Guyton makes a point about solute (Na) concentration and body water concentration. What is it??
Ability to regulate water balance independent of solute excretion critical to survival
_____ is a major contributor to osmotic pressure
Na
Kidneys have the ability to respond to changes in our physiology. They can excrete a urine as low as ___mOsm/L an excess of water over solutes or they can excrete a urine as high as _____mOsm/L (deficit of water, conserving water and excreting a very concentrated urine).
50; 1400
Range is 50mOsm-1400mOsm adjusting as need be
Why do we excrete a dilute urine?
Excessive body water in relation to solute concentration → ↓ ECF (plasma) osmolarity
How is ADH released and what happens?
Osmoreceptors in hypothalamus sense an osmolarity and will send ADH to posterior pituitary where it is secreted then goes to kidneys (distal tubules/collecting ducts) and inserts aquaporins to help reabsorb water into circulation
Explain ADH's role in excreting a dilute urine
↓ permeability of distal tubules & collecting to water
↑ volume of dilute urine excreted
We can excrete up to ___L/day of urine (very low ADH levels...)
20L
Explain the kidney's role in excreting a dilute urine
Solutes reabsorbed but not water
Ability to absorb solute > water depends on tubular segment
What is the osmolarity in the proximal convoluted tubule (PCT)?
Same as in the plasma (around 300)
As tubular fluid goes from the PCT to the descending limb of the LOH, what is the osmolarity?
Water again leaves, going out into the interstitial space and because water is leaving the tubule at that point the tubular fluid has osmolarity more concentrated (higher) so around 400.
What happens to the osmolarity in the bend of the loop of Henle?
As the fluid then continues onto the loop (Goes to 600) mainly from water leaving the tubular fluid
What happens to the osmolarity of the tubular fluid as it goes up the limb of Henle?
NaCL will be actively reabsorbed but this area is really impermeable to water.
So the interstitial fluid becomes hyperosmotic (impt) but tubular fluid leaving the ascending LOH is hyposmotic (100) so it’s very dilute at this point
Once past the LOH, what happens to the osmolarity of the tubular fluid?
It really depends on ADH at this point.
Once it gets into the distal tubule, if ADH is absent, it will continue to be diluted and more water excretion (solutes are still reabsorbed but water isn’t) and tubular fluid gets further diluted and end up w/osmolarity of like 50mOsm/L.
TRUE or FALSE. The process in the LOH is always the SAME!
TRUE! Difference really occurs in Distal and colllecting tubules is dependent on ADH and ADH secretion is dependent on plasma osmolarity
What is ADH secretion dependent upon
the plasma osmolarity
Why would we want to excrete a concentrated urine?
Water deficit not compensated by intake (no water to drink) so ECF osmolarity ↑’s
Maximal urine concentration =
1200 – 1400 mOm/L
What is the Obligatory urine volume?
70kg: 600mOsm of solute has to be excreted every day (The amount of waste products from metabolism) and the max concentration of urine is 1200mOsm.
600mOsm/day x L /1200mOsm = 0.5L/day
0.5L/day x day/24hr x 1000ml/L = 20.83ml/hr
What are the TWO requirements for excreting concentrated urine
What are the tubular segments involved in the excretion of a concentrated urine?
LOH is important piece involved with excretion of a concentrated urine, that’s where the hyperosmolar medullary interstitial fluid gets generated or maintained.
Also the distal and collecting tubules where ADH has an effect
What is the vasa recta?
They are blood vessels to the LoH (special part of the peritubular capillaries) and the collecting ducts, they are arranged in hairpin loops
What are the key contributors to osmotic gradient?
Na Cl that gets moved into the interstitial fluid, but also urea.
Why is urea interesting??
Urea is interesting, b/c it helps to form the concentrated medullary ISF, but at the same time it recycles itself so it can get excreted, b/c of course we want to get rid of it b/c it’s a waste product and we don’t want it to get reabsorbed into the circulation
Which part of the LOH is the only part permeable to water?
thin descending limb
What is responsible for maintaining the hyperosmolar medullary interstitum?
countercurrent mechanism
What moves in and out of the thick ascending LoH?
Out (into interstitial fluid): Na, Cl, K, Ca, HCO3, Mg
In (into tubular fluid): H+
What moves out in the early distal tubule ?
