Pathophysiology of Water Handling

Question 1

True or False: Serum osmolality is mostly determined by Na

Answer 1

True.

Normal serum osmolality is 280-295 mOsm/kg and in a normal person about 280 mOsm of that is from the Na.

Question 2

Osmoregulation is achieved by changes in _____ balance

Answer 2

Water.

Excretion, retention, and intake

Question 3

What 2 things trigger ADH release?

Answer 3

High plasma osmolality and low blood volume.

Question 4

True or False: In severe volume depletion, the hypovolemic stimulus can override the osmolality stimulus and release ADH even in states of hyponatremia.

Answer 4

True. It is more important to the body to preserve blood volume in cases of severely low blood volume.

ADH increases exponentially if blood volume decreases by more than 6-8%, despite a decrease in serum osmolality. Thus, severe volume depletion can cause hyponatremia.

Question 5

Explain the mechanism of vasopressin in the kidney principal cells

Answer 5

Vasopressin arrives at the principal cells from the peritubular capillaries. It attaches to the V₂R receptor (vasopressin 2 receptor) on the basolateral membrane of the principal cell which stimulates adenylyl cyclase which makes cAMP which stimulates PKA which leads to exocytosis of aquaporin water channels which insert into the apical membrane. This allows water to be absorbed.

Question 6

What causes isotonic hyponatremia?

Answer 6

It is usually a lab artifact but can happen in severe hyperlipidemia or hyperproteinemia.

Question 7

What causes hypertonic hyponatremia?

Answer 7

It is most often due to uncontrolled diabetes which causes a water shift.

Sosm = (2x Na meq/L) + (BUN mg/dL / 2.8) + (Glucose mg/dL / 18)

You can see that if glucose gets really high from uncontrolled diabetes, the osmolality of the serum will increase. Water will shift from the extracellular space into the blood stream to try to reduce the osmolality but this addition of water dilutes the Na. This causes a state of hypertonic hyponatremia.

Question 8

True or False: Hypotonic hyponatremia is the most clinically significant hyponatremia and is even called “True” hyponatremia.

Answer 8

True

Question 9

What is the first step in evaluating patients with hypotonic hyponatremia?

Answer 9

Determine their volume status: hypovolemic, euvolemic, or hypervolemic.

This can be done by…

History: trauma/blood loss, diarrhea, vomitting, etc.

BP and HR

Orthostatics is a sign of volume depletion

Weight changes

Physical exam: Edema, rales, etc

Question 10

What are causes of hypovolemic hyponatremia?

Answer 10

• Hemorrhage
• Plasma volume and EC fluid losses
  
  • GI loss
  • Renal loss (excessive use of diuretics, osmotic diuresis, mineralocorticoid deficiency)
  • Excessive sweating
  • Loss of sodium and water

Question 11

What is osmotic diuresis and how can is cause hypovolemic hyponatremia?

Answer 11

It is when the urine is high is osmolarity (common in uncontrolled diabetes). High glucose in urine will drag water and electrolytes with it which can cause days to weeks of diuresis which can cause volume depletion.

Question 12

How do you treat hypovolemic hyponatremia?

Answer 12

Normal saline.

In hypovolemia, there is decreased total body sodium. Total body water is decreased but to a lesser extent because of appropriate ADH release. Restoring plasma volume with saline will cause normonatremia and fall in ADH.

Question 13

What are 2 categories of causes for hypervolemic hyponatremia?

Answer 13

• ADH-mediated
  
  • Congestive heart failure
  • Liver cirrhosis
• Independent from ADH
  
  • Severe renal failure causing kidneys to be unable to excrete excess water

Question 14

Why is ADH released in CHF and liver cirrhosis?

Answer 14

In severe heart failure, cardiac output and tissue perfusion is very low which is sensed by the baroreceptors and the kidney as reduced “effective” blood volume. Counterregulatory hormones (e.g. renin-angiotensin-aldosterone system, sympathetic nervous system, and ADH) lead to salt and water retention by the kidneys causing edema.

