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The primary cause of arterial hypertension and of the increased morbidity and mortality in patients with insulin-dependent diabetes mellitus (IDDM) is diabetic nephropathy. About 35% of IDDM patients develop persistent albuminuria, an irreversible decline in the glomerular filtration rate and elevated blood pressure, which collectively contribute to the clinical syndrome of diabetic nephropathy. The excess mortality of IDDM patients with nephropathy is 80-100 times greater than that of an age- and sex-matched non-diabetic population. Diabetic nephropathy is the single most important cause of end-stage renal disease in the Western world, accounting for over a quarter of all such cases. Blood pressure elevation is a frequent finding, even in the early stages of diabetic nephropathy. Elevated blood pressure accelerates diabetic nephropathy, while an effective blood pressure reduction delays the progression of nephropathy and reduces albuminuria. A reduction in glomerular capillary hydraulic pressure may be the crucial factor. All previous reports dealing with the natural history of diabetic nephropathy have demonstrated a cumulative death rate of between 50% and 77% 10 years after the onset of nephropathy. Effective antihypertensive treatment has reduced this rate to 15-20%.

Nation-wide screening for microalbuminuria in Denmark was performed in 22 paediatric departments treating children with Type 1 diabetes. Over a period of 6 months 1020 children (less than or equal to 12 years) and adolescents (greater than 12 to 19 years) were screened (81% of total). Of these, 957 (94%) performed at least two timed overnight urine collections. In 209 non-diabetic subjects the upper 95% limit for normal albumin excretion rate (AER) was 20 micrograms min-1. Mean overnight AER was significantly (p less than 0.001) elevated in diabetic (3.0 x/divided by 2.3 (SD tolerance factor) micrograms min-1) and in non-diabetic (2.5 x/divided by 2.2 micrograms min-1) adolescents compared with diabetic (1.7 x/divided by 2.1 micrograms min-1) and non-diabetic (1.3 x/divided by 2.2 micrograms min-1) children. In the diabetic patients AER was positively correlated with the body surface area and age. Among the patients with Type 1 diabetes, 4.3% (18 males and 23 females) had AER greater than 20 to 150 micrograms min-1 (persistent microalbuminuria). A further 7 adolescents (0.7%) had overt proteinuria (greater than 150 micrograms min-1). Clinical data for the 41 diabetic patients with AER greater than 20 to 150 micrograms min-1 were compared with those for 569 diabetic adolescents with AER less than or equal to 20 micrograms min-1 and duration of diabetes more than 2 years. The group with AER greater than 20 to 150 micrograms min-1 had significantly higher mean age (16.5 years) than the group with AER less than or equal to 20 micrograms min-1 (15.0 years; p less than 0.001). Females with AER greater than 20 to 150 micrograms min-1 had significantly higher mean HbA1c level (10.8 +/- 1.9%) than those with AER less than or equal to 20 micrograms min-1 (9.8 +/- 1.9%, p less than 0.003); they also had impaired linear growth (standard deviation score -0.25 vs + 0.16; p = 0.003). These associations were not found in males. Mean body mass index (BMI) was significantly increased in both females (22.2 +/- 2.9 kg m-2) and males (20.8 +/- 2.7 kg m-2) with AER greater than 20 to 150 micrograms min-1, compared with diabetic patients with AER less than or equal to 20 micrograms min-1 (females 20.8 +/- 3.0 kg m-2, p = 0.02; males 19.7 +/- 2.4 kg m-2, p less than 0.006).(ABSTRACT TRUNCATED AT 400 WORDS)

The prevalence of retinopathy, albuminuria, and neuropathy were assessed in 25 patients with insulin-requiring diabetes secondary to chronic pancreatitis and in 25 patients with Type 1 (insulin-dependent) diabetes, matched for age at diabetes onset (secondary, 39 +/- 11 (+/- SD) years vs Type 1, 38 +/- 11 years) and duration of diabetes (10 +/- 6 vs 10 +/- 7 years). The prevalence of retinopathy was significantly higher in Type 1 diabetic patients (52%) than those with secondary diabetes (20%) (p less than 0.02). Median urinary excretion of albumin was 9 (range 1-206) mg 24-h-1 in patients with Type 1 diabetes and 7 (1-90) mg 24-h-1 in patients with secondary diabetes (NS). One secondary diabetic patient and five Type 1 diabetic patients had microalbuminuria (NS). Vibration perception threshold (measured at the big toe) was identical in the two groups of patients, and no patient had a threshold indicating somatic neuropathy (biothesiometry greater than 20 V). Retinopathy is more frequent in patients with Type 1 diabetes than in patients with insulin-requiring diabetes secondary to chronic pancreatitis. Retinopathy is so frequent in the latter group, however, that regular ophthalmoscopic examination is still required.

