Susanne Rudberg

Effect of angiotensin converting enzyme inhibitor or beta blocker on glomerular structural changes in young microalbuminuric patients with Type I (insulin-dependent) diabetes mellitus.

Aims/hypothesis. To investigate the influence of angiotensin converting enzyme inhibitors and beta blockers on the progression of early diabetic glomerulopathy. Methods. Thirteen patients with Type I (insulin-dependent) diabetes mellitus (mean age 18.8 years) with microalbuminuria 31 (19–160) μg/min were randomised to treatment with enalapril (group 1, n = 7) or metoprolol (group 2, n = 6). Renal biopsies were taken before and after 38 (36–48) months of treatment. Albumin excretion rate, blood pressure and HbA1 c were measured every third month. A reference group without antihypertensive treatment (group 3, n = 9), with similar age, diabetes duration and degree of microalbuminuria as group 1 and 2, had baseline and follow-up renal biopsies taken previously with an interval of 26–34 months, analysed at the same laboratory. Glomerular structures were measured by stereological methods. Results. Measurements of basement membrane thickness, mesangial and matrix volume fractions were similar among groups at baseline. Structural variables were only increased in group 3 at follow-up. Delta values in basement membrane thickness and diabetic glomerulopathy index per 24 months were lower in group 1 and 2 than in group 3 (p < 0.05). Microalbuminuria returned to normal in group 1 and 2 only. Decreased albumin excretion rate tended to inversely correlate with increased basement membrane thickness (p = 0.08) and diabetic glomerulopathy index (p = 0.05). Mean HbA1 c was similar between groups. Mean diastolic blood pressure was lower in group 1 and 2 than in group 3 (p < 0.01). Mean HbA1 c and mean diastolic blood pressure correlated to changes in basement membrane thickness, mesangial volume fraction and diabetic glomerulopathy index (p < 0.05). Conclusion/interpretation. Contrary to findings in the group without antihypertensive treatment, no progression of glomerulopathy was seen in those treated with enalapril or metoprolol. [Diabetologia (1999) 42: 589–595]

Higher Intakes of Fish Protein Are Related to a Lower Risk of Microalbuminuria in Young Swedish Type 1 Diabetic Patients

OBJECTIVE To examine the influence of dietary intake from various protein and fat sources on the occurrence of microalbuminuria in type 1 diabetic patients. RESEARCH DESIGN AND METHODS In this nested case control study, 1,150 patients with diabetes duration >5 years reported dietary habits for the previous 12 months and submitted urinary samples for the analysis of albumin excretion rate (AER). A total of 75 cases of albuminuria (overnight AER > or = 15 microg/min) were identified and compared with 225 duration-matched control subjects. RESULTS Neither mean protein, fat intake, average fish protein intake (control subjects 4.56 +/- 3.83 g/day and cases 3.82 +/- 2.87 g/day; P = 0.12), nor intake of meat and vegetable protein differed between the cases of albuminuria and the control subjects. High consumers of fish protein (greater than the 75th percentile) (12 cases and 63 control subjects, mean intake 9.35 g fish protein/day, i.e., approximately 53 g fish/day) had lower odds ratios (ORs) for microalbuminuria than individuals consuming less fish protein (mean 2.72 g/day) (crude OR 0.49 and 95% CI 0.25-0.97). When adjusted for known confounding factors, such as HbA1c, mean arterial pressure, diabetes duration, age, sex, smoking, BMI, country region, and total energy, individuals with a high intake of fish protein and fish fat showed a reduction in the risk for microalbuminuria (OR 0.22 and 0.31, respectively; 95% CI 0.09-0.56 and 0.13-0.76, respectively). When fish protein and fat were adjusted for each other, a high intake of fish protein but not of fish fat was still significantly associated with a decrease in the risk for microalbuminuria. CONCLUSIONS Total protein and fat intake were not associated with the presence of microalbuminuria, but a diet including a high amount of fish protein seemed to lessen the risk.

