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Diabetes Insipidus     Types  |  Dx  |  Rx    

Diabetes insipidus
-  is a condition in which patients produce large quantities of dilute urine due to inability to conserve water and maintain an optimum free water level, leading to symptoms of extraordinary thirst, copius water intake up to 20 L/day  (polyuria and polydipsia in a non-diabetic patients), dry skin, and constipation. 

Desmopressin (DDAVP 0.1 mg/mL nasal spray 1-2x/day, 0.1-0.2 mg tablet, 4 mcg/mL injection), a synthetic analog of vasopressin, is the drug of choice in the treatment of CDI (Central Diabetes Insipidus), but in mild cases, there are alternative drugs that can be used, including chlorpropamide, carbamazepine, thiazides, or indapamide.  (Efficacy of Indapamide in  central DI Arch Intern Med. Sep.27,1999;159:2085-2087 - - Tamer Tetiker)

Types of Diabetes Insipidus:

A.  Pituitary diabetes insipidus  
Central or neurogenic diabetes insipidus results from the failure of the posterior pituitary to make or secrete vasopressin (also called antidiuretic hormone [ADH]), and causes polydipsia and polyuria.

  1. Idiopathic (in about 50% of cases)
  2. Familial
  3. Brain tumor (primary or secondary)
  4. Head trauma; Brain radiation; Intracranial hemorrhage
  5. Postneurosurgery in the area of pituitary or hypothalamus
  6. Infection e.g. encephalitis
  7. Vasc. disorder: postpartum necrosis
  8. Systemic: sarcoidosis, tumor metastases, Hand Schuller Christian disease

B.  Nephrogenic diabetes insipidus
Nephrogenic diabetes insipidus (NDI), which can be congenital or acquired, results from failure of the kidney to respond to vasopressin (or ADH).
Most adults with NDI have an acquired abnormality, with the most common causes being lithium therapy, chronic hypercalcemia, chronic hypokalemia, protein malnutrition, and release of ureteral obstruction.

  1. Drugs: lithium carbonate, demeclocycline (Declomycin), glyburide (Micronase), amphotericin B, colchicine, Gentamicin, Loop diuretics, vinblastine, acetohexamide, tolazamide (Tolinase), propoxyphene (Darvon), methoxyflurane, the antiviral CMV drug: foscarnet (Foscavir)
  2. Acquired renal disease: CRF, chronic renal medullary disease, pyelonephritis, obstructive uropathy, polycystic kidney disease, renal transplantation; nephrocalcinosis hypercalcemia, chronic hypokalemia, chronic hypercalcemia, hyperthyroidism,
  3. Dietary abnormalities: excessive water intake, decreased NaCl initake, decreased protein intake
  4. Miscellaneous: Sickle cell disease (defect in renal concentrating capacity), multiple myeloma, amyloidosis, Sjogren's synd., Sarcoidosis, pregnancy related (vasopressinase from placenta can destroy ADH too rapidly) diabetes insipidus.
  5. Congenital or Familial nephrogenic diabetes insipidus : V2 receptor mutations (will not have a response to desmopression), Aquaporin-2 mutations (will have a response to desmopression).

C.  Psychogenic "Pseudo diabetes insipidus" compulsive water drinking

           

Diagnosis of Diabetes Insipidus:  

If the urine osmolality is <200 mOsmol/kg in the presence of polyuria (>3 L/day), diabetes insipidus is suspected.

The standard method for diagnosing diabetes insipidus is a water deprivation test.
- water deprivation lasts 4-18 hours, with hourly measurements of body weight and urine osmolality, until 2-3 consecutive samples vary by <30 mOsm/kg ( or <10%), or until the patient loses 5% of body weight.
At this point, the serum ADH level is measured, and then 5 units of ADH or 1 ug of desmopression (DDAVPa0 is injected.  Urine osmolality is then measured 30-60 minutes later.  Plasma osmolality is also measured at various points during the test.

