Incipient Nephropathy Research Articles

Urinary excretion of type IV collagen and laminin in the evaluation of nephropathy in NIDDM: comparison with urinary albumin and markers of tubular dysfunction and/or damage

To clarify the diagnostic relevance of urinary type IV collagen (IV-C) and laminin in diabetic nephropathy, the excretion of these basement membrane proteins were determined by enzyme immunoassay in 172 non-insulin-dependent diabetic patients with different grades of nephropathy and 64 non-diabetic control subjects, and were evaluated in comparison with those of urinary albumin, N-acetyl-β- d-glucosaminidase (NAG) and α 1-microglobulin (α 1MG). These excretions were also compared between a group of non-diabetic renal disease (NDRD) patients ( n = 24) and a subgroup of the diabetic patients studied ( n = 76), whose urinary albumin excretion (UAE) varied within the ranges of micro-and macroalbuminuria. Of the diabetic patients studied, 49.7%, 53.4% and 32.4% had raised urinary albumin, NAG and α 1MG excretion, respectively. In these patients, 54% and 53% exceeded the upper limit of normal for urinary IV-C and laminin. The level of IV-C and laminin excretion and the prevalence of their abnormal excretion showed a trend to increase with increasing grade of nephropathy, as assessed by UAE. In the normoalbuminuric [UAE < 20 mg/g creatinine (Cr)] stage, 28.3% and 26.3% patients had raised urinary IV-C and laminin excretion, respectively. In this stage, the excretion values for IV-C and laminin also rose significantly even when the UAE was ≤ 10 mg/g Cr ( P < 0.05 and P < 0.005, respectively). There was a close linear relationship between IV-C and laminin excretion ( r = 0.73, P < 0.0001), together with their significant relationships with albumin, NAG and α 1MG excretion. The relationship of urinary IV-C and laminin with urinary NAG and α 1MG excretion remained significant even in normoalbuminuric patients. The normoalbuminuric patients with raised NAG and/or α 1MG excretion also had a higher prevalence of raised IV-C and laminin excretion than those with normal NAG and α 1MG excretion. The excretion values for IV-C and laminin, and the excretion ratios for IV-C albumin and laminin albumin were significantly higher in diabetic patients with evidence of incipient and clinical nephropathy than in NDRD patients, though the two patient groups had a comparable level of serum Cr and UAE. We conclude that the measurement of urinary IV-C and laminin may have potential for the evaluation of diabetic nephropathy. Furthermore, their determination might be helpful for distinguishing diabetic versus non-diabetic etiologies of altered renal function in diabetic patients.

Serum sialic acid concentration is elevated in IDDM especially in early diabetic nephropathy

Elevated serum sialic acid concentration is a strong predictor of cardiovascular mortality in non-diabetic subjects. Because patients with insulin-dependent diabetes mellitus (IDDM) and albuminuria have a highly increased cardiovascular morbidity and mortality, we hypothesized that IDDM patients with albuminuria would have an increased concentration of serum sialic acid. Cross-sectional study. Outpatient clinic at Steno Diabetes Centre, Gentofte, Denmark. Twenty-six non-diabetic controls and 74 IDDM patients with normoalbuminuria (urinary albumin excretion [UAE] < 30 mg 24 h-1; n = 37), incipient nephropathy (UAE 30-300 mg 24 h-1; n = 20) and clinical nephropathy (UAE > 300 mg 24 h-1; n = 17), matched for sex, age and body mass index (BMI). Serum sialic acid concentration, concurrent fasting blood glucose, glycated haemoglobin (HbA1c), serum creatinine, plasma fibrinogen and erythrocyte sedimentation rate. Normoalbuminuric patients had a higher serum sialic acid concentration (mmol L-1) than non-diabetic controls (1.83 +/- 0.24 vs. 1.67 +/- 0.26; P < 0.02). Serum sialic acid concentration was further increased in patients with incipient nephropathy (2.02 +/- 0.37; P < 0.03) and in patients with clinical nephropathy (2.13 +/- 0.33; P < 0.002) compared with normoalbuminuric IDDM patients. Serum sialic acid correlated strongly with plasma fibrinogen (r = 0.78; P < 0.0001) and erythrocyte sedimentation rate (r = 0.62; P < 0.0001). In a multiple regression analysis including UAE, retinopathy status, fasting blood glucose, HbA1c, mean blood pressure, serum creatinine, age, BMI, duration and smoking. UAE and fasting blood glucose were the independent variables which correlated significantly with serum sialic acid concentration (P < 0.0001 and P < 0.05, respectively). Serum sialic acid is elevated in IDDM especially in albuminuric patients. Whether elevated serum sialic acid is predictive for early diabetic nephropathy and cardiovascular disease in IDDM has to be shown in the future.

