Plasma N-terminal pro-brain natriuretic peptide as an independent predictor of mortality in diabetic nephropathy

Aims/hypothesis Raised N-terminal pro-brain natriuretic peptide (NT-proBNP) is independently associated with an increased risk of death in chronic heart failure and acute coronary syndromes in nondiabetic populations. Diabetic nephropathy is characterised by an increased risk of cardiovascular morbidity and mortality. This study investigated the prognostic value of NT-proBNP in a large cohort of type 1 diabetic patients with and without diabetic nephropathy.Methods In a prospective observational follow-up study, 198 type 1 diabetic patients with overt diabetic nephropathy (122 men, age [mean±SD] 41±10 years, duration of diabetes 28±8 years, GFR 74±33 ml min^–1) and a matched control group of 188 patients with longstanding type 1 diabetes and persistent normoalbuminuria (114 men, age 43±10 years, duration of diabetes 27±9 years) were followed for 9.3 (0.0–9.5) years. Plasma NT-proBNP concentration was determined by immunoassay at baseline.Results In patients with diabetic nephropathy, plasma NT-proBNP concentration was elevated to (median [range]) 110 (5–79640) ng l^–1 vs. 27 (5–455) ng l^–1 in normoalbuminuric patients (p<0.0001). Among patients with nephropathy, 39 (39%) patients with plasma NT-proBNP concentrations above the median and 12 (12%) with values below the median died from any cause (unadjusted hazard ratio 3.86 [95% CI 2.02–7.37], p<0.0001; covariate-adjusted hazard ratio 2.28 [1.04–4.99], p=0.04). This lower mortality rate was attributable to fewer cardiovascular deaths: 31 (31%) and 7 (7%) above and below the median NT-proBNP level respectively (unadjusted hazard ratio 5.25 [2.31–11.92], p<0.0001; covariate-adjusted hazard ratio 3.81 [1.46–9.94], p=0.006).Conclusions/interpretation Elevated circulating NT-proBNP is a new independent predictor of the excess overall and cardiovascular mortality in diabetic nephropathy patients without symptoms of heart failure.Per Hildebrandt has received an honorarium and served as consultant in a scientific advisory board for Roche.     

Apolipoprotein(a) and cardiovascular disease in Type 2 (non-insulin-dependent) diabetic patients with and without diabetic nephropathy

Summary The relative mortality from cardiovascular disease is on average increased five-fold in Type 2 (non-insulin-dependent) diabetic patients with diabetic nephropathy compared to non-diabetic subjects. We assessed the possible contribution of dyslipidaemia in general and elevated serum apolipoprotein(a) (apo(a)) in particular. Type 2 diabetic patients with normo-, micro- and macroalbuminuria were compared with healthy subjects. Each group consisted of 37 subjects matched for age, sex and diabetes duration. Serum creatinine in the nephropathy group was 105 (54–740) mol/l. The prevalence of ischaemic heart disease (resting ECG, Minnesota, Rating Scale) was 57, 35, 19 and 2% in macro-, micro- and normoalbuminuric diabetic patients and healthy subjects, respectively. The prevalence of ischaemic heart disease was higher in all diabetic groups as compared to healthy subjects (p<0.05), and higher in macroalbuminuric as compared to normoalbuminuric diabetic patients (p<0.01). There was no significant difference between apo(a) in the four groups: 161 (10–1370), 191 (10–2080), 147 (10–942), 102 (10–1440) U/l (median (range)) in macro-, micro- and normoalbuminuric groups and healthy subjects. Serum total-cholesterol, HDL-cholesterol and LDL-cholesterol were not significantly different when comparing healthy subjects and each diabetic group. Apolipoprotein A-I was lower (p<0.05) in all diabetic groups as compared to healthy subjects (nephropathy vs healthy subjects): 1.50±0.25 vs 1.69±0.32 g/l (mean ± SD). Triglyceride was higher (p<0.05) in patients with nephropathy and microalbuminuria as compared to healthy subjects (nephropathy vs healthy subjects): 2.01 (0.66–14.7) vs 1.09 (0.41–2.75) mmol/l (median (range)). Apolipoprotein B was higher (p<0.02) in patients with nephropathy as compared to the other three groups (nephropathy vs healthy subjects): 1.54±0.47 vs 1.33±0.30 g/l. In conclusion, our case-control study has confirmed that Type 2 diabetic patients with increased urinary albumin excretion frequently suffer from dyslipidaemia and cardiovascular disease. However, our study revealed no significant elevation in serum concentration of apo(a) in patients with diabetic nephropathy, but numbers were small.     

