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Aims/hypothesis: The aim of this study was to investigate whether components of the renin-angiotensin system and semicarbazide-sensitive amine oxidase (SSAO) are associated with the development of pre-eclampsia in women with type 1 diabetes., Methods: This was an observational study of 107 consecutive pregnant women with type 1 diabetes (median duration 16 years [range 1-36 years], HbA(1c) 6.6% [range 4.9-10.5%]) in early pregnancy. At 8, 14, 21, 27 and 33 weeks and once within 5 days postpartum, blood was sampled for measurements of prorenin, renin, angiotensinogen, ACE and SSAO. HbA(1c), blood pressure and urinary albumin excretion were recorded. Pre-eclampsia was defined as blood pressure >140/90 mmHg and proteinuria ≥300 mg/24 h after 20 weeks., Results: Pre-eclampsia developed in nine women (8%) with longer diabetes duration (median 20 [range 10-32] vs 16 [range 1-36] years, p = 0.04), higher SSAO concentrations (592 [range 372-914] vs 522 [range 264-872] mU/l, p = 0.04) and a tendency towards higher prorenin levels (136 [range 50-296] vs 101 [range 21-316] ng angiotensin I ml(-1) h(-1), p = 0.06) at 8 weeks compared with women without pre-eclampsia. Levels of renin, angiotensinogen and ACE did not differ in the two groups. Throughout pregnancy, prorenin and SSAO levels were 30% (p = 0.004) and 16% (p = 0.04) higher, respectively, in women developing pre-eclampsia. Using multivariate logistic regression analysis, prorenin concentration at 8 weeks was associated with pre-eclampsia (OR 4.4 [95% CI 1.5-13.0], p = 0.007), i.e. an increase of prorenin of 100 ng angiotensin I ml(-1) h(-1) implies a 4.4 times higher risk of subsequent pre-eclampsia., Conclusions/interpretation: In type 1 diabetic women with pre-eclampsia, a higher concentration of prorenin in early pregnancy and higher levels of prorenin and SSAO throughout pregnancy were seen.

Aims/hypothesis: We studied the progression of diabetic retinopathy during pregnancy in women with type 2 diabetes., Methods: Fundus photography was performed at median 10 (range 6-21) and 28 (27-37) gestational weeks in 80 of 110 (73%) consecutively referred pregnant women with type 2 diabetes. Diabetic retinopathy was classified in five stages. Progression was defined as at least one stage of deterioration of diabetic retinopathy and/or development of macular oedema on at least one eye between the two examinations. Macular oedema was defined as retinal thickening and/or hard exudates within a diameter of 1,500 microm in the macula area., Results: Diabetic retinopathy, mainly mild, was present in 11 (14%) women in early pregnancy. Median duration of diabetes was 3 years (range 0-16 years). At baseline, HbA(1c) was 6.4% (1.0) (mean [SD]), systolic BP 121 (13) and diastolic BP 72 (9) mmHg. Prior to pregnancy, 22 (28%) women had been on insulin treatment. During pregnancy 74 women (93%) were treated with insulin and 11 (14%) with antihypertensive medication. Progression of diabetic retinopathy was observed in 11 (14%) women. Progression was mainly mild, but one woman with poor glycaemic control and uncontrolled hypertension progressed from mild retinopathy to sight-threatening retinopathy with proliferations, clinically significant macular oedema and impaired vision in both eyes. Progression of diabetic retinopathy was associated with a longer duration of diabetes (p = 0.03) and insulin treatment before pregnancy (p = 0.004)., Conclusions/interpretation: Despite a low risk of progression of retinopathy in pregnant women with type 2 diabetes, sight-threatening deterioration did occur.

Aims/hypothesis: The aim of this study was to describe the prevalence of complications, health-related quality of life (HRQOL) and the influence of beliefs about control over health in diabetic dialysis patients., Methods: Of 53 eligible diabetic patients on chronic dialysis during January 2004 in our clinic, 38 (76%) completed a kidney-specific (Kidney Disease Quality of Life) and a generic (SF-36) questionnaire and were characterised in terms of cardiovascular diseases and diabetic complications. Matched groups of non-diabetic dialysis patients (n = 40) and diabetic patients with a long duration of diabetes and normal kidney function (n = 38) served as controls. Generic HRQOL was compared with matched data from a survey on the Danish general population (n = 2248)., Results: Micro- and macrovascular complications were significantly more frequent in diabetic dialysis patients than in diabetic patients without renal disease. Self-rated physical health was significantly worse (p < 0.01) in diabetic dialysis patients (35 +/- 9 [mean +/- SD]) compared with non-diabetic dialysis patients (41 +/- 10), diabetic patients with normal kidney function (45 +/- 12) and the matched general population (47 +/- 19). The diabetic dialysis patients had similar levels of kidney-specific quality of life and mental health compared with the control groups. Reduced physical health was predicted by the presence of end-stage renal disease, diabetes and short time spent in education. Among the diabetic patients, those who believed more on their own ability to control their diabetes and less on chance reported better mental health and were less likely to be on dialysis., Conclusions/interpretations: Diabetic dialysis patients are characterised by a high prevalence of diabetic complications, reduced self-rated physical health but relatively good mental health.

