Frederic C. Bartter

The syndrome of inappropriate secretion of antidiuretic hormone

Abstract The syndrome of inappropriate secretion of antidiuretic hormone (SIADH) has been examined and reviewed. Typically, it is characterized by hyponatreinia without dehydration, urinary sodium loss and hypertonicity of the urine. Atypically, urinary sodium loss may be absent and urinary tonicity may be below that of serum; the only requirement is that the urine be less than maximally dilute. The syndrome is found with various tumors, notably oat cell carcinoma of the bronchus, which probably produce antidiuretic substance directly, and in a wide variety of disorders affecting the central nervous system or the lungs, in which there is probably abnormal release of endogenous antidiuretic hormone. The syndrome is also seen occasionally in patients with adrenal, thyroid or pituitary insufficiency. The possible role of the inappropriate release of antidiuretic hormone in all these disorders and in the hyponatremia which can occur postoperatively or in congestive heart failure or cirrhosis, requires further definition by new, specific assay technics.

A syndrome of renal sodium loss and hyponatremia probably resulting from inappropriate secretion of antidiuretic hormone

THis paper is a report of studies of two patients with bronchogenic carcinoma in whom hyponatremia developed as the result of unexplained failure of renal sodium conservation. The data indicate that sustained inappropriate secretion of antidiuretic hormone was probably responsible for the disorder of sodium metabolism. The physiologic abnormality appears to be analogous to that which can be produced by the continuous administration of pitressin® and water to normal subjects .

Hyperplasia of the juxtaglomerular complex with hyperaldosteronism and hypokalemic alkalosis: A new syndrome*

A new syndrome, characterized by hypertrophy and hyperplasia of the juxtaglomerular apparatus of the kidneys, aldosteronism resulting from adrenal cortical hyperplasia, and persistently normal blood pressure is described in two patients. Overproduction of aldosterone could not be prevented by sodium loading or by administration of albumin intravenously; it was associated with hypokalemic alkalosis and Pitressin-resistant impairment of urinary concentrating ability. In both subjects, increased amounts of circulating angiotensin were demonstrated; infusion of angiotensin II produced rises of blood pressure in both subjects considerably less than the rises induced by comparable doses in normal subjects. The sequence of events, (1) primary resistance to the pressor action of angiotensin, (2) compensatory overproduction of renin and thus of angiotensin, and (3) stimulation of adrenal cortex by angiotensin is consistent with all the information available about the syndrome.

Evidence for a phosphorus-depletion syndrome in man.

Abstract Antacids can impair phosphorus absorption in man. The long-term results of such impaired absorption are not fully appreciated despite knowledge of the vital role of phosphorus in life processes and the serious results of its depletion in animals. To determine depletion in man, studies were performed in three normal subjects and three patients with parathyroid dysfunction during prolonged treatment with antacids. It was found that a syndrome of phosphorus depletion characterized by hypophosphatemia, hypophosphaturia, increased gastrointestinal absorption of calcium, hypercalciuria, increased resorption of skeletal calcium and phosphorus, and debility, with anorexia, weakness, bone pain and malaise, can be produced by prolonged treatment with nonabsorbable antacids such as magnesium-aluminum hydroxides.

Bartter's syndrome: A disorder characterized by high urinary prostaglandins and a dependence of hyperreninemia on prostaglandin synthesis

Urinary prostaglandins E2 and F2alpha were measured by gas chromatography-mass spectrometry in three adult women and an adolescent girl with Bartters syndrome. On a constant metabolic diet prostaglandin E2 ranged from 293 to 1,221 ng/day (mean, 640 ng/day) and exceeded the normal range for adults of 76 to 281 ng/day in all patients. Prostaglandins F2alpha ranged from 291 to 1,061 ng/day (mean, 747 ng/day) in the adult women. Only in a young girl did prostaglandins F2alpha (1,677 ng/day) clearly exceed the normal range for adults of 422 to 871 ng/day. Treatment with indomethacin, which decreased urinary prostaglandin E-like material by 69 per cent or more, did not affect blood pressure. Plasma renin activity, which ranged from 5.2 to 22.2 ng/ml/hour (patients supine) and from 23.3 to 30.4 ng/ml/hour (patients upright), and urinary aldosterone, which ranged from 14.0 to 45.6 ng/day, decreased by 79, 65 and 52 per cent, respectively. The clearance of creatinine was lower for the eight or nine days of treatment, the balances of sodium and potassium were positive, and serum potassium was higher than in control. Ibuprofen, an inhibitor of prostaglandin synthetase which differs in structure from indomethacin, produced metabolic effects which were qualitatively similar to those of indomethacin. The results indicate that the renal synthesis of prostaglandins is increased in Bartters syndrome and that prostaglandins mediate the hyperreninemia and hyperaldosteronism which characterize the disorder. The over-production of prostaglandins by the kidney could be proximal cause of the syndrome, or secondary to intrarenal changes of an unknown nature. This study provides additional evidence for an important role for prostaglandins in the release of renin.

