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In a study of the effect of a low-protein diet on the progression of renal disease 19 insulin-dependent diabetic patients with persistent clinical proteinuria were observed for 12-39 (mean 29) months while they were on a normal-protein diet (1.13 [0.06] g/kg per day), then for 12-49 (mean 33) months on a low-protein diet (0.67 [0.03] g/kg per day). The low-protein diet had no adverse effect on nutrition or glycosylated haemoglobin concentration. Mean supine blood pressure (BP) fell slightly on the low-protein diet and was probably due to the start or modification of antihypertensive medication in 9 patients. The mean rate of decline in glomerular filtration rate fell from 0.61 (SEM 0.14) ml/min per month with the normal-protein diet to 0.14 (0.08) with the low-protein diet, and this effect remained highly significant after adjustment for blood pressure, energy intake, and glycosylated haemoglobin. The rise in the fractional clearance of albumin during a normal-protein diet stopped with the low-protein diet, and there was a significant fall in albumin excretion from 467 (95% CI 234-895) micrograms/24 h on the normal-protein to 340 (138-719) on the low-protein diet. Thus, a low-protein diet, with its reduction in protein and possibly other dietary components such as phosphate or fat, seems to retard the rate of decline of glomerular filtration rate in diabetic nephropathy independently of blood pressure changes and glycaemic control. [ABSTRACT FROM AUTHOR]

Rosiglitazone, a potent member of the thiazolidinedione class of oral antidiabetic agents, reduces hyperglycaemia by improving insulin sensitivity--an important underlying factor in the development of both type 2 diabetes and its related cardiovascular complications. Rosiglitazone has now been available in clinical practice for more than three years, so there is a large body of evidence supporting its efficacy and safety as an antihyperglycaemic agent in patients with type 2 diabetes. Given the significant burden imposed on patients and healthcare resources by diabetes-related cardiovascular disease (CVD), there is growing interest in the thiazolidinediones in terms of their potential to ameliorate CVD risk factors as a result of their insulin-sensitising action and thus improve cardiovascular outcomes in individuals with type 2 diabetes. As reviewed below, rosiglitazone has a beneficial impact on a number of factors associated with insulin resistance and CVD, including microalbuminuria, hypertension, dyslipidaemia, visceral fat, elevated plasminogen activator inhibitor-1 levels and increased concentrations of C-reactive protein. These thiazolidinedione compounds are not problem-free and the long-term implications of some of rosiglitazone side-effects such as weight gain, changes in LDL-cholesterol concentration and fluid retention remain to be resolved. Large-scale clinical outcome studies should give a clearer picture for rosiglitazone and related thiazolidinediones in relation to the extent of their impact on diabetes disease progression and incident cardiovascular events.

Unlabelled: Background genetic factors may influence the variability in the rate of progression of kidney disease in type 1 diabetes. In diabetes, progressive mesangial matrix expansion and glomerular sclerosis are, to a large extent, mediated by TGF-beta1. Decorin, a proteoglycan which is a component of the extracellular matrix, regulates TGF-beta1 activity and expression. We have examined the relationship between the 179/183/185 polymorphism of the Decorin gene and the progression of diabetic nephropathy., Methods: From a cohort of 175 European patients with diabetic nephropathy, we studied 79 patients who were selected because they had a follow-up of at least 2 years (average 6.5 years; range: 2.5-15 years), and regular measurements of serum creatinine on 5 or more occasions. Creatinine clearance (CrCl) calculated from serum creatinine concentration was used as a measure of derived glomerular filtration rate (dGFR). All patients were on antihypertensive therapy., Results: The rate of dGFR decline in the whole cohort was [median (range)] 4.6 (-3.8 to 18) ml/min/year. No patient with 185 allele was found. Patients with 179/183 and 179/179 genotype (n = 14), who were considered together and named 179 carriers, had a slower rate of GFR decline [2.1 (0.06-11.7) ml/min/year] as compared to patients with Decorin 183/183 genotype (n = 65) [5.6 (-3.8 to 18) ml/min/year; p < 0.001]. In addition, when considering individual data, patients carrying the 179 allele had a 3.0 (95%CI: 1.8-4.2)-fold higher probability to be slow progressors (i.e. GFR decline below the median). This difference could not be accounted for by differences in duration of disease, type and duration of antihypertensive therapy, albumin excretion rate, blood glucose or blood pressure control. In a multivariate logistic analysis albumin excretion rate (p < 0.001), mean arterial pressure (p = 0.07) and Decorin gene polymorphism (p = 0.036), but not HbA1c, were independently correlated with the rate of dGFR fall., Conclusion: The 179 allele variant of the Decorin gene is related to a slower progression of DN in type 1 diabetic patients with albuminuria and receiving antihypertensive therapy., (Copyright 2002 S. Karger AG, Basel)

Objective: To evaluate whether subclinical hypothyroidism (SH) affects resting energy expenditure (REE) as well as body composition, lipid profile, and serum leptin in obese patients., Research Methods and Procedures: A total of 108 obese patients with SH defined as normal free thyroxine levels and thyroid-stimulating hormone (TSH) values of > 4.38 microU/ml (mean +/- 2 SD of the values of our reference group of obese patients with normal thyroid function) were compared with a group of 131 obese patients matched for age, sex, and body mass index (BMI) but with normal TSH levels. We assessed estimated daily caloric intake by 7-day recall, REE by indirect calorimetry, body composition by bioelectrical impedance analysis, serum leptin by radioimmunoassay, and lipid profile (i.e., total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and triglycerides)., Results: All of the variables measured were not different between the euthyroid obese patients and those with SH. In a multiple regression model with REE expressed for kilograms of fat free mass (REE/kgFFM) as a dependent variable and percentage of fat mass, BMI, waist-to-hip ratio, age, TSH, free thyroxine, serum leptin, and caloric intake as independent variables, only percentage of fat mass was significantly correlated with REE/kgFFM in both groups. In the SH group only, BMI, waist-to-hip ratio, age, and TSH were related to REE/kgFFM and explained 69.5% of its variability. After dividing the patients with SH using a cutoff TSH value of 5.7 microU/ml, which represents 3 SD above the mean of TSH levels of the group of obese patients with normal thyroid function, only REE/kgFFM was significantly different and lower in the group of more severely hypothyroid patients., Discussion: In patients with obesity, SH affects energy expenditure only when TSH is clearly above the normal range; it does not change body composition and lipid profile. We suggest that, at least in obese patients, evaluation of TSH levels may be useful to rule out a possible impairment of resting energy expenditure due to a reduced peripheral effect of thyroid hormones.

