H. A. Koomans

Sodium balance in renal failure. A comparison of patients with normal subjects under extremes of sodium intake.

To gain insight into the factors involved in the maintenance of sodium balance in patients with chronic renal failure, we studied 10 patients with a creatinine clearance of 11.5 +/- 4.0 ml/min after equilibrium on 20 and 120 mEq of sodium per day. The measurements included blood pressure, plasma volume, blood volume, extracellular fluid volume, plasma renin activity, plasma aldosterone, and plasma norepinephrine. For comparison, eight normal volunteers were studied after equilibration on 20, 200, and 1128 mEq of sodium per day. The latter intake was chosen to match the high sodium intake per residual renal function in the patients. In the patients, equilibrium after raised sodium intake was accompanied by a marked increase in blood pressure and blood volume, a moderate fall in plasma renin activity and levels of aldosterone and norepinephrine, and only little expansion of the interstitial space. The 24-hour creatinine clearance rose by 21.2 +/- 7.2%. Fractional sodium excretion (X 100%) was 5.3 +/- 0.8% during the 120 mEq sodium diet. In the normal volunteers, increasing the sodium intake from 20 to 1128 mEq/day evoked no consistent change in blood pressure but caused a comparable rise in blood volume, considerable suppression of plasma renin activity, aldosterone, and norepinephrine, and a much larger increase in interstitial volume. Their creatinine clearance had risen by 22.4 +/- 6.5%, and their fractional sodium excretion during the 1128 mEq sodium intake was 3.9 +/- 0.2%.(ABSTRACT TRUNCATED AT 250 WORDS)

Lowered Protein Content of Tissue Fluid in Patients with the Nephrotic Syndrome: Observations during Disease and Recovery

To find out why most patients with the nephrotic syndrome maintain a normal blood volume despite a reduced plasma colloid osmotic pressure (COP), we measured the transcapillary (plasma-tissue fluid) COP difference in 12 patients with the nephrotic syndrome, as well as in 6 patients during complete (n = 3) and partial (n = 3) recovery. Subcutaneous nylon wicks were used to collect tissue fluid. The albumin content was also measured. The albumin content and COP were lowered in both plasma and tissue fluid in the nephrotic phase, and rose gradually during recovery. During these changes the transcapillary COP difference only rose slightly: from 6.2 +/- 1.7 mm Hg when the plasma COP was below 10 mm Hg (n = 11) to 8.7 +/- 1.5 mm Hg when the plasma COP exceeded 20 mm Hg (n = 12). These observations indicate that in hypoproteinemia preservation of the intravascular volume is strongly dependent on maintenance of the difference in oncotic pressure across the capillary wall.

Natriuretic and hypotensive effect of adenosine-1 blockade in essential hypertension.

We studied the effects of a single dose (100 mg orally) and repeated administration (100 mg o.d. for 7 days) of FK453, a novel adenosine-1 receptor antagonist, on renal sodium handling and blood pressure in eight patients with essential hypertension. Within 60 minutes after administration of FK453, sodium excretion increased threefold. This occurred in the absence of a change in renal hemodynamics, assessed from inulin and para-aminohippurate clearance, and was accompanied by increased fractional excretion of lithium, phosphate, and uric acid and by increased excretion of calcium and magnesium. Maximal free water clearance data showed an increase in maximal urine flow and distal delivery term and a decrease in the diluting segment reabsorption term. FK453 also decreased blood pressure and increased heart rate, but this did not occur until about 3 hours after ingestion, that is, when the natriuresis was already over. The natriuretic effect of FK453 was short-lasting, and continued use of FK453 was in fact accompanied by some net sodium retention. Blood pressure on the seventh day before FK453 treatment was not different from blood pressure before administration of the first dose of FK453. Again an acute natriuretic response followed, although less than after the first dose. Changes in intrarenal sodium handling parameters, blood pressure, and heart rate were similar to those seen after the first dose. The natriuretic and hypotensive effects of FK453 indicate that adenosine-1 receptor activity plays a role in the regulation of blood pressure and renal sodium handling in patients with essential hypertension.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of plasma volume expansion on renal salt handling in patients with the nephrotic syndrome.

