Amelioration of polyuria in nephrogenic diabetes insipidus due to aquaporin-2 deficiency

OBJECTIVE We have recently reported a large cluster of patients with nephrogenic diabetes insipidus (NDI) due to an autosomal recessive aquaporin-2 (AQP-2) early-stop codon, This paper describes the clinical manifestations and evaluation of therapeutic approaches to this new entity. PATIENTS AND DESIGN Nine patients with an AQP-2 mutation were studied. Urine osmolality was measured in five patients before and at 3x30min intervals after desmopressin given in increasing doses of 5-100 mu g. Urinary prostaglandins PGE(2) and B-keto PGF(1 alpha), were extracted from 24-h urine samples and estimated by radioimmunoassays. Eight NDI patients were given a combination of a low-sodium diet and hydrochlorothiazide, Four to 11 weeks later, ibuprofen was added, and the patients were retested within the following 4-9 weeks. RESULTS Urine osmolality remained unchanged after supra-pharmacological doses of desmopressin, at 60-70mOsm/kg. Urinary PGE(2) in control subjects was 0.74 +/- 0.1 mu g/g creatinine (mean +/- SD) compared to 5 0 +/- 2 6 mu g/g creatinine in AQP-2 deficient patients (P<0.05). Urinary 6-keto PGF(1 alpha), was 0.20 +/- 0.03 mu g/g creatinine in controls and 0.75 +/- 0.31 mu g/g creatinine in AQP-2 deficiency (P<0 05). Urinary volumes decreased by a mean 31% on a low-salt diet and hydrochlorothiazide, and by a mean of 38% on the combination therapy. Plasma osmolality decreased by a mean 15 mOsm/kg on the low-salt diet and hydrochlorothiazide, and by 22 mOsm/kg on the combination therapy, Urinary osmolality increased from a mean 80mOsm/kg to 96mOsm/kg on the low-salt diet and hydrochlorothiazide, and to 146 mOsm/kg on the combination therapy. CONCLUSION AQP-2 deficiency in these patients with an early-stop codon is associated with complete unresponsiveness of the collecting duct to vasopressin, implying an indispensable role for AQP-2 in vasopressin antidiuresis, Urinary PGE(2) and 6-keto PGF(1 alpha) are elevated, the former being extremely high, apparently due to the extreme vasopressin unresponsiveness. Combination therapy with a combination of a low-salt diet, thiazide and non-steroidal anti-inflammatory drug is partially effective.