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Home , Diabetes insipidus, Drinking, Fluid deprivation test, Primary polydipsia

84 Arch Dis Child 1998;79:84–89

CURRENT TOPIC Arch Dis Child: first published as 10.1136/adc.79.1.84 on 1 July 1998. Downloaded from

Diabetes insipidus

Peter H Baylis, Tim Cheetham

Over the past two decades our understanding basal aspect of the renal collecting tubular cell of the mechanisms that control balance to activate an adenyl cyclase system that stimu- in health and has increased substan- lates intracellular protein kinases. These, in tially. Following the establishment of reliable turn, control the arrangement and insertion of assay techniques to measure circulating vaso- “water channel” proteins ( 2) into pressin, the application of molecular biological the cell membrane to allow water to pass from methods to define hormonal and receptor the lumen of the nephron into the cells of the abnormalities, and a greater knowledge of collecting duct along an osmotic gradient, thus intracellular events within the renal tubular concentrating the urine. Aquaporin 4, and cells, it is now possible to characterise disorders possibly aquaporin 3, mediate the subsequent of water balance more accurately. passage of water from within the cell into the The physiology of water is renal interstitium and, finally, the circulation. A briefly discussed before the pathophysiology, total of six have been described diagnosis, and treatment of insipidus (0–5) and they appear to function as regulators are described in detail. of water transport in a diverse range of tissues, including red blood cells, the lungs, the salivary 2 Physiology of water homeostasis glands, and the eye, as well as the renal tubule. It is essential that , both intracellu- Maximum antidiuresis is attained with lar and extracellular, remains stable to allow plasma concentrations of about normal cellular functions to take place. In 2–4 pmol/l (fig 2). Under normal conditions humans, the maintenance of normal water bal- water balance is maintained by controlling ance is achieved principally by three interre- renal water excretion so that plasma osmolality lated determinants: vasopressin, , and the is confined to a narrow range of 282– kidneys. The secretion of vasopressin from the 295 mmol/kg. In circumstances where patients http://adc.bmj.com/ is under very precise con- lose large amounts of body water through—for trol. Small changes in blood solute concentra- example, excessive heat, plasma osmolality may tion (plasma osmolality) regulate vasopressin increase above 300 mmol/kg, but the increased release.1 An increase in plasma osmolality, usu- vasopressin secretion giving plasma concentra- ally indicating a loss of extracellular water, tions greater than 4 pmol/l will not be able to stimulates vasopressin secretion and, con- conserve any more renal water. Water balance, versely, a decrease in plasma osmolality inhibits in this situation, is conserved by the ingestion its release into the systemic circulation (fig 1). of fluid driven by thirst. Indeed, studies suggest on September 27, 2021 by guest. Protected copyright. Vasopressin then acts on its major target organ, that the sensation of thirst is under very fine osmotic control similar to that of vasopressin the kidneys. The hormone binds to its V2 3 receptor (the receptor) on the secretion.

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1000 16

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8 500

Endocrine Unit, Royal (pmol/l) pAVP Victoria Infirmary, 4 Newcastle Upon Tyne NE1 4LP,UK P H Baylis LD Urine osmolality (mOsmol/kg) 280 300 320 0 Department of Child pOsm (mOsmol/kg) LD2 4 6 Health, Royal Victoria Figure 1 Relation between plasma arginine vasopressin Plasma arginine vasopressin (pmol/l) Infirmary (pAVP) and plasma osmolality (pOsm) in a group of T Cheetham healthy subjects. The solid line represents the mean Figure 2 Relation between urine osmolality and plasma regression between the two variables defined by arginine vasopressin under various states of hydration. The Correspondence to: pAVP = 0.41 (plasma osmolality − 285). LD represents stippled area is the normal reference range. LD represents Professor Baylis. the limit of detection of the assay (0.3 pmol/l). the limit of detection of the assay (0.3 pmol/l). 85

