---start physio.lec.2.18----

tubular reabsorption finishing up

we talked about primary, secondary and tertiary transport. re figure 2.9, 
all transport of water is passive and is secondary to transport of 
solute, and transport of solutes are linked to transport of sodium.

glucose doesn't play a role til the distal tubule.

going to Na+Cl- reabsorption, fig6.1 p 11

compare the filtered load with tthe numbers along the tubule. about 
60-70% is resorbed in proximal tubule, about 20% in the straight proximal 
tubule, 6% in distal conv, and 2.3% in the collecting tubule. so only 
about .5 % left in urine.

sodium is reabsorbed with chloride due to charge relationship. the two 
follow each other closely. there are a number of factors influencing Na 
and Cl reabsorption.

changes in GFR- if GFR is increased for any reason, usually too much Na+ 
is being presented to kidney, and kidney will probably start excreting up 
to 5% of sodium.

aldosterone increases reabsorption of sodium.

increased dietary intake of sodium increases filtered load, increasing 
sodium excretion.

increased serum sodium concentration also reduces sodium reabsorption.

increase in BP is usually seen as volume expansion so kidney will turn 
dwn Na+ reabsorption. same w/increased blood volume. ECF volume increasse 
also reduces Na+ reabsorption.

serum potassium concentration is minor

acid base balance plays a role

a variety of hormones: aldosterone, ANP, prostoglandins - all work 
differently and may antagonize eachother. ANP and prostoglanddins reduce 
Na+ reabsorption, aldosterone increases.

diurnal rhythm - kidney tries to excrete more or less sodium in 
anticipation of dietary intake. when you eat, kidney starts changing 
reabsorption rate in anticipation...

Three major parts of nephron:

proximal tubule: reabsorption not the same here as it is elsewhere. here, 
reabsorption is considered isosmotic. the osmolarity of the fluid coming 
in is the same as plasma, and at end of tubule, the osmolarity of the 
fluid is still the same.it isn't changing even though almost 70% of 
sodium is resorbed - because water follows sodium so osmolarity stays the 
same.

see fig 6-3 - active transport of sodium into interstitial space. water 
follows passively. when space gets large there is increased hydrostatic 
pressure in lateral intercellular space, and water will cross BM and get 
into peritubular capillary.

there is a lot of bicarb absorbed in prox tubule also. sodium coming from 
filtrate will be either NaCl or NaHCO3. thereis a very active bicarb 
absorption system here also. sodium and bicarb dissociate in the lumen. 
the bicarb becomes carbonic acid and is broken into CO2 and H2O in the 
lumen, and CO2 is absorbed. this conversion in the tubule, and then 
reforming of carbonic acid in the cell and dissociation back into bicarb 
and H+ is regulated by carbonic anhydrase which is made in the brush 
border of the cell. the bicarb ion is then sent into the ECF. this allows 
for most of filtered bicarb to be taken out before reaching the end of 
the prox. tubule. this isn't NEW bicarb being formed, it'sjust 
conserviing the bicarb that came to the kidney. if this isnn't done, the 
animal goes into a state of acidosis, so filtered bicarb must be 
reclaimed.

the other anion that is going to be involved in this prox tubule is 
chloride. some Na comes linked w/Cl-. there is a preference for sodium 
bicarb reabsorption, and sodium chloride gets second seat, but does get 
absorbed.sodium is actively pulled across, and cloride is passively 
pulled with it. while a lot ofthe filtered chloride is absorbed here, not 
all of it is. so a system downstream is there to absorb it. but there is 
very little downstream bicarb absorption, so that has to happen here in 
proximal tubule. so youcan see fig 6-10....

[i missed this part, had to tell workmen to go away]

group of organic metabolites; lactate, ketone, etc, which body makes all 
the time - table 7-1: these are reabsorbed in conjunction w/sodium as 
well. 

what happens once the sodium gets out of the cell across the basement 
membrane into the interstitial space? water and sodium build up between 
cells until pressure pushes them across the basement membrane and into 
the peritubular capillary. wwhat pulls sodium and water into capillary is 
the oncotic force w/in peritubular capillary (extension of ea) which is 
generated by removal of lots of water across glomerulus but no removal of 
albumen. so oncotic pressure in peritubular capillary is high, which is 
good, 'cause it sucks in sodium and water - a passive process. not 
active. sodium reabsorption is active only at tubular cell level. now, 
osmotic forces here are low, so this is depending entirely on oncotic 
force. 

this is efficient early in peritubular capillary, and less efficient 
later, as pressure (oncotic) goes down as water is drawn in. 

now, what if animal has low serum albumen concentration? that animal has 
reduced ability to reabsorb sodium/water. 
because of dilution of oncotic pressure in normal animal, there is very 
little oncotic force beyond the prox tubule - need another  mechanism 
downstream.

