Diabetes Insipidus View Online At

Diabetes Insipidus View online at http://pier.acponline.org/physicians/diseases/d145/d145.html

Module Updated: 2013-01-29 CME Expiration: 2016-01-29

Author Robert J. Ferry, Jr., MD

Table of Contents 1. Diagnosis ...... 2 2. Consultation ...... 8 3. Hospitalization ...... 10 4. Therapy ...... 11 5. Patient Counseling ...... 16 6. Follow-up ...... 17 References ...... 19 Glossary...... 22 Tables ...... 23 Figures ...... 39

Quality Ratings: The preponderance of data supporting guidance statements are derived from: level 1 studies, which meet all of the evidence criteria for that study type; level 2 studies, which meet at least one of the evidence criteria for that study type; or level 3 studies, which meet none of the evidence criteria for that study type or are derived from expert opinion, commentary, or consensus. Study types and criteria are defined at http://smartmedicine.acponline.org/criteria.html Disclaimer: The information included herein should never be used as a substitute for clinical judgement and does not represent an official position of the American College of Physicians. Because all PIER modules are updated regularly, printed web pages or PDFs may rapidly become obsolete. Therefore, PIER users should compare the module updated date on the offical web site with any printout to ensure that the information is the most current available. CME Statement: The American College of Physicians is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing education for physicians. The American College of Physicians designates this enduring material for a maximum of 1 AMA PRA Category 1 CreditTM. Physicians should claim only credit commensurate with the extent of their participation in the activity. Purpose: This activity has been developed for internists to facilitate the highest quality professional work in clinical applications, teaching, consultation, or research. Upon completion of the CME activity, participants should be able to demonstrate an increase in the skills and knowledge required to maintain competence, strengthen their habits of critical inquiry and balanced judgement, and to contribute to better patient care. Disclosures: Robert J. Ferry, Jr., MD, current author of this module, has no financial relationships with pharmaceutical companies, biomedical device manufacturers, or health-care related organizations. Deborah Korenstein, MD, FACP, Co-Editor, PIER, has no financial relationships with pharmaceutical companies, biomedical device manufacturers, or health-care related organizations. Richard B. Lynn, MD, FACP, Co-Editor, PIER, has no financial relationships with pharmaceutical companies, biomedical device manufacturers, or health-care related organizations. PIER is copyrighted ©2013 by the American College of Physicians. 190 N. Independence Mall West, Philadelphia, PA 19106, USA.

Diabetes Insipidus

Top 1. Diagnosis Confirm the diagnosis of DI with appropriate laboratory testing in patients with chronic thirst, increased fluid intake (polydipsia) or increased urination (polyuria), urinary frequency, enuresis, or nocturia. 1.1 Perform a complete history and physical exam to identify characteristics associated with DI and to identify its etiology. Recommendations • Ask about:

 Persistent thirst, particularly craving water or cold liquids  Urinary frequency, enuresis, or nocturia  Duration or persistence of symptoms (typically of insidious onset, unless postoperative)  Appearance of the urine (typically very light colored or clear with DI)  Family history of similar symptoms or diagnosis of DI or diabetes mellitus  Headaches  Head trauma  Recent neurosurgery  History of pituitary disease and anterior pituitary hormone deficiencies  Menstrual irregularity  Pregnancy-related polyuria and polydipsia  History of renal or systemic disease  Medications and nutritional supplements • Look for:

 Signs of focal neurologic deficits  Congenital anomalies, particularly facial malformations  Visual field deficits and examination of optic nerve  Galactorrhea  Signs of secondary adrenal insufficiency or secondary hypothyroidism  Growth failure or delayed puberty in pediatric patients  Signs of dehydration, including hemodynamic and mental status changes (rare) • See table Etiologies of Central Diabetes Insipidus. • See table Etiologies of Nephrogenic Diabetes Insipidus. • See table Definitions of Diabetes Insipidus. Evidence • The risk for DI is highest with procedures near the pituitary, which are most often performed to debulk neoplasms (e.g., craniopharyngioma, astrocytoma, or retinoblastoma) (1). • A 1999 review from a German university hospital documented postoperative DI in 59.4% of adult patients undergoing transsphenoidal procedures (2). • Gestational DI is transient and typically remits by 2 months postpartum (3); it is usually responsive to desmopressin administration, but not AVP, because the placenta metabolizes AVP; desmopressin resists placental degradation. Pregnancy may exacerbate preexisting DI (4).

Diabetes Insipidus

• Less than 5% of patients with DI present with hypernatremia; their manifestations include altered mental status, lethargy, irritability, restlessness, seizures (more common in children), muscle twitching, spasticity, fever, nausea, or vomiting (5). • The defects most associated with DI appear to be holoprosencephaly or optic nerve hypoplasia with absence of the septum pellucidum (6). • The funduscopic exam may reveal papilledema due to increased CSF production or blocked CSF circulation from a CNS lesion (7). Rationale • The specific etiology of DI directs treatment and follow-up management. • Although rare, hemodynamic instability and mental status changes should be addressed emergently as evaluation of the polyuria proceeds, because hemodynamic instability occurs only when fluid intake is impaired and severe hypernatremic dehydration develops. • Nephrogenic DI can be induced by certain drugs Comments • DI is a disorder characterized by the inability to appropriately concentrate the urine, resulting from either deficient release of AVP (pituitary or central DI) or resistance to vasopressin action at the level of the distal renal tubule and collecting duct (nephrogenic DI). In the first half of the 20th century, Professor Ernest Verney first linked DI to a decrease in AVP secretion or action (8). • Historical or physical evidence of an injury, disorder, or therapy known to be a frequent cause of DI should prompt evaluation for DI. • DI itself does not usually result in any appreciable abnormal physical sign; however, absence of historical or physical evidence of a known cause does not exclude the diagnosis of DI. • Dehydration associated with DI most often occurs as a result of coexistent morbidity, such as anorexia, malabsorption, adrenal insufficiency, or cerebral salt wasting. 1.2 Measure urinary output from patients after neurosurgery or head trauma to anticipate the development of central DI. Recommendations • Measure urinary output hourly and urinary specific gravity every 4 hours throughout the initial 72 hours after head trauma or neurosurgery to monitor for dilute polyuria, which is defined as:

 Urine specific gravity <1.010  Urine output >3 mL/kg·h • See table Laboratory and Other Studies for Diabetes Insipidus. Evidence • Increased incidence of DI has been reported after transsphenoidal procedures to approach parasellar masses (9); however, the incidence appears to be lower than that with other craniotomies. • Several studies suggest that frequent, serial assessments of urinary output and serum sodium concentrations after transsphenoidal surgery reduce the severity of complications associated with DI by facilitating prompt diagnosis and early intervention (10; 11). • In a cohort study, 102 consecutive patients (85 males) who suffered severe or moderate traumatic brain injury were evaluated for DI at a median of 17 months after the injury using the 8-hour water deprivation test. Permanent DI was present in 6.9% of the patients who survived the injury (12). Rationale

Diabetes Insipidus

• After neurosurgery or head trauma, patients may not adequately respond to dehydration and are at risk for developing significant hemodynamic compromise if the central DI is not recognized promptly and treated adequately. Comments • The development of DI after trauma or after neurosurgery can present in a classic triphasic pattern that must be recognized. In the initial phase, the patient develops DI lasting 2 to 8 days due to loss of AVP regulation as a result of neuronal damage. The second phase is antidiuresis (pseudoremission of DI) lasting 1 to 21 days, which results from nonspecific AVP release as AVP- containing neurons die. If all AVP-containing neurons are destroyed, phase 3 is permanent DI (4). If some neurons remain, the result will be partial DI or full recovery. 1.3 Obtain initial screening laboratory studies if DI is suspected in the outpatient setting to determine the need for an inpatient water deprivation test with desmopressin challenge. Recommendations • Measure 24-hour urinary volume and urinary osmolality to evaluate for dilute polyuria.

 Request a voiding diary to measure and record the volume of each void for a 48- to 72-hour period during ad libitum intake  Determine whether the 24-hour urinary volume is: 2 o >2 L/m in infants o >50 mL/kg in older children and adults  For rapid turnaround (e.g., a postoperative setting), consider measuring the urine specific gravity rather than urinary osmolality (although osmolality is usually preferred). • Measure blood glucose concentration to exclude diabetes mellitus (random blood glucose concentration >200 mg/dL is consistent with diabetes mellitus). • Measure serum sodium concentration, and consider hypernatremia in the face of hypotonic polyuria to be a relative contraindication to the water deprivation test. • Perform a water deprivation test to determine the type (pituitary vs. nephrogenic vs. psychogenic polydipsia) if the diagnosis of DI has been confirmed by demonstration of dilute polyuria. Concentrated urine after water deprivation indicates psychogenic polydipsia. • If the urine does not concentrate with water deprivation, perform a desmopressin challenge to assess renal AVP sensitivity and distinguish nephrogenic from central DI. In central DI, urine osmolality will increase and urine volume will decrease in response to desmopressin. • When the water deprivation test is inconclusive in children or adults with partial AVP deficiency, consider a hypertonic saline challenge. • See table Laboratory and Other Studies for Diabetes Insipidus. • See table Testing for Diagnosis of Diabetes Insipidus. • See table Interpreting Results of the Desmopressin Challenge Test. • See table Hypertonic Saline Test. • See figure Plasma AVP Levels. Evidence • The resolution of DI on administration of vasopressin by the rise of the urine-to-plasma osmolality ratio >1 was first reported in 1954 (13). • The classic water deprivation test was first developed in adults in 1963 (14) and in children in 1967 (15). Subsequent papers reported refinements of the water deprivation test (16; 17).

