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The effects of insulin upon renal magnesium excretion were examined. Urinary magnesium excretion rates were measured in seven healthy volunteers (three men, four women) before and during a euglycaemic, hyperinsulinaemic clamp. Insulin was infused at 120 pmol m-2 min-1 and at 240 pmol m-2 min-1. Compared to baseline, the renal magnesium excretion increased 30% during the infusion of insulin at a rate of 120 pmol m-2 min-1. During infusion of insulin, 240 pmol m-2 min-1, renal magnesium excretion increased 50% compared to baseline. There were no changes in either glomerular filtration rates, plasma magnesium, urinary volume or general changes in the renal handling of divalent ions as judged by an unchanged urinary excretion rate of calcium (0% during infusion of insulin, 120 pmol m-2 min-1, and 8% increase during infusion of 240 pmol m-2 min-1 (NS). During the 120 pmol m-2 min-1 insulin infusion rate, plasma insulin rose from 46.1 pmol I-1 to 158.8 pmol I-1 and during the 240 pmol m-2 min-1 insulin infusion rate, mean plasma insulin concentration was 361.4 pmol I-1. Thus, physiological concentrations of insulin induce a specific increase in the renal excretion of magnesium. This might partly explain the magnesium depletion observed in various hyperinsulinaemic states, diabetes mellitus, atherosclerosis, hypertension, and obesity.

Diabetic patients treated with insulin injected subcutaneously are characterized by peripheral hyperinsulinaemia and an increased mass of total body exchangeable sodium. We hypothesized that this may cause, at least in part, the glomerular hyperfiltration seen in the diabetic state. Six normal subjects were studied on 2 days in random order. Day A: Basal state for 40 min, hyperinsulinaemic euglycaemic clamp for 1 h (insulin infusion rate 2 mU kg-1 min-1 and 50% glucose infusion) and hyperinsulinaemic euglycaemic clamp combined with volume expansion (2 1 isotonic sodium chloride) for 2 h. Day B: as day A, but without insulin and glucose infusion. During combined volume expansion and hyperinsulinaemia an increase in glomerular filtration rate (GFR) (128 +/- 6 vs 117 +/- 8 ml min-1 1.73 m-2, p less than 0.01) and lithium clearance (CLi) (50 +/- 4 vs 33 +/- 5 ml min-1 1.73 m-2, p less than 0.01) was observed compared with basal conditions. GFR and CLi were unchanged during day B. Insulin infusion reduced renal sodium excretion. Absolute proximal tubular reabsorption was unchanged on both days. Insulin infusion without volume expansion caused a decrease of 24% in the fractional distal sodium excretion. Superimposed volume expansion and the concomitant increase in GFR and CLi was accompanied by a subsequent enhanced fractional distal sodium excretion of 27%. The changes in plasma concentrations of aldosterone, renin, angiotensin II, atrial natriuretic peptide and catecholamines did not explain the differences in GFR. An increase in GFR of 10%, comparable with that observed in diabetic patients, was induced by combined hyperinsulinaemia and volume expansion in euglycaemic normal subjects. The enhanced GFR is probably a compensatory response to the sodium retention induced by the action of insulin on the distal tubules.

Extraction of lithium and 51Cr-EDTA across each of the two kidneys was determined during renal vein catheterization in 14 hypertensive patients with unilateral or bilateral renovascular disease before and after i.v. injection of furoserhide. Before the administration of furosemide an increased fractional lithium reabsorption was demonstrated across the affected, or more affected kidney. This difference was abolished by furosemide. Using lithium as a probe for sodium, our data suggest an increased fractional tubular sodium reabsorption in the ischaemic human kidney probably located to the proximal tubules as well as to the loop of Henle. Determination of single-kidney fractional lithium reabsorption holds promise as a new research tool for future evaluation of functional abnormalities during divided renal function studies.

Magnesium depletion is a common feature of diabetes mellitus, apparently related to glycaemic control. The aim of the study was to investigate the isolated effect of hyperglycaemia upon renal magnesium excretion. Urinary magnesium excretion rates were measured in 10 patients with Type 1 diabetes mellitus on two different days with different levels of blood glucose concentration but equal plasma insulin concentration. On a hyperglycaemic day, an i.v. infusion of 20% glucose was started at the end of a euglycaemic baseline period, increasing blood glucose concentration from 5.3 mmol/L to 12.3 mmol/L. There was no major glucosuria. On the hyperglycaemic day the renal magnesium excretion and clearance were raised by a factor of 2.4 compared to the euglycaemic day. Plasma magnesium concentration decreased 3% during hyperglycaemia. In conclusion, blood glucose excursions influence magnesium homeostasis independently of insulin levels in Type 1 diabetic patients. This effect is primarily due to an increased renal magnesium clearance during hyperglycaemia.

