Tonny Jensen

Relationship Between Blood Pressure and Urinary Albumin Excretion in Development of Microalbuminuria

Two hundred nine consecutive normotensive insulindependent diabetic (IDDM) patients were followed prospectively from November 1982 to January 1988. Patient urinary albumin excretion rate (UAE) had to be normal (<30 mg/24 h) on at least two occasions before inclusion in the study. Patients were aged 18–50 yr with a duration of diabetes of 10–30 yr. UAE was measured every 4 mo, and supine blood pressure was measured annually. Two hundred five patients completed the study. Five years later, 15 patients had developed persistent microalbuminuria with median UAE >30 mg/24 h for at least 2 yr (group 2), and 190 patients stayed normoalbuminuric (group 1). Although within normal range, initial UAE was significantly elevated in group 2 compared with group 1 (mean 19 mg/24 h [range 15–23 mg/24 h] vs. 11 mg/24 h [10–12], 95% confidence interval [Cl], P < 0.001). Initially, there was no difference in blood pressure between group 2 (mean systolic 122 mmHg [117–127], diastolic 80 mmHg [76–84]) and group 1 (mean 126 mmHg [124–128], 79 mmHg [78–80], 95% Cl), and a significant increase in diastolic blood pressure could first be detected during the 3rd yr of persistent microalbuminuria (mean systolic 132 mmHg [124–140], diastolic 85 mmHg [81–89] vs. 128 mmHg [126–130], 79 mmHg [78–80], P < 0.05). Initial hemoglobin A1c was significantly elevated in group 2 compared with group 1 (9.6% [8.8–10.4] vs. 8.5% [8.3–8.7], P < 0.01). Regarding sex, age, duration of diabetes, insulin dose, height, weight, or inverse serum creatinine, no significant differences were seen between the groups. No increase in UAE or blood pressure was detected in group 1, although 38% had experienced at least one elevated UAE during the 5-yr follow-up. Thus, a significant elevation in UAE precedes the increase of systemic blood pressure during the development of nephropathy in IDDM.

Cohort study of predictive value of urinary albumin excretion for atherosclerotic vascular disease in patients with insulin dependent diabetes.

Abstract Objective: To examine whether slightly elevated urinary albumin excretion precedes development of atherosclerotic vascular disease in patients with insulin dependent diabetes independently of conventional atherogenic risk factors and of diabetic nephropathy. Design: Cohort study with 11 year follow up. Setting: Diabetes centre in Denmark. Subjects: 259 patients aged 19-51 with insulin dependent diabetes of 6-34 years duration and without atherosclerotic vascular disease or diabetic nephropathy at baseline. Main outcome measures: Baseline variables: urinary albumin excretion, blood pressure, smoking habits, and serum concentrations of total cholesterol, high density lipoprotein cholesterol, sialic acid, and von Willebrand factor. End point: atherosclerotic vascular disease assessed by death certificates, mailed questionnaires, and hospital records. Results: Thirty patients developed atherosclerotic vascular disease during follow up of 2457 person years. Elevated urinary albumin excretion was significantly predictive of atherosclerotic vascular disease (hazard ratio 1.06 (95% confidence interval 1.02 to 1.18) per 5 mg increase in 24 hour urinary albumin excretion, P=0.002). Predictive effect was independent of age; sex; blood pressure; smoking; serum concentrations of total cholesterol, high density lipoprotein cholesterol, sialic acid, and von Willebrand factor; level of haemoglobin A1c; insulin dose; duration of diabetes; and diabetic nephropathy (hazard ratio 1.04 (1.01 to 1.08) per 5 mg increase in 24 hour urinary albumin excretion, P=0.03). Conclusion: Slightly elevated urinary albumin excretion independently predicted atherosclerotic vascular disease in patients with insulin dependent diabetes. Key messages Key messages Preliminary studies suggested that this mortality might particularly occur among patients with elevated urinary albumin excretion We studied predictive effect of slightly elevated urinary albumin excretion in development of atherosclerotic vascular disease in 259 patients with insulin dependent diabetes Patients with urinary albumin excretion of 30-300 mg/24 h had 2.5 times higher risk of atherosclerotic vascular disease than those with lower excretion rates The predictive effect was independent of conventional atherogenic risk factors and of development of diabetic nephropathy, and duration and control of diabetes

