pediatrics in review 2000 saborio 122 9

Diabetes InsipidusPablo Saborio, MD,* Gary A. Tipton, MD, and James C.M. Chan, MD

OBJECTIVES

After completing this article, readers should be able to:1. Describe the simple test that will establish the diagnosis of diabetes

insipidus.2. Explain how to differentiate central diabetes insipidus from nephro-

genic diabetes insipidus and compulsive water drinking.3. Delineate the inheritance pattern of central diabetes insipidus and

nephrogenic diabetes insipidus.4. Describe the treatments of choice for central diabetes insipidus and

nephrogenic diabetes insipidus.

Definition and EpidemiologyPolydipsia and polyuria with diluteurine, hypernatremia, and dehydra-tion are the hallmarks of diabetesinsipidus in infants and children.Patients who have diabetes insipidusare unable to conserve water andcan become severely dehydratedwhen deprived of water. The poly-uria exceeds 5 mL/kg per hour ofdilute urine, with a documented spe-cific gravity of less than 1.010. Thehypernatremia is evidenced by aserum sodium concentration inexcess of 145 mmol/L (145 mEq/L).

Three conditions give rise topolydipsia and polyuria. The mostcommon condition is central or neu-rogenic diabetes insipidus related toa deficiency of vasopressin. Lesscommon is nephrogenic diabetesinsipidus, including the X-linkedrecessive, autosomal recessive, andautosomal dominant types due torenal tubular resistance to vasopres-sin. Finally, these conditions canoccur in the compulsive waterdrinker who demonstrates physio-logic inhibition of vasopressinsecretion.

The incidence of diabetes insipi-dus in the general population is 3 in100,000, with a slightly higher inci-dence among males (60%). X-linked

nephrogenic diabetes insipidus isvery rare, with arginine vasopressinreceptor2 (AVPR2) gene mutationsamong males estimated to be 4 in1,000,000. The incidence of compul-sive water drinking is unknown, butthere appears to be a female predis-position (80%). Although the com-pulsive water drinker commonlypresents in the third decade of life,cases have been described inpatients from 8 to 18 years of age.Compulsive water drinking isencountered in 10% to 40% ofpatients who have schizophrenia.

PathophysiologyThe secretion of antidiuretic hor-mone, arginine vasopressin (AVP),from the posterior pituitary gland isregulated by paraventricular andsupraoptic nuclei. AVP acts at thetarget site of the cortical collectingduct of the kidneys (Fig. 1A). At thebasal lateral membrane of the corti-cal collecting duct (Fig. 1B), AVPbinds to a vasopressin2 receptor,which links with G protein andadenylate cyclase to produce cyclicAMP. Protein kinase A subsequentlyis stimulated and acts to promoteaquaporin2 (AQP2) in recycling vesi-cles. In the presence of AVP, exo-cytic insertion of AQP2 protein atthe apical surface of the corticaltubular cells allows water to enterthe cell. In the absence of AVP,AQP2 protein is retrieved by endo-cytic retrieval mechanisms andreturned to the recycling vesicle.Destruction of the posterior pituitarygland by tumors or trauma results in

a deficiency of vasopressin and thedevelopment of central diabetesinsipidus. Nephrogenic diabetesinsipidus arises from end-organresistance to vasopressin, either froma receptor defect or from medica-tions and other agents that interferewith the AQP2 transport of water.

PathogenesisCentral diabetes insipidus may beeither idiopathic or due to neuro-genic causes (Table 1). Approxi-mately 29% of central diabetesinsipidus in children is idiopathic(isolated or familial) compared with25% in adults. Primary brain tumorsof the hypophyseal fossa result incentral diabetes insipidus in 50% ofchildren and 30% of adults. Headtrauma to the posterior pituitarygland accounts for 2% of cases inchildren and 17% in adults. Amongadults, 9% of central diabetes insipi-dus results from inadvertent neuro-surgical destruction of the posteriorpituitary gland, 8% from metastaticcarcinoma, and 6% from intracranialhemorrhage and hypoxia. Thepostinfectious disease process andhistiocytosis X cause central diabe-tes insipidus in 2% and 16% of chil-dren, respectively.