REABSORPTION IN HENLE"S LOOP
this is totally different from proximal tubule. it's a passive system. 
we're discussng descending limb, bottom part and ascending limb.

first consider the osmolarity of the fluid inside the limb of henle. you 
can see the fluid entering is isosmotic. the fluid that passes down, 
across, and up, will become  hypertonic in direct relation to the 
hypertonicity of the interstitium - medullary interstitium is supposed to 
be kept hypertonic, not like the isotonic cortex. so here, a lot of water 
goes out into interstitium, passively, due to tonicity, due to urea, 
sodium, and chloride. at bottom, hypertonicity is greatest. as fluid 
starts moving up ascending limb it becomes diluted. some sodium and 
chloride is taken into medulla passively, and a lot of urea enters 
ascending limb. urea is critical to maintain hypertonicity, and 
hypertonicity is essential for concentrating the urine. see fig 6-6 for 
numbers of osmolarity.remember the solute gradient in the medulla. it 
gets more and more hypertonic. anyway, at the top of ascending limb, the 
osmolarity in there is back to 300, but has collected a lot of urea.

note that ascending limb of henle has most permeability to sodium (in jg 
nephron). the small cortical nephrons don't have much sodium permeability 
in the looop of henle.

DISTAL TUBULE:

four major sites. thick ascending limb, cortical bulk, cortical 
collecting duct, medullary collecting duct. see fig 6-7. MD==macula 
densa. first look at osmolarity inside lumen. we started out at the end 
of ascending limb w/osmolarity 300. the thick asending part of distal 
tubule is "diluting segment" of nephron. osmolarity becomes LOWER than 
plasma - goes to about 100, then starts increasing back to about 300. 
recall that cortex interstitium is all at 300. then, it starts 
concentrating again and ends up at about 1200-1400 mOsm.

first look at location of Na/K ATPase. this is active sodium transport 
again. you have thick ascending limb which has huge na/k atpase system, 
in both long and short nephrons. this is also present in the collecting 
duct, to a lesser degree. so, in thick ascending limb, there is that and 
also a chloride reabsorption active transport at this site - which 
promotes reabsorption of sodium as well. realize chloride pump is on 
tubular side, and sodium pump is on basolateral membrane. see fig 7-15.

fig 6-7 is diluting segment of nephron. how does this filtrate become 
dilute? on left is medullary active transport of chloride with secondary 
sodium transport. ths membrane isn't that permeable to movement of water 
out. water can't follow sodium and chloride. so the filtrate becomes very 
dilute. when sodium and cl get into interstitium, they get trapped with 
vasa recta,which are following this limb of henle - they go down while 
limb goes up. the vasa recta pick up na and cl and take them down deep 
into medulla, where they go out into interstitium to maintain 
hypertonicity of medulla.  no one is sure how they get out into 
interstitium. and most of it stays in interstitium rather than leaving.

next item: role of aldosterone- it enhances reabsorption of sodium in 
distal tubule and collecting duct, helping to reabsorb the final 3-5% of 
filtered load of sodium. w/o aldosterone, you will lose that much sodium 
and tht is disastrous- can't lose more than .5% of sodium w/o losing 
control of ECF and becoming dehydrated.

next group of cells are specialized group of intercalated cells - 
skipping this. fig 7-15 - active transport of Cl shown another way. 
there's leakiness. ions may not always do what you think they will. can 
come in and go backout.

back to intercalated cells. these cells have na/k atpase pump at 
basolateral membrane, and also have carbonic anhydrase linked H+ 
transport. fig 6-7a. in brush border tubular side of cell, there is a 
pump for bicarb...
there is antagonism for excretion of H+ and K+ - for every Na that comes 
in you can get rid of either an H or a K not both. so this part oftubule 
is under influence of other factors, like [K+] in entire vascular pool, 
and aldosterone, and amt of H+ in body as seen by renal tubule. tubule 
wants to get rid of extra H+ to keep acid/base balance. so this part of 
distal tubule helps make acid urine/maintain balance. again it is all 
tied to sodium. 

collecting duct: see fig 6-7b. basically similar to intercalated cells of 
distal tubule. hydrogen/potassium exchange. overall sodium balance seen 
in 6-7b - nice schema, includes hemodynamic events of RPF, GFR, BV, ECFV, 
filtration of solute, reabsorption of Na+. includes some hormones.

