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Nephrogenic Diabetes Insipidus in Children - Springer · PDF fileNephrogenic Diabetes Insipidus in Children Nine V. A. M. Knoersa* and Elena N. Levtchenkob aDepartments of Medical

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  • Nephrogenic Diabetes Insipidus in Children

    Nine V. A. M. Knoersa* and Elena N. LevtchenkobaDepartments of Medical Genetics, University Medical Centre Utrecht, Utrecht, The NetherlandsbDepartment of Pediatric Nephrology, Department of Growth and Regeneration, University Hospitals Leuven,Katholieke Universiteit Leuven, Leuven, Belgium


    First familial cases with diabetes insipidus were described byMcIlraith in 1892; however, he did notdistinguish between renal and neurohormonal forms of the disorder [1]. The renal type of diabetesinsipidus was appreciated as a separate entity more than 50 years ago, when it was describedindependently by two investigators: Forssman [2] in Sweden and Waring et al. [3] in the UnitedStates. In 1947, Williams and Henry [4] noticed that injection of antidiuretic hormone (ADH) indoses sufficient to induce systemic side effects could not correct the renal concentrating defect. Theycoined the term nephrogenic diabetes insipidus. Subsequent studies revealed active hormone in theserum and urine of affected persons and lent further support to the theory of renal unresponsivenessto vasopressin. Nephrogenic diabetes insipidus is synonymous with the terms vasopressin- or ADH-resistant diabetes insipidus and diabetes insipidus renalis.

    Definition and Clinical Manifestations

    Congenital nephrogenic diabetes insipidus (NDI) is a rare inherited disorder, characterized byinsensitivity of the distal nephron to the antidiuretic effects of the neurohypophyseal hormonearginine vasopressin (AVP). As a consequence, the kidney loses its ability to concentrate urine,which may lead to severe dehydration and electrolyte imbalance (hypernatremia andhyperchloremia). Patients with NDI have normal birth weight and pregnancies are not complicatedby polyhydramnios. The urine-concentrating defect in NDI is present from birth, and manifestationsof the disorder generally emerge within the first weeks of life. With breast milk feedings, infantsusually thrive and do not develop signs of dehydration. This is because human milk has a low saltand protein content and therefore a low renal osmolar load. With cows milk formula feedings, theosmolar load to the kidney increases, resulting in an increased demand for free water. This is usuallynot provided by oral feeding, and therefore hypernatremic dehydration appears. Irritability, poorfeeding, and poor weight gain are usually the initial symptoms [5]. Patients are eager to suck but mayvomit during or shortly after the feeding. Dehydration is evidenced by dryness of the skin, loss ofnormal skin turgor, recessed eyeballs, increased periorbital folding, depression of the anteriorfontanel, and a scaphoid abdomen. Intermittent high fever is a common complication of thedehydrated state, predominantly in very young children. Body temperature can be normalized byrehydration. Seizures can occur but are rare and most often seen during therapy, particularly ifrehydration proceeds too rapidly. Constipation is a common symptom in childrenwith NDI. Nocturiaand nocturnal enuresis are common complaints later in childhood.

    *Email: [email protected]

    Pediatric NephrologyDOI 10.1007/978-3-642-27843-3_36-1# Springer-Verlag Berlin Heidelberg 2014

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  • Untreated, most patients fail to grow normally. In a retrospective study of 30 male NDI patients,most children grew below the 50th percentile, most of them having standard deviation (SD) scoreslower than1 [6]. Some well-treated patients, however, may achieve normal adult height. Catch-upgrowth occurs at least in some patients after normalization of water and electrolyte balance,especially in those with adherence to treatment. Bone maturation is generally not delayed [7].Weight-for-height SD scores are initially low, followed by global normalization at schoolage [6]. Initial feeding problems and the ingestion of large amounts of low-caloric fluid resultingin a decreased appetite may play roles in failure to thrive seen in NDI [8, 9]. Furthermore, it ispossible that repeated episodes of dehydration have some as yet undetermined negative effects ongrowth.

    Mental retardation has long been considered an important complication of untreated NDI andassumed to be a sequel of recurrent episodes of severe brain dehydration and cerebral edema causedby overzealous attempts at rehydration [1012]. Additional evidence underscoring the assumptionthat NDI has adverse effects on the cerebrum is provided by several reports describing intracranialcalcifications in NDI patients [13, 14]. Such lesions are generally considered to be the result ofhemorrhage or necrosis. Most of the reported patients with cerebral calcifications were mentallyretarded. Nowadays mental retardation is rare due to earlier recognition and treatment of NDI. Exactestimates of the current frequency of mental retardation under modern treatment are unknown, but inthe largest psychometric study ever reported, only 2 of the 17 male NDI patients (aged 330 years)had a total intelligence quotient more than 2 SD below the norm. Fourteen patients had anintelligence score within or above the normal range and one patient had a general index scorebetween 1 and 2 SD [15].