Glomerular hyperfiltration increases the risk of developing microalbuminuria in diabetic children

An elevated glomerular filtration rate (GFR) is frequently detectable in type 1 diabetic children and adolescents and in those without any other evidence of incipient diabetic nephropathy. In 1982 we detected 23 patients with hyperfiltration (GFR > 140 ml/min per 1.73 m2), aged 9-15 years, with diabetes for longer than 4 years; 23 age- and sex-matched patients with diabetes of a similar duration and without hyperfiltration served as controls. Both groups were followed until March 1992, by assessing GFR every 12 months, albumin excretion rate every 6 months, blood pressure and glycated haemoglobin (HbA1) every 3 months. Dietary protein intake was similar in patients with hyperfiltration and in controls. No other drug except insulin was used throughout the study. The insulin regimen was similar in the two groups. There was no significant difference between the two groups regarding albumin excretion, blood pressure and HbA1 at the beginning of the study. Of the 23 patients with hyperfiltration, 7 developed persistent microalbuminuria (defined as an overnight albumin excretion rate > 30 micrograms/min per 1.73 m2 on at least 5 consecutive measurements); 2 of these patients had overt proteinuria. Only 1 of the diabetics with normal GFR developed persistent microalbuminuria. The positive predictive value for microalbuminuria of an initial GFR > 140 ml/min per 1.73 m2 was 63%; the negative predictive value of an initial GFR < 140 ml/min per 1.73 m2 was 94%. The increase of albumin excretion rate into the microalbuminuric range precedes the elevation of both systolic and diastolic blood pressure.(ABSTRACT TRUNCATED AT 250 WORDS)

Urinary angiotensin-converting enzyme activity in type 2 diabetes mellitus: its relationship to diabetic nephropathy.

Urinary angiotensin-converting enzyme (ACE) and urinary N-acetyl-beta-D-glucosaminidase (NAG) were measured after a 5-year interval in 38 non-azotemic type 2 diabetic patients. Of these patients at baseline, 16 had nil nephropathy, 15 had incipient nephropathy, and 7 had overt nephropathy. During the follow-up, 6 and 1 of the 16 patients with nil nephropathy developed incipient and overt nephropathy, respectively. Four of the 15 patients with incipient nephropathy progressed to overt nephropathy. The 7 patients with overt nephropathy continued to have overt nephropathy, with slight azotemia in one. Urinary ACE and NAG levels were normal at baseline and showed no significant elevations at follow-up in the patients with nil nephropathy, no significant changes in baseline and modest elevations at follow-up in the patients with incipient nephropathy, and high at baseline and marked elevations at follow-up in the patients with overt nephropathy. In all patients, urinary ACE during the follow-up was positively correlated with urinary albumin or NAG, but not with glomerular filtration rate. Urinary ACE may be of poor prognostic value for the follow-up of diabetic patients, which is at variance with urinary albumin.

Microalbuminuria in an adolescent cohort with insulin-dependent diabetes mellitus.

