Diabetes Insipidus

Introduction

  • Polydipsia and polyuria with dilute urine are the characteristic findings in diabetes insipidus (DI).
  • After excluding glucose-induced osmotic diarrhea, polydipsia and polyuria can be caused by three conditions:
    • Central DI
    • Nephrogenic DI
    • Compulsive water drinking
  • The pathophysiology behind central and nephrogenic DI involves ineffective antidiuretic hormone (ADH) signaling, resulting in a failure to concentrate urine.
  • Compulsive water drinking (also referred to as primary polydipsia) is characterized by excessive water consumption leading to excessive urine production.
  • The incidence of DI in the general population is relatively low at 3 cases per 100,000 individuals.
  • The incidence of compulsive water drinking is currently unknown, but it is encountered in 10% - 40% of patients with schizophrenia. 
  • Early identification is crucial to avoid complications from water loss and electrolyte imbalances.
  •  The water deprivation test, which is relatively easy and cheap to perform, is the gold standard for diagnosing DI and compulsive water drinking.

 

Pathophysiology

Central DI

  • Due to decreased production of ADH.
  • In normal physiology, ADH is released from the posterior pituitary in response to increases in plasma osmolality.
  • ADH activity leads to  an increased number of apical aquaporin channels in the cortical collecting ducts of the kidneys.
  • Increasing the number of functional aquaporin channels allows water to enter the collecting duct cells, thus concentrating the tubular fluid and conserving free water.
  • In Central DI, various different pathologic processes can impede the production or secretion of ADH.
  • The etiology of Central DI can be either idiopathic or neurogenic:
    • Primary brain tumor (50%)
    • Idiopathic (29%)
    • Histiocytosis X (16%)
    • The remaining cases are due to infections and head trauma.
  • Central DI may be also be familial (generally autosomal dominant) in origin
    • A thorough family history is important in order to identify pre-symptomatic individuals via genetic testing.

 

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Figure 1. Pathological causes of central DI in children and adults.

Adapted from Saborio, Pablo, Gary A. Tipton, and J. C. Chan. "Diabetes insipidus." Pediatrics in Review 21.4 (2000): 122-129

 

Nephrogenic DI

  • Due to an inadequate response to ADH at the level of the renal cortical collecting ducts.
  • ADH is effectively secreted by the posterior pituitary in response to increased plasma osmolality, but this signal does not result in increased water reabsorption.
  • Nephrogenic DI is generally divided into inherited and acquired causes.
  • Inherited Nephrogenic DI causes include:
    • Mutations that impair the function of the ADH receptor (x-linked recessive) 
    • Defects in the aquaporin channel (autosomal dominant or recessive).
    • These genetic defects often result in an early age of onset (<1 week of age) and severe hypernatremia.
  • Acquired Nephrogenic DI most often results from:
    • Adverse drug reaction: (e.g. lithium and amphotericin are thought to accumulate in the kidneys and result in an abnormal response to ADH, although the mechanism is not yet fully understood).
    • Electrolyte abnormalities: (e.g. hypercalcemia increases urinary sodium loss, diminishing the osmotic gradient for aquaporin-facilitated water reabsorption).
    • Systemic disorders: (e.g. amyloidosis, sarcoidosis, sickle cell disease, and Sjogren syndrome)
  • Acquired Nephrogenic DI tends to result in less severe polyuria and hypernatremia compared to inherited Nephrogenic DI and Central DI.

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Figure 2: Common causes of acquired nephrogenic DI.

Adapted from Saborio, Pablo, Gary A. Tipton, and J. C. Chan. "Diabetes insipidus." Pediatrics in Review 21.4 (2000): 122-129.

 

Compulsive water drinking

  • Compulsive water drinking is found in individuals that ingest up to 15-20 L of water per day and produce an equivalent amount of urine.
  • This excessive water intake results in physiologic suppression of ADH secretion and production of dilute urine.
  • Excessive diuresis can result in life-threatening episodes of hyponatremia, leading to seizures and cardiac arrest.
  • Compulsive water drinking is usually seen in patients with underlying psychiatric conditions.
  • This condition is most often seen in females (80%) and is frequently associated with a subset of patients suffering from schizophrenia.
  • Compulsive water drinking can be incredibly difficult to manage and often requires institutionalization.

Diagnosis

History

  • DI should be strongly considered in any patient with a history of hypernatremia and polyuria.
  • Family history of DI can be helpful to focus on inherited central and nephrogenic forms of DI.
  • History of head trauma, precocious puberty, and neurologic deficits should raise suspicion for Central DI.
  • Similarly, polyuria with hypernatremia in the setting of a systemic disease or treatment with a new drug points towards nephrogenic DI.
  • Psychiatric history is crucial when considering compulsive water drinking.

 

Signs and symptoms

  • Young children often present with severe dehydration, vomiting, fever, failure to thrive and growth retardation.
  • New onset nocturia and enuresis in young children is also frequently seen in DI.
  • Age of onset is important to consider when evaluating a patient with suspected DI.
  • Inherited Nephrogenic DI often manifests in the first week of life
  • Inherited Central DI typically presents between the ages of one year and six years.
  • Focal neurologic signs and neurologic deficits in the presence of polyuria should raise suspicion for central DI secondary to an intracranial mass.
    • In particular, visual defects at a young age are often associated with an intracranial mass.

