Mark Goodarzi, M.D.
I. Normal physiology
 | L-Arginine vasopressin (AVP, ADH), a nonapeptide, is synthesized in the bodies of magnocellular neurons in the paired supraoptic nuclei and paraventricular (lateral to the 3rd ventricle) nuclei and transported down axons which form the pituitary stalk in granules bound to neurophysin & glycoprotein to be stored in the posterior pituitary axon terminals. Stores are sufficient for 5-10 days of maximum antidiuresis or one month of normal antidiuresis. AVP is released in free form (does not bind to neurophysin at blood pH), and is degraded in the brain, liver, and kidney. |
| AVP has antidiuretic activity by binding V2 receptors in kidney, stimulating cAMP production by adenyl cyclase, which leads to synthesis & insertion of aquaporin-2 water channels in cells of the collecting tubules, allowing water reabsorption in the hypertonic medulla. Water exits basolaterally via constitutively expressed aquaporins 3 and 4. Absence of AVP leads to excretion of large volumes of dilute urine. |
| Other effects of AVP: acts at a pressor agent at supraphysiologic levels (as in severe hypovolemia) by binding V1 receptors on blood vessels, which increase intracellular calcium and cause smooth muscle contraction. |
| Regulation of AVP release: Integration of AVP secretion and thirst maintains plasma osmolality tightly at 280-290 mOsm/kg. |
- Plasma osmolality: Anterior hypothalamic osmoreceptors (anterior to the 3rd ventricle) are very sensitive to changes in Posm (respond to change as low as 1%), and suppress AVP release when Posm < 280 mOsm/kg. Posm values less than those necessary to turn off AVP will not result in any increase in water excretion (18-20 L/d maximum), unless intake is extreme. As Posm increases, there is a linear increase in [AVP]. When Posm exceeds 292-5 mOsm/kg, plasma AVP reaches levels (~ 6 pg/mL) sufficient for maximum antidiuresis (Uosm > 800 mOsm/kg, Uvol < 2 L/d), with no further decrease in urine volume with higher Posm. Thirst is stimulated at 290 mOsm/kg.
- Plasma volume: Baroreceptors (stimulated by hypervolemia, inhibited by hypovolemia) inhibit AVP release via cranial nerves IX, X. The atrial cardiopulmonary low-pressure baroreceptors are less sensitive than osmoreceptors, requiring a 5-10% decrease in blood volume before AVP is released. Severe hypovolemia, however, triggers the sino-aortic high-pressure baroreceptors to cause exponential increases in AVP, which may be high enough to exert a pressor effect.
- Interaction of osmo- and baroreceptors: A decrease in left atrial pressure (as in hypovolemia, hypotension) leads to a reduction of the osmotic threshold and increases the sensitivity for osmotic AVP release. Volume expansion dampens the sensitivity for osmotic AVP release.
- Nausea is a very potent and rapid stimulus for AVP release, even up to 100-1000 times basal level. May be responsible for increases in AVP seen with chemotherapy, DKA, vasovagal reactions, motion sickness, hypoxia. Pain, emotional stress also AVP.