The polyuric disorders of water balance can Table 1 Causes of diabetes insipidus

be caused by abnormalities of any of these Arch Dis Child: first published as 10.1136/adc.79.1.84 on 1 July 1998. Downloaded from three factors that determine water balance. Cranial diabetes insipidus Familial Autosomal dominant Polyuric states DIDMOAD syndrome Cerebral malformations is defined as the passage of large In association with septo-optic dysplasia 2 volumes of dilute urine, in excess of 2 l/m /24 h Laurence-Moon-Beidl syndrome or approximately 40 ml/kg/24 h in older chil- Acquired Trauma (neurosurgery, head injury) dren and adults. Diabetes insipidus is synony- Tumours (such as , germinoma, optic mous with the term polyuria. Three primary glioma) pathogenetic mechanisms are responsible for Idiopathic Hypoxic/ischaemic brain damage polyuria. The first is a deficiency of osmoregu- Lymphocytic neurohypophysitis lated vasopressin secretion known as cranial or (, sarcoid, ) hypothalamic diabetes insipidus. The second Infections (congenital cytomegalovirus and toxoplamosis, encephalitis, meningitis) mechanism is a reduction in the renal response Vascular (aneurysm, malformations) to adequate concentrations of circulating vaso- Nephrogenic diabetes insipidus pressin, termed nephrogenic diabetes insipidus. Familial X linked recessive inheritance (V receptor gene defect) Third, excessive persistent fluid intake is called 2 Autosomal recessive inheritance ( gene defect) dipsogenic diabetes insipidus, or more com- Acquired monly primary . Osmotic (diabetes mellitus) Metabolic (hypercalcaemia, hypokalaemia) Chronic renal disease CRANIAL DIABETES INSIPIDUS Drugs (, ) This disorder is defined as an abnormality of Postobstructive uropathy urine concentration resulting from the defi- Solute washout from cient secretion of osmoregulated vasopressin. Compulsive or habitual Cranial diabetes insipidus has been reviewed In association with psychological disturbance by a number of workers.45 Drugs (lithium, ) Older children with cranial diabetes insip- Hypothalamic lesion idus will present with polyuria, polydipsia, DIDMOAD, crainia diabetes insipidus (DI), diabetes mellitus , and . There is a (DM), optic atrophy (OA, and deafness (D). wide range in severity, from mild degrees that may escape early detection through to pro- following. Craniopharyngioma is a relatively found polyuria up to 400 ml/kg/24 h. Water common cause of cranial diabetes insipidus, balance and normonatraemia are maintained and tumours of the , germinoma or by adequate fluid intake. Patients with cranial teratoma, and pituitary infiltrations with leu- diabetes insipidus who are denied access to kaemia and lymphoma can have a similar water, or those with impaired thirst, will eVect.9 Infectious causes include congenital

develop hypernatraemia. Glucocorticosteroids cytomegalovirus and toxoplasmosis, viral en- http://adc.bmj.com/ are necessary for the kidneys to excrete salt free cephalitis, bacterial meningitis, and Guillain- water and so the symptoms of cranial diabetes Barré syndrome. Some patients have lym- insipidus may be masked by concomitant phocytic infiltration of the pituitary stalk, ACTH deficiency. Polyuria may then be recognised by widening of the stalk, which can apparent when corticosteroid replacement is be seen by computed tomography or magnetic instituted. resonance imaging, which resolves within a few Table 1 gives the common causes of cranial years.10 Head trauma may cause transient diabetes insipidus.5 Familial cranial diabetes cranial diabetes insipidus with polyuria lasting on September 27, 2021 by guest. Protected copyright. insipidus is rare, accounting for about 5% of all from 24 hours to a few weeks. A minority of cases. A number of kindreds have been shown these patients can have a period of antidiuresis to have nucleotide substitutions or deletions of after transient polyuria, only to develop persist- the gene on chromosome 20, which encodes ent cranial diabetes insipidus subsequently (the for the large vasopressin precursor molecule.6 triple phase response).11 Interestingly, the clinical expression of the A few studies have suggested the presence of familial autosomal dominant disorder does not circulating antibodies to the neurones that syn- occur in infants, but more usually at 5–10 thesise vasopressin in some patients with years.7 There appears to be neuronal degenera- idiopathic cranial diabetes insipidus. These tion of the vasopressin synthesising neurones. patients appear to have a higher than normal The DIDMOAD syndrome comprises cra- prevalence of other autoimmune disorders.12 nial diabetes insipidus (DI), diabetes mellitus Patients with cranial diabetes insipidus do not (DM), optic atrophy (OA), and deafness (D), have antibodies to vasopressin unless they have as well as and atonia of the received injections of pitressin (pitressin tan- bladder. It has an autosomal recessive inherit- nate in oil). ance owing to a defect of chromosomal or, possibly, mitochondrial DNA, but the precise NEPHROGENIC DIABETES INSIPIDUS genetic cause is unknown.8 Patients with DID- Patients with nephrogenic diabetes insipidus, MOAD syndrome rarely present in infancy, but like those with cranial diabetes insipidus, commonly present in early childhood. develop hypertonic and also rely Most cases of cranial diabetes insipidus are on their thirst mechanism and adequate fluid acquired, although cerebral malformations can intake to maintain their water homeostasis. lead to presentation in infancy with the clinical The renal tubules are totally or, more usually, picture described in greater detail in the partially resistant to vasopressin. 86 Baylis, Cheetham

