IMPAIRED RESPONSE TO FUROSEMIDE IN HYPERPROSTAGLANDIN-E SYNDROME - EVIDENCE FOR A TUBULAR DEFECT IN THE LOOP OF HENLE

In hyperprostaglandin E syndrome (HPS) renal wasting of electrolytes a nd water is consistently associated with enhanced synthesis of prostag landin Ep. In contrast to Bartter or Gitelman syndrome (BS/GS), HPS is characterized by its severe prenatal manifestation, leading to fetal polyuria, development of polyhydramnios, and premature birth. This dis order mimics furosemide treatment with hypokalemic alkalosis, hypochlo remia, isosthenuria, and impaired renal conservation of both calcium a nd magnesium. Therefore the thick ascending limb of the loop of Henle seems to be involved in HPS. To characterize the tubular defect we inv estigated the response to furosemide (2 mg/kg) in HPS (n = 8) and BS/G S (n = 3) 1 week after discontinuation of long-term indomethacin treat ment. Sensitivity to furosemide was completely maintained in patients with BS/GS. The diuretic, saluretic, and hormonal responses were simil ar to those of a control group of healthy children (n = 13), indicatin g an intact function of the thick ascending limb of the loop of Henle in BS/GS. In contrast, patients with HPS had a marked resistance to th is loop diuretic. Furosemide treatment increased urine output by 7.5 /- 0.7 ml/kg per hour in healthy control subjects but only by 4.4 +/- 1.2 ml/kg per hour (p < 0.5) in children with HPS. In parallel, the la tter also had a markedly impaired saluretic response (Delta Cl-urine, 0.14 +/- 0.04 mmol/kg per hour vs 0.85 +/- 0.09 mmol/kg per hour, p < 0.001; Delta Na-urine 0.23 +/- 0.06 mmol/kg per hour vs 0.77 +/- 0.09 mmol/kg per hour, p < 0.001). Furosemide therapy further enhanced pros taglandin E(2) excretion in patients with HPS (54 +/- 17 to 107 +/- 28 ng/hr per 1.73 m(2), p < 0.05), whereas no significant effect was obs erved in healthy children (20 +/- 3 to 12 +/- 3 ng/hr per 1.73 m(2)). We conclude that a defect of electrolyte reabsorption in the thick asc ending limb of the loop of Henle plays a major role in HPS.