The mode of inheritance of idio-pathic central diabetes insipidus maybe autosomal dominant or autosomalrecessive (Table 2). The autosomaldominant type usually presents after1 year of age, and the moleculardefect is a prepro-AVP2 gene muta-tion. Central diabetes insipidusinherited by autosomal recessivetraits are due to a mitochondrialdeletion of 4p16 and usually occursin children younger than 1 year ofage. Nephrogenic diabetes insipidus

*Visiting Scholar to Medical College ofVirginia (MCV) Campus of VirginiaCommonwealth University, Richmond, VAfrom the University of Costa Rica, San Jose,Costa Rica.Associate Professor of Pediatrics, Divisionof General Pediatrics, Medical College ofVirginia, Richmond, VA.Editorial Board

ABBREVIATIONSAVP: arginine vasopressinAQP2: aquaporin2AVPR2: arginine vasopressin

receptor2DDAVP: 1-desamino-8-D-arginine

vasopressin

ARTICLE

122 Pediatrics in Review Vol. 21 No. 4 April 2000 at University of Illinois at Chicago Library on February 22, 2015http://pedsinreview.aappublications.org/Downloaded from

results from a vasopressin-receptoror AQP2 water channel defect, withthe misfolding of the mutated mem-brane protein and its retention in theendoplasmic reticulum. The geneticdefect is transmitted by an X-linkedrecessive or autosomal recessive

trait. The genetic defect in theAVPR2 is transmitted by anX-linked recessive trait. The AQP2gene defect is transmitted by anautosomal recessive trait.

The acquired form of nephro-genic diabetes insipidus may result

from adverse drug reactions, electro-lyte disorders, urinary tract obstruc-tion, or other conditions (Table 3).The polyuria associated with theseconditions and medications is not assevere as that seen in central diabe-tes insipidus or nephrogenic diabetes

FIGURE 1. A. Central secretion of arginine vasopressin (AVP). AVP is secreted by the posterior pituitary in relation toparaventricular nuclear and supraoptic nuclei. AVP exerts its action at target sites in the kidney. B. Water channel recycling. Atthe basolateral membrane of the renal cortical collecting duct cell, AVP is bound to vasopressin V2 receptor (V2R). G proteinlinks V2R to adenylate cyclase (AC), increasing the concentration of cyclic adenosine monophosphate (cAMP). The cAMP-dependent protein kinase A (PKA) acts on recycling vesicles that carry the tetrameric water channel proteins. The waterchannels are fused, by exocytic insertion, to the apical basement membrane to increase water permeability. When AVP becomesunavailable, the water channels are retrieved (endocytic retrieval). Water permeability is lowered. Modified from Dean PMT,Knoers NVAM. Physiology and pathophysiology of aquaporin 2 water channel. Curr Opin Neph Hypertens. 1998;7:3742 andBichet DG. Nephrogenic and central diabetes insipidus. In: Schrier RW, Gottschalk CW, eds. Disease of the Kidney. 6th ed.Boston, Mass: Little Brown and Co; 1997.

RENAL DISORDERSDiabetes Insipidus

Pediatrics in Review Vol. 21 No. 4 April 2000 123 at University of Illinois at Chicago Library on February 22, 2015http://pedsinreview.aappublications.org/Downloaded from

insipidus. Drugs such as lithium,amphotericin, and cisplatin areimplicated regularly in this condi-tion. Common electrolyte disorders,such as hypokalemia, hypercalcemia,and hypercalciuria, also can causeacquired nephrogenic diabetes insip-idus. Associated systemic diseasesinclude sickle cell disease and trait,amyloidosis, sarcoidosis, Sjogrensyndrome, Fanconi syndrome, andrenal tubular acidosis. Obstructiveuropathy, diffuse renal injury, or anycause of renal failure can precipitatethe development of acquired nephro-genic diabetes insipidus. Finally,variance neoplasms, such as sar-coma, are associated with thiscondition.

In compulsive water drinking,also referred to as primary polydip-sia, an individual may ingest up to15 L of water daily and produce anequal volume of urine output. Thishuge water ingestion leads to physi-ologic suppression of vasopressinsecretion and results in a hypo-osmolar urine. Polyuria is decreasedat night as polydipsia ceases withsleep. Thus, moderate nocturia dis-tinguishes compulsive water drink-ing from the other forms of diabetesinsipidus (Table 4).

