William H Bergstrom

Hypercalciuria with Bartter syndrome: Evidence for an abnormality of vitamin D metabolism

Some children with Bartter syndrome have hypercalciuria. To determine the mechanism for this phenomenon, we studied tubular function and calcium metabolism in six such children. All patients had hypokalemic alkalosis, normotension, hyperreninemia, growth retardation, low fractional distal chloride reabsorption (4/5), and elevated urinary prostaglandin E2 excretion (5/6). In addition, all had hypercalciuria (urinary calcium 6.5 to 25.0 mg/kg/day), with evidence of nephrocalcinosis in five. None, however, had evidence of rickets or hyperparathyroidism. There was a marked elevation in the serum concentration of 1,25-dihydroxyvitamin D in all, and four patients had a response to oral calcium loading suggestive of absorptive hypercalciuria. Five children have had long-term therapy with indomethacin. They have had improvement in hypokalemia and reduced urinary prostaglandin E2 excretion as well as reductions in the serum concentration of 1,25-dihydroxyvitamin D and in urinary calcium excretion. These data suggest that hypercalciuria in some children with Bartter syndrome is associated with an excess of 1,25-dihydroxyvitamin D. The improvement in hypercalciuria with prostaglandin synthesis inhibition may result in part from correction of this vitamin D abnormality.

CALCEMIC RESPONSES TO PHOTIC AND PHARMACOLOGIC MANIPULATION OF SERUM MELATONIN

ABSTRACT. Phototherapy of newborn rats (NBR) resulted in a decrease in serum calcium and melatonin levels. Transcranial light penetrance in NBR increased with wavelength. Below 640 nm (penetrance = 6.9%), no hypocalcemic effect could be demonstrated. Shielding the occiput of NBR prevented a decrease in serum calcium during phototherapy and substantially reduced the decrease in melatonin found in unshielded NBR. Intraperitoneal injection of propranolol, an inhibitor of melatonin synthesis, caused a decrease in serum calcium in shaded NBR. In contrast, when melatonin was injected with propranolol a decrease in serum calcium did not occur. Additionally, intraperitoneal isoproterenol before phototherapy protected against a decrease in serum calcium. These data are consistent with an hypothesis that a decrease in serum calcium during phototherapy results from transcranial photic inhibition of melatonin synthesis.

Effects of the adrenal on calcium homeostasis in the rat

Abstract After thyroparathyroidectomy serum calcium concentration falls only if the adrenals are present or if exogenous steroids are provided. These results confirm the findings of Stoerk et al.1 This suggests that the hypocalcemia which follows parathyroidectomy probably results from an active mechanism under hormonal control. Adrenal hypertrophy occurred within 24 hours after nephrectomy only in the presence of the thyroid and parathyroids. When adrenalectomy and nephrectomy were combined, the serum calcium concentration rose to 12.3 mg. 100 ml. of serum. Thyroparathyroidectomy and nephrectomy resulted in a serum calcium of 7.2 mg. 100 ml. After simultaneous nephrectomy-thyroparathyroidectomy and adrenalectomy the serum calcium concentration was significantly higher, 8.9 mg. 100 ml. (p = 0.001). Since the hypocalcemic effect of the adrenal persisted after nephrectomy, it was apparently not mediated by the kidneys. Evisceration did not alter the degree of post-parathyroidectomy hypocalcemia. Since renal and intestinal sites of action may be excluded, hypocalcemia effected by the adrenals is probably due to a direct action on bone.

Pineal and Adrenal Effects on Calcium Homeostasis in the Rat

ABSTRACT: In human infants and newborn rats, white light at the intensity used to treat hyperbilirubinemia lowers serum calcium concentration. Occipital shielding or (in newborn rats) exogenous melatonin prevents this effect. Propranolol, by inhibiting melatonin synthesis, also causes hypocalcemia, which is preventable by melatonin. Metyrapone or adrenalectomy prevents hypocalcemia after light exposure or propranolol. Exogenous corticosterone lowers serum calcium; this is prevented by supplementary melatonin. In adult rats, the change in calcium after light, propranolol, or corticosterone is minimal. After parathyroidectomy or a diet with a high calcium/low phosphorus ratio, the hypocalcemic effect of these three agents is restored. Bone samples removed after light exposure or corticosterone administration show increased calcium uptake; this is blocked by supplementary melatonin in vivo or by addition of melatonin to the incubation medium. We postulated that the hypocalcemic effect of light or propranolol was due to an acute increase in corticosterone-mediated bone calcium uptake when circulating melatonin was decreased by reduction of the rate of melatonin synthesis. In our study, pinealectomized rats showed no change in serum calcium after light or propranolol; their hypocalcemic response to corticosterone was greater than that of shamoperated controls. Exogenous parathyroid hormone prevented light-induced hypocalcemia in newborn rats.

Prophylaxis against hypocalcemia in low-birth-weight infants requiring bicarbonate infusion

Forty-eight low-birth-weight infants with varying degrees of respiratory distress were studied with respect to serum calcium concentration and urinary calcium excretion. Serum calcium decreased over the 24-hour study period in infants who did not receive calcium infusion. The decrease was greater in those receiving bicarbonate therapy for acidosis. Continuous calcium infusion at 1 mg/kg/hr sustained relatively normal serum calcium concentration, even in those infants who required bicarbonate. Since the changes in estimated extracellular calcium could not be accounted for by urinary excretion, a shift of calcium into bone was postulated.

The cardiopulmonary effects of calcium infusion in infants with persistent pulmonary hypertension of the newborn.

