AUTHOR INFORMATION

Section 1 of 12

Authored by James CM Chan, MD, Consulting Staff, Department of Pediatrics, Maine Medical Center

Coauthored by Karl S Roth, MD, Chair, Professor, Department of Pediatrics, Creighton University School of Medicine

James CM Chan, MD, is a member of the following medical societies: Alpha Omega Alpha, American Academy of Pediatrics, American Association for the Advancement of Science, American Association of University Professors, American Chemical Society, American Heart Association, American Medical Association, American Physiological Society, American Society for Bone and Mineral Research, American Society of Nephrology, American Society of Pediatric Nephrology, International Society of Nephrology, New York Academy of Sciences, Society for Experimental Biology and Medicine, Southern Society for Pediatric Research, and Western Society for Pediatric Research

Edited by Thomas A Wilson, MD, Professor of Clinical Pediatrics, Department of Pediatrics; Director of Pediatric Endocrinology, Division of Pediatric Endocrinology, Department of Pediatrics, State University of New York at Stony Brook; Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine.com, Inc; George P Chrousos, MD, FAAP, MACP, MACE, Professor and Chair, Department of Pediatrics, Athens University Medical School; Merrily P M Poth, MD, Professor, Department of Pediatrics and Neuroscience, Uniformed Services University of the Health Sciences; and Stephen Kemp, MD, PhD, Professor, Department of Pediatrics, Section of Pediatric Endocrinology, University of Arkansas and Arkansas Children's Hospital

Author's Email:	James CM Chan, MD
Editor's Email:	Thomas A Wilson, MD

eMedicine Journal, July 26 2006, VOLUME 7, Number 7

INTRODUCTION

Section 2 of 12

Background: The word diabetes is derived from the Greek verb diabainein, which means to stand with legs apart, as in urination, or to go through. Insipidus comes from a Latin word meaning without taste. In contrast to diabetes mellitus (DM), which describes the excretion of sweet urine, diabetes insipidus (DI) describes the passing of tasteless urine because of its relatively low sodium content.

Nephrogenic DI (NDI) reached North America in 1761, carried by Ulster Scots who arrived in Nova Scotia, Canada, on a ship named Hopewell. Scottish folklore reports the existence of the disease in Scotland before 1761. According to legend, a gypsy woman traveling with her thirsty son is denied water by a housewife. The gypsy woman curses the housewife, causing the housewife's sons to crave water while condemning her daughters to pass the curse on to future generations.

Pathophysiology: The basis of water loss in DI is distinct from water loss caused by DM. The renal tubular collecting ducts are unable to concentrate urine secondary to vasopressin deficiency or resistance. The collecting duct concentrates urine by reabsorbing water, a function controlled by the posterior pituitary gland via secretion of vasopressin or antidiuretic hormone (ADH). Reabsorption of sugars, amino acids, and virtually all electrolytes is completed by the time the urine has reached this segment of the nephron. Consequently, the inability to conserve water by reabsorption in the collecting duct depletes body water, but leaves sodium unaffected. The net result is an extremely diluted, increased urine output resulting in hypernatremia. Polydipsia follows as the thirst mechanism urges replenishment of body water.

Secretion of vasopressin occurs in the posterior pituitary gland and is regulated at the paraventricular and supraoptic nuclei, which sense changes in osmolality. Destruction of the paraventricular or supraoptic nuclei or of the posterior pituitary by tumor, pressure, or surgical ablation results in decreased vasopressin secretion and central diabetes insipidus (CDI). Alternatively, DI may be idiopathic or inherited either as an autosomal dominant or as an autosomal recessive trait (locus 20p13).

NDI arises from defective or absent receptor sites at the cortical collecting duct segment of the nephron (X-linked, vasopressin V2 receptor deficiency, locus Xq28) or defective or absent aquaporin, the protein that transports water at the collecting duct (autosomal recessive, locus 12q13). The X-linked variety of NDI accounts for about 90% of all such cases.

As a consequence of one of these defects, the ducts do not respond appropriately to vasopressin. Normally, vasopressin is transported in the blood to receptor sites on the basolateral surface of the collecting duct membrane. Through a G protein–adenylate cyclase coupling, activation of the vasopressin receptor increases cyclic adenosine monophosphate (AMP) production and stimulates protein kinase A, leading to increased recycling of the protein aquaporin in the plasma membrane.

