section name header

Info


A. Definitions [4] navigator

  1. DI is due to failure of vasopressin (anti-diuretic hormone, ADH)
    1. Patients with DI produce large quantities of dilute urine
    2. This leads to loss of water > loss of sodium (and other electrolytes)
    3. Result is dehydration and hypernatremia
  2. Two Major Forms of DI
    1. Failure of production of ADH by posterior pituitary (hypothalamus) - central DI
    2. End organ (mainly kidney) insensitivity to effects of ADH - nephrogenic DI
  3. Central (Neurogenic) DI
    1. Due to failure of production of ADH
    2. More common than nephrogenic DI
    3. Due to hypothalamic and/or pituitary damage
    4. Various causes including drug induced
  4. Causes of Central DI [5]
    1. Pituitary tumors (most common)
    2. Langerhan's Cell Histiocytosis
    3. Other Granulomatous Disease (sarcoid, tuberculosis, other infections)
    4. Post-traumatic
    5. Surgery
    6. Guillain-Barre Syndrome
    7. Aneurysm
    8. Drug induced: ethanol (transient), phenytoin
    9. Autoimmune polyendocrinopathy
    10. Idiopathic (including familial)
  5. Nephrogenic DI [1]
    1. Due to failure of kidney collecting duct to sense ADH
    2. Acquired and congenital forms of disease have been described
    3. Acquired nephrogenic DI - renal disease, hypercalcemia, hypokalemia, drugs
    4. One congenital form is due to mutations in aquaporin 2 channels (AQP2) [6]
    5. Sickle cell anemia is associated with development of nephrogenic DI
    6. Various drugs can interfere with renal water handling (see below)
    7. Gestational DI is usually nephrogenic due to rise in circulating vasopressinase
  6. Drugs Causing Acquired Nephrogenic DI
    1. Lithium - ~50% of patients, likely via down regulation of AQP2 channels
    2. Amphotericin - direct tubular toxicity
    3. Foscarnet - direct tubular toxicity
    4. Demeclocycline - reduces adenyl cyclase activity in renal medulla, decreases ADH
    5. Other: methoxyflurane, vasopressin analogs

B. Normal Physiology of Vasopressin [1,3] navigator

  1. ADH
    1. ADH is nonapeptide hormone with arginine at the 8 position
    2. Normally, ADH is made directly in the hypothalamus in the supraoptic nucleus
    3. ADH is secreted into the blood stream and acts on blood vessels and kidney
    4. ADH is a weak vasoconstrictor
    5. ADH's primary function in humans is to increase water resportion in collecting ducts
  2. ADH Receptors
    1. There are three vasopressin receptor subtypes: V1a, V1b, and V2
    2. The receptors are G-protein coupled proteins (GPCR), 7 transmembrane helices
    3. The V1a and V1b GPCR promote phospholipase C activation
    4. Phospholipase C mediates breakdown of PIP2 to IP3 and Diacylglycerol (DAG)
    5. PIP2 increases intracellular calcium; DAG activates protein kinase C
    6. V2 receptors (X chromosome q28) stimulate cAMP production
    7. cAMP causes protein kinase A activation
    8. These mediators influence water-channels (aquaporin) function [2]
  3. ADH Functions [2,3]
    1. Primary function in humans is to increase water resorption in collecting ducts
    2. Binds to V2 receptors and increases mainly aquaporin 2 (AQ2) function
    3. Also acts on distal tubule cells, thick descending loop of Henle
    4. Increases permeability of terminal collecting duct to urea (10-TM protein transporters)
    5. Allows urea to move into the medullary interstitium
    6. ADH is a weak vasoconstrictor mediated by through V1a receptors
    7. V1a also mediates platelet aggregation and hepatic glycogenolysis
  4. Genetics
    1. X-linked nephrogenic DI due to mutations in V2 receptors
    2. X-linked nephrogenic DI is rare, ~4 per 1 million males
    3. Congenital nephrogenic DI due to mutations in Aquaporin 2 gene (chr 12q13)

C. Symptoms navigator

  1. Polyuria - 3-10 liters per day
  2. Polydipsia
  3. Dehydration
  4. Hypernatremia

D. Diagnosisnavigator

  1. Symptoms
  2. Hypernatremia and elevated plasma osmolality
  3. Urine osmolality usually <100 mOsm/kg
  4. Arginine vasopressin challenge should increase urine osmolality if central DI is present

E. Treatment [4,7]navigator

  1. General
    1. Drink sufficient water to avoid dehydration
    2. ADH replacement for central DI
    3. Thiazides, prostaglandin inhibition for nephrogenic DI
  2. Central DI
    1. DDAVP (desmopressin) nasal spray
    2. Dose is usually 5-10µg qd or bid as spray
    3. Aqueous vasopressin can be given as well (duration 4-6 hours)
  3. Nephrogenic DI
    1. Thiazide diuretics
    2. Amiloride may be added but caution if prostaglandin inhibitors used
    3. Prostaglandin inhibitors such as indomethacin (Indocin®) have some benefit
    4. Correct hypokalemia and hypocalcemia if present
  4. Stop offending drugs
  5. Hypernatremia is treated in standard fashion
    1. In general, ~50% of fluid/sodium deficit should be corrected in first 24 hours [7]
    2. Calculate free water deficit = BW·[(Na-140)÷ 140] where BW= Body water
    3. BW = FF·Wt(Kg) where FF= fluid fraction, 0.6 for men, 0.5-0.45 for women, and elderly
    4. Safe rate of reduction in serum sodium level is 0.5mEq/hr or 12mEq/day
    5. Correct deficit with D5W solution (may use D5-0.45% normal saline)

References navigator

  1. Sands JM and Bichet DG. 2006. Ann Intern Med. abstract
  2. Kumar S and Berl T. 1998. Lancet. 352(9123):220 abstract
  3. Bichet DG. 1998. Am J Med. 105(5):431 abstract
  4. Adrogue HJ and Madias NE. 2000. NEJM. 342(20):1493 abstract
  5. Maghnie M, Cosi G, Genovese E, et al. 2000. NEJM. 343(14):998 abstract
  6. Herbert SC. 1998. Am J Med. 104(1):87 abstract
  7. Singer I, Oster JR, Fishman LM. 1997. Arch Intern Med. 157(12):1293 abstract