To document the incidence of microalbuminuria in children and adolescents with longstanding insulin-dependent diabetes mellitus (IDDM) and to compare the clinical characteristics and determinant risk factors of those with and without microalbuminuria, 135 adolescent patients with IDDM for 5 years or longer were evaluated. The study population was divided on the basis of microalbumin excretion into normal (< 20 micrograms/min), incipient (20-200 micrograms/min), and overt (> 200 micrograms/min) nephropathy groups. There were 106 patients in the normal group, 24 patients in the incipient group, and five in the overt nephropathy group. Glycosylated hemoglobin, cholesterol concentration, and glomerular filtration rate (GFR) were analyzed. The incidence of incipient and overt nephropathy was 17.8% and 3.7%, respectively. Mean cholesterol concentration in the incipient and overt nephropathy groups (208 +/- 39 mg/dL [5.4 +/- 1.0 mmol/L]) and 227 +/- 49 mg/dL [5.9 +/- 1.3 mmol/L], respectively) was significantly higher than the normal group (186 +/- 37 mg/dL [4.8 +/- 0.9 mmol/L] P < 0.05). Similarly, systolic and diastolic blood pressures were significantly higher in the incipient and overt nephropathy groups compared to the normal group. This study confirms the high incidence of incipient and overt nephropathy in adolescents with IDDM early in the course of the disease.

Tubular Damage in Microalbuminuric Patients with Primary Glomerulonephritis and Diabetic Nephropathy

Tubular damage as suggested by enzymuria and tubular proteinuria is a recognized feature of glomerulonephritis (GN) with clinical proteinuria and both incipient and overt diabetic nephropathy (DN). However, little is known about the presence of tubulopathy in patients with primary GN, microalbuminuria [albumin excretion (AER) 30-300 mg/d] and microhematuria. Three groups were studied. The GN group comprised 17 (2 F) patients with biopsy-proven GN with microalbuminuria. The DN group comprised 35 (14 F) patients with incipient diabetic nephropathy with AER 30-300 mg/d, and controls comprised 38 (15 F) normal subjects with normal AER < 30 mg/d. Serum creatinine, albuminurinuria, transferrinuria, and markers of tubular damage such as urinary excretion of N-acetyl-glucosaminidase (NAG), leucine aminopeptidase (LAP), gamma-glutamyl transferase (gGT), and retinol binding protein (RBP) were measured. GN and DN had comparable degrees of albuminuria, transferrinuria, and LAP excretion, and these were significantly higher than controls. Serum creatinine was significantly higher in GN than DN and controls. DN had significantly higher NAG and RBP, and lower gGT than GN and controls. In both GN and DN groups, both glomerular proteins correlated with each other and NAG correlated significantly to LAP and gGT. Albuminuria correlated to tubular enzymuria in GN group but not in patients with DN. The results suggest that tubular damage is less marked in microalbuminuric patients with GN than those with DN despite similar degree of glomerular proteinuria. The pattern of tubulopathy is also different in the two groups, indicating differences in the pathogenesis of tubular damage in these two clinical settings.

Genetic predisposition to hypertension (as detected by Na+/Li+ countertransport) and risk of diabetic nephropathy in childhood diabetes

In order to evaluate whether insulin-dependent diabetes mellitus patients with incipient nephropathy have an overactivity of erythrocyte sodium-lithium countertransport (Na+/Li+ CT), 82 diabetic children and 38 healthy age-matched control subjects and their parents and grandparents were studied. The children were divided into two groups according to the presence of persistent microalbuminuria (MA). Diabetic children with MA had Na+/Li+ CT activity higher than normoalbuminuric diabetics and healthy controls. The parents and grandparents of microalbuminuric patients showed higher Na+/Li+ CT than parents and grandparents of normoalbuminuric diabetics and of the controls. This study demonstrates that predisposition to hypertension, as indicated by increased Na+/Li+ CT activity in erythrocytes, is more frequently detectable in patients with persistent microalbuminuria than in diabetics without persistent microalbuminuria or in healthy controls. Overactivity of Na+/Li+ CT is present also in parents and grandparents of diabetic children with MA. This study suggests that genetic predisposition to hypertension is more frequent in patients at risk of developing diabetic nephropathy, as well as in their parents and grandparents.