Aims/hypothesis: We investigated in normotensive Type I (insulin-dependent) diabetic patients with normoalbuminuria the role of growth hormone-induced IGF-1 in the modulation of renal haemodynamics., Methods: We measured glomerular filtration (GFR) and renal plasma flow (RPF) at baseline and at 24 h after injection of different doses of growth hormone (0.1, 0.2, 0.4 U x kg(-1) x body weight(-1) in six patients with normal GFR under a euglycaemic clamp. We also examined a 24 h profile of plasma growth hormone and IGF-1 during usual insulin therapy in two other groups each with seven patients with a lower (from 93 to 114 ml x min(-1) x (1.73 m2)(-1) and higher (from 121 to 146 ml min(-1) x (1.73 m2)(-1) GFR., Results: Plasma growth hormone concentrations peaked 2 h after its injection and plasma concentrations of IGF-1 peaked about 24 h after the growth hormone injection. There was a significant increase in GFR and RPF 24 h after the highest dose of the growth hormone injection (corresponding to the highest IGF-1 concentration), from baseline values of 115 +/- 24 and 536 +/- 141 ml x min(-1) x (1.73 m2)(-1) to 160 +/- 33 and 657 +/- 137 ml x min(-1) x (1.73 m2)(-1), respectively (p < 0.01 for GFR and p < 0.05 for RPF). No differences were observed in the 24 h profile of growth hormone and IGF-1 plasma concentrations between the two groups; growth hormone and IGF-1 concentrations were lower than those obtained after the injection of 0.4 U x kg(-1) x body weight(-1) of growth hormone., Conclusion/interpretation: These results show that pharmacological growth hormone-induced IGF-1 concentrations are required to modify renal haemodynamics in Type I diabetic patients and suggest that, under the "physiological" conditions of diabetes, IGF-1 has no role as a mediator of glomerular hyperfiltration.

Objective: Whether ACE inhibition is useful for type 2 diabetic patients with micro- and macroalbuminuria remains unknown. The Non-Insulin-Dependent Diabetes, Hypertension, Microalbuminuria, Cardiovascular Events and Ramipril (DIABHYCAR) Study was set up to address this issue through a multicenter double-blind parallel placebo-controlled > or = 3-year trial in Europe and North Africa. In this article, we report the characteristics of the randomized patients., Research Design and Methods: The main selection criteria were as follows: men or women aged > or = 50 years with type 2 diabetes treated with oral antidiabetic drugs, with or without hypertension, with a plasma creatinine level < 150 mumol/l, and with persistent micro- or macroalbuminuria, as assessed centrally by two successive urine samples containing a urinary albumin concentration > or = 20 mg/l. Patient characteristics were studied by comparing patients who were randomized to those who were not, taking their geographical origin into account., Results: There were 25,455 patients screened for urinary albumin (20,296 from France, 918 from Germany, 1,019 from Northwest Europe, 969 from Central Europe, 959 from Mediterranean Europe, and 1,294 from North Africa). Of these patients, 4,937 were randomized. Compared with the nonrandomized patients, the randomized patients were older, more often men, more obese, had higher systolic/diastolic blood pressure and plasma glucose, smoked more tobacco, drank more alcohol, and had complications more frequently. Using a logistic regression analysis, all the above-mentioned items appeared as independent determinants for randomization into the study, with the exception of alcohol intake. The contribution of each item varied slightly from one geographical origin to another., Conclusions: The physical, biological, and behavioral characteristics create a poor renal and cardiovascular prognosis for the type 2 diabetic patients randomized to the DIABHYCAR Study because of micro- and macroalbuminuria. Testing the usefulness of ACE inhibition for the type 2 diabetic patients with microalbuminuria seems feasible through the DIABHYCAR Study.

Background: Genetic factors are involved in the development of diabetic nephropathy in Type 1 diabetes. We have examined the association of four candidate genes, angiotensin converting enzyme (ACE): insertion/deletion (I/D) polymorphism, plasminogen activator inhibitor-1 (PAI-1): 4G/5G polymorphism, decorin: 179/183/185 polymorphism and Werner syndrome helicase: C/R polymorphism, with the presence of diabetic nephropathy in Type 1 diabetic patients., Methods: 175 Type 1 diabetic patients with albuminuria (59 with microalbuminuria and 116 with macroalbuminuria) were compared with 136 Type 1 diabetic patients with normoalbuminuria and duration of disease longer than 15 years (mean+/-SD: 25+/-8 years). 200 non-diabetic subjects were also studied as background population., Results: We found no association in the polymorphism of the four genes examined between patients with and without diabetic nephropathy and the control subjects., Conclusions: The genes studied are unlikely to be involved in the susceptibility to nephropathy in Type 1 diabetic patients., (Copyright 1999 John Wiley & Sons, Ltd.)

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 microg/min; group A) with that of parents of 31 insulin-dependent diabetic patients with normoalbuminuria (AER < 20 microg/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.