 

Laboratory testing

  • Initial serum and urine laboratory values can be helpful when evaluating a patient with polyuria.
  • High serum osmolality with hypo-osmolar urine suggests Central or Nephrogenic DI.
  • Low serum osmolality with hypo-osmolar urine suggests compulsive water drinking.
  • Serum glucose levels are also essential to rule out polyuria from diabetes mellitus.
  • The water deprivation test is the gold standard for diagnosing DI.
  • This two-step test differentiates between Central DI, Nephrogenic DI and compulsive water drinking.

 

The test is summarized in the figure below:

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Figure 3: Differential diagnosis for polyuria in the setting of dehydration and a summary of the water deprivation test.

Adapted from Saborio, Pablo, Gary A. Tipton, and J. C. Chan. "Diabetes insipidus." Pediatrics in Review 21.4 (2000): 122-129.

 

Water Deprivation Test

  • The water deprivation test is performed in two parts.
  • First, the patient is deprived of all fluids for up to eight hours and urine osmolality is measured after each void.
    • If the patient fails to concentrate her or his urine during the water deprivation, DI can be diagnosed.
    • If the patient is able to concentrate his or her urine, compulsive water drinking can be diagnosed.
  • Following this deprivation, synthetic ADH (DDAVP) is administered.
    • If the patient responds and begins concentrating urine, central DI is confirmed.
    • Alternatively, if there is no response to ADH nephrogenic DI is diagnosed.

urineosmchart_0_0.png

Figure 4: Summary of the urine osmolality findings during the water deprivation test and after DDAVP administration. CDI: central DI; NDI: nephrogenic DI; PP: primary polydipsia (compulsive water drinking)

Adapted from: Di Iorgi, Natascia, et al. "Diabetes insipidus–diagnosis and management." Hormone research in paediatrics 77.2 (2012): 69-84.

 

Differential Diagnosis

The differential diagnosis for polyuria and polydipsia includes the following:

  • Diabetes insipidus
  • Compulsive water drinking
  • Diabetes mellitus
  • Chronic renal failure
  • Small volume urinary frequency (secondary to cystitis, urethritis, etc.)

Diabetes mellitus can be differentiated from DI by hyperglycemia, glucosuria, and ketonuria.

Chronic renal failure will often present with other signs of azotemia such as elevated BUN and creatinine.

Other causes of urinary frequency (such as infections) are rarely associated with polydipsia and frequently have a different clinical presentation.

 

Treatment

Central DI

  • Treated primarily with the synthetic ADH analogue, DDAVP.
  • Intranasal, oral and IV preparations are available.
  • Polyuria in central DI can also be controlled with thiazide diuretics.
  • The paradoxical antidiuretic effect of thiazide diuretics in DI is due to increased sodium excretion in the urine.
  • Increased sodium excretion is thought to result in increased water reabsorption in the proximal convoluted tubule.
  • Thiazide diuretics reduce polyuria symptoms by up to 50% for most patients.

Nephrogenic DI

  • Managed primarily with a low sodium and low osmolar diet.
  • Sodium intake should be reduced to < 0.7 mEq/kg/day and a thiazide diuretic should be started to decrease polyuria.

Compulsive Water Drinking

  • There are no effective pharmacological interventions to date.
  • Institutionalization is frequently necessary to prevent life-threatening hyponatremia.
  • Treatment and management of any underlying psychiatric illnesses is also recommended.

 

Complications

  • Complications associated with DI include short attention span, hyperactivity, learning and psychomotor delays.
  • Severe dehydration and encephalopathy are now rarely encountered thanks to early detection and improved treatments.
  • Renal complications include nonobstructive functional hydronephrosis and hydroureters from volume overload.

 

Prognosis

  • The prognosis for DI is excellent as long as water is freely accessible.
  • As long as patients are able to replace their large urine outputs, they will only be inconvenienced by polyuria and polydipsia symptoms.
  • In very young patients and those unable to communicate a need for water, lack of water intake can result in life-threatening dehydration.
  • These patients require dedicated caregivers and regular follow up with primary care physicians.

 

Resources for Patients and Families

  • National Organization for Rare Disorders (NORD)

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  • Nephrogenic Diabetes Insipidus (NDI) Foundation

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References

  1. Saborio, Pablo, Gary A. Tipton, and J. C. Chan. "Diabetes insipidus." Pediatrics in Review 21.4 (2000): 122-129.
  2. Di Iorgi, Natascia, et al. "Diabetes insipidus–diagnosis and management." Hormone research in paediatrics 77.2 (2012): 69-84.
  3. Maghnie, Mohamad, et al. "Central diabetes insipidus in children and young adults." New England Journal of Medicine 343.14 (2000): 998-1007.
  4. Fujiwara, T. Mary, and Daniel G. Bichet. "Molecular biology of hereditary diabetes insipidus." Journal of the American Society of Nephrology 16.10 (2005): 2836-2846.
  5. Loffing, Johannes. "Paradoxical antidiuretic effect of thiazides in diabetes insipidus: another piece in the puzzle." Journal of the American Society of Nephrology 15.11 (2004): 2948-2950.

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