The average salt intake (sodium chloride) in Denmark is about 10 g/person/day, which is approximately 8 times higher than the estimated need. Salt added during industrial processing of foods constitutes more than 50% of the daily salt intake. Observational and experimental epidemiological studies indicate no decisive effects on blood pressure in humans caused by considerable variations in the daily salt intake. However, a small group of patients with hypertension may lower their blood pressure by reducing the daily intake of salt to 5 g. It has not been convincingly documented that high salt intake is an independent risk factor in the pathogenesis of asthma, osteoporosis, toxaemia of pregnancy or apoplectic stroke. On the other hand, several epidemiological studies point to the fact that the intake of salted foods may increase the risk of gastric cancer. It is recommended 1) that the food industry as far as possible limits the addition of salt, 2) that foods are supplied with a declaration of the salt content, and 3) that the research in this field is strengthened to facilitate the identification of persons at increased risk of developing disorders associated with high salt intake.

Lithium is the best available marker of proximal tubular reabsorption of fluid. The first part of the present thesis reviews the background for the use of the lithium clearance (CLi) method. Micropuncture studies on proximal reabsorption of lithium, showed that CLi is a reasonably correct measure of end-proximal fluid delivery rate, even during osmotic diuresis. During severe salt restriction, distal reabsorption of lithium renders the CLi method inappropriate in animals, but this problem does probably not occur in humans. The major current issue is whether a quantitatively significant reabsorption of lithium occurs in the loop of Henle. Available evidence is in accord with the interpretation that it does not occur. The interpretation of results form CLi studies depends to a surprising degree on the investigators beliefs about renal physiology. In the evaluation of proximal tubular function, the relevant parameter is the absolute proximal reabsorption rate of fluid and sodium. In the evaluation of integrated distal tubular reabsorption of sodium, the relevant parameter is the fractional distal reabsorption rate of sodium. The fractional CLi does not give meaningful information, and calculated absolute distal reabsorption rate of sodium is inherently not suited to detect modest changes in distal reabsorption leading to large changes in sodium excretion. Results from the use of the CLi method in relation to diabetes are reviewed in the second section. Even in IDDM patients with early diabetic nephropathy, the proximal reabsorption rate is elevated, resulting in a normal CLi despite glomerular hyperfiltration. Overnight euglycemia did not change GFR in IDDM patients, but during maintained euglycemia, GFR was normalized. A few hours of hyperglycemia prevented the decline in GFR, whereas CLi was unchanged. Thus hyperglycemia produced changes in renal function similar to those observed previously, but the time-course of the effect of euglycemia on kidney function is delayed. Plasma levels of atrial natriuretic peptide, renin and glucagon were not importantly affected by plasma glucose. In NIDDM patients CLi was normal, despite slight hyperfiltration, although this observation must be confirmed in a study with larger sample size. Prompted by the clinical observation of a marked decline in the GFR induced by carbonic anhydrase inhibitors, we studied the renal effects of acetazolamide in a controlled study.(ABSTRACT TRUNCATED AT 400 WORDS)

In normoalbuminuric patients with insulin-dependent diabetes mellitus, plasma atrial natriuretic factor (ANF), cyclic GMP and active renin and the renal clearances of [99Tcm]-diethylenetriaminepentaacetic acid (DTPA) lithium and sodium were studied on a hyperglycaemia day and a euglycaemia day. Baseline euglycaemia was achieved by an overnight variable insulin infusion, which during study days was fixed at the rate necessary to maintain euglycaemia in the morning. After a baseline euglycaemic clearance period of 90 min, measurements were repeated in a new 90-min period beginning 150 min later. On the hyperglycaemia day i.v. infusion of 20% glucose was started at the end of the euglycaemic baseline period, increasing blood glucose (5.3 +/- 1.3 vs 12.1 +/- 1.2 mmol l-1, p less than 0.01). On the euglycaemia day blood glucose declined (5.1 +/- 1.0 vs 4.2 +/- 1.0 mmol l-1, p less than 0.02). Glomerular filtration rate (GFR) was unchanged by acute hyperglycaemia (127 +/- 16 vs 129 +/- 24 ml min-1, NS), but nearly normalized during maintained euglycaemia on the euglycaemia day (124 +/- 17 vs 105 +/- 16 ml min-1, p less than 0.01). When comparing the hyperglycaemic study period with the similarly timed period on the euglycaemia day, GFR was elevated by hyperglycaemia (129 +/- 24 vs 105 +/- 16 ml min-1, p less than 0.01), while the renal clearances of lithium and sodium were similar. Consequently, the calculated absolute proximal reabsorption rate of sodium and water was elevated during hyperglycaemia. Hyperglycaemia reduced the slight decline in plasma concentrations of ANF and cyclic GMP observed on the euglycaemia day. Active renin, glucagon and plasma osmolality were unchanged. In conclusion, marked changes in glomerular filtration rate are induced by changes in blood glucose concentration, but the effect is delayed and thus not directly related to renal tubular transport of glucose. Hyperglycaemia does not affect renal clearances of lithium and sodium, while proximal tubular reabsorption is markedly stimulated. These changes are not related to changes in ANF, renin, glucagon or plasma osmolality.