In the presence of vasopressin stimulus, exocytic insertion of aquaporin into the apical, or luminal, surface of the tubule cell occurs. Aquaporin enhances water entry into the cell from the lumen. Absence of the vasopressin receptor does not allow this process to take place, causing inhibition of water uptake and polyuria. Alternatively, defective or absent aquaporin impairs the process in the presence of normal V2 receptors.

Frequency:

• In the US: Tumors, infiltrative lesions, malformations, and neurosurgical procedures are the most common causes of CDI. Of the genetic etiologies, the overall incidence in the general population is estimated to be 3 cases per 100,000 population (0.003%.) The male-to-female ratio is 60:40. X-linked NDI is very rare, although it exceeds the recessive variety by a ratio of 9:1. The mutation for males is 4 cases per million population.

Mortality/Morbidity:

• Dehydration results from an inability to reabsorb free water at a site distal to electrolyte reabsorption. Any patient unable to continuously replace water loss is vulnerable to dehydration, especially in warm weather when insensible water loss through perspiration and respiration substantially increases risk. Electrolyte abnormalities are caused by the loss of urinary free water, which produces hyperosmolar dehydration, leading to hypernatremia, hyperchloremia, and prerenal azotemia. Diminished blood volume increases blood viscosity and the risk of sludging and thrombosis.

• Failure to thrive occurs because of the patient's constant thirst conferring a sense of fullness that offsets the sense of hunger. The affected individual eats less than necessary for normal growth.
  
  
• Seizures are a consequence of the electrolyte abnormalities introduced in the central nervous system (CNS) by severe hypernatremia and hyperosmolar dehydration.

• Mental retardation results from the damage to the CNS caused by severe hyperosmolarity, seizures, and potential hypoxia, all of which are thought to account for the frequent occurrence of mental retardation.
  
  
• Death can occur from a hypovolemic shock or a hypernatremic seizure.

Sex:

• CDI secondary to hypothalamic-pituitary lesions occurs at random and should, therefore, be evenly distributed between the sexes.

• Autosomal dominant and autosomal recessive CDI occur equally in both sexes.

• NDI caused by an X-linked mutation affects males only. Autosomal dominant and autosomal recessive forms of NDI affect both sexes equally.

Age:

• DI occurs in people of a wide age range.

• Children who present with autosomal recessive CDI are generally younger than 1 year. Children who present with autosomal dominant CDI are often older than 1 year.

• NDI forms (including X-linked, autosomal dominant, and autosomal recessive forms) develop in early infancy, often in neonates younger than 1 week.

CLINICAL

Section 3 of 12

History:

• Diagnosis may be difficult in infants and children because of nonspecific presenting features (eg, poor feeding, failure to thrive, irritability). Therefore, a high index of suspicion is necessary.



• The earliest signs of diabetes insipidus (DI) include a vigorous suck with vomiting, fever without apparent cause, constipation, and excessively wet diapers from urination.



• In older infants and young children, irritability is generally due to a borderline state of dehydration coupled with hypernatremia and, sometimes, fever.



• Nocturia is common and expected because of increased urine production.



• CDI tends to develop suddenly.

Physical:

• The typical examination shows an irritable infant with a dripping wet diaper, along with detectable signs of dehydration (eg, dry mucous membranes, diminished skin turgor, decreased tearing, tachycardia). Often, skin turgor is not diminished in individuals with hypernatremic dehydration despite significant dehydration.



• In severely dehydrated patients, the pulse may be thready and rapid. Hypotension may be present because of hypovolemic shock.



• Mobile fecaliths may be palpable in the abdomen.

Causes: DI is due either to (1) deficiency of vasopressin secretion by the pituitary gland (CDI or neurogenic DI) or to (2) renal tubular unresponsiveness to vasopressin (NDI).

• Nongenetic causes


• • Typical injuries include head trauma, tumor, and neurosurgical procedures.
  
  
  
  • At all ages, destructive lesions of the pituitary and/or hypothalamus are the most common cause of DI.
  
  
  
• Genetic causes


• • CDI with an autosomal dominant pattern inheritance is due to a mutation in the prepro-arginine vasopressin (prepro-AVP2) gene, mapped to locus 20p13.
  
