Comparison of reduction in microalbuminuria by enalapril and hydrochlorothiazide in normotensive patients with insulin dependent diabetes.

OBJECTIVE--To compare the effects of sodium depletion and of angiotensin I converting enzyme inhibition on microalbuminuria in insulin dependent diabetes. DESIGN--Randomised, double blind, double dummy parallel study of normotensive diabetic patients with persistent microalbuminuria (30-300 mg/24 h) treated with enalapril or hydrochlorothiazide for one year after a three month, single blind placebo period. SETTING--Diabetic clinic in a tertiary referral centre. PATIENTS--10 diabetic patients with low microalbuminuria (30-99 mg/24 h) and 11 with high microalbuminuria (100-300 mg/24 h). INTERVENTIONS--11 subjects (six with low microalbuminuria, five with high microalbuminuria) were given enalapril 20 mg plus placebo hydrochlorothiazide once daily and 10 (four with low microalbuminuria, six with high microalbuminuria) hydrochlorothiazide 25 mg plus placebo enalapril once daily. MAIN OUTCOME MEASURES--Monthly assessment of urinary albumin excretion and mean arterial pressure; plasma active renin and aldosterone concentrations and renal function studies at 0, 6, and 12 months. RESULTS--Median urinary albumin excretion decreased from 59 (range 37-260) to 38 (14-146) mg/24 h with enalapril and from 111 (33-282) to 109 (33-262) mg/24 h with hydrochlorothiazide (analysis of variance, p = 0.0436). During the last three months of treatment with enalapril five patients had persistent normoalbuminuria (2-3 times below 30 mg/24 h), five low microalbuminuria, and one high microalbuminuria; in the hydrochlorothiazide group one had normoalbuminuria, three low microalbuminuria, and six high microalbuminuria (chi 2 test = 6.7; p = 0.03). Mean arterial pressure did not differ before (98 (SD 7) with enalapril v 97 (9) mm Hg with hydrochlorothiazide) or during treatment (88 (7) with enalapril v 90 (7) mm Hg with hydrochlorothiazide (analysis of variance, p = 0.5263)). Glomerular filtration rate did not vary. The aldosterone to active renin ratio was decreased by angiotensin I converting enzyme inhibition and increased by sodium depletion, showing treatment efficacy. CONCLUSION--Angiotensin I converting enzyme inhibition by enalapril effectively reduces microalbuminuria in normotensive diabetic patients whereas hydrochlorothiazide is not effective. Changes in blood pressure and activity of the renin-angiotensin-aldosterone system may contribute to these different effects.     

Converting enzyme inhibition and kidney function in normotensive diabetic patients with persistent microalbuminuria.

The effects of a long term reduction in blood pressure on the kidney function of normotensive diabetic patients who had persistent microalbuminuria (30-300 mg albumin/24 hours) were studied in two groups of 10 such patients before and during six months of treatment with either 20 mg enalapril or placebo daily. Treatments were assigned randomly in a double blind fashion. Before treatment both groups had similar clinical characteristics, weight, diet, total glycosylated haemoglobin, median albumin excretion rate (enalapril group 124 mg/24 h, placebo group 81 mg/24 h), and mean arterial pressure (enalapril group 100 (SD 8) mm Hg, placebo group 99 (6) mm Hg). During treatment weight, urinary urea excretion, and total glycosylated haemoglobin remained unchanged. The mean arterial pressure decreased in the enalapril group but not in the placebo group (enalapril group 90 (10) mm Hg, placebo group 98 (8) mm Hg). The median albumin excretion rate also fell in the enalapril group but not in the placebo group (enalapril group 37 mg/24 h, placebo group 183 mg/24 h.) The glomerular filtration rate rose in the enalapril group from 130 (23) ml/min/1.73 m2 to 141 (24) ml/min/1.73 m2, and total renal resistances and fractional albumin clearance decreased while fractional albumin clearance increased in the placebo group. These results show that in patients who have diabetes but not hypertension a reduction in blood pressure by inhibition of converting enzyme for six months can reduce persistent microalbuminuria, perhaps by decreasing the intraglomerular pressure.     

Efficacy of captopril in postponing nephropathy in normotensive insulin dependent diabetic patients with microalbuminuria.