In liver cirrhosis, there is excessive vasodilation in the splanchnic vasculature, which is also sensed by baroreceptors as reduced “effective” blood volume, stimulating ADH.

ADH release in these settings can cause hyponatremia which is a poor prognostic sign.

Question 15

Explain hypervolemic hyponatremia independent from ADH and a therapy that is a frequent cause of hyponatremia, particularly in the elderly.

Answer 15

When hypervolemic hyponatremia is independent from ADH, it means that the mechanism is intrinsic to the kidney. Either the diluting mechanism in the distal tubules does not work or renal blood flow and glomerular filtration rate are too low, as in cases of advanced chronic kidney disease.

Thiazide diuretics impair dilution and are a frequent cause of hyponatremia, particularly in the elderly.

Question 16

How do you treat hypervolemic hyponatremia?

Answer 16

Water and salt restriction

Loop diuretics

Stop thiazides

Inotropes for CHF

Question 17

True or False: Euvolemic hyponatremia is usually due to ADH secretion

Answer 17

True

Question 18

What stimuli can cause excessive ADH release resulting in euvolemic hyponatremia? (7)

Answer 18

1. Hypothyroidism
2. Adrenal insufficiency
3. Nausea
4. Pain
5. Psychosis
6. Many medications (SSRIs, antipsychotics, NSAIDS, and others)
7. SIADH (syndrome of inappropriate ADH secretion)

Question 19

What is SIADH?

Answer 19

Syndrome of inappropriate ADH secretion. It is a diagnosis of exclusion and is when a patient has euvolemic hyponatremia and urine that is not maximally dilute (greater than 50-100 mOsm/kg)

Question 20

What causes SIADH?

Answer 20

SIADH is commonly caused by carcinomas which cause ectopic ADH production. It can also be caused by CNS disorders of the hypothalamus or pituitary or pulmonary diseases.

Question 21

Symptoms of hyponatremia depend on what 2 things?

Answer 21

Speed of onset and severity.

If it develops slowly (days to weeks), sometimes patient don’t even have symptoms.

Question 22

What are symptoms of hyponatremia? (8)

Answer 22

1. Anorexia
2. Nausea
3. Vomiting
4. Weakness
5. Lethargy
6. Confusion
7. Seizures
8. Death

Question 23

Symptoms of hyponatremia are likely due to _____ edema

Answer 23

cerebral edema

Question 24

How do you treat euvolemic hyponatremia that presents with seizures?

Answer 24

Hypertonic saline

Question 25

How do you treat asymptomatic euvolemic hyponatremia?

Answer 25

Water restriction and correction of underlying disorder or removal of offending drugs.

If underlying causes cannot be treated, you can give ADH antagonists.

Question 26

How do you treat chronic euvolemic hyponatremia (greater than 48 hours of duration) or unknown duration?

Answer 26

You have to slow the correction to avoid central pontine myelinolysis (osmotic demyelination syndrome).

The brain adapts over time to hyponatremia. Initially, when serum osmolality is low, water goes from the serum into the brain which causes brain edema. However, the brain adapts by reducing its intracellular sodium and osmoles so that water flows out of the brain and intercranial pressure goes back to normal. If you rapidly correct serum osmolality, then the brain cells are hypotonic to the serum plasma so the cells will lose even more water and the neuron cells will shrink and lead to demyelination.

Question 27

True or False: Hypernatremia and hyponatremia are disorders of water balance and do not indicate anything about total body sodium.

Answer 27

True

Hypernatremia can have decreased, normal, or increased total body sodium and so can hyponatremia.

Question 28

True or False: Hypernatremia causes severe thirst

Answer 28

True. It causes an increase in serum osmolality which causes severe thirst.

Question 29

Hypernatremia only develops in 2 cases. What are they?

Answer 29

1. Patients who do not have access to water (often hospitalized patients)
2. Patients with CNS pathology impairing thirst

Question 30

What are causes of hypernatremia?