  
  
  • CDI with diabetes mellitus, optic atrophy, and mental retardation (Wolfram syndrome) may be inherited in an autosomal recessive pattern (locus 4p16) or may be due to mitochondrial deletions.
  
  
  
  • X-linked NDI occurs from mutations in the antidiuretic arginine vasopressin V2 receptor (AVPR2) gene, mapped to Xq28.
  
  
  
  • NDI with an autosomal dominant or recessive pattern is due to mutations in the gene designated AQP2; this gene directs water channel formation in the distal membrane and has not yet been mapped.
  
  
  

DIFFERENTIALS

Section 4 of 12

Head Trauma
Medullary Cystic Disease
Sickle Cell Anemia

Other Problems to be Considered:

Histiocytosis X
Hypercalcemic nephropathy
Hypokalemic nephropathy
Interstitial nephritis
Posterior fossa tumor
Neurosurgical ablation of neurohypophysis
Psychogenic polydipsia
Water intoxication (excessive consumption)

WORKUP

Section 5 of 12

Lab Studies:

• The urine specific gravity of the first morning urine is helpful in assessing renal ability to concentrate urine. Dilute urine with a relatively high serum sodium and osmolarity effectively establishes the diagnosis. The serum sodium may be as high as 170 mEq/L, while the serum osmolarity is greater than 300 mOsm/kg. Patients with prerenal azotemia present with severe dehydration.



• In young infants, finding a distinction between normal and pathological inability to concentrate the urine may be difficult because infants generally exhibit a constitutional hyposthenuria.



• The definitive diagnostic study is the water deprivation test, which can be used both to confirm the diagnosis and to distinguish between central diabetes insipidus (CDI) and NDI by response to a vasopressin analogue. The water deprivation test is performed as follows:


• • Collect baseline urine and blood for osmolality and electrolytes. Deprive the patient of water after breakfast until significant dehydration occurs. Weigh the patient every 2 hours and limit dehydration to 2-5% loss of body weight.
  
  
  
  • Monitor urine specific gravity hourly; if the specific gravity is 1.014 or greater, terminate the test and obtain appropriate urine and blood specimens for osmolality. Limit water deprivation to 4 hours for infants and 7 hours for children. If polyuria persists, administer intranasal desmopressin (see Medication) and replace urine output with fluids. After 4 hours (2 h in infants), obtain urine and blood for osmolality.
  
  
  
  • The normal response to dehydration or desmopressin acetate (DDAVP) includes urine osmolality greater than 450 mOsm/kg, urine/serum osmolality greater than or equal to 1.5, and an increase in urine/serum osmolality from baseline of 1.0 or more. A normal response should be observed in CDI and psychogenic DI but not in NDI.
  
  
  
• An accurate 24-hour urine collection is important. The total urine output is high, and the number of osmoles excreted per day is small.



• Serum potassium and calcium concentrations are important to exclude the possibility of polyuria secondary to hypokalemia or hypercalcemia, both of which interfere with renal concentrating mechanisms.

Imaging Studies:

• Cranial MRI can be used to exclude pituitary cysts, hypoplasia, and destruction secondary to mass lesions. Often, the bright spot that is thought to represent vasopressin-secreting neurons in the posterior pituitary is absent in CDI.

TREATMENT

Section 6 of 12

Medical Care:

• Treat patients in an inpatient setting because of the risk of severe dehydration. Destructive or compressive intracranial lesions mandate inpatient stay.



• Distinguishing between central and nephrogenic etiology is essential to the treatment modality.

Surgical Care: Demonstration of an intracranial mass necessitates surgical care.

Consultations:

• Nephrologist



• Endocrinologist: The presence of central diabetes insipidus should prompt an evaluation of anterior pituitary function.



• Diagnostic radiologist

Diet:

• Provide affected infants a breast milk diet to decrease solute load. Protein should comprise 6% of caloric intake, and sodium should be reduced to 0.7 mEq/kg/d.



• Provide young children 8% of their caloric intake as protein to enable normal growth. Sodium intake must be maintained at 0.7 mEq/kg/d.

Activity:

• Activities resulting in increased insensible water loss should be moderated in the presence of massive urinary water loss to prevent dehydration.



• Heat exposure should be minimized, especially when participating in sports.