Table 1 give the causes of nephrogenic Table 2 Protocol of water deprivation/ test

diabetes insipidus. The X linked form of the Arch Dis Child: first published as 10.1136/adc.79.1.84 on 1 July 1998. Downloaded from disorder is rare, but it will usually result in pro- Preparation Fluid given overnight before test found polyuria and consequent dehydration, Avoid caVeine , constipation, , irritability, and a Weigh patient failure to thrive in infancy.13 Infants who are Liaise with laboratory before test begins Dehydration phase breast fed may present later than those who are Draw blood and collect urine for osmolality measurements and bottle fed because of the reduced osmotic load, urine volume measurement at 08:00 and their history may contain important clues Restrict fluids—an eight hour fast will usually suYce Weigh patient at two hourly intervals such as a desire for water feeds as well as milk. Collect blood and urine for osmolality and volume There may also be a history of hydramnios. measurements at regular intervals—ideally every two hours Episodes of dehydration and hypernatraemia Stop test if weight loss exceeds 5% of starting weight or if thirst becomes intolerable may lead to developmental problems and men- Supervise test closely to avoid patient tal retardation in later life. Desmopressin phase: if diabetes insipidus has not been excluded Molecular studies of aVected members of Inject intramuscular, subcutaneous or intravenous kindreds with nephrogenic diabetes insipidus desmopressin 0.3 µg (this can be administered by fine have identified a number of genetic mutations insulin syringe if given subcutaneously) or 5 µg intranasally after the dehydration phase (at about 16:00) or deletions of the gene that encodes for the Allow patient to eat and up to 1.5 times the urine 13 volume passed during dehydration phase and beyond antidiuretic (V2) receptor located on Xq28. Collect urine for osmolality and volume at about 20:00 The V2 receptor is a classic seven domain Draw blood and collect urine for osmolality and volume transmembrane protein, and genetic abnor- measurements at 09:00 next morning malities have been located in the transmem- brane domain as well as the external and inter- nal segments of the receptor. Some studies interpret without a concomitant serum sample. have defined another, rarer, form of autosomal Fluids should not be restricted at home until a recessive familial nephrogenic diabetes insip- diagnosis has been made. idus, which is caused by genetic abnormalities The standard diagnostic approach to deter- of the water channel protein aquaporin 2.14 15 mine the pathogenetic mechanism causing Metabolic causes of nephrogenic diabetes polyuria is a fluid deprivation test coupled to a insipidus are well recognised. The most study to check urinary concentrating ability in common is diabetes mellitus, which induces an response to exogenous vasopressin. Particular osmotic diuresis, thereby reducing the osmotic care is required in very young children, and this gradient across the renal tubule, which is type of protocol is clearly unsuitable in infants. necessary for the action of vasopressin. Hyper- Numerous water deprivation tests have been described, but a commonly used protocol is calcaemia and hypokalaemia impair the action 16 of vasopressin on the distal nephron. Renal based on Dashe’s original test. Table 2 gives an outline of the protocol. A seven hour fast is concentrating ability after prolonged metabolic 17 disturbance may take a number of weeks to usually of suYcient duration ; it is important to http://adc.bmj.com/ recover completely, despite correction of the allow free access to fluids before starting fluid disturbance. restriction and to supervise the patient closely to avoid surreptitious drinking. After the administration of desmopressin, the patient PRIMARY POLYDIPSIA (DIPSOGENIC DIABETES may eat and drink, but fluid ingestion should be INSIPIDUS) Excessive fluid intake will suppress vasopressin controlled (see table 2) to avoid copious fluid secretion and induce polyuria. Patients usually intake in a primary polydipsic child rendered remain normonatraemic despite large fluid antidiuretic who is then at risk of developing on September 27, 2021 by guest. Protected copyright. 18 intakes, although plasma osmolality may be profound and symptomatic hyponatraemia. low to normal or slightly reduced. Table 3 gives a guide to the interpretation of The causes of primary polydipsia include the results from the water deprivation/desmo- compulsive or habitual excessive fluid intake. pressin test. Plasma osmolality within the nor- Frank psychiatric illness or rare hypothalamic mal reference range (282–295 mmol/kg) com- defects, which lead to increased thirst, are bined with a maximum urine osmolality uncommon causes in children. A few patients greater than 750 mmol/kg after dehydration who appear to be psychologically normal show excludes significant water imbalance. Although a lowered osmotic threshold for the onset of an unequivocal diagnosis can often be made thirst sensation, but normal osmoregulated from these results it is not unusual for urine vasopressin secretion. osmolalities to fall within the range given in the final row (table 3) and a clear diagnosis cannot Diagnosis of the cause of diabetes Table 3 Interpretation of fluid deprivation and insipidus desmopressin tests in polyuric patients Before embarking on time consuming and expensive investigations it is essential that the Urine osmolality (mmol/kg) 24 hour urine volume is documented and After fluid After polyuria confirmed. Preliminary tests to meas- deprivation desmopressin Diagnosis ure blood glucose, serum , and serum should be performed to exclude < 300 > 750 Cranial diabetes insipidus < 300 < 300 Nephrogenic diabetes insipidus common causes of nephrogenic diabetes insip- > 750 > 750 Primary polydipsia idus. Although the osmolality of an early 300–750 < 750 ? Partial cranial diabetes insipidus, morning urine sample obtained at home will ? partial nephrogenic diabetes, or ? primary polydipsia provide some information, it is diYcult to Diabetes insipidus 87

