1998 Global Conference Proceeding
March 02 - 04, 1998
| Conference: | 1998 Global Conference |
|---|---|
| Title: | Amelioration of Polyuria in Nephrogenic Diabetes Insipidus due to Aquaporin-2 Deficiency |
| Author: | Hochberg, Ze'ev |
| Institution: | Rambam Medical Center |
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. The present report describes the clinical manifestations and evaluation of therapeutic approaches to this new entity of AQP-2 deficiency.
Patients & Design: Nine patients with an AQP-2 mutation were studied. Desmopressin was given nasally to two patients in increasing doses from 5-100 µg. Urine osmolality was measured in five patients before and at 3 x 30 min. fractions after desmopressin given in increasing doses of 5-100 µg. Urinary prostaglandins PGE2 and 6-keto PGF1a, were extracted from 24-hour urine and estimated by radioimmunoassays. Eight NDI patients were given a combination of 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. cr. (mean ± SD) compared to 5.0 ± 2.6 µg/g. cr. in AQP-2 deficient patients (p<0.05). Urinary 6-keto PGF1a, was 0.20 ± 0.03 µg/g. cr. in controls and 0.75 ± 0.31 µg/g. cr. in AQP-2 deficiency (p<0.05). Urinary volumes decreased by a mean 31 % on low salt diet and hydrochlorothiazide, and by a mean 38% on the combination therapy. Plasma osmolality decreased by a mean 15 mOsm/kg on 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 low salt diet and hydrochlorothiazide, and to 146 mOsm/kg on the combination therapy.
Conclusions: 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 PGF1a are elevated, with the former being extremely high, apparently due to the extreme vasopressin unresponsiveness. Combination therapy with low salt diet, thiazide and NSAID is partially effective.
Nephrogenic diabetes insipidus (NDI) can also be caused by mutations in the gene that encodes the water-transporting protein called aquaporin-2 (AQP-2). In this report, nine patients with an AQP-2 mutation were studied to see if certain therapeutic approaches were effective. Seven of the patients were treated with desmopressin. Eight of the patients were given a combination of a low sodium diet and the drug hydrochlorothiazide. Four to 11 weeks later, another drug, ibuprofen, was added to the treatment regime. Urine concentration, volume and chemistry, and blood plasma concentration were the variables tested to measure treatment effectiveness.
Desmopressin had no therapeutic effect on urine concentration. However, the variables showed a positive, if partial, response to the low sodium diet and hydrochlorthiazide, and a slightly higher response when ibuprofen was added to the treatment. The study further confirmed the importance of AQP-2 in proper kidney function.