Plasma prorenin as an early marker of nephropathy in diabetic (IDDM) adolescents

We studied a group of 50 adolescents, average age 16 years, with diagnosed IDDM present for about seven years. Twenty-five had microalbuminuria (MA) averaging 111.0 +/- 34.0 (SEM) micrograms/min albumin excretion rate versus 6.7 +/- 7.4 micrograms/min in the 25 without MA. In other respects, such as sex ratio, age, body mass index, duration of IDDM, hemoglobin A1c, and normotensive systolic, diastolic and mean blood pressures (BP), these subgroups were closely matched. We compared them with a control group of 39 normotensive adolescents, of whom 18 were carefully matched siblings of the IDDM subjects with MA and 21 were similarly matched siblings of the IDDM non-MA subjects. Plasma renin concentration was determined by a direct radioimmunoassay method (Sanofi-Pasteur) and found to be virtually the same in the control and IDDM adolescents as a whole. There was also no real difference between the MA and non-MA subgroups. In contrast, plasma prorenin was significantly higher in the combined IDDM group (197.5 +/- 9.3 vs. control, 134.0 +/- 7.9 pg/ml, P < 0.0001). It was also higher in the MA subgroup than in the non-MA subgroup (226.4 +/- 13.6 vs. 168.5 +/- 10.1 pg/ml, P < 0.001). Interestingly, the 18 control siblings matching the MA subgroup had higher plasma prorenin than the 21 control siblings matching the non-MA subgroup (P < 0.001), suggesting a familial predisposition that precedes detectable diabetes and nephropathy. Our findings confirm and extend reports by other workers that elevated plasma prorenin is associated with incipient nephropathy, manifested by MA. The exclusive renal origin of this prorenin, its role in plasma, and the mechanism responsible for its elevation in IDDM with MA, are yet to be demonstrated, as is the general applicability of these findings to different populations of diabetics, with a higher incidence and severity of complications.

Effects of hypolipidemic drugs on the in vitro oxidizability of non-HDL lipoproteins in insulin-dependent diabetic patients with incipient nephropathy

Effects of hypolipidemic drugs on the in vitro oxidizability of non-HDL lipoproteins in insulin-dependent diabetic patients with incipient nephropathy

Limited joint mobility in type 1 diabetic patients: correlation to other diabetic complications

To examine the association between limited joint mobility (LJM) and complications of diabetes in adult patients with type 1 diabetes. Cross-sectional study in diabetic patients and healthy controls. The study was performed at the department of medicine in Turku University Hospital (n = 103), a private diabetes outpatient clinic (n = 153) and the municipal health centre of Turku (n = 29), Finland. We studied 285 diabetic patients [age (mean +/- SD): 33.4 +/- 10.0 years] and 288 healthy nondiabetic controls [age (mean +/- SD): 32.3 +/- 9.2]. The limitations of several joints were examined with a goniometer. The diabetic patients were assessed in terms of the following complications: background and proliferative retinopathy, peripheral symmetrical polyneuropathy, autonomic neuropathy, impotence as well as clinical and incipient nephropathy; serum lipid values were also measured. The prevalences of LJM were 58% and 14% in diabetic patients and in healthy controls, respectively. The diabetic patients with LJM had a 2.8-fold risk of proliferative retinopathy [95% confidence interval (CI): 1.1-7.3] and a 3.6-fold risk of nephropathy (95% CI: 1.4-9.3) compared to patients without LJM, when the confounding effect of the duration of diabetes was excluded. LJM was not related to metabolic control of diabetes, microalbuminuria, autonomic neuropathy or impotence. The association between LJM and peripheral symmetrical polyneuropathy was exclusively explained by the duration of diabetes. The correlation between LJM and serum total and low-density lipoprotein cholesterol was dependent on the association between LJM and nephropathy. LJM did not relate to serum high-density lipoprotein cholesterol or triglyceride values. The diabetic patients with LJM had an increased risk of proliferative retinopathy and nephropathy compared to patients without LJM.

