Suzanne Lazorick, MD
August 23, 1999
Polyuria and Diabetes Insipidus
Definition: Urine output > 30cc/kg/day or > 3 liters/day.
Patients usually become symptomatic at 4-6 l/day.
Differential diagnosis: in outpatient setting patients will
nearly always have either uncontrolled diabetes mellitus and glucosuria,
diabetes insipidus, or psychogenic polydipsia; but must also consider salt-wasting
nephropathy, hypercalcemia, hypokalemia or medications. Distinguish between
water diuresis (DI) and solute diuresis (glucose, diuretics, resolving
acute renal failure).
Definition: excess urinary loss of solute free water.
Uncommon: approx. 3/100,000
Patients present with marked polyuria and polydipsia with
high serum osmolarity (>295) and inappropriately LOW urine osmolarity (<300).
Results from either insufficient or absent ADH or renal insensitivity
to ADH (antidiuretic hormone or arginine vasopressin).
Patient is unable to conserve water if deprived access to
Thought to be under-recognized.
Recall actions of ADH. There are two known receptors Vasopressin
1 (V1) has vasoconstrictor and prostaglandin activity, and Vasopressin
2 (V2) has antidiuretic, vasodilator, and coagulation factor mediator (causes
release of factor VIIIc and vonWillebrand factor from endothelial cells)
Normal serum osmolarity is maintained in narrow range: 285-295
mOsm or mMol/kg,. Urine osmolarity ranges from 100-1200 mOsm/kg, depending
on the need to conserve or excrete free water.
When dehydrated, rising serum osmolarity (>280) is sensed
by osmoreceptors of the anterior pituitary triggering release of ADH by
the posterior pituitary.
ADH binds to V2 receptors of renal collecting duct causing
increased permeability to water (water channels called aquaporins float
free in the cytosol and are signaled by ADH to embed in the membrane) and
thus more free water is absorbed by the kidneys. Concentrating ability
is maximal when serum osm is >295 mOsm/kg.
Thirst is triggered (osmoreceptors of thirst center
of the hypothalamus) when serum osmolarity exceeds 290 mOsm/kg.
Thus, in setting of water deprivation or dehydration, the
body compensates by concentrating urine and by stimulating the urge to
Note that for maximal renal concentrating ability, the renal
medullary gradient must be intact.
Other stimulants of ADH secretion include hypovolemia (>10%
loss of blood vol), hypoglycemia, nausea, some drugs (nicotine, carbamazepine,
Classification of Diabetes Insipidus:
DIABETES INSIPIDUS occurs when this compensating mechanism
is disrupted. The person excretes large volume of dilute urine and must
take in large volume of dilute solution to maintain normal fluid and electrolyte
•Neurogenic or Central – absent or insufficient ADH Can
be 1° (familial autosomal dominant, or idiopathic thought to be autoimmune),
or 2° usually due to some intracranial event (trauma, surgery, tumor).
•Nephrogenic or Peripheral – renal insensitivity to ADH.
Can be 1° (familial, X-linked recessive defect in V2 receptor or very
rare in aquaporin)), or 2° most often to Lithium (impairs cAMP
in collecting duct and thus inhibits water reabsorption), but also from
infiltration (inflammation or infection, e.g. sarcoid, Sjogrens,
TB), or from hypercalcemia.
Excessive destruction of ADH by vasopressinases.
Polydipsia – either dipsogenic (abnormal thirst center) or
Disorder occurs with range of severity (termed partial central
or partial nephrogenic). Mild forms do exist in which patients can partially
respond to fluid restriction by increasing resorption of water at the level
of the proximal tubule or by making use of baseline partial permeability
of the collecting duct in the absence of ADH. Elderly persons and persons
with renal failure have a mild renal insensitivity to ADH, but this is
Neurogenic: Idiopathic; Acquired: neoplastic
(craniopharyngioma, lymphoma, meningioma, met. Carcinoma, other brain tumor),
head trauma, neurosurgery, Ischemia (shock, s/p arrest, Sheehan’s syndrome,
aneurysms, sickle cell crisis); granulomatous (sarcoid, histiocytosis),
Infectious (TB, encephalitis, meningitis), autoimmune, familial.
Nephrogenic: Familial, Acquired: Drug induced
(lithium, demeclocycline, methoxyflurane), metabolic (hypokalemia, hypercalciuria
usually with hypercalcemia), renal disease (polycystic kidneys, obstructive
uropathy, chronic pyelonephritis, sickle cell nephropathy, sarcoid, chronic
renal failure, multiple myeloma, Sjogren’s disease, analgesic nephropathy);
Thirst, often craving cold water, nocturia, polyuria (volumes
can be 3-18 l/day).
Dilute urine, specific gravity < 1.005, osmolarity <
Serum osmolarity nears 300 mOsm/kg, but may be normal with
ready access to fluids.
If fluids withheld, serum osmolarity rises dramatically!
Leads to hypertonic encephalopathy. Mental status change is due to fluid
shifts at cellular level in the brain. Patients present with marked dehydration,
MS changes and neurologic symptoms.
Absence of nocturia or low serum osmolarity should raise
suspicion of psychogenic polydipsia.
