RESISTANCE TO FUROSEMIDE IN HYPERPROSTAGLANDIN E SYNDROME: EVIDENCE FOR A PROSTAGLANDIN-INDEPENDENT DEFECT IN THE LOOP OF HENLE. † 2162

Abstract

Hyperprostaglandin E syndrome (HPS), a prenatal variant of Bartter's syndrome, is characterized by impaired renal salt conservation and fetal polyuria leading to poly-hydramnios and premature birth. Moreover HPS mimics chronic furosemide treatment with isosthenuria, hypochloremia, hypercalciuria, hypokalemic alkalosis, and hyperaldosteronism. To date inadequate formation of PGE2 is considered to be a primary event in HPS. In a group of 9 children with HPS (median age 10.3, range 7.7 to 11.7 years) long-term indomethacin treatment sufficiently suppressed urinary excretion of PGE2 (54±18 to 5±2 ng/h/1.73m2) and corrected hyperreninemia, hyperaldosteronism and hyperkaliuria. However, renal loss of sodium chloride persisted (2.8±0.4 to 3.3±0.3 and 3.2±0.2 to 3.0±0.4 mmol/kg/d, resp.) and the children still remained isosthenuric (227±18 to 270±18 mosmol/kg). In addition polyuria, hypercalciuria and hypermagnesiuria were improved only partially. These observations indicate a tubular defect independent of renal PGE2 release. To study the capacity of electrolyte reabsorption in the thick ascending limb of Henle's loop (TALH), furosemide was administered to the patients 7 days after interruption of indomethacin treatment. Compared to a group of 13 healthy children (median age 10.2, range 6.4 to 15.1 years) patients with HPS presented a marked resistance to the loop diuretic. Data were obtained from 3-hour urine collections subsequent to a single oral dose of 2 mg/kg furosemide (means ± SEM; *p<0.05) We conclude that a prostaglandin-independent defect of furosemide-sensitive salt reabsorption in the TALH plays a major pathophysiological role in renal dysfunction of HPS.Table