The effect of 18 months' inhibition of angiotensin-converting enzyme by captopril on the leakage of fluorescein through the blood-retina barrier was examined in a prospective, randomized control study of 20 normotensive insulin-dependent diabetic patients with nephropathy and background retinopathy. After 18 months, 15 patients remained in the study. Fluorescein leakage remained nearly unchanged in the captopril-treated group, being 4.1 +/- 4.1 (mean +/- SD) x 10(-7) cm/s at baseline and 4.2 +/- 4.1 x 10(-7) cm/s after 18 months' treatment. The permeability increased significantly (P less than 0.01) from 3.3 +/- 2.2 x 10(-7) cm/s to 5.6 +/- 3.5 x 10(-7) cm/s at 18 months in the control group. Arterial blood pressure was nearly constant in both groups throughout the study. The results indicate that angiotensin-converting enzyme inhibition with captopril can arrest or delay a progressive breakdown of the blood-retina barrier in normotensive insulin-dependent diabetic patients with nephropathy and background retinopathy.

Proximal tubular reabsorption of sodium and water was investigated in long-term insulin-dependent diabetic patients with normoalbuminuria (group I, n = 19), microalbuminuria (group II, n = 39), diabetic nephropathy (group III, n = 12) and in 13 healthy age-matched subjects. Glomerular filtration rate was measured with the single injection, 51Cr-EDTA technique. The fluid flow rate out of the proximal tubules was assessed by the renal lithium clearance. Although glomerular filtration rate was significantly elevated in the diabetic patients (Group I: 122 +/- 16, Group II: 121 +/- 18, Group III: 110 +/- 17, CONTROLS: 105 +/- 13 ml/min X 1.73 m2), lithium clearance was similar in the four groups (Group I: 19 +/- 6, Group II: 22 +/- 7, Group III: 19 +/- 5, CONTROLS: 23 +/- 4 ml/min X 1.73 m2). Both absolute and fractional proximal reabsorption of sodium and water was enhanced in diabetes. Indices of distal tubular function did not differ between controls and patients with insulin-dependent diabetes. Sodium clearance was about the same in the four groups. Our study suggests that the enhanced proximal reabsorption of sodium and water in insulin-dependent diabetic patients is still observed despite the presence of incipient or overt diabetic nephropathy.

The prevalence and causes of microscopic haematuria were examined in all Type 1 (insulin-dependent) diabetic patients with persistent proteinuria (diabetes duration greater than or equal to 5 years) attending the outpatient clinic at Hvidöre Hospital during 1985. One hundred eighty-four patients (69F/115M) out of 1024 Type 1 patients had persistent proteinuria (18%). Microscopic haematuria was defined as greater than or equal to 3 erythrocytes per high power field in two or more sterile urine samples. Twenty-three Type 1 patients with persistent proteinuria (7F/16M, aged 35.4 +/- 13 years) had microscopic haematuria (12.5%). No significant changes were found between the group with and without microscopic haematuria: blood pressure 148/89 +/- 22/11 versus 145/91 +/- 20/11 mmHg, duration of diabetes when persistent albuminuria occurred 17 +/- 8 versus 20 +/- 10 years, serum creatinine 99 +/- 24 versus 98 +/- 31 mumol/l, simplex retinopathy 61 versus 54%, proliferative retinopathy 39 versus 42%, and no signs of retinopathy 0 versus 4%. Kidney biopsy was performed in 13 out of the 23 patients with microscopic haematuria. Diabetic glomerulosclerosis was present in all 13 patients, but 9 patients had a non-diabetic renal disease superimposed (mesangioproliferative glomerulonephritis (n = 5), membranous glomerulonephritis (n = 3) and sarcoidosis (n = 1). Microscopic haematuria is a rare finding, frequently reflecting superimposed non-diabetic glomerulopathies, in Type 1 diabetic patients with diabetic nephropathy and well preserved kidney function.