| Thirst regulation: osmoreceptors located nearby (not the same) initiate thirst at a higher Posm than the threshold for AVP release. Hypovolemia also triggers thirst even if Posm is normal. |
Pathogenesis of Diabetes Insipidus
Neurohypophyseal
Acquired
Pituitary hypothalamic surgery
Head trauma
Neoplasms
Hypothalamic (craniopharyngioma, germinoma, meningioma)
Anterior pituitary (suprasellar extension)
Metastatic (lung, breast, leukemia, lymphoma)
Granulomas (neurosarcoid, histiocytosis, tuberculosis, Wegener’s dz)
Infections (chronic meningitis, encephalitis)
Congenital malformations (e.g. holoprosencephaly)
Ischemia (shock, Sheehan’s syndrome, aortocoronary bypass, TTP)
Aneurysms (cavernous part of internal carotid)
Hematoma
Inflammation (lymphocytic infundibuloneurohypophysitis or hypophysitis)
Chemical toxins (tetrodotoxin, snake venom, ethanol-induced [transient])
Autoimmune
Miscellaneous
Post-supraventricular tachycardia
Anorexia nervosa
Acute fatty liver of pregnancy
Cysts
Guillain-Barré syndrome
Genetic
Autosomal dominant (AVP-neurophysin II gene mutations)
Wolfram syndrome
Idiopathic (30% of cases of central DI)
Nephrogenic
Acquired
Drugs (lithium, foscarnet, clozapine, demeclocycline, methoxyflurane, amphotericin B, aminoglycosides, ifosfamide, analgesic nephropathy, vasopressin V2-receptor antagonists. Single case reports: rifampin, cidofovir, cyclophosphamide, epirubicin, lobenzarit, dopamine, inamrinone, triamterene/hctz, cisplatin)
Electrolyte disturbances (hypercalcemia, hypercalciuria, hypokalemia)
Obstruction (after relief of chronic urinary obstruction)
Vascular (sickle cell disease and trait)
Granuloma (sarcoid)
Infection (chronic pyelonephritis)
Neoplasm (sarcoma)
Infiltrative (amyloid)
Polycystic kidneys, medullary cystic disease
Chronic renal failure
Sjögren’s disease
Genetic
X-linked recessive (V2-receptor gene)
Autosomal recessive (aquaporin II gene)
Idiopathic
Psychogenic
Acquired
Schizophrenia
Mania
Neurosis (compulsive water drinking)
Dipsogenic
Acquired
Granuloma (neurosarcoid)
Infection (tuberculous meningitis)
Autoimmune (multiple sclerosis)
Drugs (lithium, carbamazepine)
Head trauma
Genetic (?)
Idiopathic
Gestational
II. Diabetes Insipidus
| Definition: Excretion of large volume of dilute urine (hypotonic polyuria), urine volume > 30-50 mL/kg/d (during ad libitum fluid intake), Uosm < 300 mOsm/kg, urine specific gravity < 1.010. Caused either by lack of AVP secretion (most common cause), renal insensitivity to AVP, increased water intake suppressing AVP production, or increased metabolic clearance of AVP. DI affects 3 out of 100,000 people. |
CENTRAL (NEUROGENIC) DIABETES INSIPIDUS
| Destruction of AVP-producing magnocellular neurons of the posterior pituitary (neurohypophysis) causing inadequate secretion of AVP (loss of >75-90% secretory capacity), causing inappropriately dilute urine in the presence of strong osmotic or non-osmotic stimuli for AVP production; absence of intrinsic renal disease; rise in Uosm following administration of AVP. |
| Central DI is caused either by a large hypothalamic lesion (destroying the multiple sources of AVP production) or a stalk lesion, never by a discrete lesion in the pituitary fossa, since new secretory terminals may form above the sella. As few as 10% of AVP-producing cells can keep urine output < 4 L/d, above which most patients notice polyuria. There is little change in urine volume until the last few cells are gone. |
| Typical lab findings: urine volume > 3 L/d; Uosm < 200 mOsm/kg; urine specific gravity < 1.010; slightly elevated Posm (290-300 mOsm/kg); inappropriately low serum AVP levels despite slightly elevated Posm. |
| Clinical manifestations: polyuria, polydipsia, and thirst. Urine volume can range from a few (partial DI) to 20 liters/day (complete DI), and onset is usually abrupt. Patients tend to prefer cold, iced water. Nocturia is often the initial complaint. Enuresis in children. Physical exam is essentially normal if patient is drinking adequately. Some patients learn to live with their symptoms for a very long time, delaying diagnosis. |
| Intact thirst is essential to offset hyperosmolality resulting from polyuria. If intact, Posm will stabilize at a level only slightly above normal. Impaired thirst (thirst centers damaged by same process which damaged AVP secretion) or loss of access to water (nausea/vomiting, unconscious, NPO for surgery, in restraints, too young or old to regulate own water intake, mental/physical handicap) can lead to hypernatremia and hyperosmolarity which can be life-threatening: CNS irritability, mental dullness, ataxia, hyperthermia, coma. Brain shrinkage due to acute hypernatremia can cause vascular rupture, with cerebral bleeding, subarachnoid hemorrhage, and permanent neurologic dysfunction or death. |