The figure shows the typical changes in urine osmolality in response to water deprivation and to the administration of exogenous vasopressin in healthy individuals and in patients with diabetes insipidus. This test, which also distinguishes between persons with complete versus partial versions of each type of diabetes insipidus, is usually performed by restricting a patient's water intake, beginning after dinner. However, if the patient is producing more than 10 L of urine per day, then water restriction is only done during the day under close supervision and is not done after midnight. Spot urine samples for measuring osmolality are collected hourly, beginning at 7:00 a.m., until 3 successive measurements are within 50 to 100 mmol/kg of each other. Blood is then drawn to measure serum osmolality and plasma vasopressin levels. Next, vasopressin (or desmopressin) is administered and urine is obtained for osmolality every 30 minutes during the next 3 hours. This is done to account for a bladder with a large capacity and/or with the time-lag required to reconstruct the medullary gradient.

  1. In healthy individuals,
    water deprivation increases plasma osmolality, which stimulates secretion of vasopressin by the posterior pituitary. This then acts on the kidney to increase urine osmolality to 1000 to 1200 mmol/kg and to restore plasma osmolality to normal levels    . Administration of exogenous vasopressin does not increase urine osmolality further because it is already maximal in response to the individual's endogenous release of vasopressin.  The urine osmolality is > plasma osmolality following fluid restriction, and the urine osmolality increases only minimally (<10%) after 5 units of ADH injection.
  2. In patients with complete diabetes insipidus,
    water deprivation increases plasma osmolality but urine osmolality remains below 290 mmol/kg and does not increase    . In those with complete central diabetes insipidus, urine osmolality will increase by approximately 200 mmol/kg in response to exogenous vasopressin. In contrast, vasopressin will not increase urine osmolality in patients with complete NDI.  In Central Diabetes Insipidus, urine osmolality remains < plasma osmolality after dehydration.  After ADH injection, urine osmolality increases by >50%.
    In Nephrogenic Diabetes Insipidus, urine osmolality remains < plasma osmolality.  After ADH injection, urine osmolality increases by <50%.  
  3. In patients with partial diabetes insipidus
    water deprivation will increase some urine osmolality to 400 to 500 mmol/kg, levels that are well below those in healthy individuals. Administration of exogenous vasopressin will increase urine osmolality by approximately 200 mmol/kg in patients with partial central diabetes insipidus    , but not in patients with partial NDI. A water deprivation study will not distinguish between patients with partial NDI and those with primary (psychogenic) polydipsia. Measuring urine volume during a water deprivation test is not useful.

It is useful to measure levels of plasma vasopressin in the differential diagnosis of polyuria. Patients with complete or partial central diabetes insipidus have levels of plasma vasopressin that are subnormal relative to plasma osmolality. In contrast, patients with complete or partial NDI or those with primary psychogenic polydipsia have elevated levels of plasma vasopressin

Water deprivation test. 
The diagram shows the typical response after water deprivation in healthy individuals, in patients with complete or partial central diabetes insipidus (DI), in patients with complete or partial nephrogenic DI, and in patients with primary or psychogenic polydipsia. The 200 mmol/kg straight line is for schematic representation because patients with full phenotype (either central or nephrogenic DI) have a urine osmolality less than 100 mmol/kg. See text for additional details. dDAVP = desmopressin.

  

REF:  Ann Intern Med 7 February 2006;144 186-194  "Nephrogenic Diabetres Insipidus"  

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Causes of Acquired NDI (Nephrogenic Diabetes Insipidus) 

Lithium Therapy

Lithium has become the most frequent cause of acquired NDI.  Nephrogenic diabetes insipidus occurs in approximately 55% of patients receiving long-term lithium therapy, and approximately 20% of patients produce more than 3 L of urine per day.  Lithium causes NDI, at least in part, by inhibiting adenylyl cyclase in principal cells in the collecting duct.   Of interest, amiloride can reduce lithium uptake into principal cells in the collecting duct in patients receiving long-term lithium therapy, which could lessen the inhibitory effect of intracellular lithium on production of cyclic AMP and water reabsorption.  Lithium also causes NDI by reducing the protein abundances of AQP2, UT-A1, and UT-B, thereby reducing medullary interstitial osmolality.   Thus, lithium interferes with several components of the urine-concentrating mechanism and results in NDI.  Lithium-induced NDI often becomes irreversible if it is not diagnosed quickly and if lithium therapy is not discontinued. 