ABSTRACT: Low blood ionized calcium levels have been reported previously in association with alkalosis in infants undergoing hyperventilation for persistent pulmonary hypertension. We investigated the effect of acute calcium infusions on the cardiopulmonary status of 10 hypocalcemic, hyperventilated infants with persistent pulmonary hypertension. Acid-base status, arterial partial pressure of oxygen, vital signs, and echocardiographically determined right and left systolic time interval ratios and left ventricular shortening fractions were obtained before and after rapid infusions of calcium gluconate or saline. At 5 and 15 min after calcium infusion, but not after saline infusion, there were significant decreases in both right and left ventricular systolic time interval ratios, and an increase in transcutaneous PO2 and PaO2 that coincided with peak levels of ionized calcium. These findings provide evidence that high levels of ionized calcium in newborns with persistent pulmonary hypertension transiently improve myocardial performance and oxygenation.

Conjunctive effects of fibroblast growth factor and glycosaminoglycan on bone metabolism in neonatal bartter syndrome.

The calciotropic activity of urine from a subject with neonatal Bartter syndrome (NBS) has been partially purified using ion-exchange and gel chromatographic techniques. A bioassay using bone disk from rat calvaria was used to estimate calciotropic activity, which in the urine of the subject with NBS appears to be due to basic fibroblast growth factor (bFGF) bound to a glycosaminoglycan susceptible to heparitinase digestion. The calciotropic activity is eluted from DEAE-Sephacel and Sepharose CL-6B in a narrow band in association with metachromatic material and is destroyed by heparitinase and blocked by an antibody to bFGF. After treatment of purified preparations with heparitinase, a component that is inactive alone but develops calciotropic activity in association with heparin can be isolated by affinity chromatography on heparin-Sepharose columns. This component is recovered from the column at NaCl concentrations expected to elute bFGF and is inactivated by antibodies to bFGF. No calciotropic activity can be shown in glycosaminoglycan-containing fractions from urine from a normal boy or a normal man, but such fractions exhibit calciotropic activity if bFGF is added to the assay system. When bFGF is added to urine from either normal subject followed by ion-exchange chromatography on DEAE-Sephacel, calciotropic activity is eluted at NaCl concentrations closely similar to those found to elute calciotropic activity from the urine of the NBS subject. It appears that the abnormal findings in NBS urine are due to excess bFGF, although they could be due to some abnormality of the glycosaminoglycan component.

Glucagon-induced hypocalcemia in the rat: effects of maturation and insulin.

Summary: In adults of several species including man, a small transient decrease in serum calcium concentration follows glucagon administration in doses of 1 to 10 mg/kg. The effects of maturation and insulin on this phenomenon were assessed by comparing the response of newborn and adult rats to equivalent doses of glucagon with and without prior insulin administration. After injection of 1 μg/g of glucagon, the decrease in serum calcium concentration at 60 min was significant in the newborn rats (-1.75 mg/dl; P < 0.001) and not significant in the intact adults (-0.07 mg/dl; P > 0.1).In pancreatomized adults, the decrease in serum calcium after the same dose of glucagon became significant (-1.23 mg/dl; P ≤ 0.01). This hypocalcemic effect was prevented in the pancreatectomized adult rat if insulin in a dose of 0.01 μg was given 15 min before glucagon. In the newborn rats, the same dose of insulin decreased the hypocalcemic effect, but the change was still significant (-0.74 mg/dl; P ≤ 0.01).Glucagon decreased serum calcium at one hr in newborn rats but not in adults. After pancreatectomy, the adult response to glucagon was significant and similar to that of the newborn. Insulin cancelled this effect of glucagon in the pancreatectomized adults and reduced it in the newborns.Speculation: Hypocalcemia in the neonatal period is a common and probably multifactorial disorder. Glucagon is known to be a hypocalcemic agent; this effect is decreased by insulin. Because insulin secretion is sluggish in the neonatal period, glucagon may have a clinically significant effect on serum calcium concentration at this time.The frequency and severity of hypocalcemia within the first 48 hr of life are increased by prematurity, perinatal trauma, hypoxia, and maternal diabetes (3,10). Functional hypoparathyroidism has been demonstrated in some of these situations (3,10), but not all instances of hypocalcemia can be explained on this basis (3). Inasmuch as neonatal hypocalcemia is evidently a multifactorial disorder, all agents capable of affecting calcium homeostasis deserve consideration. Glucagon can lower serum calcium concentration in a variety of mammals including man (2, 6–9, 11), but no studies of this phenomenon in the neonatal period have been reported. Grajwer el al. (5) have pointed out that a large increase in immunoreactive plasma glucagon occurs within the first two hr after delivery. Because the newborn infant is particularly susceptible to disturbances of calcium homeostasis, we designed the following experiments to test the effects of maturation on the response of serum calcium concentration to exogenous glucagon.

Neonatal Bone Mineral Uptake Is Measurably Affected by Local pH and Concentrations of Inorganic Phosphate, Ionized Calcium and Ionized Magnesium

Neonatal Bone Mineral Uptake Is Measurably Affected by Local pH and Concentrations of Inorganic Phosphate, Ionized Calcium and Ionized Magnesium

Calcium and Phosphorus Metabolism

During normal human pregnancy, the fetus accumulates approximately 30 g calcium and 24 g phosphorus, most of which is deposited in the skeleton, and is born with approximately 11 mg calcium and 5.6 mg phosphorus/dl serum. (36) These figures are independent of maternal intakes of calcium, phosphorus, and calciferol (“vitamin D”) over rather wide ranges. In the neonatal period, especially in premature infants, clinically significant fluctuations in serum calcium and phosphorus concentration are common. In this chapter, we shall discuss the factors that contribute to intrauterine stability and postpartum perturbations of calcium and phosphorus metabolism.