| The most common causes of central DI are neurosurgery or trauma, primary or secondary tumors or infiltrative diseases (such as Langerhans cell histiocytosis) and idiopathic DI (30-50% of central DI). |
| Central DI following trauma or surgery can follow one of 3 patterns: 1. Transient: abrupt onset within 24 hours of injury and resolves within a few days. [Rarely, very late recovery may occur]. 2. Permanent: abrupt onset of DI which persists. 3. Triphasic (particularly with stalk section): a. immediate post injury period of DI due to axon shock and lack of function, which lasts several hours to several days (typically begins within 24 hours and lasts 4-5 days), then b. antidiuretic phase (2-14 days) urine flow falls and osmolality rises as AVP is released from necrotic posterior pituitary axon terminals (typically on days 6-11), then c. final phase of usually permanent polyuria. Thus, acute central DI mandates frequent checks of Uosm and serum sodium until the DI is stabilized. Not all patients pass through all three phases. |
| Langerhans cell histiocytosis (histiocytosis X or eosinophilic granuloma) is characterized by proliferation of dendritic cells and can result in interstitial lung disease (particularly in male smokers). Extrapulmonary involvement may be focal (e.g. solitary eosinophilic granuloma of bone) or involve one or several bony sites (long bones, spine, skull, jaw), or the posterior pituitary/stalk/hypothalamus (Hand-Schüller-Christian disease). Letterer-Siwe disease is a fulminant visceral form resembling lymphoma (seen in infants) |
| Genetic form is autosomal dominant, caused by mutations in gene for AVP-neurophysin II, the polypeptide precursor of AVP (chromosome 20). Heterogeneous point mutations result in selective postnatal death of AVP-producing neurons, possibly by interfering with folding of the protein, which inhibits processing and release leading to toxic accumulation in the endoplasmic reticulum. Age of onset ranges from 1 to 28 years, and a posterior pituitary bright spot on MRI (usually absent in central DI) may be visible (possibly due to accumulated precursor). |
| Wolfram syndrome (DIDMOAD syndrome) is inherited in an autosomal recessive fashion with incomplete penetrance, characterized by central DI, diabetes mellitus, optic atrophy and deafness. Mutation is in the transmembrane protein wolframin. |
| Idiopathic central DI may actually be due to an autoimmune process. In patients with autoimmune disease, the presence of cytoplasmic antibodies directed against vasopressin-cells has been associated with development of DI. The autoimmune process is characterized by lymphocytic inflammation of the stalk and posterior pituitary that resolves after destruction of the target neurons. Of note, development of anterior pituitary deficiencies other than GH deficiency suggests an underlying structural lesion (e.g. germinoma). Stalk thickening on MRI may represent idiopathic DI or may prove to be germinoma or histiocytosis, making biopsy wise if the lesion enlarges on surveillance MRI. Idiopathic DI tends not to recover as only post-traumatic DI can. If no suprasellar mass or systemic disease is found after 4 years of follow-up, idiopathic DI is likely. |
| A study of 79 children and young adults with central DI (41 idiopathic, 18 tumor (germinoma, craniopharyngioma), 12 Langerhans cell histiocytosis, 2 post traumatic, 1 autoimmune polyendocrinopathy) suggested that in children idiopathic DI may not be due to an autoimmune process since sometimes the stalk thickens with time & those with stalk thickening usually had anterior pituitary deficits developing within 6 years of diagnosis of DI (usually GH deficiency). In 10 patients, central DI developed during or 2 months after a viral illness (varicella, mumps). Stalk thickening (seen in idiopathic, germinoma, Langerhans) and change in the stalk over time were nonspecific. Reduction in the size of the anterior pituitary (vascular damage vs. deficiency of hypothalamic hormones) was a risk factor for development of anterior pituitary deficits. |
| Adrenal insufficiency or hypothyroidism (panhypopit.) can cause inability to excrete a water load, masking the signs and symptoms of central DI. |
| Essential hypernatremia: DI due to absent osmoreceptor input (with no thirst sensation) but intact baroreceptor input to the neurohypophysis. Patients excrete dilute urine until they are hypovolemic, then AVP is released, resulting in hypernatremia with concentrated urine. |