OBJECTIVE--To assess the effect of long term antihypertensive treatment on prognosis in diabetic nephropathy. DESIGN--Prospective study of all insulin dependent diabetic patients aged under 50 with onset of diabetes before the age of 31 who developed diabetic nephropathy between 1974 and 1978 at Steno Memorial Hospital. SETTING--Outpatient diabetic clinic in tertiary referral centre. PATIENTS--Forty five patients (20 women) with a mean age of 30 (SD 7) years and a mean duration of diabetes of 18 (7) years at onset of persistent proteinuria were followed until death or for at least 10 years. INTERVENTIONS--Antihypertensive treatment was started a median of three (0-13) years after onset of nephropathy. Four patients (9%) received no treatment, and 9 (20%), 13 (29%), and 19 (42%) were treated with one, two, or three drugs, respectively. The median follow up was 12 (4-15) years. MAIN OUTCOME MEASURES--Arterial blood pressure and death. RESULTS--Mean blood pressure at start of antihypertensive treatment was 148/95 (15/50) mm Hg. Systolic blood pressure remained almost unchanged (slope -0.01 (95% confidence interval -0.39 to 0.37) mm Hg a year) while diastolic blood pressure decreased significantly (0.87 (0.65 to 1.10) mm Hg a year) during antihypertensive treatment. The cumulative death rate was 18% (8 to 32%) 10 years after onset of nephropathy, in contrast to previous reports of 50% to 77% 10 years after onset of nephropathy. As in previous studies, uraemia was the main cause of death (9 patients; 64%). CONCLUSIONS--The prognosis of diabetic nephropathy has improved during the past decade largely because of effective antihypertensive treatment.

To study the relationship between glomerular and tubular function we investigated glomerular filtration rate (GFR), urinary albumin excretion, and urinary excretion of epidermal growth factor (EGF, a mitogenic peptide synthesized in the renal tubular cells) in normal subjects (group I, n = 7) and in Type 1 (insulin-dependent) diabetic patients with normoalbuminuria (group II, n = 11); with incipient nephropathy (microalbuminuria) (group III, n = 9); with nephropathy and normal GFR (group IV, n = 12); and with reduced GFR (group V, n = 8). EGF (nmol 24 h-1) decreased with progressive glomerular involvement, from 7.9 (4.1-10.5) (median and range) in group I, to 6.7 (1.3-9.2) in group II, 5.0 (3.6-7.4) in group III, 4.1 (2.5-9.5) in group IV, and 1.1 (0.1-2.5) in group V. The urinary excretion of EGF was significantly reduced in patients with elevated UAE (group III, IV, and V) compared with normal control subjects (p less than 0.05). A significant correlation between urinary excretion of EGF and GFR (r = 0.71, p less than 0.001) and an inverse correlation between the urinary excretion of EGF and albumin (r = -0.35, p less than 0.05) was demonstrated in the Type 1 diabetic patients with GFR greater than 90 ml min-1. Our study demonstrates that urinary excretion of epidermal growth factor diminishes with increasing nephron impairment, and that renal tubular function as judged by the excretion of EGF is reduced early in the development of diabetic kidney disease.

The extracellular volume (ECV) and plasma volume (PV) were determined simultaneously in nine men with untreated essential hypertension and in nine healthy matched control subjects, using a single injection of inulin and of 131I-labelled human serum albumin, respectively. The average mean arterial blood pressure in the hypertensive group was 178/118 mmHg. ECV was nearly the same in the two groups, viz. 151 ml/kg body weight (SD 17) in the hypertensive group compared to 147 ml/kg (SD 16) in the control group. The corresponding figures for PV were 38.2 ml/kg body weight (SD 4.7) and 43.7 ml/kg (SD 7.9) respectively (P less than 0.1). The calculated interstitial fluid volume (IV) was 113 ml/kg (SD 16) and 103 ml/kg (SD 10) (P less than 0.2). The PV/IV ratio was significantly lower (P less than 0.02) in the hypertensive group (0.34, SD 0.06) than in the normal group (0.42, SD 0.06). The difference might suggest increased transcapillary water filtration in hypertension.

GFR, RPF, and kidney size were measured in nine young recently diagnosed insulin-dependent diabetics before (days 0) and 3 and 8 days after the beginning of the initial insulin treatment and in comparable control subjects. Kidney function was measured by a constant infusion technique using I-125-iothalamate and 131-I-hippuran. Kidney size was determined by means of ultrasound. Before insulin treatment elevated values for GFR (+44%, P less than 0.01), RPF (+18%, P less than 0.05), and kidney size (+29%, P less than 0.01) were found. Near-normal metabolic control was achieved in all patients using either multiple subcutaneous injections of insulin or an artificial betacell. GFR decreased from 160 +/- 9 SEM to 141 +/- 6 ml/min X 1.73 m2 (P less than 0.01) and further to 133 +/- 5 ml/min X 1.73 m2 (P less than 0.01, compared to day 0). Renal plasma flow was 601 +/- 33 and 588 +/- 44 ml x 1.73 m2 at days 0 and 3, respectively (NS) and decreased to 558 +/- 35 ml/min x 1.73 m2 at day 0 (P less than 0.01). By contrast no statistically significant changes in kidney volume were observed; the results on day 0, 3 and 8 were 145 +/- 7, 162 +/- 11 and 143 +/- 9 ml/1.73 m2, respectively. The present study demonstrates that kidney size and function are elevated at the onset of insulin-dependent diabetes. Near-normal metabolic control; for 8 days induces a reduction but not a complete normalization in kidney function. From the present observations it is suggested that the rapidly reversible part of the elevation in GFR cannot be explained by concomitant changes in kidney and glomerular size (morphological origin) but is probably due to a reduction in renal plasma flow and to a decreased transglomerular pressure (functional origin).