High prevalence of risk factors for cardiovascular disease in parents of IDDM patients with albuminuria

Summary Life expectancy is shorter in the subset of insulin-dependent diabetic (IDDM) patients who are susceptible to kidney disease. Familial factors may be important. In this study the prevalence of cardiovascular disease mortality and morbidity and of risk factors for cardiovascular disease was compared in the parents of 31 IDDM patients with elevated albumin excretion rate (AER > 45 μg/min; group A) with that of parents of 31 insulin-dependent diabetic patients with normoalbuminuria (AER < 20 μg/min; group B). The two diabetic patient groups were matched for age and duration of disease. Information on deceased parents was obtained from death certificates and clinical records and morbidity for cardiovascular disease was ascertained using the World Health Organization questionnaire and Minnesota coded ECG. Hyperlipidaemia was defined as serum cholesterol higher than 6 mmol/l and/or plasma triglycerides higher than 2.3 mmol/l and/or lipid lowering therapy; arterial hypertension as systolic blood pressure higher than 140 mmHg and/or diastolic blood pressure higher than 90 mmHg and/or antihypertensive treatment. The percentage of dead parents was similar in the two groups (26 vs 20 % for parents of group A vs group B, respectively), but the parents of the diabetic patients with elevated AER had died at a younger age (58 ± 10 vs 70 ± 14 years; p < 0.05). Parents of diabetic patients with nephropathy had a more than three times greater frequency of combined mortality and morbidity for cardiovascular disease than that of the parents of diabetic patients without nephropathy (26 vs 8 %; odds ratio 3.96, 95 % CI 1.3 to 12.2; p < 0.02). Living parents of group A had a higher prevalence of arterial hypertension (42 vs 14 % p < 0.01) and hyperlipidaemia (49 vs 26 % p < 0.05) as well as higher levels of lipoprotein (a) [median (range) 27.2 (1–107) vs 15.6 (0.2–98) mg/dl; p < 0.05]. They also had reduced insulin sensitivity [insulin tolerance test: median (range) K_itt index: 3.7 (0.7–6.2) vs 4.8 (0.7–6.7)% per min; p < 0.05]. In the families of IDDM patients with elevated AER there was a higher frequency of risk factors for cardiovascular disease as well as a predisposition to cardiovascular disease events. This may help explain, in part, the high prevalence of cardiovascular disease mortality and morbidity in those IDDM patients who develop nephropathy. [Diabetologia (1997) 40: 1191–1196] Received: 4 March 1997 and in revised form: 9 May 1997     

Prevalence of hypertension in Type 1 (insulin-dependent) diabetes mellitus

Summary The prevalence of hypertension in a representative sample (n=10202) of the Danish general population aged 16–59 years was assessed to 4.4% based on three blood pressure readings. In Type 1 (insulin-dependent) diabetic patients of similar age (n=1703) the prevalence was determined in a similar way to 14.7% (p<0.00001). The excess prevalence in Type 1 diabetic patients was due to hypertension in patients with incipient and clinical nephropathy as the prevalence of hypertension among diabetic patients with normal urinary albumin excretion (essential hypertension) was 3.9%, similar to that observed in the general population. The patients with Type 1 diabetes and essential hypertension had higher systolic (146±19 vs 133±18 mmHg, p<0.00001) and diastolic blood pressure (87±12 vs 79±7mmHg, p<0.00001), but less changes in the eye background than patients with incipient nephropathy (urinary albumin excretion 30–300 mg/24 h) (p<0.03), indicating that the two groups were also different with respect to other microangiopathic lesions. Patients with essential hypertension were defined as having a normal urinary albumin excretion before and during antihypertensive treatment (if any). They were followed-up for a 58 (6–234) month period. We confirmed that hypertension is more common among Type 1 diabetic patients than in the general population and found the prevalence of essential hypertension similar in Type 1 diabetic patients to the non-diabetic population. This supports our hypothesis that hypertension is very unlikely to be the cause of diabetic nephropathy.     