Antihypertensive drugs slow the progressive decline in renal function seen in patients with insulin-dependent diabetes and nephropathy. In a recent study, the ACE inhibitor captopril protected against this deterioration in renal function. We developed an economic model to analyse the cost impact of ACE inhibitor treatment on progression to endstage renal failure (ESRF) in diabetic patients over 4 years. Two scenarios were compared: one describing the progression of a cohort of 1000 patients receiving 25 mg captopril three times daily, and the other for an equivalent cohort without such prophylactic treatment. Previously published data were used to estimate the transition rates for each stage from the onset of renal failure until death. All direct costs were discounted by an annual rate of 6%, and were subjected to sensitivity analysis. The discounted cost saving of ACE inhibitor treatment for a cohort of 1000 patients was estimated as 0.95 million pounds over 4 years. Under sensitivity analysis, these results were very robust to variations in the costs of ESRF treatment. Prophylactic treatment with ACE inhibitors was predicted to provide substantial increases in life expectancy and reduction in the incidence of ESRF, while also providing significant economic savings.

The rate of development and progression of renal disease varies greatly in insulin-dependent diabetic (IDDM) patients. The cellular and molecular reasons for this difference are largely unknown but could be related to early cell differentiation, a phenomenon recently reported in IDDM patients with nephropathy. In this study we compared cell differentiation and cell volume between IDDM patients with and without nephropathy and investigated the cell ageing characteristics in relation to the rate of evolution of renal disease in the IDDM patients with diabetic nephropathy. Cell volume was larger and the percentage of post-mitotic fibrocytes was higher in skin fibroblasts derived from IDDM patients with diabetic nephropathy compared to those from IDDM patients without kidney disease (mean +/- SD in arbitrary units 817.3 +/- 25.7 vs 760 +/- 32.8; p = 0.005; and mean +/- SD % 33.6 +/- 11.8 vs 20.8 +/- 10; p = 0.02 respectively). Analysis of the interaction of the time to proteinuria (TTP) and the rate of change of glomerular filtration rate (GFR) with glycaemic control, arterial blood pressure and cell volume and the state of cell differentiation showed that glycated haemoglobin and the percentage of post-mitotic fibrocytes were negatively correlated to TTP (r = -0.68; p = 0.008; r = 0.52; p = 0.05 respectively) and positively associated with the rate of change of GFR (r = 0.76; p = 0.03; r = 0.56; p = 0.037 respectively). Cell volume was negatively correlated to TTP (r = -0.53; p = 0.05). Diastolic blood pressure was also related to the rate of GFR change (r = 0.56; p = 0.039). In a multiple linear regression analysis glycated haemoglobin maintained its significance independent relationship with TTP at the 1% level, while the strength of the association between the percentage of post-mitotic cells and cell volume was reduced to the 11 and 9% level, respectively. Cultured skin fibroblasts from IDDM patients with nephropathy show signs of early differentiation. Glycaemic control is a key factor in the rate of onset of proteinuria and different rates of cell ageing appear to contribute to the rate of development and progression of diabetic nephropathy. Their interaction may be responsible for the severity of renal involvement in susceptible IDDM patients.

Background and Aims: Hyperglycaemia is a strong risk factor for the development of renal disease in insulin dependent diabetes mellitus but it is uncertain whether it contributes to the progression of incipient or established nephropathy. The rigorous treatment of blood pressure in recent years may help uncover the contribution of hyperglycaemia, if any, to the progression of renal failure. Our aim therefore, was to assess in a current cohort of insulin dependent diabetic patients with diabetic nephropathy the relative importance of glycaemic control and blood pressure on disease progression., Methods: All insulin dependent diabetic patients with persistent albuminuria (> 300 mg/24 h) attending the diabetic clinic at Guy's Hospital between 1977 and 1993 were recruited. Serial measurements of blood pressure, HbA1 and GFR were performed every 6 months until end-stage renal disease or death. Only patients with at least 1 year of follow up were analysed. The mean follow up period was 8 years (range 1.5-15.5 years). Baseline and time dependent variables were related to the rate of change of GFR using weighted linear regression and stepwise multiple regression analysis. The impact of each variable on the change of GFR with time was adjusted for the effect of other potentially confounding variables by analysis of co-variance., Results: Patients had well-controlled blood pressure throughout the observation period (mean arterial pressure 97 +/- 8 mmHg) and the average rate of decline of GFR was 4.32 +/- 4.08 ml/min/year. In univariate analysis baseline and mean HbA1 were linearly related to the rate of decline of GFR (baseline r5-0.565, P < 0.001; mean r-0.5107, P < 0.001) with those with a higher HbA1 having a faster rate of progression. In stepwise multivariate analysis both mean HbA1 mean diastolic blood pressure (P < 0.0001 and P = 0.019, respectively) was significantly and independently related with a faster rate of decline of GFR., Conclusions: Worse glycaemic control is associated with a faster rate of progression of diabetic nephropathy once blood pressure is controlled. Thus improvement of glycaemic control in patients where good blood pressure control has been achieved may potentially further delay the progression of nephropathy.