MEDICATION

Section 7 of 12

For central diabetes insipidus (CDI), the treatment of choice is desmopressin (a synthetic vasopressin analogue). It is available in parenteral, intranasal, and oral dosage forms. The doses are quite different depending upon the preparation used, so take care to calculate the dose correctly. Other useful medications include chlorpropamide and thiazide diuretics. The latter 2 can result in a 25-75% reduction in urine volume and can be used in combination with each other.

NDI cannot be treated effectively with desmopressin because the receptor sites are defective and the kidney is prevented from responding. Thiazide diuretics, amiloride, and indomethacin or aspirin are useful when coupled with a low-solute diet.

Drug Category: Pituitary hormones -- DI of central origin is due to absence of vasopressin secretion by the pituitary. Consequently, use of a synthetic vasopressin analogue (ie, desmopressin) is required. The natural compound vasopressin (ie, ADH) may be used to diagnose NDI. It has a very short natural half-life. This permits its safe use in distinguishing CDI from NDI by obviating prolonged fluid accumulation in the former. As an aqueous preparation, it can be administered parenterally, IM, or SC.

Drug Name	Desmopressin acetate (DDAVP) -- A synthetic analogue (1-[3-mercaptopropionic acid]-8-D-arginine vasopressin monoacetate trihydrate) of pituitary ADH. Increases cellular permeability of collecting ducts, resulting in reabsorption of water by kidneys. Dosage must be individualized. Drug is supplied as parenteral (4 mcg/mL), nasal (100 mcg/mL rhinal tube), and PO (0.1- and 0.2-mg tab) preparations.
Adult Dose	0.5-1 mL/d (2-4 mcg/d) IV/SC divided bid 0.1-0.4 mL/d (10-40 mcg) intranasally divided bid/tid 0.1-1.2 mg/d PO divided bid/tid
Pediatric Dose	0.05-0.5 mL/d (0.2-2 mcg/d) IV/SQ divided bid 0.05-0.3 mL/d (5-30 mcg/d) intranasally qd or divided bid/tid >4 years: 0.05-0.2 mg/d PO divided bid/tid
Contraindications	Documented hypersensitivity; platelet-type von Willebrand disease; water loss due to NDI
Interactions	Coadministration with demeclocycline and lithium decreases effects; fludrocortisone and chlorpropamide increase effects of desmopressin
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Use carefully and monitor serum sodium and body weight because of the danger of overdose and consequent water intoxication; hyponatremia may occur from overdose; every patient must be individually evaluated for optimal dose

Drug Name	Vasopressin (Pitressin) -- Has vasopressor and antidiuretic hormone (ADH) activity. Increases water resorption at distal renal tubular epithelium (ADH effect) and promotes smooth muscle contraction throughout vascular bed of renal tubular epithelium (vasopressor effects). However vasoconstriction also increased in splanchnic, portal, coronary, cerebral, peripheral, pulmonary, and intrahepatic vessels. Use only the aqueous preparation, which has a short half-life. Vasopressin tannate in oil, which has a longer action, should not be used.
Adult Dose	0.5 mU (0.0005 unit)/kg/h IV continuous infusion initially, dilute in 0.9% NaCl or 5% glucose to 0.1-1 U/mL; dosage may be doubled q30min prn; not to exceed 10 mU/kg/h 5-10 U IM/SC bid/qid prn; not to exceed 60 U/d
Pediatric Dose	IV: Administer as in adults IM/SC: 2.5-10 U IM/SC bid/qid prn
Contraindications	Documented hypersensitivity; chronic renal disease with nitrogen retention
Interactions	Decreased biological activity reported with lithium, demeclocycline, epinephrine, heparin, and alcohol; increased biological activity reported with chlorpropamide, carbamazepine, tricyclic antidepressants, clofibrate, and fludrocortisone
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Use with care in seizure disorders, migraines, asthma, vascular disease, renal disease, cardiac disease, goiter, and arteriosclerosis

Drug Category: Diuretic agents -- Thiazide diuretics impair sodium chloride reabsorption in the distal tubule, reducing the loss of free water to the collecting system and increasing urine concentration. Reduction in urine volume derives from a concomitant action on the proximal tubule, which causes enhanced reabsorption of isoosmotic sodium chloride from the glomerular filtrate, thus drawing additional water along. The net result of both processes is a smaller volume and a higher concentration of the urine.

