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

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Abstract
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 × 30 min intervals after desmopressin given in increasing doses of 5–100 μg. Urinary prostaglandins PGE2 and 6‐keto PGF1α, 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 μg/g creatinine (mean ± SD) compared to 5.0 ± 2.6 μg/g creatinine in AQP‐2 deficient patients (P < 0.05). Urinary 6‐keto PGF1α, was 0.20 ± 0.03 μg/g creatinine in controls and 0.75 ± 0.31 μg/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 PGF1α 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.