Amelioration of Polyuria in Nephrogenic Diabetes Insipidus Due to Aquaporin-2 Deficiency

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Title: Amelioration of Polyuria in Nephrogenic Diabetes Insipidus Due to Aquaporin-2 Deficiency
Authors: Hochberg, Ze'ev; Even, Lea; Danon, Abraham
Publisher: Clinical Endocrinology
Date Published: July 01, 1998
Reference Number: 444
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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.

This translation by the NDI Foundation is to assist the lay reader. To provide a clear, accessible interpretation of the original article, we eliminated or simplified some technical detail and complicated scientific language. We concentrated our translation on those aspects of the article dealing directly with NDI. The NDI Foundation thanks the researchers for their work toward understanding and more effectively treating this disorder.
© Copyright NDI Foundation 2007 (JC)

Hochberg, et al., studied the effect of a specific therapeutic regime on eight patients with nephrogenic diabetes insipidus caused by a mutation in their AQP2 gene. The patients were given a low-sodium diet in combination with hydrochlorothiazide. Four to 11 weeks later, ibuprofen, a nonsteroidal anti-inflammatory drug, was added to the therapeutic regime.

The low-sodium diet combined with hydrochlorothiazide alone decreased the patients' urinary output by an average of 31%. Adding ibuprofen to the regime decreased the output by an average of 38%. Measurements of the patients' plasma osmolality (a measure of the concentration of the osmotically active particles in the plasma) showed plasma osmolality decreased by an average of 15 mOsm/kg on the low-salt diet and hydrochlorothiazide, and by 22 mOsm/kg when ibuprofen was added. The patients' urinary osmolality increased from an average of 80 mOsm/kg to 96 mOsm/kg on low-sodium and hydrochlorothiazide alone. It increased to 146 mOsm/kg on the combination therapy.

These measures indicate that a combination of a low-salt diet, hydrochlorothiazide and ibuprofen is partially effective in reducing the excessive urination that is one of the primary symptoms of NDI.