Drug Name	Hydrochlorothiazide (Esidrix, HydroDIURIL, Microzide) -- Thiazide diuretic. Combination of decreased free water delivery to distal tubule and increased sodium chloride reabsorption in proximal tubule underlies the efficacy in DI therapy.
Adult Dose	25-50 mg/d PO
Pediatric Dose	<2 years: 2-4 mg/kg/d PO bid/qd; not to exceed 37.5 mg/d >2 years: 2-4 mg/kg/d PO bid/qd; not to exceed 100 mg/d
Contraindications	Documented hypersensitivity; anuria; renal decompensation
Interactions	Thiazides may decrease effects of anticoagulants, antigout agents, and sulfonylureas; thiazides may increase toxicity of allopurinol, anesthetics, antineoplastics, calcium salts, loop diuretics, lithium, diazoxide, digitalis, amphotericin B, and nondepolarizing muscle relaxants
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Monitor urine output and serum electrolytes carefully; caution in renal disease, hepatic disease, gout, diabetes mellitus, and systemic lupus erythematosus

Drug Name	Amiloride (Midamor) -- Potassium-sparing diuretic. Has a potassium-sparing effect, so risk of hypokalemia is decreased in combination with hydrochlorothiazide. In addition, the 2 agents are synergistic with respect to antidiuresis.
Adult Dose	5-10 mg/d PO; not to exceed 20 mg/d
Pediatric Dose	Titrate dose gradually;, not to exceed 20 mg/1.73 m2/d PO divided bid/tid; may induce nausea in children <4 y
Contraindications	Documented hypersensitivity; elevated serum potassium levels (>5.5 mEq/L); impaired renal function; acute or chronic renal insufficiency; evidence of diabetic nephropathy
Interactions	Concomitant therapy with potassium supplementation may increase serum potassium levels so use caution and monitor serum potassium levels frequently if concomitant use of these agents is indicated because of demonstrated hypokalemia; lithium generally should not be administered with diuretics because they may reduce renal clearance and add a high risk of lithium toxicity; administration of nonsteroidal anti-inflammatory agents can reduce diuretic, natriuretic, and antihypertensive effects of loop, potassium-sparing, and thiazide diuretics when used concomitantly, observe patient closely to determine if desired effect of diuretic is obtained; indomethacin and potassium-sparing diuretics, including amiloride, may be associated with increased serum potassium levels, consider potential effects on potassium kinetics and renal function
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Monitor electrolytes and renal function carefully if evidence of renal functional impairment is present, ie, BUN >30 mg/100 mL or serum creatinine levels >1.5 mg/100 mL

Drug Category: Nonsteroidal anti-inflammatory agents -- These agents act synergistically with thiazides to diminish urine volume, although precise mechanism is unknown.

Drug Name	Indomethacin (Indocin) -- Nonsteroidal prostaglandin inhibitor with antipyretic properties.
Adult Dose	25 mg PO bid/tid; not to exceed 200 mg/d
Pediatric Dose	<2 years: Do not use >2 years: 2 mg/kg/d PO divided bid/qid doses; not to exceed 150 mg/d
Contraindications	Documented hypersensitivity; GI bleeding; renal insufficiency
Interactions	Coadministration with aspirin increases risk of inducing serious NSAID-related adverse effects; probenecid may increase concentrations and, possibly, toxicity of NSAIDs; may decrease effect of hydralazine, captopril, and beta-blockers; may decrease diuretic effects of furosemide and thiazides; may increase PT when taking anticoagulants (instruct patients to watch for signs of bleeding); may increase risk of methotrexate toxicity; phenytoin levels may be increased when administered concurrently
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Category D in third trimester of pregnancy; acute renal insufficiency, hyperkalemia, hyponatremia, interstitial nephritis, and renal papillary necrosis may occur; increases risk of acute renal failure in patients with preexisting renal disease or compromised renal perfusion; reversible leukopenia may occur (discontinue if persistent leukopenia, granulocytopenia, or thrombocytopenia is present)

Drug Category: Sulfonylurea compounds -- These compounds are an alternative therapy to desmopressin and can be used in combination with thiazide diuretics. Sulfonylurea compounds have the reported property of causing a syndrome identical to inappropriate ADH secretion.

