Michael F. Michelis

Impaired water excretion in myxedema

Abstract The response to acute water ingestion (20 ml/kg body weight) was determined in sixteen patients with myxedema and eighteen control subjects. Comparison of the results in the two groups indicated an abnormality in water excretion in the patients with myxedema. This impaired water diuresis in the patients with myxedema, including those with significant hyponatremia, appeared to be related to decreased volume delivery to the distal diluting segment of the nephron rather than to persistent secretion of antidiuretic hormone. The reevaluation of eleven patients with myxedema after thyroid replacement therapy revealed significant improvement in the response to water ingestion.

“Essential” hypernatremia due to ineffective osmotic and intact volume regulation of vasopressin secretion

A physiological explanation for sustained hyperosmolality was sought in a patient with histiocytosis. During 23 days of observation with only sodium intake regulated at 100 mEq daily, elevation (mean 310 mOsm/kg of water) and fluctuation (range 298-323) of the fasting plasma osmolality were recorded. The presence of endogenous vasopressin was indicated by the patients ability to concentrate the urine to as high as 710 mOsm/kg of water with a creatinine clearance of 84 cc/min, and by dilution of the urine in response to alcohol. The failure of increasing fluid intake to as high as 6.2 liters daily to lower the plasma osmolality indicated that deficient fluid intake was not solely responsible for the elevated plasma osmolality. Hypertonic saline infusion during water diuresis resulted in the excretion of an increased volume of dilute urine. The water diuresis continued despite a rise in plasma osmolality from 287 to 339. An isotonic saline infusion initiated during hydropenia resulted in a water diuresis which continued despite a rise in the plasma osmolality from 303 to 320. Stable water diuresis induced during recumbency by either oral ingestion of water or intravenous infusion of normal saline was terminated by orthostasis and resumed with the return to the recumbent position. Antecedent alcohol ingestion blocked the antidiuresis of orthostasis. The data are interpreted as indicating impairment of the osmoreceptor mechanism as the primary cause of the hyperosmolar syndrome. They also indicate that vasopressin secretion was regulated primarily by changes in effective blood volume. Chlorpropamide was found to be an effective treatment for the syndrome.

Decreased bicarbonate threshold and renal magnesium wasting in a sibship with distal renal tubular acidosis

Abstract Two siblings with impaired distal renal tubular acidification and nephrocalcinosis associated with vasopressin-resistant polyuria are described. They also exhibit decreased renal bicarbonate threshold and defective renal magnesium conservation with a concomitant hypomagnesemia. Evaluation of other family member revealed no such abnormalities. Parathyroid hormone (PTH) has been shown to affect the renal tubular handling of both bicarbonate and magnesium. The role of the hormone in the development of the observed abnormalities of excretion of these substances was evaluated in both siblings. Following initial determinations, which in the older child suggested increased PTH effect, studies were performed on the two siblings to assess levels of PTH secretion both by indirect methods and by direct immunoassay of their sera. The results indicated excessive PTH secretion in the older sibling, but not in the younger. It was concluded that increased PTH secretion was not responsible either for the abnormalities of bicarbonate excretion or for the excessive urinary magnesium losses demonstrated in the two siblings. Further, neither vitamin D resistance nor secondary hyperparathyroidism appears necessary for the development of nephrocalcinosis in such disorders. Finally, responses to therapy indicate that the acidosis in both siblings was corrected, as expected, by alkali administration, but the hypomagnesemia did not correct (due to increased urinary losses) with either oral on parenteral magnesium supplements.