Partial Normalization by Dietary Cod-Liver Oil of Increased Microvascular Albumin Leakage in Patients with Insulin-Dependent Diabetes and Albuminuria

In a double-blind crossover study, we compared the effects of eight weeks of dietary supplementation with cod-liver oil with the effects of supplementation with olive oil on endothelial permeability, blood pressure, and plasma lipid levels in 18 patients with insulin-dependent diabetes mellitus and albuminuria. When the patients received the cod-liver-oil supplement, the mean (+/- SEM) transcapillary escape rate of albumin (as compared with the base-line rate) decreased from 8.7 +/- 0.5 to 6.9 +/- 0.6 percent per hour (P less than 0.01), and the blood pressure decreased from 146 +/- 4/90 +/- 2 mm Hg to 139 +/- 4/85 +/- 2 mm Hg (P less than 0.05). There was no correlation, however, between cod-liver oils effect on the transcapillary escape rate of albumin and its effect on blood pressure. There was no change from base line after the patients received the olive-oil supplement. During dietary supplementation with cod-liver oil, the plasma concentration of high-density lipoprotein cholesterol increased and the concentrations of very-low-density lipoprotein cholesterol and triglycerides decreased (P less than 0.05 for all comparisons), but the level of low-density lipoprotein cholesterol did not change. In contrast, during supplementation with olive oil, the concentration of low-density lipoprotein cholesterol decreased and the levels of very-low-density lipoprotein cholesterol and triglyceride increased (P less than 0.05 for all comparisons), but there was no change in the level of high-density lipoprotein. No changes were observed in the glomerular filtration rate, degree of albuminuria, insulin requirement, glycosylated hemoglobin level, or blood glucose level during supplementation with either oil. We conclude that dietary supplementation with cod-liver oil lowers the elevated transcapillary escape rate of albumin characteristic of patients with insulin-dependent diabetes and albuminuria, independently of its effect on blood pressure--perhaps by decreasing vascular permeability. We did not find any effect of cod-liver oil on urinary albumin excretion.

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

Abstract. Objectives. 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.

Cardiovascular Autonomic Neuropathy and Subclinical Cardiovascular Disease in Normoalbuminuric Type 1 Diabetic Patients

Cardiovascular autonomic neuropathy (CAN) is associated with increased mortality in diabetes. Since CAN often develops in parallel with diabetic nephropathy as a confounder, we aimed to investigate the isolated impact of CAN on cardiovascular disease in normoalbuminuric patients. Fifty-six normoalbuminuric, type 1 diabetic patients were divided into 26 with (+) and 30 without (−) CAN according to tests of their autonomic nerve function. Coronary artery plaque burden and coronary artery calcium score (CACS) were evaluated using computed tomography. Left ventricular function was evaluated using echocardiography. Blood pressure and electrocardiography were recorded through 24 h to evaluate nocturnal drop in blood pressure (dipping) and pulse pressure. In patients +CAN compared with −CAN, the CACS was higher, and only patients +CAN had a CACS >400. A trend toward a higher prevalence of coronary plaques and flow-limiting stenosis in patients +CAN was nonsignificant. In patients +CAN, left ventricular function was decreased in both diastole and systole, nondipping was more prevalent, and pulse pressure was increased compared with −CAN. In multivariable analysis, CAN was independently associated with increased CACS, subclinical left ventricular dysfunction, and increased pulse pressure. In conclusion, CAN in normoalbuminuric type 1 diabetic patients is associated with distinct signs of subclinical cardiovascular disease.

