Renal Salt Loss Research Articles

Pseudohypoaldosteronism in Eight Families: Different Forms of Inheritance Are Evidence for Various Genetic Defects

Pseudohypoaldosteronism is a rare hereditary disorder presenting in early infancy with renal salt loss leading to hyponatremia and hyperkalemia despite high levels of plasma aldosterone. The patients are insensitive to mineralocorticoids; however, sodium supplementation is able to correct electrolyte abnormalities. Absent or greatly diminished type I aldosterone receptors in peripheral mononuclear leucocytes have been recently demonstrated and explain the lack of response to mineralocorticoids. We have studied the mode of inheritance in eight families with a total of nine patients. There was evidence for an autosomal recessive form of inheritance in four families, while the other four families appeared to have an autosomal dominant mode of transmission. In three families the autosomal recessive form was characterized by normal receptor as well as hormone data in both parents, while in one family receptor levels in both parents were greatly reduced, but hormone levels were normal. In the four families with an autosomal dominant mode of transmission there was always one parent with reduced receptor binding in peripheral mononuclear leucocytes and elevated serum hormone levels. These parents were entirely asymptomatic. In an extended family we were able to study an aunt and her newborn daughter, who were both also biochemically affected but clinically asymptomatic. It, therefore, appears that this dual pattern of genetic transmission may indicate differing genetic defects which cause the same clinical picture of pseudohypoaldosteronism.

Vasopressin and Hypertension in Man

The role of vasopressin in human hypertension was examined in a series of studies. In patients with primary hyperaldosteronism and benign essential hypertension, circulating vasopressin was generally lower than in normotensive subjects. In contrast, plasma vasopressin was increased (p less than 0.001) in patients with malignant-phase hypertension. However, compared to infused vasopressin in normal subjects, when plasma levels of up to 120 pg/ml did not affect blood pressure, the increased levels found in malignant hypertension could not account for the hypertension. The possibility that there may be an increased pressor sensitivity to vasopressin in hypertension was examined by infusing the peptide into nine patients with essential hypertension. This showed a slight increase in sensitivity compared to normotensive subjects, but again this was insufficient to account for the discrepancy between the circulating level of vasopressin and the extent of the raised blood pressure in the hypertensive patients. The effect of chronically elevated levels of vasopressin was studied in a group of patients with the syndrome of inappropriate ADH excess as a consequence of bronchogenic carcinoma. In spite of having chronically elevated levels of vasopressin, these patients had normal blood pressures for their age and sex. Our results suggest that, although vasopressin is elevated in malignant hypertension, it does not contribute significantly to the raised blood pressure, and its increase is probably a consequence of volume shrinkage through renal salt and water loss.

The role of urinary precipitates in the excretion of electrolytes and urate in the domestic fowl.

1. In order to quantify losses of Na and K associated with precipitate fractions in semi-solid avian urines, Na, K, uric acid and urates (UA + U) and inulin were measured in plasma, in whole ureteral urine, and in urinary precipitates of hens. Ten animals were used, five fed a control commercial poultry meal (Diet A) and five maintained on a high protein, low-Na feed (Diet B). 2. In ureteral urines from hens on Diet A, dried precipitate accounted for 5.6% of the total whole urine weight, on the average. UA + U constituted about two-thirds of the precipitates' weight and 80% of the total excreted UA + U load of 97.4 mM. The average molar fractions, [Na]/[UA + U] and [K]/[UA + U], in precipitates were in the range 0.1-0.2; and the Na and K lost in these fractions were 12.8 mequiv and 9.6 mequiv, respectively, per 1 whole urine. These losses represent 9% and 23% of total Na and K excretion. 3. Diet B was used to accentuate potential cation loss in precipitates if obligatory binding of K and especially Na were to occur in precipitates. Urinary [UA + U] in whole urine rose to 146 mM of which 95% was found in precipitates. The average molar fraction [Na]/[UA + U], however, fell to 0.06 and that of [K]/[UA + U] to 0.08. Renal loss of Na was 8.5 mequiv and of K was 11.5 mequiv per 1 whole urine. 4. These experiments reveal that significant but minor fractions of excreted Na and K are associated with precipitates of avian urine, although the loss is insignificant compared to that reported in starlings (Braun, 1978). They further indicate that the Na/inulin clearance ratio, based on measurements in whole urine and plasma, adequately reflects fractional excretion which, on Diet A, was 1.8% of the filtered load and, on the Na-poor Diet B, less than 0.1%. These values place the Na-reabsorbing abilities of these birds easily within the range reported for ureotelic vertebrates and suggest that uricotelism does not impose a major renal salt loss in birds.