Clinical AspectsThe diagnosis of diabetes insipidusin infants and children requires a

high index of suspicion because thepresenting clinical features of poorfeeding, failure to thrive, and irrita-bility are nonspecific. Symptomsusually occur a few weeks afterbirth. The mother initially noticesnothing unusual because humanmilk delivers a low renal soluteload. Later in life, as food is intro-duced to the diet, the increased sol-ute load causes more waterexcretion.

Neonates who have diabetesinsipidus suck vigorously duringfeeding but vomit immediately after-wards. Nocturia often is reported inchildren who have diabetes insipi-dus, and the parents describe thediapers as dripping in urine. Thesepatients usually are irritable as aresult of hypernatremia, dehydration,and fever. Because the fever fre-quently is intermittent and high,affected infants who have diabetesoften are evaluated initially for feverof unknown origin. In addition, theymay present with constipation orpebble-like hardened stools. Parentsusually report relief of these symp-toms when water is given.

Because of excessive fluid con-sumption, the appetite is blunted,and growth retardation is a commonfeature of children who have diabe-tes insipidus. Frequent hypernatre-mic dehydrations and seizures led toreports of mental retardation as acommon feature of diabetes insipi-dus in the past. With earlier recogni-tion and better management today,seizures are less common, and men-tal retardation no longer is consid-ered a hallmark of the disease.These children often suffer fromhyperactivity and short-term mem-ory disorders, which are believed tobe due to frequent urination, con-

TABLE 1. Pathogenesis of Central Diabetes InsipidusETIOLOGY CHILDREN ADULTS

Primary brain tumor: craniopharyngioma,glioma, neoplasm, leukemia,lymphoma, meningioma, germinoma

50% 30%

Idiopathic (isolated or familial) 29% 25%Head trauma 2% 17%

Neurosurgery 9%

Metastatic carcinoma 8%

Intracranial hemorrhage and hypoxia,postpartum pituitary necrosis (Sheehansyndrome), aneurysm, thrombosis,sickle cell crisis

6%

Infection: tuberculosis, meningitis,encephalitis, intracranial abscess,syphilis

2%

Histiocytosis X 16%

Granulomatosis, sarcoidosis, alcohol,phenytoin, clonidine

5%

TABLE 2. Modes of Inheritance of Diabetes Insipidus (DI)

TYPE INHERITANCE MOLECULAR GENETICSAGE OFPRESENTATION

Central DI Autosomal dominant Prepro-AVP2 gene mutations .1 y

Central DI Autosomal recessive Mitochondrial deletions 4p16 ,1 y

Nephrogenic DI X-linked recessive AVPR2 gene mutations ,1 wk

Nephrogenic DI Autosomal recessive or dominant AQP2 gene mutations ,1 wkAVPR2 5 arginine vasopressin receptor2; AQP2 5 aquaporin2.



stant search for fluids, and continualdisruptions of normal activities andfocus.

A typical physical examinationmay reveal an irritable infant whohas a dripping diaper. There usuallyare findings suggesting dehydration,such as a notable decrease in tear-ing, a depressed anterior fontanelle,sunken eyes, and mottled anddoughy skin turgor. In infants andolder children, the pulse usually isweak, and hypotension is mani-fested. Mobile fecaliths often presentas abdominal masses.

Table 4 summarizes the presenta-tions of central diabetes insipidus,nephrogenic diabetes insipidus, andthe compulsive water drinker. Withcentral diabetes insipidus, the onset

of polyuria is sudden, the volume ofurine is large, nocturia is frequent,and there is a marked preference forice water. Diabetes insipidus due totrauma or neurosurgical injury ischaracterized by polyuria that oftenis triphasic: an initial, intense poly-uria lasting for hours to severaldays, followed by an antidiureticphase of equal duration, and finallyreturn of transient or permanentpolyuria. Polyuria, nocturia, and pref-erence for ice water are more variablein nephrogenic diabetes insipidus andthe compulsive water drinker.

