H.-H. Parving

INCREASED URINARY ALBUMIN-EXCRETION RATE IN BENIGN ESSENTIAL HYPERTENSION

Abstract 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.

Renal function in streptozotocin-diabetic rats

SummaryRenal function was examined with micropuncture methods in the insulin-treated streptozotocin-diabetic rat. Kidney glomerular filtration rate was significantly higher in the diabetic rats (1.21 ml/min) than in the control group (0.84 ml/min) Nephron glomerular filtration rate increased in proportion to the rise in kidney glomerular filtration rate (diabetic rats: 37.0 nl/min; control rats: 27.9 nl/min). Likewise renal plasma flow was significantly higher in the diabetic rats (4.1 ml/min) than in the control group (3.0 ml/min). Glomerular capillary pressure was identical in both groups (56.0 and 56.0 mmHg, respectively). The proximal intratubular pressure was significantly reduced in the diabetic rats (10.4 mmHg; control value: 12.5 mmHg). The effective glomerular ultrafiltration coefficient was slightly but not significantly higher in the diabetic rats (0.027 nl s-1mmHg-1) than in the control group (0.023 nl s-1mmHg-1). Kidney weight was significantly higher in the diabetic rats (1.15 g; control rats: 0.96 g) while body weight was similar in both groups (diabetic rats: 232 g; control rats: 238 g). Calculations indicate that the increases in transglomerular hydraulic pressure, renal plasma flow and ultrafiltration co-efficient of the glomerular membrane contribute about equally to the rise in glomerular filtration rate. The increases in the values of the determinants of glomerular filtration rate may be the result of renal hypertrophy. These studies suggest that this model provides a useful method for investigating kidney function in diabetes, which may have relevance for our understanding of the kidney abnormalities in human diabetes.

Kidney function and size in normal subjects before and during growth hormone administration for one week

Abstract. 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 β2‐microglobulin (radioimmunoas‐says) 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±4ml/min x 1.73 m2 (P <0.01) and renal plasma flow increased from 554 ±30 to 601 ±36 ml/min ×1.73 m2(P < 0.01). Kidney size and urinary excretion rates of albumin and β2‐microglobulin did not change significantly.

Impaired autoregulation of glomerular filtration rate in Type 1 (insulin-dependent) diabetic patients with nephropathy

SummaryThe effect of acute lowering of arterial blood pressure upon kidney function in nephropathy was studied in 13 patients with long-term Type 1 (insulin-dependent) diabetes. Ten normal subjects (six normotensive and four hypertensive) and five short-term Type 1 diabetic patients without nephropathy served as controls. Renal function was assessed by glomerular filtration rate (single bolus 51Cr-EDTA technique) and urinary albumin excretion rate (radial immunodiffusion). The study was performed twice within 2 weeks, with the subjects receiving an intravenous injection of either clonidine (225 μg) or saline (0.154 mmol/l). The arterial blood pressure was similar in the diabetic patients with nephropathy (mean 136±11 mmHg) and in the non-diabetic control subjects 88±5 (mean 140±25 mmHg). The clonidine injection induced sim- 92±15 ilar reductions in mean arterial blood pressure in all three groups (16–18 mmHg). While glomerular filtration rate and urinary albumin excretion rate remained unchanged in both control groups after clonidine injection, glomerular filtration rate dimished from 78 to 71 ml/min per 1.73 m2 (p<0.01), and urinary albumin excretion declined from 1707 to 938 μg/min (p<0.01) in the patients with diabetic nephropathy. Our results suggest that an intrinsic vascular (arteriolar) mechanism underlying the normal autoregulation of glomerular filtration rate, i. e. the relative constancy of glomerular filtration rate that occurs in response to rather wide variations in perfusion pressure, is defective in diabetic nephropathy.

The effect of glucagon infusion on kidney function in short-term insulin-dependent juvenile diabetics

SummaryKidney function was studied in nine, metabolically well controlled, short-term insulin-dependent male diabetics before and during glucagon infusion of 4 to 5 and 8 to 10 ng/kg/min. Glomerular filtration rate, effective renal plasma flow (steadystate infusion technique, with urinary collections, using 125I-iothalamate and 131I-iodohippurate), and urinary albumin and β2-microglobulin excretion rates were measured. The mean plasma glucagon concentration increased during infusion from 254±19 pg/ ml to 440±31 pg/ml (low dose) and 730±52 pg/ml (high dose). Glomerular filtration rate increased in all subjects from 133±5 before the glucagon infusion to 141±4 with the low dose, and 148±7 ml/min/1.73 m2 with the high dose (p<0.01). The increase in glomerular filtration rate correlated with the rise in plasma glucagon concentration (r=0.67; p<0.01). Renal plasma flow increased from 530 ±21 before the glucagon infusion to 555±20 with the low dose and 572±29 ml/min/1.73 m2 with the high dose (p<0.01). Urinary β2-microglobulin excretion rate rose from 5.8±1.0 before infusion to 8.7±1.7 with the low dose, and 17.9±5.7 μg X 10-2/min with the high dose (p<0.01). Urinary albumin excretion remained unchanged during the glucagon infusion. These results suggest that glucagon may contribute to the reversible elevation of glomerular filtration rate typically found in poorly regulated insulin-dependent diabetics, but not to the moderate elevation found in well controlled diabetics.