In a comparative study the influence of changes in dietary sodium intake on blood pressure, renal function, extracellular fluid volume, the renin-angiotensin-aldosterone system and plasma concentrations of arginine vasopressin, atrial natriuretic factor and cyclic guanosine monophosphate (GMP) was investigated in 12 patients with essential hypertension and in 10 normotensive controls. The subjects were studied after 4 days on a low (50 mmol/day), medium (180 mmol/day) or high (380 mmol/day) sodium intake. Renal sodium handling was assessed by simultaneous measurements of 51Cr-ethylenediaminetetraacetic acid (EDTA), lithium and sodium clearances. Identical values for the extracellular fluid volume, glomerular filtration rate and proximal and distal tubular resorption rates of sodium and water were found in the hypertensive patients and the controls at all three levels of sodium intake. In both groups, raising the sodium intake from low to high significantly increased 51Cr-EDTA and lithium clearance (an indirect measure of end-proximal fluid delivery), with intermediate values for the medium-sodium diet. The estimated values of fractional proximal and distal sodium resorption decreased when sodium intake was raised; the absolute proximal sodium resorption rate did not change, whereas the absolute distal sodium resorption rate as well as the extracellular fluid volume and sodium clearance increased. Blood pressure and the heart rate were unaffected by sodium intake. In both hypertensives and controls, plasma concentrations of active renin, angiotensin II and aldosterone decreased with increasing sodium intake, arginine vasopressin did not change, and atrial natriuretic factor and cyclic GMP increased.(ABSTRACT TRUNCATED AT 250 WORDS)

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.

Active and total plasma renin concentration, as well as plasma angiotensin II, aldosterone and renin substrate concentrations were measured in venous blood samples from 17 normal 85-year-old people at rest. No discernible sex-related differences were seen. Active plasma renin and plasma aldosterone concentrations were significantly lower in the old people compared to a group of normal 40-year-old people. Plasma angiotensin II concentration showed no decrease with increasing age. Active plasma renin concentration constituted approximately 20% of total plasma renin concentration, with a significant correlation between the two renin moieties. The values for plasma renin substrate concentration are similar to those reported for younger age groups. The lack of standardization of methods severely hampers inter-laboratory comparisons of both active plasma renin and total plasma renin concentrations.

Insulin action on kidney function was evaluated in 8 healthy subjects, (mean age 27 years) using the euglycaemic clamp technique. Insulin was infused at rates of 0, 20 and 40 mU.min-1.m-2 over consecutive periods of 120 min resulting in plasma insulin concentrations of 8 +/- 2, 29 +/- 7 and 66 +/- 14 mU/l. The renal clearance of 51Cr-EDTA, lithium, sodium and potassium was determined during the last 90 min of each period. Sodium clearance declined with increasing plasma insulin concentrations (1.3 +/- 0.4, 1.0 +/- 0.3 and 0.5 +/- 0.2 ml.min-1.1.73 m-2, p less than 0.001), while glomerular filtration rate (108 +/- 21, 104 +/- 21 and 108 +/- 20 ml.min-1. 1.73 m-2) and lithium clearance (a marker of fluid flow rate from the proximal tubules) 29 +/- 5, 29 +/- 4 and 30 +/- 4 ml.min-1.1.73 m-2) remained unchanged. Calculated proximal tubular reabsorption of sodium and water was unchanged, while calculated distal fractional sodium reabsorption increased (95.5 +/- 1.5, 96.4 +/- 1.2 and 98.1 +/- 0.7%, p less than 0.001). Potassium clearance and plasma potassium concentration declined, whereas plasma aldosterone and plasma renin concentrations were unchanged. In conclusion, elevation of plasma insulin concentration within the physiological range has a marked antinatriuretic action. This effect is located distally to the proximal renal tubules.