Diagnosis

HISTORYDiabetes insipidus must be consid-ered in any dehydrated infant whohas a history of polyuria and labora-tory findings of hypernatremia andurinary concentration defect. A fam-ily history of diabetes insipidus mayfocus the diagnosis on specific dis-orders. Polyuria following headtrauma or injury or the presence ofneurologic deficits or precociouspuberty point to neurogenic diabetesinsipidus. A weak urinary streamand a dilated collecting systemshould alert the physician to thediagnosis of obstructive uropathy.

PRESENTATIONInfants who have nephrogenic diabe-tes insipidus often present with feverdue to dehydration, which mayresult in convulsions. Infants andchildren who have nephrogenic dia-betes insipidus frequently presentwith hypernatremia, hyperchloremia,and prerenal azotemia as well as

acidosis, which is dependent on theseverity of dehydration and hypovo-lemia. These abnormalities, togetherwith hyperosmolality, are reversedwith rehydration. Serum uric acidgenerally is elevated because of thedehydration, and urinary sodium andchloride levels often are below nor-mal. The urine continues to bedilute, despite hypernatremia inexcess of 180 mmol/L (180 mEq/L).Because of the large urine volumethat passes through the lower uri-nary tract system, older childrenwho have a long history of nephro-genic diabetes insipidus often havefunctional hydronephrosis and anenlarged bladder.

LABORATORY TESTSA 24-hour urine collection is neededto quantitate the polyuria and toestimate the rate of excretion ofosmoles. The urinary specific grav-ity of the first morning voiding pro-vides a simple estimation of therenal concentration capacity. How-ever, the urinary specific gravity isaffected by the presence of glucos-uria, proteinuria, or radiocontrastmaterial. Serum calcium, glucose,creatinine, potassium, and urea lev-els provide additional clues to thecorrect diagnosis. Low serum osmo-lality coupled with hypo-osmolarurine suggest the diagnosis of acompulsive water drinker. A highserum osmolality in the presence ofnormal serum glucose and urea con-centrations points to a deficiency orinsensitivity to vasopressin.

A diagnostic approach to a childwho has polyuria and hypernatremicdehydration is shown in Fig. 2. The

TABLE 3. AcquiredNephrogenic Diabetes

InsipidusDrug-induced:

AminoglycosideAmphotericin BCisplatinColchicineDemeclocyclineDiphenylhydrationFoscarnetFurosemideGentamicinIsophosphamideLithiumMethicillinMethoxyfluraneNicotineRifampinVasopressinoic acidVinblastine

Electolyte disorders:HypokalemiaHypercalcemiaHypercalciuria

Systemic disorders:AmyloidosisDiffuse renal injury or any

cause of renal failureFanconi syndromeObstructive uropathyRenal tubular acidosisSarcoidosisSickle cell disease and traitSjogren syndrome

Neoplasm:Sarcoma

TABLE 4. Presentations of Central Diabetes Insipidus (CDI),Nephrogenic Diabetes Insipidus (NDI), and Compulsive Water

Drinker (CWD)CDI NDI CWD

Onset of polyuria Sudden Variable Variable

Volume of urine Large Large Variable

Nocturia Frequent Frequent Moderate

Preference for ice water Great Variable VariableModified from T Berl, RW Schrier. Disorder of serum sodium concentration. In:McGaw Fluid and Electrolytes Monogram Series. Irving, Calif: McGaw Laboratories;1979.



water deprivation test (Table 5)should be performed during daytimehours because of the better availabil-ity of medical and nursing person-nel. An elevation of plasma osmolal-ity in excess of 10 mOsm/kg overbaseline, with the urine specificgravity remaining less than 1.010after a short water deprivation test,establishes the diagnosis of diabetesinsipidus. The next diagnostic stepuses 1-desamino-8-D-arginine vaso-pressin (DDAVP) intranasally at5 mcg for neonates, 10 mcg forinfants, and 20 mcg for children todifferentiate the type of diabetesinsipidus. If the urine osmolality isincreased by more than 450 mOsm/kg, central diabetes insipidus isestablished. If the urine osmolalityremains less than 200 mOsm/kg,nephrogenic diabetes insipidus is thelikely diagnosis. Urine osmolality

increasing in excess of 750 mOsm/kgsuggests a compulsive water drinker.If rhinitis or sinusitis preclude intrana-sal administration, DDAVP can beadministered intravenously at 1/10 theintranasal dose.