Na, Cl, Ca, Mg
Describe the countercurrent mechanism
1. start of LOH as the urine is leaving PCT the urine (tubular fluid) has osmolarity equal to that of plasma (300)
2. The active pump in the thick ascending limb of LOH will cause Na Cl solutes to move into the interstitial fluid and that has 2 effects (the interstitial osmolarity is higher, now 400 and the tubular osmolarity is lower, now 200)
3. Because the osmolarity of interstitial fluid is higher, water gets reabsorbed (moves out of the descending LOH-the only section where water can move out) to try and equilibrate what the osmolarity is between the descending limb and the interstitial fluid and because water moves out of the tubule the tubular fluid becomes hyperosmotic.
4. As we get more bulk flow from the proximal convoluted tubules, causing a flow through the loop of henle, new filtrate into the LOH from the PCT (again has osmolarity similar to plasma, 300)
5. More solutes getting reabsorbed again from ascending limb of LOH which further dilutes the tubular fluid in LOH (200 down to 150)
6. Now water again is going from the descending limb of LOH into the interstitial fluid and that’s because of increase in osmolarity in the interstitial fluid because what has moved d/t bulk flow
NET result is adding solute to the medulla in excess of water. This multiplies the concentration gradient established by active transport.
Why is it important that most of the water reabsorbed (when ADH is present) is in the cortical intersitital fluid?
Most of the water reabsorbed is into the cortical (cortex) interstitial fluid. Reason this is important is because if the water were going into the medullary interstitial fluid, it would dilute out the hyperosmotic medullary interstitum which is really essential. (to concentrate the urine)
How is urea reabsorbed?
Passively reabsorbed in presence of ADH from cortical collecting tubule into medullary interstitium
TRUE or FALSE. Most of the urea reabsorption will occur in the ascending LoH.
FALSE. urea is reabsorbed from the medullary collecting ducts into the interstitial fluid. (if ADH levels are high)
Water is reabsorbed in the descending limb of the loop of henle, that will concentrate the urea coming from the proximal convoluted tubule. Very little urea reabsorption will occur in the ascending loop of henle.
Why is urea somewhat dependent on ADH if it is passively reabsorbed?
With ADH levels being high and kidney forming a concentrated urine then urea levels will increase even more allowing a large concentration gradient which makes the urea want to passively move into the interstitial fluid
Urea recirculates and a fair amount of the urea that goes into the medullary interstitum will end up back in the thin segment of the loop of henle. What is the purpose of this?
It helps to concentrate the medullary fluid even further and still allowing us to excrete the waste and at the same time conserve water in the presence of ADH
How much does urea contribute to hyperosmotic renal medulla interstitium?
40-50% of osmolarity is due to recycling of urea or about 500-600 mOsm/L. So again close to half of that 1200 mOsm.
What is medullary blood flow called?
Vasa recta (countercurrent exchange)
Countercurrent exchange allows us to concentrate the blood in the vasa recta. What is the goal of that?
to preserve this hyperosmotoic medullary interstitium
What are the pecial characteristics of the blood flow in the medulla that will contribute to preserving the hyperosmotic medullary interstitum?
1. flow to the medulla is relatively low
2. blood in the vasa recta goes deeper into the medulla (long LOH) becomes more concentrated
How low is the blood flow to the medulla and why is this important?
less than 5% of total renal Blood flow
because the blood flow is low, the concentrated solutes in the interstitial fluids don’t go into circulation and get whisked away but enough BF to maintain the metabolic needs of the tissues.
What is the vasa recta exactly?
They are loops of capillaries that come off the efferent arteriole, (Essentially peritubular capillaries that will loop around the LOH in the juxtamedular nephrons –long LOH)
So as the blood in the vasa recta goes deeper into the medulla (long LOH) becomes more concentrated for 2 reasons, what are they?
1. solute will leave the medullary interstitum and go into the blood
2. water will go from the blood and enter the intersitium
As the vasa recta vessel goes back up to the cortex, two things will happen, what are they?
1. solutes will diffuse out of the capillary and into the interstitial space again (reverse direction)
2. water will move by osmosis into the vasa recta. (reverse)
That’s why it’s called the counter current exchange
What is the purpose of the counter current exchange?