NEPHROGENIC DIABETES INSIPIDUS
| Hypotonic polyuria resulting from renal insensitivity to antidiuretic effect of AVP (defect in collecting tubules or medulla), characterized by normal GFR and solute excretion, persistently hypotonic urine, normal or high levels of AVP, failure of exogenous AVP to raise Uosm or reduce urine volume. |
| Electrolyte disturbances: hypokalemia can lead to a prostaglandin E2-mediated inhibition of cAMP production in response to AVP. Hypercalcemia reduces the medullary solute content and inhibits cAMP production, which decreases trafficking of water channels to the membrane, and also decreases aquaporin mRNA expression. |
| Medications: demeclocycline and lithium inhibit cAMP production. Lithium is the most commonly implicated medication; nephrogenic DI occurs in ~25% of patients on lithium. Except in the case of long-term lithium use, nephrogenic DI usually improves if the offending drug or electrolyte disorder is eliminated. |
| Familial X-linked form is transmitted from mother to male children. Defect is in AVP receptor V2 type (renal), resulting in diminished cAMP production in response to AVP or diminished transport of the receptor to the cell surface. Mother may have mild symptoms of DI. Polyuria is present at birth; unrecognized, it can lead to hypertonic injury to the CNS. Autosomal recessive form caused by mutation in aquaporin II water channel, resulting in retention in the endoplasmic reticulum. |
PRIMARY POLYDIPSIA
| Excessive water intake causes expansion and dilution of body fluids, causing Posm to fall which suppresses AVP secretion, inducing production of dilute urine. Prolonged excessive water intake also washes urea out of the renal medulla, reducing maximal concentrating capacity. Also, chronic AVP deficiency leads to decreased aquaporin channels available to go quickly to cell surface, also reducing concentrating ability. |
| Psychogenic polydipsia: Plasma osmolality stabilizes at a lower level, approximating the osmotic threshold for AVP secretion. Psychogenic polydipsia is usually a late manifestation of schizophrenia, occurring in 10-40% of such patients [irrational belief that drinking water is healthy; thirst not given as reason for drinking]. May also occur in manic phase of bipolar disorders (usually transitory). There is an unexplained predisposition toward episodes of inappropriate AVP secretion and water intoxication. |
| Dipsogenic DI: Osmotic threshold for thirst is paradoxically lower than that for AVP secretion, resulting in chronic thirst, polydipsia, and polyuria, low or normal Posm, low Uosm, and low AVP levels. Sometimes caused by diseases, injuries, or drugs affecting the CNS (see table), but 75% of cases have no known brain pathology. Patients are prone to severe water intoxication during acute infections like influenza, which induces inappropriate AVP secretion. |
GESTATIONAL DIABETES INSIPIDUS
| A significant AVP deficiency (especially if there was a preexisting subclinical DI) can result from the 4-6 fold increase in metabolic clearance of AVP seen during pregnancy. The placenta produces an amino-terminal peptidase (vasopressinase) which rapidly degrades AVP and oxytocin. Polyuria usually begins in 3rd trimester and resolves spontaneously (~2 weeks) after delivery. Measured AVP levels are low (a vasopressin RIA may be artifactually elevated). Note: in normal pregnancy (due to volume expansion), Posm and sodium levels are ~5 mEq/L lower than in the non-pregnant state. |
DIAGNOSIS OF DIABETES INSIPIDUS
| Differentiate hypotonic polyuria from osmotic diuresis by measuring serum and urine osmolality, which discloses osmotic diuresis due to glucose, mannitol, etc. Serum chemistry picks up renal failure, hypercalcemia, hypokalemia. Urinalysis should be negative for glucose and solute excretion rate normal (urine volume (L) x Uosm < 15 mOsmol/kg body weight/d). |
| Polyuria per se results in a reduction in maximum urinary concentrating capacity (reduces maximum Uosm achieved on AVP administration) due to "wash out" of the medullary concentration gradient. This blunts the antidiuretic response to an acute rise in AVP. |
| Fasting or early morning spot urines should not be used to screen for DI because thirst and drinking are decreased at night, and the resultant slight increase in hypertonic dehydration increases urine concentration. |
| A history of head trauma or surgery on the hypothalamic-pituitary region, with sudden onset polyuria, suggests central DI. |
