were no differences in the serum concentrations of NCl between the diabetics and healthy controls. As a group, the diabetics had a higher urinary excretion of NCl than the controls (20.1 vs 12.5 ng/min, 2p less than 0.05). Furthermore, the results showed that the excretion of NCl in the urine was normal when the urinary albumin excretion rate (AER) was normal (less than 6.5 micrograms/min). The excretion was increased during the early stage of incipient diabetic nephropathy (AER 6.5-30 micrograms/min) and decreased to normal values with progression to clinical diabetic nephropathy (AER above 500 micrograms/min). Thus, it is suggested that an increased urinary excretion of NCl may be an early marker for incipient diabetic nephropathy.