Purpose of this exchange is not to create the hyperosmolar state in medullary interstitum but rather to prevent it from being dissipated.
What is the cheat equation to figure out the plasma osmolarity?
Na concentration x 2.1 will provide estimate for plasma osmolarity.
List six stimuli for ADH
Plasma osmolarity
BP
Blood volume
Nausea
Hypoxia
Medications
How does BP and Blood volume affect ADH secretion? (what is is mediated by?)
mediated by baroreflexes and the cardiopulmonary reflexes of aortic arch, carotid sinus and the cardiac atria.
Quantitatively what is the most potent stimulus for ADH secretion?
Quantitatively plasma osmolarity is more potent stimulus for ADH secretion than blood volume.
It would take a more dramatic decrease in blood volume to stimulate ADH secretion while just a small change in hydration status that would effect plasma osm that would cause ADH secretion.
ADH secretion will increase with even __% increase in osm but takes about __% decrease in blood volume before there is a noticeable change in ADH secretion
1%; 10%
When can nausea really increase ADH secretion?
Can increase substantially if vomiting is present. Makes sense because vomiting = losing volume and need to conserve volume so increase in ADH will help to reabsorb water and maintain intravascular vol
What medications will alter ADH secretion
Morphine will stimulate ADH secretion.
Alcohol inhibits secretion.
Typical meal can include up to 50mEq/ can raise plasma level by almost 3mEq/L, why isn't this a problem?
but a lot of that K initially goes into the cell and gets stored until the kidneys can eliminate it.
How does insulin effect K+ distribution?
Insulin-causes ECF to go into the cell. After meal, a lot goes into cell because carbohydrate causes insulin secretion, also puts K into cells until kidney can eliminate it.
Diabetic patient may have an impaired ability to move the K+ they take in a meal from the ECF to the ICF, more likely to be hyperkalemia independent of kidney function
How is aldosterone important in terms of K+ distribution?
Aldosterone secretion will be stimulated by increased intake of K. (Aldosterone will increase the permeability of the luminal side of the cell to K.)
Aldosterone will move the K into the cell.
Will you see hyper or hypo K in Conn syndrome?
Conn syndroe (secrete excess aldosterone) results in hypokalemia because the excess hormone will move the K from ECF to ICF.
Opposite is true, Addison's disease (hypoaldosteronism) so those individuals will have hyperkalemia
How does Beta stimulation effect K+ distribution?
Catecholamines: epi will cause K to move into the cell (Beta 2 mechanism) so patient that are on non-selective betablock are at risk for hyperkalemia because it’s staying in the ECF not moving into the cell
How does Acid Base balance effect K+ distribution?
Acid base balance: metabolic acidosis will cause an increase in plasma K and metabolic alkalosis does the reverse. D/t effect of H+ ion on K+ distrubution. Thought that increased H+ will decrease the effectiveness of the Na/K ATPase pump.
How does integrity of the cell membranes effect K+ distribution?
Lysis of cells: will cause a release of K that is inside the cell.
How does exercise effect the K+ distribution?
Exercise: cause a mild increase in K. If exercise is strenuous, diabetic, and on a non selective betablocker, especially significant if patient also DM and on non-selective BB
How does ECF osmolarity effect K+ distribution?
Increased ECF osmolarity: causes cellular dehydration and water will then move out of the cell. K+ will also move out of the cell and into the ECF. So that could occur again in diabetic patient, particularly in hyperosmolar state from hyperglycemia
The things that would move K+ into cell are:
insulin, aldosterone, catecholamines (particularly epinephrine) and metabolic alkalosis
The things that would K+ into the into the ECF (plasma), effectively increasing K+ levels as we measure them, would be:
metabolic acidosis, exercise, increased ECF osmolarity and lysis of cells.
how do we figure out how much K+ is filtered?
equal to the plasma K concentration multiplied by the GFR.
(filtered K+ = plasma K+ x GFR)
if GFR drops dramatically then what can happen to the plasma K+ levels?
hyperkalemia can result.
About __% of the filtered K+ is reabsorbed also in the proximal convoluted tubule, with another __-___% in thick ascending of LOH by co-transport w/Na and Cl.