In 10 patients with the nephrotic syndrome (NS) and edema persisting despite a NaCl-poor diet, the effect of a single infusion of hyperoncotic albumin (75 g) on NaCl excretion was studied. 6 patients had minimal lesions, and 2 patients were studied twice. On half of the occasions the glomerular filtration rate was reduced. Blood volume (BV), calculated from plasma volume and hematocrit, was slightly elevated before infusion, and increased to 136 and 120% of normal at 4 and 20 h after it, respectively. Plasma renin activity (PRA) and plasma aldosterone (PA) both decreased to suppressed levels at 20 h after infusion. Sodium excretion increased from 9.2 +/- 7.6 muEq/min before, to 3.10 +/- 22.4 (0-4 h) and 43.1 +/- 36.3 muEq/min (4-20 h) after infusion. In 6 of these patients clearance studies were done before and after the infusion, maximal free water clearance being used as marker for distal NaCl reabsorption. Proximal fractional NaCl reabsorption was elevated before (94.9 +/- 1.4%) and decreased after the infusion (92.8 +/- 1.7%). Distal fractional NaCl reabsorption was also elevated before (93.0 +/- 6.4%), but unaltered after infusion (93.0 +/- 5.6%). Thus, after marked expansion of BV and suppression of PRA and PA, sodium excretion remained low despite the present edema. The results indicate that in many patients with the NS, including minimal lesion NS, intravascular hypovolemia is not the sole cause of sodium retention.

Haemodynamic and hormonal changes during acute and chronic diuretic treatment in essential hypertension

SummaryThe short- and long-term effects of diuretic treatment with chlorthalidone 50 mg/day on haemodynamic and hormonal parameters in patients with essential hypertension (WHO grade I) were investigated. After three days of treatment, all patients showed a rise in plasma renin activity (PRA), plasma aldosterone (PA), urinary norepinephrine excretion (UNE) and heart rate (HR), and a decrease in body weight (BW) and extracellular volume (ECV) and blood volume (BV); the change in blood pressure (BP) was variable. The changes in BP were correlated with those in BV. After three months of therapy, the signs of volume depletion tended to fade, but the lower ECV persisted. In contrast to the 4-day study, after three months the change in BP correlated inversely with changes in ECV and renin dependency (saralasin response), and positively with PRA and changes in UNE. It is concluded that the BP response to diuretic treatment is determined by the adaptation with time of the haemodynamic reactions to the volume-depleted state. Whether this adaptation will take place cannot be predicted from the control values of the parameters studied, or from acute changes observed during the first days of treatment.

Lithium clearance during variations in sodium intake in man: effects of sodium restriction and amiloride

Abstract. Assuming that lithium is exclusively reabsorbed in the proximal tubules in proportion to sodium and water, the lithium clearance (CLi) has been advanced as an index of filtrate delivery from the proximal tubules. However, studies in the rat and dog showed that CLi drops sharply at fractional sodium excretion rates (FELi) below 0·4% due to lithium reabsorption in the amiloride‐sensitive segment of the distal nephron, which disqualified CLi as an index of distal filtrate delivery during sodium restriction in these animals. In order to investigate whether this phenomenon also occurs in man, we studied CLi in 103 normal subjects at varying sodium intakes, including marked sodium restriction. In contrast to findings in the rat and dog, no sharp drop but a gradual fall in CLi was observed at decreasing FENa values down to 0·02%. Maximum urine flow, another index of filtrate delivery from the proximal tubules, decreased proportionally, suggesting that the fall in CLi was due to enhanced proximal and not distal lithium reabsorption. Amiloride (15 mg p.o.) did not affect CLi despite unequivocal effects in the distal nephron in eight normal subjects at a mean FENa of 0·1%. In conclusion, a low FENa due to severe sodium restriction in man is not accompanied by strongly enhanced distal lithium reabsorption sensitive to amiloride. Thus, in contrast to the rat and dog, a low FENa forms no objection to use CLi as an index of sodium and filtrate delivery from the proximal tubules in humans.