    The psychological development of NDI patients is influenced by a persistent desire for drinkingand the need for frequent voiding, which compete with playing and learning. Therefore, many NDIpatients are characterized by hyperactivity, distractibility, short attention span, and restlessness. Inthe psychometric study mentioned earlier, the criteria for attention-deficit/hyperactivity disorderwere met in 8 of 17 tested NDI patients [15].

    Persistent polyuria can result in the development of megacystis, trabeculated bladder wall,hydroureter, and hydronephrosis [6, 16, 17]. Urinary tract distension may be seen on ultrasoundexamination even in infants [18] and young children [19]. Potential complications of urinary tractdilatation are rupture of the urinary tract, infection, intractable pain, improper bladder function,and/or kidney failure. These complications may occur as early as the second decade of life. Large-capacity hypotonic bladder dysfunction might require clean intermittent catheterization[17]. Patients should be trained to void regularly in order to assure that maximal urinary bladdercapacity remains within normal range. Both patient groups with AVPR2 and AQP2 mutations candevelop urinary tract dilatation and bladder dysfunction [16, 20].

    Diagnostic Procedures

    The observation of polyuria in a dehydrated infant, together with the finding of a high serum sodiumconcentration and inappropriately diluted urine (Uosm < Posm), provides presumptive evidencefor a renal concentrating defect. To confirm the concentrating defect and to distinguish the renal formof diabetes insipidus from the central form, a vasopressin test is performed with 1-desamino-8-D-arginine vasopressin (DDAVP), a synthetic analogue of the natural arginine vasopressin that

    Pediatric NephrologyDOI 10.1007/978-3-642-27843-3_36-1# Springer-Verlag Berlin Heidelberg 2014

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  • produces a high and prolonged antidiuretic effect. In the test, DDAVP (10 mg for infants1 year old) is administered intranasally. Urine is collected during the subsequent5.5 h. The first collected portion of the urine should be discarded. The maximal urine osmolality inany collected aliquot is chosen as a measure of the concentrating capacity [21]. After DDAVPadministration, NDI patients are (1) unable to increase urinary osmolality, which remains below200 mOsm/kg H2O (normal values: 600, between 1 and 2 years old between 600 and800, >2 years old >800 mOsm/kg H2O), and (2) cannot reduce urine volume or free-waterclearance.

    Plasma vasopressin levels are normal or only slightly increased in affected children. Otherlaboratory findings have been described, which mainly result from chronic dehydration. Serumsodium concentration is generally elevated and may be above 170 mmol/L. There is also anincrease in serum chloride concentration and retention of urea and creatinine. All values arenormalized by adequate rehydration. In addition, reduced glomerular filtration rate (GFR) andrenal blood flow can return to normal when a normal hydration state has been achieved.

    The primary congenital form of NDI has to be differentiated from central diabetes insipidus (dueto lack of AVP) and from the secondary or acquired forms, which are much more common [22].In our experience, the urinary osmolality obtained after DDAVP administration in secondarydisorders is always higher than in NDI. Several secondary causes, some of which will be discussedlater, are listed in Table 1.

    Table 1 Causes of secondary nephrogenic diabetes insipidus

    Monogenetic diseases associated with secondary NDI

    Renal Fanconi syndromes

    Bartter syndrome (type 1 or type 2)

    Familial hypomagnesemia with hypercalciuria and nephrocalcinosis

    Distal renal tubular acidosis (dRTA)

    Apparent mineralocorticoid excess (AME)

    Ciliopathies (nephronophthisis, BardetBiedl syndrome, etc.)

    Other renal diseases

    Obstructive uropathy

    Renal dysplasia

    Postischemic damage



    Chronic renal failure

    Renal impairment in sickle-cell disease or trait

    Drug induced



    Amphotericin B


    Biochemical abnormalities

    Hypercalcemia, hypercalciuria, and nephrocalcinosis


    Pediatric NephrologyDOI 10.1007/978-3-642-27843-3_36-1# Springer-Verlag Berlin Heidelberg 2014

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  • Cellular Physiology of Arginine Vasopressins Antidiuretic Action in theDistal Nephron

    The physiologic action of vasopressin on the renal collecting duct has been one of the mostintensively studied processes in the kidney.