65%; 25-30%
Any day to day variations in K+ excretion are usually not due to what goes on in PCT or the LOH but rather have to do
w/distal and cortical collecting tubules. Particularly the principal cells of the late distal and the cortical collecting tubules.
So in this part of tubules, the distal and the cortical collecting tubules, K+ can be reabsorbed or secreted depending on the demand. So we can take in per day about 100mEq of K+, some of it is eliminated in feces (8mEq) but the rest has to be handled by the kidneys (the remaining 92mEq). About a 1/3 of that 92mEq will be secreted by those end sections, the distal and cortical collecting tubules. Why is this mechanism so important?
This mechanism is so sensitive that we can actually secrete more than we filter so if need arises we can get rid of more K+, if our kidneys are working well, than we actually filter.
Principal cells, make up about ___% of tubular epithelial cells in the distal and collecting tubules of the nephron
90%
K+ secretion (by the principal cells) is 2 step process:
1st step: Uptake of K+ from interstitial fluid into the cell. This is the Na+/K+ ATPase pump. So starting in interstitial fluid the Na/K ATPase pump and into the principal cells which are these special tubular epithelial cells.
2nd step: passive diffusion of K+ from the cell into the tubular fluid. There are actually special channels on this luminal side that are specifically permeable to K+ which is somewhat unique to these principal cells, well suited to the diffusion of K+ into the tubular fluid.
What is so unique about the luminal side of the principal cells?
specifically permeable to K+ allowing passive diffusion of K from the cell into the tubular fluid
How do the intercalated discs effect K+ secretion?
Reabsorb K+ and secrete H+ ions into the tubular lumen. (to NOT secrete K+)
Could closely adjusting secretion and reabsorption of K+ as we needed to.
In situations where there is a severe K+ depletion, the secretion of K+ stops and we actually get a net reabsorption of K+ in these same distal and collecting tubules.
Plasma K+ concentration is major stimulant for K+ secretion (again by the distal and cortical collecting tubules). It’s most dramatic when the plasma K+ level reaches around ......
4.1 (which is well within normal range).
How does the increase in plasma K level stimulate aldosterone secretion???
The increase in plasma K level will stimulate aldosterone secretion by zone of glomerulosa in the adrenal cortex and this will also stimulate K+ secretion.
What is the aldosterone K connection
such that when K levels are high, the high level of K and aldosterone will work together to bring the level back to normal because of increased renal excretion of K
How does flow rate in the distal tubule effect K+ secretion?
If increased flow rate, stimulate K secretion. When this might happen, if there is a high Na diet, Na and water go together so increase in plasma volume or in the case of the patient on diuretics.
And this helps to keep K excretion normal when the Na intake changes. This will cause a decrease in aldosterone, and a decrease K uptake into cells and therefore an increase in plasma K+.
How does acidosis (acute and chronic) effect K+ secretion??
An acute increase in H+ concentration, acute acidosis, causes an decrease in K+ secretion, by inhibiting Na/K ATPase pump.
With chronic acidosis over several days, there will be an inhibition of Na and Water reabsorption from the proximal convoluted tubule and that will increase the flow rate in the distal tubule. Again, increase in flow rate in the distal tubule is flushing out potassium stimulates secretion of potassium by the Principal cells
___% of calcium is stored in the bone and ___% stored in ECF
99%; 0.1%
Major physiologic effect of PTH is to maintain Ca homeostasis. How is PTH release regulated?
Tight negative feedback control based on the plasma calcium levels.
There is a Calcium sensing receptor on parathyroid cells and so parathyroid release is this tight feedback by the tight calcium levels.
For a given calcium level, there’s an optimal level of parathyroid hormone
How does PTH increase plasma Ca+??
↑ plasma calcium by resorption from bone and activation of Vit D
What does PTH do to the kidney??
Directly stimulates increased Ca reabsorption from the renal tubules.
Will increase Ca reabsorption and at the same time decreases phosphate reabsorption by the renal tubules.
Calcium: About ___% is the ionized form, normal level is about ____mEq/L.
50%; 2.4mEq/L
Where is calcitonin from and what does it do???
Calcitonin from thyroid
↓ plasma calcium
TRUE or FALSE. Only ionized calcium can be filtered
TRUE!
