Treatment of Nephrogenic Diabetes Insipidus with Hydrochlorothiazide and Amiloride

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 inhibitors (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 hydrochlorothiazide/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 hydrochlorothiazide/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. In polyuria with low urinary osmolality, a dehy- addition, salt restriction was recommended but dration test with subsequent DDAVP admini- a specific diet was not required. We instructed stration was performed and the diagnosis of the parents to take care that the children NDI was established. The patient was first received a generous fluid supply, especially treated with hydrochlorothiazide and at the age during early childhood. In case of vomiting, of 14 months amiloride was added. The boy’s diarrhoea, refusal of fluid intake, or fever, the development is satisfactory and no electrolyte parents were told to contact us immediately. imbalance has been noticed since then. We routinely checked height, weight, and serum concentrations of electrolytes, uric acid, Case 4 and creatinine several times each year. Bone This patient is a girl of 7 years and 7 months, age was determined annually according to the sister of case 1. Pregnancy and delivery were method of Greulich and Pyle.16 550 Kirchlechner, Koller, Seidl, Waldhauser

Age (years) Age (years) Arch Dis Child: first published as 10.1136/adc.80.6.548 on 1 June 1999. Downloaded from A 78645321 109 1112131415161718 B 78645321 109 1112131415161718

Centiles Centiles Height (cm) Body height, 97 Height (cm) 190 Body height, 97 190 90 90 170 girls 1–18 years 75 170 boys 1–18 years 75 50 180 50 180 160 25 160 25 Case 4 10 170 Case 1 10 170 3 Case 2 3 150 % 150 160 Case 3 160 140 140 150 140 130 140 120 90 130 90

Height (cm) 110 80 120 80 Height (cm) 100 70 110 70 Weight (kg) Weight (kg) 100 90 60 60 90 80 50 50 80 70 40 70 40 30 30

20 20 20 20 Body weight Body weight 10 10 10 10 Weight (kg) Weight 0 0 (kg) Weight 0 0 321 78645 109 1112131415161718 321 78645 109 1112131415161718 Age (years) Age (years) Figure 1 Length and weight charts for one girl (A) and three boys (B) with nephrogenic diabetes insipidus.

During the last year, we performed 24 hour and creatinine, 0.41 (0.10) mg/l (n = 15; nor- fluid balance, ultrasonic examination of the mal range, 0.2–0.8). Each individual value was kidney and the urinary tract, cranial computer within the specified normal range. tomography (CT), and investigation of psycho- However, 24 hour urine volumes were motoric development in each patient. substantially increased to 2.2–7.4 l/m2/day (normal range, 0.9–1.0 l/m2/day)21 (table 2). Every patient suVered either from enuresis Results nocturna or nocturia (cases 1 and 4). At a SOMATIC DEVELOPMENT sonographic examination, three of four chil- The patients all demonstrated adequate growth dren showed a regular kidney image without and weight gain (fig 1), with minor delay in signs of a non-obstructive urinary tract dilata- http://adc.bmj.com/ bone maturation (table 2). tion. However, in case 1, first signs of hydronephrosis grade 1 with normal morphology of the NEUROLOGICAL AND MENTAL DEVELOPMENT kidney were detected at the age of 4 years and Three of the four patients showed normal psy- 8 months. He was also the patient with the chomotor development; only one (case 1) highest urine production (7.4 l/m2/day). Exag- displayed discrete signs of motor retardation— gerated urine flow has been repeatedly re- walking at the age of 18 months, mild muscu- ported as a cause of urinary tract dilatation.45 lar hypotony, and delay in coordination. on September 28, 2021 by guest. Protected copyright. All the patients demonstrated a normal cra- HOSPITALISATION nial CT scan, and in particular, no signs of After starting treatment with hydrochloro- intracerebral calcifications were detectable as thiazide/amiloride, the children were admitted described after hypertonic dehydration.17–20 to our hospital three times over a period of 14.5 years of treatment (case 1 once, case 2 twice, FLUID AND ELECTROLYTE BALANCE cases 3 and 4 not admitted). The admissions Mean (SD) serum concentrations of repeated were required because of febrile infections, measurements at the routine checks outlined diarrhoea, or refusal of fluid intake; even in were as follows: sodium, 139.5 (2.6) mmol/l these situations neither severe dehydration nor (n = 32; normal range, 135–147); potassium, electrolyte imbalance was observed. The treat- 4.1 (0.6) mmol/l (n = 32; normal range, 3.4– ment of the patients was limited to intravenous 5.4); chloride, 101.9 (3.4) mmol/l (n = 32; fluid substitution, tube feeding, and control of normal range, 95–112); uric acid, 4.1 fluid and electrolyte balance. Almost all the (1.0) mg/l (n = 23; normal range, 2.0–6.2); admissions occurred during the 1st year of life,