Time course and setting of presentation often provides
clue to etiology:
Neurogenic usually presents abruptly after insult
but can be insidious with tumor or idiopathic (familial presents age 1-2,
idiopathic usually occurs 3:2 in males:females with mean age presentation
16 yrs). In 5-10% of pts with DI after CNS insult, DI usually follows 3
predictable phases: initial polyuric/hypotonic phase followed by some improvement
as damaged pituitary cells leak residual ADH (days 6-11), then permanent
DI due to lack of ADH.
Nephrogenic is usually more gradual; unless familial
- congenital absence of V2 receptors or aquaporins causes presentation
in the neonatal period (fever, vomiting, MS changes, hypernatremia) leading
to CNS damage.
Pregnancy often unmasks mild DI. Placenta produces
vasopressinases, threshold for thirst and ADH are altered, renal sensitivity
to ADH is altered. Gestational DI improves post-partum.
Psychogenic Polydipsia – mimics DI (actually is a form of
DI). Water intake can reach 20 l/day and the medullary gradient is depleted
causing diminished renal concentrating ability. Can be behavioral (most
often middle-aged women), psychiatric + drugs, or can be from lesion in
thirst center "dipsogenic polydipsia" (e.g. sarcoid).
Medications causing dry mouth stimulate water intake (antipsychotics,
In the inpatient setting polyuria may be caused by the above,
but also watch for:
Uncontrolled diabetes mellitus.
High-protein feeding – urea load leads to solute diuresis.
Post-operative diuresis due to intraoperative hydration.
Medications (mannitol, steroids)
s/p resuscitation – diereses of large volume of fluids given.
History is often suggestive but usually need to confirm
DI unless hypertonicity makes water deprivation dangerous.
Water Deprivation ADH Stimulation Test:
Confirms DI and distinguishes between neurogenic, nephrogenic
or psychogenic polydipsia.
Induce state of mild dehydration . Try to get serum osm >300,
because at this point further ADH will not be effective in normal situation.
(may need to give 3% NaCl to get osm > 300)
Measure UOP, urine sp gr, serum Na, serum osm hourly
(note if urine osm reaches >600-800 at this point, then the
ADH and renal response are adequate/normal, no need to proceed).
Document adequate dehydration (5% wt loss, serum osm >295)
, steady state ( < 30 mOsm change in urine osm for 2 consecutive measurement).
Measure ADH level. (special collection method, on ice)
Interpret by evaluating the relation of the urine
and serum osmolarities and ADH in response to dehydration and ADH administration.
Absolute numbers are less important than the relative changes. Test is
inconclusive in 10% of cases, in which case plotting ADH level/ osm measurement
on nomogram can be helpful.
Continue to measure urine and serum osmolarity and UOP hourly.
DI is confirmed if urine osm stays low despite increased
Response to ADH:
Central – urine osm will increase by at least 50% and UOP,
Na, and serum osm will decrease.
Partial central or partial nephrogenic - urine osm increases
Nephrogenic - no change in urine osm.
Psychogenic polydipsia - urine osm increases but by <
Absolute ADH level after water deprivation - <1.0 in neurogenic;
high in nephrogenic
Abort test if patient develops symptoms of vascular compromise
or hyperosmolarity. Testing and interpretation may need to be modified
Future possibilities for diagnosis: measurement of aquaporin
level in urine (expensive, not widely available)
Treatment is indicated if symptoms of polyuria and polydipsia
are debilitating and due to risks if access to fluids is in question. Patients
can tolerate symptoms for years so disorder is often overlooked.
Goal: correct pre-existing deficits and reduce ongoing
Central: Try to determine cause, may need CNS imaging. Treat
with DDAVP 10mcg qhs or BID– nasal vasopressin, a synthetic analog of ADH
without the pressor or uterine effects. Nasal form is best tolerated, easiest
to administer, and most consistently absorbed. Duration of effect varies
from 8-20 hours. Cost $2/dose. Undertreat to avoid volume overload and
hyponatremia. Need to watch serum sodium very closely! Can supplement with
short acting lysine vasopressin.
Side effects of DDAVP (usu. mild) include headache,
nausea, nasal congestion, rhinitis, flushing, abdominal cramping. Can cause
angina and blood pressure.
Partial DI: may respond to drugs which stimulate ADH and
potentiate its action: chlorpropramide, but hypoglycemia may be limiting
factor. ADH is also stimulated by carbamazepine and clofibrate.
Nephrogenic: Some meds can decrease polydipsia by decreasing
total body salt so isotonic absorption of water by the proximal tubule
is increased. Usually use thiazides, amiloride, or both. Patients need
to adhere to low salt diet. Need to watch fluid status closely. Although
it seems counter-intuitive to give diuretics, this works essentially by
inducing a state of mild dehydration and thus causing maximal compensation
by other renal mechanisms.
Adjunctive treatment is NSAIDs (via prostaglandin effects
to increase response to ADH)
Treatment of choice for Lithium induced DI is amiloride (mechanism
not clear), but usually not effective if pt has been on Lithium for a long
Once treatment is started, very important to avoid unplanned
treatment withdrawal. Unplanned withdrawal usually occurs from :
For patients who also have disrupted thirst mechanism, treatment
is extremely difficult.
1. pt noncompliance (pt education VERY important)
2. Medical emergency (pts should wear medic alert tag specifying
3. Iatrogenic inadvertence (pt made NPO for some reason…
record needs to be flagged that pt is undergoing tx for DI)
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