T. Deckert

Albuminuria reflects widespread vascular damage

SummaryAlbuminuria in Type 1 (insulin-dependent) diabetes is not only an indication of renal disease, but a new, independent risk-marker of proliferative retinopathy and macroangiopathy. The coincidence of generalised vascular dysfunction and albuminuria, advanced mesangial expansion, proliferative retinopathy, and severe macroangiopathy suggests a common cause of albuminuria and the severe renal and extrarenal complications associated with it. Enzymes involved in the metabolism of anionic components of the extracellular matrix (e.g. heparan sulphate proteoglycan) vulnerable to hyperglycaemia, seem to constitute the primary cause of albuminuria and the associated complications. Genetic polymorphism of such enzymes is possibly the main reason for variation in susceptibility.

Diabetic nephropathy in type 1 (insulin-dependent) diabetes: An epidemiological study

SummaryA follow-up of 1475 Type 1 (insulin-dependent) diabetic patients diagnosed before 1953 (815 males, 660 females) and before the age of 31 years was conducted. All patients were seen at the Steno Memorial Hospital and were referred from all parts of Denmark; 91 (6%) could not be traced. The rest (94%) were followed until death or for at least 25 years; 249 (17%) were followed for >40 years. Clinical diabetic nephropathy developed in 531 (41%) of the 1303 patients in whom sufficient information was available regarding proteinuria. Other causes of proteinuria were found in 3%, and 57% did not develop persistent proteinuria. The prevalence of diabetic nephropathy was 21% after 20–25 years of diabetes duration followed by a decline to 10% after 40 years. Two incidence peaks of the onset of proteinuria were seen, one after 16 and another after 32 years duration of diabetes. Incidence increased steeply 10 years after onset of diabetes and was low after 35 years duration. The cumulative incidence was 45% after 40 years of diabetes. A male preponderance was seen among patients with nephropathy. A significant difference in the pattern of annual incidence rates of diabetic nephropathy was seen, when groups with onset of diabetes before 1933, between 1933–1942, and 1943–1952, respectively, were compared. An association between daily insulin requirement and nephropathy incidence was found. Patients with nephropathy had a much poorer survival than those without proteinuria; 40 years after onset of diabetes, only 10% of patients who developed nephropathy were alive, whereas >70% of patients who did not develop nephropathy survived. Uraemia was the cause of death in 66% of the patients with nephropathy; 7 years after the onset of persistent proteinuria, 49% of the patients had died. It is concluded that diabetic nephropathy is the major life threatening complication in Type I diabetes of juvenile onset.

The effect of proteinuria on relative mortality in type 1 (insulin-dependent) diabetes mellitus

SummaryWe followed 1, 134 patients with Type 1 (insulin-dependent) diabetes, diagnosed between 1933 and 1952, until 1982 or death or until their emigration. Their age at onset of diabetes was under 31 years. Information concerning the development of persistent proteinuria was sought in every case. In 104 cases, the data were either questionable or the patient could not be traced. Twenty-nine patients developed non-diabetic proteinuria. Among the remaining 1,001 patients, 406 developed persistent proteinuria (350 died) and 595 did not (166 died). The incidence of persistent proteinuria was highest among men; it decreased with increasing year of diabetes onset from 1933 to 1952, and decreased with increasing age at onset. The relative mortality was extremely high among patients with persistent proteinuria, increasing to a maximum of about 100 at age 35 years. Patients not developing proteinuria had a relatively constant low relative mortality of about 2. The decreasing incidence of persistent proteinuria and the decreasing mortality with increasing calender year of diabetes onset resulted in a 50% increase in life-expectancy among patients diagnosed in 1950 compared with patients diagnosed in 1935. In patients who developed persistent proteinuria, relative mortality was higher in women than men at all ages. In patients who did not develop proteinuria, relative mortality was similar in men and women after the age of 35. Uraemia was the main cause of death in patients with persistent proteinuria, although cardiovascular deaths were more frequent than in patients without proteinuria. Thus, proteinuria is associated not only with death from uraemia but also from cardiovascular disease. It is concluded that the development of persistent proteinuria is a major life-threatening complication in patients with early-onset Type 1 diabetes. Patients who do not develop proteinuria have almost a normal life expectancy.