OBJECTIVE--To assess the effectiveness of angiotensin converting enzyme inhibition in preventing the development of diabetic nephropathy (albuminuria greater than 300 mg/24h). DESIGN--Open randomised controlled study of four years'' duration. SETTING--Outpatient diabetic clinic in tertiary referral centre. PATIENTS--44 normotensive (mean blood pressure 127/78 (SD 12/10) mm Hg) insulin dependent diabetic patients with persistent microalbuminuria (30-300 mg/24h). INTERVENTIONS--The treatment group (n = 21) was initially given captopril (25 mg/24 h). The dose was increased to 100 mg/24 h during the first 16 months and thiazide was added after 30 months. The remaining 23 patients were left untreated. MAIN OUTCOME MEASURES--Albuminuria, kidney function, development of diabetic nephropathy (albuminuria greater than 300 mg/24 h), and arterial blood pressure. RESULTS--Clinical and laboratory variables were comparable at baseline. Urinary excretion of albumin was gradually reduced from 82 (66-106) to 57 (39-85) mg/24 h (geometric mean (95% confidence interval)) in the captopril treated group, whereas an increase from 105(77-153) to 166 (83-323) mg/24 h occurred in the control group (p less than 0.05). Seven of the untreated patients progressed to diabetic nephropathy, whereas none of the captopril treated patients developed clinical overt diabetic nephropathy (p less than 0.05). Systemic blood pressure, glomerular filtration rate, haemoglobin A1c concentration, and urinary excretion of sodium and urea remained practically unchanged in the two groups. CONCLUSIONS--The findings suggest that angiotensin converting enzyme inhibition postpones the development of clinical overt diabetic nephropathy in normotensive insulin dependent diabetic patients with persistent microalbuminuria.     

Short term effect of captopril on microalbuminuria induced by exercise in normotensive diabetics.

OBJECTIVE--To investigate whether captopril has any effect on microalbuminuria induced by exercise in normotensive diabetic patients with early stage nephropathy. DESIGN--Randomised, double blind, crossover trial. SETTING--Outpatient department. PATIENTS--22 diabetics with stage II nephropathy (urinary albumin excretion rate less than 20 micrograms/min; 15 with type I diabetes and seven with type II), 32 patients with stage III nephropathy (urinary albumin excretion rate 20-200 micrograms/min; 14 with type I diabetes and 18 with type II), and 10 normal subjects. INTERVENTIONS--Four exercise tests on a cycle ergometer: the first two under basal conditions and the third and fourth after subjects had received captopril (two 25 mg doses in 24 hours) or placebo (two tablets in 24 hours). END POINT--Exercised until 90% of maximum heart rate achieved. MEASUREMENTS AND MAIN RESULTS--Mean urinary excretion one hour after the first two exercise tests was 21 micrograms/min in normal subjects, 101 micrograms/min in diabetic patients with stage II nephropathy, and 333 micrograms/min in those with stage III nephropathy. Similar results were obtained after placebo. After captopril the urinary excretion rate one hour after exercise was significantly decreased in diabetics with stage II (36 micrograms/min) and stage III (107 micrograms/min) disease compared with placebo but not in normal subjects. Systolic and diastolic pressures were similar in the three groups after placebo and captopril had been given. CONCLUSIONS--Captopril significantly reduces microalbuminuria induced by exercise in normotensive diabetics without affecting systemic blood pressure. Captopril may reduce renal intracapillary pressure.     

Contrasting effects of enalapril and metoprolol on proteinuria in diabetic nephropathy.