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

The autoregulation of blood flow in subcutaneous tissue was investigated at the level of the lateral malleolus by the local 133Xenon washout technique. We have investigated eight long-term insulin-dependent diabetics and seven healthy controls. All diabetics had moderate diabetic nephropathy and retinopathy. The blood flow remained constant in all normal subjects, when the arterial perfusion pressure was varied between 70 and 150 mm Hg. All diabetics had impaired or reduced autoregulation of the subcutaneous blood flow. The blood flow increased and decreased almost linearly with the changes in arterial perfusion pressure. The mechanism underlying the defect autoregulation of blood flow in diabetics is uncertain; possibilities include structural changes of the arterioles and/or alterations of local metabolic factors.

We investigated whether the glomerular synthesis of prostaglandins modulates the glomerular filtration rate and urinary albumin excretion in incipient diabetic nephropathy (defined as urinary albumin excretion between 30 and 300 mg/24 h (microalbuminuria) in two out of three sterile ketone-free 24-h urine collections in patients having insulin-dependent diabetes mellitus (IDDM) without hypertension or other kidney disease). The urinary excretion of prostaglandin E2 was significantly elevated in 8 insulin-dependent diabetic patients with incipient nephropathy as compared with 9 normoalbuminuric IDDM patients and 11 healthy controls: 317 (182-1273); 95 (67-225); 132 (54-263) pg/min, respectively (2p less than 0.01). Glomerular filtration rate (single bolus 51Cr-EDTA technique) and albuminuria (radioimmunoassay) were measured twice within 2 weeks in 8 females having IDDM with incipient nephropathy. The study design was a randomized double-blind trial with the patients receiving either indomethacin (150 mg/day) or placebo for 3 days prior to the kidney function studies. Indomethacin treatment induced a significant reduction in urinary prostaglandin E2 excretion (73%) (2p less than 0.01), urinary albumin excretion rate diminished from 207 (63-253) to 87 (49-147) mg/24 h (2p less than 0.01), fractional clearance of albumin declined (70%) (2p less than 0.01). Glomerular filtration rate remained stable (108 (88-133) versus 110 (95-142) ml/min). Blood glucose and blood pressure were comparable during the placebo and indomethacin treatment (12.6 +/- 3 versus 13.4 +/- 5 mmol/l and 122/79 +/- 3/9 versus 122/82 +/- 4/10 mmHg, respectively). Our results suggest that enhanced glomerular synthesis of vasodilating prostaglandins may accelerate microalbuminuria in incipient diabetic nephropathy.

The transcapillary escape rate of albumin (TERalb), i.e., the fraction of intravascular mass of albumin that passes to the extravascular space per unit of time, was determined from the disappearance of intravenously injected 125I-labeled human serum albumin during the first 60 minutes after injection in 10 subjects with chronic right heart failure. The investigation was repeated after sodium and water depletion. Before treatment TERalb was significantly elevated (mean 8.3 +/- 1.6% (SD)/hour, in comparison to values for normal subjects (mean 5.4 +/- 1.1%/hour, P less than 0.001). With treatment TERalb decreased significantly (mean 5.9 +/- 1.2%/hour, P less than 0.01). Right atrial pressure decreased from an average of 10 mm Hg to 6 mm Hg during treatment. A statistically significant, positive correlation was found between TERalb and right atrial pressure (r = 0.77, P less than 0.001). Our results best can be explained by increased filtration, mainly through the venous end of the microvasculature, due to the increased venous pressure in heart failure.

Transcapillary escape rates of albumin and IgG (fractions of intravascular mass of albumin and IgG that pass to the extravascular space per unit time) were determined simultaneously from the initial disappearance of intravenously injected 131I human albumin and 125I human IgG in seven untreated subjects suffering from essential hypertension. The average mean arterial blood pressure of these subjects 193/119 mmHg; four subjects had grade I-III funduscopic changes. Transcapillary escape rates of albumin (TERalb) and IgG (TERIgG) were found significantly increased in the hypertensive subjects, average 7.8 +/- 0.9 (SD) and 4.7 +/- 1.0 (SD) %/h, respectively, compared with normal values of mean 5.2 +/- 1.0 (SD) and 3.0 +/- 0.7 (SD) %/h, respectively (P less than 0.01). There was a statistically significant positive correlation between the mean arterial blood pressure and TER of albumin and of IgG (P less than 0.001). The TERIgG/TERalb ratio was about the same in the hypertensives and the normals. Confirming a previous observation, we found an increase in the daily urinary albumin excretion rate from a normal average of 9.1 (range, 2.4-20.4)mg/24 h to 96 (range, 5.6-565) mg/24 h, P less than 0.05. The present findings can best be explained by increased filtration through normal pores between the endothelial cells in the microvasculature, due to the high arterial blood pressure.

