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Flashcards in Water Handling Deck (52):
1

What's up with hypotonic hyponatremia?




• Alteration between ratio of ECF Na and ECF water
• Most common mechanism of hyponatremia is the non-osmotic release of ADH that means water reabsorption despite low serum osmolality

2

What are the causes of euvolemic hypotonic hyponatremia?

• Losing sodium, but gaining water
§ SIADH, primary polydipsia, hypthyroidism, adrenal insufficiency

3

What is the flow-chart of considering hypotonic hyponatremia?

• Hypovolemic vs. euvolemic vs. hypervolemic
• Hypovolemic
○ Associated with high serum uric acid
○ Losing Na more than water
§ Renal loss or extrarenal loss, the cutoff is Urine Na of 20mEq/dL. Renal loss if over, extrarenal loss if under
• Euvolemic
○ Losing sodium, but gaining water
§ SIADH, primary polydipsia, hypthyroidism, adrenal insufficiency
• Hypervolemic
○ Way increased water, and increased sodium
○ Urinary sodium cutoff of 20mEq/dL for the different causes
○ Under 20, CHF, cirrhosis, nephrotic syndrome
○ Over 20, ARF, CKD

4

What's up with isotonic hyponatremia?

• Normal plasma osmolality due to an artifact of hyperlipidemia or hyperproteinemia
• Lab measurement assumes water is 93% of plasma, and reducing that amount by too much lipid or too much protein will mess with sodium calculation by that way
• UNCOMMON problem, artifact of flame photomoetry
• The clue is lipemic serum = cloudy serum after centrifugation

5

What are the three categories of hyponatremia?


• Hypertonic
○ Over 300 mOsm/kg
• Isotonic
○ 280-300 mOsm/kg
• Hypotonic
○ Less than 280 mOsm/kg

6

What's up with hypertonic hyponatremia?

• Hyponatremia due to a shift of water from cells in response to a non-sodium solute that causes an increased serum osmolality
• Caused by hyperglycemia and mannitol or glycerol admin (medically)
• 100 mg/dL increase in glucose, serum sodium decrease of 1.6 mEq/L
○ Made up of glucose molecular weight and distrbution of water as 2/3 intracellular and 1/3 extracellular
• Getting serum glucose is super important for determining serum osmolality

7

What is hyponatremia caused by?

• Inability to maximally dilute the urine coupled with continued water intake
• ECF water increases causing a fall in plasma sodium concentration
• First step in evaluation = determine serum osmolality
○ This differentiates hypertonic, isotonic, hypotonic

8

Who eventually wins when it comes to vasopressin secretion, the volume contral loop or the osmolality control loop?



• Hypovolemia has the more drastic of physiological consequences so the volume control loop wins
• Thus, in defense of plasma volume, there may be lots of ADH secretion even when serum osmolality is already low
• After 6-7% of volume depletion volume response takes over

9

At what point does the volume response dominate the osmolality response?

• After 6-7% of volume depletion

10

How does the body generate a hypertonic interstitium?



• Loop of henle acts as a countercurrent multiplier
• Derives energy from active transport of Cl in the water impermeable thick ascending limb
○ Na/K/2Cl cotransporter
• This dilutes tubular fluid and renders interstitium progessively hypertonic from cortex to papilla (through medulla)
• Thus, cortex is least hypertonic, medulla is more, and the papilla is the most hypertonic
• Thus, vasopressin making collecting duct (medulla and papilla) water-permeable means water leaves to interstitium and urine is concentrated

11

If you are given a maximal Uosm (likely less than 600 and thus reflecting renal pathology), how do you calculate obligate volume of excretion?

• Assume 600 mOsm is the average daily solute load and your given Kidney's max is 300mOsm/kg water
• 600mOsm/300mOsm/kg water = 2 kg water or 2L
• That's a daily intake and output so that means you need to excrete 2L of water in a day to get rid of the AVERAGE daily solute load
• That's a one way track to dehydration

12

What is the normal response of the collecting duct to vasopressin?

• If vasopressin doesn't make the collecting ducts maximally water soluble the maximum Uosm will decrease from 600 to 300 and it will take a larger volume to get ride of the daily excess solute intake
• The large volume depletion means you are on the one-way track to dehydration

13

If someone drinks A TON of water, and has normal kidneys, can they give themselves hyponatremia?

