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Neuro: 2:00 - 3:00
Monday, May 4, 2009
Dr. Shafer
I.
II.
Introduction to Renal Structure and Function
Scribe: Brittney Wise
Proof: Laura Adams
Page 1 of 6
[S1] Picture
[S2] Introduction: His email is [email protected]. He might be leaving town right before the exam so make sure
that you have his email.
a. What to know for the exam?
i. What he says in lecture is the most important information and is what you should concentrate on.
ii. Don’t read the book and learn all that info. Use the book as a backup if you don’t understand something.
III. [S3] Introduction to renal structure and function
a. This is an introduction to the renal system in terms of its excretory, regulatory, and endocrine functions as an
organ.
b. We will then talk about what it is that the kidney regulates and in particular the body fluid compartments, their
volume, and their composition.
c. Then we will talk about mass balance, a general term, to try and give us an overall idea of what the kidney is
doing in terms of regulating fluid and electrolytes between these body fluid compartments.
d. Finally, we will talk a little bit, almost as a review, of the Starling forces that are responsible for fluid exchange
across capillaries. As you will see when we get into talking about glomerular filtration, one of the primary
processes of the kidney, is a process that involves the Starling Forces and involves filtration across capillary
membranes and, in this case, capillaries in the glomerulus of the kidney.
IV. [S4] Physiology of the kidney … What are the functions of the kidney?
a. Functions of the kidney:
i. Detoxification – clearing metabolic byproducts; the first thing that comes to mind is what happens when the
kidneys don’t work. Most of us think you will get poisoned. We aren’t getting rid of byproducts of
metabolism and we aren’t getting rid of potential toxins and drugs and so forth. Certainly, one function of
the kidney is detoxification; 2 particular byproducts that we will mention in the course of the lectures are:
1. Urea – the byproduct of the metabolism of amino acids
a. when amino acids are deaminated and deaminated, urea is the byproduct
b. urea isn’t further metabolized
c. it is a way of getting rid of nitrogen in the urine
d. this is how you get rid of this nitrogenous waste
2. Creatinine – it is a byproduct of creatine phosphate
a. this is also not further metabolized and has to be excreted
b. creatinine comes in part from the muscle fiber that’s in our diet that we eat and the creatine
phosphate that we break down, but more importantly it’s due to the overall turnover of muscle
in our body; we are constantly breaking down muscle and reforming muscle and as a part of
this process we are constantly producing creatinine
c. we are making a fairly substantial amount on the order of about 1 ½ to 2 grams a day
3. Kidneys are great at getting rid of toxins; the liver is good for this too but the kidneys are particularly
great because they are great at eliminating substances completely from the body
4. Notice the importance in the clearance of drugs - the kidney doesn’t really make out a difference
between what might be a useful drug and a bad drug/toxin
a. the kidney is responsible for getting rid of drugs just as if they were toxins
b. the importance of this clinically is that if you give a patient an antibiotic or you determine a
dosage of a medicine you want to give them, you assume that the kidneys and liver are
operating normally
c. if the kidneys or the liver aren’t working properly you have to adjust the doses of drugs
downwards so that you aren’t poisoning the patient with an overdose of the drug
d. there are tables that will allow you to make a quantitative estimate of kidney function and how
much the dose of a drug should be reduced
ii. Endocrine functions
1. Produces renin – this is intimately involved in salt balance in the body, control of the normal
extracellular fluid, volume, and blood pressure
2. Produces erythropoietin – this hormone acts in the bone marrow to increase the production of RBC’s
and it’s made from the kidney
a. One consequence when people develop kidney failure and they are no longer producing
erythropoietin at normal levels, they tend to become anemic. This is one of the side effects of
chronic renal disease.