Insulin-dependent diabetes mellitus (IDDM) patients may have an increased intrarenal angiotensin II activity. In diabetic patients, captopril increases the renal hemodynamic response to an amino acid infusion. We investigated the effects of two salt diets on arterial pressure and renal response to a protein load in 10 normotensive (blood pressure < 140/90 mm Hg) IDDM patients (aged 30 +/- 3 years) who had diabetes for 7 +/- 4 years and normoalbuminuria levels [albumin excretion rate 4.8 (2.5-19.1) microg/min]. After 1 week of normal (approximately 100 mmol/day; approximately 100 mEq/l) and 1 week of high (approximately 300 mmol/day; approximately 300 mEq/l) salt intake, renal hemodynamic studies were performed at baseline and after a protein load (meat meal) of 100 g/1.73 m2. The mean 24-hour urinary sodium excretion levels were 99 +/- 27 and 293 +/- 80 mmol (mEq) with normal and high salt intake, respectively. No significant changes were seen in plasma sodium and glucose control with the normal and high salt diets, respectively: plasma sodium 135 +/- 3 vs. 137 +/- 1 mmol/l (mEq/l), (p = 0.08) and glycated hemoglobin 9.1 +/- 1.9 vs. 9.4 +/- 2.1% (p = 0.36). The body weight (70.9 +/- 12 vs. 71.8 +/- 13 kg; p = 0.015) was significantly higher with a high salt diet. The mean arterial pressure was similar with both diets (normal vs. high salt diet 91 +/- 9 vs. 89 +/- 6 mm Hg, p = 0.25). The plasma renin concentration [28 +/- 15 vs. 16 +/- 6 microU/ml(168 +/- 90 vs. 96 +/- 36 pmol/l), p = 0.013] and angiotensin II [8.8 +/- 4.4 vs. 6.4 +/- 3.5 pg/ml (0.052 +/- 0.025 vs. 0.038 +/- 0.021 nmol/l), p = 0.016] were significantly lower with the high salt diet. Following protein loading, the glomerular filtration rate increased with both diets: normal salt diet 114 +/- 26 vs. 128 +/- 30 ml/min/1.73 m2(1.9 +/- 0.43 vs. 2.13 +/- 0.50 ml/s/1.73 m2), p = 0.04; high salt diet 118 +/- 23 vs. 127 +/- 29 ml/min/1.73 m2 (1.97 +/- 0.38 vs. 2.12 +/- 0.48 ml/s/1.73 m2), p = 0.13. The change in renal plasma flow was similar to that of the glomerular filtration rate with normal and high salt intake, respectively: 566 +/- 94 vs. 617 +/- 142 ml/min/1.73 m2 (9.44 +/- 1.57 vs. 10.29 +/- 2.37 ml/s/173 m2), p = 0.0017; 572 +/- 125 vs. 600 +/- 110 ml/min/1.73 m2 (9.54 +/- 2.08 vs. 10.00 +/- 1.83 ml/s/1.73 m2), p = 0.057. In this subset of normotensive normoalbuminuric IDDM patients, a high salt intake did not promote an exaggerated renal response to the protein load despite inhibition of the renin-angiotensin system.

To determine whether cytokines could have a role in the development of insulin-dependent diabetes mellitus (IDDM), we measured serum levels of cytokines derived from T helper 1 (interleukin-2 and interferon-gamma), T helper 2 (interleukin-4 and interleukin-10) lymphocytes and macrophages (tumour necrosis factor-alpha, interleukin-1 alpha and interleukin-1 beta) in patients before and after the onset of IDDM. Recently diagnosed IDDM patients had significantly higher levels of interleukin-2, interferon-gamma, tumour necrosis factor-alpha and interleukin-1 alpha than patients with either long-standing IDDM, non-insulin-dependent diabetes (NIDDM), Graves' disease, or control subjects (p < 0.05 for all). Compared with control subjects, patients with long-standing IDDM and those with NIDDM had higher interleukin-2 and tumour necrosis factor-alpha levels (p < 0.01 for all). Interleukin-4 and interleukin-10 were detectable in sera of patients with Graves' disease only, while interleukin-1 beta was not detectable in the serum of any control or test subject. To investigate whether high cytokine levels precede the onset of IDDM, we studied 28 non-diabetic identical co-twins of patients with IDDM, followed-up prospectively for up to 6 years after the diagnosis of the index. Levels of tumour necrosis factor-alpha and interleukin-1 alpha were elevated above the normal range more frequently in the eight twins who developed diabetes than in those 20 who did not (p < 0.005). Analysis of T helper 1 and T helper 2 profiles of the twin groups did not reveal a clear difference between prediabetic twins and twins remaining non-diabetic. These results support the notion that T helper 1 lymphocytes may play a role in the development of IDDM. This is associated with release of macrophage-derived cytokines, which is also a feature of the prediabetic period. The lack of evidence of a dominant T helper 1 profile of cytokine release before diabetes onset suggests that additional events, activating this arm of the cellular immune response, are required in the immediate prediabetic period.

Diabetic nephropathy is associated with functional changes in the glomerular filtration barrier but the structural counterpart remains unknown. Width of glomerular epithelial cell foot processes and of filtration slits were determined by morphometric methods in 11 non-diabetic kidney donors and in 28 diabetic patients with albumin excretion rates ranging from normal to proteinuria. Foot process width was estimated from the ratio of tuft surface density to length density of slits. At high magnification independently sampled, perpendicularly cut slits were classified. Foot process width on peripheral basement membrane was increased in microalbuminuric compared to normoalbuminuric diabetic patients (p<0.05) but showed no significant correlation with the level of albumin excretion when patients with increased barrier permeability were considered. Width of filtration slits in normo- and microalbuminuric diabetic patients exceeded that in non-diabetic control subjects (p<0.05). Filtration slits were narrower in patients with overt proteinuria than in patients with microalbuminuria (p<0.05) and correlated with glomerular filtration rate in all of the diabetic patients (r=0.65, p<0.005). The results show that insulin-dependent diabetic patients with nephropathy present changes of epithelial cells and filtration slits, demonstrable already in the stage of microalbuminuria. The mechanism of albumin leakage is not achieved by these measures. The dimension of filtration slits may play a contributing role in the level of glomerular filtration rate in diabetic patients.

Several studies have shown an association between blood pressure and nephropathy, but few have been large enough to examine whether, or how, this relation is influenced by retinopathy. We have therefore examined the independent relations of blood pressure to urinary albumin excretion and retinopathy in a cross-sectional observational study of over 3000 insulin-dependent diabetic patients (the EURODIAB IDDM Complications Study). The relation of blood pressure to urinary albumin excretion differed strikingly between patients with (46%) and without (54%) retinopathy. In those with retinopathy, mean urinary albumin excretion rate was normal (< 20 micrograms/min) below median diastolic pressure (75 mmHg) and increased steeply (p < 0.001) with blood pressure above this level. However, in patients without retinopathy, mean albumin excretion rate was normal across the range of diastolic pressure. This finding could not be explained by differences in glycaemic control or duration of diabetes between patients with and without retinopathy. These data identify a subgroup of patients whose high risk of nephropathy may reflect abnormal renal vulnerability to mildly raised blood pressure. Retinopathy is a close correlate of this vulnerability. Detection of even mild retinopathy, together with raised blood pressure, may be important in assessing nephropathy risk.