LDL subclasses in IDDM patients: relation to diabetic nephropathy

To answer the question whether the elevation of LDL-cholesterol in IDDM patients with incipient and established diabetic nephropathy is accompanied by changes in LDL size or composition, we studied distribution of LDL particles in 57 normoalbuminuric [AER 7 (1–19) μg/min, median and range], in 46 microalbuminuric [AER 50 (20–192) μg/min] and in 33 proteinuric [AER 422 (233–1756) μg/min] IDDM patients as well as in 49 non-diabetic control subjects with normoalbuminuria. The three diabetic groups were matched for duration of diabetes and glycaemic control. The mean particle diameter of the major LDL peak was determined by nondenaturing gradient gel electrophoresis. Composition and density distribution of LDL were determined in the subgroups of each patient group by density gradient ultracentrifugation. Normoalbuminuric IDDM patients had larger LDL particles than non-diabetic control subjects (260 Å vs 254 Å, p<0.05). LDL particle diameter was inversely correlated with serum triglycerides in all groups (p<0.05 for normoalbuminuric and p<0.001 for other groups). Triglyceride content of LDL was higher in three IDDM groups compared to control group (p<0.05). The elevation of LDL mass in microalbuminuric and proteinuric IDDM groups compared to normoalbuminuric IDDM group (p<0.05 for both) was mainly due to the increment of light LDL (density 1.0212–1.0343 g/ml). There were no significant changes in the density distribution or composition of LDL between the three diabetic groups. In conclusion the increase of LDL mass without major compositional changes suggests that the elevation of LDL in incipient and established diabetic nephropathy is primarily due to the increased number of LDL particles. The prevalence of atherogenic small dense LDL particles in IDDM patients with microalbuminuria and proteinuria is closely dependent on plasma triglyceride concentration.

Sodium-lithium Transport in Adolescents With IDDM: Relationship to incipient nephropathy and glycemic control

The aims of this study were to examine genetic and environmental influences in the development of early diabetic nephropathy and to assess the value of measuring membrane sodium transport as a marker for early nephropathy. We measured erythrocyte sodium-lithium (Na-Li) countertransport, blood pressure (BP), HbA1c, and microalbuminuria (MA) in 84 adolescents with insulin-dependent diabetes mellitus (IDDM), 29 of whom had MA. Twenty-nine non-MA patients were selected and matched for age, sex, and IDDM duration with the 29 diabetic subjects with MA. The 84 diabetic adolescents were also compared with 85 nondiabetic siblings. The erythrocyte Na-Li countertransport was significantly greater in the IDDM group than in the sibling group (mean +/- SD, 0.41 +/- 0.14 vs. 0.30 +/- 0.11 mmol Li.liters of erythrocytes-1.h-1, respectively, P < 0.0001), but a significant correlation was noted between the results in IDDM subjects and their siblings (r = 0.42, P < 0.0008). Na-Li countertransport was not different in the diabetic subjects with or without MA (0.43 +/- 0.13 vs. 0.37 +/- 0.13 mmol Li.liters of erythrocytes-1.h-1, respectively). There was a significant correlation in the IDDM group between recent diabetic control (HbA1c) and Na-Li countertransport (r = 0.37, P < 0.003). Diastolic BP was significantly higher in the IDDM group with MA than in those without MA (60 +/- 6 vs. 55 +/- 6 mmHg, respectively, P < 0.03). These results suggest that erythrocyte Na-Li countertransport is influenced by the diabetic milieu. However, there was also evidence in our subjects of a genetic contribution to Na-Li countertransport as seen by the correlation between levels in the IDDM subjects and their siblings. Using Na-Li countertransport, we were not able to segregate those IDDM adolescents with and without early nephropathy.