Table 6 shows the serum andurine osmolality associated with thedifferent types of diabetes insipidusin the basal state and after waterdeprivation or antidiuretic hormoneadministration.

Fig. 3 shows how the plasmaarginine vasopressin correlates withplasma osmolality and allows thedistinction of central diabetes insipi-dus from normal and from nephro-genic diabetes insipidus.

MAGNETIC RESONANCEIMAGING (MRI)Both the anterior and posterior pitu-itary glands and stalk can be visual-

ized by use of MRI. The posteriorpituitary lobe appears as a round,high-intensity signal (bright spot)in the sella turcica; the presence ofsuch a signal is inconsistent with adiagnosis of central diabetesinsipidus.

In addition, MRI has been usedto delineate the cause of central dia-betes insipidus. Sagittal MRIenhanced with gadolinium maydemonstrate a large suprasellarmass. Loss of the brightT1-weighted signal within the sellamay indicate a pituitary cyst, pitu-itary hypoplasia, or an atopic lobe ofthe posterior pituitary, which can bethe cause of complete or partialvasopressin deficiency. In combina-tion with a displaced bright signal ofthe posterior gland, such a findingindicates an ectopic gland.

POLYURIC DEHYDRATION

SOLUTE DIURESIS WATER DIURESIS

c Urine-to-plasma osmolalityratio .0.7

c Urine-to-plasma osmolalityratio ,0.7

c Osmotic clearance .3 mL/min c Osmotic clearance ,3 mL/minc Polyuria .5 mL/kg per hourc Urine specific gravity ,1.010

2

SHORT WATER DEPRIVATION

c Elevation of plasma osmolality.10 mOsm/kg over baseline

c Urine specific gravity ,1.0102

DIABETES INSIPIDUS

c 1-desamino-8-D-argininevasopressin (DDAVP) intranasally5 mcg for neonates10 mcg for infants20 mcg for children

2 2 2Urine osmolality.450 mOsm/kg

Urine osmolality.750 mOsm/kg

Urine osmolality,200 mOsm/kg

CENTRAL DIABETESINSIPIDUS

COMPULSIVE WATERDRINKER

NEPHROGENICDIABETESINSIPIDUS

FIGURE 2. Differential diagnostic evaluation for polyuric dehydration, including the use of short water deprivation and1-desamino-8-D-arginine vasopressin (DDAVP).

2 2



Differential DiagnosisThe differential diagnosis of poly-dipsia or polyuria should includediabetes mellitus. This is easily dif-ferentiated from diabetes insipidusby the hyperglycemia, ketonuria,glucosuria, and high anion gap aci-dosis associated with diabetic keto-acidosis. Chronic renal failure alsomust be included in the differentialdiagnosis. Although the polyuria ofchronic renal failure is less severethan that seen in diabetes insipidus,it is more difficult to reverseazotemia with hydration.

Diabetes insipidus always shouldbe differentiated from small-volumeurinary frequency. In this condition,the polyuria is not accompanied bypolydipsia. Increased urinary fre-quency may be due to cystitis, mas-turbation, sexual abuse, urethral irri-tation, and urethritis.

Polyuria may follow solute (glu-cose, saline, mannitol, urea) diuresis.A urine-to-plasma osmolality ratiogreater than 0.7 and clearance ofosmolality of more than 3 mL/minpoints to solute-induced diuresis,instead of water diuresis, whichoccurs in diabetes insipidus. Thehypernatremia of primary hyperaldo-steronism is mild and accompaniedby hypertension, hypervolemia, andsuppression of plasma renin activity.

ManagementThe treatment of choice for centraldiabetes insipidus is intranasalDDAVP at doses of 5 to 20 mcgdaily. Rhinitis and sinusitis mayreduce intranasal absorption of thisdrug. Antibodies to this syntheticanalog of vasopressin have not beenencountered. The dose of oral prepa-rations is 20-fold greater than theintranasal dose. Aqueous vasopressinor desmopressin (4 mcg/mL ampule)can be used intravenously for acutehypophysectomy diabetes insipidusand often is used in brain-deadorgan donors.