Lp(a) was measured in 64 normoalbuminuric, 52 microalbuminuric, and 37 proteinuric Type 1 diabetic patients and 54 healthy subjects. Microalbuminuric and proteinuric Type 1 diabetic patients had higher median Lp(a) values (133 (16-1932) and 169 (17-1149) mg l-1) than patients with normal AER (73 (15-1078) mg l-1; p = 0.048 and p = 0.027). Lp(a) in healthy subjects (110 (15-1630)mg l-1) did not differ from the diabetic subgroups. The frequency of Lp(a) values in the upper quarter of the normal distribution was similar in the diabetic groups and did not differ between diabetic and control subjects. The cumulative distribution of Lp(a) was similar in all groups. Lp(a) concentrations were not related to AER, age, gender, duration of diabetes, body mass index, glycaemic control, serum creatinine, free insulin or systolic blood pressure. Cholesterol, LDL-cholesterol, triglycerides, and apo B were higher in microalbuminuric and proteinuric than in normoalbuminuric Type 1 diabetic patients. Lp(a) was independently related to diastolic blood pressure, fibrinogen, and macroangiopathy. In conclusion, median Lp(a) concentrations tend to be higher in Type 1 diabetic patients with early and established renal disease, although the differences are small and the overlap between groups large. Lp(a) is related to diastolic blood pressure and fibrinogen, and this association of powerful risk factors suggests that Lp(a) may play a role in the pathogenesis of cardiovascular disease in Type 1 diabetic patients with proteinuria. Whether Lp(a) is an independent determinant of increased cardiovascular risk in these patients needs to be elucidated by prospective studies.

The biochemical and structural alterations responsible for the renal and vascular complications of diabetes mellitus are likely to be the result of common processes. It is now well recognized that microalbuminuria is a powerful predictor of cardiovascular morbidity and mortality in diabetic patients. Increased cell growth and vascular tone and insulin resistance are among the contributors that lead to the renal and vascular complications of diabetes. Angiotensin-converting enzyme inhibitors, which may decrease the negative impact of these contributors, are effective therapeutic agents that reduce the risk of progression of renal disease and early mortality.

To answer the question whether the elevation of LDL-cholesterol in IDDM patients with incipient and established diabetic nephropathy is accompanied by changes in LDL size or composition, we studied distribution of LDL particles in 57 normoalbuminuric [AER 7 (1-9) micrograms/min, median and range], in 46 microalbuminuric [AER 50 (20-192) micrograms/min] and in 33 proteinuric [AER 422 (233-1756) micrograms/min] IDDM patients as well as in 49 non-diabetic control subjects with normoalbuminuria. The three diabetic groups were matched for duration of diabetes and glycaemic control. The mean particle diameter of the major LDL peak was determined by nondenaturing gradient gel electrophoresis. Composition and density distribution of LDL were determined in the subgroups of each patient group by density gradient ultracentrifugation. Normoalbuminuric IDDM patients had larger LDL particles than non-diabetic control subjects (260 A vs 254 A, p < 0.05). LDL particle diameter was inversely correlated with serum triglycerides in all groups (p < 0.05 for normoalbuminuric and p < 0.001 for other groups). Triglyceride content of LDL was higher in three IDDM groups compared to control group (p < 0.05). The elevation of LDL mass in microalbuminuric and proteinuric IDDM groups compared to normoalbuminuric IDDM group (p < 0.05 for both) was mainly due to the increment of light LDL (density 1.0212-1.0343 g/ml). There were no significant changes in the density distribution or composition of LDL between the three diabetic groups. In conclusion the increase of LDL mass without major compositional changes suggests that the elevation of LDL in incipient and established diabetic nephropathy is primarily due to the increased number of LDL particles.(ABSTRACT TRUNCATED AT 250 WORDS)

We measured Na+/Li+ CT in 16 IgA nephropathy patients. Records were reviewed (mean observation period 5.5 years) for serial measurements of blood pressure (BP), urinary protein excretion, GFR (51Cr-EDTA) and plasma creatinine. Na+/Li+ CT correlated with the slope of the plot of GFR versus time (rs = -0.66, p = 0.005) systolic BP at diagnosis (rs = 0.62, p = 0.011) and both systolic and diastolic BP at the end of follow-up (rs = 0.69, p = 0.003, and rs = 0.56, p = 0.023). A diastolic blood pressure (DBP) > or = 95 mm Hg was associated with a faster rate of GFR decline (rate of change of GFR: -0.40 vs. -0.14 ml/min/month, p = 0.07; for DBP > or = 95 vs. < 95 mm Hg, respectively). In a multiple regression analysis with the rate of decline of GFR as dependent variable, Na+/Li+ CT emerged as a significant and independent determinant of the rate of fall of GFR (beta coefficient -1.56, SE beta 0.49, p = 0.006) and explained 52.7% of the variation in the GFR fall. Higher activities of Na+/Li+ CT are significantly associated with an increased rate of deterioration of renal function in IgA nephropathy; part of this effect could be mediated by higher blood pressure values.

Proteinuric diabetic patients have an increased risk of cardiovascular disease and almost always have hypertension. In the early stages of diabetic renal disease (microalbuminuria) when renal function is well preserved, systemic arterial blood pressure is already elevated compared to insulin-dependent diabetic patients without microalbuminuria. Prospective studies have shown that normoalbuminuric patients who progress to microalbuminuria have higher blood pressures (albeit within the normal range) than those who persistently remain normoalbuminuric. Parents of insulin-dependent diabetic patients with nephropathy have a higher prevalence of hypertension and cardiovascular disease compared to those of patients without nephropathy. Moreover, diabetic nephropathy clusters within families. Erythrocyte sodium-lithium countertransport activity, the most consistent marker for essential hypertension and its cardiorenal complications, is elevated in diabetic patients with nephropathy and in their non-diabetic parents. These data suggest that a familial predisposition to arterial hypertension and cardiovascular disease increases the risk for the development of nephropathy and its associated cardiovascular complications in insulin-dependent diabetes. Arterial hypertension is a state of insulin resistance and diabetic patients susceptible to nephropathy have been found to be less insulin sensitive. Preventive strategies of diabetic kidney disease in the future will have to take into account its metabolic hemodynamic and familial basis.

