What happens to total body water following Na+ infusion?
It shifts (water moves from the ICF to the ECF)
What happens to compartmental water balance following infusion of pure water?
The water redistributes equally to both ICF and ECF (water is freely permeant across membranes)
Why is it important to maintain a relatively constant serum osmolarity?
The brain cannot tolerate small changes in osmolarity (it will swell or shrink)
Consequences of brain shrinkage
Pulls apart from meninges → hemorrhage, meningeal tears, neuronal/glial tears
Consequences of brain swelling
Herniation beyond the tentorium → compression of the brainstem
Why can the brain tolerate minor changes in serum osmolarity?
Blood-brain barrier
Most dysnatremias are [mild, moderate, or severe] and SNa is in the range [#]-[#] mM
Mild; 125-155 nM
What kinds of patients most often have dysnatremias?
Hospitalized, institutionalized, or “polypharmacied” patients
T/F: Dysnatremias are often emergencies and require aggressive treatment
False – most are non-emergent and require only a “tweak” in treatment
Define osmoregulation
Maintenance of constant Sosm (serum osmolarity)
What areas of the brain sense changes in Sosm?
Supraoptic nucleus (SON)
Hypothalamic thirst nucleus
Hypothalamic cells can sense Sosm changes of [%] once the level is about [#] mOsm
1%; 285-290 mOsm
How do these nuclei respond to increased Sosm? SON Hypothalamic thirst nucleus
ADH secretion
Increase thirst drive
How do stimuli from the baroreceptor and brainstem nuclei affect ADH release?
Lower the threshold for ADH release
Stimuli that can lower the threshold for ADH release from the SON
Decreased PO2
Decreased BP
Decreased ECFV
Pain/stress
Nausea
Drugs
ADH is released from the [anterior or posterior] pituitary
posterior
Operational definition of euvolemia
Intravascular volume required to maintain the least preload for optimizing stroke volume
How is preload measured?
Swan-Ganz catheter
Practical definition of euvolemia
Intravascular volume that maintains stable BP and HR (lying or standing), without peripheral pitting edema or pulmonary vascular congestion
Diuretics lead to which one? A. Too much water for the amount of salt B. Too little salt for the amount of water C. Too much salt and water, but more water than salt
B. Too little salt for the amount of water
Cirrhosis leads to which one? A. Too much water for the amount of salt B. Too little salt for the amount of water C. Too much salt and water, but more water than salt
C. Too much salt and water, but more water than salt
Molecular mechanism for SON response, leading to decreased ADH release
Decreased Sosm → SON cell swelling → closure of stretch-inactivated cation channels → less depolarization → fewer APs → decreased Ca2+ entry at terminal → decreased ADH release
Molecular mechanism for decreased ADH resulting in decreased urine osmolarity
Decreased ADH binding at V2 receptors in collecting duct → less exocytosis of aquaporins into apical membrane → decreased water permeability → decreased urine osmolarity (urine is more dilute)
Increased renal free water clearance → [increase or decrease] in Sosm
increase
4 major causes of hyponatremia
Stimulus for inappropriate thirst
Stimulus for massive ADH release
Salt wasting with water replacement
Overactivation of CVMP
Osmolarity of the most dilute urine possible
50 mOsm/L
ADH release is inappropriate if Sosm falls below [#]
280 mOsm
CVMP is a [non-osmolar or osmolar] drive for ADH secretion
non-osmolar
Methods for determining a patient’s volume status
Weight
Recent photograph
Orthostatic BP changes
Central venous pressure
How can cancer cause hyponatremia?
Paraneoplastic secretion of an ADH-like substance
How can CNS inflammation or injury cause hyponatremia?
Cytokine stimulation of SON neurons → ADH release
How can affective disorders cause hyponatremia?
Psychotic thirst
Antidepressants → non-osmotic induction of ADH release
The urine of a hyponatremic patient should be below [#] mOsm
100 mOsm
How can you measure renal function?
Serum creatinine
The urine of a hyponatremic patient should have UNa below [#] mEq/L
20 mEq/L
A hyponatremic patient should be hyper-osmolar, with Sosm < [#] mOsm
285-290 mOsm
What could produce a falsely reduced serum sodium?