The effect of antihypertensive treatment on blood-retinal barrier leakage of fluorescein in background retinopathy was studied in nine hypertensive Type 1 (insulin-dependent) diabetic patients suffering from nephropathy. The patients were investigated before and after 7 (3 to 13) months of treatment with captopril (n = 8; 25 to 100 mg daily) and a diuretic, either frusemide (n = 4; 80 to 200 mg daily) or bendrofluazide (n = 2; 2.5 mg daily). Retinal function was assessed by fundus photography, fluorescein angiography, vitreous fluorometry, and renal function by glomerular filtration rate, and albuminuria. The antihypertensive treatment induced a significant reduction (p less than 0.05) in: blood pressure from 152/97 +/- 14/8 mmHg to 134/82 +/- 11/6 mmHg; blood-retinal barrier leakage of fluorescein from 2.4 +/- 1.1 to 1.4 +/- 0.5.10(-7) cm/second; albuminuria from 1391 (range: 168-4852) micrograms/min to 793 (range: 35-2081) micrograms/min. Glomerular filtration rate declined from 88 +/- 15 to 78 +/- 23 ml.min-1.1.73 m2 (0.05 less than p less than 0.10). The metabolic control of the patients as reflected by their blood glucose and HbA1c levels remained stable during the study. Our study suggests that systemic blood pressure elevation contributes to the abnormal blood-retinal barrier permeability to fluorescein characteristically found in diabetic background retinopathy and that this abnormality can be reversed during antihypertensive treatment.

The effect of acute arterial blood pressure lowering upon albumin extravasation was studied in 10 patients with nephropathy and retinopathy due to long-standing Type 1 (insulin-dependent) diabetes. The following variables were measured: transcapillary escape rate of albumin (initial disappearance of intravenously injected 125I-labelled human serum albumin), and urinary albumin excretion rate (radial immunodiffusion). The study was performed twice within 2 weeks, with the patients receiving an intravenous injection of either clonidine (225 micrograms) or saline (0.154 mmol/l). The clonidine injection induced the following changes: arterial blood pressure decreased from 134/87 to 107/73 mmHg (p less than 0.01), transcapillary escape rate of albumin declined from 8.1 to 6.7% of the intravascular mass of albumin/h (p less than 0.01), albuminuria diminished from 1434 to 815 micrograms/min (p less than 0.01), and plasma volume raised slightly from 2916 to 2995 ml (p less than 0.05). Our findings demonstrate that the enhanced albumin passage through the wall of the microvasculature characteristically found in long-term Type 1 diabetic patients with clinical microangiopathy is pressure-dependent to a large extent. This may be due to elevated hydrostatic pressure in the microcirculation.

Hemodynamic variables (blood pressure, cardiac output, heart rate, plasma volume, splanchnic blood flow, and peripheral subcutaneous blood flow) and plasma concentrations of norepinephrine, epinephrine, and renin were measured in the supine position and after 30 min of quiet standing. This was done in normal subjects (n = 7) and in juvenile-onset diabetic patients without neuropathy (n = 8), with slight neuropathy (decreased beat-to-beat variation in heart rate during hyperventilation) (n = 8), and with severe neuropathy including orthostatic hypotension (n = 7). Blood pressure decreased precipitously in the standing position in the diabetics with orthostatic hypotension, whereas moderate decreases were found in the other three groups. Upon standing, heart rate rose and cardiac output and plasma volume decreased similarly in the four groups. The increases in total peripheral resistance, splanchnic vascular resistance and subcutaneous vascular resistance were all significantly lower (P less than 0.025) in the patients with orthostatic hypotension compared with the other three groups. The increase in plasma norepinephrine concentrations in the patients with orthostatic hypotension was significantly lower (P less than 0.025) than in the patients without neuropathy, whereas plasma renin responses to standing were similar in the four groups. We conclude that in diabetic hypoadrenergic orthostatic hypotension the basic pathophysiological defect is lack of ability to increase vascular resistance, probably due to impaired sympathetic activity in the autonomic nerves innervating resistance vessels; cardiac output and plasma volume responses to standing are similar to those found in normal subjects and in diabetics without neuropathy.