Leucocyte Na+/H+ antiport activity in Type 1 (insulin-dependent) diabetic patients with nephropathy

Summary The development of proteinuria in Type 1 (insulin-dependent) diabetic patients may depend on predisposition to essential hypertension in addition to poor glycaemic control. Previous work has shown increased leucocyte Na^–/H⁺ antiport activity in essential hypertension and increased erythrocyte Li⁺/Na⁺ exchange in Type 1 diabetic patients with proteinuria. To test whether susceptibility to nephropathy in Type 1 diabetes was linked to abnormalities of leucocyte Na⁺/H⁺ antiport activity, we measured the intracellular pH and kinetics of the Na⁺/H⁺ antiport in 19 Type 1 diabetic subjects with, and 15 diabetic subjects without albuminuria and compared them to 25 matched normal control subjects. Intracellular pH (mean ±SD 7.59 ± 0.14) and maximal transport capacity of the antiport (V_max 87.7 ±24.9 mmol· 1^–1·min^–1) were higher in diabetic subjects with albuminuria compared to normotensive control subjects (pH 7.44±0.09; V_max 55.6±10.3 mmol·1^–1min^–1; p <0.001 for both), similar to the defect described in essential hypertension. These differences were not seen in diabetic subjects with normal urinary albumin/creatinine ratios (pH 7.46 ±0.09; V_max 61.0 ±13.6mmol·1^–1min^–1). Buffering characteristics of the leucocytes at different pH in the Type 1 diabetic subjects with albuminuria differed from normal control subjects and diabetic subjects with normal urinary albumin/creatinine ratios. We conclude that increased leucocyte Na⁺/H⁺ antiport activity, a known marker of essential hypertension, is usually associated with nephropathy in Type 1 diabetes.     

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

Summary Type 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 HbA_1c>8.0% had significantly higher very low density lipoprotein- and lower high density lipoprotein cholesterol concentrations compared with patients with HbA_1c<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.     

Incidence of cardiovascular disease in Type 1 (insulin-dependent) diabetic subjects with and without diabetic nephropathy in Finland

Summary This study evaluates the impact of diabetic nephropathy on the incidence of coronary heart disease, stroke and any cardiovascular disease in the Finnish population, which has a high risk of Type 1 (insulin-dependent) diabetes mellitus and cardiovascular disease. We performed a prospective analysis of the incidence of coronary heart disease, stroke and cardiovascular disease in all Type 1 subjects in the Finnish Type I diabetes mellitus register diagnosed before the age of 18 years between 1 January 1965 and 31 December 1979 nationwide. The effect of age at onset of diabetes, attained age at the end of follow-up, sex, diabetes duration and of the presence of diabetic nephropathy on the risk for cardiovascular disease was evaluated. Cases of nephropathy, coronary heart disease, stroke and all cardiovascular diseases were ascertained from the nationwide Finnish Hospital Discharge Register and National Death Register using computer linkage with the Type I diabetes mellitus register. Of the 5148 Type 1 diabetic patients followed up, 159 had a cardiovascular event of which 58 were coronary heart diseases, 57 stroke events and 44 other heart diseases. There were virtually no cases of cardiovascular disease before 12 years diabetes duration. The cumulative incidence of cardiovascular disease by the age of 40 years was 43 % in Type 1 diabetic patients with diabetic nephropathy, compared with 7 % in patients without diabetic nephropathy, similarly in men and women. The relative risk for Type 1 diabetic patients with diabetic nephropathy compared with patients without diabetic nephropathy was 10.3 for coronary heart disease, 10.9 for stroke and 10.0 for any cardiovascular disease, similarly in men and women. The presence of nephropathy in Type I diabetic subjects increases not only the risk of coronary heart disease, but also of stroke by tenfold. [Diabetologia (1998) 41: 784–790] Received: 14 August 1997 and in final revised form: 2 March 1998     