OBJECTIVE--To assess whether angiotensin converting enzyme inhibition reduces proteinuria in diabetic nephropathy more than blood pressure reduction with other antihypertensive treatment. DESIGN--Prospective, open randomised study lasting eight weeks in patients with diabetic nephropathy. SETTING--Outpatient nephrology clinics. PATIENTS--40 Patients with type I diabetes and diabetic nephropathy with reduced renal function. INTERVENTION--Antihypertensive treatment with enalapril or metoprolol, usually combined with frusemide. MAIN OUTCOME MEASURES--Arterial blood pressure and urinary excretion of albumin and protein. RESULTS--Arterial blood pressure after eight weeks was 135/82 (SD 13/7) mm Hg in the group given enalapril and 136/86 (16/12) mm Hg in the group given metoprolol. Proteinuria and albuminuria were similar in both groups before randomisation. After eight weeks'' treatment, the geometric mean albumin excretion was 0.7 (95% confidence interval 0.5 to 1.2) g/24 h in the patients given enalapril and 1.6 (1.1 to 2.5) g/24 h in the patients given metoprolol (p less than 0.02). The proteinuria was 1.1 (0.7 to 1.7) and 2.4 (1.6 to 3.6) g/24 h respectively (p less than 0.02). CONCLUSIONS--Antihypertensive treatment with enalapril reduced proteinuria in patients with diabetic nephropathy more than an equally effective antihypertensive treatment with metoprolol. This points to a specific antiproteinuric effect of the angiotensin converting enzyme inhibitor independent of the effect on systemic blood pressure.     

Effect of captopril on blood pressure and kidney function in normotensive insulin dependent diabetics with nephropathy.

OBJECTIVE--To assess whether inhibition of angiotensin converting enzyme protects kidney function in diabetic nephropathy. DESIGN--Open, randomised follow up study of normotensive insulin dependent diabetics with nephropathy either treated or not with captopril for one year. SETTING--Outpatient diabetic clinic in a tertiary referral centre. PATIENTS--32 Normotensive patients with insulin dependent diabetes complicated by nephropathy who were randomised either to the treatment group (n = 15) or to the control group (n = 17). INTERVENTIONS--The treatment group was given captopril (25-100 mg/day) for 12 months, the average dose during the second six months of the study being 40 mg daily. Controls were not treated. MAIN OUTCOME MEASURES--Albuminuria, arterial blood pressure, and the glomerular filtration rate. RESULTS--Mean arterial blood pressure fell by 3 (SE 2) mm Hg in the captopril treated group and rose by 6 (1) mm Hg in the controls. In addition, albuminuria declined by 11% in the captopril treated group and rose by 55% in the controls, fractional albumin clearance fell by 17% in the captopril treated group and increased by 66% in the controls, and the glomerular filtration rate declined by 3.1 (2.8)ml/min/1.73 m2 with captopril and by 6.4 (3.1) ml/min/1.73 m2 in the controls. CONCLUSION--Inhibition of angiotensin converting enzyme arrests the progressive rise in albuminuria in normotensive insulin dependent diabetics with nephropathy.     

Comparison between perindopril and nifedipine in hypertensive and normotensive diabetic patients with microalbuminuria. Melbourne Diabetic Nephropathy Study Group.

OBJECTIVE--To compare the efficacy of angiotensin converting enzyme inhibition with calcium antagonism in diabetic patients with microalbuminuria. DESIGN--Randomised study of diabetic patients with microalbuminuria treated with perindopril or nifedipine for 12 months and monitored for one or three months after stopping treatment depending on whether they were hypertensive or normotensive. Patients were randomised separately according to whether they were hypertensive or normotensive. SETTING--Diabetic clinics in three university teaching hospitals. PATIENTS--50 diabetic patients with persistent microalbuminuria. In all, 43 completed the study: 30 were normotensive and 13 hypertensive; 19 had type I diabetes and 24 had type II diabetes. INTERVENTIONS--For 12 months 20 patients were given perindopril 2-8 mg daily and 23 were given nifedipine 20-80 mg daily. MAIN OUTCOME MEASURES--Albumin excretion rate, blood pressure, and glomerular filtration rate. RESULTS--Both perindopril and nifedipine significantly reduced mean blood pressure. During treatment there was no significant difference between those treated with perindopril and those treated with nifedipine with respect to albuminuria or mean blood pressure. Stopping treatment with both drugs was associated with a sustained increase in albuminuria and mean blood pressure. There was a significant correlation between mean blood pressure and albuminuria and also between the reduction in mean blood pressure and the decrease in albuminuria during treatment with both drugs. In hypertensive patients both drugs caused significant decreases in mean blood pressure and albuminuria. In normotensive patients there was no significant reduction in albuminuria with either regimen. CONCLUSIONS--In diabetic patients with microalbuminuria blood pressure seems to be an important determinant of urinary albumin excretion. Perindopril and nifedipine have similar effects on urinary albumin excretion, both preventing increases in albuminuria in normotensive patients and decreasing albuminuria in hypertensive patients.     