Haemodynamic changes during graded exercise in patients with diabetic autonomic neuropathy

SummaryHaemodynamic variables were measured during supine rest and during ergometer cycle exercise at two work loads (50 W and 100 W) in normal subjects (n = 7), in insulin-dependent diabetic subjects without neuropathy (n = 8), in insulin-dependent diabetic subjects with slight autonomic neuropathy (decreased beat-to-beat variation in heart rate, which is considered due to a cardiac parasympathetic defect; n = 8), and in insulin-dependent diabetic subjects with severe autonomic neuropathy, including orthostatic hypotension (n = 7). Compared with normal subjects, cardiac stroke volume was lower in the diabetic subjects with autonomic neuropathy, both at rest and during exercise (p < 0.025), whereas intermediate values were found in the diabetic subjects without neuropathy. The increase in cardiac output in response to exercise was smaller (p < 0.05) in both diabetic groups with autonomic neuropathy compared with the normal and diabetic subjects without autonomic neuropathy. The increase in hepato-splanchnic vascular resistance was smaller in the diabetic subjects with severe autonomic neuropathy than in the normal subjects and the diabetic subjects without autonomic neuropathy (p < 0.025), whereas intermediate values were found in the diabetic subjects with slight autonomic neuropathy. We conclude that, in diabetic patients with severe autonomic neuropathy, the responses of the heart and the splanchnic resistance vessels to exercise are impaired. While sympathetic neuropathy may be responsible for impaired function of splanchnic resistance vessels, both cardiac sympathetic neuropathy and diabetic cardiomyopathy may be involved in the impaired cardiac response to exercise in diabetic subjects with autonomic neuropathy.

Increased transcapillary escape rate of albumin and IgG in essential hypertension

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.

Increased Metabolic Turnover Rate and Transcapillary Escape Rate of Albumin in Essential Hypertension

The metabolic turnover rate and the transcapillary escape rate of albumin were studied using 131I-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/m2(−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.

Short-term Inhibition of Prostaglandin Synthesis has no Effect on the Elevated Glomerular Filtration Rate of Early Insulin-dependent Diabetes

Glomerular filtration rate and renal plasma flow (constant infusion technique using 125I‐iothalamate and 131I‐hippuran) were measured twice within a 1‐week interval in nine young males with insulin‐dependent diabetes of short duration (2–5 years). The study was performed in a randomized double‐blind design, with the patients receiving either indomethacin (150 mg/day) or placebo for 3 days before the study. Measures of metabolic control did not change. No differences were found in glomerular filtration rate (144 ± 9 versus 144 ± 9 ml/min × 1.73 m2, mean ± S.E.M.) or renal plasma flow (579 ± 43 versus 560 ± 52 ml/min × 1.73 m2), when measured during placebo or indomethacin treatment, respectively. It is concluded that the steady‐state enhancement of glomerular filtration rate and renal plasma flow found in early insulin‐dependent diabetes is not due to an excessive activity of the prostaglandin system.

Decreased distensibility of a passive vascular bed in diabetes mellitus: an indicator of microangiopathy?

SummaryThis study was undertaken to determine whether the distensibility of a passive vascular bed is reduced in Type 1 (insulin-dependent) diabetic patients with microangiopathy. The change in blood flow induced by 45° head-up tilting was studied in two systems: (a) following maximal ischaemic exercise and (b) in a vascular bed locally paralysed by the injection of papaverine. Five normal subjects, six patients with long-standing Type 1 diabetes and six non-diabetic patients with severe atherosclerosis affecting the legs were studied. Blood flow was measured in the anterior tibial muscle by the isotope washout technique. The median increase in blood flow produced by tilting was greater in normal subjects than in diabetic subjects in both the locally-relaxed bed (58% and 14% respectively) and after maximal ischaemic exercise (45% and 4% respectivley). In the atherosclerotic subjects, the increase in blood flow in the locally relaxed bed was 77%. The results are consistent with the hypothesis that the reduced distensibility seen in the diabetic subjects was related to the presence of microvascular disease and that the behaviour of a vascular bed relaxed by the local injection of papaverine might be an appropriate model to study this condition.