be established. This is probably because after

prolonged polyuria of any cause, the renal 1200 Arch Dis Child: first published as 10.1136/adc.79.1.84 on 1 July 1998. Downloaded from interstitial solute is “washed out”, so that there is a reduction in the osmotic gradient across the distal renal tubular cell, which is essential for the action of vasopressin. Therefore, there 800 will be a degree of renal resistance to vasopressin irrespective of the underlying cause of the polyuria. The greater the degree of 400 polyuria the greater the resistance to vaso- pressin. Measurement of plasma vasopressin

during the dehydration phase does not usually Urine osmolaity (mmol/kg) increase the discriminatory power of the test, 0 although urinary vasopressin measurements LD 2 4 6 may be helpful.19 Plasma AVP (pmol/l) In infants and younger children the clinical picture and results of investigations at presen- Figure 4 Relation between urine osmolality and plasma arginine vasopressin (AVP) after a period of fluid tation may leave little doubt about the diagno- restriction. The shaded area represents the normal relation. sis and the response to desmopressin will usu- Patients with nephrogenic diabetes insipidus have results ally confirm the diagnosis. displaced to the right of normal (hatched area). In older children (age > 5 years) a definitive diagnosis of cranial diabetes insipidus can be the partial forms of nephrogenic diabetes made by measuring the plasma vasopressin insipidus.417 response to increasing plasma osmolality in- The third diagnostic approach is to perform duced by a hypertonic 5% (850 mmol/l) a therapeutic trial of low dose desmopressin. It infusion over a period of two hours at a rate of is undoubtedly helpful in younger patients and 0.05 ml/kg/h20 or until a plasma osmolality of if there is no facility to measure plasma 300 mmol/kg is achieved. This is of value when vasopressin. After a period of three to four days a deprivation test has shown equivocal results, during which daily weight, plasma , but is rarely used in children. The limited urine volume, and osmolality are monitored, availability of a reliable arginine vasopressin the patient is given a small dose of subcutane- assay and the practical diYculties that may ous or intramuscular desmopressin daily for accompany the administration of irritant hyper- about seven to 10 days. A dose of 0.3–0.5 µg in tonic saline solution to children are possible younger children or 0.5–1.0 µg in teenagers is reasons for this. Figure 3 indicates the normal appropriate. Measurements are continued dur- response of healthy subjects and, in the hatched ing the desmopressin trial and for a few days area, the subnormal vasopressin response diag- after stopping the drug. Patients with cranial