• Yes, but it's really hard to do so
• With normal renal function EXCESSIVE WATER INTAKE ALONE DOES NOT cause hyponatremia unless it exceeds 1 L per hour
• Maximal free water excretion is equal to about 20% of a GFR
• Normal GFR = 120 L/d
• Distal delivery to diluting site is 20% of filtered load = 24L and thus 1 L/d is the maximum free water excretion limit
• The other way to get hyponatremia by water drinking is to reduce GFR, which allows for less fluid to reach the diluting site or collecting ducts

14

What besides drinking over 1L/hour will give you hyponatremia by water intake?

• Only reducing GFR, which reduces the amount of water you can excrete
• Reduce GFR by 80%, you can only drink 4 liters of water per day and not have problems

15

What is the normal renal concentrating mechanism?

• Allows for excretion of a urine as much as four times as concentrated as plasma
• Maximum urine concentration is 1200 mOsm/kgH2O
• Average daily solute load = amount of solute that needs to be excreted = 600 mOsm
• Thus, you only need to excrete 0.5 liters to account for average daily solute load
• Thirst is the main way the body deals with concentration balance

16

What are the three components of the body's urine concentrating mechanism?

• Ability to generate hypertonic interstitium
• Secretion of ADH
• Normal collecting duct responsiveness to vasopressin

17

Describe the normal delivery of tubular fluid to the distal diluting segment of the nephron?



• NORMAL GFR means normal proximal reabsorption of tubular fluid
• Fluid is isotonic in proximal tubule, but proximal reabsorption is an important determinant of water excretion
• If proximal reabsorption increases and cuases decreased distal delivery, volume of dilute urine excreted will be decreased (less fluid overall)

18

How does absence of vasopressin help the normal diluting system?

• Vasopressin renders collecting duct water-permeable.
• With vasopressin, water can move to establish osmotic equilibrium between tubule lumen and interstitium.
• Water movement out into the interstitium concentrates urine and impairs water excretion
• With normal renal function EXCESSIVE WATER INTAKE ALONE DOES NOT cause hyponatremia unless it exceeds 1 L per hour
• Maximal free water excretion is equal to about 20% of a GFR

19

What are the three essential features of a normal diluting system?


• Normal function of the diluting segment
• Normal delivery of tubular fluid to the distal diluting segment of the nephron
• Absence of vasopressin

20

What two areas of the nephron are responsible for diluting urine and what channels allow this to happen?

• Thick ascending limb and distal convoluted tubule
• The Na/K/2Cl transporter is responsible for dilution in the thick ascending limb
• The thiazide sensitive NaCl cotransporter is responsible for dilution in the distal convoluted tubule

21

How is serum osmolality estimated and what factors are involved?


• Estimated by the osmolality formula:
○ S-osm(mOsm/kg) = 2*[na(mEq/L] + (BUN(mg/dL/2.8) + (glucose(mg/dL)/18)
• Sodium is the greatest contributor, BUN is another contributer and glucose is the smallest contributor
• Directly measured by freezing point depression or vapor pressure techniques

22

What is the normal range of osmolality?

• 280-295mOsm/kg
• Kidney maintains by resorbing or excreting water

23

What is the normal response of the kidney to INCREASED osmolality?

• Since water is the main way to affect osmolality as a whole and not have to worry about the individual parts, it uses water.
• Make a concentrated urine by resorbing water back into the blood stream
• High specific gravity and high osmolality

24

What is the normal function of the diluting segment?

• Tubular fluid is diluted in the water-impermeable ascending limb of Loop of Henle AND distal convoluted tubule by the resorption of sodium chloride
• It is about the sodium going out or in, not water going out or in
• The Na/K/2Cl transporter is responsible for dilution in the thick ascending limb
• The thiazide sensitive NaCl cotransporter is responsible for dilution in the distal convoluted tubule

25

What is the normal response of the kidney to DECREASED osmolality?

• Excrete free water and production of a dilute urine
• Low specific gravity and osmolality

26

How much vasopressin is released as serum osmolality rises?