3. Vitamin D – kidney is responsible for turning this vitamin into its most active form
a. Vitamin D 1,25 dihydroxy-cholecalciferol (calcitriol or vitamin D3)
Neuro: 2:00 - 3:00
Monday, May 4, 2009
Dr. Shafer
Scribe: Brittney Wise
Proof: Laura Adams
Introduction to Renal Structure and Function
Page 2 of 6
b. this active form is responsible for promoting calcium reabsorption in the kidney as well as in
the gut
c. so the kidney is extremely important in calcium metabolism
iii. Metabolism
1. The kidney is a main organ of gluconeogenesis; this is turning the normal consumption of glucose
backwards, using amino acids to generate glucose and by doing this it produces ammonium.
2. The kidney has realized that a way to get rid of excess hydrogen ions is by removing ammonium (the
kidney metabolizes ammonium).
iv. Regulation of total body mass and balance of water and ions (*the main function that we will focus on)
1. In particular we will talk a lot about Na+, Cl-, K+, pH (HCO2-), Ca2+, Mg2+, phosphate
2. What we are concerned with here is that the kidney is the primary organ that’s going to balance what
we take in via our diet in terms of these important ions and water, is going to balance our output of
those substances to the amount that we are taking in. This is the concept of mass balance.
3. The kidneys are trying to achieve is a homeostasis of the internal environment. This means
maintaining a constant composition of the body in terms of the concentrations of these important
electrolytes and other solutes and the body fluid levels, keep them constant and at an optimal
operational level.
V. [S5] Whole Body Mass Balance
a. Let’s put this in a really simple overview of the body.
b. With homeostasis, we want to keep in the body the total content of the various ions and water and so forth, we
want to keep that constant and at the optimum level that’s defined as homeostasis.
c. We are constantly taking in these substances in the form of food and drink. Furthermore, with respect to urea
and creatine and other substances, we are constantly producing some of these by metabolism. All of these are
tending to increase the total body content.
d. You have to match this production and intake with an output. Some of this is done by the following:
i. Respiration (for example this is good for removal of CO2 but not really good for the removal of Na+)
ii. Perspiration – this can help us but it varies; it depends on how much you are sweating and your
temperature
iii. Feces can also do this but we put out relatively little salt and water in this form and it’s not as well regulated
as the kidney
e. The main way that we are going to achieve this balance between output of these substances and the rate that
they are taken in or produced by metabolism is excretion in the urine.
i. This is the thing that can adapt over the widest range and the thing that is most closely regulated that is
going to achieve this overall balance.
VI. [S6] Mass balance by the kidney
a. The kidney too has to maintain a mass balance in the sense that what goes in must come out.
i. What goes in? The arterial inflow coming in through the renal artery.
ii. What goes out? The venous outflow plus the little contribution of the lymphatic drainage to the venous
outflow. What also goes out is what’s excreted from the body via the ureters and the bladder (the lower
urinary tract).
b. The difference between the arterial inflow and the venous outflow is what goes out in the ureter.
i. Let’s look at the concentration of water. A typical plasma flow of fluid flowing into the kidney via the renal
artery is about 650 mL/min. The typical urine flow is about 1 or 2 mL/min. What does this mean in terms of
mass balance? How much is flowing back to the body?
1. It’s the 650, minus the 1 or 2 you lost, and is about 648 or 649 flowing back. So what the kidney is
doing is excreting some of the fluid flow in the form of urine.
c. If you take an extreme example of a substance as often is used in the research setting to measure renal plasma
flow. This is a substance called PAH (para-aminohippurate). This substance is not normally present in our
plasma but if it were, we would fine that when PAH is present in the arterial inflow into the kidney, we would find
none is present in the venous outflow. In other words, the kidney operates so efficiently in getting rid of PAH
that all of the PAH that flows into the kidney winds up going out in the ureters. We say that this is completely
cleared from the kidney.
i. This involves 2 processes. The process of filtering the PAH and also of actively secreting it or
metabolically using energy to put it into the final urine.
VII. [S7] Superficial and juxtamedullary nephrons
a. Let’s put this in terms of the nephron. The kidney’s parenchyma consists of individual functional units that we
refer to as nephrons.
b. The nephrons all have their glomeruli (aka blind or beginning end) out in the cortex (outer region of the kidney).