Venous compliance and the venodilatory effect of nitroglycerin in insulin‐dependent diabetic patients with and without (incipient) nephropathy

The venous system plays a pivotal role in volume and blood pressure homeostasis. We tested the hypothesis that the visco-elastic properties of the peripheral venous system are reduced in patients with (incipient) diabetic nephropathy. Twenty-two normotensive patients with long-term insulin-dependent diabetes mellitus (IDDM), 11 without and 11 with (incipient) nephropathy (eight microalbuminuria and three proteinuria, serum creatinine below 100 mumol l-1), and 14 healthy age/sex matched controls were studied. Forearm venous compliance (VENCOMP) was determined using strain gauge plethysmography and direct intravenous pressure measurements. Furthermore, the venodilatory effect of 0.4 mg sublingual nitroglycerin (NTG) was studied. In comparison with healthy controls, VENCOMP was decreased in patients without and with (incipient) nephropathy, without any differences between the two diabetic groups: 0.059 (0.052-0.066), 0.044 (0.038-0.059) and 0.049 (0.046-0.058) ml 100 ml-1 mmHg-1, respectively (medians and interquartile ranges) (P < 0.05). No differences in the increase of forearm volume after NTG were observed: 0.34 (0.11-0.51), 0.37 (0.19-0.50) and 0.39 (0.20-0.55) ml 100 ml-1, respectively. In conclusion, the visco-elastic properties of the peripheral venous system are reduced in patients with long-term IDDM. This reduction is not related to the presence of nephropathy. No major differences were observed in NTG-induced venodilation between diabetic patients and healthy subjects.

Incipient and Overt Diabetic Nephropathy in African Americans With NIDDM

OBJECTIVE--To determine the prevalence of incipient and overt nephropathy in African-American subjects with non-insulin-dependent diabetes mellitus (NIDDM) attending a hospital clinic. Contributory factors, such as blood pressure (BP), duration and age at onset of diabetes, hyperglycemia, hyperlipidemia, and body mass index (BMI) also were evaluated. RESEARCH DESIGN AND METHODS--We recruited 116 African-American subjects with NIDDM for this cross-sectional, descriptive, and analytical study. BP, BMI, 24-h urine albumin excretion, creatinine clearance, serum creatinine, lipids, and GHb levels were measured. Albumin excretion rate (AER) was calculated, and subjects were divided into three groups: no nephropathy (AER < 20 micrograms/min), incipient nephropathy (AER 20-200 micrograms/min), and overt nephropathy (AER > 200 micrograms/min). Frequency of hypertension and nephropathy was analyzed by chi 2 testing, group means were compared using analysis of variance, and linear correlations were performed between AER and other variables. Multiple regression analysis was used to examine the association of these variables while controlling for the effects of other variables. RESULTS--Increased AER was present in 50% of our subjects; 31% had incipient and 19% had overt nephropathy. Hypertension was present in 72.4%; nephropathy, particularly overt nephropathy, was significantly more prevalent in the hypertensive group. Mean BP and diastolic blood pressure (dBP) were higher in the groups with incipient and overt nephropathy, and systolic blood pressure (sBP) was increased in overt nephropathy. Men with either form of nephropathy had higher sBP, dBP, and mean BP, whereas only women with overt nephropathy had increased sBP and mean BP. Subjects with incipient or overt nephropathy had a longer duration of diabetes, and those with overt nephropathy had a younger age at onset of diabetes. By multiple regression analysis, AER correlated with younger age at diabetes onset, but not with diabetes duration. No correlation with age, lipid levels, or GHb was noted. BMI correlated with AER. CONCLUSIONS--Incipient and overt nephropathy were observed frequently in these African-American subjects with NIDDM. Albuminuria correlated with BP, younger age at diabetes onset, and BMI. Association of albuminuria and increased cardiovascular mortality may place 50% of inner-city African-American patients with NIDDM at risk for developing cardiovascular complications.