Effect of prostaglandin E 1 on certain renal actions of parathyroid hormone

Parathyroid hormone increased basal adenyl cyclase activity and that increase was inhibited by prostaglandin E(1) (PGE(1)). Tissue cyclic 3,5-adenosine monophosphate (cyclic AMP) concentrations were increased by parathyroid hormone and that increase was likewise inhibited by PGE(1). Both parathyroid hormone and dibutyryl cyclic AMP increased (32)P incorporation into renal cortical phospholipids. PGE(1) diminished the effect of parathyroid hormone but not dibutyryl cyclic AMP to influence that parameter. PGE(1) likewise modulated the effect of parathyroid hormone but not dibutyryl cyclic AMP to decrease fractional phosphate reabsorption by the renal tubule. It is suggested that PGE(1) inhibits the effect of parathyroid hormone by decreasing its effect on adenyl cyclase. Such interaction may be important in modulating the intracellular action of parathyroid hormone on kidney cortex.

Reset of osmoreceptors in association with normovolemic hyponatremia

After developing a stable hyponatremia (serum sodium 125-126mEq/liter) a patient was studied during a standard oral water load and during isotonic and hypertonic saline infusions. The patient excreted the water load in four hours, excreted dilute and then concentrated urine in response to isotonic saline, and concentrated her urine in response to hypertonic saline. Normal responses to these maneuvers while the patient was hyponatremic suggested reset of her osmoreceptors at a decreased serum sodium level. Data during the development of the hyponatremia demonstrated negative sodium balance, but neither negative water balance nor a decrease in body weight was seen, suggesting, as did her response to water loading, that the patient was normovolemic. It is proposed that reset does occur and can be demonstrated if hyponatremia develops while intravascular volume is maintained at normal levels.

Standard oral water load to determine the site of action of diuretics in man With data on metolazone, a new diuretic

Two male volunteers were given metolazone, a new diuretic, intravenously during a stable protracted water diuresis. The drug caused a mean decrease in CH2O of 2.8 c.c. per minute, a mean increase in sodium excretion of 419.5 μEq. per minute and no Significant change in urine flow rate or clearance of either inulin or PAH. The data suggested that metolazone affects the diluting segment of the nephron reducing the ability to clear free water. Five volunteers were given a standard water load with and without metolazone 10 mg. orally. The data revealed that total free water cleared in the 4 hours following the administration of water decreased (387.6 C.c. S.E. ± 73.9, P < 0.02), while osmols cleared increased (546.6 C.c., S.E. ± 106.7, P < 0.01) and sodium excretion increased (60.6 mEq., S.E. ± 10.5, P < 0.01). Urine volumes and potassium excretion were unchanged. Similar studies with oral water loads given to 4 volunteers who were also given 50 mg. of hydrochlorothiazide, which acts on the diluting segment of the nephron, produced changes such as those seen with metolazone. The data suggest, therefore, that metolazone, like hydrochlorothiazide, acts on the diluting segment of the nephron and that the standard oral water load is an accurate and convenient means of determining the site of action of diuretics.

“Bicarbonate Resistant” Metabolic Acidosis in Association with Ethylene Glycol Intoxication

A case of massive ingestion of ethylene glycol is described. The clinical characteristics of this disorder such as persistent metabolic acidosis and oxaluria as well as changes in serum osmolality that may accompany ingestion of certain toxins are emphasized. The rapid clearance of ethylene glycol from the blood during hemodialysis is noted and the use of ethyl alcohol to block metabolic conversion of ethylene glycol to oxalic acid, which is also a toxin, is described. The importance of early diagnosis and therapy is stressed.

Complications of Diuretic Therapy: Severe Alkalosis and Syndrome Resembling Inappropriate Secretion of Antidiuretic Hormone