Lowered Tissue-Fluid Oncotic Pressure Protects the Blood Volume in the Nephrotic Syndrome

We have studied the role of adjustments of tissue-fluid colloid osmotic pressure (COP) in the maintenance of the blood volume in 10 patients with the nephrotic syndrome before and after diuretic treatment until dry weight. A mean weight reduction of 13.5 +/- 6.4 kg was attended by a fall in blood volume in 3 patients and no change in 6, but the final blood volume was within the normal range: 84.3 +/- 3.7 ml/kg (normal value: 87.6 +/- 8.8 ml/kg). Albumin content and COP of tissue-fluid, obtained with subcutaneous wicks, were low before edema removal and rose slightly after it, parallel to changes in the plasma. Thus, the transcapillary gradient in COP did not change: 6.5 +/- 1.5 mm Hg before and 6.2 +/- 1.7 mm Hg after diuretic treatment. Considering the low COP, 8.6 +/- 1.6 mm Hg in edematous and 11.7 +/- 3.7 mm Hg in dry conditions, this gradient was only slightly below the value of about 10 mm Hg normally found with this technique. We conclude that a lowered tissue-fluid COP is important for the preservation of blood volume in dry patients with the nephrotic syndrome. In addition, this adaptation can explain why the blood volume is often normal and not expanded despite the sometimes huge overhydration in these patients.

Enalapril attenuates natriuresis of atrial natriuretic factor in humans.

We studied the effect of converting enzyme inhibition with enalapril on the natriuresis observed after administration of atrial natriuretic factor (human ANF-[99-126], given as a 100-micrograms bolus i.v. injection) in eight healthy humans consuming a 100 mmol sodium diet. Without enalapril, sodium excretion rose from 127 +/- 19 (mean +/- SE) to 437 +/- 103 mumol/min in the first 20 minutes after ANF was administered. Clearance studies performed during maximal water diuresis indicated a rise in glomerular filtration rate (inulin clearance), free water clearance, phosphate, lithium, uric acid, and magnesium excretion. Four days of enalapril (20 mg b.i.d.) increased effective renal plasma flow (p-aminohippurate clearance) and reduced blood pressure (from 114/71 +/- 2/2 to 105/60 +/- 2/1 mm Hg). Under these conditions baseline sodium excretion was not different from the control study, but it rose less after ANF (from 117 +/- 22 to 242 +/- 63 mumol/min), and the increments in glomerular filtration rate, free water clearance, phosphate, lithium, uric acid, and magnesium were all blunted and nonsignificant. In addition, effective renal plasma flow tended to fall; this effect was not observed when ANF was given without enalapril. These results support the notion that the effects of ANF on renal hemodynamics and on tubular sodium handling depend on renal angiotensin II and that blood pressure reduction may interfere with the ANF-induced natriuresis.

Renal Function during Recovery from Minimal Lesions Nephrotic Syndrome

We followed renal function through the natriuretic phase of 6 occasions of drug-induced recovery from minimal lesions nephrotic syndrome (MLNS). Protein excretion started to fall 1-3 days prior to the start of the natriuresis. The natriuresis was accompanied by a rise in glomerular filtration rate (GFR, inulin clearance). The filtration fraction, calculated from the GFR and the p-aminohippurate clearance, rose steadily in 5 subjects in whom it was low before therapy. Proximal and distal sodium reabsorption fractions, estimated from the changes in maximum free water clearance, fell, and fractional sodium, lithium, uric acid and free water clearance rose. At the time of these changes plasma protein had hardly risen, whereas renin activity was down. These results are in agreement with the notion that the sodium retention of MLNS is due to a renal defect. Repair of the glomerular filter, evident from the disappearance of proteinuria and the rise in filtration fraction, apparently normalizes the elevated tubular sodium reabsorption proximal to the macula densa, which leads to a fall in renin release.

Variant of Bartter’s Syndrome with a Distal Tubular Rather than Loop of Henle Defect

A 19-year-old normotensive patient had all of the clinical features of Bartter’s syndrome: hypokalemia, elevated renin and aldosterone levels and increased excretion of prostaglandin E. In contrast to