Plasma apolipoprotein (a) is increased in Type 2 (non-insulin-dependent) diabetic patients with microalbuminuria

Summary Patients with Type 2 (non-insulin-dependent) diabetes mellitus complicated by microalbuminuria or albuminuria, have an increased risk of developing macrovascular disease and of early mortality. Because lipoprotein abnormalities have been associated with diabetic nephropathy, this study tested the hypothesis that levels of apolipoprotein (a) are elevated in patients with Type 2 diabetes and increased levels of urinary albumin loss. Levels of apolipoprotein (a) in diabetic patients with microalbuminuria (n = 26, geometric mean 195 U/1, 95 % confidence interval 117–324) and albuminuria (n = 19, 281 U/1,165–479) were higher than in non-diabetic control subjects (n = 140,107 U/1, 85–134,p < 0.05), and in the albuminuric group than diabetic patients without urinary albumin loss (n = 58, 114 U/1, 76–169,p < 0.05). Patients with microalbuminuria and albuminuria had levels comparable with patients undergoing elective coronary artery graft surgery (n = 40,193 U/1,126–298). Apolipoprotein (a) levels were higher in diabetic patients with macrovascular disease than in those without (n = 49, 209 U/1, 143–306 vsn = 54, 116 U/1, 78–173,p < 0.05). These preliminary results suggest that raised apolipoprotein (a) levels of Type 2 diabetic patients with microalbuminuria and albuminuria may contribute to their propensity to macrovascular disease and early mortality.     

Effect of protein kinase C modulators on the leucocyte Na+/H+ antiport in Type 1 (insulin-dependent) diabetic subjects with albuminuria

Summary It is uncertain why only one third of Type 1 (insulin-dependent) diabetic patients develop nephropathy. One suggestion is the inheritance of a predisposition to essential hypertension. We have previously found elevated Na⁺/H⁺ antiport activity and a raised intracellular pH in leucocytes from hypertensive and Type 1 diabetic subjects with albuminuria using a novel double ionophore fluorimetric technique. These changes are not found in Type 1 diabetic subjects without albuminuria. We wished to test the effect of a protein kinase C inhibitor staurosporine (100 nmol/l) on the elevated antiport activity, and the degree of stimulation achieved by exogenous diacyl glycerol. Raised leucocyte Na⁺/H⁺ antiport activity of Type 1 diabetic subjects with albuminuria (73.8±17.2 mmol·l^–1·min^–1) was restored to normal levels with staurosporine (54.9±17.9 mmol·l^–1·min^–1, p<0.001). The leucocyte Na⁺/H⁺ antiport activity of diabetic subjects without albuminuria fell significantly also with staurosporine but to a lesser extent (57.3±11.6 to 50.0±12.8 mmol/l, p<0.003). In contrast, leucocytes from normal control subjects showed no change in antiport activity with staurosporine (54.3±8.5 to 52.6±10.4 mmol ·1^–1·min^–1). Dioctanoyl glycerol stimulated the leucocyte Na⁺/H⁺ antiport in normal subjects and diabetic patients without albuminuria, with significantly less stimulation in diabetic patients with albuminuria. We conclude that reversal by staurosporine of the elevated Na⁺/H⁺ antiport activity in Type 1 diabetic subjects with albuminuria could indicate a role for protein kinase C in activating the antiport. This hypothesis is supported by the reduced stimulation of the antiport by dioctanoyl glycerol in this group of patients.     

Diabetic nephropathy is associated with low-grade inflammation in Type 1 diabetic patients

