I. What every physician needs to know.

Diabetes insipidus (DI) is a disease characterized by polyuria (greater than 3 liters a day) and polydipsia, due to congenital or acquired absence of, or resistance to, vasopressin (or antidiuretic hormone, ADH) action, leading to failure to concentrate urine.

Countercurrent exchange mechanisms in the kidney allow for regulation of water reabsorption in the collecting duct by vasopressin. Upon release from the anterior hypothalamus in response to changes in plasma osmolality or to decreased effective circulating volume, ADH binds to vasopressin 2 (V2) receptors in the collecting duct, activating signaling pathways that result in the insertion of aquaporin-2 (AQP-2) water channels in the luminal membrane. In the presence of an intact medullary interstitial osmotic gradient, water is reabsorbed into the cell through AQP-2 channels and exits via AQP-3 and AQP-4 channels into the systemic circulation. Partial or complete absence of vasopressin release from the hypothalamus leads to central diabetes insipidus, whereas nephrogenic diabetes insipidus occurs when ADH is present in the circulation, but the collecting duct cells are unable to respond due to failure at any of the steps in the signaling pathway.

Congenital or hereditary forms of central and nephrogenic DI have been described, but are rare. Mutations in the arginine vasopressin (AVP) gene, encoding vasopressin, have been associated with autosomal dominant or autosomal recessive forms of central DI, typically diagnosed after the first year of life when polyuria and polydipsia are noted. X-linked nephrogenic DI has been reported in males carrying mutations in the arginine vasopressin receptor 2 (AVPR2) gene, which codes for the V2 receptor. Finally, mutations in the aquaporin 2 (collecting duct)(AQP2) gene lead to mutant and defective forms of the aquaporin 2 channel, for which both autosomal dominant and recessive forms of nephrogenic DI have been reported in the literature.

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II. Diagnostic Confirmation: Are you sure your patient has diabetes insipidus?

Patients with diabetes insipidus present with the excretion of abnormally large volumes (greater than 3L/day) of dilute urine (urine osmolality less than 250mosmol/kg).

A. History Part I: Pattern Recognition:

In patients with central diabetes insipidus, onset of polyuria is typically abrupt. In patients with a more gradual onset of polyuria, nephrogenic diabetes insipidus or primary polydipsia should be suspected. Classically, patients with central DI have a preference for cold or iced water. Patients drink a lot of fluids and this is driven primarily by thirst. Patients typically will wake up several times during the night to urinate, and will feel the urge to drink as well. When deprived of water, symptoms of intravascular volume depletion may develop.

B. History Part 2: Prevalence:

Central DI may develop in patients with craniopharyngiomas, particularly after transphenoidal surgery. Additionally, metastatic diseases involving the hypothalamus or pituitary gland, commonly lung and breast cancers, may likewise present with symptoms of DI. Granulomatous diseases, including sarcoidosis or tuberculosis, as well as infiltrative diseases, such as histiocytosis X and Wegener’s granulomatosis, may also lead to failure to secrete ADH. Diminished ADH secretion may also be seen with hypoxic encephalopathy or ischemia, associated with cardiopulmonary arrest or shock. In 30% of patients, no known etiologies are identified and lymphocytic inflammation of the hypothalamic-pituitary tract due to an autoimmune process may be involved.

Causes of nephrogenic DI include electrolyte disorders, particularly hypercalcemia and hypokalemia. Elevated calcium levels (Ca greater than 11mg/dL) result in reversible concentrating defect via impaired generation of the medullarly osmotic gradient and through downregulation of aquaporin-2 expression and delivery. Hypokalemia reduces tubular responsiveness to ADH by decreasing cyclic adenosine monophosphate (AMP) generation. Lithium therapy can result in polyuria in as many as 30% of patients within several weeks of initiation, and may involve several mechanisms including decreased ADH receptor density and aquaporin-2 downregulation. Other drugs that result in nephrogenic DI include demeclocycline, ifosfamide, and foscarnet.