Role of glycaemic control in development of microalbuminuria in patients with insulin dependent diabetes.

OBJECTIVE--To ascertain which factors determine the progression from very low rates of albumin excretion to persistent microalbuminuria in patients with insulin dependent diabetes mellitus. DESIGN--A 10 year prospective study of a cohort of diabetic patients. SETTING--Outpatient department of the Portsmouth District Hospitals. SUBJECTS--97 patients with insulin dependent diabetes mellitus who were initially free of microalbuminuria and hypertension. MAIN OUTCOME MEASURE--Urinary albumin: creatinine ratio. RESULTS--Eight of the 97 patients had developed microalbuminuria (urinary albumin:creatinine ratio > 3 mg/mmol in three consecutive early morning samples) by the 10 year follow up. The group who developed microalbuminuria had higher baseline log10 plasma glucose concentrations (mean (SD), 1.210 (0.122) v 0.984 (0.196) mmol/l, P < 0.001) and glycated haemoglobin concentrations (1.112% (0.069%) v 0.997% (0.076%), P < 0.001) and a younger age at onset of diabetes (10.0 (5.5) v 15.6 (7.8) years, P < 0.05). There was no difference in baseline duration of diabetes, smoking, sex, insulin dose, body mass index, serum creatinine concentration, or systolic, diastolic, or mean arterial blood pressure between the two groups. Multiple linear regression analysis showed that urinary albumin:creatinine ratio at 10 years was influenced by initial albumin:creatinine ratio (P = 0.006), initial glycated haemoglobin concentration (P = 0.002), and duration of diabetes (P = 0.045). Genotype for angiotensin converting enzyme was not related to the development of microalbuminuria nor, in a larger group of patients, the presence of any degree of diabetic nephropathy. CONCLUSION--In patients with insulin dependent diabetes mellitus the progression of minimal albuminuria and the development of microalbuminuria is determined primarily by poor long term glycaemic control. There is a weaker relation with longer duration of disease and younger age at onset of diabetes, but blood pressure does not seem to be implicated. Gene polymorphism for angiotensin converting enzyme is not linked to the development of microalbuminuria or established diabetic nephropathy.     

Effect of captopril on kidney function in insulin-dependent diabetic patients with nephropathy.

The influence of angiotensin II on kidney function in diabetic nephropathy was assessed by studying the effect of 12 weeks'' monotherapy with captopril (25-50 mg twice a day) in 16 hypertensive insulin dependent diabetic patients with persistent albuminuria. In an initial one week randomised single blind trial of captopril versus placebo, captopril (for nine patients) reduced arterial blood pressure from 148/94 (SD11/6) to 135/88 (8/7) mm Hg (p less than 0.05) and albuminuria from 1549 (range 352-2238) to 1170 (297-2198) micrograms/min (p less than 0.05), while glomerular filtration rate remained stable. No significant changes occurred in seven patients treated with placebo. During the 12 weeks of captopril treatment arterial blood pressure in all patients fell from 147/94 (11/6) to 135/86 (13/7) mm Hg (p less than 0.01), albuminuria fell from 1589 (range 168-2588) to 1075 (35-2647) micrograms/min (p less than 0.01), and glomerular filtration rate fell from 99 (SD19) to 93 (25) ml/min/1.73 m2 (p less than 0.01). The renin-angiotensin system showed suppressed plasma concentrations of angiotensin II and increased concentrations of angiotensin I and renin. The study showed that glomerular filtration rate is not dependent on angiotensin II, that captopril reduces albuminuria, probably by lowering glomerular hypertension, and that captopril represents a valuable new drug for treating hypertension in diabetics dependent on insulin with nephropathy.     