Aims/hypothesis Increased concentrations of C-reactive protein and interleukin-6, a finding suggestive of the presence of inflammation, have been observed in Type 2 diabetes. In such patients, C-reactive protein was predictive of diabetic nephropathy. Studies on low-grade inflammatory markers and nephropathy in Type 1 diabetic patients have shown conflicting results. Therefore we studied whether low-grade inflammation is associated with diabetic nephropathy in Type 1 diabetic patients.Methods We divided 194 Type 1 diabetic patients into three groups from the Finnish Diabetic Nephropathy Study based upon their albumin excretion rate. Patients with normoalbuminuria (n=67) had no antihypertensive medication or signs of cardiovascular disease, while patients with microalbuminuria (n=64) or macroalbuminuria (n=63) were all treated with an angiotensin-converting enzyme inhibitor, a drug that could attenuate low-grade inflammation. As a measure of insulin sensitivity we used estimated glucose disposal rate. C-reactive protein was measured by radioimmunoassay and interleukin-6 by high sensitivity enzyme immunoassay.Results C-reactive protein was higher in micro- and macroalbuminuric patients compared to normoalbuminuric patients (normoalbuminuria 2.0±1.7, microalbuminuria 2.6±1.7, macroalbuminuria 2.9±2.5 mg/l; p=0.016), while interleukin-6 increased in parallel with the severity of the renal disease (1.9±1.5, 2.9±3.3, 3.6±3.1 ng/l; p<0.0001). In multiple regression analysis albumin excretion rate was the only variable independently associated with C-reactive protein (p=0.03), whereas albumin excretion rate (p=0.0003), HDL-cholesterol (p=0.0135) and duration of diabetes (p=0.0176) were independently associated with interleukin-6.Conclusions/interpretation Low-grade inflammatory markers are associated with diabetic nephropathy in Type 1 diabetic patients. The predictive value needs to be assessed.Abbreviations DN diabetic nephropathy - CRP C-reactive protein - eGDR estimated glucose disposal rate - FinnDiane finnish diabetic nephropathy study - MDRD modification of diet in renal disease     

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

Summary Diabetic 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.     

Magnetic resonance imaging of the kidney in Type 1 (insulin-dependent) diabetes mellitus

Summary Reductions in the physiological cortical to medullary signal intensity ratio are found in magnetic resonance scans of the kidney in non-diabetic glomerular disease. Whether this abnormality can also characterise patients with Type 1 (insulin-dependent) diabetes mellitus and nephropathy is not known. We measured the cortical to medullary signal intensity ratio in magnetic resonance images of the kidney in 34 patients with Type 1 diabetes (ten with either clinical proteinuria or raised serum creatinine or both, nine with microalbuminuria, seven with normal urinary albumin excretion and long duration of diabetes and eight with Type 1 diabetes of short duration). The cortical to medullary signal intensity ratio showed a trend to cluster at lower values in the normoalbuminuric patients with normal serum creatinine rather than in the nine healthy individuals, independent of Type 1 diabetes duration (1.47 ± 0.06 and 1.41 ± 0.13 vs 1.63 ± 0.16; five groups-Scheffé F-test p = 0.05–0.1). Among the Type 1 diabetic patients, significant reductions in the cortical to medullary signal intensity ratio characterised overt nephropathy (1.19 ± 0.15, p <0.05 vs all groups), but not microalbuminuria (1.47 ± 0.13, p = NS), concomitantly with low glomerular filtration rate and elevated fractional excretion of uric acid, but independent of glycaemic control. The determinants of the renal cortical to medullary signal intensity ratio in Type 1 diabetes are uncertain. Reductions in the cortical to medullary signal intensity ratio may be a late finding in diabetic nephropathy, and parallel the accompanying impairment in kidney haemodynamics. Magnetic resonance imaging of the kidney may not offer clues in the early diagnosis of diabetic nephropathy.     

Ten-year cardiovascular mortality in relation to risk factors and abnormalities in lipoprotein composition in Type 2 (non-insulin-dependent) diabetic and non-diabetic subjects