Amyloid deposition and lymphocytic infiltration of collecting ducts in patients with amyloidosis and Sjogren’s syndrome, respectively, rarely also lead to a urinary concentrating defect. Patients with advancing chronic renal failure develop resistance to ADH due to chronic tubulointerstitial damage and aquaporin-2 downregulation. Chronic renal medullary ischemia in sickle cell disease results in diminished concentrating ability. In rare cases, abnormally elevated levels of the enzyme vasopressinase released by the placenta has been associated with DI in pregnancy, due to rapid degradation of endogenous ADH.

C. History Part 3: Competing diagnoses that can mimic disease diabetes insipidus.

Polyuria must first be distinguished from urinary frequency. In some patients, an accurate recording of urine output in a 24-hour period may be necessary. In patients with greater than 3-4 liters of urine output daily, causes of osmotic or solute diuresis will need to be ruled out. Common causes include surreptitious or prescribed diuretic use and diabetes mellitus. In hospitalized patients, high-protein tube feeds may result in brisk urine output, as well as in patients at risk for cerebral salt wasting. Additionally, polyuria is frequently seen in the recovery phase of acute tubular necrosis (ATN) or upon relief of obstructive nephropathy.

Patients with primary or psychogenic polydipsia will also present with polyuria as a consequence of compulsive water drinking. In the hospital setting, water intake can be more closely monitored; however, the diagnosis of primary polydipsia may require additional testing when the patient is being evaluated as an outpatient.

D. Physical Examination Findings.

No specific physical examination findings are characteristic of diabetes insipidus. As long as patients are able to drink in order to match their urine output, intravascular volume depletion will not occur. However, if fluid intake is restricted, signs of volume depletion/dehydration, including hypotension, dry mucous membranes, decreased skin turgor, or altered mental status due to hypernatremia may develop. This is of particular concern in patients who undergo surgical procedures.

In patients with central diabetes insipidus, hypothalamic dysfunction may develop due to pituitary adenomas. In such patients, visual field defects, notably, bitemporal hemianopsia, may be present on physical examination due to compression of the optic chiasm. Additionally, physical findings suggestive of panhypopituitarism should be investigated.

E. What diagnostic tests should be performed?

1. What laboratory studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

Initial evaluation of the polyuric patient requires measurement of the basic metabolic panel, particularly the serum sodium (Na) level, and urine osmolality. In patients with diabetes insipidus, the urine osmolality will be less than 250mosmol/kg. Levels greater than 300mosmol/kg are suggestive of osmotic or solute diuresis. In addition, the metabolic panel may help in identifying patients with renal insufficiency and electrolyte disturbances that may lead to nephrogenic DI. The serum Na level may be useful in distinguishing DI from primary polydipsia. In the former, serum Na levels will be on the high-normal range (140-145mEq/L), whereas patients with primary polypdipsia will tend to have serum Na levels in the low-normal range (135-140mEq/L).

The water-restriction test is critical in differentiating diabetes insipidus from primary polydipsia, and in distinguishing central from nephrogenic forms of DI. During the test, simultaneous measurements of the plasma (Posm) and urine (Uosm) osmolality, along with serum Na levels, are performed, while urine output and vital signs are monitored on an hourly basis. The patient is restricted from water intake until the Posm reaches 295mosmol/kg, at which point endogenous ADH secretion is maximally stimulated. At this point, desmopressin is administered intranasally (10mcg) or intravenously (1-2mcg).

In normal individuals or patients with primary polydipsia, water restriction will result in maximal or submaximal concentration of urine, with Uosm ranging from 500mosmol/kg to 800mosmol/kg, and a decrease in urine output to less than 30mL/hr. No further augmentation of urinary osmolality is seen upon administration of dDAVP. In patients with central DI, the administration of desmopressin will result in a rise in the Uosm by 100% to 800%, whereas a 15% to 50% increase may be expected in partial central DI. An equivalent fall in the urine output will occur. Patients with nephrogenic DI will show little to no response to desmopressin and close monitoring for intravascular volume depletion is imperative.

