548 Arch Dis Child 1999;80:548–552 Treatment of nephrogenic diabetes insipidus with Arch Dis Child: first published as 10.1136/adc.80.6.548 on 1 June 1999. Downloaded from hydrochlorothiazide and amiloride Veronika Kirchlechner, Dieter Y Koller, Reiner Seidl, Franz Waldhauser Abstract Treatment of NDI focuses on the reduction Nephrogenic diabetes insipidus (NDI) is of polyuria to avoid dehydration and hypernat- characterised by the inability of the raemia and therefore on prevention of early kidney to concentrate urine in response to and late onset complications. In 1959, Craw- arginine vasopressin. The consequences ford and Kennedy introduced hydrochlorothi- are severe polyuria and polydipsia, often azide combined with a low sodium intake in the 6 associated with hypertonic dehydration. treatment of NDI, by which a reduction of the Intracerebral calcification, seizures, psy- urine solute load of 20–50% can be expected. chosomatic retardation, hydronephrosis, Long term treatment with hydrochlorothi- and hydroureters are its sequelae. In this azide, however, frequently results in 7 study, four children with NDI were treated hypokalaemia associated with cardiac arrhyth- with 3 mg/kg/day hydrochlorothiazide and mias. Potassium intake itself, required to prevent hypokalaemia, may result in gastro- 0.3 mg/kg/day amiloride orally three times 8 a day for up to five years. While undergo- intestinal complications. ing treatment, none of the patients had In the 1980s, prostaglandin synthesis inhibi- tors (such as indomethacin) were introduced in signs of dehydration or electrolyte imbal- the treatment of NDI. The combination of ance, all showed normal body growth, and indomethacin/hydrochlorothiazide has been there was no evidence of cerebral calcifi- described as being even more eVective than cation or seizures. All but one had normal indomethacin alone in diminishing urine pro- psychomotor development and normal duction by 50–70%.910 However, hypokalae- sonography of the urinary tract. However, mia must still be expected, as well as other normal fluid balance was not attainable severe adverse eVects induced by indometh- (fluid intake, 3.8–7.7 l/m2/day; urine out- 2 acin, such as renal, gastrointestinal, and put, 2.2–7.4 l/m /day). The treatment was haematopoetic complications.11 well tolerated and no side eVects could be Studies by Alon and Chan12 and Knoers and detected. Prolonged treatment with Monnens11 showed that the combination of hydrochlorothiazide/amiloride appears to hydrochlorothiazide/amiloride is as eVective as http://adc.bmj.com/ be more eVective and better tolerated than the previous combination. In addition, no just hydrochlorothiazide. Its eYcacy ap- potassium intake is necessary and patients do pears to be similar to that of not need to suVer the side eVects of indometh- hydrochlorothiazide/indomethacin but acin. without their severe side eVects. However, there is no experience with long (Arch Dis Child 1999;80:548–552) term usage of the combination hydro- chlorothiazide/amiloride in the treatment Keywords: hydrochlorothiazide; amiloride; of NDI.11 13 Here, we describe four children on September 28, 2021 by guest. Protected copyright. nephrogenic diabetes insipidus; long term treatment with NDI being treated with hydrochloro- thiazide/amiloride over a period of one to five Nephrogenic diabetes insipidus (NDI) is a rare years. inherited disease characterised by the failure of the kidney to respond to arginine vasopressin Patients and methods (AVP) because of a receptor or postreceptor PATIENTS defect, despite raised serum concentrations of 1 Case 1 AVP. As a consequence, the kidney produces A boy (currently 4 years and 9 months old) enormous quantities of hypotonic urine. Thus, was admitted to our clinic at the age of 2 patients with NDI have dramatic polyuria and months. Pregnancy and delivery were un- polydipsia, and any episode of additional water eventful, birth weight 3404 g, and birth length Department of loss (fever, diarrhoea, vomiting) may lead to 54 cm. The patient’s history consisted of Pediatrics, University potential life threatening dehydration and polyuria, lack of weight gain, refusal of oral of Vienna, Währinger hypernatraemia, especially in infants and tod- fluid intake, and vomiting. In another hospital, Gürtel 18–20, A-1090 dlers. A strong relation between repeated NDI was suspected and treatment with hydro- Vienna, Austria episodes of hypernatraemic dehydration and V Kirchlechner chlorothiazide initiated. Because of ongoing mental retardation, seizures, and cerebral vomiting the patient was admitted to our D Y Koller 23 R Seidl calcifications has been documented. Fur- department. After discontinuation of hydro- F Waldhauser thermore, the course of NDI may also be com- chlorothiazide we found hypernatraemia, plicated by dilatation of the urinary tract owing polyuria, and decreased urinary osmolality. Correspondence to: to excessive urine production45and by growth The