Determinants of Progression of Microalbuminuria in Adolescents With IDDM

OBJECTIVE To evaluate the significance of microalbuminuria in adolescents with IDDM and to study the relative importance of blood pressure (BP), metabolic control, and albumin excretion rate (AER) on progression of microalbuminuria. RESEARCH DESIGN AND METHODS A cohort of 155/156 children and adolescents followed from onset up to 18.3 years of IDDM participated. In a previous follow-up in July 1991 (up to 15 years of duration), 17 patients had developed persistent microalbuminuria (≥20 μg/min). In these adolescents, we analyzed whether microalbuminuria had progressed (in mean ≥5% per year), had remained unchanged, or had normalized (<20 μg/min) after another 3 years. The predictive values of mean HbA1c, diastolic blood pressure (dBP), systolic blood pressure (sBP), overnight AER, sex, age, and duration of diabetes for the progression of microalbuminuria were determined using multiple regression modeling. RESULTS Seven of 17 patients with microalbuminuria in July 1991 had normalized, 6 of 17 patients had progressed, and 4 of 17 patients had remained unchanged after 3 years. Progressors had higher mean HbA1c during the first 5 years of IDDM and higher mean sBP in 1991 than nonprogressors. Patients with normalized microalbuminuria all had AER <30 μg/min in 1991, were younger at onset of microalbuminuria, had lower mean HbA1c, and had lower dBP before normalized AER than nonregressors at the same duration of microalbuminuria. In multivariate analysis, independent significant predictors for progression were first 5-year mean HbAlc, mean AER, and mean sBP in 1991 (R2 = 0.76, P = 0.001). CONCLUSIONS Progression of microalbuminuria in adolescents with IDDM is predicted by early sustained hyperglycemia, later elevated sBP, and increased AER per se. Microalbuminuria is frequently normalized in adolescents, and this is associated with better prevailing metabolic control, younger age, and lower dBP.

Predictors of Renal Morphological Changes in the Early Stage of Microalbuminuria in Adolescents With IDDM

OBJECTIVE To evaluate the impact of glycemic control, blood pressure, lipid levels, glomerular filtration rate (GFR), age, and duration of IDDM on the degree of structural glomerular changes in the transitional stage of microalbuminuria. RESEARCH DESIGN AND METHODS Fifteen adolescents (seven boys and eight girls) with > 5 years of duration of IDDM and with low-grade microalbuminuria (15–30 micrograms/min) participated. Seventeen living kidney donors served as healthy control subjects. Five-year mean HbA1c; 5-year mean systolic and diastolic blood pressure; GFR, cholesterol, and triglycerides 2–5 years before renal biopsy; age; and duration of IDDM were investigated and related to basement membrane thickness (BMT), mesangial and matrix volume fractions, and the overall glomerulopathy index [(BMT/10 + mat/glom, %) + matrix star volume]. RESULTS BMT and the overall diabetic glomerulopathy were increased in diabetic patients as compared with control subjects (P < 0.001), whereas matrix volume fraction, but not mesangial volume fraction, tended to be increased (P = 0.11). In multivariate analysis, BMT was predicted by 5-year mean HbA1c, diabetes duration, and previous GFR (R2 = 0.71, P = 0.003). With matrix volume fraction as the dependent variable, BMT and diabetes duration were the only significant determinants (R2 = 0.63, P = 0.003). Diabetes duration, 5-year mean HbA1c, and GFR were the variables with an independent influence on the overall diabetic glomerulopathy index (R2 = 0.72, P = 0.003). Preceding blood pressure and lipid levels or age had no significant independent influence on these morphometric measures. CONCLUSIONS In the very early stage of microalbuminuria in IDDM adolescents, a high percentage of the variation in BMT and overall severity of glomerulopathy is explained by prolonged hyperglycemia and diabetes duration. Previous glomerular hyperfiltration may also add to the prediction of these morphological changes.

Glomerular volume and the glomerular vascular pole area in patients with insulin-dependent diabetes mellitus

Abstract The vascular pole area (VPA) and glomerular volume were measured in renal biopsies from 9 insulin-dependent diabetes mellitus (IDDM) patients with normal albumin excretion rate (IDDM group 1), 38 IDDM patients with albumin excretion rate >15 μg/min (IDDM group 2) and 10 living kidney donors (ND). The volume of individual glomeruli was estimated as the sum of profile areas factored by the measured distance between levels, t∼ 10 μm, and VPA as the sum of chords multiplied by t. Mean glomerular volume was increased in IDDM patients but reached statistical significance only in IDDM group 2 (P = 0.002 vs ND). VPA was significantly different among the groups, mean (CV%) was 2036 (29) μm2 in ND, 3555 (34) μm2 in IDDM group 1, and 3528 (48) μm2 in IDDM group 2, p = 0.004 and 0.001, IDDM versus ND. VPA calculated as a percentage of the surface area of the corresponding glomerulus was 2.4 (23)% in ND, 3.4 (27)% in IDDM group 1, and 3.3 (42)% in IDDM group 2; P = 0.007 and 0.01, IDDM versus ND. The intra-biopsy coefficient of variation was high (20–35%) and of the same order in all groups for all three measurements. Glomerular volume and absolute as well as relative size of VPA showed a positive correlation with estimates of mesangial expansion in IDDM group 2 and the VPA showed a negative correlation with GFR. Thus, part of the enlargement may represent a compensatory phenomenon triggered by the development of structural and functional abnormalities in the diabetic kidney.