Aims/hypothesis: We investigated the survival rate of Danish diabetic patients with end-stage renal disease (ESRD) between 1990 and 2005 and evaluated possible predictors of survival rate., Materials and Methods: Data were obtained from the Danish National Register on Dialysis and Transplantation and from the Scandiatransplant database. Survival rates in different patient groups and association with age, sex, calendar time, waiting-list status and renal transplantation were evaluated using a multivariate Cox regression model., Results: During the study period 8,421 patients (13% type 1 diabetic, 9% type 2 diabetic and 78% non-diabetic) started renal replacement therapy. The overall survival rate improved by 15% per five calendar years (hazard ratio [HR]=0.85, 95% CI: 0.81-0.88). The percentage of patients within each group who received renal transplantation was: type 1 diabetic: 26%, type 2 diabetic: 5%, non-diabetic: 24%. The survival rate of transplanted patients with diabetes mellitus (types 1 and 2) compared with non-diabetic patients at 1 year was: 95 vs 93%, at 5 years: 80 vs 85% and at 10 years: 52 vs 71%. Among diabetic patients survival rate was better in transplanted than in waiting-list patients (HR = 0.21, 95% CI 0.13-0.34), whereas the survival rate in waiting-list patients seemed to be superior to the survival rate among non-transplantation candidates (HR = 0.75, 95% CI 0.53-0.1.02, p = 0.07)., Conclusions/interpretation: The survival rate of diabetic patients with ESRD has improved during the last 15 years. Although some selection bias may exist, significantly improved survival rate was observed among transplanted patients compared with dialysis patients on the waiting-list for transplantation. Renal transplantation should therefore be offered to diabetic patients with ESRD whenever possible.

Aims/hypothesis: To evaluate the value of 24-h blood pressure monitoring compared to office blood pressure and urinary albumin excretion in predicting pre-eclampsia in Type I (insulin-dependent) diabetes mellitus., Methods: The study included 136 consecutive pregnancies in Caucasian women with Type I diabetes before gestation without diabetic nephropathy, anamnestic hypertension or early abortion. Values of urinary albumin excretion and office blood pressure before pregnancy and the HbA1C value at the time of conception were obtained. Microalbuminuria was defined as urinary albumin excretion of 30-300 mg/24 h in two out of three consecutive urine samples. Single measurements of 24-h urinary albumin excretion, office blood pressure and HbA1C were done five 5 times during pregnancy. In a subgroup of 74 women 24-h blood pressure measurements were done at 10 and 28 weeks of gestation. Pre-eclampsia was defined as office blood pressure higher than 140/90 mmHg accompanied by proteinuria above 0.3 g/24 h later than 20 weeks of gestation., Results: Urinary albumin excretion and systolic blood pressure were higher before and throughout pregnancy in 14 women developing pre-eclampsia compared with women remaining normotensive (p <0.001; p < 0.05, respectively). By logistic regression analysis the best predictor for pre-eclampsia was microalbuminuria before pregnancy (p < 0.05) with no additive predictive effect of 24-h blood pressure or office blood pressure measurement. The night:day ratio of blood pressure was similar in the two groups., Conclusion/interpretation: Microalbuminuria before pregnancy is the strongest predictor of pre-eclampsia in Type I diabetes. Measuring 24-h blood pressure early in pregnancy did not improve the ability to identify women at risk.

A familial predisposition has been proposed as a major determinant of the increased morbidity and mortality from cardiovascular disease demonstrated in Type 1 (insulin-dependent) diabetic patients with nephropathy. We assessed this concept by studying 91 parents of Type 1 diabetic patients with nephropathy and 94 parents of aged-matched Type 1 diabetic patients with normoalbuminuria. The two groups of parents were of a similar age (58 +/- 8 vs 58 +/- 7 years). The prevalence (%) of death and cardiovascular diseases (World Health Organisation questionnaire) was 10 (4-18)% and 12 (6-21)% in parents of nephropathic patients compared to 8 (3-16)% and 13 (6-23)% in parents of normoalbuminuric Type 1 diabetic patients. The frequency of risk factors for cardiovascular disease were about the same in both groups of parents. Microalbuminuria was found in 5% and 11%, hypercholesterolaemia (greater than 6.5 mmol/l) in 25% and 26% and smokers constituted 40% and 34% of parents of patients with and without proteinuria, respectively. A familial predisposition to cardiovascular disease cannot explain the increased morbidity and mortality from cardiovascular disease in young patients with diabetic nephropathy.