| Large urine volume and low Posm < 285 mOsm/kg, with a history of psychiatric disease or episodic polyuria, suggests primary polydipsia. |
| If testing suggests central DI which was not previously suspected, cerebral MRI must be done to rule out neoplasm. If MRI is negative, consider workup for metastatic disease or idiopathic DI. Serum and CSF hCG and AFP levels are done to assess for germinoma, and a chest X ray, skeletal survey, or bone marrow biopsy can be done to detect histiocytosis. Can measure angiotensin converting enzyme looking for sarcoid. |
| If the diagnosis is uncertain, advanced testing will be needed: |
| I. Water deprivation test. Involves fluid restriction followed by AVP administration. In normals, dehydration causes maximum AVP release, which produces maximal urine concentration. Thus, administration of exogenous AVP will have no further effect on Uosm. |
| Method: All fluids are withheld until patient is sufficiently dehydrated to provide a potent stimulus for AVP secretion (Posm > 295 mOsm/kg). Deprivation lasts 4-18 hours (4-6 hours [start at 6 a.m.] in patients with U.O. > 10 L/d, longer for milder polyuria [start at 10 p.m.-midnight], and 16+ hours for patients with primary polydipsia, with hourly measurements of body weight and Uosm, until 2-3 consecutive samples vary by less than 30 mOsm/kg (or < 10%) or until patient loses 5% of body weight. At this point, AVP is measured and 5 U AVP or 1 µg of DDAVP (use DDAVP if patient pregnant) is injected SC, and Uosm is measured 30 and 60 minutes later. Posm is measured before starting fluid deprivation, at the end of fluid deprivation, and after AVP administration. If severe weight loss or dehydration occurs, prompt measures to restore hydration should be taken. |
| Interpretation: 95% sensitivity/specificity if performed properly. |
a. If dehydration does not increase Uosm above Posm despite evident dehydration, primary polydipsia can be excluded. If neither Uosm nor Posm increases during dehydration and body weight does not decrease according to the urinary volume, surreptitious drinking should be suspected.
b. Normal individuals and those with dipsogenic DI display Uosm > Posm following fluid restriction, and a minimum (< 10%) increase in Uosm after AVP injection. Test is not diagnostic of disease if Uosm > Posm (see below).
c. In central DI, Uosm remains below Posm after dehydration, and after AVP injection, Uosm increases by > 50%.
d. In nephrogenic DI, Uosm remains below Posm, and after AVP injection, Uosm increases by < 50%. Uosm may also increase < 50% in partial central DI. The level of AVP at the end of dehydration is elevated in nephrogenic DI (10-20 pg/mL); also, there is no increase in urinary aquaporin-2 levels after DDAVP is given.
e. In partial (central or nephrogenic) DI (and dipsogenic DI), dehydration may lead to Uosm > Posm (Uosm/Posm = 1-1.4 may indicate partial central DI). Response to AVP is not informative in this case. Further testing must be done to distinguish partial central vs. partial nephrogenic DI vs. dipsogenic DI:
II. Concurrent measurements of plasma AVP (measured before and during a fluid deprivation test) plotted against Posm, and Uosm. In partial central DI, AVP levels will be low for the concurrent level of Posm, while in partial nephrogenic DI, AVP levels are elevated (more reliable in general than low-normal values). For this method to be accurate, must achieve Posm of 295 mOsm/kg during water deprivation; if not, then infuse 3% saline (at 0.1 mL/kg/min).
III. Therapeutic trial of desmopressin (10-25 µg intranasally qd or 2-4 µg SC bid for 2-3 days). In central DI, this will abolish polyuria and polydipsia, while in dipsogenic DI, polyuria will stop but polydipsia persists and results in water intoxication, and in nephrogenic DI, it will have no effect.
IV. Hypertonic saline infusion. 3% saline is infused to achieve plasma Na of 145-150 mmol/l, and AVP and Posm are measured. Patients with primary polydipsia and nephrogenic DI exhibit normal stimulation of AVP release in response to hypertonicity; whereas those with central DI exhibit little or no rise in AVP.
V. MRI to determine the presence of the posterior pituitary "bright spot" on T1 images. This brightness is present in normal people (80%) and those with nephrogenic DI or dipsogenic DI, and usually absent (but not always) in central DI. The frequency of this hyperintensity decreases with age in normal people. If it is present in a patient with central DI, it is often absent on a subsequent MRI. Significant number of false positives and negatives.