Blood Pressure Response to Physical Exercise in Healthy Adolescents and Adolescents with Insulin-Dependent Diabetes Mellitus

1. Reference values for systolic blood pressure during exercise are provided for 88 healthy adolescents (12-22 years of age) of both sexes. Data were related to oxygen uptake, heart rate, blood lactate concentration, rate of perceived exertion, age, sex, body size and physical fitness. 2. The same variables were measured in 55 adolescents of both sexes with insulin-dependent diabetes mellitus of about 12 years duration and were analysed with respect to the healthy control group, to degree of metabolic control and to late diabetic complications. 3. In healthy adolescents the pressure response was not related to sex or age. When compared with control subjects diabetic patients had a higher diastolic blood pressure at rest and a more marked blood pressure increase, 23 versus 19 mmHg W-1 kg-1 body weight, during exercise with no sex difference. The blood pressure rise was not related to metabolic control, glomerular hyperfiltration or physical fitness. 4. Prolonged exercise tests were no more informative regarding the blood pressure response to exercise than the stepwise increased load test. Analysing the blood pressure increase versus relative work load (W/kg body weight) during exercise reveals blood pressure differences otherwise not noted. A diabetic patient with blood pressure above the 97.5% confidence limit during exercise seems to have a higher risk of developing incipient nephropathy 5 years later.

Early Diabetic Nephropathy

Diabetic nephropathy affects approximately 35% of patients with insulin-dependent diabetes mellitus and about 5% to 10% of patients with non-insulin-dependent diabetes mellitus. Diabetic kidney disease can be detected early by special methods that measure microalbuminuria in the range of 15 to 140 micrograms/min or 0.02 to 0.20 g/d. Specific strategies have been proved beneficial in patients with this early diabetic kidney disease, also called "incipient nephropathy." Protein restriction, tight control of blood sugar and blood pressure, and specific therapy with angiotensin-converting enzyme inhibitors have been shown independently to reduce microalbuminuria and preserve renal function in these patients. We review the pathogenesis of diabetic kidney disease and discuss the effects of these treatment strategies on the renal, cardiovascular, metabolic, and other abnormalities found in early (incipient) and overt diabetic nephropathy.

Value of Ambulatory Blood Pressure Monitoring in Type I (Insulin-Dependent) Diabetic Patients With Incipient Diabetic Nephropathy

Ambulatory blood pressure monitoring (ABPM) is currently proposed for measuring blood pressure in type I, insulin-dependent diabetic subjects with incipient diabetic nephropathy. However, the value of this method, in comparison with conventional ones in detecting blood pressure differences between normotensive type I, insulin-dependent diabetic subjects with or without microalbuminuria, is questionable. We obtained systolic, diastolic, and mean blood pressures (SBP/DBP/MBP) in 10 hospitalized normotensive type I, insulin-dependent diabetic subjects with microalbuminuria, and in 29 others without, using a mercury sphygmomanometer (method 1) and an automatic device (Dinamap; method 2) to obtain morning (9 to 11 AM) measurements, and ABPM (SpaceLabs 90207; method 3) to obtain daytime (7 AM to 10 PM) and nighttime (10 PM to 7 AM) measurements. During the daytime, SBP/DBP/MBP values were higher in microalbuminuric than in normoalbuminuric patients, whatever the blood pressure measurement method used (P = .034/.061/.033, two-factor ANOVA). Analysis of 24-h ABPM also showed higher SBP/DBP/MBP in microalbuminuric than in normoalbuminuric patients (P = .022/.040/.016), and demonstrated a defect in nocturnal SBP decrease in microalbuminuric compared with normoalbuminuric patients (P = .028). Stepwise multiple regression analysis indicated nocturnal SBP as the only independent factor determining for microalbuminuria (F = 6.72). Thus ABPM, in relation to other methods, indicates above all that the most relevant blood pressure change in type I insulin-dependent diabetic subjects with microalbuminuria is a defect in nocturnal SBP decrease.