Diabetes Insipidus

• The hypertonic saline test was described in 1988 and has been used in patients with familial partial central DI in whom the water deprivation test may be equivocal (16; 18). • The first radioimmunoassay to quantify plasma AVP levels was developed in the 1970s (19). Normal subjects and patients with nephrogenic DI displayed a significant increase of AVP levels upon dehydration, whereas patients with primary polydipsia showed a moderate increase, and patients with central DI showed minimal rise (16). Subsequent investigators evaluating clinical responses to exogenous desmopressin administration to distinguish the various forms of DI confirmed these findings (20). • Copeptin is the c-terminal part of the AVP molecule and testing for copeptin has been used in place of AVP. A small study suggests the test has poor sensitivity (58%) for central DI (21). Rationale • Measuring specific gravity in the afternoon avoids false-positive or false-negative results, which occur most often with a fasting morning specimen or with sampling after a big meal; however, urinary osmolality remains the preferred test. • It is important to distinguish central DI and nephrogenic DI from primary polydipsia (psychogenic polydipsia) because the appropriate treatments differ dramatically. • The fluid deprivation test in combination with the desmopressin challenge usually provides the definitive method for diagnosis to distinguish these types of DI but does not identify the underlying etiology. Comments • All patients with developmental disabilities carry a risk for primary polydipsia, particularly institutionalized individuals. Screen for this problem with a standard questionnaire (22). Positive responses warrant formal laboratory assessment as described above. • Measurement of plasma osmolality or serum electrolytes is rarely of value to screen for DI, but it is diagnostic in the context of a water deprivation test. 1.4 If the diagnosis of central DI is confirmed, perform an MRI of the brain to determine the etiology. Recommendations • Obtain MRI of the head, with fine sections through the pituitary, hypothalamus, and pituitary stalk. • Look for the following on MRI of the brain:

 Thickened pituitary stalk  Ectopic, posterior pituitary tissue  Hypoplastic anterior pituitary • See table Laboratory and Other Studies for Diabetes Insipidus. • See table Etiologies of Central Diabetes Insipidus. Evidence • MRI of the head with fine (<1 mm) slices through the pituitary, hypothalamus, and pituitary stalk can be useful in determining the etiology of DI (23, 24), although formal studies have not assessed its utility. • At least 70% of normal children display a hyperintense signal, or ‘bright spot,’ in the posterior

pituitary in T1-weighted MRI; this proportion exceeds 95% in normal young adults and declines with advancing age (25). Over 95% of children and adults with DI lack this bright spot on T1- weighted MRI (1; 17); thus, the presence of a bright spot is much more specific in ruling out DI (95% specificity) than is the absence of a bright spot to rule in the diagnosis.

Diabetes Insipidus

• Using a scale from 1 (least appropriate) to 9 (most appropriate), the American College of Radiology in 1999 published appropriateness criteria that rank an MRI without contrast as 8, and an MRI with contrast as 6, for imaging the brain when the diagnosis of DI is considered (26). Rationale • DI is often a secondary disease process; thus, the primary process (e.g., brain tumor) must be identified and appropriately treated. 1.5 Obtain further studies to evaluate patients with nephrogenic DI to determine its etiology. Recommendations • Base evaluation of nephrogenic DI in adults on the most frequent etiologies:

 Electrolyte disturbances (e.g., hypokalemia)  Urologic anomalies  Specific drugs (e.g., lithium)  Renal failure • Perform renal ultrasound and voiding cystourethrogram to exclude anatomic pathology in patients with any form of nephrogenic DI that cannot be attributed to a metabolic disturbance or drug. • Suspect congenital nephrogenic DI in the pediatric patient, and conduct appropriate molecular genetic analysis. • See table Laboratory and Other Studies for Diabetes Insipidus. • See table Etiologies of Nephrogenic Diabetes Insipidus. Evidence • Molecular genetic analysis allows for early diagnosis of congenital nephrogenic DI, which leads to early treatment and prevention of growth failure or mental retardation. The mutation in >90% of patients with congenital nephrogenic DI is X-linked, and the remaining mutations are autosomal recessive (27). • Preadolescent patients without an obvious cause should be referred for genetic testing (e.g., the AVP-NPII gene of familial neurohypophyseal DI) (28). • Lithium, hypokalemia, and urethral obstruction comprise the most common causes of acquired nephrogenic DI (27). • Genetic mutations causing DI have been reported: AVP neurophysin II (AVP-NPII in familial neurohypophyseal DI) (28; 29; 30); wolframin (WFS1 in the DIDMOAD syndrome) (31; 32); and Foxa1 (linked to vasopressin resistance in mice) (33). In 2004, Spanish investigators reported the prenatal diagnosis of DIDMOAD by DNA sequencing (34). Rationale • Nephrogenic DI is most often acquired in adults. • Congenital nephrogenic DI presents at birth and can result in significant sequelae if not recognized and treated rapidly. Comments • Congenital nephrogenic DI usually presents in neonates or infants in association with the following signs and symptoms: polyuria, irritability, frequent vomiting, constipation, unexplained fevers, failure to thrive, multiple admissions for dehydration, hypernatremic seizures, and mental retardation.

Diabetes Insipidus

1.6 Consider the differential diagnosis of polyuria and polydipsia as the first step in the evaluation of any patient with suspected DI. Recommendations • Exclude the more common causes of polyuria and polydipsia, particularly diabetes mellitus, before performing the water deprivation test or desmopressin challenge. • Exclude primary polydipsia of the psychogenic, iatrogenic, or dipsogenic type. • Always consider the contributing or modulating effect, or concurrent anterior pituitary or other hormonal disorders. • See table Differential Diagnosis of Diabetes Insipidus. • See table Etiologies of Primary Polydipsia. Evidence • In a 2000 study of 79 children and young adults with central DI, 61% had concurrent anterior pituitary hormone deficiencies, including growth hormone deficiency (59%), secondary/tertiary hypothyroidism (28%), hypogonadism (24%), and secondary/tertiary adrenal insufficiency (22%) (1). • Patients with hypothalamic-pituitary disturbances after traumatic brain injury can possess abnormal ACTH reserve, hypothyroidism, and variable somatotropin production in conjunction with central DI (39). • The prevalence of primary polydipsia in mobile residents with developmental disabilities at a large public institution was reported as 5% (40). Rationale • The primary differential diagnosis is between DI (water diuresis) and a solute diuresis (e.g., glucosuria or contrast dyes); and among pituitary DI, nephrogenic DI, and primary polydipsia; however, gestational DI is limited to pregnancy. • Primary polydipsia is fluid intake in excess of physiologic requirement and is divided into psychogenic, iatrogenic, and dipsogenic forms. • The psychogenic form of polydipsia represents drinking excessive amounts of water for primary gain. • The iatrogenic form of polydipsia is due to medical treatment, usually the excess administration of intravenous fluids. • The dipsogenic form of polydipsia is defined as a primary disorder of thirst due to reset osmostat in the hypothalamic thirst center. Comments • Patients with primary polydipsia disrupt the renal medullary concentrating gradient and blunt the maximal concentrating abilities of the kidney. In these patients, restoration of the concentration gradient occurs within hours to days upon restricting free water and physiologic replacement of sodium. However, patients with nephrogenic DI become dehydrated with free water restriction, and restoration of the concentration gradient does not occur. • Primary or secondary adrenal insufficiency produces impaired renal diluting ability or salt wasting (hyponatremia), which can mask the presence of coincident DI.

Diabetes Insipidus

Top 2. Consultation Consult an endocrinologist for help in diagnosing DI and consult other subspecialists as needed depending on the suspected etiology. Consult an appropriate specialist to assist in the initiation of fluid and drug therapies, managing complications, or carrying out necessary procedures. 2.1 Consult an endocrinologist to assist in the inpatient diagnostic evaluation of polyuria; consult other subspecialists as needed. Recommendations • Obtain consultation with:

 An endocrinologist for help in interpreting diagnostic tests or when the diagnosis of DI is uncertain  A nephrologist if the patient has nephrogenic DI due to renal failure or is at risk for developing renal failure  A pediatric endocrinologist for the specific evaluation of DI in infants or young children  A geneticist for evaluation of a patient with affected relatives or presentation before adolescence to provide a genetic diagnosis and plan counseling to the family Evidence • Several studies and clinical experience confirm that lack of appropriate monitoring or lack of prompt intervention in patients with DI can result in serious morbidity and mortality (1; 42). Rationale • Due to the complexities of the diagnosis and management of DI, consultation with an endocrinologist should be promptly obtained when this disorder is suspected. • Consulting an expert who regularly deals with this relatively rare but potentially life-threatening disorder will reduce onerous and expensive retesting. 2.2 Refer patients with central DI to an endocrinologist for help in evaluating, diagnosing, and managing DI and its complications. Recommendations • Refer patients with central DI to an endocrinologist for:

 Adjustment of fluid and vasopressin therapy  Acute emesis or AVP-unresponsive polyuria, which could represent dehydration, adrenal insufficiency, or cerebral salt wasting  Electrolyte abnormalities, which might require inpatient management  Preoperative consultation before hypothalamic, pituitary, or transsphenoidal procedures  Preoperative consultation for any surgery or procedure in which the patient may be unconscious or receive intravenous fluids  Significant adverse effects that may require transition to another therapy Evidence • Hyponatremia can induce cerebral edema, and overly rapid correction to eunatremia places the patient at risk for central pontine myelinolysis (5). In contrast, hypernatremia can cause dehydration and tissue injury with overly rapid correction leading to cerebral edema (43). • Patients with DI who develop mental status changes are at risk for dysnatremia because they become nonadherent and cannot respond appropriately to their thirst (9).