Other Causes

Hypercalcemia, hypokalemia, low-protein diets, and the release of ureteral obstruction are causes of acquired NDI.   These acquired types are rarely as severe as congenital NDI but can result in urine outputs of 3 to 4 L/d.  These different causes of acquired NDI all result in downregulation of aquaporins and urea transporters, thereby interfering with the patient's ability to concentrate urine.

Aging

Normal aging results in a reduced maximal urine-concentrating ability in both people and rats.  Thus, the urine-concentrating defect in aging may be attributable to both partial nephrogenic and partial central diabetes insipidus.

Therapy of Acquired NDI (Nephrogenic Diabetes Insipidus)  
(Current Rx are only limited and only partialy beneficial)

The most important therapy is ensuring adequate water intake.  This is difficult at the extremes of age if the patient cannot sense thirst and obtain water.  A very low-sodium diet, a thiazide diuretic, and indomethacin may partially decrease urine volume. 

Because the kidney is unresponsive to vasopressin, there is no benefit to providing exogenous vasopressin. Patients with NDI may excrete up to 20 L of urine per day. Drinking and excreting this much fluid per day is challenging. These patients rarely sleep more than 1 to 2 hours at a time because of the need to urinate and drink. An extremely low-sodium diet (< 500 mg/d) and a thiazide diuretic can be beneficial in decreasing urine volume. Indomethacin can also be beneficial but has serious gastrointestinal side effects. These patients can develop bladder dysfunction, which can lead to renal failure if unrecognized and untreated. Patients should have bladder and renal ultrasonography annually to ensure that bladder dysfunction is detected and renal dysfunction is prevented.  In acquired NDI, treating or removing the underlying cause, if possible, is often beneficial. However, prolonged lithium therapy can lead to irreversible NDI, even after lithium therapy is withdrawn.
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Treatment:

For central DI:

  1. Adequate water intake is essential: in sufficient quantity, it will correcta ny metabolic abnormality due to excessive dilute urine.
  2. Desmopressin DDAVP a synthetic analog of vasopressin, is the drug of choice in the treatment of CDI,
    but in mild cases, there are alternative drugs that can be used, including chlorpropamide (Diabinese), carbamazepine (Tegretol), Clofibrate (Atromid-S), diuretics as thiazides or indapamide (Lozol).
    - nasal spray (0.1 mg/mL)10-40 ug (0.1-0.4 mL)1-2x/day    ,
    - tablet (0.1-0.2 mg) PO dose 0.05 - 1.2 mg daily
    - injection IV/SC 2-4 ug injection (0.5 -1 mL    ), a synthetic analog of vasopressin, is the drug of choice in the treatment of CDI,

For nephrogenic DI:  (it does not respond to ADH as Desmopressin DDAVP Rx)

  1. Adequate water intake  
  2. Correct the underlying cause as discontinuing any drugs that may be causing it, correcting hypokalemia, correcting hypercalcemia.
  3. Thiazide diuretics are used along with modest salt restriction to reduce the delivery of filtrate to the diluting segments of the nephron.

Ref:

REF: 
Ann Intern Med 7 February 2006;144 186-194   "Nephrogenic Diabetres Insipidus" - Jeff M. Sands and Daniel G. Bichet   
Cleveland Clinic J of Med Jan 2006;73:65-71   "Diabetes Insipidus: Dx & Rx of a complex disease" - Amgad N. Makaryus and Samy I. McFarlane

         

2006