Treatment of Nephrogenic Diabetes Insipidus with Hydrochlorothiazide and Amiloride

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Title: Treatment of Nephrogenic Diabetes Insipidus with Hydrochlorothiazide and Amiloride
Authors: Kirchlechner, Veronika; Koller, Dieter Y.; Seidl, Reiner; Waldhauser, Franz
Publisher: Archives of Disease in Childhood
Date Published: June 01, 1999
Reference Number: 480
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Abstract • Article • Translation
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/m2/day; urine output, 2.2-7.4 l/m2/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. Its efficacy appears to be similar to that of hydrochlorothiazide/indomethacin but without their severe side effects.
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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)

Nephrogenic diabetes insipidus (NDI) is a rare disease characterized by the kidneys' inability to concentrate urine in a response to the antidiuretic hormone, arginine vasopressin (AVP). As a result, the NDI patient experiences polyuria (chronic passage of large volumes of urine) and polydipsia (chronic excessive thirst). NDI may either be inherited or acquired. When it is inherited, its symptoms manifest in the first days of life. They include, in addition to polyuria and polydipsia, irritability, fever, failure to thrive, constipation, and sometimes anorexia. If NDI goes unrecognized and untreated, the excessive urination could result in severe dehydration and high blood levels of sodium. This could lead to mental and physical retardation, seizures, calcification of brain tissues and even death. Fortunately, knowledge of congenital NDI has advanced, and early diagnosis and treatment, consisting of adequate water supplies, low sodium diets and medications which reduce the patient's polyuria are drastically reducing the incidence of severe consequences of untreated NDI.

One of the first medications used to treat NDI patients was hydrochlorothiazide. It reduces urine output by 20 to 50 percent. However, long-term treatment with hydrochlorothiazide alone results in low blood levels of potassium. Thus, potassium supplementation is required with hydrochlorothiazide, but taking the necessary levels of potassium can result in gastrointestinal complications.

Later, prostaglandin synthesis inhibitors such as indomethacin were combined with hydrochlorothiazide. This combination reduces urine output 50 to 70 percent. However, NDI patients taking this combination still lose excessive amounts of potassium and in addition, can experience complications in the gastrointestinal tract, kidney, and in the formation and development of blood cells.

A more promising pharmaceutical treatment of NDI is a combination of hydrochlorothiazide and amiloride. This is as effective as the hydrochlorothiazide/indomethacin combination but eliminates the need for potassium supplementation and does not induce the side effects indomethacin does.

To test the long-term effects of hydrochlorothiazide/amiloride, Kirchlechner, et al., treated four NDI patients over a period of one to five years. While undergoing treatment, no patients experienced dehydration or electrolyte imbalances, seizures or calcification of brain tissues, and all showed normal body growth.

One patient displayed discrete signs of motor retardation: not walking until 18 months, diminished tone in the skeletal muscles and delay in coordination. This same patient also showed a mild distention of his kidney. The other three subjects showed normal psychomotor development and had no distention of the kidney. Though the patients' urine production was reduced, they continued to experience greater than normal urine output and liquid intake. In short, prolonged treatment with hydrochlorothiazide/amiloride was well tolerated, had no side effects and was as effective as the hydrochlorothiazide/indomethacin combination.