We re-examined 69 of the 70 patients entering the two independent Steno Studies of effects of improved metabolic control on progression of late diabetic complications. They were analysed according to an intent to treat after follow-up for 8 years (Steno Study 1) and 5 years (Steno Study 2). The glycaemic control had improved in the insulin infusion group compared with the conventional treatment group (mean HbA1c) by 2.0 +/- 0.6% vs 0.7 +/- 1.2 in Steno Study 1 and by 1.8 +/- 1.2% vs 0.4 +/- 1.3 (p less than 0.01) in Steno Study 2. In the insulin infusion groups three patients had died during episodes of ketoacidosis. These were not caused by malfunction of the insulin infusion pumps. In the conventional treatment groups, three patients suffered five cardiovascular events causing two deaths. From the sixth month of Steno Study 1 the annual change of the glomerular filtration rate was -3.7 (-5.4 to -2.0) ml.min-1.1.73 m-2 vs -1.0 (-2.1 to -0.1) (conventional vs insulin infusion group, mean (95% confidence interval, p less than 0.01]. The change in urinary albumin excretion was associated with the glycaemic control (n = 69, r = 0.49, p less than 0.0002). No progression was observed among 32 patients with low range microalbuminuria (30 to 99 mg/24 h).(ABSTRACT TRUNCATED AT 250 WORDS)

Genetic 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 mm Hg and 0.33 vs 0.32 mmol/(1 cells x h) respectively). The proportion of parents who had died or received antihypertensive 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 less than 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 countertransport activity do not appear to be risk markers for the development of clinical nephropathy in Type 1 diabetic patients.

Patients 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 less than 200 micrograms/min (normal less than or equal to 20 micrograms/min). The best predictor of persistent proteinuria or an albumin excretion rate greater than 200 micrograms/min was the initial urinary albumin excretion rate. During the longitudinal study, seven patients with an urinary albumin excretion rate of more than 70 micrograms/min at the start of the study developed persistent proteinuria or an albumin excretion rate greater than 200 micrograms/min. In contrast, only three out of the remaining 64 patients with urinary albumin excretion rate less than or equal to 70 micrograms/min developed urinary albumin excretion rate greater than 200 micrograms/min. Patients with an urinary albumin excretion rate greater than 70 micrograms/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.

We studied 73 Type 1 (insulin-dependent) diabetic patients, 18 to 50 years of age, with a diabetes duration of more than five years. Group 1: normal urinary albumin excretion below 30 mg per 24 h (n = 19); group 2: microalbuminuria, 30-300 mg per 24 h (n = 36); and group 3: diabetic nephropathy, above 300 mg per 24 h (n = 18). Fifteen nondiabetic persons matched for sex and age served as control subjects. The sodium intake evaluated on the basis of 24-h urine sodium excretion was similar in patients and control subjects. Blood pressure in groups 1 and 2 and control subjects was below 160/95 mmHg. The blood pressure was increased in group 3 as compared with the other groups (systolic/diastolic 161 +/- 22/101 +/- 9 mmHg vs 131 +/- 13/84 +/- 10, mean +/- SD, p less than 0.0001). Exchangeable sodium was increased in patients (p less than 0.01) and correlated to the mean blood pressure (n = 70, r = 0.41, p less than 0.01). Extracellular volume was increased in patients (p less than 0.05), whereas plasma volume was normal. Supine serum angiotensin II was suppressed in the patients (p less than 0.001). A negative correlation was found between mean blood pressure and supine serum aldosterone (n = 68, r = -0.24, p less than 0.05), and exchangeable sodium and aldosterone (n = 66, r = -0.36, p less than 0.002) in all patients. The catecholamine levels were also suppressed or normal in the patients.(ABSTRACT TRUNCATED AT 250 WORDS)

The 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 group n = 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 x 24 h-1, median (quartiles] and serum creatinine (87(14) vs (85(16) mumol x 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 less than 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.

The prevalence of microalbuminuria was determined in children aged 7 to 18 years with Type 1 (insulin-dependent) diabetes of more than 2 years' duration. All patients (n = 102) attending 2 diabetes clinics were asked to collect 2 overnight timed urine samples for albumin analysis by radioimmunoassay. Complete urine collection was obtained in 97 patients (95%). Overnight urinary albumin excretion rates were also measured in 36 healthy children matched for age and sex. Nineteen of the 97 patients (20%) had microalbuminuria, i.e. overnight urinary albumin excretion rates above the upper normal level (14 micrograms/min) in both urine collections. Microalbuminuria was only demonstrated in patients aged greater than or equal to 15 years, prevalence 37% (19/52 patients). Arterial blood pressure was elevated, mean 122/84 +/- 11/9mmHg, in the microalbuminuric group (19 patients) compared to the age-matched normoalbuminuric diabetic group (33 patients), mean 117/74 +/- 10/10mm Hg, p less than 0.001. The prevalence of simplex retinopathy was identical in these two groups, i.e. 25%. Glycosylated haemoglobin was slightly higher in the microalbuminuric patients, p less than 0.10. Our cross-sectional study reveals a high prevalence (37%) of persistent microalbuminuria, a stage highly predictive of later development of diabetic nephropathy, in Type 1 diabetic children aged greater than or equal to 15 years.