A correlation between microalbuminuria and anti-insulin antibodies in type I diabetics

A link between circulating anti-insulin antibodies and diabetic glomerulopathy has been suggested. This paper presents two different studies aiming to detect a relationship between incipient nephropathy (indicated by microalbuminuria) and anti-insulin antibodies. In 64 type I diabetics, overnight urinary albumin excretion during an exercise-test was found to be correlated with systolic blood pressure (r = 0.258 p less than 0.05), anti-insulin antibodies (r = 0.258 p less than 0.05), and glycosylated hemoglobin (r = 0.258 p less than 0.05) whereas no correlation was found among these three parameters. In another group of 80 type I diabetics, urinary albumin excretion during a standardized exercise-test was also correlated with anti-insulin antibodies (r = 0.360 p less than 0.001). In this latter group, diabetics with elevated (greater than 200 microU/ml) levels of anti-insulin antibodies had higher values of microalbuminuria after exercise (p less than 0.001) when compared to those with lower or undetectable levels, although they did not differ with respect to blood pressure and glycemic control. Therefore, we confirm preliminary reports indicating a statistical relationship between anti-insulin antibodies and microalbuminuria. We hypothesize that anti-insulin antibodies may be an additional factor of risk in the pathogenesis of early (reversible) stages of diabetic nephropathy.     

Protection of kidney function and decrease in albuminuria by captopril in insulin dependent diabetics with nephropathy.

STUDY OBJECTIVE--To assess whether long term inhibition of angiotensin converting enzyme with captopril and frusemide or bendrofluazide protects kidney function in diabetic nephropathy. DESIGN--Non-randomised controlled before-after trial of matched hypertensive insulin dependent diabetics with nephropathy treated with captopril and frusemide or bendrofluazide. SETTING--Outpatient diabetic clinic in tertiary referral centre. PATIENTS--Treatment group of 18 hypertensive insulin dependent diabetics with nephropathy (mean age 33), who had not been treated previously. Control group of 13 patients (mean age 32) fulfilling the same entry criteria from a prospective study. INTERVENTIONS--Treatment group was given daily captopril 37.5-100.0 mg and frusemide (mean) 98 mg (10 patients) or bendrofluazide (mean) 4 mg (seven). Treatment was continued for about two and a half years. Controls were not treated. END POINT--Measurement of arterial blood pressure, albuminuria, and glomerular filtration. MEASUREMENTS AND MAIN RESULTS--Baseline values were identical in treated and untreated groups respectively: mean blood pressure 146/93 (SE 3/1) mm Hg v 137/95 (2/1) mm Hg; geometric mean albuminuria 982 (antilog SE 1.2) micrograms/min v 936 (1.2) micrograms/min; and mean glomerular filtration rate 98 (SE 5) ml/min/1.73 m2 v 96 (6) ml/min/1.73 m2. Mean arterial blood pressure fell by 8.7 (1.3) mm Hg with captopril and rose by 6.6 (1.5) mm Hg in controls, (p less than 0.001); Albumin excretion decreased to 390 (1.1) micrograms/min with captopril and rose to 1367 (1.3) micrograms/min in controls (p less than 0.001). The rate of decrease in glomerular filtration rate was lower with captopril (5.8 (0.7) ml/year v 10.0 (1.3) ml/year) (p less than 0.01). Rate of fall in glomerular filtration rate and mean arterial blood pressure were significantly correlated (n = 31, r = 0.37, p less than 0.05). CONCLUSIONS--Captopril is a valuable new drug for treating hypertension in insulin dependent diabetics with nephropathy.     

Controlled trial of enalapril in patients with chronic fluid overload undergoing dialysis

About one third of patients receiving dialysis for end stage renal failure have chronic fluid overload despite advice to restrict their oral fluid intake. To investigate the potential of an angiotensin converting enzyme inhibitor in reducing the urge to drink and consequent gain in weight, a double blind, placebo controlled crossover trial of enalapril was conducted in 25 patients receiving dialysis who had fluid overload. The trial comprised a baseline period of four weeks; two periods of treatment, each of four weeks, during which patients received either placebo or enalapril 5 mg twice each week; and a follow up period of four weeks. Five patients withdrew from the trial, one because of an adverse drug reaction to enalapril. A range of biochemical and behavioural variables was measured during the baseline period, at the completion of periods 1 and 2, and during follow up. These variables included gain in weight between dialysis sessions; blood pressure; plasma concentrations of sodium, angiotensin II, and vasopressin; plasma renin and angiotensin converting enzyme activities; osmolality; and estimations of thirst, intake of fluid, and control of drinking. Enalapril caused a significant reduction in gain in weight between dialysis sessions, thirst, and oral intake of fluid in parallel with significantly increased renin activity, significantly decreased angiotensin converting enzyme activity, and decreased concentrations of angiotensin II. Gain in weight and angiotensin converting enzyme activity returned to baseline values once patients stopped taking enalapril.These results suggest that enalapril may act on the renin-angiotensin system and reduce intake of fluid by inhibiting angiotensin converting enzyme.     