The effect of hypotensive therapy on the transcapillary escape rate of albumin (TERalb) was studied in eight hypertensive insulin-dependent diabetic patients (mean age 29, range 19-42 years) with nephropathy and retinopathy. Transcapillary escape rate of albumin (initial disappearance of intravenously injected 125I-labelled human serum albumin), urinary albumin excretion rate (radial immunodiffusion), and glomerular filtrate rate (single bolus 51-Cr-EDTA technique) were measured. After hypotensive treatment (mean duration, 23 months, range 7-39 months) with combinations of metoprolol, hydralazine, and frusemide or thiazide diuretics, arterial blood pressure fell from 152/103 +/- 18/6 mmHg (mean +/- SD) to 133/81 +/- 12/10 mmHg (p less than 0.01), transcapillary escape rate of albumin from 10.2 +/- 1.8 to 8.1 +/- 1.8% of intravascular mass of albumin/h (p less than 0.01), albuminuria from 1803 (370-5066) micrograms/min to 940 (101-2676) micrograms/min (median and range, p less than 0.05), and glomerular filtration rate from 103 +/- 23 to 84 +/- 22 ml/min/1.73 m2 (p less than 0.01). Our study suggests that effective hypotensive treatment reduces the abnormally elevated albumin leakage characteristically found in insulin-dependent diabetic patients with clinical microangiopathy. This may be due to a reduction in the hydrostatic pressure in the microcirculation.

Autoregulation of blood flow in subcutaneous tissue was studied at the level of the lateral malleolus in eight long-term Type 1 (insulin-dependent) diabetic patients with clinical microangiopathy, eight short-term Type 1 diabetic patients without clinical microangiopathy and seven healthy control subjects. Blood flow was measured by the local 133Xenon washout technique. Mean arterial blood pressure was reduced by a maximum of 23 mmHg by elevating the limb above heart level and elevating to a maximum of 70 mmHg by head-up tilt; in the latter position venous pressure was kept constant and low by activation of the leg muscle vein pump (heel raising). Mean arterial blood pressure was thus varied between 60 and 160 mmHg. In normal and short-term diabetic subjects blood flow remained within 10% of control values during the changes in arterial blood pressure. In six of the eight Type 1 diabetic patients with clinical microangiopathy, autoregulation of blood flow was impaired, blood flow changing ap proximately 20% per 10 mmHg change in arterial blood pressure; the slope of the autoregulation curves was significantly higher compared with the two control groups (p

Kidney function and size were studied in seven normal male subjects before and after administration of highly purified human growth hormone for 1 week. Glomerular filtration rate, renal plasma flow (steady-state infusion technique with urinary collections using 125I-iothalamate and 131I-hippuran) kidney size (ultrasonic scanning) and urinary excretion rates of albumin and beta 2-microglobulin (radioimmunoassays) were measured. Highly purified growth hormone was injected subcutaneously, 2 IU in the morning and 4 IU in the evening. Glomerular filtration rate increased from (mean +/- SEM) 114 +/- 5 to 125 +/- 4 ml/min x 1.73 m2 (P less than 0.01) and renal plasma flow increased from 554 +/- 30 to 601 +/- 36 ml/min x 1.73 m2 (P less than 0.01). Kidney size and urinary excretion rates of albumin and beta 2-microglobulin did not change significantly. Our results show that raising plasma growth hormone into a range similar to that found in insulin-dependent diabetics enhances glomerular filtration rate and renal plasma flow, while kidney size remains unchanged. Increased renal plasma flow is the major determinant of growth hormone induced elevation in glomerular filtration rate. Growth hormone may thus contribute to the enhancement of glomerular filtration rate and renal plasma flow typically found in insulin-dependent diabetics.

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.

We investigated whether the glomerular synthesis of prostaglandins modulates the glomerular filtration rate and albuminuria in diabetic nephropathy. The urinary excretion of immunoreactive prostaglandin E2 (253 pg/min) was significantly elevated in eight Type 1 (insulin-dependent) diabetic women with nephropathy as compared with nine normoalbuminuric Type 1 diabetic women (95 pg/min) and 11 non-diabetic women (132 pg/min), respectively (p less than 0.01). Glomerular filtration rate (single bolus 51Cr-EDTA technique) and albuminuria (radioimmunoassay) were measured twice within two weeks in the eight Type 1 diabetic women with nephropathy. All eight patients were on a diabetic diet without sodium restriction. The study was performed as a randomized double-blind trial, with the patients receiving either indomethacin (150 mg/day) or placebo for three days prior to the kidney function studies. Indomethacin treatment induced a significant reduction in urinary prostaglandin E2 excretion (73%, p less than 0.01), glomerular filtration rate diminished from 120 +/- 18 to 106 +/- 17 ml/min/1.73 m2 (p less than 0.05), albuminuria declined from 148 to 69 micrograms/min (median and range) (p less than 0.05) and fractional clearance of albumin diminished 42% (p less than 0.05). Blood glucose concentrations were comparable during the placebo and indomethacin treatment, 13.4 +/- 4 versus 14.2 +/- 3 mmol/l, respectively. Our results suggest that glomerular filtration rate in early diabetic nephropathy is dependent on the enhanced glomerular synthesis of vasodilating prostaglandins.