• Osmoreceptors in the hypotalamus regulate the secretion of AVP from the posterior pituitary gland
• Secretion increases by 0.38pg/mL for every 1mOsm/kg increase in serum osmolality above 283mOsm/kg
• This drives up Uosm (urine osmolality), with 1pg/mL ADH increase resulting in Uosm increase of 225 mOsm/kg

27

If the major factor concerning water handling is water secretion, what controls water secretion and is therefore the overlord of water handling?

• ADH = anti-diuretic hormone = vasopressin
○ Aka - arginine vasopressin or AVP
• Osmoreceptors in the hypotalamus regulate the secretion of AVP from the posterior pituitary gland
• Secretion increases by 0.38pg/mL for every 1mOsm/kg increase in serum osmolality above 283mOsm/kg
• This drives up Uosm (urine osmolality), with 1pg/mL ADH increase resulting in Uosm increase of 225 mOsm/kg

28

What is the most common clinical cause of hyponatremia?


• Too much water. A relative excess of water.
• The usual process is non-osmotic release of vasopressin
• Vasopressin = ADH = anti-diuretic hormone

29

What equation links sodium concentration and tonicity/osmolality?

• Sodium is the most abundant cation in the ECF and thus it's a major determinant of the osmolality
• Estimated by the osmolality formula:
○ S-osm(mOsm/kg) = 2*[na(mEq/L] + (BUN(mg/dL/2.8) + (glucose(mg/dL)/18)

30

Is the sodium concentration gathered from lab values a measure of total body sodium content?

• No. it reflects only the relative amounts of the two contributors, the sodium and the water
• [ECF Na] = ECF na/ECF H2O
• Thus a low concentration can result from too much water or too little sodium

31

What are the 5 direct actions of ANP?

• Decrease secretion of ADH (probably hypothalamus or pituitary)
• Block ADH action on tubules
• Increase dilation of efferent and afferent arteriole (increases GFR, which increases flow rate which increases excretion)
• Decreases renin release (decreases aldosterone secretion and decreases osmotic gradient for water reabsorption)
• Blocks aldosterone action on tubules
• ALL THESE THINGS LEAD TO INCREASED WATER AND SODIUM EXCRETION

32

Why is ANP called atrial natriuretic peptide?

• First discovered in granules in atrial myocytes that disappeared in volume expanded animals
• Purified from these granules and shown to have Na excreting properties.

33

What is the pathway to active ANP?

• Stretch in atrial myocytes leads to pro-ANP secretion
• Cleavage by peptidases in blood result in active 28 amino acid ANP
• Circulating active ANP will increase urine production

34

Which regulatory loop is more sensitive to changes: the osmoregulatory loop or the volume regulatory loop?

• The osmoregulatory loop is exceptionally sensitive to very small changes in osmolarity from normal
• The volume regulatory loop doesn't win until over 10% volume reduction occurs
• There are ADH level changes associated with a deviation of 1% from normal in osmolarity

35

In general, how can ECF water regulation be characterized?

• It's primarily an osmoregulatory system with an emergency low-volume override

36

Characterize the change in ADH secretion as osmolarity increases

• From 5% below normal to 20% above normal osmolarity there is a LINEAR increase in ADH secretion
• In contrast, ADH secretion stays constant in decreased ECF volume untill a greater than 10% decrease in ECF is seen, then it really steeply climbs.
*thus, eventually the ECF fluid reduction response "WINS"

37

What happens to ADH secretion in the case of losing volume by diarrhea and then drinking most of it back?

• The loss of diarrhea is isotonic so the ECF volume is decreased but osmolarity is not changed
• Thus, the ADH secretion is volume-associated secretion and is massive
• However, when almost that whole volume is ingested in drinking water the ECF volume-associated ADH secretion is much less
• However, osmolarity has definitely changed in pure water ingestion, so ADH is turned OFF by the osmolarity pathway.
• NET RESULT IS VERY LITTLE ADH SECRETION AND NEAR MAXIMAL WATER EXCRETION

38

What is the flow-chart for ADH secretion/feedback in the case of severe sweating?