with sodium intake, serum sodium rises, causes thirst, with cuases us to 
drink/expand volume. this affects volume receptors in heart, kidney, 
liver, brain. they start making natriuretic peptides, which go to kidney 
and reduce Na reabsorbtion. also causes decrease in sympathetic tone, 
which decreases renal arterial tone, reducing vascular resistance, 
increasing GFR for a few hrs, leading to increased delivery of Na+ to 
kidney (for excretion) causing increase in peritubular hydrostatic 
pressure, decreasing tubular reabsorption of Na.
volume expansion also increases perfusion pressure, turning down renin, 
at II, and aldosterone prod, also causing decreased tubular reabsorption 
of sodium. filtered sodium load is obviously increased by eating ---see 
the diagram 6-7b :)

all of this makes intuitive sense and works pretty easily...review and 
understand.

----break----

moving on to potassium.
there are some relationships between Na and K but they are quite 
different. K+ has bidirectional transport and that changes everything. it 
can be reabsorbed or actively secreted. sodium can only be reabsorbed. 
fig 8-1.
potassium is an intracellular electrolyte. there is a small amt of it in 
ECF. cells have high concentration of K+ compared to plasma. plasma conc 
== 5 mEq/L.
potassium stores in cells are in equilibrium with the small amt of EC K+. 
dietary intake about 100 mEq/day. our gut will absorb about 65or 70 mEq 
of that to present to kidney. we will excrete some of that in urine and a 
very small amt in stool. about 92 in urine and 8 in stool, out of 100. so 
we usually think of potassium as being regulated through the kidney. but 
since the kidney can reabsorb and secrete potassium, the kidney [...]

if you have a decrease in intake, kidney will absorb proportionally more. 
if you have dietary excess, kidney will get rid of extra. it can turn 
down reabsorption and turn on active secretion. very efficient. so in a 
nutshell that's what happens. how does it happen? well first go back to 
na/k atpase pump. there are two basic mechanisms existing simultaneously 
- the neutral exchnage pump at basolateral membrane - sodium pumped out 
and potassium pumped in or electrogenic mechanism, where sodium is pumped 
out and K+ follows passively. the former has a nice fixed regulated 
movement of potassium into cell. if latter, passive system, then it's 
possible a different  cation could replace potassium, and then we can't 
move it into cells as efficienty. purists would say you have to have 
neutral exchange to have good control. we think that both are working 
together though.

tubular secretion fig 6A.let S = potassium. the filtered load is going to 
be GFR x [S], but is lower than sodium since plasma potassium conc isonly 
about 5 meq/L. the filtered load can be absorbed or secreted. in 6A we 
see potassium being secreted. so you end up with MORE potassium in the 
urine than was originally filtered. we're pulling it out of the 
peritubular compartment via sodium/potassium pump.

prox tubule. potassium coming in, high conc in cells. brush border; 
active K+ reabsorption pump, turned on when we have reduced dietary K+ 
intake, woudl reabsorb all potassium and not secrete. this changes every 
time you eat a meal, the pumps turn up and turn down.

reabsorption in limb of henle: 29-9 only 5-10% of K+ handled here; 
passive transport. fig 6-11 distal tubule, younow have aldosterone 
enhancing potassium secretion. aldosterone feedback system...aldosterone 
is produced in adrenal glands all the time, at low rate. there are two 
copmartments to consider in terms of potassium and aldosterone in kidney. 
first is plasma [K+] vs aldosterone (top graph).if there is excessive 
[K+], eg from recent meal, that will change amt of aldosterone being 
produced. youw ant to excrete more potassium, and aldosterone enhances 
that, so you want to increase amt aldosterone released from adrenal gland 
and that does happen. now, look at amt aldosterone presented to distal 
tubule vs amt K+ excreted in urine (bottom chart). system continually 
adjusts itself minute to minute.

[K+] usually 3.5-5.0 in serum. if goes above 5, serum aldosterone level 
rises quite sharply. aldosterone comes to tubular cell from the 
peritubular capillary, to receptor on basolateral membrane, turns on a 
bunch of stuff in cell, regulating potassium channels, increases number 
of available potassium channels, some active and some passive, on brush 
border side.

aldosterone has major role in distal tubule for potassium, but does 
affect potassium reabs throughout tubule (but for sodium only distal 
tubule). 