The effects of strict metabolic control (multiple insulin injections for 1 week) on urinary albumin excretion, glomerular filtration rate and extracellular fluid volume was evaluated in long-term Type 1 diabetic patients with (n = 9) and without (n = 10) incipient nephropathy. Investigations were carried out in poor (blood glucose 15 (interquartile range, 13-18) mmol l-1) and good metabolic control (5 (4-8) mmol l-1). In patients with incipient nephropathy glomerular filtration rate was 125 (SD 26) (poor control) vs 125 (20) ml min-1 (good control), urinary albumin excretion 60 (range 37-247) vs 60 (13-359) mg 24 h-1, fractional albumin clearance 6.1 (0.9-67.6) vs 6.7 (2.1-65.4) x 10(-6), extracellular fluid volume 13.4 (2.3) vs 14.3 (2.8) l (p less than 0.10). Apart from an increase in extracellular fluid volume during improved metabolic control (12.2 (1.6) vs 13.6 (2.5) l, p less than 0.02) all the above mentioned variables remained unchanged in the patients with normal urinary albumin excretion. In conclusion, strict metabolic control for 2-7 days has no effect on urinary albumin excretion and glomerular filtration rate in long-term Type 1 diabetic patients with or without incipient diabetic nephropathy.

The acute effects on kidney function of acetazolamide (250 mg) given intravenously were evaluated in seven healthy subjects. Glomerular filtration rate was measured as the renal clearance of 51Cr-EDTA, and fluid flow rate out of the proximal tubules was assessed by measurement of the renal lithium clearance. An 18% decline in glomerular filtration rate (ml/min) was observed after acetazolamide administration (109 +/- 16 vs 89 +/- 14, p less than 0.02), while lithium clearance (ml/min) increased by 35% (30 +/- 5 vs 38 +/- 8, p less than 0.02). Absolute proximal tubular reabsorption of water (ml/min) was reduced by about one third (79 +/- 12 vs 51 +/- 9, p less than 0.02), and fractional proximal reabsorption of water and sodium (%) declined (73 +/- 2 vs 58 +/- 6, p less than 0.02). Renal sodium clearance and absolute distal reabsorption of sodium increased, while fractional distal reabsorption of sodium declined. Acetazolamide reduces absolute and fractional proximal tubular reabsorption of sodium and water, and glomerular filtration rate. Primarily, this induces an increase in the output of fluid from the proximal tubules accounting for the diuretic effect of the drug. The acute fall in glomerular filtration rate is probably mediated by a temporary increase in proximal intratubular pressure and activation of the tubuloglomerular feedback mechanism.

Plasma concentrations of atrial natriuretic factor (ANF) and cyclic guanosine monophosphate (cGMP) were measured in 10 patients with essential hypertension and 10 normotensive controls on the fifth day of a low (50 mmol/day), a medium (180 mmol/day) and a high (380 mmol/day) dietary sodium intake. Plasma ANF and cGMP concentrations were less on the low than on the high sodium intake. Values for ANF on the medium sodium intake were intermediate. In normotensive subjects cGMP concentrations did not differ significantly on the low and the medium sodium intake. As compared with the controls plasma concentrations of cGMP were significantly increased in hypertensive patients on all three levels of sodium intake, while ANF concentrations were identical in the two groups. Since cGMP is a second messenger to ANF the data suggest an increased cellular response to ANF in patients with essential hypertension.

The long-term (1) effect of multiple insulin injections in clinical practice was evaluated prospectively in 168 unselected consecutive insulin-dependent diabetic patients, age 31 (10-77) yr, attending a diabetic clinic. All patients received three or more daily injections of short acting insulin using a pen injector (NovoPen) plus one injection of intermediate acting insulin at bedtime. Haemoglobin A1c remained nearly unchanged, baseline: 8.6 (5.7-11.8)%, and after intensified treatment for 12 months: 8.3 (5.7-12.3)%. The frequency of keto-acidosis (0.08 (conventional treatment) versus 0.02 episodes/patient/yr, p less than 0.05) and severe hypoglycaemia (0.69 (conventional treatment) versus 0.38 episodes/patient/yr, p less than 0.005) diminished during intensified treatment. Ninety percent of the patients reported improvement in general well-being and only three percent felt worse. We conclude that multiple insulin injections with a pen injector applied in clinical practice improves general well-being, diminishes the risk of acute metabolic complications, while the overall metabolic control as reflected by haemoglobin A1c remains unaltered.

To evaluate the validity of the lithium clearance method as a marker of overall proximal tubular fluid delivery in moderately sodium-depleted humans, the effects of a single dose of 10 mg amiloride on lithium clearance and glomerular filtration-rate were studied in normal volunteers maintained on a sodium diet of 50 mmol/day. Amiloride caused no changes of the glomerular filtration-rate or of lithium clearance. The effects of amiloride on tubular sodium, potassium and water handling were in accordance with a distal tubular action of amiloride. The results suggest that significant distal lithium reabsorption does not occur in measurable amounts during moderate sodium depletion in humans. The lithium clearance method may, therefore, be used to assess proximal fluid delivery in man when dietary sodium intake is as low as in the present study.