Vasopressin I
Where is vasopressin synthesized and stored?
Vasopressin aka antidiuretic hormone/8-arginine vasopressin/B-hypophamine
Synthesized in magnocellular neurons in the hypothalamus
Transported to the posterior pituitary gland for storage via the pituitary stalk
Entire process of AVP synthesis, transport, and storage takes 1-2 hours
G protein-coupled receptors
What is diabetes insipidus?
Disease of excessive urinary electrolyte free-water (free water) loss characterized by the clinical signs of marked polyuria (>50 ml/kg/day) and an obligate polydipsia to replenish the excreted volume.
Excessive free water loss can occur with the absent or insufficient circulating arginine vasopressin or a reduced or absent receptor response to AVP.
What is the SIADH?
Syndrome of inappropriate antidiuretic hormone secretion
Describes the release of ADH in the absence of increases in serum osmolarity or decreased effective circulating volume
Clinically manifests as euvolemic hyponatremia in conjunction with concentrated urine
Can provide information about water balance, effective circulating volume, and electrolyte and acid-base disorders
What is the half-life of vasopressin?
What are the principal effects of the V1-receptor?
When should DI be suspected in a critically ill patient? What are causes of acquired central and nephrogenic DI?
DI should be suspected in any critically ill patient that develops hypernatremia and marked polyuria in the absence of an osmotic diuresis, particularly if they have any conditions that have been associated with acquired DI.
Central DI: brain trauma, neoplasia, infectious/inflammatory (toxoplasmosis, cryptococcus, meningitis), vascular injury, immune-mediated neurohypophysis, idiopathic
Nephrogenic DI: drugs (ofloxacin, amphotericin B, aminoglycosides, cisplatin, vinblastine), electrolyte abnormalities (hypocalcemia, hypokalemia), bacterial infection (E. coli, Streptococcus spp., Leptospirosis spp.), degenerative (amyloidosis, CKD), paraneoplastic (intestinal leiomyosarcoma)
What diseases have been associated with SIADH?
Cats: liver disease, vinblastine therapy
Dogs: aspiration pneumonia, meningoencephalitis, hydrocephalus, neoplasia, liver disease, and general anesthesia
Humans: neoplasia and medication induced most common in one study, followed by idiopathic causes, pulmonary infections, pain, and nausea
What are two means of measuring urine concentrating ability?
Measurement of urine osmolality gives a quantified value for the concentration of solute in urine and is considered the most accurate measure of urine concentrating ability.
Urine specific gravity by light refractometry can be used as a substitute.
Synthetic colloids and radiocontrast agents will increase USG making USG an inaccurate measure of renal concentrating ability.
What are stimuli for AVP release? What are the most potent stimuli?
Most potent stimuli for release are increased plasma osmolarity, decreased blood pressure, and a decrease in circulating blood volume
Pain, nausea, hypoxia, hypercarbia, pharyngeal stimuli, glycopenia, drugs and chemicals (acetylcholine, high-dose opioids, dopamine, angiotensin II, prostaglandins, glutamine, histamine, malignant tumors, mechanical ventilation
What are the principal effects of the V2-receptor?
How are changes in plasma osmolarity sensed and what is physiological response?
Minute changes in plasma osmolarity is sensed by osmoreceptors in the organum vasculosum laminae terminalis (OVLT) which is a circumventricular organ within the rostral portion of the hypothalamus that lacks a blood-brain barrier. The quantity of AVP release parallels the degree of rise in plasma osmolarity. AVP binds to Gs protein-coupled V2-receptors in the renal collecting ducts to allow movement of solute-free water down its concentration gradient.
Separate osmoreceptors near the OVLT stimulate thirst sensation to trigger increased water intake.
How is SIADH diagnosed?
Diagnosis of exclusion.
Human criteria for diagnosis:
- Hypo-osmolar hyponatremia
- Euvolemia
- Inappropriately concentrated urine - urine osmolarity >100 mmol/L
- Urine sodium concentration >30 mmol/L
- Hypoadrenocorticism excluded
What are the two determinants of urinary free water clearance?
Amount of water ingested
ADH release
What substances inhibit AVP release?
Glucocorticoids, low-dose opioids, atrial natriuretic factor, y-aminobutyric acid
What are the principal effects of the V3-receptor?
True or False. DDAVP should be continued during hospitalization in a critically ill patient with previously diagnosed central DI.
True.
It should be continued to help prevent marked urinary free water loss resulting in hypernatremia. This does put them at risk of developing progressive hyponatremia with iatrogenic administration of excessive enteral water through feeding tubes or hypotonic IV fluid administration.
What are four considerations when managing SIADH?
- Severity and duration of hyponatremia
- Potential underlying causes of SIADH and their removal
- Careful fluid restriction: aim for water intake to be less than water excretion
- Consideration of diuretic administration: loop diuretics promote water excretion (furosemide 0.1-0.5 mg/kg IV in dogs)
What is the urinary free water clearance(%)? Is it an appropriate finding?
Serum Na 170 mEq/L
Serum K 5 mEq/L
Urine sodium 104 mEq/L
Urine potassium 91 mEq/L
Urinary free water clearance (%) = 1 - ((urine Na + urine K)/plasma Na)
= 1 - ((104+91)/170) = -0.14 = -14%
This is a negative free water clearance which is appropriate response. There is likely extra-renal hypotonic fluid loss if the patient is hypovolemic, such as gastrointestinal losses.
In a hypernatremic patient, a negative free water clearance would indicate an appropriate renal response secondary to ADH stimulating renal water reabsorption.
In contrast, a positive free water clearance suggests that renal free water loss is the cause of hypernatremia.
Name the vasopressin receptors and where they are located.
V1-receptor: vascular endothelium, platelets
V2-receptor: basolateral membrane of the distal tubule, principal cells of cortical and medullary collecting duct, vascular endothelium
V3-receptor: anterior pituitary gland
Oxytocin receptor: uterus, mammary gland, gastrointestinal tract
What are the principal effects of the oxytocin receptor?
How could you develop a fluid plan to account for free water loss in a patient with nephrogenic DI in an adipsic patient?
Urinary clearance of free water can be calculated to estimate the amount of free water being lost in the urine per hour. It is the volume of urine excreted that is free of solute.
The urinary free clearance of water is a rough estimate of the rate (ml/hr) at which water will likely need to be administered to help maintain normonatremia.
CFW = Vu × (1 − [([Na+]u + [K+]u) ÷ [Na+]p])
What does a urine sodium concentration of >30 mmol/L support a diagnosis of SIADH?
In patients with normal renal function, a urine sodium concentration of <30 mmol/L is suggestive of low effective circulating blood volume and stimulation of renin-angiotensin-aldosterone system.
Urine sodium helps assess the volume status of a patient.
In hypovolemic states, aldosterone mediates sodium conservation. Urine sodium concentration should be less than 20 mmol/L. If the urine sodium concentration is >40 mmol/L, then the kidney interprets adequate effective circulating volume. Values of urine sodium between 20 and 40 mmol/L are equivocal (grey zone).
A 20 kg dog with a serum sodium of 160 mEq/L, a serum potassium of 4 mEq/L, produces 400 ml of urine over 2 hours. The sodium concentration of the urine is 25 mEq/L and the potassium concentration is 5 mEq/L. What is the volume of free water loss over this 2 hour period?
Urinary clearance of free water = urine volume * (1 - ((urine Na + urine K)/plasma Na))
= 400 * (1 - ((25+5)/160)) = 325 ml