Diabetes Insipidus

Rationale • Patients who develop vomiting or diarrhea are at high risk for developing hypernatremia. • Patients who become unresponsive to drug therapy may develop hypernatremia or hyponatremia if a second disorder has developed, overlying the DI. 2.3 Consider referring patients with nephrogenic DI to a nephrologist or an endocrinologist for help managing complications of their disease. Recommendations • Refer patients with nephrogenic DI to a nephrologist or endocrinologist for:

 Acute vomiting or diarrhea requiring a change in fluid or drug therapy  Electrolyte abnormalities requiring inpatient management  Increase in symptoms of polyuria or polydipsia, or >5% weight loss suggesting resistance to drugs  Worsening renal function, suggested by rising blood urea nitrogen and creatinine  Recurrent urinary tract infections, particularly in pediatric patients  Adverse reactions to drugs or lack of appropriate response to medical therapy Evidence • Clinical severity of nephrogenic DI can vary over time in the individual patient for unclear reasons (45), and treatment should be adjusted accordingly. • Overly rapid correction of hypernatremia has been shown to increase the risk for cerebral edema (43), and places the patient at risk for developing central pontine myelinolysis (5). • Patients with DI who develop mental status changes are at risk for dysnatremia because they become nonadherent with prescribed therapy and cannot respond appropriately to their thirst (9). Rationale • Patients with acute gastrointestinal symptoms impairing fluid absorption or clinical unresponsiveness to treatment are at the highest risk for developing hypernatremia and potential hemodynamic compromise from dehydration. • Alteration in disease severity also places the patient at risk for either hypernatremia or hyponatremia. 2.4 Consult appropriate specialists for causes of DI other than tumors. Recommendations • Obtain a consultation with:

 A neurologist for evaluation and management of disorders such as multiple sclerosis  A psychiatrist for evaluation and management of disorders such as compulsive water drinking  An immunologist for the evaluation and management of disorders such as neurosarcoidosis Evidence • Consensus. Rationale • Diverse causes of DI may require input from specialists with a broad array of expertise.

Diabetes Insipidus

Top 3. Hospitalization Hospitalize patients with suspected DI for management of severe electrolyte derangements. 3.1 Hospitalize patients to carry out the water deprivation test and desmopressin challenge to monitor response to initial treatment and to manage complications during therapy. Recommendations • Always perform water deprivation testing and desmopressin challenge in an inpatient setting. • Observe response to initial treatment in an inpatient setting once the patient is diagnosed with DI. • Admit patients with:

 Mental status changes  Significant dehydration and hemodynamic instability  Significant electrolyte imbalances, such as hypernatremia or hyponatremia  Central DI and underlying CNS lesions requiring neurosurgical procedures Evidence • Severe hypernatremia associated with neuronal dehydration has induced seizures, lethargy, or labored respiration (5). Uncorrected hyponatremia may cause significant cerebral edema (5). • Overly rapid correction of hypernatremia can cause cerebral edema, and overly rapid correction of hyponatremia can cause central pontine myelinolysis (43). Rationale • The water deprivation test requires close surveillance to prevent inappropriate fluid intake and to avoid severe dehydration. • Patients should be monitored in the hospital after initiation of treatment to assure appropriate response and to evaluate for electrolyte imbalances.

Diabetes Insipidus

Top 4. Therapy Ensure adequate free water replacement in all patients with DI and discontinue causative agents whenever possible. Tailor drug therapy to the specific etiology of DI. 4.1 Ensure access to free water in patients with partial central or nephrogenic DI and intact thirst, and replace free water judiciously in other settings. Recommendations • Consider managing the patient with free water replacement as long as the polyuria and polydipsia are not inconvenient to the patients or caretakers and the patient has intact thirst. • Initiate drug therapy if adequate control is not achieved with free water replacement alone. • Manage complete or partial central DI in infants by administration of dilute formula one-tenth- strength dilution with water ad libitum. • Instruct the patient to drink only as much as is required to satisfy thirst. • Calculate daily maintenance requirements for patients with DI who are impaired in some way from determining their thirst or from satisfying it. Evidence • Humans maintain their serum osmolality within a narrow range of 280 to 295 mOsm/kg by responding initially with AVP release and later with increased thirst (44). • Patients with DI who retain an intact thirst mechanism can respond to hyperosmolality simply by drinking more water (9). • Patients who lack an intact thirst mechanism or lack adequate access to water are those at highest risk for developing hypernatremia and/or hemodynamic compromise from DI (9). Rationale • It is safe for patients with DI to drink sufficient water to satisfy their thirst. Restricting access to water results in hypernatremia or dehydration even if the patient is receiving antidiuretic (desmopressin) therapy. • Management of DI in infants should usually exclude exogenous desmopressin administration because infants receive their nutrition in liquid form as milk or formula and antidiuresis would decrease liquid intake, thus interfering with adequate caloric intake. Comments • It is unwise to encourage high fluid intake in patients with DI because adherence to such a recommendation has been responsible for many cases of hyponatremia during desmopressin therapy. Instead, urge patients to drink only when they are truly thirsty, in order to minimize hyponatremia. • Patients who are too young to walk or talk, who have aphasia or stroke, or who lack a normal thirst mechanism will require continuous assessment by the caretaker and direct supervision of their water balance. This is best achieved by daily weighing of the patient. • In infants, despite the inconvenience of uncontrolled polyuria, dilute formula is the safest therapy with respect to growth and to prevent adverse events related to drug therapy. A pediatric endocrinologist is most qualified to supervise such management.

Diabetes Insipidus

4.2 Use desmopressin in the outpatient setting to manage chronic central DI in patients who have intact thirst. Recommendations • Administer intranasal desmopressin every 12 to 24 hours as needed (by determining the dose empirically) in adult patients with complete central DI to control polyuria. • If the patient lacks intact thirst, determine the serum sodium concentration every 4 to 6 hours during the first 48 hours of desmopressin replacement therapy to identify the dosing regimen that consistently maintains a normal serum sodium concentration. • Allow patients with new-onset central DI to have breakthrough polyuria at least once a week, unless they have long-standing stable DI and no history of secondary hyponatremia. • Advise patients that loss of drug potency can occur rarely with overheating or prolonged storage before use. • See table Drug Treatment for Diabetes Insipidus. Evidence • Since the 1960s, multiple clinical studies have confirmed that the AVP analog desmopressin effectively controls central DI (4; 45), although randomized trials have not been performed. • For patients with chronic central DI, breakthrough polyuria prevents hyponatremia and allows for recognition of the rare cases in which the disease remits (10). Patients with DI after trauma or neurosurgery have recovered normal urinary concentrating ability and normal urine output as late as 10 years after the initial insult (9). Rationale • Appropriate treatment of DI prevents electrolyte disturbances and improves quality of life for patients with significant polyuria and polydipsia. • Allowing for breakthrough polyuria at least once a week relieves the kidneys from maximum concentrating function. Comments • Therapy with desmopressin is optimal for gestational DI because it exerts less uterotonic action than vasopressin (9). Gestational DI often requires slightly higher doses to achieve control (45). Healthy pregnant women have serum sodium concentrations lower than healthy nongravid women by ~5 mEq/L. • Gestational DI is best managed by administration of desmopressin every 8 to 12 hours, and it usually requires doses higher than for central DI to adequately control polyuria. • In some patients with osmoregulator dysfunction (hypothalamic adipsia), there is no desmopressin regimen that will sufficiently maintain a normal serum sodium concentration. These patients often require a regimen that forces a daily fixed amount of fluid intake. • Patients do not overdose on desmopressin; rather, they can overdose on free water while under the antidiuretic effect of desmopressin. In patients receiving desmopressin who develop significant hyponatremia and low urinary output (water intoxication), consider the following: cortisol deficiency, use of carbamazepine, inappropriate volumes of intravenous fluids, inappropriately high oral fluid intake, and misdiagnosis of primary polydipsia due to an abnormal thirst mechanism. • Intranasal and oral desmopressin are both effective. However, the bioavailability of the oral form is about 10-fold less. Many patients find the nasal spray more convenient because of its more rapid onset of action and greater predictability of absorption.