An alternative is to measure plasma vasopressin levels, although results are less likely to be immediately available in most institutions. Normal patients will have plasma vasopressin levels greater than 2ng/L after dehydration, whereas patients with central DI will have low (less than 1.5ng/L) to undetectable levels. Owing to hormone resistance, plasma vasopressin levels in patients with nephrogenic DI will be at maximal levels (greater than 5ng/L).

2. What imaging studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

Radiographic studies are helpful only in patients with confirmed central diabetes insipidus, in whom magnetic resonance imaging (MRI) of the brain to rule out a hypothalamic or pituitary lesion is essential. In patients with nephrogenic DI, a search for the underlying etiology may require additional radiographic testing but this depends upon the leading diagnoses.

F. Over-utilized or “wasted” diagnostic tests associated with this diagnosis.

Not applicable.

III. Default Management.

Management of a patient with polyuria due to diabetes insipidus requires initial attention to correction of both intravascular volume deficit, which may occur in patients with limited access to fluids, as well as to correction of serum osmolality. This may require intravenous fluid therapy to replete both water and sodium (less frequent) deficits. Thereafter, the focus should be on clarifying whether polyuria is due to the absence of, or resistance to, ADH action. In patients with central DI, initiation of desmopressin therapy and identifying the appropriate dose is essential. Patients with nephrogenic DI present a greater challenge and trials of diuretic and/or nonsteroidal anti-inflammatory drugs (NSAID) therapy will require long-term oversight.

A. Immediate management.

For a patient with polyuria in whom diabetes insipidus is being considered, immediate concerns relate to maintenance of intravascular volume and correcting any issues of hypernatremia. In the hypotensive patient, volume repletion with isotonic saline is warranted. On the other hand, euvolemic patients with hypernatremia should be managed with water repletion (intravenous or oral). After repleting the water deficit, matching urine output with oral or intravenous fluids will be necessary, paying close attention to maintaining normal serum Na levels.

B. Physical Examination Tips to Guide Management.

Close monitoring of the patient’s volume status and hemodynamic stability are important considerations in the patient with diabetes insipidus. During fluid resuscitation, water repletion, and desmopressin therapy, frequent measurement of vital signs and urine output are critical. In the hypernatremic patient, the presence of altered mental status may signal significant free water deficit; on the other hand, rapid correction of the serum Na level puts the patient at risk for cerebral edema, for which a thorough neurologic exam is helpful.

C. Laboratory Tests to Monitor Response To, and Adjustments in, Management.

Therapy of diabetes insipidus puts the patient at risk for hyponatremia and volume overload. Monitoring of desmopressin therapy or therapy with thiazide diuretics or amiloride (in patients with lithium induced nephrogenic DI) requires frequent measurement of serum Na levels and urine osmolality, and dose adjustment as needed.

D. Long-term management.

Several strategies for managing diabetes insipidus are available.

Hormone replacement. Desmopressin therapy provides exogenous ADH activity without the vasopressor effects of endogenous vasopressin. Long-term management involves achieving hemodynamic stability and correction of urinary concentrating defect with the appropriate dose. Once or twice daily administration of 5-20mcg doses of intranasal desmopressin or 0.1-0.2mg of oral desmopressin may suffice, but dosage titration following urine output and serum Na levels will be necessary. An injectable form of desmopressin is also available for use in the hospitalized patient.

Diuretic therapy.Hydrochlorothiazide (HCTZ) has been used primarily in patients with nephrogenic DI at doses of 12.5-25mg daily. Urine output decreases in these patients owing to the volume depletion, leading to attenuated water excretion. Recent studies also point to HCTZ-induced upregulation of aquaporin-2 and distal renal Na transporters as mechanisms responsible for the antidiuretic properties of thiazides. In patients with lithium induced nephrogenic DI, amiloride therapy appears to be efficacious via the inhibitory effects on amiloride on lithium entry via the distal epithelial Na channel.

Non-steroidal antiinflammatory drugs (NSAID).In patients with nephrogenic DI or lithium toxicity, some NSAIDs have been shown to have an antidiuretic effect, improving urinary concentration ability by impairing renal prostaglandin synthesis. Attention should be paid, however, to the differential effects of NSAIDs on renal prostaglandins, indomethacin appearing to be superior to ibuprofin or sulindac.