Transcapillary escape rate of albumin in hypertensive patients with Type 1 (insulin-dependent) diabetes mellitus

SummaryDiabetic patients with elevated urinary albumin excretion rate (incipient or clinical nephropathy) also have an increased transcapillary escape rate of albumin. This study was designed to clarify whether this is caused by a general vascular dysfunction or by elevated systemic blood pressure. The systemic blood pressure and the transcapillary escape rate of albumin were measured in the following groups after 4 weeks without antihypertensive treatment: Group 1 — eleven healthy control subjects. Group 2 — ten Type 1 (insulin-dependent) diabetic patients with incipient nephropathy (urinary albumin excretion rate: 30–300 mg/24 h) and normal blood pressure. Group 3 — eleven non-diabetic patients with essential hypertension. Group 4 — nine Type 1 diabetic patients with hypertension but normal urinary albumin excretion (<30 mg/24 h). Group 5 — eleven Type 1 diabetic patients with nephropathy (urinary albumin excretion rate > 300 mg/24 h) and hypertension. Systolic and diastolic blood pressure were similar in the three hypertensive groups: group 3, 148±8/95±6; group 4, 150±12/94±8 and group 5; 152±12/92±7mmHg, but significantly elevated (p<0.001) compared to control group 1,117±12/74±9 and group 2, 128±7/82±4 mm Hg. The transcapillary escape rate of albumin was similar in the control subjects (5.2±2.7%) and the subjects in the normoalbuminuric groups 3 and 4 (6.2±1.9 and 5.1±1.4 %, respectively) and significantly lower (p<0.001) than in patients with elevated urinary albumin excretion without or with hypertension group 2, 10.1±2.8 and group 5, 11.4±5.7 %. The increased transcapillary escape rate of albumin in patients with elevated urinary albumin excretion is unrelated to moderate systemic hypertension and may therefore be caused by alterations in the properties of the capillary walls.

A Comparison of Spirapril and Isradipine in Patients with Diabetic Nephropathy and Hypertension

The effects of spirapril and isradipine on blood pressure, urinary albumin excretion and sodium-volume homeostasis in hypertensive insulin-dependent diabetic patients with nephropathy were assessed. Fifteen Type 1 diabetic patients aged 28-53 years with a diabetes duration of 19-37 years were studied. All had hypertension and diabetic nephropathy with a urinary albumin excretion of more than 300 mg/24 h. After a single blind placebo treatment period of 4 weeks the patients were randomly assigned to treatment with the calcium antagonist isradipine SRO 5 mg once daily or the ACE inhibitor spirapril 6 mg once daily for 6 months in a double-blind design. Isradipine lowered ambulatory systolic blood pressure from 152 +/- 12 to 141 +/- 11 mmHg (p < 0.05) and ambulatory diastolic pressure from 91 +/- 9 to 86 +/- 8 mmHg (p < 0.05). The blood pressure lowering effect of spirapril was similar: 156 +/- 13 vs 143 +/- 11 mmHg (p < 0.01) and 90 +/- 4 vs 84 +/- 4 mmHg (p < 0.05). The fractional albumin clearance was unchanged on isradipine but decreased after 6 months treatment with spirapril with on average 20% (p < 0.05). Total body exchangeable sodium decreased on spirapril treatment: 2994 +/- 296 vs 2636 +/- 194 meq/1.73 m2 (p < 0.05) and extracellular volume tended to do so (p = 0.12). On isradipine treatment these parameters remained unchanged. In conclusion both isradipine and spirapril lowered blood pressure in patients with diabetic nephropathy. Only the ACE inhibitor had demonstrable beneficial effects on urinary albumin excretion rate and the sodium-volume expansion seen in these patients.