Most of the blood supply also goes to the outer rim of the kidney.
Neuro: 2:00 - 3:00
Scribe: Brittney Wise
Monday, May 4, 2009
Proof: Laura Adams
Dr. Shafer
Introduction to Renal Structure and Function
Page 3 of 6
c. The nephrons are in 2 general forms.
i. Some of the nephrons have short loops of Henle that extend just into the outer part of what we call the
medulla (inner region of the kidney).
ii. Some have very long loops that reach all the way down to the tips of the pyramids and then into the
calyces where the urine is collected.
d. Let’s just consider these nephrons in a very simplistic form where they have a filtering end up in the glomerulus
and a defined length of the tubule. What we will be talking about next are the processes of 1st filtration.
i. Filtration is a bulk process whereby fluid and small solutes, things smaller than the size of albumin, are
being filtered out of the blood just like capillary filtration.
ii. Then we have a process of reabsorption, where it turns out that most of the substances like salt and water
are actually returned right back to the blood stream. This is the process of being transferred through the
epithelium back to the blood and being taken up in the paratubular capillaries that surround these
nephrons.
e. For some substances for example PAH, there is also active energy requiring processes that can secrete these
substances. In the case of secretion, the most substances that are secreted are ones that they body wants to
get rid of or is treating like potential toxins. So, toxins and a lot of drugs are actively secreted and the kidney
works to clear the body of these substances.
f. What we are really concerned with though is what we really get rid of. What’s going to determine what we finally
get rid of?
VIII. [S8] Mass balance in the kidney
a. This excretion rate that we have here is going to be the difference between what’s filtered up here in the 1 st
place, minus what we reabsorbed, plus whatever is secreted.
b. What determines the rate of filtration and what things might alter it. This is sort of a gross/mass process of
filtration.
c. Most of the regulation of the excretion goes on in determining the rates of reabsorption and filtration. So it turns
out that largely and in most of our day to day operation of the kidney, the filtration rate remains pretty much the
same but reabsorption and secretion are what are altered on a day by day or even minute by minute basis so
that we can achieve in the kidney/nephron a mass balance.
d. There is a mass balance where we are making the excretion what we want to and making it appropriate for
maintaining whole body homeostasis by adjusting rates of absorption and secretion.
e. We need to learn a little bit about the details of how substances are reabsorbed or secreted and how those
processes are in turn regulated by hormones and other factors so that the final excretion rate can be made
optimal and can lead to then homeostasis of the body’s fluid volumes and the body fluid composition.
IX. [S9] Body Fluid Compartments
a. Where/what are these body fluid compartments, how big are they, and what are their compositions?
b. We can divide the total body water into these into 3 different compartments
i. Intracellular fluid – fluid that’s inside the cells
ii. Extracellular fluid - on the outside of the cells (can be divided into 2 further compartments that are
separated by the capillary endothelium)
1. Inside the capillaries are blood plasma, the RBC’s, and leukocytes.
2. You also have the interstitial fluid that is outside the capillaries that surrounds the cells.
c. What are the volumes of these compartments? The volume of these compartments is figured out the easiest by
the “60, 40, 20” rule. This means that approximately 60% of the total body weight is water.
i. So if you take a 70 kg person, they have about 42 liters of water.
d. Now, whether it’s 60% or not differs for a lot of people. It turns out that a big factor that determines the % of
body water is the amount of adipose tissue that you have. Why? Because fat doesn’t contain much water.
i. Heaver individuals have a lower percentage of body weight that’s water.
ii. Leaner people have higher percentage of water.
iii. Women have a lower percentage of body weight that’s water (because women tend to have more subdermal adipose tissue). They have slightly higher lipid content in their body and therefore slightly lower
percentage of water.
e. As far as the distribution between inside of cells and outside of cells, about 40% (2/3rds) is inside of the cells,
and about 1/3 is in the extracellular fluid representing about 20% of the body weight.
f. If we further break up this extracellular compartment we find that about ¾ of it is in the interstitial fluid and about
¼ in the plasma.
g. Remember total blood volume in a 70kg individual is about 5 liters and with a typical hematocrit of about 40%
that means that there’s about 3 liters of plasma and it would give you roughly on the order of about 11-12 liters
of interstitial fluid.
