Nephrogenic Diabetes Insipidus Treatment with Hydrochlorothiazide and Amiloride

Nephrogenic diabetes insipidus (NDI) is characterised by the inability of the kidney to concentrate urine in response to arginine vasopressin. The consequences are severe polyuria and polydipsia, often associated with hypertonic dehydration. Intracerebral calcification, seizures, psychosomatic retardation, hydronephrosis, and hydroureters are its sequelae.

In this study, four children with NDI were treated with 3 mg/kg/day hydrochlorothiazide and 0.3 mg/kg/day amiloride orally three times a day for up to five years. While undergoing treatment, none of the patients had signs of dehydration or electrolyte imbalance, all showed normal body growth, and there was no evidence of cerebral calcification or seizures. All but one had normal psychomotor development and normal sonography of the urinary tract.

However, normal fluid balance was not attainable (fluid intake, 3.8–7.7 l/m 2/day; urine output, 2.2–7.4 l/m 2/day). The treatment was well tolerated and no side effects could be detected. Prolonged treatment with hydrochlorothiazide/amiloride appears to be more effective and better tolerated than just hydrochlorothiazide. It appears to be similar to that ofhydrochlorothiazide / indomethacin but without their severe side effects.

During the past few years, knowledge of the pathophysiology and genetics of NDI has increased remarkably. In healthy subjects, AVP acts to increase the permeability of the luminal membrane in the collecting ducts to water by insertion of water channels (aquaporine 2) via V2 receptors by means of a cAMP dependent mechanism. This permits the water to flow by passive diVusion from the tubule into the hypertonic medullary interstitium in the kidney, and the urine can be concentrated.

AVP induces incorporation of aquaporine 2 into the membrane via coated pits, as well as recycling via coated vesicles. Unresponsiveness to AVP or a deficiency of AVP results in impaired incorporation and recycling of water, which means that water channels are stored in cytoplasmatic vesicles. Patients with NDI may have one of two defects, either a V2 receptor defect (X chromosomal recessive) or rarely an aquaporine 2 defect (autosomal recessive).

In conclusion, long term treatment of our patients with NDI with hydrochlorothiazide/ amiloride has resulted in normal growth and normal mental development. Furthermore, the treatment seems to be more effective and better tolerated than just hydrochlorothiazide. Urinary volume can be reduced but not to normal volumes; thus, polyuria and polydipsia will continue, but in a less intensive form than in untreated patients.