TREATMENT OF DIABETES INSIPIDUS
| Symptomatic hypernatremia, if it developed over a period of hours can be corrected rapidly. More chronic hypernatremia should not be corrected at a rate exceeding 0.5 mmol/L/hr to avoid the risk of developing cerebral edema due to accumulation of organic osmoles in the brain cells (a response to reduce brain shrinkage in the hypertonic setting). |
| Goal is to normalize lifestyle by preventing polyuria and polydipsia. Dosages may need to be modified depending on daily activities. Patients should wear medical alert tags and carry a card describing their therapy. |
I. Central DI
| Desmopressin (DDAVP, 1-Desamino-8-D-arginine-vasopressin): Most widely used, intranasal DDAVP provides antidiuretic (V2) activity for 6-24 (usually 8-12) hours with negligible pressor effect (V1 receptor). 2000 times more specific for antidiuresis than natural AVP, with 1-2 hr onset of action. Dose ranges from 5-20 µg qd-tid. Best started at night to find lowest dose which prevents nocturia. Occasionally, this also provides adequate control for the following day (1/4-1/3 of patients). If not, a morning dose can be added and titrated to prevent polyuria during the day. Titrate night dose first, then the morning dose (reverse if patient prefers nocturia over daytime polyuria). Usually 10 µg qhs or bid (standard spray delivers 10 µg). A calibrated nasal catheter is available which allows 5-20 µg dose titration but requires proper training to use. Control is confirmed by measuring [Na] or Posm. Absorption is diminished by nasal mucosal atrophy, scarring, congestion, or blockage. A parenteral form (5-10 X more potent than intranasal, same duration, SC, IM, or IV) is available for those unable to take it intranasally (children, post-op) or for use in acute DI (1-4 µg IV, dose frequency and magnitude based on desired hourly urine flow). An oral form (0.1-0.8 mg/d, taken bid-qid, usually tid, onset of action in 1-2 hr, duration about 8 hours) is available, with the benefit of not needing to be refrigerated as does the intranasal form. Individual oral doses > 0.2 mg add little additional duration of action. Combinations of oral and nasal DDAVP may be used to fit the patient’s lifestyle. Adverse effects of DDAVP include headache (usually subsides on dose reduction), nausea, abdominal cramps, flushing, nasal congestion or rhinitis, and hypertension at very high doses. DDAVP is expensive (costs $50-100 per month). Some experts advocate periodic withdrawal even as frequently as once a week to prevent excess water retention (also makes sure DI is still present, important in post-traumatic DI which may very rarely recover within the year after injury); others say this is unnecessary since the normal thirst mechanism down-regulates fluid intake to maintain normal water balance. |
| Other effects of DDAVP: may decrease blood pressure (especially if given rapid IV), increase plasma renin activity, and cause release of both coagulation factor VIIIc and von Willebrand factor (therapeutically used at much higher doses to treat mild/moderate hemophilia A or type 1 von Willebrand’s disease, tachyphylaxis common). DDAVP may cause thrombocytopenia in type 2b or platelet-type von Willebrand's disease; rarely arterial thrombosis. Also used to treat bleeding in renal failure (platelet & endothelial dysfunction). |
| L-arginine vasopressin (Pitressin, aqueous vasopressin) is the natural vasopressin of all mammals except the pig. Given SC, onset of action in 1-2 hours, and duration 4-8 hours. IV use avoided because of even shorter duration and potential significant pressor effects (hypertension, angina). Pitressin may also induce anti-AVP antibodies which decrease efficacy. |
| Lysine vasopressin (Diapid): a synthetic form of porcine ADH is available as nasal spray, which has a short duration of action (2-6 hours). |
| If a large basal hypothalamic lesion has destroyed vasopressinergic neurons and the osmoreceptors, the patient will have DI and absent thirst with a high risk of dehydration and hypernatremia. Best therapy is to induce maximal antidiuresis with DDAVP and then adjust water intake to result in a normal sodium (300-500 mL q8hr) with daily sodium monitoring initially, followed by weekly monitoring. |
| Chlorpropamide can be used in partial central DI, since it enhances AVP action in the kidney and possibly enhances AVP secretion. Dose ranges 250-500 mg qd may reduce urine output to near normal levels, maximal antidiuresis is observed after 4 days. About 50-80% of those with partial central DI respond to this dose. Some patients with partial central DI may be well treated with chlorpropamide alone or in combination with DDAVP (allows dose reduction in DDAVP). Hypoglycemia is a potentially dangerous side effect, particularly in children, elderly, those with anterior pituitary compromise, renal insufficiency, severe exercise or dieting. 30% of patients develop flushing reactions to alcohol while on chlorpropamide, but this may subside with time. Not to be used in pregnancy (teratogenic). Chlorpropamide is considered safer and more effective than clofibrate or carbamazepine. |