Incidence of bullosis diabeticorum – a controversial cause of chronic foot ulceration

Bullosis diabeticorum (BD) is considered a rare and relatively harmless skin manifestation with tense blisters appearing rapidly and mostly on the feet. Most papers report only a few cases and the cause of the blisters is not known. We have experienced that the lesions are not so rare and may turn into chronic foot ulcers with complications. Retrospective study of 25 consecutive patients with 35 outbreaks and 93 bullae in a population of 5000 people with diabetes treated during a 3‐year period. The bullae were deroofed in order to examine the bulla base and treated as foot ulcers including debridement, antibiotics, bandage and protective footwear. The incidence of BD per year in the present diabetic population is 0·16%. In 29 outbreaks, there were hypoglycaemic episodes or highly varying blood glucose. Antibiotics were given in 17 of 35 episodes. Time to healing was as much as median 2·5u2003months (range 0·5–23u2003months). Two patients had minor amputations. BD should be well known to all members of diabetic foot care teams. Blood glucose control with special attention to hypoglycaemia at the time of eruption, deroofing of the bullae and foot ulcer care are recommended.

Lack of effect of fish oil supplementation on coagulation and transcapillary escape rate of albumin in insulin-dependent diabetic patients with diabetic nephropathy

OBJECTIVEnWe studied the effect of a diet supplementation with fish oil in insulin-dependent diabetic patients with nephropathy in order to evaluate whether abnormal transcapillary escape rate of albumin and procoagulant activity in these patients could be modified.nnnMETHODSnA double-blind, randomized, controlled study was carried out at a tertiary referral centre. The subjects were 29 insulin-dependent diabetic patients with nephropathy. One year of fish oil supplementation (4.6 g n-3 fatty acids/day) was compared with placebo (olive oil). The main outcome measures were N-3 fatty acid proportions of platelet lipids, transcapillary escape rate of albumin, prothrombin fragment 1 + 2, thrombin-antithrombin complexes, markers of fibrinolysis, fibrinogen, factor VII antigen and activity, thrombomodulin, von Willebrand factor, platelet factor 4 and beta-thromboglobulin. These were measured every 6 months.nnnRESULTSnNeither transcapillary escape rate of albumin (7.4 (median) (5.0-9.8) (range) % vs. 7.0 (4.6-10.6) %) nor prothrombin fragment 1 + 2 (0.97 (0.72-2.40) nmol/L vs. 1.01 (0.59-3.11) nmol/L) changed after 12 months of fish oil supplementation.nnnCONCLUSIONnIncreased transcapillary escape rate of albumin and activity could not be modified during diet supplementation with fish oil in insulin-dependent diabetic patients with nephropathy.

Aspects of haemostatic function in healthy subjects with microalbuminuria--a potential atherosclerotic risk factor

Microalbuminuria, i.e., slightly elevated urinary albumin excretion rate (UAER), notifies increased risk for atherosclerotic disease and may reflect an early generalized vascular abnormality in healthy subjects. This study was designed in order to examine whether such abnormality is associated with a shift of the haemostatic balance in prothrombotic direction. The following haemostatic factors were measured in two representative groups of clinically healthy subjects, 28 with microalbuminuria (UAER of 6.6-150 micrograms/min) and 60 age- and sex-matched controls with normoalbuminuria (UAER < 6.6 micrograms/min): Coagulation factors: blood platelet count and mean volume, plasma Factor VII antigen concentration and coagulant activity, and plasma concentrations of prothrombin fragment 1 + 2, thrombin-antithrombin III complexes, fibrinogen, and fibrinopeptide A; fibrinolytic and endothelial factors: plasma concentrations of tissue plasminogen activator antigen and plasminogen activator inhibitor type 1 antigen; and endothelial factor: plasma von Willebrand factor antigen concentration. The fibrinolytic and endothelial factors were measured both before and after 10 minutes of venous occlusion of the arm. None of the haemostatic factors were significantly altered in the microalbuminuric group. Plasma fibrinogen concentration tended to be elevated but not statistically significant ((mean (95% C.I.) 7.8 (7.2-8.3) vs. 7.2 (6.9-7.5) mumol/l; p < 0.1). Neither did any of the haemostatic factors correlate with UAER in regression analyses. It is concluded that the haemostatic balance is unaltered in healthy subjects with microalbuminuria. It is unlikely that a prothrombotic state is present as an intermedial factor early in a causal chain between microalbuminuria and atherosclerotic vascular disease.