Beneficial effects of angiotensin converting enzyme inhibition on renal function in patients with diabetic nephropathy.

The effects of angiotensin converting enzyme inhibition with captopril were investigated in patients with diabetic nephropathy and hypertension. After nine days'' treatment with captopril glomerular filtration rate was unchanged in 13 patients, whereas renal plasma flow had increased from 265 to 302 ml/min/1.73 m2 body surface area (p less than 0.05) and the filtration fraction had decreased from 14.3 to 12.8% (p less than 0.025). During two years'' treatment with captopril in 14 patients the mean arterial blood pressure had fallen by 5 mm Hg (p less than 0.005) and the deterioration in glomerular filtration rate had decreased from 10.3 to 2.4 ml/min/year (p less than 0.005). There was no correlation between the fall in blood pressure and the reduction in the deterioration of glomerular filtration rate. These findings suggest that the effects of angiotensin converting enzyme inhibition on renal haemodynamics protect renal function. Inhibitors of angiotensin converting enzyme should be considered for lowering blood pressure in patients with diabetic nephropathy.     

Effect of deletion polymorphism of angiotensin converting enzyme gene on progression of diabetic nephropathy during inhibition of angiotensin converting enzyme: observational follow up study.

OBJECTIVE: To evaluate the concept that an insertion/deletion polymorphism of the angiotensin converting enzyme gene predicts the therapeutic efficacy of inhibition of angiotensin converting enzyme on progression of diabetic nephropathy. DESIGN: Observational follow up study of patients with insulin dependent diabetes and nephropathy who had been treated with captopril for a median of 7 years (range 3-9 years). SETTING: Outpatient diabetic clinic in a tertiary referral centre. PATIENTS: 35 patients with insulin dependent diabetes and nephropathy were investigated during captopril treatment (median 75 mg/day (range 12.5 to 150 mg/day)) that was in many cases combined with a loop diuretic, 11 patients were homozygous for the deletion allele and 24 were heterozygous or homozygous for the insertion allele of the angiotensin converting enzyme gene. MAIN OUTCOME MEASURES: Albuminuria, arterial blood pressure, and glomerular filtration rate according to insertion/deletion polymorphism. RESULTS: The two groups had comparable glomerular filtration rate, albuminuria, blood pressure, and haemoglobin A1c concentration at baseline. Captopril induced nearly the same reduction in mean blood pressure in the two groups-to 103 (SD 5) mm Hg in the group with the deletion and 102 (8) mm Hg in the group with the insertion-and in geometric mean albumin excretion-573 (antilog SE 1.3) micrograms/min and 470 (1.2) micrograms/min, respectively. The rate of decline in glomerular filtration rate (linear regression of all glomerular filtration rate measurements during antihypertensive treatment) was significantly steeper in the group homozygous for the double deletion allele than in the other group (mean 5.7 (3.7) ml/min/year and 2.6 (2.8) ml/min/year, respectively; P = 0.01). Multiple linear regression analysis showed that haemoglobin A1c concentration, albuminuria, and the double deletion genotype independently influenced the sustained rate of decline in glomerular filtration rate (R1 (adjusted) = 0.51). CONCLUSION: The deletion polymorphism in the angiotensin converting enzyme gene reduces the long term beneficial effect of angiotensin converting enzyme inhibition on the progression of diabetic nephropathy in patients with insulin dependent diabetes.     

Enalapril in the treatment of hypertension with renal artery stenosis.

