---start physio.lec.02.12.97---

handout: tubular reabsorption and secretion.

now we're talking about functional structure of glomerular membrane and 
such.

dynamics of filtration fig 4-4 and 4-3

we're looking at balance of pressures 

glomerular capillary pressure = hydrostatic pressure = positive driving 
force, 60 mmHg
hydrostatic pressure in bowman's space = 10 mmHg- the pressure of the 
filtrate, opposing further pushing of fluid into space
plasma oncotic pressure in glomerular capillary: pressure that is 
produced by presence of solutes esp albumin that can't pass across 
glomerulus and stays in plasma, so is an oncotic force holding water 
inside capillary = 30 mmHg-

note that "freely permeable" doesn't mean all particles pass. passing of 
any particle is dependent on pressure as well as permeability.

oncotic pressure in bowmans space = 0 mmHg
so net ultrafiltration pressure is 20 mmHg driving filtration.

only 20% of plasma only becomes filtrate. this is due to permeability 
these forces being outlined.

so in our graph we have pressure on y axis and the length of glomerular 
capillary on x axis.
the first pressure seen is the net ultrafiltration pressure, which is sum 
of others. the hydrostatic pressure inside glomerular capillary is seen 
as unchanging, almost. 62 to 58 or so. plasma oncotic pressure starts out 
at about 22 and rises so that at end of glom cap it's like 43 so net 
ultrafiltration pressure is almost zero, as pressure in bowman's space 
remeains constant at ten.
note that at the end of the capillary,, very little filtration is 
occuring, as oncotic pressure is rising and holding water in the 
capillary at that point.

fig 4-4
we see the glomerulus and the proximal tubule. aa =afferent a, ea = 
efferent a.
hydrostatic pressures are black numbers, white numbers in circles are 
oncotic pressures. note that hydrostatic pressure drops in the efferent 
arteriole (but stays similar within the capillary) to about 15, as blood 
prepares to join venous circulation.

oncotic pressure RISES in the glomerular capillary
oncotic pressure drops in efferent arteriole and at the end of venous 
circulation will be all the way back to 25. but if it weren't for the 
increased oncotic pressure in the ea, we wouldn't be able to pull water 
into peritubular capillaries and conserve it. but it does drop as water 
is pulled in.

look at hydrostatic pressure in lumen of nephron - it's 10 to 15 the 
whole time, until it gets to the bladder which is more distensible, where 
pressure will drop to 5 to 10 mmHg. oncotic pressure of filtrate should 
be zero, unless you're leaking protein due to a membrane defect or 
something.

EFP effective filtration pressure = Pgc - Pt - pi gc

Pgc: pressure in glom cap
Pt: tubular pressure
pi gc: oncotic pressure in glom cap.

structural basis of glom permselectivity fig 10-2

two major cells: endothelial and epithelial

you have lumen of capillary, capillary endothelial cells sitting on 
trilayered basement membrane, and on oustide of that is foot processes of 
epithelial cells.

let's talk about these. the endothelial cells are not simply static cells 
that give architecture to the iside of the capillary. they have large # 
of metabolic activities and have receptors for many hormones, so are 
influenced by many factors unrelated to the kidney. the BM is the central 
most selective filtering membrane and is associated w/metabolic activity 
of the epi cell, not the endo cell. the epi cell is the "nurse" cell 
which helps to maintain the BM. BM turns over all the time. not static. 
constantly being replaced. if the epi cell is damaged and that happens 
w/dz, there is a breakdown in the permselectivity of BM and then large 
solutes eg protein can leak out and be lost into urine. so epi cells very 
important!
another cell important here is the mesangial cell. in fig 10-2, they're 
the ones on top of the capiillary. there are two or three of them 
under/between BM between adjoining capillaries. mesangial cell is 
modified "do it all" cell. it assists in integrity of maintenance of BM, 
aids the epi cell, but can't replace it. it is phagocytic, can move away, 
slide under BM, and sit under foot process of epi cell if needed to 
remove foreign proteins that get stuck in membrane. it can move or send 
foot processes. it can also recognize hormones and respond to them by 
setting up a cleanup antiinflammatory system, or perform immunologic 
function, or make local hormones/cytokines to aid in maintaining health 
ofwhole network. other thing it does isactually change the shape of the 
capillary. is modified sm muscle cell, can reach under the place between 
endo cell and BM and can twist capillary to change shear force across it 
or change size and position of slits in membrane to change amt of solute 
going across. in health, they do this quietly,in dz they are inflammatory 
cells and can be destructive.