Diabetes Insipidus

• A report suggests that methylprednisolone pulse therapy can effectively improve lymphocytic hypophysitis, obviating surgery while resolving the associated DI (46). • Desmopressin intranasal formulations are no longer FDA-approved for the treatment of primary nocturnal enuresis and should not be used in hyponatremic patients or patients with a history of hyponatremia, according to an FDA alert. 4.3 Tailor the drug treatment of nephrogenic DI to its specific etiology. Recommendations • Administer thiazide diuretics and prescribe salt restriction to manage non-drug forms of nephrogenic DI. • Consider amiloride the drug of choice for treating lithium-induced nephrogenic DI. • Consider indomethacin, in conjunction with thiazides, to increase renal water reabsorption in patients with nephrogenic DI. • Recognize that patients with nephrogenic DI often require multidrug therapy to control their polyuria. • Encourage a diet low in sodium and protein. • See table Drug Treatment for Diabetes Insipidus. Evidence • Salt restriction in conjunction with thiazide diuretics and either indomethacin or amiloride can decrease the polyuria by 50% to 70% (45). • Thiazide diuretics effectively block sodium reabsorption in the distal renal tubule, thereby causing natriuresis (10). • Amiloride controls lithium-induced nephrogenic DI by blunting the action of lithium on the collecting duct (47). Rationale • The AVP insensitivity underlying nephrogenic DI necessitates indirect methods of treatment, such as decreased salt intake and increased salt excretion in order to maintain eunatremia. 4.4 Consider drug therapy for partial DI as needed. Recommendations • Consider chlorpropamide for treatment of partial central DI solely on the basis of lower cost, and closely monitor for hypoglycemia. • In patients with partial nephrogenic DI, consider a combination of desmopressin, thiazide diuretics, and a salt-restricted diet. • See table Drug Treatment for Diabetes Insipidus. Evidence • Patients with partial nephrogenic DI are effectively treated with desmopressin because they have an incomplete renal resistance to AVP (10). Rationale • Although desmopressin and proper fluid management will always control polyuria or dehydration complicated by electrolyte abnormalities, the expense of desmopressin may justify alternative therapy. • Optimal therapy may require drugs that act both centrally and peripherally or synergistically.

Diabetes Insipidus

• Patients with partial nephrogenic DI may respond to desmopressin, although usually not as monotherapy, and they often require much higher doses (5 to 10 times) than that which is effective for central DI. Combination of desmopressin with thiazide diuretics and a salt-restricted diet are usually required to control their symptoms. Comments • In theory, chlorpropamide should be reserved for a patient who develops antibodies to desmopressin, which has not yet been reported. Chlorpropamide works by stimulating AVP release and potentiating its renal effect; clofibrate and carbamazepine act only by stimulating AVP release (48). • There is no longer any indication to use clofibrate and carbamazepine, which exert unacceptable adverse effects and do not match the efficacy of desmopressin. 4.5 Treat patients in the acute setting after neurosurgery or head trauma with intravenous fluids, alone or in conjunction with vasopressin. Recommendations • Ensure that patients receive intravenous age-appropriate maintenance fluid replacement in addition to replacement of urinary losses. • In adults with acute DI after neurosurgery or head trauma:

 Replace urine output with intravenous fluid of 5% dextrose in 0.45% sodium chloride  If significant hyperglycemia occurs, administer iv (regular or lispro) insulin to maintain euglycemia, starting at 0.02 U/kg body weight per hour  If the patient tolerates water by mouth, allow the patient to drink to satisfy thirst • In children aged >2 years with DI:

 Provide fluid resuscitation orally or parenterally  To maintain eunatremia, replace urinary output >3 mL/kg·h, milliliter for milliliter, with water by mouth  If unable to tolerate oral intake, replace with intravenous 2.5% dextrose in 0.45% sodium chloride (saline) • If urinary output is excessively high to replace conveniently, or if the patient develops electrolyte abnormalities:

 Administer desmopressin by continuous peripheral intravenous infusion or intermittent subcutaneous injection, and titrate to control polyuria  Avoid parenteral vasopressin due to its often undesirable vasopressor effect  Avoid oral desmopressin in the acute setting because absorption is too unpredictable to provide reliable antidiuresis  In infants, avoid vasopressin tannate in oil, which lasts too long for the exclusively liquid diet of infants • Monitor urinary output, urinary osmolality, serum sodium concentration, and serum osmolality every 1 to 4 hours after initiation of treatment to prevent water intoxication and cerebral edema. • Monitor for remission of polyuria if treatment is stopped because some patients develop transient DI in association with neurosurgery or head trauma. • See table Drug Treatment for Diabetes Insipidus. Evidence • After neurosurgery or head trauma, patients often develop transient DI, which resolves completely over several weeks and does not require long-term treatment (10), as long as the neurohypophyseal anatomy remains intact. This form of DI appears to occur most frequently in the hours immediately after tumor debulking. • A solution containing 0.45% saline minimizes the chance of excess sodium loading with high- volume administration rates while maintaining the osmolality of the administered fluid >200

Diabetes Insipidus

mOsm/kg. Therefore, 0.45% saline solution is the fluid of choice for replacement in most situations, except in neonates who require a lower saline dose (49). The infantile kidney cannot adequately excrete a high solute load, resulting in hypertension upon excessive salt administration. Rationale • Patients in the acute care setting should be treated in a manner that permits rapid titration, because they may have an evolving disease process. • Aqueous AVP can be titrated easily because it has a short half-life. • Parenteral desmopressin is equally suitable for management of DI in the acute care setting. Comments • For patients with combined DI and cerebral salt wasting, a two-bag system provides a convenient treatment modality. Two bags of appropriate intravenous fluids, differing only with respect to sodium content, are connected by a Y- or T-shaped connector to the single tubing provided to the patient. One bag contains 3% saline solution and the other contains 5% dextrose in water with no sodium chloride. Direct titration of the infusion rate from each bag permits immediate adjustment to meet the patient's changing sodium requirements, with independent control of the overall rate of fluid administration (41; 50). 4.6 Do not consider resection of CNS lesions in patients with central DI as primary treatment. Recommendations • Note that multiple CNS disorders can present with DI, and that not all CNS lesions require surgical or radiologic therapy. • Base the decision to resect CNS lesions on indications other than the presence of DI. • Recognize that preoperative DI is unlikely to resolve after the surgery. • Monitor any patient closely for DI after radiologic or surgical procedures performed in proximity to the hypothalamus or pituitary. • See table Etiologies of Central Diabetes Insipidus. Evidence • The incidence of DI in patients with craniopharyngiomas was reported by one group to increase from 16.9% preoperatively to 59.4% postoperatively (51). • Pituitary adenomas are rarely a cause of DI (52). One report of 255 consecutive transsphenoidal procedures performed at a U.S. academic medical center disclosed that only 0.4% of the patients in whom DI developed postoperatively had DI beyond 1 year after surgery (53). • DI due to a Rathke's cleft cyst typically does not resolve after surgery (54, 55). Rationale • DI is not a surgical indication for any CNS disorder, because neurosurgery will not improve DI. Indeed, procedures in the region of the neurohypophysis typically result in permanent DI.

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Top 5. Patient Counseling Use patient education as a key element in the overall management of patients with DI. 5.1 Ensure that patients understand the significance of thirst, access to water, urinary output, and proper use of medications. Recommendations • Explain the importance of responding to thirst and having access to water. • Instruct patients on the appropriate use of the metered-dose, intranasal inhaler for desmopressin. • Monitor weight and urinary output during acute illness. • Instruct patients, or the parents of pediatric patients, to contact a physician if there is any change in:

 Mental status  Lethargy  Respiratory distress  Restlessness  Significant increase or decrease in urinary output  Decrease in weight by ≥5% over a 6- to 24-hour period • Instruct patients to contact an endocrinologist if emesis or diarrhea develops or if previously well- controlled polyuria becomes acutely unresponsive to exogenous desmopressin. • Advise parents of pediatric patients to be more vigilant of these symptoms because infants have less reserve than adults. • Advise patients to wear a medical identification bracelet or necklace at all times. Evidence • DI is primarily managed on an outpatient basis; therefore, patient understanding and adherence to appropriate treatment is critical to effective management (10). • If a patient should become comatose due to acute electrolyte changes, a medical identification tag can be life saving when the patient presents to healthcare personnel (10). Rationale • Patients lacking an intact thirst mechanism should monitor input and output daily to avoid water intoxication. • Vigilance by the patient or caretaker should prevent electrolyte imbalances and the neurologic sequelae secondary to these disturbances. • An informed patient or caretaker can anticipate problems quickly.