The converting enzyme inhibitor enalapril, in single daily doses of 10-40 mg, was given to 20 hypertensive patients with renal artery stenosis. The blood pressure fall six hours after the first dose of enalapril was significantly related to the pretreatment plasma concentrations of active renin and angiotensin II and to the concurrent fall in angiotensin II. Blood pressure fell further with continued treatment; the long term fall was not significantly related to pretreatment plasma renin or angiotensin II concentrations. At three months, 24 hours after the last dose of enalapril, blood pressure, plasma angiotensin II, and converting enzyme activity remained low and active renin and angiotensin I high; six hours after dosing, angiotensin II had, however, fallen further. The rise in active renin during long term treatment was proportionally greater than the rise in angiotensin I; this probably reflects the fall in renin substrate that occurs with converting enzyme inhibition. Enalapril alone caused reduction in exchangeable sodium, with distinct increases in serum potassium, creatinine, and urea. Enalapril was well tolerated and controlled hypertension effectively long term; only two of the 20 patients required concomitant diuretic treatment.     

Effect of protein restriction in insulin dependent diabetics at risk of nephropathy.

Persistent proteinuria is strongly associated with increased mortality in insulin dependent diabetes, and risk of this condition can be predicted many years in advance by subclinical increases in albumin excretion rate (microalbuminuria). Eight normotensive insulin dependent diabetics with microalbuminuria who had overnight albumin excretion rates of between 15 and 200 micrograms/min underwent a three week randomised crossover study of their normal protein diet (median 92 (range 55-117) g/day) and a low protein diet (47 (38-57) g/day). Both diets were isoenergetic, and the low protein diet was supplemented with calcium and phosphate. Median overnight albumin excretion rate fell from 23.0 (15.0-170.1) micrograms/min during the normal diet to 15.4 (4.1-97.8) micrograms/min during the low protein diet. No consistent change was found in urinary excretion of beta 2 microglobulin during the two diets. The reduction in albumin excretion rate was accompanied by a significant fall in median glomerular filtration rate and fractional renal clearance of albumin. Kidney volume remained unchanged. There were no significant changes in glycaemic control or arterial blood pressure. In these few patients restriction of dietary protein had a beneficial effect on microalbuminuria, independent of changes in glucose concentrations and arterial blood pressure.     

Effects of low dose ramipril on cardiovascular and renal outcomes in patients with type 2 diabetes and raised excretion of urinary albumin: randomised,double blind,placebo controlled trial (the DIABHYCAR study)

Objective To investigate whether a low dose of the angiotensin converting enzyme (ACE) inhibitor ramipril lowers cardiovascular and renal events in patients with type 2 diabetes who have microalbuminuria or proteinuria.Design Randomised, double blind, parallel group trial comparing ramipril (1.25 mg/day) with placebo (on top of usual treatment) for cardiovascular and renal outcomes for at least three years.Setting Multicentre, primary care study conducted mostly by general practitioners in 16 European and north African countries.Participants 4912 patients with type 2 diabetes aged >50 years who use oral antidiabetic drugs and have persistent microalbuminuria or proteinuria (urinary albumin excretion ≥ 20 mg/l in two consecutive samples), and serum creatinine ≤ 150 μmol/l.Main outcome measures The primary outcome measure was the combined incidence of cardiovascular death, non-fatal myocardial infarction, stroke, heart failure leading to hospital admission, and end stage renal failure.Results Participants were followed for 3 to 6 (median 4) years. There were 362 primary events among the 2443 participants taking ramipril (37.8 per 1000 patient years) and 377 events among the 2469 participants taking placebo (38.8 per 1000 patient years; hazard ratio 1.03 (95% confidence interval 0.89 to 1.20, P = 0.65)). None of the components of the primary outcome was reduced. Ramipril lowered systolic and diastolic blood pressures (by 2.43 and 1.06 mm Hg respectively after two years) and favoured regression from microalbuminuria (20-200 mg/l) or proteinuria (> 200mg/l) to normal level (< 20 mg/l) or microalbuminuria (P < 0.07) in 1868 participants who completed the study.Conclusions Low dose (1.25 mg) ramipril once daily has no effect on cardiovascular and renal outcomes of patients with type 2 diabetes and albuminuria, despite a slight decrease in blood pressure and urinary albumin. The cardiovascular benefits of a daily higher dose (10 mg) ramipril observed elsewhere are not found with an eightfold lower daily dose.     