E. Common Pitfalls and Side-Effects of Management

Therapies available for management of diabetes insipidus are generally well-tolerated. Desmopressin and diuretic therapy should be monitored for their attendant risks of hyponatremia and volume overload due to excessive water retention. Otherwise, desmopressin is rarely associated with hypertension and hypotension, headache, and rare thrombotic events.

IV. Management with Co-Morbidities

A. Renal Insufficiency.

Patients with stage 3 chronic renal disease (estimated glomerular filtration rate (eGFR) less than 50mL/min) are at increased risk of hyponatremia with the administration of desmopressin, hence is a contraindication for use. However, desmopressin is a potential therapy for short-term control of uremic bleeding due to platelet dysfunction.

B. Liver Insufficiency.

No change in standard management.

C. Systolic and Diastolic Heart Failure

Increased risk of hyponatremia and volume overload due to water with desmopressin therapy needs to be considered.

D. Coronary Artery Disease or Peripheral Vascular Disease

Desmopressin administration is rarely associated with an increased risk of thrombosis, possibly acute myocardial infarction. Additionally, there is an increased risk of hypertension particulary in patients with significant water retention.

E. Diabetes or other Endocrine issues

No change in standard management.

F. Malignancy

No change in standard management.

G. Immunosuppression (HIV, chronic steroids, etc).

No change in standard management.

H. Primary Lung Disease (COPD, Asthma, ILD)

No change in standard management.

I. Gastrointestinal or Nutrition Issues

No change in standard management.

J. Hematologic or Coagulation Issues

Desmopressin therapy is contraindicated in patients with von Willebrand disease type 2B due to increased risk of platelet aggregation and thrombosis.

K. Dementia or Psychiatric Illness/Treatment

Therapy with desmopressin requires close monitoring in patients with habitual polydipsia due to increased risk of hyponatremia.

V. Transitions of Care

A. Sign-out considerations While Hospitalized.

In patients with diabetes insipidus who are hospitalized, inconsistent water intake may be a concern, as with patients scheduled for surgical intervention or made nil per os (NPO) prior to a procedure. Intravenous fluid therapy will be critical in preventing the development of hypernatremia and volume depletion. On the other hand, inpatients in whom desmopressin therapy is continued are at increased risk of hyponatremia and close monitoring of the serum Na levels and adjustment of the desmopressin dose is warranted.

B. Anticipated Length of Stay.

The diagnosis and management of diabetes insipidus may be carried out in the outpatient setting. Hence, length of stay should not be impacted upon by diabetes insipidus. However, a stable hemodynamic and natremic control needs to be achieved or maintained during the inpatient stay with desmopressin therapy.

C. When is the Patient Ready for Discharge.

Not applicable

D. Arranging for Clinic Follow-up

1. When should clinic follow up be arranged and with whom.

Long-term follow-up of the patient with diabetes insipidus is typically arranged with an endocrinologist, particularly in those with panhypopituitarism. Alternatively, nephrologists manage individuals with nephrogenic diabetes insipidus, especially when concurrent chronic renal disease or electrolyte disturbances is present. Neurosurgical evaluation and management may be necessary in patients with central DI due to hypothalamic or pituitary masses.

2. What tests should be conducted prior to discharge to enable best clinic first visit.

Not applicable

3. What tests should be ordered as an outpatient prior to, or on the day of, the clinic visit.

On the day of the clinic visit, measurement of the basic metabolic panel may be useful to ensure that the dose of desmopressin is appropriate. Desmopressin administration leads to nonsuppressible ADH activity, which may lead to water retention and hyponatremia if the dose is too high. Similar concerns with long-term thiazide or amiloride (in the case of lithium induced nephrogenic DI) hold.

E. Placement Considerations.

Not applicable

F. Prognosis and Patient Counseling.

Prognosis in patients diagnosed with diabetes insipidus depends entirely upon the underlying etiology. Early recognition of DI in congenital forms is crucial to prevent mental and growth retardation due to recurrent episodes of volume depletion and hypotension. In patients with adult onset disease, therapy with desmopressin can mitigate the symptoms of polyuria and polydipsia once a stable dose is achieved.