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Top 6. Follow-up Schedule periodic follow-up to ensure adequate control of DI. 6.1 Follow-up with patients annually to ensure normal fluid and electrolyte balance. Recommendations • Schedule an annual follow-up visit, unless problems develop, once the optimal dose of desmopressin is established for an adult with DI. • Inquire at follow-up visits about:

 Polyuria  Polydipsia  Significant weight changes  Focal neurologic deficits  Change in mental status  Adverse effects of drugs • Quantify levels of serum sodium, serum potassium, serum osmolality, and urinary specific gravity or urinary osmolality, and obtain other studies appropriate to the primary cause. • Monitor closely for disease resolution in patients with DI due to neurosurgical procedures, head trauma, or drugs. • Advise patients to promptly report:

 Changes in treatment efficacy  Changes in mental status  Occurrence of dehydration  Acute illnesses • Instruct patients who lack intact thirst to keep a daily log of:

 Weight  Fluid intake  Time of each void  Time of each drug dose Evidence • Consensus. Rationale • Appropriate outpatient follow-up will anticipate and aid prevention of significant sequelae. 6.2 Obtain additional studies over time to evaluate patients with DI for occult or developing underlying disease processes. Recommendations • Obtain serial MRI of the brain every 6 months for 3 years in young adults with ‘idiopathic’ central DI to survey for occult lesions. • Consider renal ultrasonography every 5 years in patients with congenital nephrogenic DI to look for hydronephrosis. • Screen periodically for anterior pituitary hormone deficiencies in all patients by obtaining:

Diabetes Insipidus

 Fasting serum cortisol level obtained between 7:00 A.M. and 8:00 A.M.  Serum level of IGF binding protein-3

 Serum free thyroxine (T4) level by equilibrium dialysis • In patients with progressive pituitary stalk thickening or new pituitary dysfunction in the context of pre-existing stalk thickening:

 Obtain serum and CSF levels of β-human chorionic gonadotropin and α-fetoprotein to evaluate for possible germinoma  Consider pituitary biopsy  Consider bone scan (or survey) for possible histiocytosis  Consider the diagnosis of lymphocytic infundibuloneurohypophysitis Evidence • Idiopathic central DI, particularly in children and young adults, warrants serial MRI of the brain every 6 months for the first 3 years after presentation to monitor closely for slow-growing occult lesions (1; 56). Patients with ‘idiopathic’ DI should undergo brain MRI at least every 5 years for life due to the delay in presentation of slow-growing germinomas and infiltrative lesions, such as histiocytosis X (1; 9). • Serum levels of IGF-I and IGF-binding protein-3 provide useful screening tools for growth hormone deficiency in euthyroid, prepubertal patients with annual linear growth <4 to 6 cm (57). • A study from the Netherlands of 30 male patients (ages 1 month to 40 years) with nephrogenic DI revealed a high rate of development of severe urologic complications (particularly hydronephrosis) (58). • Re-evaluate the need for continuing medical treatment (9). After stabilization of a patient with central DI, one study suggests an MRI scan for initial evaluation and annually thereafter for 4 years to establish the etiology. Annual intervals in adults are reasonable (1). • In one study of 79 patients with central DI (ages 1 month to 24 years of age) in whom serial MRIs were obtained every 4 to 12 months, germinomas were the intracranial tumors most frequently associated with DI. Frequent imaging permitted significantly earlier diagnosis of germinomas and other neoplasms in patients previously diagnosed with ‘idiopathic’ central DI (1). • Serum and CSF levels of β-human chorionic gonadotropin and α-fetoprotein may be useful in patients with progressive pituitary stalk thickening to evaluate for possible germinoma (59). • Lymphocytic infundibuloneurohypophysitis is an autoimmune process involving the posterior pituitary that accounts for as much as 50% of spontaneous cases of DI in adults previously diagnosed as having idiopathic DI (60). Rationale • Several occult disease processes may not be detected at the time of initial diagnosis of DI, but they become apparent with additional testing over time. • Occult disease processes include a variety of infiltrative and neoplastic diseases as well as lymphocytic infundibuloneurohypophysitis, which is an autoimmune process involving the posterior pituitary that accounts for as much as 50% of spontaneous cases of DI in adults previously diagnosed as idiopathic.

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Top References 1. Maghnie M, Cosi G, Genovese E, Manca-Bitti ML, Cohen A, Zecca S, et al. Central diabetes insipidus in children and young adults. N Engl J Med. 2000;343:998-1007. (PMID: 11018166) 2. Honegger J, Buchfelder M, Fahlbusch R. Surgical treatment of craniopharyngiomas: endocrinological results. J Neurosurg. 1999;90:251-7. (PMID: 9950495) 3. Durr JA. Diabetes insipidus in pregnancy. Am J Kidney Dis. 1987;9:276-83. (PMID: 3554998) 4. Seckl JR, Dunger DB. Diabetes insipidus. Current treatment recommendations. Drugs. 1992;44:216-24. (PMID: 1382016) 5. Kumar S, Berl T. Sodium. Lancet. 1998;352:220-8. (PMID: 9683227) 6. Fox CB, Treadway AK, Blaszczyk AT, Sleeper RB. Megestrol acetate and mirtazapine for the treatment of unplanned weight loss in the elderly. Pharmacotherapy. 2009;29:383-97. (PMID: 11865282) 7. Cooper HL, Ferry R, Gay CT. Papilledema and spinal cord ependymoma. J Child Neurol. 1996;11:229-30. 8. Sawin CT. Vasopressin is a hormone: the work of Ernest Basil Verney (1894-1967). Endocrinologist. 2000;10:79-82. 9. Buonocore CM, Robinson AG. The diagnosis and management of diabetes insipidus during medical emergencies. Endocrinol Metab Clin North Am. 1993;22:411-23. (PMID: 8325295) 10. Singer I, Oster JR, Fishman LM. The management of diabetes insipidus in adults. Arch Intern Med. 1997;157:1293-301. (PMID: 9201003) 11. Harrigan MR. Cerebral salt wasting syndrome: a review. Neurosurgery. 1996;38:152-60. (PMID: 8747964) 12. Agha A, Thornton E, O’Kelly P, Tormey W, Phillips J, Thompson CJ. Posterior pituitary dysfunction after traumatic brain injury. J Clin Endocrinol Metab. 2004;89:5987-92. (PMID: 15579748) 13. Dreifus LS, Frank MN, Bellet S. Determination of osmotic pressure in diabetes insipidus: a new diagnostic test. N Engl J Med. 1954;251:1091-4. (PMID: 13223960) 14. Dashe AM, Cramm RE, Crist CA, Habener JF, Solomon DH. A water deprivation test for the differential diagnosis of polyuria. JAMA. 1963;185:699-703. (PMID: 14025190) 15. Frasier SD, Kutnik LA, Schmidt RT, Smith FG Jr. A water deprivation test for the diagnosis of diabetes insipidus in children. Am J Dis Child. 1967;114:157-60. (PMID: 4951539) 16. Robertson GL. Differential diagnosis of polyuria. Ann Rev Med. 1988;39;425-42. (PMID: 3285784) 17. Baylis P, Cheetham T. Diabetes insipidus. Arch Dis Child. 1998;79:84-9. (PMID: 9771260) 18. Davies JH, Penney M, Abbes AP, Engel H, Gregory JW. Clinical features, diagnosis and molecular studies of familial central diabetes insipidus. Horm Res. 2005;64:231-7. (PMID: 16254433) 19. Robertson GL, Mahr EA, Athar S, Sinha T. Development and clinical application of a new method for the radioimmunoassay of arginine vasopressin in human plasma. J Clin Invest. 1973;52:2340-52. (PMID: 4727463) 20. Zerbe RL, Robertson GL. A comparison of plasma vasopressin measurements with a standard indirect test in the differential diagnosis of polyuria. N Engl J Med. 1981;305:1539-46. (PMID: 7311993) 21. Fox CB, Treadway AK, Blaszczyk AT, Sleeper RB. Megestrol acetate and mirtazapine for the treatment of unplanned weight loss in the elderly. Pharmacotherapy. 2009;29:383-97. (PMID: 21367924) 22. Hayfron-Benjamin J, Peters CA, Woodhouse RA. Screening patients with mental retardation for polydipsia. Canadian J Psychiatry. 1996;41:523-7. (PMID: 8899239) 23. Chen S, Leger J, Garel C, Hassan M, Czernichow P. Growth hormone deficiency with ectopic neurohypophysis: anatomical variations and relationship between the visibility of the pituitary stalk asserted by magnetic resonance imaging and anterior pituitary function. J Clin Endocrinol Metabol. 1999;84:2408-13. (PMID: 10404812) 24. De Buyst J, Massa G, Christophe C, Tenoutasse S, Heinrichs C. Clinical, hormonal and imaging findings in 27 children with central diabetes insipidus. Eur J Pediatr. 2006. (PMID: 16944241) 25. Terano T, Seya A, Tamura Y, Yoshida S, Hirayama T. Characteristics of the pituitary gland in elderly subjects from magnetic resonance images: relationship to pituitary hormone secretion. Clin Endocrinol (Oxf). 1996;45:273-9. (PMID: 8949564) 26. American College of Radiology ACR Appropriateness Criteria 2000: diabetes insipidus (563-71). Radiology. 2000;215 Suppl:1- 1511. (PMID: 11228658) 27. Bichet DG. Nephrogenic diabetes insipidus. Am J Med. 1998;105:431-42. (PMID: 9831428)