Incipient nephropathy in Type 1 (insulin-dependent) diabetes

SummaryPatients with Type 1 (insulin-dependent) diabetes without proteinuria were studied to define those patients who will later develop persistent proteinuria (more than 0.5 g protein/24 h). Two investigations were performed; 71 patients were studied longitudinally for 6 years and another 227 patients were studied cross-sectionally. All were less than 50 years of age and had developed diabetes before the age of 40 years. At entry into the study they had no proteinuria (Albustix method), had normal blood pressure and urinary albumin excretion rates < 200 μg/min (normal ⩽ 20 μg/min). The best predictor of persistent proteinuria or an albumin excretion rate > 200 μg/min was the initial urinary albumin excretion rate. During the longitudinal study, seven patients with an urinary albumin excretion rate of more than 70 μg/min at the start of the study developed persistent proteinuria or an albumin excretion rate > 200 μg/min. In contrast, only three out of the remaining 64 patients with urinary albumin excretion rate ⩽ 70 μg/min developed urinary albumin excretion rate > 200 μg/min. Patients with an urinary albumin excretion rate > 70 μg/min are thus at risk of developing diabetic nephropathy. We designate this stage of renal involvement incipient nephropathy. Patients with incipient nephropathy were further characterized in the cross-sectional study. Compared with normoalbuminuric patients, patients with incipient nephropathy had increased systolic and diastolic blood pressure, but normal serum creatinine. The glomerular filtration rate was higher than normal in patients with incipient nephropathy though not different from that of normoalbuminuric patients.

Prognosis of Diabetics with Diabetes Onset before the Age of Thirtyone I. Survival, Causes of Death, and Complications

A follow-up on three hundred and seven patients diagnosed before 1933 and before the patient was thirty-one years old was conducted as of 1.1. 1973, i.e. after at least forty years of diabetes. All patients were seen at the Steno Memorial hospital and were referred from all parts of Denmark. A small proport ion of the patients (5.9%) could not be traced. Of the remaining two hundred and eightynine patients 40% were alive. Three-hundred and six patients were insulin dependent, 87% being treated with insulin twice daily. More than 50% survived their diabetes for more than thirty-five years. The mortality rate was 2-6 times that in an ageand sexmatched non-diabetic population. In 31% of the deceased patients the cause of death was uraemia; in 25% myocardial infarction. The excess mortality among patients exhibiting persistent proteinuria before forty years of diabetes was 3 -4 times higher than in patients who did not have proteinuria after forty years. 167/o of the whole study population became blind, and another 14% had severely impaired vision; 21% exhibited objective signs of myocardial infarction, 10% of stroke, and 12% had gangrene or had undergone amputation of the foot or lower leg; 38% had proteinuria and 22% uraemia. Death with or from hypoglycaemia was more common than death in ketoacidotic coma. Clinical manifestations of late diabetic complications were considerably less common in patients who were still alive after more than forty years of diabetes than in patients who died before their fortieth year of diabetes.SummaryA follow-up on three hundred and seven patients diagnosed before 1933 and before the patient was thirty-one years old was conducted as of 1.1.1973, i.e. after at least forty years of diabetes. All patients were seen at the Steno Memorial hospital and were referred from all parts of Denmark. A small proportion of the patients (5.9%) could not be traced. Of the remaining two hundred and eightynine patients 40% were alive. Three-hundred and six patients were insulin dependent, 87% being treated with insulin twice daily. More than 50% survived their diabetes for more than thirty-five years. The mortality rate was 2–6 times that in an age- and sexmatched non-diabetic population. In 31% of the deceased patients the cause of death was uraemia; in 25% myocardial infarction. The excess mortality among patients exhibiting persistent proteinuria before forty years of diabetes was 3–4 times higher than in patients who did not have proteinuria after forty years.16% of the whole study population became blind, and another 14% had severely impaired vision; 21% exhibited objective signs of myocardial infarction, 10% of stroke, and 12% had gangrene or had undergone amputation of the foot or lower leg; 38% had proteinuria and 22% uraemia. Death with or from hypoglycaemia was more common than death in ketoacidotic coma. Clinical manifestations of late diabetic complications were considerably less common in patients who were still alive after more than forty years of diabetes than in patients who died before their fortieth year of diabetes.