The metabolic turnover rate and the transcapillary escape rate of albumin were studied using 131 I-labeled human albumin in nine untreated subjects suffering from essential hypertension. The average mean arterial blood pressure of these subjects was 162/109 mm Hg; seven subjects had grade I-II funduscopic changes. Plasma albumin concentration was normal, but plasma volume was reduced ( P < 0.05) in these subjects. Thus, the previously reported moderate decrease in the intravascular albumin mass of hypertensive subjects was confirmed; the average value for intravascular albumin mass in the present study was 62.8 g/m2 surface area compared with a normal value of 70.6 g/m 2 (-11%, P < 0.05). A surprising finding was a marked enhancement of albumin metabolic rate in essential hypertension. The fraction of intravascular albumin mass metabolized per 24-hour period was on the average 14.4% compared with a normal value of 8.4% (+72%, P < 0.001). The rate of synthesis was 9.1 g/24 hours m -2 compared with a normal value of 5.9 g/24 hours m -2 (+54%, P < 0.001). Total body albumin mass was decreased proportionally to intravascular albumin mass. Confirming a previous observation, we found an increase in the transcapillary escape rate of albumin (fraction of intravascular mass passing to the extravascular space per unit time) from a normal average of 5.6%/hour to 7.5%/hour (+34%, P < 0.001). There was a statistically significant positive correlation between the transcapillary escape rate of albumin and blood pressure ( P < 0.05). These findings can best be explained by increased filtration due to the high arterial blood pressure. There was also a positive correlation between the transcapillary escape rate and the fractional catabolic rate of albumin ( P < 0.05). This finding supports the concept that albumin is catabolized in connection with its permeation through the capillary endothelium.

Fifteen patients with confirmed myxedema at a median age of 48 years (range 32 to 60 years) were referred for audiological evaluation before and after treatment with levothyroxine. The median interval between the pretreatment and posttreatment investigations was 18 months (range 9 to 27 months). In addition, 13 patients at a median age of 78 years (range 64 to 95 years) were audiologically reexamined after long-standing levothyroxine treatment. The observation period upon treatment with levothyroxine was 40 months (range 32 to 46 months). No improvement in hearing sensitivity could be demonstrated either in the younger patients or in the elderly. When compared to an age- and sex-matched unscreened population, the myxedematous patients did not demonstrate any different degree of hearing loss. Histological investigation of the temporal bones from an 83-year-old woman with myxedema, however, showed no morphological changes or deposition of glycosaminoglycans, changes which are compatible with true age-related hearing loss. It is concluded that no association exists between myxedema and hearing impairment and that no morphological or structural changes due to myxedema can be demonstrated in the temporal bones.

During exposure to high altitude the red cell metabolism was stimulated. An increase in the phosphofructokinase reaction occurred secondary to the elevated blood pH. An increase in the triosephosphate pool occurred secondary to PFK stimulation and a relative inhibition of the GAPDH reaction, which was due to the decrease in the concentration of inorganic phosphate. The low inorganic phosphate levels in both red cells and plasma were a consequence of a shift of phosphate from the extracellular fluid to other body cells during hyperventilation. The forward reaction of GAPDH was stimulated when the exposure to high altitude was accompanied by a moderate degree of physical exercise. This was indicated by the significant increase in red cell levels of 2,3-DPG, and 3PG and 2PG. This stimulation of the GAPDH reaction was probably due to an increased availability of NAD+, brought about by the influx of pyruvate from the muscles. The changes in the red cell metabolism influenced their oxygen affinity through chang...

Six normal volunteers were exposed to a simulated altitude of 4500 meters, and changes in urine and serum erythropoietin levels were related to the changes in acid-base status. During the initial six hours of exposure the volunteers had respiratory alkalosis, which produced a definite increase in red-cell oxygen affinity. These conditions were associated with an increase in urinary and serum erythropoietin. The continued alkalosis and hypocapnia gradually raised red-cell 2,3-diphosphoglycerate concentrations and lowered red-cell oxygen affinity. These changes are thought to lead to the decreased erythropoietin concentration seen after continued exposure. Treatment of the same volunteers with acetazolamide prevented the initial respiratory alkalosis and reduced erythropoietin response. These findings demonstrate that erythropoietin concentrations in urine and serum were influenced by the acid-base status of the volunteers.