Table 2 Clinical features of patients while on treatment with hydrochlorothiazide and amiloroide

Fluid intake Urine volume Serum* sodium Serum* potassium Body* Body* height Case Age* Bone* age (l/m2/day) (l/m2/day) (mmol/l) (mmol/l) weight (kg) (cm) 1 4 y 10 m 4 y 3 m 7.7 7.4 139 3.0 15.7 102.0 2 1 y 8m 1 y 1 m 4.0 3.3 145 4.7 10.2 83.1 3 5 y 11 m 6 y 5.9 3.5 140 3.6 21.3 113.5 4 7 y 7 m 8 y 3.8 2.2 141 3.3 22.6 125.0

*At last examination. Treatment of nephrogenic diabetes insipidus 551

because infants are very sensitive to fluid loss urinary tract (that is, hydronephrosis, megau- and the oral administration of fluid may be reter) is regarded as a consequence of Arch Dis Child: first published as 10.1136/adc.80.6.548 on 1 June 1999. Downloaded from extremely diYcult at that age. excessive urine production.45 We have never observed the known side SIDE EFFECTS eVects of monotherapy with hydrochloro- No adverse eVects as a result of the treatment thiazide, such as hypokalaemia or with hydrochlorothiazide/amiloride were re- hyperuricaemia,7 or of the combination ported, either by the patients or their parents. hydrochlorothiazide/indomethacin, such as Repeated medical examinations did not reveal renal or gastrointestinal complications.11 So any adverse reactions either. far, the morbidity of our children has been relatively low and the admissions mentioned Discussion have been of short duration and somewhat As demonstrated by the growth charts (fig 1), prophylactic, to avoid dehydration. long term treatment with hydrochlorothiazide/ During the past few years, knowledge of the amiloride resulted in normal growth and there pathophysiology and genetics of NDI has was normal bone maturation in our patients increased remarkably. In healthy subjects, AVP with NDI (table 2). Only one patient (case 1) acts to increase the permeability of the luminal showed height and weight development at the membrane in the collecting ducts to water by third centile. In inadequately treated patients insertion of water channels (aquaporine 2) via with NDI, failure of normal growth has been V2 receptors by means of a cAMP dependent frequently seen and attributed to reduced mechanism. This permits the water to flow by intake of solid food because of very high fluid passive diVusion from the tubule into the consumption.222 hypertonic medullary interstitium in the kid- None of the children presented with intra- ney, and the urine can be concentrated. AVP cerebral calcifications or seizures. Psychomotor induces incorporation of aquaporine 2 into the development was also within the normal range membrane via coated pits, as well as recycling and only one patient (case 1) suVered from via coated vesicles. Unresponsiveness to AVP discrete motor deficiencies. Intracerebral calci- or a deficiency of AVP results in impaired fications and seizures have been noticed incorporation and recycling of water, which repeatedly in NDI. They have been ascribed to means that water channels are stored in endothelial injuries caused by hypertonic cytoplasmatic vesicles.27–29 Patients with NDI dehydration occurring particularly during in- may have one of two defects, either a V2 recep- fancy, when the patients are not able to tor defect (X chromosomal recessive)30–32 or compensate for fluid losses by themselves.17–20 rarely an aquaporine 2 defect (autosomal In less recent studies, especially, psychologi- recessive).14 33 34 In both cases, the clinical cal disturbances and mental retardation were symptoms are alike and there is still no causal reported repeatedly in children with NDI.23 24 treatment available.1