PLASMA RENIN ACTIVITY AND ALDOSTERONE CONCENTRATION IN NORMAL SUBJECTS AND PATIENTS WITH SALT‐LOSING TYPE OF CONGENITAL ADRENAL HYPERPLASIA DURING INFANCY

SUMMARYPlasma renin activity (PRA) and aldosterone concentration (PAC) were determined in normal infants aged 20 days to 1 year as well as in normal neonates and older children. The responses of PRA and PAC to five intramuscular injections of synthetic ACTH‐Z at 6‐hour intervals while on replacement cortisol therapy were also studied in nine infants with salt‐losing type of congenital adrenal hyperplasia due to 21‐hydroxylase deficiency (CAH) of varying severity, using the data obtained in normal infants as control. The mean PRA and PAC decreased with age from the neonatal period, but in infants aged 20 days to 3 months these variables remained as high as those in newborns. They were also remarkably higher in infants aged 4 to 12 months than in older children. In two cases of CAH (cases 1 and 2) where salt wasting symptoms had been only transiently observed during the neonatal period, PAC was markedly elevated in response to ACTH administration, while in the remaining seven infants with CAH (cases 3–9) with persistent salt wasting symptoms, PAC was not elevated at all or only slightly so. PRA, on the other hand, increased with time during the ACTH stimulation in cases 3–9, while it increased and then decreased in cases 1 and 2. These findings suggest that the salt‐wasting symptoms in CAH may arise where there is a tendency toward renal salt loss due to the overproduction of ACTH‐dependent steroids characteristic of this disease, and cannot be compensated for by sufficient secretion of aldosterone. In cases 3–9, the maximal PAC under the ACTH stimulation was 17–44 ng/dl. These levels are comparable to or even higher than the normal range for control older children aged 2–8 years, but the levels were inappropriately low for the marked elevation of PRA in all of them when compared with the mean level in normal infants. Therefore, these data also seem to explain at least in part the well known clinical fact that the salt wasting symptoms in CAH are severe during infancy, requiring the administration of mineralocorticoids in addition to cortisol. However, beyond infancy only the replacement cortisol therapy is necessary to remit the symptoms.

The importance of intracellular volume in the control of vascular volume

The effect of change in extracellular (interstitial) volume on vascular volume (VV) is mediated through interstitial pressure. Since the effect of swollen or shrunken cells on interstitial pressure should be identical to that of changes in interstitial volume on interstitial pressure, it would be appropriate to consider that intracellular volume (ICV) as well as extracellular volume (ECV) contributes to control of VV. Total body water rather than ECV, therefore, should be considered as the fluid volume which regulates VV. Support for these conclusions has been provided by theoretical analysis of the factors that regulate capillary fluid exchange. In further support of this hypothesis, clinical examples are described, in which renal salt retention was observed despite increase in ECV (ICV was markedly decreased), and in which renal salt loss occured despite decrease in ECV (in the presence of increased cell volume).

Tubular Na, K-ATPase deficiency, the cause of the congenital renal salt-losing syndrome.

In the serum of two infant sisters with a congenital renal salt-losing syndrome, Na was rather low and K considerably increased. Even with Na levels of 126 mval/1, sodium was excreted in the urine. Creatinine and hippurate clearances were normal. Primary disturbances of the steroid metabolism were not detectable; plasma cortisol was normal, aldosterone and renin were compensatorily increased. Treatment with DOCA was unsuccessful. Whereas the first infant died (in another hospital), the second one throve well with high oral substitution of NaCl. There was no pathological findings other than a moderate hyperplasia of the juxtaglomerular apparatus, in a kidney biopsy. Except for minimal activity in the ascending limb of Henle's loop, there was no membrane bound Na, K-ATPase in the microdissected tubules. This finding most probably explains the renal salt loss, as this enzyme is necessary for the transcellular flow of sodium and potassium.