Transcapillary escape rates of albumin and IgG (fractions of intravascular mass of albumin and IgG that pass to the extravascular space per unit time) were determined simultaneously from the initial disappearance of intravenously injected 131I human albumin and 125I human IgG, in 10 long-term juvenile diabetics with microangiopathy (mean duration 20 years), and 9 non-diabetic subjects. Transcapillary escape rates of albumin (TERalb) and IgG (TERIgG) were found significantly increased in the long-term diabetic group, average 7.4 ± 1.1 (mean ± S.D.) and 4.4 ± 1.0 per cent/hour, respectively, compared to the non-diabetic group, mean 5.2 ± 1.0 and 3.0 ± 0.7 per cent/hour, respectively (p < 0.005). The TERIgG/TERalb ratio was nearly identical in the two groups, and very close to the ratio of the proteins' free diffusion coefficients. We assume that the present findings reflect an increased microvascular permeability to macromolecules, owing to an increased number or size of the large pores per unit sur...

To assess the effect of an angiotensin receptor blocker (ARB) on serum potassium and the effect of a serum potassium change on renal outcomes in patients with type 2 diabetes and nephropathy.We performed a post hoc analysis in patients with type 2 diabetes participating in the Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan (RENAAL) study. Renal outcomes were defined as a composite of doubling of serum creatinine or end-stage renal disease.At month 6, 259 (38.4%) and 73 (10.8%) patients in the losartan group and 151 (22.8%) and 34 (5.1%) patients in the placebo group had serum potassium a parts per thousand yen5.0 mmol/l and a parts per thousand yen5.5 mmol/l, (p In this study, we found that treatment with the ARB losartan is associated with a high risk of increased serum potassium levels, which is in turn associated with an increased risk of renal outcomes in patients with diabetes and nephropathy. Whether additional management of high serum potassium would further increase the renal protective properties of losartan is an important clinical question.

The daily urinary albumin-excretion rate was measured by a sensitive radioimmunoassay in eight normal subjects (average blood-pressure 126/83 mm. Hg), fourteen patients effectively treated for benign essential hypertension (average blood-pressure 143/89 mm. Hg), and eighteen untreated or insufficiently treated patients with benign essential hypertension (average blood-pressure 182/ 112 mm. Hg). None of the patients had albuminuria as judged by the 'Albustix' test. Albumin excretion was significantly increased in the insufficiently treated hypertensive group compared with the average normal value of 8.5 mg. per 24 hours. Five hypertensive patients had a distinctly increased albumin-excretion rate (mean 87 mg. per 24 hours), while a more moderate but still statistically significant increase was found in the remaining thirteen (mean 16.9mg. per 24 hours). The excretion-rate was normal in the patients treated effectively for hypertension (mean 7.8 mg. per 24 hours). Since the daily urinary 2–microglobulin-excretion rate was normal in the patients, indicating a normal tubular reabsorption of protein, it is concluded that transglomerular passage of albumin is increased in benign essential hyper-tension. This finding is compatible with the hypothesis that hypertensive extravasation of plasma- proteins, with subsequent deposition in the vascular wall-i.e., the concept of plasmatic vasculosis.

Cold hands is a common complaint in myxoedema and were reported by 15 of 17 patients before treatment of myxoedema with 4 having Raynaud's phenomenon. An increased cold sensitivity of the digital arteries could be demonstrated during finger cooling in about half of the patients and Raynaud's phenomenon was verified in the 4 patients as digital arterial closure. The cold sensitivity decreased significantly after treatment with L-thyroxine. The increased cold sensitivity in untreated myxoedema is probably due to an increased sympathetic discharge to the hands that might disclose a predisposition for Raynaud's phenomenon.

We investigated the validity of a one plasma sample method (I) compared with a multiple plasma sample method (II) for routine clinical determination of glomerular filtration rate (GFR) in 35 insulin-dependent diabetic patients suffering from nephropathy. GFR was measured after an intravenous bolus injection of 100 microCi 51Cr-EDTA by determination of plasma radioactivity in venous blood samples taken from the other arm 180, 200, 220 and 240 min after the injection (II). The plasma radioactivity in the sample drawn 240 min after injection was used in method I. During the mean investigation period of 32 months (12-62 months) a total of 184 GFR determinations were performed. The average interval between the GFR measurements was 6 months (1-21 months). In 127/184 of the study intervals method I indicated a decrease in GFR. The corresponding figure for method II was almost identical, 130/184. The mean decline in GFR was 8.1 +/- 7.2 and 7.8 +/- 6.9 ml year-1 1.73 m-2 using methods I and II, respectively (NS). The methods essentially provided the same GFR values in absolute terms (r = 0.98, P less than 0.001). We conclude that the one plasma sample method can be used as a valid routine technique in non-uraemic patients with nephropathy.