nostic of cranial diabetes insipidus. Polyuric diabetes insipidus will be identified by a reduc- http://adc.bmj.com/ patients who have nephrogenic diabetes insip- tion in thirst, a progressive reduction in urine idus or primary polydipsia will have vaso- output, and plasma sodium will remain in the pressin values in the normal reference range.421 normal range during desmopressin administra- Direct measurement of plasma vasopressin tion. Nephrogenic diabetes insipidus is charac- after a period of water restriction confirms the terised by a lack of response to desmopressin diagnosis of nephrogenic diabetes insipidus with a persistence of thirst and polyuria. Those when plotted against urine osmolality (fig 4). with primary polydipsia will remain thirsty and This test is particularly useful in identifying develop progressive hyponatraemia.4 on September 27, 2021 by guest. Protected copyright. Once the pathogenetic mechanism responsi- ble for causing polyuria has been clarified, it is mandatory to search for the underlying cause of the type of diabetes insipidus. Magnetic resonance imaging of the pituitary, hypothala- 20 mus, and surrounding structures should be performed to look for pituitary and parapitui- tary masses, craniopharyngioma, pinealoma, or pituitary stalk abnormalities. In many patients (70%) with cranial diabetes insipidus there is a loss of the normal hyperintense signal in T1 10 weighted magnetic resonance imaging of the posterior pituitary,22 although this may also be

Plasma AVP (pmol/l) a feature of nephrogenic diabetes insipidus. In the former this is because of reduced vaso- pressin production and in the latter to LD enhanced release. The signal will be normal in primary polydipsia. It is important to perform 280 300 320 serial magnetic resonance imaging in all cases of Plasma osmolality (mmol/kg) idiopathic cranial diabetes insipidus because of Figure 3 Relation between plasma arginine vasopressin the possibility of evolving disease not detected (AVP) and plasma osmolality following hypertonic 5% initially.23 Genetic studies to identify the abnor- saline infusion. The shaded area is the normal response. Patients with cranial diabetes insipidus show subnormal mality in the precursor vasopressin molecule in responses (hatched area). familial cases might be appropriate. 88 Baylis, Cheetham