Drug Name	Chlorpropamide (Diabinese) -- Promotes renal response to ADH. In CDI, ADH secretion is absent, although ADH receptor sites remain present in the kidney. Thus, interaction of the receptors with sulfonylurea compounds can produce a physiologic antidiuresis. Dosage must be individualized. Available only in tablet form.
Adult Dose	150-250 mg/d PO initially, slowly increase in 50 mg/d increments q3-5d if hypoglycemia does not supervene; not to exceed 750 mg/d
Pediatric Dose	Not established; limited data suggests a starting dose of 50 mg/d PO, may increase by 50 mg/d increments q3-5d; not to exceed 150 mg/d; carefully monitor blood sugar
Contraindications	Documented hypersensitivity; ketoacidosis; type 1 DM
Interactions	Clofibrate, fenfluramine, histamine (H2) antagonists, androgens, azole antifungals, anticoagulants, chloramphenicol, fluconazole, gemfibrozil, magnesium salts, methyldopa, MAOIs, probenecid, salicylates, sulfinpyrazone, urinary acidifiers, and sulfonamides may enhance hypoglycemic effects; nicotinic acid, PO contraceptives, isoniazid, hydantoins, estrogens, diazoxide, corticosteroids, cholestyramine, beta-blockers, calcium channel blockers, phenothiazines, rifampin, thiazide diuretics, urinary alkalinizers, and sympathomimetics may decrease hypoglycemic effects; may increase effects of digitalis glycosides
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Monitor carefully for hypoglycemia, hyponatremia, and fluid overload; caution in hepatic and renal impairment; cardiovascular disorders may occur

FOLLOW-UP

Section 8 of 12

Further Inpatient Care:

• Subsequent admissions are determined by the need for intravenous rehydration, especially during intercurrent gastrointestinal illnesses.

Further Outpatient Care:

• Regular follow-up visits with an endocrinologist (for central diabetes insipidus [CDI]) or a nephrologist (for NDI) are necessary for dosage adjustment.



• When indomethacin is used in long-term therapy, carefully observe renal function for any signs of toxicity.

In/Out Patient Meds:

• In addition to the medications already listed, aqueous vasopressin (Pitressin) and desmopressin (DDAVP) preparations are available for intravenous use in emergency circumstances.

Transfer:

• Transfer to an academic center is highly advised for initial diagnosis and treatment, especially because CDI may require involved diagnostic studies and neurosurgical or oncologic treatment.



• Subsequent episodes requiring intravenous rehydration can be treated by routine admission.

Deterrence/Prevention:

• Reduce or eliminate activities resulting in increased insensible fluid losses.



• Avoid creating barriers to drinking water.

Complications:

• Growth failure



• Nocturia and enuresis



• Hypernatremic dehydration



• Seizures



• Mental retardation

Prognosis:

• Long-term survival in cases of CDI depends on the precipitating cause. In primary CDI, the prognosis is excellent with early recognition and appropriate DDAVP therapy.



• The earlier onset of NDI and the reduced ability to treat this variety of the disease renders the child more prone to attention deficits, hyperactivity, learning disorders, and psychomotor delay.



• As long as water remains available at all times to replace the massive losses, long-term survival is not in question.

Patient Education:

• Parents must replace water in infants and young children who cannot express thirst or access fluids without assistance.



• Gastrointestinal illnesses that cause decreased intake, increased stool losses, or both must receive early and serious attention to prevent life-threatening electrolyte and fluid balance abnormalities.

MISCELLANEOUS

Section 9 of 12

Medical/Legal Pitfalls:

• Failure to recognize excessive fluid losses



• Failure to diagnose an underlying condition causing secondary central diabetes insipidus



• Overtreatment with DDAVP resulting in hyponatremia and seizures

Special Concerns:

• Surgical procedures of any kind require replacement of fluids at a much higher rate than normal maintenance; inattention to this may result in serious consequences.

TEST QUESTIONS

Section 10 of 12

CME Question 1: Which of the following is the most common cause of diabetes insipidus (DI) in people of all ages?

A: X-linked inheritance
B: Autosomal dominant inheritance
C: Idiopathic causes
D: Autosomal recessive inheritance
E: Lesions of the pituitary

The correct answer is E: DI is due to a dysfunction of the collecting duct. The physiologic purpose of the collecting duct is to concentrate the final urine by reabsorption of water, a function that is under the control of the posterior pituitary gland. Destruction of the posterior pituitary by tumor or the pressure of surgical ablation is often the cause of CDI.