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28. Rittig S, Siggaard C, Ozata M, Yetkin I, Gregersen N, Pedersen EB, et al. Autosomal dominant neurohypophyseal diabetes insipidus due to substitution of histidine for tyrosine(2) in the vasopressin moiety of the hormone precursor. J Clin Endocrinol Metabol. 2002;87:3351-5. (PMID: 12107248) 29. Christensen JH, Siggaard C, Corydon TJ, Robertson GL, Gregersen N, Bolund L, et al. Differential cellular handling of defective arginine vasopressin (AVP) prohormones in cells expressing mutations of the AVP gene associated with autosomal dominant and recessive familial neurohypophyseal diabetes insipidus. J Clin Endocrinol Metab. 2004;89:4521-31. (PMID: 15356057) 30. Wahlstrom JT, Fowler MJ, Nicholson WE, Kovacs WJ. A novel mutation in the preprovasopressin gene identified in a kindred with autosomal dominant neurohypophyseal diabetes insipidus. J Clin Endocrinol Metab. 2004;89:1963-8. (PMID: 15070970) 31. Inoue H, Tanizawa Y, Wasson J, Behn P, Kalidas K, Bernal-Mizrachi E, et al. A gene encoding a transmembrane protein is mutated in patients with diabetes mellitus and optic atrophy (Wolfram syndrome). Nat Genet. 1998;20:143-8. (PMID: 9771706) 32. Strom TM, Hörtnagel K, Hofmann S, Gekeler F, Scharfe C, Rabl W, et al. Diabetes insipidus, diabetes mellitus, optic atrophy and deafness (DIDMOAD) caused by mutations in a novel gene (wolframin) coding for a predicted transmembrane protein. Hum Mol Genet. 1998;7:2021-8. (PMID: 9817917) 33. Behr R, Brestelli J, Fulmer JT, Miyawaki N, Kleyman TR, Kaestner KH. Mild nephrogenic diabetes insipidus caused by Foxa1 deficiency. J Biol Chem. 2004 ;279:41936-41. (PMID: 15252040) 34. Domènech E, Kruyer H, Gómez C, Calvo MT, Nunes V. First prenatal diagnosis for Wolfram syndrome by molecular analysis of the WFS1 gene. Prenat Diagn. 2004;24:787-9. (PMID: 15503287) 35. Diederich S, Eckmanns T, Exner P, Al-Saadi N, Bahr V, Oelkers W. Differential diagnosis of polyuric/polydipsic syndromes with the aid of urinary vasopressin measurement in adults. Clinical Endocrinol(Oxf). 2001;54:665-71. (PMID: 11380498) 36. Palevsky PM, Bhargrath R, Greenberg A. Hypernatremia in hospitalized patients. Ann Intern Med. 1996;124:197-203. [Full Text] (PMID: 8533994) 37. Rutishauser J. Copeptin: diagnostic parameter, biomarker, or both? [in German]. Ther Umsch. 2009;66:731-4. (PMID: 19885789) 38. Barakat AJ, Pearl PL, Acosta MT, Runkle BP. 22q13 deletion syndrome with central diabetes insipidus: a previously unreported association. Clin Dysmorphol. 2004;13:191-4. (PMID: 15194959) 39. Yuan XQ, Wade CE. Neuroendocrine abnormalities in patients with traumatic brain injury. Front Neuroendocrinol. 1991;12:209- 30. (PMID: 11538874) 40. Hayfron-Benjamin J, Peters CA, Woodhouse RA. A demographic study of polydipsia in an institution for the intellectually disabled. Can J Psychiatry. 1996;41:519-22. (PMID: 8899238) 41. Ferry RJ Jr, Kesavulu V, Kelly A, Levitt Katz LE, Moshang T Jr. Hyponatremia and polyuria in children with central diabetes insipidus: challenges in diagnosis and management. J Pediatr. 2001;138:744-7. (PMID: 11343054) 42. Laredo S, Yuen K, Sonnenberg B, Halperin ML. Coexistence of central diabetes insipidus and salt wasting: the difficulties in diagnosis, changes in natremia, and treatment. J Am Soc Nephrol. 1996;7:2527-32. (PMID: 8989730) 43. Fried LF, Palevsky PM. Hyponatremia and hypernatremia. Med Clin North Am. 1997;81:585-609. (PMID: 9167647) 44. Robertson GL, Aycinena P, Zerbe RL. Neurogenic disorders of osmoregulation. Am J Med. 1982;72:339-53. (PMID: 7036730) 45. Robertson GL. Diabetes insipidus. Endocrinol Metab Clin North Am. 1995;24:549-72. (PMID: 8575409) 46. Jo YS, Lee HJ, Rha SY, Hong WJ, Song CJ, Kim YK, et al. Lymphocytic hypophysitis with diabetes insipidus: improvement by methylprednisolone pulse therapy. Korean J Intern Med. 2004;19:189-92. (PMID: 15481611) 47. Batlle DC, von Riotte AB, Gaviria M, Grupp M. Amelioration of polyuria by amiloride in patients receiving long-term lithium therapy. N Engl J Med. 1985;312:408-14. (PMID: 3969096) 48. Adam P. Evaluation and management of diabetes insipidus. Am Family Physician. 1997;55:2146-53. (PMID: 9149642) 49. Rogers MC, Helfaer MA, eds. Handbook of Pediatric Intensive Care. 3d ed. Philadelphia; Lippincott Williams & Wilkins: 1999. 50. Janss AJ, Heller G, Grimberg A, Ferry R. Neuro-oncology-endocrinology interface: A patient who earned her salt. Med Pediatr Oncol. 1999;33:413-7. (PMID: 10491556) 51. Fahlbusch R, Honegger J, Paulus W, Huk W, Buchfelder M. Surgical treatment of craniopharyngiomas: experience with 168 patients. J Neurosurg. 1999;90:237-50. (PMID: 9950494) 52. Shin JH, Lee HK, Choi CG, Suh DC, Kim CJ, Hong SK, et al. MR imaging of central diabetes insipidus: a pictorial essay. Korean J Radiol. 2001;2:222-30. (PMID: 11754330) 53. Black PM, Zervas NT, Candia GL. Incidence and mangement of complications of transsphenoidal operation for pituitary adenomas. Neurosurgery. 1987;20:920-4. (PMID: 3614573)

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54. Shin JL, Asa SL, Woodhouse LJ, Smyth HS, Ezzat S. Cystic lesions of the pituitary: clinicopathological features distinguishing craniopharyngioma, Rathke's cleft cyst, and arachnoid cyst. J Clin Endocrinol Metab. 1999;84:3972-82. (PMID: 10566636) 55. Fox CB, Treadway AK, Blaszczyk AT, Sleeper RB. Megestrol acetate and mirtazapine for the treatment of unplanned weight loss in the elderly. Pharmacotherapy. 2009;29:383-97. (PMID: 21502327) 56. Mootha SL, Barkovich AJ, Grumbach MM, Edwards MS, Gitelman SE, Kaplan SL, et al. Idiopathic hypothalamic diabetes insipidus, pituitary stalk thickening, and the occult intracranial germinoma in children and adolescents. J Clin Endocrinol Metab. 1997;82:1362-7. (PMID: 9141516) 57. Rosenfeld RG. Biochemical diagnostic strategies in the evaluation of short stature: the diagnosis of insulin-like growth factor deficiency. Horm Res. 1996;46:170-3. (PMID: 8950616) 58. Knoers NV, Monnens LL. Nephrogenic diabetes insipidus. Semin Nephrol. 1999;19:344-52. (PMID: 10435672) 59. Seregni E, Massimino M, Nerini Molteni S, Pallotti F, van der Hiel B, Cefalo G, et al. Serum and cerebrospinal fluid human chorionic gonadotropin (hCG) and alpha-fetoprotein (AFP) in intracranial germ cell tumors. Int J Biol Markers. 2002;17:112-8. (PMID: 12113577) 60. Tanaka S, Tatsumi KI, Kimura M, Takano T, Murakami Y, Takao T, et al. Detection of autoantibodies against the pituitary- specific proteins in patients with lymphocytic hypophysitis. Eur J Endocrinol. 2002;147:767-75. (PMID: 12457452) 61. Sohara E, Rai T, Yang SS, Uchida K, Nitta K, Horita S, et al. Pathogenesis and treatment of autosomal-dominant nephrogenic diabetes insipidus caused by an aquaporin 2 mutation. Proc Natl Acad Sci U S A. 2006;103:14217-22. (PMID: 16968783)

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Top Glossary ACTH adrenocorticotropic hormone ADH antidiuretic hormone AVP arginine vasopressin CNS central nervous system CSF cerebrospinal fluid DI diabetes insipidus DIDMOAD diabetes insipidus, diabetes mellitus, optic atrophy, deafness FDA Food and Drug Administration FSH follicle-stimulating hormone GH growth hormone HEENT head, ears, eyes, nose, throat IGF insulin-like growth factor LH luteinizing hormone MRI magnetic resonance imaging NaCl sodium chloride SIADH syndrome of inappropriate secretion of antidiuretic hormone TSH thyroid-stimulating hormone, thyrotropin

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Top Tables

Laboratory and Other Studies for Diabetes Insipidus

Test Sensitivity (%) Specificity (%) Notes

Urinary volume >95 <50 Polyuria is defined as urinary volume >50 mL/kg body weight per day in adults, or >75 mL/kg body weight per day in children aged under 16

Urinary osmolality >95 >90 (except for nephrogenic DI) Urine is considered dilute when urinary osmolality is <300 mOsm/kg (16). In patients not taking diuretics, urinary osmolality is a useful screening test. Urinary osmolality measurements are essential components of the water deprivation test

Urinary specific gravity >95 >90 (except for nephrogenic DI) Urinary specific gravity <1.010 is considered dilute (16)