VI. Patient Safety and Quality Measures

A. Core Indicator Standards and Documentation.

Not applicable.

B. Appropriate Prophylaxis and Other Measures to Prevent Readmission.

Not applicable.

VII. What's the evidence?

Fujiwara, TM, Bichet, DG. “Molecular biology of hereditary diabetes insipidus”. J Am Soc Nephrol. vol. 16. 2005. pp. 2836-46.

Komninos, J, Vlassopoulou, V, Protopapa, D, Korfias, S, Kontogeorgos, G, Sakas, DE, Thalassinos, NC. “Tumors metastatic to the pituitary gland: case report and literature review”. J Clin Endocrinol Metab. vol. 89. 2004. pp. 574-80.

Pivonello, R, De Bellis, A, Faggiano, A, Di Salle, F, Petretta, M, Di Somma, C, Perrino, S, Altucci, P, Bizzarro, A, Bellastella, A, Lombardi, G, Colao, A. “Central diabetes insipidus and autoimmunity: relationship between the occurrence of antibodies to arginine vasopressin-secreting cells and clinical, immunological, and radiological features in a large cohort of patients with central diabetes insipidus of known and unknown etiology”. J Clin Endocrinol Metab. vol. 88. 2003. pp. 1629-36.

Wang, WH, Lu, M, Hebert, SC. “Cytochrome P-450 metabolites mediate extracellular Ca(2+)-induced inhibition of apical K+ channels in the TAL”. Am J Physiol. vol. 271. 1996. pp. C103-11.

Kim, JK, Summer, SN, Berl, T. “The cyclic AMP system in the inner medullary collecting duct of the potassium-depleted rat”. Kidney Int. vol. 26. 1984. pp. 384-91.

Hensen, J, Haenelt, M, Gross, P. “Lithium induced polyuria and renal vasopressin receptor density”. Nephrol Dial Transplant. vol. 11. 1996. pp. 622-7.

Marples, D, Christensen, S, Christensen, EI, Ottosen, PD, Nielsen, S. “Lithium-induced downregulation of aquaporin-2 water channel expression in rat kidney medulla.”. J Clin Invest. vol. 95. 1995. pp. 1838-45.

Pham, PT, Pham, PC, Wilkinson, AH, Lew, SQ. “Renal abnormalities in sickle cell disease”. Kidney Int. vol. 57. 2000. pp. 1-8.

Durr, JA, Hoggard, JG, Hunt, JM, Schrier, RW. “Diabetes insipidus in pregnancy associated with abnormally high circulating vasopressinase activity”. N Engl J Med. vol. 316. 1987. pp. 1070-4.

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. vol. 305. 1981. pp. 1539-46.

Earley, LE, Orloff, J. “The mechanism of antidiuresis associated with the administration of hydrochlorothiazide to patients with vasopressin-resistant diabetes insipidus”. J Clin Invest. vol. 41. 1962. pp. 1988-97.

“Antidiuretic effect of hydrochlorothiazide in lithium-induced nephrogenic diabetes insipidus is associated with upregulation of aquaporin-2, Na-Cl co-transporter, and epithelial sodium channel”. J Am Soc Nephrol. vol. 15. 2004. pp. 2836-43.

Knoers, N, Monnens, LA. “Amiloride-hydrochlorothiazide versus indomethacin-hydrochlorothiazide in the treatment of nephrogenic diabetes insipidus”. J Pediatr. vol. 117. 1990. pp. 499-502.

Walker, RM, Brown, RS, Stoff, JS. “Role of renal prostaglandins during antidiuresis and water diuresis in man”. Kidney. vol. 21. 1982. pp. 365-70.

Libber, S, Harrison, H, Spector, D. “Treatment of nephrogenic diabetes insipidus with prostaglandin synthesis inhibitors”. J Pediatr. vol. 108. 1986. pp. 305-11.