Protective effect of captopril on the blood-retina barrier in normotensive insulin-dependent diabetic patients with nephropathy and background retinopathy

The effect of 18 months' inhibition of angiotensin-converting enzyme by captopril on the leakage of fluorescein through the blood-retina barrier was examined in a prospective, randomized control study of 20 normotensive insulin-dependent diabetic patients with nephropathy and background retinopathy. After 18 months, 15 patients remained in the study. Fluorescein leakage remained nearly unchanged in the captopril-treated group, being 4.1 ± 4.1 (mean ± SD) × 10^–7 cm/s at baseline and 4.2±4.1 × 10^–7 cm/s after 18 months' treatment. The permeability increased significantly (P<0.01) from 3.3±2.2 × 10^–7 cm/s to 5.6±3.5 × 10^–7 cm/s at 18 months in the control group. Arterial blood pressure was nearly constant in both groups throughout the study. The results indicate that angiotensin-converting enzyme inhibition with captopril can arrest or delay a progressive breakdown of the blood-retina barrier in normotensive insulin-dependent diabetic patients with nephropathy and background retinopathy.The authors have no commercial or proprietory interest in the drugs or instruments used in this study     

Dual blockade of the renin-angiotensin system in type 1 patients with diabetic nephropathy.

BACKGROUND: Albuminuria and hypertension are predictors of poor renal and cardiovascular outcome in patients with diabetes. Approximately 30% of type 1 patients with diabetic nephropathy (DN) have albuminuria >1 g/day, and blood pressure >135 and/or >85 mmHg despite antihypertensive therapy with recommended doses of ACE inhibitor (ACEI) and diuretics. We tested the effect of dual blockade of the renin-angiotensin system (RAS) in these patients. METHODS: We performed a randomised double blind crossover trial with 2 months treatment with Irbesartan 300 mg o.d. and placebo added on top of previous antihypertensive treatment. We included 21 type 1 patients with DN responding insufficiently to ACEI and diuretics, as defined above. At the end of each treatment period, albuminuria, 24-h blood pressure and glomerular filtration rate (GFR) were measured. RESULTS: Addition of 300 mg Irbesartan to the patients' usual antihypertensive therapy induced a mean reduction in albuminuria of 37% (95% CI 20-49, P<0.001); from 1574 mg/24 h (95% CI 1162-2132) to 996 mg/24 h (95% CI 699-1419), a reduction in 24-h blood pressure of 8 mmHg systolic (95% CI -2 to 18) and 5 mmHg diastolic (95% CI 1-9) (P=0.11 and 0.01, respectively) (from placebo, mean (SE) 146 (4)/80 (2) mmHg). GFR remained unchanged. Serum potassium increased (mean 4.3 to 4.6 mmol/l, P=0.02). Intervention to reduce serum potassium was needed in two patients with GFR <35 ml/min/1.73 m(2). Otherwise the dual blockade with Irbesartan was safe and well tolerated. CONCLUSIONS: Dual blockade of the RAS may offer additional renal and cardiovascular protection in type 1 patients with DN responding insufficiently to conventional antihypertensive therapy, including recommended doses of ACEI and diuretics.     

Is diabetic nephropathy an inherited complication?

For yet unidentified reasons less than 50% of patients with insulin-dependent mellitus develop diabetic nephropathy. Genetic factors have been suggested as risk markers for development of nephropathy in diabetes. To further evaluate this hypothesis we studied the prevalence of nephropathy in diabetic siblings of diabetic patients with and without nephropathy. From a representative sample of 619 patients with insulin-dependent diabetes, we identified 20 patients with and 29 patients without nephropathy having diabetic siblings. Diabetic nephropathy (defined as urinary albumin excretion greater than 300 mg/24 hr) was found in 7 out of 21 siblings to patients with nephropathy and 3 out of 30 siblings to normoalbuminuric patients (P less than 0.04). No significant differences between the two groups of siblings with respect to age, diabetes duration, sex distribution, blood pressure or glycosylated hemoglobin A1c-levels were found. A significant correlation within sib-pair of glycosylated hemoglobin A1c was found (r = 0.47; P less than 0.001). We conclude that familial clustering of diabetic nephropathy does occur. This clustering may either be due to genetic inheritance or to sib-similarities due to shared environment, as indicated by the correlation of glycosylated hemoglobin A1c within sib-pairs.     

Mechanisms of edema formation in myxedema--increased protein extravasation and relatively slow lymphatic drainage.

We assessed extravascular accumulation of albumin and fluid in primary myxedema by measuring metabolic turnover and transcapillary escape of 131I-labeled human albumin in seven patients. In the hypothyroid state, we found a low plasma volume (P less than 0.05), a reduced rate of albumin synthesis and catabolism (P less than 0.01), an increased transcapillary escape rate of albumin (P less than 0.01), a remarkable increase in the extravascular mass of albumin (1500 micronmol; P less than 0.01) and a longer mean transit time through the extravascular spaces in primary myxedema than in other states of generalized edema (P less than 0.05). All variables returned to normal during l-thyroxine treatment. The extravascular accumulation of albumin, and presumably of all other plasma proteins, is important in the generalized edema typically found in myxedema. Inadequate lymphatic drainage may also explain the formation of exudates in the serous cavities that are well known in myxedema.     