CME Question 2: Which of the following is not useful in the treatment of diabetes insipidus (DI)?

A: Thiazide diuretics
B: Aspirin
C: Furosemide
D: Amiloride
E: Indomethacin

The correct answer is C: For CDI the treatment of choice is desmopressin (DDAVP), a synthetic analogue of vasopressin. Other useful medications are chlorpropamide (Diabinese), clofibrate (Atromid-5), and thiazide diuretics. The latter 3 drugs can result in a 25-75% reduction in urine volume and can be used in combination with each other.

Nephrogenic DI (NDI) cannot be treated effectively with DDAVP because the receptor sites are defective and the kidney is prevented from responding. Thiazide diuretics, amiloride, and indomethacin or aspirin are useful when coupled with a low-solute diet. Thiazides impair sodium chloride reabsorption in the distal tubule, reducing the loss of free water to the collecting system and increasing urine concentration. Reduction in urine volume derives from a concomitant action on the proximal tubule, which causes enhanced reabsorption of isoosmotic sodium chloride from the glomerular filtrate, thus drawing additional water along. The net result of both processes is a smaller volume and higher concentration of the urine.

Pearl Question 1 (T/F): The etiology of hypernatremia in diabetes insipidus may involve increased sodium reabsorption into the vascular space at the level of the distal tubule.

The correct answer is False: Solute concentration of the urine occurs chiefly in the loop of Henle, so urine reaching the distal collecting system is dilute in relation to plasma. At this point, the vast bulk of filtered sodium has already been reabsorbed. Failure to reabsorb free water from the dilute distal tubular fluid results in concentration of the reabsorbed sodium in the vascular space, resulting in hypernatremia.

Pearl Question 2 (T/F): Central diabetes insipidus (CDI) and nephrogenic diabetes insipidus (NDI) cannot be differentiated, even under controlled conditions.

The correct answer is False: The water deprivation test is used to distinguish between CDI and NDI by depleting body water under controlled conditions. Because CDI is the result of absent vasopressin secretion, administration of desmopressin (DDAVP) results in an increase in renal concentrating ability and increasing urine osmolarity in cases of CDI. However, in NDI, the absence of a response to administered vasopressin unequivocally demonstrates the diagnosis. CDI and NDI may also be distinguished by determining serum antidiuretic hormone (ADH) concentration in the presence of hypernatremia. In CDI, serum ADH concentration is inappropriately low, whereas, in NDI, serum ADH concentrations are appropriately elevated.

Pearl Question 3 (T/F): The therapeutic advantage of using thiazides in treating nephrogenic diabetes insipidus is manifested in 2 processes.

The correct answer is True: Thiazides impair sodium chloride reabsorption in the distal tubule, reducing the loss of free water to the collecting system and increasing urine concentration. Reduction in the urine volume derives from a concomitant action on the proximal tubule, which causes enhanced reabsorption of isoosmotic sodium chloride from the glomerular filtrate, thus drawing additional water along. The net result of both processes is a smaller volume and higher concentration of the urine.

Pearl Question 4 : Diagnosis of diabetes insipidus (DI) in infants is easily made based on clinical findings.

The correct answer is : Diagnosis may be very difficult in infants and children because of nonspecific presenting features (eg, poor feeding, failure to thrive, irritability). Therefore, a high index of suspicion is necessary. The earliest signs of DI include a vigorous suck with vomiting, fever without apparent cause, constipation, and excessively wet diapers from urination.

PICTURES

Section 11 of 12

Caption: Picture 1. Carbs for Kids-Count Them In: The Constant Carbohydrates Diet.
Picture Type: Movie
Caption: Picture 2. Diabetes Sick Day Rules.
Picture Type: Movie
Caption: Picture 3. Taking Diabetes Back to School.
Picture Type: Movie

BIBLIOGRAPHY

Section 12 of 12

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• Bichet DG, Arthus MF, Lonergan M, et al: X-linked nephrogenic diabetes insipidus mutations in North America and the Hopewell hypothesis. J Clin Invest 1993 Sep; 92(3): 1262-8[Medline][Full Text].
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• Davies JH, Penney M, Abbes AP, et al: Clinical features, diagnosis and molecular studies of familial central diabetes insipidus. Horm Res 2005; 64(5): 231-7[Medline].
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