Microalbuminuria is a predictor of persistent proteinuria, renal failure and cardiovascular disease and therefore accurate determination of urinary albumin concentration is important. We examined the stability of albumin in urine under different conditions of storage, temperature and sample preparation. There was no significant difference in urinary albumin concentration between fresh urine and urine stored at either 4 degrees C or 20 degrees C for up to 7 days. Similarly in urine samples from diabetic patients there was no significant difference in albumin concentration at levels ranging from 1.3 to 1999.3 mg/l between fresh urine at 4 degrees C and urine stored frozen for 1 week, 1 month or 6 months. Neither storage temperature (-20 degrees C or -40 degrees C) nor centrifugation of sample prior to assay made a significant difference to the albumin concentration. Multiple freezing and thawing of urine samples during 6 weeks of storage at -20 degrees C made no difference to albumin concentrations. Storage of urine samples in either polypropylene, polystyrene or borosilicate glass tubes did not result in a significant change in urinary albumin concentration after either 1 week or 1 month at -20 degrees C although, after 1 month of storage, urinary albumin concentrations tended to be lower by an average of approximately 7%. In tubes to which gelatine had been added this was reduced to 4%. We conclude that fresh urine can be kept at 4 degrees C or 20 degrees C for up to 7 days. Frozen urine samples can be stored for up to 6 months before assay without any loss of albumin concentration.(ABSTRACT TRUNCATED AT 250 WORDS)

The effect of hyperglycaemia on renal function in diabetic nephropathy remains poorly understood. We investigated the renal haemodynamic response to an acute plasma glucose rise from sustained euglycaemia to sustained hyperglycaemia in eight persistently proteinuric Type 1 (insulin-dependent) diabetic patients. Studies were performed in a double-blind cross-over manner after i.v. injection of 450 mg lysine acetylsalicilate (equivalent to 250 mg acetylsalicilic acid) or equal volume of 0.9% NaCl (isotonic saline). In the isotonic saline experiments hyperglycaemia produced a significant rise, by approximately 35%, in glomerular filtration rate in all patients from 41.5 +/- 5.2 to 55 +/- 6 ml.min-1.1.73 m-2 (p < 0.005) and an increase in sodium paraminohippurate clearance from 178 +/- 22.7 to 220 +/- 20.0 ml.min-1.1.73 m-2 (p < 0.05). These changes took place within the first 30 min of glucose infusion and were maintained for a 90 min hyperglycaemic period. Filtration fraction did not change significantly. Infusion of lysine acetylsalicilate lowered baseline glomerular filtration rate (isotonic saline vs lysine acetylsalicilate 41.5 +/- 5.2 vs 30.0 +/- 5.7 ml.min-1.1.73 m-2; p < 0.05) and significantly blunted the rise in glomerular filtration rate during hyperglycaemia (glomerular filtration rate increment: saline vs lysine acetylsalicilate: 13.6 +/- 2.8 vs 5.3 +/- 1.8 ml.min-1.1.73 m-2; p < 0.005). The effects on renal plasma flow were similarly blunted. In five additional patients, time- and volume-controlled isotonic saline experiments during sustained euglycaemia showed no significant changes in glomerular filtration rate and sodium paraminohippurate clearance.(ABSTRACT TRUNCATED AT 250 WORDS)

Objective: To analyse the cost-benefit of screening for and antihypertensive treatment of early renal disease indicated by microalbuminuria in patients with insulin dependent diabetes mellitus., Design: Previously published data were used to estimate transition probabilities for each step from normoalbuminuria until death. The effect of intervention on urinary albumin excretion rate by antihypertensive treatment was arbitrarily set at three different levels. All direct costs (screening, antihypertensive treatment, treatment of end stage renal failure) were included in the cost-benefit analysis by using real discount rates of 2.5% and 6%., Setting: Computer simulation., Subjects: Simulated cohort of 8000 patients., Main Outcome Measures: Mortality, incidence of diabetic nephropathy, incidence of end stage renal failure, and costs versus savings., Results: Assuming treatment effects of 33% and 67% median life expectancy increased by four to 14 years, respectively, and the need for dialysis or transplantation decreased by 21% to 63%. Costs and savings would balance if the annual rate of increase of albuminuria was decreased from 20% to 18% a year., Conclusions: Screening and intervention programmes are likely to have life saving effects and lead to considerable economic savings.

Studies of nondiabetic renal disease suggest that thromboxane may be an important mediator of abnormal renal function. The role of thromboxane in diabetic nephropathy is not fully understood. We measured in a double-blind, randomized, placebo-controlled crossover study the effect of a thromboxane synthase inhibitor (FCE 22178, 400 mg two or three times per day) on urinary excretion of thromboxane B2 and 6-keto-prostaglandin F1 alpha, glomerular filtration rate (measured as clearance of polyfructosan), effective renal plasma flow (clearance of para-aminohippuric acid), fractional clearances of albumin and immunoglobin G and the reabsorption rate of beta 2-microglobulin in 15 patients with type 1 (insulin-dependent) diabetic nephropathy. In seven additional patients, the effect of the thromboxane synthase inhibitor given as 400 mg twice per day was compared with that of the thromboxane synthase inhibitor given as 400 mg three times per day. FCE 22178 administration caused a significant inhibition in the excretion of urinary thromboxane B2 and 2,3-dinor-thromboxane B2 compared with placebo (12.3 +/- 2.1 vs 24.6 +/- 5.1 ng/gm creatinine, p = 0.006, and 78.5 +/- 20.3 vs 335.5 +/- 84.1 ng/gm creatinine, p = 0.004, respectively) without any compensatory increase of 6-keto- prostaglandin F1 alpha or 2,3-dinor-6-keto-prostaglandin F1 alpha that reflect prostacyclin I2 biosynthesis. Glomerular filtration rate, effective renal plasma flow, renal vascular resistance, and filtration fraction were not significantly different after placebo or thromboxane synthase inhibitor treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