• In sweating, you lose more water then salt. THUS there is the increased ECF osmolarity pathway that is activated and the decreased ECF volume that is activated
• Both these arms will lead to increased activation of ADH synthesizing neurons and secretion of ADH from the posterior pituitary (through decreased left atrial pressure and increased baroreceptor response AND through increased hypothalamic osmoreceptor response
• The net result is increased water reabsorption in the late distal tubule and collecting duct and ADDITION OF INGESTED WATER TO ECF

39

What sensors "sense" decreased ECF volume and where are they? What hormone do they secrete in response?

• Low pressure baroreceptors in the left atrial appendage and they sense a decreased filling of the left atrium (stretch receptors)
• ADH-synthesizing hypothalamic neurons are activated and ADH is secreted from the posterior pituitary
• The net result is sodium and water reabsorption

40

Describe the sodium possibilities in a hypovolemic patient

• Hyponatremic
○ Greater sodium loss than water loss
• Normal sodium
○ Equal sodium and water loss (isotonic loss like diarrhea)
• Hypernatremic
○ More water loss than sodium loss

41

Describe the VOLUME possibilities for a hyponatremic person

• If decreased sodium is far more than decreased water, HYPOVOLEMIC
• If sodium stays the same but water increases, EUVOLEMIC
• If sodium increases a bit but water increases a ton, HYPERVOLEMIC

42

When does Euvolemic hyponatremia occur?

• In patients who are normal in sodium balance but they have a positive water balance
• Often when ADH is inappropriately released and the kidneys cannot excrete the water injested, but they are not impaired in sodium handling

43

When does hypervolemic hyponatremia occur?

• Common in heart, liver and renal failure
• Renal excretion of sodium is impaired and thus the kidneys hold on to sodium and water and volume expands
• EABV being low releases ADH, and thus drinking just leads to water retention and a hypervolemic state

44

What is the normal kidney response in a negative water balance situation?

• Increased serum sodium (over 142mEq/L)
• Increased vasopressin release and increased thirst
• Increased renal water and sodium reabsorption and increased water intake due to thirst

45

What is the normal kidney response to a positive water balance?

• Decreased Serum sodium (less than 135mEq/L)
• Decreased thirst and suppression of vasopressin
• Decreased water intake and increased renal water excretion

46

What does vasopressin do?

• Once released, binds to V2 receptor on the basolateral side of the epithelial cells in the collecting ducts of the distal nephron
• Initiates cAMP signalling that results in synthesis and incorporation of aquaporin channels AND sodium channels in the apical membrane
• Water can be reabsorbed now where once it could not have been due to water impermeability

47

At what osmolarity does the sensation of thirst kick in?

• At about 290mOsm/L (at the upper range of normal)
• Beyond this point the kidneys are unable to conserve more water by concentrating the urine further (maximum is 1200mOsm/L)

48

What is the way to calculate serum osmolarity?

• Serum osmolarity = 2*[Na} + BUN/2.8 + glucose/18

49

What does the sympathetic nervous system do in terms of sodium and water balance?

• Decrease in MAP (EABV) activates the sympathetic nervous system (SNS)
• Through direct innervation of renin secreting cells in JGA as well as catecholamines, SNS activates RAAS
• SNS also decreses renal blood flow through constriction of afferent arteriole, results in sodium reabsorbtion

50

What are the steps in the body's response to decreased ECF Na?

• Shift of water into cells due to osmolarity shift
• Decreased ECF and EABV (MAP in this case) leads to increased baroreceptor reflexes both in the arteries and the JGA
• Increased renin secretion through SNS activity. Renin is the first step in RAAS activation
• RAAS activation leads to aldosterone secretion in adrenal cortex
• Aldosterone increases sodium reabsorption in distal tuble and cortical collecting duct
• Resorbed sodium means reabsorbed water to correct loss of ECF volume (and corrects sodium too)

51

What effectors of ECF volume lead to sodium excretion and vasodilation?

• Natriuretic peptides, prostaglandins E2 and I2, bradykinin, dopamine

52

The change in [Na] should be how much in proportion to the resultant change in ECF water volume?

• The water volume is 2X the change of the sodium concentration
• Thus, the body senses sodium changes in the body by sensing water changes
• The water changes more than the sodium does because of the overall larger ICF compartment then ECF compartment