Treatment can reduce urine output by 40% in 29 30 CRANIAL DIABETES INSIPIDUS infants. act by enhancing Arch Dis Child: first published as 10.1136/adc.79.1.84 on 1 July 1998. Downloaded from The drug of choice is desmopressin, which is a sodium excretion at the expense of water and synthetic analogue of the native hormone, reducing the glomerular filtration rate. They arginine vasopressin.24 Two minor structural may need to be administered with a potassium alterations to the vasopressin molecule have sparing drug such as . A similar created a drug with prolonged antidiuretic reduction in urine flow may be achieved with action and minimal pressor activity. the prostaglandin synthetase inhibitor indo- Desmopressin may be administered orally, methacin, given in doses of 1.5–3.0 mg/kg. A intranasally, or parenterally. There are wide relatively new and promising approach is the individual variations in the doses required to combination of a thiazide, indomethacin, and control diuresis.25 Daily requirements for the desmopressin, which may reduce urine output preparations given by mouth vary from 100 to by up to 80%. It is essential that all these 1000 µg in two or three divided doses; for the patients drink adequate fluid volumes to intranasal preparations around 2–40 µg are quench their thirst. given (in children older than 1 year); and for the parenteral preparations 0.1–1 µg are given. PRIMARY POLYDIPSIA A low dose should be used initially and this It may be appropriate to reduce water intake can then be increased as necessary. As little as once the diagnosis of compulsive or habitual 0.5 µg of the nasal solution twice daily may water intake has been made. In older children suYce in neonates, and the hospital pharmacy there may be an underlying psychological or can prepare a manageable volume by diluting psychiatric disorder which must be treated to standard desmopressin solution. This can then settle the water disturbance. be administered by a 1 ml syringe, which will allow the small dose to be dropped accu- 1 Robertson GL, Shelton RL, Athar S. The osmoregulation of rately into the supine child’s nostrils. The vasopressin. Int 1976;10:25–37. 2 King LS, Agre P. Pathophysiology of the aquaporin water treatment of small children with diabetes channels. Ann Rev Physiol 1996;58:619–48. insipidus can be very diYcult, with rapid and 3 Thompson CJ, Bland J, Burd J, Baylis PH. The osmotic thresholds for thirst and vasopressin release are similar in sometimes unexplained changes in healthy man. Clin Sci 1986;71:651–6. osmolality.26 It is important for the family to be 4 Robertson GL. Diabetes insipidus. Clinical disorders of fluid and metabolism. Endocrinol Metab Clin closely involved from the onset so that they are North Am 1995;24:549–72. able to gauge what is an appropriate fluid 5 Wang LC, Cohen ME, DuVner PK. Etiologies of central diabetes insipidus in children. Pediatr Neurol 1994;11:273–7. intake and urine output. Desmopressin given 6 Miller WL. Molecular of familial central diabetes by mouth has been shown to be particularly insipidus. J Clin Endocrinol Metab 1993;77:592–5. 27 7 McLeod JF, Kovacs L, Gaskill MB, Rittig S, Bradley GS, helpful in childhood and many paediatricians Robertson GL. Familial neurohypophyseal diabetes insip- now use this treatment beyond infancy. idus associated with a signal peptide mutations. J Clin Endocrinol Metab 1993;77:599A–G. Dilutional hyponatraemia is the only potential 8 Rotig A, Cormier V, Chatalain P. Deletion of the mitochon- hazard if desmopressin is administered in drial DNA in a case of early-onset diabetes mellitus, http://adc.bmj.com/ diabetes insipidus, optic atrophy and deafness, Wolfram excess over a prolonged time period. This syndrome. J Clin Invest 1993;91:1095–8. can be prevented in older children by adjusting 9 Catagnola C, Movra E, Bernasconi P, Astori C, Santgostino A, Bernasconi C. Acute myeloid leukaemia and diabetes the regimen to allow a periodic “break- insipidus. Acta Haematol 1995;93:1–4. through” when the urine output is allowed to 10 Imura H, Nakao K, Shimatsu A, et al. Lymphocytic infundibulo-neurohypophysitis as a cause of central increase. diabetes insipidus. N Engl J Med 1993;329:683–9. Children with adipsia or hypodipsia are a 11 Lindsay RS, Seckl JR, Padfield PL. The triple phase response—problems of water balance after pituitary diYcult challenge and are best managed by fix- surgery. 1995;71:439–41.