Hyperlipidemia (lipids take up too much of the non-protein component of blood; if you subtract the lipid component, SNa is normal)
What hormone might have residual activity if the urine of a hyponatremic patient is not maximally dilute?
ADH
SIADH What does it stand for? It is also called “[?] hyponatremia”
Syndrome of inappropriate ADH secretion
Euvolemic
SIADH occurs in the [presence or absence] of ineffective intravascular volume
Absence
In SIADH, SNa and Sosm are low enough that [hormone] should be shut off, but it isn’t
ADH
In SIAD, the urine [is or is not] maximally dilute
Abnormal loss of hypotonic fluid without access to free water
Cause of central diabetes insipidus
Reduced ADH secretion secondary to surgery, intrapituitary bleed, head trauma, intracranial malignancy (i.e., damage to the pituitary)
Causes of nephrogenic diabetes insipidus
Reduced ADH response due to receptor or aquaporin deficit
Reduced transport of Na+ or urea into medullary interstitium
Loss of vasa recta (sickle cell disease)
Causes of hypernatremia secondary to abnormal hypotonic fluid loss
Impaired skin integrity
Intense sweat + fever/heat exposure
Heat exhaustion or stroke
Osmotic diarrhea
Hyperventilatory water loss
In osmotic diarrhea, the lost fluid is [hypertonic or hypotonic]
hypotonic
3 drugs that result in nephrogenic diabetes insipidus
Lithium
Amphotericin B
Calcium
Drug-induced diabetes insipidus results in disruption of the [hormone] pathway, causing decreased insertion of [?] in the apical [nephron segment] membrane
ADH; aquaporins; collecting duct
How does lithium cause ADH blockade?
Enter cell through ENaC → inhibit adenylate cyclase → interrupt ADH signaling cascade
How does amphotericin B cause ADH blockade?
Amphotericin B monomers form a non-selective cation channel in the apical membrane of the collecting duct → Na+ enters cell and K+ leaves → loss of K+ causes malfunction of adenylate cyclase → interrupt ADH signaling cascade
How does calcium cause ADH blockade?
Ca2+ binds its own GPCR in the basolateral membrane → release of an inhibitory G-protein subunit → inhibition of adenylate cyclase → interrupt ADH signaling cascade
Urinary concentration deficits secondary to lithium/amphotericin B/calcium have a [rapid or slow] onset
rapid
Treat hypernatremia if serum sodium is > [#] mEq/L
155 mEq/L
Why must hypernatremia always be treated?
Patients could develop significant CNS pathology
Maximum rate of SNa decrease when treating hypernatremia Consequences if SNa decreases too quickly
0.5 mEq/L/hr (12 mEq/day) until SNa = 150
Brain swelling
Treatment for acute hypernatremia
Infusion of D5W (5% dextrose; essentially “free water”)
Treatment options for chronic hypernatremia
ADH agonist (DDAVP)
SON stimulant
Mild reduction in GFR (tricky)
Treatment for a hypovolemic hypernatremic patient
First, correct hypovolemia with normal saline
If patient is still hypernatremic, infuse D5W
During treatment of hypernatremia, rebound will occur if you don’t…
replace urinary and insensible free water loss
Formula for estimated water deficit in hypernatremic patients
0.45*(lean body weight)*(measured SNa/140 – 1)
In the formula for estimated water deficit, what does “0.45” represent?
Fraction of body weight that is total body water (in a lean person)
T/F: The calculated water deficit might not be accurate depending on the BMI of the patient
True
T/F: Vaptans (ADH receptor antagonists) can be used to treat hypernatremia
True – they are effective in both hypo- and hypernatremia
Mechanism of vaptans in the treatment of hypernatremia
Vaptans enter cell → bind defective ADH receptor → chaperone the receptors through the ER/Golgi → insertion in the basolateral membrane of the collecting duct
Mechanism of cGMP phosphodiesterase inhibitors in the treatment of hypernatremia
Raise intracellular [cGMP] → cGMP acts like cAMP → target aquaporins to the apical membrane of the collecting duct
Example of a cGMP phosphodiesterase inhibitor
Viagra
Hypernatremic patients have [oliguria or polyuria]
polyuria
Major cause of hypernatremia in the elderly
Defect in thirst (or lack of accessibility to water)