Abstract Two patients with benign illnesses who developed life-threatening complications from therapy with ethacrynic acid (Case 1) and furosemide (Case 2) are described. Case 1 presented in a semi-comatose state with severe alkalosis (pH 7.70) on a daily dose of 50 to 100 mg. of ethacrynic acid. Case II presented with marked hyponatremia (sodium, 112 mEq./L.) associated with a normal BUN (10 mg.%), a concentrated urine (600 mOsm/Kg. H 2 O) and high urinary sodium concentration (60 mEq./L.). This combination initially suggested the syndrome of inappropriate secretion of antidiuretic hormone. However, the latter diagnosis was excluded by the correction of the hyponatremia with saline infusion and the history of furosemide ingestion. Case 2 had developed recurrent severe hyponatremia during a two year period while on furosemide therapy. Hyponatremia (130 mEq./L.) recurred during a controlled therapeutic trial with furosemide (20 mg. daily) in the hospital. This hyponatremia resulted in part from water retention which appeared to occur in response to the initial acute volume contraction produced by a single dose of the diuretic in this patient. This initial volume contraction was presumably a stimulus for antidiuretic hormone secretion. The possible mechanisms for the development of severe alkalosis and hyponatremia with these agents are discussed. The need for determination of individual responsiveness to these agents and for careful monitoring of serum electrolytes subsequently is emphasized.

Parathyroid hormone responsiveness in hypoparathyroidism with hypomagnesemia.

The failure to respond normally to parathyroid hormone (PTH) administration has been reported in patients with severe hypomagnesemia. A patient with hypoparathyroidism and a markedly decreased serum concentration of magnesium (0.7 mEq/liter), but a normal red blood cell magnesium level, is described who increased serum calcium concentration and decreased per cent renal tubular reabsorption of phosphate when parathyroid extract was given. It is suggested that PTH responsiveness in hypomagnesemic patients may, at least in part, be dependent upon the adequacy of intracellular magnesium stores. This interpretation is supported by the normal cellular (red blood cell) magnesium concentrations observed in this patient and in comparable studies in which PTH responsiveness in the presence of hypomagnesemia was demonstrated. In addition, a failure of optimal renal conservation of magnesium was noted to occur in this patient since, despite hypomagnesemia, urinary magnesium excretion was greater than the 1 mEq/day loss that is seen when magnesium conservation is induced by means such as dietary restriction.

BIOLOGIC ACTIVITY OF NEUROPHYSIN: NATRIURESIS*

Much of the data presented at this meeting, including our own data on human neurophysins, has tended to support the association of one neurophysin with oxytocin and another with vasopressin. However, it was also mentioned that during renal failure and during estrogen administration, plasma neurophysin may be elevated while the levels of oxytocin and vasopressin are not known to be increased. If neurophysins can be secreted by stimuli that do not cause a secretion of oxytocin and vasopressin, the possibility that neurophysins have an independent function is suggested. Even if neurophysins are not secreted independently, the concept of body economy might be better met if these peptides had biologic activity. Indeed, on a milligram basis, neurophysins may be the major secretory product of the neurohypophysis. We investigated neurophysins biologic activity on the kidney because we had previously shown that there was an increase in plasma neurophysin in response to hypertonic saline administration. Furthermore, a number of investigators have suggested the neurohypophysis as a possible site of origin of a third f a ~ t o r , ~ ~ ~ the postulated circulating effector that produces the natriuretic response to volume expansion. For these studies, we utilized bovine neurophysin I (BNp I) and neurophysin I1 (BNp 11), which we have previously d e ~ c r i b e d . ~ Some of this material had been stored frozen for as long as three years and was, therefore, rechromatographed on G-75 SephadexB prior to injection. The study protocolS involved the use of hydropenic mongrel dogs that were lightly anesthetized. The animals were surgically prepared by placement of arterial, venous and urethral catheters so that inulin administration, blood sampling and urine collection could be accomplished. Following the collection of three 30-minute baseline urines and midpoint bloods, neurophysin was administered intraveneously as a bolus. Four more 30-minute urines with midpoint bloods were then collected. In control experiments, the same protocol was used, but no neurophysin was given. FIGURE 1 demonstrates the increase in sodium excretion in ten dogs given BNp I. The stable baseline is demonstrated in the first three collection periods by the narrow standard error of the mean. The arrow indicates the time of administration of neurophysin. An increase in Na+ excretion was noted in every dog given BNp I with a range of 3to 25-fold increase. The peak mean natriuretic response can be seen to occur in the third or fourth 30-minute experimental collection period. However, some individual dogs peaked in the second period and hed returned to near baseline by the end of the study.