Summary The purpose of the present study was to examine 10-year cardiovascular morbidity and mortality in patients with newly-diagnosed Type 2 (non-insulin-dependent) diabetes mellitus and non-diabetic control subjects and to evaluate the effects of general risk factors, plasma insulin, urinary albumin excretion, lipoprotein abnormalities characteristic of Type 2 diabetes and the degree of hyperglycaemia in diabetic patients on cardiovascular mortality. Furthermore, the extent to which the above-mentioned factors could contribute to the excessive cardiovascular mortality observed in diabetic patients was examined. In the years 1979–1981, altogether 133 (70 men, 63 women) newly-diagnosed patients with Type 2 diabetes and 144 (62 men, 82 women) non-diabetic control subjects aged 45–64 years were studied. Both groups were re-examined in the years 1985–1986 and 1991–1992. The impact of different factors on cardiovascular mortality was examined by univariate analyses after adjustment for age and sex and by multiple logistic regression analyses. The age-standardized total and cardiovascular mortality rates were substantially higher in diabetic men (17.8 and 15.0%, total and cardiovascular mortality, respectively p = 0.06 and NS) and women (18.5 and 16.6%, p<0.01 for both) than in non-diabetic control men (5.2 % both total and cardiovascular mortality) and women (4.2 and 2.2 %). Cardiovascular mortality was not related to the treatment modality (diet, oral drugs, insulin) at 5 years from diagnosis. Use of diuretics, beta-blocking agents or their combination at baseline did not make a significant contribution to cardiovascular mortality either. In multiple logistic regression analysis on diabetic patients, age, LDL triglycerides, smoking, blood glucose and ischaemic ECG at baseline had independent associations with cardiovascular mortality. Interestingly, urinary albumin excretion rate measured at 5-year examination also predicted 10-year cardiovascular mortality after adjustment for the effects of major risk factors including lipoprotein abnormalities, but its predictive power reduced to a nonsignificant level when the effect of plasma glucose was taken into account. The relative risk of cardiovascular mortality associated with diabetes was 8.2 after allowing for age alone, but it declined to 3.7 when all contributing factors from the baseline examination (except blood glucose) were taken into account. In conclusion, the present results indicate that LDL triglycerides and/or other changes in lipoprotein composition characteristic of Type 2 diabetes and manifesting as elevated serum triglycerides are atherogenic and they strongly predict increased cardiovascular mortality. Furthermore, it is hypothesized that the consequences of long-term hyperglycaemia could explain a large proportion of the remaining excessive cardiovascular mortality risk among Type 2 diabetic patients.     

Absolute level and rate of change of albuminuria over 1 year independently predict mortality and cardiovascular events in patients with diabetic nephropathy.

AIMS: To determine the nature of the association between baseline albuminuria and risk of all-cause mortality and cardiovascular disease, and to determine if the rate of change of albuminuria from baseline over 1 year predicts these endpoints in patients with diabetic nephropathy. METHODS: Cohort study of 427 patients (161 Type 1 and 266 Type 2) with diabetic nephropathy defined as urinary albumin excretion (UAE) > or = 30 mg/24 h at baseline (mean age 53.4 years). Patients were recruited at the time of referral to a diabetic nephropathy clinic and followed up annually for an average of 5 years. UAE rate was re-measured at 1 year and the rate of change from baseline calculated. RESULTS: All-cause mortality and cardiovascular disease increased significantly and continuously across quintiles of baseline UAE (P for linear trend < 0.001 in both outcomes). The rate of change of albuminuria over 1 year (log10) independently predicted all-cause mortality (hazard ratio (95% confidence interval) 1.76 (1.39, 3.11)) and cardiovascular mortality (1.57 (1.13, 5.22)). Taken as a categorical variable, a rate of change of albuminuria > or = 30% independently predicted mortality and cardiovascular events (2.07 (1.5, 4.30) and 1.89 (1.33, 4.06), respectively). CONCLUSIONS: The rate of change of albuminuria over 1 year independently predicts mortality and cardiovascular disease in diabetic nephropathy and may have clinical utility as a risk marker in identifying a subgroup of patients at particular risk. The risk of these outcomes is continuous across the range of baseline albuminuria in patients with diabetic nephropathy.     

The impact of a family history of Type II (non-insulin-dependent) diabetes mellitus on the risk of diabetic nephropathy in patients with Type I (insulin-dependent) diabetes mellitus

