K. Borch-Johnsen

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.

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.

Improved survival in patients with diabetic nephropathy

SummaryThe effect of early antihypertensive treatment on survival of patients with diabetic nephropathy was evaluated by studying two cohorts of Type 1 (insulin-dependent) diabetic patients developing persistent proteinuria in I: 1957–1973 (late treatment group n=49) and II: 1979–1983 (early treatment groupn=71). At onset of nephropathy, the two cohorts were comparable with regard to age (29(8) vs 30(8) years, mean (SD)), duration of diabetes (16(6) vs 18(7) years), blood pressure (132(16)/85(11) vs 134(16)/86(8) mm Hg), proteinuria (0.8 (0.5–1.2) vs 0.8 (0.6–1.2) g × 24 h−1, median (quartiles)) and serum creatinine (87(14) vs 85(16) μmol×1−1). The patients were followed frequently at the outpatients’ clinic until death or for a median duration of 8 years. In the first cohort antihypertensive treatment was seldom used, whereas, in the second cohort antihypertensive treatment was started when blood pressure reached 144(18)/93(7) mm Hg. The probability of survival with a functioning kidney for more than 8 years was 48% in the first cohort and 87% in the second cohort, p<0.001. The improvement of survival was due mainly to a decreased mortality from uraemia. Early antihypertensive treatment is the most likely explanation for this improvement.

Increased blood pressure and erythrocyte sodium/lithium countertransport activity are not inherited in diabetic nephropathy

SummaryGenetic predisposition to essential hypertension, represented by maximal erythrocyte sodium/lithium countertransport activity, has been suggested as a marker for the risk of developing clinical nephropathy in Type 1 (insulin-dependent) diabetes mellitus. To evaluate this hypothesis we measured arterial blood pressure and maximal sodium/lithium countertransport activity of erythrocytes in 80 parents of 49 Type 1 diabetic patients with clinical nephropathy, 78 parents of 49 normoalbuminuric patients and 17 age-matched non-diabetic individuals. The two diabetic groups were carefully matched. In the two groups of parents blood pressure and cell sodium/lithium countertransport activity showed no significant differences (137/83 vs 133/81 mmHg and 0.33 vs 0.32 mmol/(1 cells x h) respectively). The proportion of parents who had died or received anti-hypertensive drugs was similar in the two groups.The patients with Type 1 diabetes had significantly higher sodium/lithium countertransport compared to the 39 non-diabetic control subjects independently of the presence or absence of nephropathy (p<0.002). However, patients with nephropathy tended to have higher sodium/lithium countertransport activity than normoalbuminuric patients (0.48 vs 0.41 mmol/(1 cells x h), p = 0.06). We conclude that genetic predispositions to essential hypertension and increased maximal erythrocyte sodium/lithium counter-transport activity do not appear to be risk markers for the development of clinical nephropathy in Type 1 diabetic patients.

Incidence of retinopathy in type I (insulin-dependent) diabetes: association with clinical nephropathy.

The association between the incidence of diabetic retinopathy and the development of diabetic nephropathy was studied in 110 Type I (insulin-dependent) diabetic patients during a period from 10 years before to 5 years after the onset of persistent proteinuria. This group of patients was compared with 110 diabetic patients, who were matched according to sex, age, and diabetes duration, but who were without proteinuria during the observation period. The cumulative incidence of proliferative retinopathy was 74% in patients with clinical nephropathy and 14% in patients free of proteinuria. The incidence of background retinopathy was 93% and 37%, respectively, and the incidence of retinopathy increased dramatically 5 years before the onset of proteinuria. Neither gender, age at onset of diabetes, nor blood pressure seemed to have much influence on the incidence of severe retinopathy. It is concluded that development of clinical diabetic nephropathy implies an extremely high risk of developing severe retinopathy. A common pathogenetic link may be suspected.

A multinational assessment of complications in type 1 diabetes: the DiaMond substudy of complications (DiaComp) Level 1

The objectives of this study were to describe the global geographic variation of microvascular and macrovascular complications in childhood onset type 1 diabetes (T1D) and to relate any such variation to diabetes care activities such as self blood glucose monitoring and intensive insulin therapy. The DiaComp study is a multinational (17 countries) cross-sectional study of complications in T1D (n=2, 657). All participants were diagnosed at < 15 years of age and had a diabetes duration of 5-24 years when surveyed. Complications were assessed by self-report of physician diagnosis. Twenty-two centres in 17 countries achieved at least a 67% response rate and are included in the analyses. Central European centres exhibited high rates of retinopathy (Lithuania=31. 6%, Romania=24. 2%), laser treatment (Lithuania=25. 4%) and neuropathy (Lithuania=29. 9%, Romania=12. 4%) in those with short duration of diabetes (5–15 years), as did Cuba for neuropathy (15. 4%). For retinopathy the geographic variation in the short-duration group was also pronounced, ranging from 1. 6% in Italy to 41. 6% in Lithuania, and from 0% in Brazil, Italy and Australia, to 29. 9% in Lithuania for laser treatment. Variation was less dramatic for the prevalence of complications in the long-duration group (15–25 years). Hypertension and duration were strong consistent predictors of all complications, while women had higher prevalence for half the complications (retinopathy, laser treatment and renal disease). Intensive insulin therapy and self-monitoring of blood glucose showed little association with prevalence of complications. In conclusion, this first population-based account of the geographic variation of T1D complications has demonstrated substantial variation. However, the healthcare practice variables that were measured contributed little toward explaining this variation.

Natural history of diabetic complications: early detection and progression.

Until recently Type 1 diabetes has been characterized by a considerable degree of mortality, mainly associated with the development of diabetic nephropathy. Diabetic nephropathy is characterized by persistent proteinuria, decreasing glomerular filtration rate (GFR), increasing blood pressure, and morphological changes. Proteinuria represents a late stage in a prolonged process, which begins at the onset of Type 1 diabetes, when urinary albumin excretion is at the lower end of its normal range (< 10 mg 24‐h‐1). However, in those patients who will later develop persistent proteinuria, urinary albumin excretion increases exponentially at about 20% per year. These patients also tend to have rising blood pressure and falling GFR, higher rates of proliferative retinopathy and coronary heart disease, and elevated levels of cardiovascular risk factors. As intervention is possible in all these areas, identification of such patients is required and especially as the imposition of strict metabolic control may postpone or arrest progression to overt nephropathy. Where patients deteriorate despite such control the institution of early antihypertensive therapy and the effective management of end stage renal disease will bring further improvements in the prognosis of diabetic nephropathy.

Combined response from the authors

Despite the fact that Deckert et al. quoted 113 references to support their case it is more likely that the enhanced extravasation and glomerular filtration of albumin in diabetic patients are consequences of blood viscosity-related increases in intracapillary pressure rather than to compositionally-induced increases in basement membrane permeability. The clinical significance of this conclusion is that the blood viscosity of diabetic patients is potentially correctable.