We determined whether the serum lipoprotein levels in insulin-dependent diabetic patients (IDDM) with nephropathy and in patients on haemodialysis or continuous ambulatory peritoneal dialysis were affected by beta-blocker therapy. A case control study was performed in 18 IDDM patients with diabetic nephropathy, in 18 patients receiving chronic haemodialysis (HD) and 16 patients undergoing continuous ambulatory peritoneal dialysis (CAPD). In IDDM patients with diabetic nephropathy very low density lipoprotein-cholesterol (VLDL-CHOL) (0.680 +/- 0.17 vs 0.197 +/- 0.04 mmol/l, p = 0.004), total triglycerides (1.71 +/- 0.23 vs 0.808 +/- 0.14 mmol/l, p = 0.004) and very low density lipoprotein triglyceride (VLD-TG) were higher in the beta-blocker therapy group. In haemodialysis patients, beta-blocker therapy caused no significant changes in the serum lipoprotein profiles compared to the control group. In patients receiving continuous ambulatory peritoneal dialysis VLDL-CHOL was significantly higher (1.47 +/- 0.24 vs 1.08 +/- 0.21 mmol/l, p = 0.042) and cholesterol-high density lipoprotein (HDL-CHOL) was lower in the beta-blocker therapy group. The elevated VLDL-CHOL level (0.96 +/- 0.12 vs 1.24 +/- 0.14 mmol/l, p = 0.021) was correlated with the duration of CAPD in patients receiving beta-blocker therapy. Antihypertensive therapy with beta-blockers in IDDM patients with persistent proteinuria and in patients on continuous ambulatory peritoneal dialysis appears to adversely effect serum lipoproteins which may add to their cardiovascular risk.

A cohort of 63 Type 1 insulin-dependent diabetic patients were first characterized for overnight urinary albumin excretion rate (AER) in 1967. In 1981, seven out of eight (87%) patients with initial AER greater than or equal to 30 less than or equal to 140 micrograms/min (microalbuminuria) developed clinical proteinuria compared to only 2 out of 55 (4%) patients with initial AER less than 30 micrograms/min. The same cohort of patients was reassessed in 1990 after a total follow-up period of 23 years. The aim was to investigate the role of microalbuminuria in the prediction of total/cardiovascular mortality and the development of renal failure, in addition to clinical proteinuria. The initially microalbuminuric patients had a significantly higher risk of developing not only clinical proteinuria (relative risk 9.3, 95% C.I. 1.36 to 3.10, P less than 0.05), but also of dying from a cardiovascular cause (relative risk 2.94, 95% C.I. 1.18 to 7.34, P less than 0.05). The rate of progression to renal failure was higher but not significantly so in the microalbuminuric (2 of 8) compared to the normoalbuminuric (4 of 53) group (relative risk 3.31, 95% C.I. 0.72 to 15.24, NS). In insulin-dependent diabetic patients microalbuminuria is a powerful predictor of clinically overt diabetic renal disease as well as cardiovascular mortality.

Background: An understanding of the structural basis for cardiovascular and renal complications in diabetes and hypertension is critical to design-focused intervention strategies., Hypothesis: The processes leading to vascular damage in the kidney and in the arteries in diabetes and hypertension appear to be characterized by hypertrophic/hyperplastic changes in a number of cell types (such as smooth muscle cells, fibroblasts, mesangial cells) and by excessive deposition of extracellular matrix material. Markers of cell growth/proliferation, such as Na(+)-H+ exchange, show increased activity in diabetic patients with renal disease and in patients with essential hypertension. Insulin resistance is a feature of arterial hypertension and diabetes and may contribute to renal and cardiovascular damage in these patients. A number of risk factors for cardiovascular disease cluster in the subset of diabetic patients prone to renal disease. These include dyslipidaemia, left ventricular hypertrophy and hypertension. It is postulated that a familial predisposition to renal and cardiovascular disease is the underlying reason for the susceptibility to the diabetic cardiorenal syndrome., Conclusion: In the management of diabetes and hypertension, it may prove possible to instigate preventive strategies by using therapeutic agents such as angiotensin converting enzyme inhibitors, which have the potential to interfere with the haemodynamic, growth and insulin sensitivity processes that contribute to vascular damage.

Whole blood and plasma viscosity, erythrocyte aggregation and deformability, plasma fibrinogen, lipids, lipoproteins, apolipoproteins, and measures of blood glucose control were compared between 21 Type 1 diabetic patients with microalbuminuria (overnight albumin excretion rate 30-200 micrograms min-1) and 21 patients with albumin excretion below this range matched for age, sex, and duration of diabetes. Patients with microalbuminuria had significantly higher glycosylated haemoglobin (9.4 +/- 1.6 (+/- SD) vs 7.9 +/- 1.8% (normal range 5.0 to 7.6%)), total-cholesterol (5.6 +/- 1.1 vs 4.6 +/- 1.3 mmol l-1), apolipoprotein B (0.82 +/- 0.21 vs 0.66 +/- 0.14 g l-1), and apolipoprotein B:A1 ratio (0.58 +/- 0.18 vs 0.50 +/- 0.15) than those without microalbuminuria (all p less than 0.05). HDL-cholesterol was also raised (1.71 +/- 0.46 vs 1.43 +/- 0.37 mmol l-1, p less than 0.05). Lipoprotein(a) concentration was possibly higher in the microalbuminuric group (median (95% Cl) 105 (82-140) vs 72 (52-114) mg l-1, p = 0.06). No differences were seen in any of the rheological measurements. These results confirm the presence of potentially atherogenic lipoprotein changes in Type 1 diabetic patients with microalbuminuria, but suggest that altered blood rheology does not predate the development of nephropathy.