Central diabetes insipidus hasresponded to chlorpropamide with a25% to 75% reduction in polyuria.The antidiuretic mechanism of thishypoglycemic agent is not entirelyclear. Clofibrate also has beenshown to reduce polyuria in centraldiabetes insipidus and may be used

alone or in conjunction withDDAVP or chlorpropamide. Finally,thiazide diuretics (hydrochlorothia-zide 2 to 3 mg/kg per day) decreasethe frequency of urination by 50%or more when accompanied by saltrestriction and are effective in bothcentral and nephrogenic diabetesinsipidus.

Oral repletion of water often issufficient to reverse acute dehydra-tion in diabetes insipidus. However,if parenteral rehydration is required,3% rather than 5% dextrose is pre-ferred. Glucose infusion exceedingthe rate of glucose utilization mayworsen the patients pre-existingstate of hyperosmolality. In addition,the ensuing glucosuria may result inan osmotic diuresis, which aggra-vates the hyperosmolality and dehy-dration further.

There are no effective pharmaco-logic agents to treat a compulsivewater drinker. Small, short-actingdoses of DDAVP administered atbedtime may reduce nocturia,although this therapeutic approach iscontroversal. Headaches and hyper-tension may result from water reten-tion caused by the DDAVP. Thisapproach should be used cautiously.

A low-osmolar, low-sodium dietshould be initiated to manage con-genital nephrogenic diabetes insipi-dus. Human milk is preferred ininfancy because protein constitutes6% of caloric intake. Sodium intakeshould be reduced to 0.7 mEq/kgper day. In a child who has nephro-genic diabetes insipidus, proteinintake should constitute 8% ofcaloric intake, and sodium intakeshould be less than 0.7 mEq/kg perday. This low-solute diet should becoupled with thiazide diuretics(hydrochlorothiazide 2 to 3 mg/kgper day in three divided doses orchlorothiazide 30 mg/kg per day).The diuretics increase sodium lossby inhibiting its reabsorption in thecortical diluting tubule. The ensuingextracellular fluid contraction aug-ments proximal tubular reabsorptionof water. These maneuvers usuallyresult in a 50% reduction in poly-uria. Side effects of thiazide diuret-ics include hypokalemia and (rarely)neutropenia. The tendency towardhypokalemia can be countered withpotassium supplementation or theuse of potassium-sparing diuretics,

TABLE 5. WaterDeprivation Test

Methodc Collect baseline urine and

blood (osmolality andelectrolytes).

c Deprive of water afterbreakfast until significantdehydration occurs.

c Weigh every 2 hr; limitdehydration to 3% to 5%loss of body weight.

c Monitor urine specificgravity hourly; if 1.014 orgreater, terminate test andobtain appropriate blood andurine specimens forosmolality.

c Limit water deprivation to7 hr (4 hr for infants).

c Collect urine and blood forosmolality and electrolytes.

c If polyuria persists,administer intranasalDDAVP.*

c Replace urine output withfluid.

c After 4 hr (2 hr in infants),obtain urine and bloodosmolality.

Resultsc Normal response to

dehydration or DDAVP:Urine osmolality

.450 mOsm/kg.Urine/serum osmolality

$1.5.Urine/serum osmolality

increases from baseline1.0 or more.

c Expect normal response incentral and psychogenicdiabetes insipidus.

c Above criteria not met innephrogenic diabetesinsipidus.

*DDAVP 5 1-desamino-8-D-argininevasopressin, 10 mcg for infants and20 mcg for children.Modified from Linshaw MA. Congenitalnephrogenic diabetes insipidus. In:Jacobson HR, Sticker GE, Klahr S, eds.Principles and Practice of Nephrology.Philadelphia, Penn: BC Decker Inc;1991:426430.



such as amiloride 0.1 to 0.2 mg/kgper day to a maximum of 10 mg/m2per day. No long-term side effectshave been reported with this combi-nation of medications. In addition,indomethacin 0.25 to 3 mg/kg perday in two divided doses or aspirin10 to 30 mg/kg per day in twodivided doses has an additive effecton hydrochlorothiazide in reducingwater excretion in some patients.Long-term side effects of indometh-acin, such as deterioration of renalfunction, require careful monitoring.Accordingly, such nonsteroidal anti-inflammatory medication should beused only after other therapies havefailed.