| Clofibrate (Atromid-S, 500 mg qid) stimulates AVP release and may be used in partial central DI. Not widely used due to reports of gallbladder disease and carcinoma. |
| Carbamazepine (Tegretol, 200-600 mg/d) may be useful in partial central DI because it stimulates AVP release and increases renal sensitivity to AVP. Not widely used due to potential toxicities. |
| Thiazide diuretics or indomethacin may be used in central DI (see below). NSAIDS can prolong the effect of an administered dose of DDAVP. |
II. Nephrogenic DI
| DDAVP, AVP, or drugs which stimulate AVP release or increase renal sensitivity are generally ineffective. Very large doses of DDAVP (200-400 µg intranasally tid) may be effective in partial nephrogenic DI, but this is too costly. |
| Thiazide diuretics combined with mild salt restriction is the most effective therapy for nephrogenic DI (can reduce polyuria as much as 50-70%). Thiazides (e.g. HCTZ 50-100 mg/d) induce mild salt depletion (block Na reabsorption in cortical diluting site) which results in volume contraction, decreased GFR, increased isotonic proximal fluid absorption and thus decreased delivery of fluid to the collecting duct. Salt restriction augments this effect. Potassium should be given as needed to prevent hypokalemia. Main limitation is symptomatic volume depletion. Volume depletion may decrease lithium excretion, increasing risk of lithium toxicity. |
| Amiloride: Agent of choice in lithium-induced nephrogenic DI since it may block lithium uptake in distal tubules and collecting ducts. Allows lithium use to be continued. May also have thiazide-like action since it causes a negative Na balance. Must monitor for hyperkalemia and cannot use in renal insufficiency. May be combined with thiazide for additive antidiuretic effect and to balance potassium. |
| Prostaglandin synthesis inhibitors (indomethacin, ibuprofen, aspirin). Prostaglandins increase medullary blood flow and diminish medullary solute reabsorption, which modestly decreases the osmotic gradient for water reabsorption. Prostaglandins (E series) also antagonize AVP action. Thus, NSAIDS can increase water reabsorption and Uosm and reduce urine volume. Mainly used adjunctively in treating nephrogenic DI (combined with thiazides). Usefulness limited by side effects: gastrointestinal ulceration, decreased GFR, hyperkalemia. |
III. Primary Polydipsia
| The above therapies should be avoided since they reduce water excretion without reducing water intake, therefore, in the face of continued excessive water consumption, serious water intoxication (hyponatremia, confusion, coma) may result. Treatment should focus on behavior modification to reduce water intake. |
| The only pharmacologic relief may be a small, short-acting dose of DDAVP or lysine-8-vasopressin (Diapid) at bedtime to reduce or eliminate nocturia. A dose titrated to have no antidiuretic effect the next day should not result in water retention because the patient’s fluid intake is usually much lower at night. |
IV. Gestational DI
| Polyuria does not respond to exogenous AVP but does respond to desmopressin (DDAVP) which is less susceptible to degradation by vasopressinase. The only safe and effective treatment (4-75 fold less oxytocic/uterotonic action than AVP), DDAVP is given in the same or slightly higher doses than in central DI. When checking for water retention, remember that normal basal osmolality and sodium are lower during pregnancy. Treatment is stopped when the DI remits (~2 weeks after delivery). DDAVP is secreted in breast milk, but in small amounts and is poorly absorbed from the GI tract. |
Uvol is very high only if AVP is very low. Evaluation of central DI with no clear etiology
ADDENDUM: CAUSES OF HYPERNATREMIA
|
Net Water Loss |
Hypertonic sodium gain |
|
Pure water:
Hypotonic fluid
|
Hypertonic sodium bicarbonate infusion Hypertonic feeding preparation Ingestion of sodium chloride Ingestion of sea water Sodium chloride-rich emetics Hypertonic saline enemas Intrauterine injection of hypertonic saline Hypertonic sodium chloride infusion Hypertonic dialysis Primary hyperaldosteronism Cushing's syndrome |
|
Net Water Loss |
Hypertonic sodium gain |
|
Pure water:
Hypotonic fluid
|
Hypertonic sodium bicarbonate infusion Hypertonic feeding preparation Ingestion of sodium chloride Ingestion of sea water Sodium chloride-rich emetics Hypertonic saline enemas Intrauterine injection of hypertonic saline Hypertonic sodium chloride infusion Hypertonic dialysis Primary hyperaldosteronism Cushing's syndrome |
References (v1.3.7)