A causal association with recurrent dehydra- In conclusion, long term treatment of our http://adc.bmj.com/ tion, electrolyte shift, and consequent endothe- patients with NDI with hydrochlorothiazide/ lial damage was assumed.23 25 Alternatively, the amiloride has resulted in normal growth and permanent requirement for drinking and void- normal mental development. Furthermore, the ing may lead per se to reduced periods of treatment seems to be more eVective and better undisturbed concentration and placid behav- tolerated than just hydrochlorothiazide. Its iour in playing and social integration. Because eYcacy appears to be similar to that of retardation appears to be most prominent in hydrochlorothiazide/indomethacin, without

the first 2 years of life and it can be caught up the severe side eVects reported with this on September 28, 2021 by guest. Protected copyright. later in childhood, electrolyte imbalance with combination. Urinary volume can be reduced its sequelae may play a more important role in but not to normal volumes; thus, polyuria and the development of these symptoms. Interest- polydipsia will continue, but in a less intensive ingly, in more recent studies, mental retarda- form than in untreated patients. tion is being described less frequently, which might be the result of improvement in 24 The authors thank Dr EH Hoefsloot, University Hospital treatment modalities. Nijmegen, for performance of the DNA analysis in case 2. After starting treatment with hydrochlorothiazide/amiloride, none of our patients 1 Bichet DG, Oksche A, Rosenthal W. Congenital nephro- showed any signs of dehydration. Fluid intake genic diabetes insipidus. J Am Soc Nephrol 1997;8:1951–8. 2 Knoers N, Monnens LA. Nephrogenic diabetes insipidus: and urine output, however, were very high and clinical symptoms, pathogenesis, genetics and treatment. the children had to consume fluid during the Pediatr Nephrol 1992;6:476–82. 3 Reeves WB, Andreoli TE. Nephrogenic diabetes insipidus. night. All suVered either from enuresis In: Scriver, CR, Beaudet AL, Sly WS, Valle D, eds. The nocturna or nocturia. The amount of urine metabolic and molecular bases of inherited disease. New York: 2 McGraw Hill 1995:3045–71. produced by our patients (2.2–7.4 l/m /day) 4 Stevens S, Brown BD, McGahan JP. Nephrogenic diabetes was similar to the quantities reported by insipidus: a cause of severe nonobstructive urinary tract 11 12 dilatation. J Ultrasound Med 1995;14:543–5. others and for patients treated with 5 Uribarri J, Kaskas M. Hereditary nephrogenic diabetes hydrochlorothiazide/indomethacin.26 Despite insipidus and bilateral nonobstructive hydronephrosis. Nephron 1993;65:346–9. this large fluid turnover, normal energy intake 6 Crawford JD, Kennedy GC. Chlorothiazide in diabetes with adequate growth and weight gain were insipidus. Nature 1959;183:891–2. 7 Morgan DB, Davidson C. Hypokalaemia and diuretics: an obviously attainable (fig 1). Only one child analysis of publications. BMJ 1980;280:905–8. (case 1) displayed signs of mild hydro- 8 McMahon FG, Ryan JR, Akdamar K, Ertan A. Upper nephrosis at the age of 4.5 years. In patients gastrointestinal lesions after potassium chloride supplements: a controlled clinical trial. Lancet 1982;2: with NDI, non-obstructive dilatation of the 1059–61. 552 Kirchlechner, Koller, Seidl, Waldhauser

9 Monn E. Prostaglandin synthetase inhibitors in the 22 Knoers N, van Lieburg AF, Monnens LA, Van Oost BA,

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