Aims/hypothesis. There is substantial evidence for a role of genetic factors in the development of diabetic nephropathy. In Pima Indians, a link between susceptibility to diabetic nephropathy and Type II (non-insulin-dependent) diabetes mellitus has been proposed. In this study, our aim was to examine the association between a family history of Type II diabetes and diabetic nephropathy in patients with Type I (insulin-dependent) diabetes mellitus. Methods. In a cross-sectional case-control study, we assessed the prevalence of Type II diabetes in the parents of 137 Type I diabetic patients with diabetic nephropathy (albuminuria > 300 μg/min in two of three overnight urine collections) compared with the parents of 54 Type I diabetic patients without nephropathy (albuminuria < 20 μg/min). Results. Thirty-four (25 %) of the patients with nephropathy compared with five (9 %) of the patients without nephropathy had a parental history of Type II diabetes (p = 0.019). A parental history of Type II diabetes was associated with a three-fold risk [odds ratio 2.95 (95 % confidence interval: 1.03 to 8.40), p = 0.043] of diabetic nephropathy after adjustment for sex, glycaemic control and family history of hypertension. Furthermore, there was an excess of risk factors for development of Type II diabetes (higher fasting plasma glucose concentrations, higher prevalence of hypertension, higher waist-hip ratio and a tendency towards more glucose intolerance) among previously non-diabetic parents of patients with nephropathy. Conclusion/interpretation. Genetic or environmental factors or both related to familial Type II diabetes increase susceptibility to diabetic nephropathy in patients with Type I diabetes. [Diabetologia (1999) 42: 519–526] Received: 30 September 1998 and in final revised form: 28 December 1998     

Diabetic nephropathy: a risk factor for diabetes mellitus in offspring

Summary Both non-insulin-dependent diabetes mellitus and diabetic nephropathy show familial aggregation. If diabetes and renal disease have independent determinants (genetic or otherwise), offspring of parents with diabetic renal disease should have a similar risk of diabetes to those offspring of parents with diabetes alone. To test this hypothesis, the prevalence of diabetes was examined in a population-based pedigree study in Pima Indian offspring of three mutually exclusive parental types: 1) diabetic with renal disease, 2) diabetic, but without renal disease and 3) non-diabetic. Among offspring of one diabetic parent and one non-diabetic parent (n=320) the prevalence of diabetes at ages 15–24 years and 25–34 years was 0% and 11%, respectively if the diabetic parent did not have renal disease compared with 6% and 28% respectively if the diabetic parent did have renal disease. Corresponding rates for offspring of two diabetic parents (n=121) were 10% and 17%, respectively if neither parent had renal disease compared with 30% and 50%, respectively if one parent did have renal disease. The presence of renal disease in a parent with diabetes relative to diabetes alone was associated with 2.5 times the odds of diabetes (95% confidence interval 1.4–4.3) in the offspring controlled for age, age at onset of parental diabetes and diabetes in the other parent using logistic regression. These findings provide support for parental diabetic renal disease, independent of age at onset of parental diabetes, conferring an increased risk for diabetes in the offspring. The results are compatible with the hypothesis that the susceptibility to renal disease in the parents and to diabetes in the offspring are due to shared familial environmental factors or to the same gene or set of genes.Abbreviations NIDDM Non-insulin-dependent diabetes mellitus - ESRD end-stage renal disease     

A nationwide population-based study of the familial aggregation of Type 1 (insulin-dependent) diabetes mellitus in Denmark

Summary The objective of the present study was to assess the prevalence of familial aggregation of Type 1 (insulin-dependent) diabetes mellitus among Danish families with a diabetic child aged 20 years or less and to compare epidemiological data for familial and sporadic cases. We attempted to identify all patients with Type 1 diabetes aged 0–19 years in Denmark treated at paediatric departments or at departments of internal medicine. This comprises more than 98% of all patients with Type 1 diabetes in this age group. Patients were identified through the local diabetic out-patient registry and asked to complete a questionnaire regarding data on diabetes onset and family history. Of 1574 probands 1419 agreed to participate (90.2%). Additional cases of Type 1 diabetes were found in 171 families (12.8%). Of these 115 were parent-offspring affected families, and in 56 families at least two siblings had Type 1 diabetes and healthy parents. Significant correlation in age at onset of Type 1 diabetes in concordant siblings was observed (r=0.5, p=0.0004). Significantly more probands had an affected father with Type 1 diabetes than a mother affected (p<0.0001). Heterogeneity in epidemiological characteristics was observed between familial and sporadic cases, i.e. familial index cases were younger at onset of the disease, their parents were younger at birth of the index case, and there was no difference in gender of familial cases in contrast to sporadic cases where significantly more males were found. Over a 4-year period (1986–1989) an increasing trend in incidence was observed. However, an increase in incidence compared to previous Danish data from the 1970s and 1980 s could not be demonstrated.The Danish Study Group of Diabetes in Childhood is an association of paediatricians with a special interest in diabetes research. For participating departments in the present study see Acknowledgements     