The effect of the relationship between tissue-type plasminogen activator and plasminogen activator inhibitor type 1 on tissue-type plasminogen activator activity in insulin-dependent diabetes mellitus

Background: Changed fibrinolytic activity in insulin-dependent diabetes mellitus (IDDM) may give information on the interaction between tissue-type plasminogen activator (t-PA) and plasminogen activator inhibitor type 1 (PAI-1). Aim: To investigate the relationship between t-PA and PAI-1 in IDDM patients with and without diabetic nephropathy. Patients: 17 IDDM patients with normal urine albumin excretion (< 30 mg/24-h, normoalbuminuria), 19 IDDM patients with albumin excretion in the range 30–300 mg/24-h (incipient nephropathy) and 13 IDDM patients with albumin excretion > 300 mg/24-h (clinical nephropathy). 14 nondiabetic subjects served as controls. Results: Given as mean (range). t-PA antigen was lower in IDDM irrespective of the level of albuminuria (3.3 (1.2–5.5) ng/ml, p < 0.05; 4.2 (1.4–12.9) ng/ml, p = 0.07 and 3.4 (1.2–8.7) ng/ml, p < 0.05 vs. 5.4 (2.1–9.6) ng/ml in non-diabetic controls). PAT-1 antigen was also lower in IDDM with normoalbuminuria (4.2 (2.3–7.0) ng/ml vs. 11.0 (3.4–29.8) ng/ml in non-diabetic controls, p < 0.001) and in incipient and clinical nephropathy the pattern was the same (5.9 (1.1–16.7) ng/ml, p < 0.05 and 5.8 (2.7–10.3) ng/ml, p = 0.07 vs. non-diabetic controls, respectively). t-PA activity was increased in IDDM with normoalbuminuria (0.7 (0.4–3.3) iU/ml p < 0.05) compared to the level in non-diabetic controls (0.6 (0.0–2.2) IU/ml), while the level in nephropathy was not different from non-diabetic controls. Conclusion: A shift in the relation between t-PA and PAI-1 antigen levels result in an increased activity of t-PA in IDDM patients without nephropathy.

Diabetes and hypertension.

Hypertension is about twice as common in diabetics as in non-diabetics. The increased prevalence may relate to insulin resistance and its sequelae. Hypertension is a major risk factor for both large and small vessel disease, contributing to accelerated atherogenesis and progression of diabetic nephropathy and retinopathy. Treating raised blood pressure in diabetics is beneficial in the context of large vessel disease and in slowing progression of overt nephropathy. There is controversy as to whether antihypertensives, and particularly ACE inhibitor drugs, will prevent progression from incipient to overt nephropathy. All the major classes of antihypertensives can be used in diabetics, but the thiazide diuretics and beta-blockers have metabolic side-effects which make them less appropriate as first line agents. The calcium antagonists and ACE inhibitors have better metabolic profiles and the latter reduce insulin resistance. ACE inhibitors may also have a renal protective effect in incipient nephropathy although the studies have been fairly short-term and with small patient numbers. Although ACE inhibitors and calcium antagonists are suitable as first line antihypertensives in diabetics, evidence is still lacking that these drugs reduce morbidity and mortality over and above that seen with other antihypertensives.

Human urinary intestinal alkaline phosphatase as an indicator of S3-segment-specffic alterations in incipient diabetic nephropathy

Urinary enzymes were determined in a controlled study including 28 type I diabetes mellitus patients. Fifteen patients had persistent microalbuminuria and were compared to 13 normoalbuminuric patients with comparable age and sex distribution. All patients had normal renal function as measured by serum creatinine. Human intestinal alkaline phosphatase (hIAP), a specific marker of the proximal tubular S3 segment, was elevated in the urine of microalbuminuric patients while human tissue non-specific alkaline phosphatase (hTNAP), indicating effects mainly at the S1-S2 segments, was not. Urinary hIAP was correlated with serum glycated haemoglobin. These results suggest that tubular alterations are present at an early stage of diabetic nephropathy, especially at the S3 segment, and that hIAP may have promise as an early marker.