Study on the site of renal salt loss in 3 patients with Bartter's syndrome

A sodium loss syndrome has been shown in some patients with Bartter's syndrome. According with Chaimovitz's experience, we tried to localise the site of renal salt loss in this syndrome. We have studied 3 children with Bartter's syndrome submitting them to an intravenous 045% hypotonio saline infusion, until a total dose of 2.000 ml/m/1.73 m2, adjusting the rythm of perfusion to exceed urinary flow by 5 ml/m/1.73 m2 and having begun the perfusion at a rate of 5 ml/m/1.73m2. The results obtained in a group of 6 healthy children, gave to us the following figures( all them referred to 100 ml of GFR ), V/m: 15.9 co/m; ClH2O: 11.6 cc/m; ClNa 1.800/, ClH2O+ClNa: 13.4 cc/m; UNa; 262 Eq/m' UKV: 51 Eq/m; being ClH2O/ClH2+ClNax100: 86% and Clin 111.6 cc/m/1.73 m2. In two of our patients, V/m and Na delivery were found normal; ClNa, UNeV and UKV were increased, and ClH2O and ClH2O/ ClH2O+ClNax100 were reduced. The third patient showed an increase of UNaV, UKV and ClNa, but Na delivery, as well as ClH2O were significantly increased while ClH2O/ClH2O+ClNax100 remained low. These results suggest that the site of renal salt loss in the two first patients is the ascendent limb of Henle. On the other hand, the third patient seems to demonstrate a defective proximal tubular Na reabsorption with a good compensatory mechanism in the ascendent limb of Henle.

Studies on the site of renal salt loss in a patient with Bartter's syndrome.

Extract: A child with growth retardation, hypokalemic alkalosis, and urinary salt losing is described. Pressor response to angiotensin II was reduced and renal biopsy showed striking hyperplasia of the juxtaglomerular apparatus. Renal tubular function was studied in the patient and in healthy control subjects during hypotonic saline diuresis. Glomerular filtration rate (GFR) was 128 ml/min/ 1.73 m2 in the patient and 129 ± 30 ml/min/1.73 m2 in the control subjects. Fractional sodium delivery to the distal nephron, as estimated by ( + CNa)/100 ml GFR, was 13.3 ml and 11.1 ± 3.5 ml in the patient and normal subjects, respectively. Sodium transport at the diluting segment [( / + CNa) × 100] was markedly impaired in the patient, 32% versus 80% ± 9.2% in the control subjects. The natriuretic effect of chlorothiazide was normal in the patient, which suggests that the reabsorptive capacity of the thiazide-sensitive segment of the distal nephron is preserved. The evidence presented suggests that the defective reabsorption of sodium in the patient is due to an impaired sodium transport in the ascending limb of Henle's loop. The present study raises the possibility that a similar tubular defect may be responsible for the impaired renal handling of sodium that is often observed in patients with Bartter's syndrome. Speculation: Impaired transport of sodium localized in the distal nephron, that results in failure of the kidney to conserve salt adequately, is probably the primary disorder in some patients with Bartter's syndrome.

Inappropriate antidiuretic hormone secretion. Hypothalamic glioma in a child.

THE SYNDROME of inappropriate antidiuretic hormone (SIADH) secretion is characterized by serum hyponatremia and hyposmolality associated with relative urinary hyperosmolality and excessive renal salt loss; there is an absence of clinical evidence of fluid volume depletion, and renal and adrenal function are normal. 1 The subject of this report, a child with a hypothalamic glioma, fulfilled all of these criteria and, in addition, showed several atypical features of the SIADH. These included a normal response to an acute water load, the occasional failure to respond to severe water restriction, and the discontinuous secretion of a measurably elevated ADH co-existing with persistent hyponatremia. These features are not inconsistent with the inappropriate secretion of ADH. A possible alternative explanation is that a malfunctioning hypothalamic osmostat may be an associated defect. Report of a Case This 6-year-old boy was hospitalized on Oct 19, 1968, because of headaches and vomiting of several

Salt-losing nephropathy

Summary A case of medullary cystic disease and chronic renal failure with severe sodium wastage is described. Urinary sodium and calcium concentrations were fixed at a level approximating plasma ultrafiltrate. Renal salt loss was flow dependent. It is suggested that the main cause of the severe salt loss was a tubular and medullary defect of sodium transport; hyperfiltration and increased osmotic load per nephron played a contributory role.In the patient described, calcium was excreted in the urine in quantities that were unusually large for chronic renal failure but were commensurate with the renal salt loss.

Inappropriate Antidiuretic Hormone Secretion in Carcinoma of the Lung

Four cases with inappropriate antidiuretic hormone syndrome associated with carcinoma of the long are reported. It is concluded that certain tumors manifest a capability to synthesize and release a substance similar to antidiuretic hormone which enhances water reabsorption, leading to dilution and expansion of the extracellular fluid volume. These changes in the extracellular fluid volume stimulate the third factor mechanism which depresses proximal tubular sodium reabsorption, resulting in a continued renal salt loss despite the existing hyponatremia. The simple restriction of fluid intake to 500–750 ml per day along with an adequate intake of sodium will result in correction of the hyponatremia and relief of the distressing symptoms. Permanent cure is possible when complete removal of the tumor is technically feasible.