Type 2 (non-insulin-dependent) diabetes mellitus and cardiovascular disease — putative association via common antecedents; further evidence from the whitehall study

Summary Fifteen year mortality rates are reported for men participating in the Whitehall Study in 1968–1970. Subjects were divided into four groups — normoglycaemic (centiles 1–95 of the blood glucose distribution: n=17,051), glucose intolerant (centiles 96–100: n = 999), newly diagnosed diabetic patients (n=56) and previously diagnosed diabetic patients (n=121) treated with diet±tablets. Relative risks for all causes mortality and from coronary and cardiovascular disease deaths were calculated. Age adjusted relative risks were highest in the newly diagnosed diabetic patients and were also increased in glucose intolerant and previously diagnosed diabetic men (p<0.05), but did not increase with increasing duration of diabetes. With adjustment for other risk factors, relative risks were similar in newly diagnosed and previously diagnosed diabetic men. There was no significant linear trend of adjusted relative risks with duration of diabetes when all diabetic men were pooled and person years at risk calculated. The lack of effect of duration upon relative risk together with other observations suggests common, possibly genetic, antecedents of both Type 2 (non-insulin-dependent) diabetes and coronary heart disease.     

Subclinical hypothyroidism is a risk factor for nephropathy and cardiovascular diseases in Type 2 diabetic patients.

AIMS: The purpose of this study was to determine the relationship between subclinical hypothyroidism and prevalence of retinopathy and nephropathy, incident cardiovascular disease, and mortality in Type 2 diabetic patients without taking thyroid medication. METHODS: Serum thyrotropin and free thyroxine concentrations were measured in 588 Type 2 diabetic subjects in Taipei Veterans General Hospital, Taiwan. In a cross-sectional study, we examined the prevalence of retinopathy and nephropathy. In a longitudinal study, we examined the risk of cardiovascular disease events, cardiovascular mortality and total mortality in the 4-year follow-up. RESULTS: In the cross-sectional analysis, subclinical hypothyroidism was associated with a greater prevalence of diabetic nephropathy (odds ratio, 3.15 [95% CI, 1.48-6.69]) and did not show a high prevalence of diabetic retinopathy (odds ratio, 1.15 [95% CI, 0.59-2.26]) compare to euthyroid diabetics. During the 44.0 +/- 7.4 months of follow-up, 51 participants had cardiovascular events. The risk of cardiovascular events was significantly increased in Type 2 diabetics with subclinical hypothyroidism after adjustment for age, sex, A1C, other standard cardiovascular risk factors and medication (hazard ratio, 2.93; 95% CI, 1.15-7.48; P = 0.024), but it became nonsignificant after additional adjustment for urinary albumin-to-creatinine ratio (hazard ratio, 2.06; 95% CI, 0.67-6.36; P = 0.211). The rates of cardiovascular-related and total mortality did not significantly differ by thyroid status. CONCLUSIONS: Type 2 diabetic patients with subclinical hypothyroidism are associated with an increased risk of nephropathy and cardiovascular events, but not with retinopathy. Our data suggest that the higher cardiovascular events in subclinical hypothyroidism with Type 2 diabetes may be mediated with nephropathy.     

Erythrocyte sodium-lithium countertransport is not different in Type 1 (insulin-dependent) diabetic patients with and without diabetic nephropathy

Summary We studied erythrocyte sodium-lithium countertransport in 33 patients with Type 1 (insulin-dependent) diabetes mellitus with diabetic nephropathy, 18 patients with Type 1 diabetes without diabetic nephropathy and in 42 nondiabetic patients with various other renal diseases. No significant differences were found in sodium-lithium countertransport between these three groups (median (range) 322 (162–676) vs 321 (189–627) vs 300 (142–655) mol·1 cells^–1·h^–1). We conclude, that sodium-lithium countertransport cannot be used as a marker for diabetic nephropathy.