Calcium homeostasis and hypercalciuria in hyperprostaglandin E syndrome

Children with hyperprostaglandin E syndrome, a neonatal variant of Bartter syndrome with enhanced renal and systemic formation of prostaglandin E2, have hypercalciuria, nephrocalcinosis, and osteopenia. Because prostaglandin E2 affects tubular calcium handling, stimulates the formation of calcitriol in vitro, and has osteolytic activity, we studied calcium homeostasis and the influence of prostaglandin E2 formation on hypercalciuria in nine patients with hyperprostaglandin E syndrome during long-term indomethacin treatment and after its withdrawal. Suppression of prostaglandin E2 formation by indomethacin resulted in improvement of biochemical and clinical features of hyperprostaglandin E syndrome. However, hypercalciuria, osteopenia, and nephrocalcinosis did not completely resolve. Despite a low calcium diet, daily urinary calcium excretion was enhanced during and after withdrawal of indomethacin treatment (median 6.3, range 5.3 to 14, and median 9.4, range 4.4 to 38 mg/kg per day, respectively). Daily urinary calcium excretion was greater after withdrawal than during indomethacin treatment. Urinary calcium excretion was not correlated with urinary prostaglandin E2 excretion. Plasma levels of intact parathyroid hormone (median 11, range 6.8 to 12 pmol/L) and calcitriol (median 157, range 108 to 236 pg/ml) were elevated during indomethacin treatment and decreased after withdrawal of indomethacin. These data suggest that hypercalciuria in hyperprostaglandin E syndrome is mainly due to a renal leak of calcium, which is caused by enhanced renal formation of prostaglandin E2 and a tubular defect not related to prostaglandin E2 formation. There is no evidence for prostaglandin-stimulated calcitriol formation. Decreasing plasma levels of parathyroid hormone in the presence of renal calcium losses after withdrawal of indomethacin treatment may be due to a bone resorption process caused by systemic prostaglandin formation; the process may contribute to hypercalciuria in the patient not receiving indomethacin.