Nephrogenous Cyclic Adenosine Monophosphate as a Parathyroid Function Test

Nephrogenous cyclic AMP (NcAMP), total cyclic AMP excretion (UcAMP), and plasma immunoreactive parathyroid hormone (iPTH), determined with a multivalent antiserum, were prospectively measured in 55 control subjects, 57 patients with primary hyperparathyroidism (1 degrees HPT), and 10 patients with chronic hypoparathyroidism. In the group with 1 degrees HPT, NcAMP was elevated in 52 patients (91%), and similar elevations were noted in subgroups of 26 patients with mild (serum calcium </=10.7 mg/dl) or intermittent hypercalcemia, 19 patients with mild renal insufficiency (mean glomerular filtration rate, 64 ml/min), and 10 patients with moderate renal insufficiency (mean glomerular filtration rate, 43 ml/min). Plasma iPTH was increased in 41 patients (73%). The development of a parametric expression for UcAMP was found to be critically important in the clinical interpretation of results for total cAMP excretion. Because of renal impairment in a large number of patients, the absolute excretion rate of cAMP correlated poorly with the hyperparathyroid state. Expressed as a function of creatinine excretion, UcAMP was elevated in 81% of patients with 1 degrees HPT, but the nonparametric nature of the expression led to a number of interpretive difficulties. The expression of cAMP excretion as a function of glomerular filtration rate was developed on the basis of the unique features of cAMP clearance in man, and this expression, which provided elevated values in 51 (89%) of the patients with 1 degrees HPT, avoided entirely the inadequacies of alternative expressions. Results for NcAMP and UcAMP in nonazotemic and azotemic patients with hypoparathyroidism confirmed the validity of the measurements and the expressions employed.

Evidence for a prostaglandin-independent defect in chloride reabsorption in the loop of henle as a proximal cause of Bartter's syndrome☆

Maximal free-water clearance was measured in five patients with Bartters syndrome and in five patients with the hypokalemic alkalosis of persistent psychogenic vomiting. Hypokalemic alkalosis, hyperreninemia, hyperaldosteronism and excessive renal production of prostaglandin E2 were present in the patients with both disorders. Maximal free water clearance was abnormally low, in association with a high clearance of chloride, in all the patients with Bartters syndrome; it was normal in all the patients with psychogenic vomiting. In the patients with Bartters syndrome, apparent distal delivery of proximal tubular fluid was inversely related to glomerular filtration rate and was excessive only in those patients with a low glomerular filtration rate. Patients with psychogenic vomiting showed mean distal fractional chloride reabsorption of 0.92 +/- 0.04 (standard error [SE]). In the patients with Bartters syndrome, distal fractional reabsorption of chloride was 0.49 +/- 0.08 and was the same (0.46 +/- 0.06) during inhibition of prostaglandin synthesis with indomethacin therapy. Thus, a prostaglandin-independent defect in chloride reabsorption in the loop of Henle is the most proximal cause for the abnormalities in Bartters syndrome thus far identified.

THE EFFECT OF ACTH, RENIN, ANGIOTENSIN II, AND VARIOUS PRECURSORS ON BIOSYNTHESIS OF ALDOSTERONE BY ADRENAL SLICES

Angiotensin II has been shown to increase the excretion (1) and secretion (2) of aldosterone by normal human subjects, and the secretion of aldosterone by hypophysectomized, nephrectomized dogs (3-5). In the latter preparation (3), renin, which leads to the liberation of angiotensin in the circulation (6), has been shown to stimulate aldosterone secretion. The present studies were done to determine whether angiotensin and renin can act directly on the adrenal cortex. It will be shown that angiotensin II, like ACTH, does have such a direct effect, and renin does not. The effect of various precursors on the biosynthesis of aldosterone was determined and compared with their effect in the presence of ACTHand angiotensin II. In this way, we have sought to identify and compare the loci of action of ACTHand angiotensin II in the biosynthesis of aldosterone.

NORMOCALCEMIC PRIMARY HYPERPARATHYROIDISM

Abstract In recent years it has become recognized that patients with primary hyperparathyroidism, particularly those with renal stones, may present with serum calcium concentrations that are within the normal range. The three patients described herein all presented with a long history of recurrent renal calculi, normal serum calcium and phosphorus concentrations, and hypercalciuria while taking an unregulated diet. In all three patients, the diagnosis of primary hyperparathyroidism was proved by surgical exploration of the neck and biopsy of all four parathyroid glands. In two, a parathyroid adenoma was found; in the third, parathyroid hyperplasia. The disease in these three patients was classified as normocalcemic primary hyperparathyroidism.

Dual mechanism regulating adrenocortical function in man

Abstract Secretion of aldosterone and secretion of hydrocortisone by the human adrenal cortex appear to be regulated by distinctly different mechanisms, as shown by the following observations. 1.1. Sodium deprivation results in large increases in aldosterone output but does not appreciably affect 17-hydroxycorticoid output. 2.2. Certain diseases (congestive heart failure, cirrhosis and nephrosis) are characterized by an increase in aldosterone output without clinical or laboratory evidence of more general hyper-adrenocorticism. 3.3. Administration of ACTH results in relatively large increases in hydrocortisone (17-hydroxycorticoid) output but results in only comparatively small increases in aldosterone output. 4.4. Suppression of ACTH release by administration of cortisone or by damage to the pituitary reduces hydrocortisone secretion to minimal amounts but has relatively little effect on secretion of aldosterone. Thus it appears that the secretion of aldosterone is responsive to changes in water and electrolyte metabolism, whereas the secretion of hydrocortisone is regulated by production of ACTH.