diagnosis was confirmed by fluid restric- Dr Waldhauser. failure, which is thought to be caused by inad- tion and 1-desamino-8-D-arginine vaso- Accepted 9 February 1999 equate energy intake.2 pressin (DDAVP) administration (table 1). Treatment of nephrogenic diabetes insipidus 549 Table 1 Clinical features of patients before treatment with hydrochlorothiazide and amiloroide Arch Dis Child: first published as 10.1136/adc.80.6.548 on 1 June 1999. Downloaded from Serum Serum 24hurine 24 h urine Urine osmolality Urine osmolality Age* sodium potassium volume osmolality before DDAVP after DDAVP Plasma AVP Genetic mutation of V2 receptor Case (months) (mmol/l) (mmol/l) (ml/kg bw) (mmol/l) (mmol/l) (mmol/l) (pg/ml)†‡ gene 1 6 161 4.7 384 83 128 135 3.25 2 5 160 4.7 360 89 190 210 Point mutation ( T975 →A) 3 14 166 6.1 432 118 64 152 3.0 Point mutation ( T727 →G)14 4 33 145 5.8 336 82 82 105 3.1 Point mutation ( T727 →G)14 *At onset of treatment. †While normally rehydrated. ‡Reference values mean (SD) 1.1 (0.6) pg/ml.15 Treatment with hydrochlorothiazide was re- uneventful, birth weight 3090 g, and birth sumed. In the following months, several length 50 cm. At 10 days of age the girl was episodes of fluid refusal and vomiting occurred admitted to another hospital because of and once even hypernatraemia (161 mmol/l) diarrhoea and hypertonic dehydration. Blood and hypokalaemia (2.2 mmol/l) were noticed. culture revealed infection with Escherichia coli Thus, at the age of 6 months amiloride was and antibiotics were administered. Two years added to the treatment. Subsequent examina- later, after delivery of her brother and his diag- tions revealed minor abnormalities (for details nosis of NDI, detailed re-examination for the see below). occurrence of NDI was performed. At normal serum electrolyte concentrations and normal Case 2 serum osmolality, polyuria, and polydipsia with The second patient is a boy who is currently 1 low urinary osmolality (82 mmol/l) were iden- year and 8 months old. He was delivered by tified. Because neither fluid restriction nor caesarean section because of inadequate labour DDAVP resulted in an increase in urine osmo- at 38 weeks of gestation, with a birth weight of lality, the diagnosis of NDI was established and 4148 g and a birth length of 54 cm; parents are confirmed by genetic analysis (table 1).14 not consanguineous. The patient’s history con- After treatment with hydrochlorothiazide for sisted of screaming attacks, agitation, and fever six months, amiloride was added owing to per- from the 2nd day of life. Further examinations sistent hypokalaemia. Since that time, serum revealed hypernatraemia and increased serum electrolyte concentrations have been in the osmolality. After diagnosis of NDI in another normal range continuously and she has shown hospital, treatment with indomethacin was ini- normal growth and weight gain. tiated. However, at the age of two months the boy was admitted to our hospital because of fever and fluid refusal. After discontinuation of METHODS treatment and subsequent fluid restriction, the Diagnosis of NDI diagnosis of NDI was confirmed owing to a After two 24 hour urine collections and assess- lack of response to DDAVP (table 1). Thereaf- ment of fluid intake, fluid was restricted for a ter, treatment with hydrochlorothiazide was period of four to eight hours followed by intra- http://adc.bmj.com/ initiated and amiloride was added at the age of venous application of DDAVP (1 µg for infants 5 months. During the 1st year of life the patient and 2 µg for toddlers). We determined urine had been hospitalised twice as a result of vom- volume and osmolality, as well as serum iting without electrolyte imbalance. His growth electrolyte concentrations and osmolality, be- and weight gain are adequate. fore and after administration of DDAVP (table 1). Case 3 At well hydrated conditions blood was drawn This boy is now 5 years and 11 months old. for the assessment of AVP by means of a on September 28, 2021 by guest. Protected copyright. Pregnancy and delivery were uneventful, birth recently published radioimmunoassay.15 weight 3190 g, and birth length 50 cm. At the Analysis of the vasopressin type 2 (V2) age of 10 days he was first admitted to our hos- receptor gene was performed at the depart- pital because of fever, diarrhoea, and hyper- ment of human genetics, University Children´s tonic dehydration, with a serum sodium Hospital, Nijmegen, the Netherlands.14 concentration of 166 mmol/l, potassium of 6.1 mmol/l, and serum osmolality of 357 mmol/l, whereas urinary osmolality was Treatment and follow up only 64 mmol/l. Despite these data, polyuria For a period of one to five years, we treated the was noticed. Diabetes insipidus centralis was four patients with NDI with a combination of suspected and treatment with DDAVP initi- hydrochlorothiazide (3 mg/kg/day) and amilo- ated. Because the boy continued to suVer from ride (0.3 mg/kg/day) orally three times a day.