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.


METHODS
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.


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 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.
Hochberg
Z
Z
Department of Pediatrics, Rambam Medical Center, Haifa, Israel. rprzeev@tx.technion.ac.il
Even
L
L
Danon
A
A
D015121:6-Ketoprostaglandin F1 alpha / Q000652:urine; D000328:Adult; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use; D051399:Aquaporin 2; D051403:Aquaporin 6; D020346:Aquaporins / Q000172:deficiency* / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D003131:Combined Modality Therapy; D003894:Deamino Arginine Vasopressin; D018500:Diabetes Insipidus, Nephrogenic / Q000178:diet therapy / Q000188:drug therapy / Q000209:etiology*; D004039:Diet, Sodium-Restricted; D015232:Dinoprostone / Q000652:urine; D004232:Diuretics / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D006852:Hydrochlorothiazide / Q000627:therapeutic use; D007052:Ibuprofen / Q000627:therapeutic use; D007223:Infant; D008297:Male; D009994:Osmolar Concentration; D011141:Polyuria / Q000178:diet therapy / Q000188:drug therapy / Q000209:etiology*; D014667:Vasopressins / Q000097:blood
C496023:AQP2 protein, human; D000894:Anti-Inflammatory Agents, Non-Steroidal; D051399:Aquaporin 2; D051403:Aquaporin 6; D020346:Aquaporins; D004232:Diuretics; D006852:Hydrochlorothiazide; D014667:Vasopressins; D015121:6-Ketoprostaglandin F1 alpha; D003894:Deamino Arginine Vasopressin; D015232:Dinoprostone; D007052:Ibuprofen