Plasma endothelin-1 levels and albumin excretion rate in normotensive,microalbuminuric type 2 diabetic patients

BACKGROUND: Endothelin-1 (ET-1) is able to determine functional and structural renal alterations and plasma levels of this vasoconstrictor peptide are increased in diabetic patients. In a selected group of type 2 normotensive diabetic patients with microalbuminuria, we investigated circulating ET-1 levels compared to a control group and verified whether there is a relationship between ET-1 levels and albumin excretion rate in diabetics. SUBJECTS AND METHODS: Thirty-two microalbuminuric type 2 diabetic patients (12 males and 20 females; mean age 57 +/- 8 years) without hypertension, renal failure, hypercholesterolemia or atherosclerotic damage were selected. The control group was made up of 28 healthy subjects matched for sex and age. Blood pressure, creatinine clearance, serum cholesterol and plasma ET-1 values were determined in diabetic and control group. In diabetic patients, glycosilated hemoglobin and urinary albumin excretion rate were also assayed. Mean ET-1 values in diabetics and controls were compared using Student's t-test. Linear regression test was done to relate two variables. Statistical significance was set at p<0.05. RESULTS: Mean ET-1 values were significantly higher in the diabetic group than in controls (11.77 +/- 1.16 pg/ml vs 8.9 +/- 2.1 pg/ml; p<0.05). No relationship (p>0.05) was found between circulating ET-1 and blood pressure, creatinine clearance, serum cholesterol and metabolic control in diabetics. There was a significant positive correlation (r=0.403; p=0.03) between plasma ET-1 levels and albumin excretion rate in diabetic patients. CONCLUSIONS: Our results showed that circulating ET-1 values were increased in microalbuminuric, normotensive, type 2 diabetic patients and correlated with albumin excretion rate. These findings confirm that endothelial dysfunction, as expressed by ET-1 levels, occurs early in these patients and support the hypothesis of a potential role for this peptide in development of microalbuminuria in diabetic nephropathy.     

Blood pressure and blood lipids in normotensive patients with diabetes mellitus type I with microalbuminuria]

The study involved 50 normotensive men (means age = 34 years) with diabetes mellitus type I (mean duration of the disease 14 years). Group I included 29 patients with normal albumin excretion with the urine (UAE below 30 mg daily), and group II-21 patients with microalbuminuria (UAE 30-300 mg daily). Both groups were similar in relation to the age and duration of diabetes mellitus. Blood cholesterol was significantly higher in patients of group II than in patients of group I (p = 0.02) similarly to blood triglycerides levels (p = 0.01). Mean arterial pressure was lower in patients of group I than that in patients of group II (94.3 +/- 7.0 vs 99.1 +/- 6.0 mm Hg; p = 0.01). HbA1c was positively correlated with blood cholesterol (p = 0.01) and blood triglycerides levels (p = 0.05).     

Impact of enalapril therapy on in vitro coronary artery responsiveness in pacing-induced heart failure.

In vitro coronary artery responsiveness to angiotensin I, angiotensin II, noradrenaline, phenylephrine, BHT 920, and potassium chloride together with functional relaxation to acetylcholine was investigated in dogs with pacing-induced heart failure treated with enalapril (oral administration of 10 mg.day-1) for a mean duration of 26 days. Although maximal responses generated to both angiotensin I and angiotensin II were unaltered in the enalapril-treated group, angiotensin II became more potent following enalapril treatment: the EC50 for angiotensin II following placebo treatment was 2.4 (0.6-5.8; 95% confidence limits) nM and following enalapril treatment was 0.03 (0.007-0.1; 95% confidence limits) nM. In addition to the above changes, coronary artery rings from dogs treated with enalapril developed significantly less tension to noradrenaline, phenylephrine, and BHT 920. In contrast, responses to potassium chloride were unaltered following enalapril treatment. However, the relaxation to acetylcholine was enhanced from 38.9 +/- 3.0 to 50.4 +/- 3.5% (placebo versus enalapril, p < 0.05). These findings indicate that enalapril may possess alpha-blocking properties and enhance the relaxation response to acetylcholine through an endothelial-dependent mechanism in addition to inhibiting converting enzyme.