Serum osmolality 5 35 Serum osmolality <282 mOsm/kg, or >295 mOsm/kg, is always abnormal (17; 35). Subnormal serum vasopressin level for concurrent serum osmolality is the gold standard for diagnosis of central DI. Serum osmolality can be used as a screening test, and it is also measured during the water deprivation test

Serum sodium concentration 85 25 Hypernatremia is defined as serum sodium concentration >145 µmol/L. With intact thirst and access to water, patients usually maintain eunatremia (36)

Serum potassium concentration Hypokalemia, a potential etiology of acquired nephrogenic DI, should be excluded (16). Serum potassium concentration is not a useful screening test for DI

Blood glucose concentration Exclude the diagnosis of diabetes mellitus in the evaluation of polyuria and polydipsia. The easiest way to exclude diabetes mellitus is by documenting the absence of glucosuria, because glucosuria is always present when it is the cause of polyuria

Serum calcium level Hypercalcemia, with calcium levels above the normal range specific to that test, can be an etiology of acquired nephrogenic DI (17)

Serum creatinine level High-output renal failure can present with

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polyuria

Plasma AVP level Inter- and intra-assay variability are so substantial that the frequent overlap of reported values hampers the utility of this test. A subnormal plasma AVP level for concurrent serum osmolality (particularly when serum osmolality is >295 mOsm/kg) confirms central DI

Plasma copeptin level 58% in patients with complete or partial central Unclear role; could potentially replace plasma DI; abnormal in both patients with nephrogenic AVP(21; 37) DI

MRI of the head Patients with idiopathic central DI should undergo MRI of the brain no less frequently than annual intervals to exclude occult lesions, which may lag the clinical presentation of DI by as long as 20 years (17; 24)

Renal ultrasound Exclude anatomic abnormalities such as polycystic kidney disease, which may present as nephrogenic DI

Molecular genetic analysis Order DNA testing when nephrogenic DI is suspected (AVP type-2 receptor [AVPR2 gene], aquaporin-2 water channel [AQP2 gene], or Foxa1) or when central DI is suspected (AVP gene, FISH for 22q11 deletion) (33; 38)

AVP = arginine vasopressin; DI = diabetes insipidus; DNA = deoxyribonucleic acid; FISH = fluorescent in situ hybridization; MRI = magnetic resonance imaging.

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Differential Diagnosis of Diabetes Insipidus

Disease Characteristics

Central DI Polyuria and polydipsia, often in the context of neurologic abnormalities. Polyuria decreases in response to AVP Identify underlying cause

Primary polydipsia Inappropriate fluid intake is the primary problem of this syndrome, which encompasses the distinct etiologies of dipsogenic polydipsia (where the thirst mechanism is affected), psychogenic polydipsia (in disorders such as mania), and the iatrogenic form caused by excess intravenous fluids Polydipsia is distinguished from DI by the fluid deprivation or hypertonic saline challenge. Etiologies of psychogenic polydipsia include schizophrenia and mania, and those of dipsogenic polydipsia include granulomatous disease, sarcoidosis, vasculitis, and multiple sclerosis (16). Patients with primary polydipsia will appropriately concentrate the urine given sufficient osmotic stress

Cerebral salt wasting Obligate diuresis with natriuresis is due to inappropriate release of natriuretic peptides and results in hyponatremia Cerebral salt wasting most often occurs after neurosurgery and has also been reported with other CNS injuries or chemotherapy (41). Inappropriate administration of AVP in the setting of cerebral salt wasting aggravates hyponatremia (41). The diuresis of cerebral salt wasting does not respond to AVP or its analogs

Nephrogenic DI Hereditary defect in water reabsorption at the distal collecting duct Although rare, these forms of DI are the most difficult to manage. Patients typically present during the first few weeks of life

Diabetes mellitus Insufficient insulin action resulting in hyperglycemia and glucosuria, the latter as a result of increased solute load on the kidney Diabetes mellitus is a far more frequent cause of polyuria and polydipsia than DI. Glucosuria is the hallmark of diabetes mellitus, which distinguishes it from mild DI

Renal tubular acidosis A group of disorders characterized by metabolic acidosis as a result of the inability of the kidney to retain sufficient bicarbonate or to excrete acid appropriately Patients with renal tubular acidosis display non-anion gap acidosis, whereas patients with mild DI typically display normal acid-base balance

Chronic renal failure Hallmark signs and symptoms include elevated blood urea nitrogen, elevated serum creatinine level, anemia, renal osteodystrophy (relatively common in children and rare in adults), and hypertension Chronic renal failure of any etiology is associated with elevated serum creatinine level. Patients with mild DI display normal serum creatinine level

Acute tubular necrosis Acute tubular necrosis results from injury to the kidney, which can occur from hypoxia, ischemia, toxins, trauma, or disseminated intravascular coagulation that clogs the tubular lumen. Characterized by proteinuria and inability to resorb solutes. Initially, the patient is usually oliguric Polyuria usually occurs as renal function improves. Proteinuria is not a manifestation of DI

Diabetes Insipidus

Fanconi syndrome Impaired proximal tubular dysfunction impairs resorption of amino acids, glucose, phosphate, citrate, urate, or bicarbonate, resulting in obligate diuresis Children typically present with rickets, whereas adults present with osteopenia and osteomalacia. Abnormal excretion of solutes is not a manifestation of DI

Urinary tract infections Urine culture is positive for the infective organism(s) Urine is sterile in patients with DI

Cushing's syndrome (primary or secondary) Patients with hypercortisolism display polyuria secondary to increased free water clearance. Classic findings of steroid excess include central obesity, moon facies, buffalo hump, protuberant abdomen, thin extremities, and hypertension. Laboratory studies reveal elevated 24-hour urinary free cortisol level, hyperglycemia, glucosuria, and hypokalemia Cushing's syndrome occurs either from excess endogenous cortisol production or exogenous steroid administration. The gold standard screening test for endogenous hypercortisolism remains the quantification of 24- hour urinary free cortisol release. Patients with DI do not display the clinical findings associated with hypercortisolism

Renal tubulointerstitial disease Chronic tubulointerstitial disease may present as polyuria due to either vasopressin insensitivity or inability to concentrate the urine Common causes to consider include vesicoureteral reflux, chronic analgesic ingestion (e.g., nonsteroidal anti-inflammatory drugs), or obstructive uropathy. Renal damage will be indicated by elevated serum creatinine level or by abnormal excretion of protein in the urine

Osmoreceptor dysfunction Damage to the anterior hypothalamic osmoreceptive system, resulting in hypernatremia in the absence of thirst Also called hypothalamic adipsia and occasionally referred to by the misleading term ‘essential hypernatremia;’ although rare, it is most often observed with congenital brain malformations (such as holoprosencephaly) or after brain injury

Primary aldosteronism Patients develop hypernatremia, hypokalemia, alkalosis, low plasma renin level, and diastolic hypertension The most common etiology is aldosterone-hypersecreting adrenal adenoma (Conn's syndrome), followed by bilateral cortical nodular hyperplasia. Patients with mild DI typically lack alkalosis and hypertension

AVP = arginine vasopressin; CNS = central nervous system; DI = diabetes insipidus.

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Drug Treatment for Diabetes Insipidus

Drug or Drug Class Dosing Side Effects Precautions Clinical Use

Desmopressin (DDAVP, Minirin) PO: Initially, 0.05 mg bid. Usual dose Hyponatremia, water intoxication, Avoid if CrCl<50. Caution with elderly, For outpatients with chronic central DI 0.1-1.2 mg total daily dose, dosed bid- headache cardiac disease and intact thirst. Combine with thiazide tid. Intranasal (0.01% nasal solution): diuretic for partial nephrogenic DI Initially, 10 μg in the PM. Intranasal maintenance is 10-40 μg total daily dose, dosed qd-tid. IV or SC: 1-2 μg bid

Hydrochlorothiazide (Microzide, Oretic) 50-100 mg total daily dose, dosed qd Polyuria, hypokalemia, orthostatic Caution with: CKD, sulfonamide For nephrogenic DI or bid hypotension, hypovolemia hypersensitivity, elderly, diabetes, gout, hepatic disease

Amiloride (Midamor) 5-20 mg bid-qd Polyuria, hyperkalemia, orthostatic Hyperkalemia. Caution with: CKD, Drug of choice for lithium-induced hypotension, hypovolemia, GI side sulfonamide hypersensitivity, elderly, nephrogenic DI effects diabetes, hepatic disease. Monitor serum potassium

Indomethacin (Indocin) Regular-release: 50 mg tid or 100 mg Abnormal renal function, elevated CV risk and GI risk. Avoid with: Combine with a thiazide in nephrogenic bid hepatic enzymes, platelet dysfunction, aspirin-sensitive asthma, severe CKD, DI anemia, GI side effects, headache, third trimester pregnancy. Decrease dizziness, tinnitus dose with hepatic disease, CKD. Caution with: CV disease, elderly. Drug interactions with CYP2C9 inhibitors or inducers

Chlorpropamide (Diabinese) 125-250 mg qd Hypoglycemia Avoid with: CrCl<50, elderly. Decrease For partial central DI dose with: hepatic disease, CrCl<80

= black box warning; bid = twice daily; CKD = chronic kidney disease; CNS = central nervous system; CrCl = creatinine clearance; CV = cardiovascular; CYP = cytochrome P450 isoenzyme; DDAVP = 1- deamino-8-D-arginine vasopressin; DI = diabetes insipidus; GI = gastrointestinal; IM = intramuscular; IV = intravenous; PM = evening; PO = oral; q12hr = every 12 hours; qd = once daily; qid = four times daily; SC = subcutaneous; SCr = serum creatinine; tid = three times daily. PIER provides key prescribing information for practitioners but is not intended to be a source of comprehensive drug information.