Postgrad Med J on September 27, 2021 by guest. Protected copyright. ing the desmopressin dose and fluid intake, ini- 12 De Bellis A, Bizzarro A, Amoresano PV, et al. Detection of vasopressin cell antibodies in some patients with autoim- tially in the hospital setting. Daily weights can mune endocrine without overt diabetes insipidus. be used as an index of fluid balance, but regu- Clin Endocrinol 1994;40:173–7. 13 Bichet DG, Birnbaumer M, Lonergan M, et al. Nature and lar will also be required, particu- recurrence of AVPR2 mutations in X-linked nephrogenic larly in the initial phase.28 The shorter acting diabetes insipidus. Am J Hum Genet 1994;55:278–86. 14 Van Lieburg AF, Knoers NV, Deen PM. Discovery of preparation, lysine vasopressin, is not recom- aquaporins: a breakthrough in research on renal water mended because of its pressor activity. Rarely, transport. Pediatr Nephrol 1995;9:228–34. 15 Deen PMT, Vedijk MAJ, Knoers NVAM, et al. Requirement direct treatment of the underlying cause of cra- of human renal water channel aquaporin-2 for vasopressin nial diabetes insipidus cures the polyuria (for dependent concentration of urine. Science 1994;264:92–5. 16 Dashe AM, Cramm RE, Crist CA, Habener JF, Soloman example, steroid treatment of hypothalamic DH. A water deprivation test for the diVerential diagnosis ). of polyuria. JAMA 1963;185:699–703. 17 Frasier SD, Kutnik LA, Schmict RT, Smith FG. A water deprivation test for the diagnosis of diabetes insipidus in NEPHROGENIC DIABETES INSIPIDUS children. Am J Dis Child 1967;114:157–60. 18 Koskimies O, Pylkkanen J, Vilska J. in EVective treatment of nephrogenic diabetes infants cause by the urine concentration test with insipidus still poses major problems, except for vasopressin analogue (DDAVP). Acta Paediatr Scand 1984; 73:131–2. forms that are drug induced or related to 19 Dunger DB, Seckl JR, Grant DB, Yeoman L, Lightman SL. metabolic disorders (table 1). Withdrawal of A short water deprivation test incorporating urinary arginine vasopressin estimations for the investigation of the drug or correction of the metabolic distur- posterior pituitary function in children. Acta Endocrinol bance often reverses the renal resistance to 1988;117:13–18. 20 Baylis PH, Robertson GL. Plasma vasopressin response to vasopressin, but correction may take a number hypertonic saline infusion to assess posterior pituitary of weeks. function. JRSocMed1980;73:255–60. The profound polyuria caused by the famil- 21 Baylis PH, Thompson CJ. Osmoregulation of vasopressin secretion and thirst in health and disease. Clin Endocrinol ial forms of nephrogenic diabetes insipidus are 1988;29:549–76. 22 Sato N, Ishizaka H, Yagi H, Matsumoto M, Endo K. Poste- particularly diYcult to manage. Salt restriction rior lobe of the pituitary in diabetes insipidus: dynamic MR combined with the administration of a thiazide imaging. Radiology 1993;186:357–60. Diabetes insipidus 89

23 Mootha SL, Barkovich AJ, Grumbach MM, et al. Idiopathic 27 Fjellestad-Paulson A, Laborde K, Czernichow P. Water bal- hypothalamic diabetes insipidus, pituitary stalk thickening, ance hormones during long-term follow-up of oral DDAVP and the occult intracranial germinoma in children and treatment in diabetes insipidus. Acta Paediatr 1993;82:752– Arch Dis Child: first published as 10.1136/adc.79.1.84 on 1 July 1998. Downloaded from adolescents. J Clin Endocrinol Metab 1997;82:1362–7. 7. 24 Vavra I, Machova A, Holecek V, Cort JH, Zaoral M, Sorm F. 28 Ball SG, Vaidja B, Baylis PH. Hypothalamic adipsic EVects of a synthetic analogue of vasopressin in animals syndrome: diagnosis and management. Clin Endocrinol and in patients with diabetes insipidus. Lancet 1968;i:948– 1997;47:405–9. 52. 25 Kauli R, Galatzer A, Laron Z. Treatment of diabetes insip- 29 Niaudet P, Dechaux M, Leroy D, Broyer M. Nephrogenic idus in children and adolescents. In: Czernichow P, Robin- diabetes insipidus in children. In: Czernichow P, Robinson son AG, eds. Diabetes insipidus in man. Frontiers of hormonal AG, eds. Diabetes insipidus in man. Frontiers of hormonal research. Basel: Karger, 1985;13:304–13. research 1985;13:224–31. 26 Masera N, Grant DB, Stanhope R, Preece MA. Diabetes 30 Uyeki TM, Barry FL, Rosenthal SM, Mathias RS. Success- insipidus with impaired osmotic regulation in septo-optic ful treatment with and amiloride in an dysplasia and agenesis of the corpus callosum. Arch Dis infant with congenital nephrogenic diabetes insipidus. Child 1994;70:51–3. Pediatr Nephrol 1993;7:554–6.

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