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 3 x 30 min intervals after desmopressin given in increasing doses of 5-100 micrograms. Urinary prostaglandins PGE2 and 6-keto PGF1 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 60-70 mOsm/kg. Urinary PGE2 in control subjects was 0.74 +/- 0.1 microgram/g creatinine (mean +/- SD) compared to 5.0 +/- 2.6 micrograms/g creatinine in AQP-2 deficient patients (P < 0.05). Urinary 6-keto PGF1 alpha, was 0.20 +/- 0.03 microgram/g creatinine in controls and 0.75 +/- 0.31 microgram/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 80 mOsm/kg to 96 mOsm/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 PGE2 and 6-keto PGF1 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.