fig 4-5
the BM is made of glycoproteins that have a predominant neg charge in 
this fig, lumen of capillary is below diagram. we are shown solutes both 
pos and neg and both,and their movement. since membrane is made of neg 
charged molecules, pos charged molecules are more likely to be attracted 
and to wiggle through, aidedby their charge. so there's lots of movement 
for pos mols, and negatively charged molecules tend to get stuck in there 
and need to be removed if theydon't bounce back out. molecules of mixed 
charge have varying success and crossing speeds.
charge also changes w/dz. you can damage the membrane such that neg 
charge is removed and this changes selectivity.

slide: three BM. you can label diff sized solutes and see how they 
migrate through. ferritin coated molecules are getting stuck on endo 
cells at first, then enter first portion of BM, but it takes time to get 
through all three layers. finally you see them getting into filtrate. you 
can do this with diff molecules and see what selectivity is at work...can 
change charge, add hormones, do lots of things.

AUTOREGULATION OF GFR

realize that as GFR rises, you make more filtrate, so urine volume will 
increase...but that's decieving. not EVERY time you increase GFR do you 
increase urine volume. urine volume is a product of concentrating 
capacity of kidney. if you can concentrate well, you can increase GFR by 
20 or more percent and not increase urine volume. note that GFR closely 
follows RBF for most of the curve. very similar regulation. with the 
exception that glomerulus does have some local control mechanisms that 
arne't used with RPF. they're poorly understood, related to changes in 
oncotic pressure and metabolic activity of mesangial cell as it changes 
shape of capillary. 

AFFERENT ARTERIOLAR VASODILATOR FEEDBACK:

feedback in terms of kidney usually thought of as tubular-glomerular 
feedback. tubule signals glomerulus to change GFR. so you assume there's 
been a primary reduction of GFR. then, there will be decreased delivery 
to the distal tubule (macula densa), which will cause vasodilation of aa 
via juxtaglom. app. (JGA),  resulting in increased GFR.
so animal tries to maintain volume by increasing GFR to counter the 
initial decrease in GFR. that mechanism clearly exists and is very 
complex and not fully understood. when renin angiotensin mechanism is 
turned down, can increase GFR, but GFR and hydrostatic pressure require 
basal tone level of course. 

you'll see kidney normally regulates self to maintain basal GFR,and also 
to maintain ECFvolume (ECFV).

in volume deficiency state, kidney tries to adjust everything to conserve 
volume and keep core volume in animal. if animal has fluid overload, 
kidney will try to stop absorbing sodium and water.

EFFERENT ARTERIOLAR VASOCONSTRICTOR FEEDBACK:

assumption here is we've decreased delivery of solute to distal tubule. 
so this patient is on reduced sodium diet for five days, ok? kidney will 
recognize this and will start absorbing more sodium in proximal tubule, 
so less is presented to distal tubule, turning on renin-at system, 
producing ATII, which constricts the efferent arteriole, trapping 
hydrostatic pressure in glom cap, increasing GFR - look at fig 4-3 and 
see that hydrostatic pressure falls from 61 to 59 normally when ea is 
relaxed. but now, if ea constricts, the hydrostatic pressure is raised, 
back to 61,which widens the net ultrafiltration and increases GFR about 
3-5%. 

ARTERIOLE CONSTRICTION
fig 10-3

arterial pressure and influence on glomerular oncotic pressure. we have 
three glomeruli under a. normal influence, b. afferent a constriction, c. 
ea constriction. what are the responses?

note that normally, our filtration pressure is 10. 
in b, with aa constriction, we have a change in pressure entering 
glomerular capillary. hydrostatic pressure drops from 60 to 43, and 
oncotic pressure goes from -32 to -28, so our filtration pressure drops 
to 1 (also a reduction in hydrostatic pressure in the nephron). so we 
lose a lot of filtration capacity, and GFR drops 80-90%.
in c w/ea constriction, we have say we gave AT II, and hydrostatic 
pressure coming in is MAP 100, and you have increased pressure in glom 
due to constriction at the ea, and filtration pressure rises to 11. 
oncotic pressure has gone up to -50, see. so you gain some filtration 
capacity. GFR will increase about 10% over normal.
in real life, when you have a change in efferent you also have change in 
afferent, and not always in same direction. could have constriction of 
efferent while dilating afferent. that's a different situation.

list of hormone receptors in glomeruli:

totally illegible from here. too much light is on. 

adenosine (systemic)
AT II (systemic or local)
ANP (systemic)
dexamethasone (synthetic)
dopamine, epi, insulin, leukotrienes, norepi, many other things, many 
prostoglandins.
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