relationship of potassium to acid/base balance. fig 8-28 if htere is  a 
control state, we're excreting about 24% of filtered load of potassium. 
in metabolic acidosis, there's NO potassium excretion - because the 
intercalated cells know about the acidosis, and instead of secreting K+ 
they are preferentially putting hydrogen into the filtrate, which 
disallows movement of potassium - can only move either H+ or K+. if 
acidosis is only a few hrs, there won't be a change in plasma potassium 
concentration. if acidosis lasts more than 12 hrs, the animal will become 
hyperkalemic. this will cause release of aldosterone, but that won't 
help. potassium will go up to say 10, when it becomes very dangerous.
a respiratory acidosis has a minimal effect on potassium handling in 
kidney - will secrete about 27%of filtered load. but metabolic ALKALOSIS 
causes excretion of about 64% of K+. this is because there isn't much H+ 
to excrete, so the intercalated cells have to secrete K+ instead. these 
animals are at risk of hypokalemia. if you have a mixed met/resp 
alkalosis, you excrete 75% of K+. this is uncommon in domestic animals. 
acidosis ismore common.

. animals w/different levels of arterial pH. 7.1 (acidotic), 7.4 
(normal), 7.5 (alkalotic). animals that have acidosis excrete LESS 
potassium than others.

fig 8-24 shows what happens if you change dietary potassium intake. low 
potassium diet vs control vs high potassium diet. we're looking at 
potassium delivery vs secretion. low K+ diet - no potassium excretion, 
low distal tubule delivery of potassium (all was reabsorbed in prox tub). 
high potassium diet - LOTS of secretion, increases with delivery.

that ends potassium. 
now. acid base.

p 16 of handout. overview. 

the two organs maintaining acid/base balance are lung and kidney.lung can 
change quickly by changing respiratory rate but can't excrete ion or make 
new ion - only kidney can do that, but kidney is slow, takes hours or 
days.lung is fast.

relation  of tubular bicarb reabsorption and H+ excretion:
primary active transport of H+ in tubular epithelium. carbonic anhydrase 
is in the cell as always. acidotic animal wants to excrete H+ into urine. 
CO2 is absorbed by cell, and H+ secreted.

fig 8-4 p 15 reabsorption of bicarb - primarily in prox tubule, linked to 
sodium potassium pump. 

on p 16 we discuss first mechanism for reaabsorption of bicarb - 
reabsorption of preformed bicarb. bicarb reabsorption is very efficient 
in proximal tubule. three factors influence it. first is seen in fig 8-6 
- pCO2. as pCO2 increases, bicarb reabsorption increases as well. normal 
pCO2 is about 40 and is always +/- 10 of that (or animal dies). so bicarb 
reabsorption is in a close range. if pCO2 is low, resorption of bicarb is 
low, if high, high. 

also plasma K+ concentration - see fig 8-7. assume we're talking bout 
increased dietary intake of K+ resulting in increased concentration. then 
more K+ is presented to kidney. this would influence H+ excretion 
(reducing it). if you can't excrete H+, you limit reabsorption of bicarb. 
so increased K+ reduces bicarb reabsorption.

also plasma Cl- concentration. primarily a function of [Cl-] seen in 
proximal tubule. normally, Cl- 110-120 mEq/L. if increased a lot, that 
lowers bicarb reabsorption. this is rare. if it does happen, excessive 
Cl- delivered to filtrate, that Cl is now competing for reabsorption 
w/bicarb, lowering bicarbonate reabsorption. but this rarely happens,see. 
would be an abberation.

now, another way to keep acid base balance- creation of titratable acid 
and formation and reabsorption of newly formed bicarb. you can make 
bicarb and excrete H+ by involving phosphate. there is a small amt of 
Na2HPO4 in filtrate (from serum inorganic phosphate). this molecule comes 
into the filtrate and sodium dissociates and can be pulled into cell, 
leaving NaHPO4- +H+ (H+ comes out of cell from an H2CO3). then we get 
NaH2PO4 in filtrate which is "titratable acid" - then we absorb the HCO3- 
and the sodium and put them together into a new molecule. this runs all 
the time.

also: ammonia generation and excretion of H+. entirely different 
system....
still depends on carbonic anhydrase as above, and na/k atpase. this 
system uses deaminization of AAs eg glutamine. breaks down AAs and we 
form NH3 which diffuses out of cell, picking up free H+ becoming NH4 
which binds w/sulfates. when NH3 is made, it is highly fluid/permeable. 
once it gets into the lumen it becomes NH4 and is trapped, can't leave 
tubular lumen. so in acidotic animals, if there is adequate carbonic 
anhydrase and Na pumping, we just have to turn up the break down of AAs 
to generate more ammonia, which becomes ammonium, which causes excretion 
of H+. a bicarb ion is absorbed in conjunction w/this.

acidosis increases this activity 3-5 x.

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