In hereditary diabetes insipidus,genetic counseling and follow-up areimportant. Finally, the body temper-ature, appetite, and linear growthshould be monitored at all follow-upclinic visits.

TABL

E6.

Inte

rpre

tatio

nofS

erum

an

dU

rine

Osm

olal

ity

SU

BJE

CT

S

BA

SA

LS

TA

TE

PLA

TE

AU

AFT

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H2O

DE

PR

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NA

FTE

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DH

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ILY

UR

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LUM

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)

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(ME

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)

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G)

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INE

SG

UR

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OS

MO

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TY

PLA

SM

AV

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OP

RE

SS

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SM

AV

AS

OP

RE

SS

IN

UR

INE

OS

MO

LALI

TY

(MO

SM

/KG

)

CH

AN

GE

INU

RIN

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SM

OLA

LIT

Y

Nor

mal

0.5

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0*13

5to

145

280

.1.

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50to

1,40

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orm

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sed

.80

0,

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300

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200

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170

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150

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)4

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170

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1.00

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300

Nor

mal

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dH

igh

300

,50

%

CWD

2.5

to20

140

,28

0,

1.02

0,

200

Dec

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crea

sed

600

,5%

CDI

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FIGURE 3. Correlation of plasmaarginine vasopressin (AVP) with plasmaosmolality in normal subjects, inpatients who have central (pituitary)diabetes insipidus, and in those whohave nephrogenic diabetes insipidus.Reprinted with permission fromRobertson GL, Mahr EA, Athar S, SinhaT. Development of clinical application ofa new method for radioimmune assay ofarginine vasopressin in human plasma.J Clin Invest. 1973;82:23402352. Bycopyright permission of The AmericanSociety for Clinical Investigation. Asmodified by Culpepper RM, Hebert SC,Andreoli TE. Nephrogenic diabetesinsipidus. In: Stanbury JB, WyngaardenJB, Fredrickson DS, Goldstein JL,Brown MS, eds. The Metabolic Basis ofInherited Disease. New York, NY:McGraw Hill Book Company; 1983:18671888.



PrognosisAlthough mental retardation result-ing from hypernatremic dehydrationand encephalopathy has been associ-ated with diabetes insipidus in thepast, early recognition and treatmenthave eliminated this feature of thedisease. However, short attentionspan, hyperactivity, and learning andpsychomotor delays continue to beseen. Nonobstructive functionalhydronephrosis and hydrouretersmay be encountered and should befollowed by renal ultrasonographyand urography. Chronic renal insuf-ficiency may occur by the seconddecade of life in children who havenephrogenic diabetes insipidus dueto glomerular thromboembolic com-plications of dehydration.

Transient diabetes insipidus mayfollow neurosurgery, although thisusually resolves spontaneously. Ifvasopressin deficiency persistsbeyond a few weeks, however, per-manent diabetes insipidus willensue. On rare occasions, chroniccentral diabetes insipidus has remit-ted spontaneously despite persistentdeficiency of vasopressin. The mecha-nism of this remission is not known.

As long as water is available toreplace the large urine output,patients remain asymptomatic exceptfor the inconvenience of the poly-dipsia and polyuria. However, whenthe need for water cannot be com-municated, such as in infancy, orwhen patients are anesthetized orunconscious, the lack of waterreplacement precipitates a life-threatening risk of dehydration.

Recent DevelopmentsPerinatal testing for carrier detectionof X-linked nephrogenic diabetesinsipidus with mutation analysis ofthe AVPR2 gene now is available.Cord blood obtained immediatelyafter delivery and before placentalextraction has yielded favorableresults for such early geneticdiagnosis.