Diabetes Insipidus

Definitions of Diabetes Insipidus*

Complete central DI No AVP production by CNS

Partial central DI Some AVP production by CNS, but at low levels

Complete nephrogenic DI No renal response to normal or high serum AVP levels

Partial nephrogenic DI Diminished renal response to normal or high serum AVP levels

Gestational DI Inadequate AVP production occurring during pregnancy

*AVP synthesized in the hypothalamus is transported via the pituitary stalk and stored in the posterior pituitary (pars distalis). Increased serum osmolality stimulates vasopressin release, which in turn acts on the collecting ducts in the kidney to increase free water absorption. This understanding of the pathophysiology makes the various definitions of DI self-evident. AVP = arginine vasopressin; CNS = central nervous system; DI = diabetes insipidus.

Diabetes Insipidus

Testing for Diagnosis of Diabetes Insipidus

Water deprivation test*

Allow access to fluid ad libitum the night before testing

Start fluid deprivation for 7 or 8 hours at 8:00 a.m.

Measure serum osmolality, urinary osmolality, urinary volume, and patient weight at the start of the test, every 2 hours during the test, and at completion of the test

Also collect serum AVP level at completion of test (48)

If the patient begins to concentrate the urine without developing minor hyperosmolality or hypernatremia, consider administration of 3% saline at the rate of 0.1 mL/kg·min for 2 hours, while closely monitoring serial levels of serum osmolality and serum AVP

Abort the test if patient loses >5% of weight from baseline

Desmopressin challenge test (immediately following the water deprivation test)

Administer desmopressin at 0.3 µg im, iv, or sc; or 10 µg intranasally

Allow patient free access to fluids

Determine urinary osmolality and volume 4 hours after administration

See table Interpreting Results of the Desmopressin Challenge Test

Differentiating partial DI from primary polydipsia†

Administer desmopressin daily for several days at a dose of 1-2 µg sc q 12 h

Monitor daily weight, plasma sodium, urinary volume, urinary osmolality, and intake of fluids

Interpretation of results

Resolution of polyuria and polydipsia indicates central DI

No effect indicates nephrogenic DI

Progressive thirst with hyponatremia indicates primary polydipsia (be cautious to prevent dangerous levels of hypo-osmolality and hyponatremia)

* If 3% NaCl is used to increase the plasma osmolality and serum [Na+] to hyperosmolar ranges (so that the plasma AVP level can be interpreted more accurately), it confounds subsequent desmopressin challenge because the saline load from the infusion will cause natriuresis and increase urinary osmolality artifactually. Desmopressin challenge tests under these circumstances must be interpreted very cautiously. † If desmopressin is used to differentiate partial DI from primary polydipsia, serum [Na+] should be checked every 1 to 2 days for the first week because patients with primary polydipsia can reach dangerously low levels of serum [Na+] in short periods of time. AVP = arginine vasopressin; desmopressin = 1-deamino-8-D-arginine-vasopressin (desmopressin); DI = diabetes insipidus; im = intramuscularly; iv = intravenously; NaCl = sodium chloride; sc = subcutaneously.

Diabetes Insipidus

Interpreting Results of the Desmopressin Challenge Test

Results at End of Water Deprivation Test Results after Desmopressin Challenge

Urine-to-Serum Osmolality Ratio Serum AVP Level Rise in Urine Osmolality

Normal >1 1-5 NA

Complete central DI <1 <1 >50% rise

Complete nephrogenic DI <1 >5 0%

Primary polydipsia >1 1-5 <10% rise

Partial central DI >1 1-5 10% to 50% rise

Partial nephrogenic DI >1 >5 0% to 10% rise

AVP = arginine vasopressin; desmopressin = 1-deamino-8-D-artinine-vasopressin; DI = diabetes insipidus.

Diabetes Insipidus

Hypertonic Saline Test

To assess the ADH response to a hypotonic stimulus, administer a water load (20 mL/kg of 5% dextrose intravenously over 2-3 hours) before the hypertonic challenge

Keep the patient supine beginning 30 minutes before the challenge and throughout the test

Begin the hypertonic challenge with 0.9% NaCl administered continuously (0.05 mL/kg·min for all ages) by way of an indwelling catheter until plasma osmolality reaches 300 mOsm/kg, up to the maximum of 3 hours

Sample blood in lithium heparin tubes starting 30 minutes before the hypertonic challenge and then at 30-minute intervals

Determine plasma sodium levels, plasma ADH levels, and serum osmolality

Also collect urine before the start of the test and at 60-minute intervals after the test begins to assess urinary sodium and urinary osmolality

Record thirst sensation and blood pressure every 30 minutes

Look for an increase in plasma ADH levels as the plasma osmolality exceeds 280 mOsm/kg as a normal response

ADH = antidiuretic hormone; NaCl = sodium chloride. Adapted from 16.

Diabetes Insipidus

Etiologies of Central Diabetes Insipidus

Idiopathic

Head trauma

Postneurosurgery

Neoplasm

Pituitary tumor

Craniopharyngioma

Meningioma

Leukemia/lymphoma

Metastatic tumor

Pineal tumor

Germinoma

Glioma

Benign cysts

Ischemia

Brain death

Sheehan's syndrome

Infiltration

Histiocytosis (formerly called Letterer-Siwe disease)

Sarcoidosis

Granulomatosis with polyangiitis (Wegener's)

Bronchocentric granulomatosis

Infection

Viral encephalitis

Bacterial meningitis

Tuberculosis

Syphilis

Blastomycosis

Toxoplasmosis

Autoimmune (lymphocytic infundibuloneurohypophysitis)

Congenital

Diabetes Insipidus

Familial (autosomal dominant)

Prepro-arginine vasopressin-neurophysin II gene mutation

Septo-optic dysplasia (de Morsier syndrome): HESX1 mutation

DIDMOAD

Hypopituitarism

PROP1 mutation

Pit1 mutation

Cytomegalovirus infection

Rathke cleft cyst

DIDMOAD = diabetes insipidus, diabetes mellitus, optic atrophy, and deafness.

Diabetes Insipidus

Etiologies of Nephrogenic Diabetes Insipidus*

Electrolyte disturbances

Hypokalemia

Hypercalcemia (resulting in hypercalciuria)

Hypermagnesemia

Genetic (familial)

X-linked dominant

Vasopressin V2 receptor (AVP2R; http://www.ncbi.nlm.nih.gov/omim?db=OMIM)

Autosomal recessive and autosomal dominant

Aquaporin-2 water channel (AQP2 gene; OMIM #222000427)(61)

Psychogenic polydipsia with loss of the medullary concentrating gradient

Cerebral salt wasting

Neurosurgery

Irradiation

Head trauma

Tumor-related: usually hypothalamic or pituitary neoplasms

Fever

Autonomic failure

Drugs

Loop diuretics (e.g., furosemide )

Phenytoin

Reserpine

Cisplatin

Rifampin

Ethanol

Lithium : may become permanent

Demeclocycline

Chlorpromazine

Volatile anesthetics

Foscarnet

Amphotericin B

Diabetes Insipidus

α-interferon

Mannitol

Olanzapine

Chronic tubulointerstitial diseases

Analgesic abuse nephropathy

Sickle cell nephropathy

Multiple myeloma

Amyloidosis

Sarcoidosis

Sjögren's syndrome

Autoimmune/lupus

Renal medullary cystic disease

Polycystic kidney disease

* Note that adrenal insufficiency mimics nephrogenic DI but does not cause it. Secondary adrenal insufficiency causes an SIADH-like picture from water retention. Primary adrenal insufficiency causes renal salt wasting, but there is no defect of urine concentrating ability in most patients. The other listed causes of excessive natriuresis or salt wasting impair the renal concentrating ability, which resembles nephrogenic DI clinically; however, treatment should be directed to the primary disease rather than to symptomatic relief of nephrogenic DI. DI = diabetes insipidus; SIADH = syndrome of inappropriate secretion of antidiuretic hormone.

Diabetes Insipidus

Etiologies of Primary Polydipsia

Psychogenic (schizophrenia, mania)

Dipsogenic

Granulomatous (sarcoid)

Infectious

Vascular (vasculitis)

Tumors, rarely

Other (multiple sclerosis)

Diabetes Insipidus

Top Figures

Plasma AVP Levels Relationship of plasma osmolality to AVP levels during water deprivation (dehydration) in patients with diabetes insipidus. Note that patients with neurogenic DI or partial neurogenic DI have vasopressin levels below 1 pg/mL. Patients with nephrogenic DI or dipsogenic DI have AVP levels that are greater than or equal to normal levels. Reprinted with permission from 16© 1988 by Annual Reviews www.AnnualReviews.org.