Coronary heart disease in young type 1 (insulin-dependent) diabetic patients with and without diabetic nephropathy: incidence and risk factors

SummaryFifty-nine Type 1 (insulin-dependent) diabetic patients with (group I) and 59 patients without nephropathy (group II) pair-matched according to sex (30 males and 29 females), age (33 years, range 15–48) and diabetes duration (19 years, range 6–42) were followed for a period of 10 years from about 5 years before to 5 years after onset of proteinuria. The cumulative incidence of coronary heart disease was estimated, and blood pressure and serum cholesterol were followed. Within six years after onset of proteinuria the cumulative incidence of coronary heart disease was increased eight-fold in group I (40%) compared with group II (5%), (p<0.001). Blood pressure was higher in group I compared with group II from before onset of proteinuria (135/86±17/9 mmHg vs 129/80±15/8 mmHg, p<0.001), and serum cholesterol elevated from onset of proteinuria in group I (6.3±1.2 mmol/l) vs. group II (5.5±1.0 mmol/l), (p<0.005). Patients in group I who developed coronary heart disease had similar age (36 years, range 21–51, vs 38 years, range 21–53), sex (50% males vs. 52% males), smoking frequency (50% vs 49%), diabetes duration (22 years, range 9–39, vs 24 years, range 10–42) and serum creatinine (110 μmol/l, range 69–284, vs 108 μmol, range 72–1024) compared with patients not developing coronary heart disease. However, the patients with coronary heart disease had higher blood pressure (135/87mmHg±16/9 vs 128/82±15/7, p<0.05) and serum cholesterol (7.3 mmol/l+ 1.2 vs 6.4 mmol/l±0.9, p<0.05) than patients without coronary heart disease. Thus, patients developing clinical nephropathy have a highly increased incidence of coronary heart disease compared with patients not developing nephropathy. Patients who developed coronary heart disease were characterized by higher blood pressure and serum cholesterol.

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 less than 0.01). The albumin transcapillary escape rate was significantly higher in groups II and III than in group I and normal controls (p less than 0.01). The basal plasma level of von Willebrand factor was higher in groups III (p less than 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.

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.

Two-Year Experience with Continuous Subcutaneous Insulin Infusion in Relation to Retinopathy and Neuropathy

Thirty patients with insulin-dependent diabetes mellitus (IDDM) who had advanced background retinopathy were randomized to unchanged conventional treatment (UCT) or to continuous subcutaneous insulin infusion (CSII). They were followed prospectively for 2 yr. The mean blood glucose and hemoglobin A1c (HbA1c) were significantly lower in the CSII group than in the UCT group. The mean blood glucose and HbA1c did not change from the first to the second year in either of the treatment groups in spite of less frequent home-monitoring of blood glucose and less frequent outpatient visits during the second year. Four patients in the CSII group and five in the UCT group developed proliterative retinopathy. However, a marginally significant trend was found toward more frequent improvement of retinal morphology in the CSII group (47%) than in the UCT group (13%). Beat-to-beat variation was found to deteriorate significantly with UCT compared with a nonsignificant improvement with CSII therapy. Vibration sense was unchanged in both treatment groups. It is concluded that near-normal blood glucose levels can be maintained with CSII therapy in spite of less frequent home-monitoring of blood glucose and outpatient visits. Furthermore, established background retinopathy may progress to proliferative retinopathy in spite of 2 yr of near-normal blood glucose levels. However, a marginally significant trend toward more frequent improvement of retinal morphology was found among CSII-treated patients compared with conventionally treated patients. Large-scale, prospective, randomized studies are needed to confirm these results.

Abnormalities in plasmas concentrations of lipoproteins and fibrinogen in type 1 (insulin-dependent) diabetic patients with increased urinary albumin excretion

SummaryType 1 (insulin-dependent) diabetic patients with clinical nephropathy have a more than ten-fold increase in mortality of cardiovascular diseases compared with diabetic patients without nephropathy. The risk factors for cardiovascular disease, plasma concentrations of lipoproteins and fibrinogen, were investigated in 74 long-term diabetic patients: 37 with normal urinary albumin excretion, 20 with incipient nephropathy and 17 with overt clinical nephropathy based on urinary albumin excretion. The groups were matched according to sex, age and diabetes duration. The concentration of plasma cholesterol, very low density lipoprotein cholesterol, low density lipoprotein cholesterol, triglyceride and fibrinogen rose with increasing urinary albumin excretion. The plasma concentrations of these lipoproteins and fibrinogen were 11–14% higher in the patients with incipient nephropathy and 26–87% higher in the patients with overt clinical ne phropathy compared with the patients without nephropathy. The plasma concentration of high density lipoprotein cholesterol was unaffected by albuminuria. Patients with normal urinary albumin excretion and HbA1c>8.0% had significantly higher very low density lipoprotein- and lower high density lipoprotein cholesterol concentrations compared with patients with HbA1c<8.0%. Simple addition of the described risk factors can only account for a minor part of the greatly increased cardiovascular mortality in patients with diabetic nephropathy. An additional and possibly more decisive factor might be a change in the arterial wall, a change which promotes lipid accumulation and/or facilitates thrombus formation.