Answer 30

1. Renal or extrarenal water loss that exceeds sodium loss
2. Addition of hypertonic fluids (hypervolemic hypernatremia). This is usually iatrogenic (caused by medical intervension e.g. hypertonic saline, TPN, or bicarbonate infusion)
3. Lack of ADH effect in diabetes insipidus (water diuresis, very dilute urine)

Question 31

What is Diabetes Insipidus? What are the 2 kinds?

Answer 31

Diabetes insipidus (DI) is a condition characterized by excessive thirst and excretion of large amounts of severely dilute urine, with reduction of fluid intake having no effect on the concentration of the urine.

DI can be central or nephrogenic.

Central DI is when there is no ADH secreted or if there is ADH deficiency.

Nephrogenic DI is when the kidneys do not respond to ADH or have ADH resistance.

Question 32

What do patients with diabetes insipidus complain of?

Answer 32

Polyuria (excessive urine volume) and Polydipsia (excessive thirst)

Question 33

What are causes of central DI?

Answer 33

30-50% of cases are idiopathic (hypothesized as autoimmune?)

Diseases of hypothalamus or pituitary gland (head trauma, surgery, tumors, encephalitis)

Question 34

How do you treat central DI?

Answer 34

You give long-acting nasally administered vasopressin analogue (DDAVP). You don’t give ADH because ADH has a short halflife.

Question 35

What are causes of nephrogenic DI?

Answer 35

Congenital:

gene mutations in either V2R vasopressin receptor or Aquaporin water channels

Acquired:

caused by medications, electrolyte disorders, or chronic kidney disease

Question 36

What age group does congenital nephrogenic DI typically appear in? How do these patients present? How is it treated?

Answer 36

It typically presents in infants who have failure to thrive, polyuria, fever, vomiting, seizures, and sometimes death.

Treatment is meticulous attention to water balance.

Question 37

True or False: congenital nephrogenic DI is usually less severe than acquired nephrogenic DI and is much more common

Answer 37

False. Acquired nephrogenic DI is much more common than congenital disease and is typically less severe and at least partially reversible.

Question 38

What are causes of acquired nephrogenic DI? (7)

Answer 38

1. Hypercalcemia or chronic hypokalemia can damage the distal tubules and collecting ducts.
2. Long term therapy with lithium
3. Other drugs (cidofovir, foscarnet, amphotericin B, ifosfamide)
4. Treatment with vasopressin receptor antagonists (tolvaptan)
5. CKD causes a concentrating defect due to tubular dysfunction (medulla not maximally hypertonic) as well as ADH resistance
6. Sickle cell anemia and PKD cause early concentrating defects by disrupting the medulla
7. Chronic urinary obstruction also causes ADH resistance

Question 39

What is gestational DI? Does it need to be treated? If so, how?

Answer 39

In the second half of pregnancy, the placenta creates vasopressinase. This degrades endogenous vasopressin which can cause polyuria and polydipsia. It’s typically not that severe but if it is then it can be treated with synthetic DDAVP (which is resistant to vasopressinase).

Question 40

What are symptoms of hypernatremia?

Answer 40

Extreme thirst

Neuromuscular irritability with twitches, hyperreflexia, and seizures.

Altered mental status, confusion coma

Failure to thrive in infants

High mortality rate in both adults and children as hypernatremia often indicates a serious underlying disease.

Question 41

How do you treat hypernatremia?

Answer 41

Calculate water deficit and replace the deficit in addition to ongoing free water losses.

In most cases, D5W should be given not half-normal saline.

Slow correction is required if hypernatremia is present for more than 48 hours (because of the brain adapting to chronic states of hypo/hypernatremia)

Question 42

True or False: For chronic management of nephrogenic DI, thiazide diuretics have been shown to reduce polyuria.

Answer 42

Yes. It seems counter-intuitive but it has been shown empirically to help.

Question 43

True or False: The brain adapts to chronic (greater than 48 hours) hypo- or hypernatremia, so that overly fast correction can cause severe neurological damage.

Answer 43

True