The effect of polymorphisms in the renin-angiotensin-aldosterone system on diabetic nephropathy risk

OBJECTIVES The risk of diabetic nephropathy (DN) can be increased by elevated intraglomerular pressure and glomerular filtration rate, leading to glomerular damage. This can be controlled by the renin-angiotensin-aldosterone (RAA) system, which has an important function regulating both systemic and intrarenal blood pressure. Smoking increases the risk of DN, but not all diabetic patients who smoke develop DN. There is a possibility that smoking has different effects depending on the different genotypes of the individual. We investigated the association of DN with seven polymorphisms in the RAA system and their possible interaction with smoking. SUBJECTS AND METHODS In the present case-control study, type 1 diabetic patients with diabetes duration > or =20 years, without albuminuria and without antihypertensive treatment (n=197), were included as controls. An albumin excretion rate (AER) of 20-200 microg/min (n=73) was considered as incipient DN, and an AER >200 microg/min was considered as overt DN (n=48). Smoking habits were obtained from questionnaires. RESULTS Homozygosity for the A allele, of the angiotensin II type 1 receptor (AGTR1) A1166C polymorphism, was associated with increased risk of overt DN (OR=3.04; 99% CI=1.02-9.06), independently of the other associated variables: age, duration of diabetes, ever smoking, HbA1c, and sex. The effect of the AA genotype was enhanced to a four times risk increase among ever-smoking patients. Two alleles of the microsatellite marker adjacent to the angiotensinogen gene were less common among nephropathy cases than among controls, but this was not significant when controlling for the same variables as above. CONCLUSIONS The risk of having overt DN was increased in patients homozygous for the A1166 allele, and smoking seemed to enhance the effect of the AGTR1 genotype.

Indications of Low Sex Hormone Binding Globulin (SHBG) in Young Females with Type 1 Diabetes, and an Independent Association to Microalbuminuria

Sex hormone binding globulin (SHBG) is normally decreased during puberty and inversely related to insulin resistance. Microalbuminuria is rare before puberty in Type 1 diabetes implicating that sex hormones may contribute to its development. We investigated SHBG levels in young females with >5 years of Type 1 diabetes, and the association to microalbuminuria. Ten diabetic females with, and 15 without microalbuminuria, and 17 healthy controls in pubertal stage 4–5 were compared regarding anthropometric data, fasting serum levels of SHBG, testosterone, insulin, insulin‐like growth factor‐1 (IGF‐1), lipids and lipoproteins. Multiple regression analyses were performed to study variables with independent influences on SHBG and albumin excretion rate (AER), respectively, in Type 1 diabetes. SHBG was lower and testosterone/SHBG ratio higher in normoalbuminuric females with diabetes than in controls. This was further emphasized in diabetic patients with microalbuminuria. IGF‐1 was lower in Type 1 diabetes than in controls, and significantly decreased in microalbuminuric as compared to normoalbuminuric diabetic patients. IGF‐1 was only correlated to SHBG in healthy controls. In Type 1 diabetes, applying stepwise multiple regression analysis, insulin dose, BMI, and HbA1c had a significant and independent inverse influence on SHBG (r2 = 0.77, p < 0.001). With log AER as the dependent variable, low SHBG, low IGF‐1, HbA1c, and age added to the regression (r2 = 0.65, p = 0.004), whereas BMI, insulin dose and blood pressure did not. In conclusion, SHBG is decreased in young females with Type 1 diabetes, influenced by increased insulin requirements, BMI and HbA1c. In turn, low SHBG seems to be independently associated to elevated AER in these patients. Prospective studies are necessary to confirm our results.

Association Between Lipoprotein(a) and Insulin-Like Growth Factor I During Puberty and the Relationship to Microalbuminuria in Children and Adolescents With IDDM