HLA associations in insulin-dependent diabetes: search for heterogeneity in different groups of patients from a homogeneous population

A total of 317 unrelated Danish patients with insulin-dependent diabetes mellitus (IDDM) have been HLA-DR typed and the antigen and phenotype frequencies compared with those in 1177 unrelated Danish controls. The strong positive associations with DR3 and 4 and the strong negative one with DR2 were confirmed, and the remaining antigens showed a hierarchy from weakly positive to strongly negative associations: DRw9, w8, 1, 5, w6, 7. The study population included various special groups of patients selected in order to study heterogeneity: very early (less than 5 years) and very late (greater than 40 years) onset IDDM, pregnancy-induced IDDM, IDDM nephropathy, and long-term (greater than 40 years) survivors without complications. When comparing these groups, the following minor differences were seen: the DR3,4 phenotype is significantly (p = .02) more frequent in IDDM with onset before age 20 (35%) than in other cases (24%), and in familial IDDM (48%) than in other cases (28%); the frequency of the DR4 antigen was significantly (p = .008) more frequent in long-term survivors (86%) than in other patients (69%), while it was significantly (p = .02) less frequent in IDDM nephropathy (63%) than in long-term survivors. However, apart from the age-at-onset heterogeneity, which was suspected a priori, these differences may be due to chance, and the main conclusion of this study is that the HLA-DR associations in IDDM are indeed extraordinarily homogeneous irrespective of the clinical characteristics at onset and course of the disease.     

Mixed solvent exposure and hearing impairment: an epidemiological study of 3284 men. The Copenhagen male study

Animal experiments and human studies have indicated an effecton auditory functions from exposure to organic solvents. Inthis study the relationship between self-assessed hearing problemsand occupational exposure to solvents was investigated in across-sectional design with 3284 participating men aged 53–74years. Exposure to solvents for five years or more resultedin an adjusted relative risk (RR) for hearing impairment of1.4 (95 per cent Cl: 1.1–1.9) in men without occupationalexposure to noise. Factors adjusted for were age, noise traumas,chronic middle ear infection and family history of hearing impairment.The prevalence of hearing impairment in men not exposed to organicsolvents was 24 per cent and the attributable risk from solventexposure was 9.6 per cent. Exposure for less than five yearshad no effect on hearing capacity. Occupational exposure tonoise for five years or more had an effect twice that of solvents,RR: 1.9 (95 per cent Cl: 1.7–2.1). In men exposed to bothsolvents and noise the effect of the latter dominated and noadditional effect from solvents was found. A subsample of 51men was examined with pure tone audiometry and 20 of 21 menwho reported abnormal hearing also fulfilled an audiometriccriterion for hearing impairment. In conclusion a damaging effecton hearing ability from long-term solvent exposure was foundin the present study. The relative effect was moderate but witha high background frequency of hearing problems in the unexposedsample the absolute effect, ie attributable risk, was considerableand of both clinical and preventive importance.     

Causes of albuminuria in patients with type 2 diabetes without diabetic retinopathy

BACKGROUND: The causes of albuminuria in patients with type 2 diabetes are heterogeneous and are scantily investigated, particularly if the patient has a lack of diabetic retinopathy. Therefore, we evaluated the structural background of albuminuria in a large consecutive group of Caucasian patients with type 2 diabetes without retinopathy. METHODS: Three hundred forty-seven consecutive patients with type 2 diabetes with persistent albuminuria (>300 mg/24 h) were recorded. Fundus photo (80%) and ophthalmoscopy were performed. Ninety-three (27%) had no retinopathy, and a kidney biopsy was performed in 52 (56%) of these patients. An insufficient tissue sample was obtained in one patient. The biopsies were evaluated by three masked nephropathologists. RESULTS: The biopsies revealed diabetic glomerulopathy in 69% of the patients (28 males and 7 females), while the remaining 31% (95% CI, 18 to 44) had either nondiabetic glomerulopathies such as glomerulonephritis (N = 7, 6 males and 1 female, 13%) or normal glomerular structure (N = 9, 7 males and 2 females, 18%). No significant differences in sex, age (56 +/- 8 vs. 53 +/- 10 years, mean SD), body mass index (30 +/- 4 vs. 31 +/- 8 kg/m2), known duration of diabetes (6 +/- 6 vs. 4 +/- 3 years), GFR (95 +/- 29 vs. 89 +/- 31 mL/min/1.73 m2), albuminuria (1304 +/- 169 to 4731 vs. 1050 +/- 181 to 5176 mg/24 hours), blood pressure (150/87 +/- 16/9 vs. 145/89 +/- 16/9 mm Hg), prevalence of hypertension (89 vs. 100%), hemoglobin A1c (8.2 +/- 1.6% vs. 9.0 +/- 2.5%), and serum total cholesterol (7.1 +/- 2.4 vs. 6.3 +/- 1.6 mmol/L) were found between patients with and without diabetic glomerulopathy. CONCLUSIONS: Albuminuric patients with type 2 diabetes without diabetic retinopathy have a prevalence of biopsies with normal glomerular structure or nondiabetic kidney diseases of approximately 30%. A separation between diabetic and nondiabetic glomerular lesions was not possible based on demographic, clinical, or laboratory data. Consequently, such patients may require further evaluation, including a kidney biopsy.