Diabetic patients who develop proteinuria show a marked increase in cardiovascular morbidity and mortality. The precise pathogenesis of human diabetic kidney disease and the factors responsible for the susceptibility to it remain, in part, obscure. However, there is now evidence that renal disease clusters in families and that genetic factors may be of central importance in determining susceptibility. Predisposition to arterial hypertension has been suggested as playing a contributory role in the development of kidney disease. Hypertrophic processes may be implicated in the susceptibility to arterial wall damage and glomerular injury in diabetes. Interestingly, fibroblasts of patients with diabetic nephropathy show a higher Na+/H+ antiport activity and a greater 3H-thymidine incorporation into DNA than fibroblasts of diabetic patients without nephropathy. The first clinical signs of renal involvement are the appearance of microalbuminuria and a small elevation in arterial pressure. Mesangial expansion accompanies these changes. Microalbuminuria is associated with abnormalities of lipoprotein profiles and higher Na+/Li+ countertransport rates. The environmental changes brought about by diabetes could lead in susceptible individuals to increased systemic and intraglomerular pressures on the one hand and to mesangial expansion on the other. These two processes would cause proteinuria and glomerulosclerosis. Lipid abnormalities may further aggravate the renal histological damage and, in combination with hypertension, contribute to the accelerated atherosclerosis typical of patients with diabetic kidney disease. A vicious circle would thus be triggered, involving reduction in renal function, further hypertension, proteinuria, glomerular obsolence and hyperlipidaemia, and eventually end-stage renal failure or premature cardiovascular death.

The precise pathogenesis of human diabetic kidney disease and the factors responsible for the susceptibility to it remain to be established. However, there is now evidence that renal disease clusters in families and that genetic factors are of central importance in determining liability. A predisposition to arterial hypertension has been suggested as playing a contributory role in the development of kidney disease. Genetically controlled hypertrophic processes may be implicated in the susceptibility to arterial wall damage and glomerular injury in diabetes. This suggestion derives from the observation that the fibroblasts of patients with diabetic nephropathy show a higher Na+/H+ antiport activity and a greater 3H-thymidine incorporation into DNA than fibroblasts of diabetic patients without nephropathy. The first sign of renal damage is the appearance of microalbuminuria and of a small elevation in arterial pressure, changes associated with significant mesangial expansion. Microalbuminuria is associated with abnormalities of lipoprotein profiles possibly as a consequence of insulin-resistance-induced hyperinsulinemia. It could be postulated that the environmental changes brought about by diabetes lead in susceptible individuals to increased systemic and intraglomerular pressure on the one hand and mesangial expansion on the other. These two processes would cause proteinuria and glomerulosclerosis. Lipid abnormalities would further aggravate the renal histological damage and, in combination with hypertension, contribute to the accelerated atherosclerosis typical of patients with diabetic kidney disease. A vicious circle would thus be triggered of reduction in renal function, more hypertension, more proteinuria, more glomerular obsolence, more hyperlipidemia and eventually end-stage renal failure or premature cardiovascular death.

The effect of the administration of a single oral dose of placebo, oxprenolol and metoprolol on insulin-induced hypoglycemia was investigated in seven insulin-dependent diabetics in a double-blind randomized study. Neither of the beta-blocking agents accelerated the plasma glucose lowering effect of insulin. Plasma glucose recovery from hypoglycemia was grossly impaired in diabetics whether blocked or not, and all investigations had to be terminated by i.v. glucose injection after 1 hr of sustained hypoglycemia. During the period of observation, no further delaying effect by either beta-blocker was observed. The lack of plasma glucose recovery seems to be at least in part related to a retarded and reduced glucagon response to hypoglycemia. Both drugs blocked the hypoglycemia-induced pulse rate increase, but neither caused bradycardia. A significant increase in diastolic pressure was recorded with oxprenolol, whereas a drop in systolic pressure was noted with metoprolol. Oxprenolol suppressed the NEFA rise after insulin-infusion termination to a greater extent than did metoprolol. Hypoglycemic symptoms were not affected by beta-blockade. The results suggest that neither drug further worsens the already grossly impaired plasma glucose recovery, but that oxprenolol and metoprolol may differ in their effects on hemodynamic response to hypoglycemia. This aspect of the problem requires further study under careful control in hypertensive diabetics.

Human insulin synthesised by recombinant DNA technology was compared with highly purified porcine insulin in healthy men. Intracutaneous injection over a wide range of concentrations of both insulins into five subjects gave rise to no local reactions over a 48 h period. The glycaemic response to standard subcutaneous injection at high and low dose levels was measured with both insulins in each of six men. Plasma glucose decrement with the two insulins was similar but human insulin was perhaps slightly more potent than porcine insulin at the low dose, and slightly less so at the high. The glycaemic response to the isulins, each infused intravenously at high and low concentrations for 1 h in a further six subjects, showed a similar trend. Depression of glycaemia with human insulin slightly exceeded that with porcine insulin at the low concentration infusion and fell slightly short of it at the high. Genetically synthesised human insulin seems to be safe and effective in man. Its dose-response relationship may differ from that of porcine insulin.

Microalbuminuria in insulin-dependent diabetics appears to indicate early renal damage rather than susceptibility to it, yet a series of relatively small, short-term intervention studies in insulin-dependent diabetes mellitus patients have already demonstrated reduction in albumin excretion rates or arrest in the increase of fractional clearance of albumin. Treatments have ranged from the use of angiotensin-converting enzyme inhibitors aimed at lowering BP to the use of diets restricted to 0.5 to 0.6 g/kg protein and strict blood glucose control by intensified insulin treatment. Large, long-term intervention studies of cohorts of insulin-dependent and non-insulin-dependent diabetic patients with microalbuminuria are now needed to assess the effects of the different modalities of care on the development of persistent proteinuria, end-stage renal disease, and cardiovascular mortality as well as associated quantitative changes in the renal structure.