The rest is bound to protein or complexed to anions and too large to be filtered.
99% of filtered calcium is reabsorbed. Name the percentages for each part of the tubules and what stimulates the reabsorption
65% in PCT – (volume status)
25-30% in L of H – (PTH)
4-9% in distal & collecting tubules – (PTH)
What is the phosphate connection to the calcium filtration and resabsorption??
Plasma phosphate levels, as they increase, PTH is secreted and that will increase Ca reabsorption, decreasing Ca excretion
How does acid base balance effect Calcium filtration and reabsorption?
Metabolic acidosis will increase Ca reabsorption.
Metabolic alkalosis will decrease Ca reabsorption.
List the things that will decrease Calcium excretion
Increased PTH
Decreased ECF volume
Decreased BP
Increased Phosphate levels
Metabolic acidosis
Vitamin D
List the things that will increase Ca excretion
Decreased PTH
Increased ECF volume
Increased BP
Decreased Phosphate levels
Metabolic alkalosis
When is all of phosphate reabsorbed?
if level of filtrate is less than tubular maximum, what the tubule can handle, then all is reabsorbed
How are the kidneys involved with magnesium??
We take in about 250-300mg/day of mag only ½ is reabsorbed in GI tract, so kidneys have to excrete about ½ of the intake to maintain homeostasis.
When BP increases acutely (30-50mmHg) the amount of Na excreted will increase ____x independent of any hormones.
2-3x
Pressure naturesis and pressure diuresis. These are the mechanism where BP effects both Na and water excretion respectively. Why is this important?
To control of blood volume, ECF volume, Na+ and fluid balance.
What are the Sympathetic nervous system reflexes that effect the kidneys??
Baroreceptor & Low pressure stretch receptor
SNS activation from a decrease in blood volume that will cause a vasoconstriction of the renal arterioles and a decrease in GFR.
An increase tubular reabsorption of Na and water and also an increase release of renin
In case of Conn syndrome (hyperaldosteronism), there is an aldosterone escape mechanism, what is this??
The increase in Na reabsorption (from high aldosterone) is transient.
After 1-3 days of Na and water retention, there will be an increase in both ECF volume and BP which allow the kidneys to escape the effect of aldosterone and go back to excreting Na+ that’s lined up with the daily intake of Na+, even if aldosterone levels remain high.
The reason for this is the pressure diuresis and natiuresis
What is the effect of ANP?
Released from atrial stretch. Causes an increase in GFR and decrease in Na reabsorption. An increase excretion of water and salt.
Brønsted-Lowry theory of acids and bases, what is it???
an acid is a substance that can donate a hydrogen ion to another molecule or ion and a base is a substance that can accept a hydrogen ion from an acid
An acid-base reaction is ......
one in which a proton is transferred
What is a strong acid?
an acid that gives up H+ easily and is essentially 100% dissociated in water
What is a weak acid?
an acid that gives up H+ with difficulty and is less than 100% dissociated in water
What is acid dissociation?
the splitting apart of an acid in water to give hydrogen ion and an anion
Name 4 things that H+ concentration is significant for?
Optimal functioning of enzymes
Proper distribution of electrolytes
Optimization of myocardial contractility
Optimal saturation of hemoglobin
Normal [H+] in arterial blood & extracellular fluid =
36 – 44 nmol/liter equivalent to an arterial pH (pHa) of 7.44 – 7.36 respectively
Normal plasma [HCO3-] is
24 ± 2 mEq/L
What is pH?
A convenient means of expressing hydrogen ion concentration
pH = -log [H+] = log of 1/[H+]
[H+] = 10 to the -pH
[H+] = 10 to the (-3 moles/liter)
then the pH =
3
What are the two sources of acid??
Carbon dioxide (Volatile acid)
Hydrogen ion (non-volatile acid, fixed acid)
__-__mols of CO2 are produced each day from aerobic metabolism via…
How is there no net gain or loss of volatile acid?
Equal amount eliminated by the lungs under normal conditions
__ mEq/kg (__-___mEq) of nonvolatile acid is produced each day from......
1 mEq/kg (50-100mEq);
Protein metabolism (phosphoric and sulfuric acids)
Lactic acid (from anaerobic CHO metabolism)
Ketone bodies (from triglycerides)
Carbon dioxide formed from aerobic metabolism undergoes hydration to form carbonic acid. Hydration of CO2 in the plasma is a slow process but in rbcs this reaction is sped up by
the presence of the enzyme carbonic anhydrase.