SUGGESTED READINGAlon U, Chan JCM. Hydrochlorothiazide-

amiloride in the treatment of nephrogenicdiabetes insipidus. Am J Nephrol. 1985;5:913

Leung AKC, Robson WLM, Halperin ML.Polyuria in childhood. Clin Pediatr. 1991;11:634640

Mulders SM, Bichet DG, Rijss JPL, et al. Anaquaporin-2 water channel mutant whichcauses autosomal dominant nephrogenicdiabetes insipidus is retained in the Golgicomplex. J Clin Invest. 1998;102:5766

Yamamoto T, Sasaki S. Aquaporins in thekidney: emerging new aspects. Kidney Int.1998;54:10411051

AcknowledgmentsThe authors thank Betty Timozekfor secretarial assistance and KenleyWard, BSc, and Rosalind Bradley,MDiv, for editorial assistance.

PIR QUIZQuiz also available online atwww.pedsinreview.org.

7. A 2-month-old infant presents withfever, vomiting, and irritability for3 days. His mother states that hedrinks large quantities of milk andwater, and his diapers are frequentlywet, dripping in urine. Examinationreveals an irritable child who has drymouth. Respirations are 40 breaths/min, heart rate is 150 beats/min,temperature is 38.5C (101.3F), andblood pressure is 78/50 mm Hg. Theskin has a doughy feel withdecreased turgor. Laboratory evalua-tion reveals: serum sodium,165 mmol/L (165 mEq/L); potas-sium, 4 mmol/L (4 mEq/L); chloride,130 mmol/L (130 mEq/L); bicar-bonate, 20 mmol/L (20 mEq/L); andblood urea nitrogen, 20.35 mmol/L(57 mg/dL). The infant passes a largeamount of urine during examination.Urine specific gravity is 1.004, andthe urine is negative for blood,glucose, and protein. An abnormalityat which of the following sites bestexplains this childs illness?A. Collecting tubule.B. Distal tubule.C. Glomerulus.D. Loop of Henle.E. Proximal tubule.

8. A 14-year-old girl presents with poly-dipsia and polyuria for the past 2months. She states that she feels verythirsty and has to ingest 7 to 8 L offluid every day. She also passes largeamounts of urine 10 to 12 times aday. She appears well-hydrated andhas normal vital signs. Results of herurinalysis are normal, and her urinespecific gravity is 1.004. Serum elec-trolyte levels are within normallimits. Her basal state plasma vaso-pressin is low. After water depriva-tion for 7 hours, her urine volumedecreases and has a specific gravityof 1.018. Which of the following isthe most likely diagnosis?A. Central diabetes insipidus.B. Compulsive water drinking.C. Nephrogenic diabetes insipidus.D. Obstructive uropathy.E. Syndrome of inappropriate antidi-

uretic hormone secretion.

9. A 2-month-old male infant presentswith vomiting and irritability of3 days duration. He appears moder-ately dehydrated, with dry mucousmembranes and doughy skin. Labora-tory examination reveals: serumsodium, 158 mmol/L (158 mEq/L);potassium, 4 mmol/L (4 mEq/L);chloride, 120 mmol/L (120 mEq/L);bicarbonate, 22 mmol/L (22 mEq/L);and blood urea nitrogen,16.4 mmol/L (46 mg/dL). Findingson urinalysis are normal, and theurine specific gravity is 1.004. Afterappropriate rehydration, a 4-hourwater deprivation test is performed.The infant continues to pass urine ata rate of 5 to 6 mL/kg per hourwithout appreciable response to vaso-pressin administration. Which of thefollowing is the most appropriatelong-term management?A. Intranasal desmopressin.B. Lithium.C. Low-osmolar diet.D. Mineralocorticoids.E. Water restriction.

10. Which of the following conditionsis most likely associated with neuro-genic diabetes insipidus?A. Absent corpus callosum.B. Ataxia telengiectasia.C. Cerebellar astrocytoma.D. Chiari malformation.E. Craniopharyngioma.



DOI: 10.1542/pir.21-4-1222000;21;122Pediatrics in Review

Pablo Saborio, Gary A. Tipton and James C.M. ChanDiabetes Insipidus

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Pablo Saborio, Gary A. Tipton and James C.M. ChanDiabetes Insipidus

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