OBJECTIVE To study pubertal changes in serum lipoprotein(a) [Lp(a)] and insulin-like growth factor I (IGF-I) in insulin-dependent diabetes mellitus (IDDM) and the relationship to microalbuminuria. RESEARCH DESIGN AND METHODS Seventy-nine children and adolescents (59 with normoalbuminuria, 20 with microalbuminuria) with ≥ 5 years of IDDM were investigated together with 54 healthy control subjects in a cross-sectional study. Fasting serum Lp(a); apolipoprotein (apo) A-1 and B; total, low-density lipoprotein (LDL), and high-density lipoprotein cholesterol; triglycerides; and IGF-I were analyzed as were HbA1c and overnight albumin excretion rate (AER). Pubertal development was assessed by Tanner staging. RESULTS Lp(a), apoB, triglycerides, and total and LDL cholesterol were higher (P < 0.001) and apoA-1 was lower (P = 0.03) in normoalbuminuric IDDM patients than in healthy control subjects. Lp(a) was increased during puberty (stages 2–4) in IDDM patients but not in healthy subjects, whereas IGF-I was significantly increased during puberty in healthy control subjects only. In IDDM patients Lp(a) correlated to insulin dose, total cholesterol, and LDL cholesterol, but not to IGF-I, HbA1c, systolic and diastolic blood pressure, diabetes duration, age, or sex. In multiple regression analysis with Lp(a) as the dependent variable, puberty was the only significant contributor to the regression (r2 = 0.33, P = 0.008). Microalbuminuria was seen only in the pubertal stage 4–5. Lp(a) tended to be higher (P = 0.06) as did apoB, whereas IGF-I was lower (P < 0.001) in this group than in normoalbuminuric patients of the same pubertal stages. In multivariate analysis, with log AER as the dependent variable, apoB/apoA-1, systolic blood pressure, age, and IGF-I but not Lp(a) added to the regression (r2 = 0.47, P < 0.0001). CONCLUSIONS Lp(a) is elevated during puberty in normoalbuminuric subjects with IDDM, independent of metabolic control and IGF-I. Lp(a) tends to be further increased in microalbuminuria but does not seem to be a contributing determinant of log AER whereas low IGF-I does. Prospective studies are required to establish the temporal relationship between increased Lp(a) and microalbuminuria in children and adolescents with IDDM.

Indomethacin but not metoprolol reduces exercise-induced albumin excretion rate in type 1 diabetic patients with microalbuminuria.

The effects of a single oral dose of indomethacin (1 mg kg−1), metoprolol (1.5 mg kg−1) and placebo on exercise‐induced albumin excretion rate (AER) were compared in a randomized, crossover design in 14 normotensive, young Type 1 diabetes patients, nine of them with microalbuminuria (AER > 15 μg min−1) and five without microalbuminuria at rest. The albumin excretion rate, blood pressure, heart rate, blood glucose, and plasma concentrations of indomethacin and metoprolol were determined before and after 30 min submaximal physical exercise. In microalbuminuric patients the rise in albumin excretion rate after exercise on indomethacin (7 μg min−1) was lower than after placebo (29 μg min−1, p < 0.001) whereas the rise in albumin excretion rate with metoprolol during exercise (18 μg min−1) did not differ from placebo (p = 0.48), in spite of the expected less marked increase in blood pressure. In normoalbuminuric patients no significant increase in albumin excretion rate was noted by exercise in any of the treatment periods. A tendency to a linear correlation (r = −0.54, p = 0.07) was seen between the plasma concentration of indomethacin and the inhibition of exercise‐induced increase in albumin excretion rate. No correlations were observed between exercise‐induced changes in albumin excretion rate and systolic blood pressure, heart rate or blood glucose. In conclusion, acute indomethacin treatment, presumably through inhibition of renal prostaglandin synthesis, reduces the exercise‐induced rise in albumin excretion rate in Type 1 diabetic patients with microalbuminuria. Such an effect was not seen after acute administration for the beta‐1‐adrenoceptor blocking drug metoprolol, in spite of a less marked rise in blood pressure.

Enlargement of the juxtaglomerular apparatus in insulin-dependent diabetes mellitus patients with microalbuminuria.

Abstract Kidney biopsies from 15 insulin-dependent diabetes mellitus (IDDM) patients with microalbuminuria were investigated to obtain quantitative data on the juxtaglomerular apparatus. The IDDM patients were young and normotensive with a mean duration of microalbuminuria of 2 years. Eight healthy kidney donors served as controls. Measurements taken by light microscopy, using 1-µm serial sections of epon blocks, included volumes of the juxtaglomerular apparatus and of glomeruli, areas of the macula densa and luminal area of the juxtaglomerular (afferent and efferent) arterioles at the level of the glomerular vascular pole. The volume of the juxtaglomerular apparatus was significantly larger in the IDDM group than in controls [6.08 (2.96–18.8) 104µm3 vs 3.48 (1.84–5.21) 104µm3, P=0.003, median and (range)], as was the volume of the juxtaglomerular apparatus relative to glomerular volume [1.89(1.28–4.21)% vs 1.48 (1.13–1.71)%, P=0.004]. The area of the macula densa was also larger in the IDDM patients (1370 µm2 vs 937 µm2, P=0.03). Luminal areas of the afferent and efferent arterioles and the ratio between them did not differ significantly between the two groups. In conclusion, the juxtaglomerular apparatus is enlarged more than would be expected from the glomerular hypertrophy in IDDM patients with microalbuminuria.