TRUE or FALSE. Dissociation of carbonic acid to hydrogen ions & bicarbonate ions is spontaneous
What does the 0.03 stand for in the Henderson-Hasselbalch Equation?
0.03 is solubility coefficient is the CO2 in plasma
What is the definition of a buffer?
any substance that can reversibly bind hydrogen ions
Buffer + H+ ↔ H Buffer
Is the H Buffer a weak or strong acid?
Weak acid
Can dissociate back to H+ + Buffer
Reaction follows LeChatelier
What is the importance of the buffer?
80 mEq/day (50-100) of H+ is produced or ingested
Normal ECF concentration (of H+?) is
0.00004 mEq/L
TRUE or FALSE. The retention of bicarbonate is quantitatively less significant than the secretion of H+ ion.
FALSE. The retention of bicarbonate is quantitatively more significant than secretion of H+ ion.
Over ____mEq/day of bicarb are filtered, and only __mEq/day is excreted, then most of the filtered bicarbonate is reabsorbed and very little is excreted.
4000mEq/day; 1
The _________________ is the primary buffer of the ECF.
the bicarbonate buffer system
The reabsorption of bicarbonate and the excretion of H+ are both dependent on
the secretion of H+ ion.
What needs to happen in order for bicarbonate reabsorption to occur??
bicarbonate has to combine w/a secreted H+ ion.
H+ plus bicarbonate ion will form carbonic acid
In order for that to occur, equal amounts of bicarbonate ion to H+ ion must be secreted
In alkalosis, what will happen in the kidneys?
There will be a decrease in level of H+ ions and the kidneys can’t reabsorb all filtered bicarbonate so consequently more of it is excreted.
So the effect of excreting more bicarbonate is really the same as increasing the H+ ion concentration.
So the ultimate effect is w/a H+ concentration will increase, decreasing the pH back to normal.
In the case of acidosis, the kidneys will
reabsorbed all the filtered bicarbonate and in addition will reduce the elimination of bicarbonate, and in addition will produce more bicarbonate again, returning pH back to normal.
So, all parts of the tubules–except the_________ –will secrete hydrogen ions and reabsorb bicarb
descending, and the thin ascending loop of Henle
(so, the proximal convoluted tubule, the thick ascending loop of Henle, and the early distal tubule will do this)
About 80-90% of H+ ion secretion and bicarb reabsorption is in the
PCT. Only a very small amount will reach the distal and collecting tubules.
You see that out of almost 4,000mEq that’s filtered, about 3600 will get reabsorbed (85% in the proximal convoluted tubule). The mechanism for hydrogen ion secretion is
the sodium/hydrogen ion counter transport that you can see on the luminal side there. (a form of secondary active transport)
looking at reabsorption from the tubule, 1st thing is that Na ions reabsorbed by concentration gradient by Na K pump on the basement membrane side, then H+ ion are secreted by the counter-transport on the luminal side.
For every hydrogen ion secreted, a bicarbonate ion is reabsorbed into the blood, explain this process of bicarb reabsoprtion...
the bicarbonate ions that get filtered combine w/the secreted H+ ion to form carbonic acid which then dissociates to form CO2 and water, the CO2 will diffuse into the cell, combines w/H20 to form carbonic acid again and then dissociates to bicarb and H+ and bicarb will move into interstitial fluid, down concentration gradient and eventually into pertitublar capillary
Where does Primary Active Hydrogen Ion Secretion occur?
Intercalated cells of late distal tubule & Collecting tubules
What is the difference between primary active H+ secretion and the kind of H+ secretion that occurs in the PCT and LoH?
In primary active transport the hydrogen ions will move across the luminal membrane by an active hydrogen pump with ATP rather than by counter transport.
The secretion of hydrogen ions by the intercalated discs of the late distal tubule and the collecting tubule is quantitatively less than in the earlier segments, (~__%) so why is it important?
5% of the total secreted, but this mechanism becomes important for the secretion of an acidic urine.