X. [S10] Composition of intra- and extracellular fluid compartments
Neuro: 2:00 - 3:00
Scribe: Brittney Wise
Monday, May 4, 2009
Proof: Laura Adams
Dr. Shafer
Introduction to Renal Structure and Function
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a. What is going to determine the differences between the 2 is the characteristics of the cell membrane. We know
that the cell membrane is very selectively permeable and doesn’t let everything through. It also has specialized
transport processes and one of the most important ones is the sodium/potassium ATPase pump that pumps
sodium out into the extracellular fluid and potassium in to the intracellular fluid.
b. What’s the relative composition of the intra- and extracellular fluid volume? Note: the chart differentiates
between the intracellular and extracellular components and then it separates the anions and cations.
i. The first big difference is the cations:
1. Sodium – high in the extracellular and low in the intracellular
2. Potassium – typical plasma values in the range of 3.5 to 5 millimoles per liter; much higher and
ranging up to 150 millimolar inside of the cells
3. Magnesium – important intracellular ion; we need this for ATPase’s to work for the hydrolysis for ATP
4. Calcium – present but at low concentrations inside of cells; it is sequestered largely in the
sarcoplasmic reticulum and in mitochondria
ii. The anions are:
1. Chloride – 1st main anion in the extracellular; about 100 millimolar
2. Bicarbonate – 2nd main anion in the extracellular; about 25 millimolar
3. Phosphate –
4. Sulfate
5. Di-carboxylic amino acids
iii. Chloride and bicarbonate are pretty permeable across most cell membranes. We also know that the inside
of cells is negative. So, if chloride and bicarbonate can move fairly passively and you have a negative
charge inside the cells, which way do you think chloride and bicarbonate are going to go? They will move
toward the outside of the cell. If the chloride and bicarbonate are distributed passively, their concentrations
inside a cell are much lower than on the outside of the cell.
iv. Then you say that you have to have electro-neutrality. You have to have as many anions as you do
cations, so what makes up the anions inside a cell?
1. It’s largely inorganic phosphate and organic anions like ADP, ATP, and all of the phosphorylated
intermediates of the glycolytic pathway and citric acid cycle.
2. All of these large organic ions and also proteins, because most proteins have a net negative charge,
make up the most of the charge. The important part is that these are big molecules and they don’t
move across cell membranes, they are trapped inside the cell. This is one reason you have to set up
the sodium/potassium ATPase so you can balance the osmotic effect that would be produced by
these intracellular impermeable anions by distributing the other cations appropriately so cells don’t
just swell.
a. This is actually what happens when cells become ischemic. Na/K ATPase can’t work as well.
These ions begin to redistribute and then you have the un-buffered effect of the intracellular
anions that are impermeable and causing cells to swell and eventually to lyse. Cells that lyse
are the final consequence of ischemic damage.
3. So proteins and big organic ions are the primary thing inside the cell.
c. SQ: The chart shows calcium in the intra- and extracellular compartments. Can you explain this?
d. Answer: Yes calcium is present in both. The calcium is present at about 1-2 millimolar depending on whether
you are talking about bound or free concentration extracellularly. Intracellularly, its concentration is in the
nanomolar range when you are talking about its free concentration. There is more calcium inside of cells but it’s
bound up in the sarcoplasmic reticulum and the mitochondria. (He then said that magnesium was more
important than calcium in terms of its free concentration).
XI. [S11] Body fluid compartments
a. Let’s take a look at the distribution of fluid between the plasma and the interstitial fluid.
b. We said the membrane between the 2 is the capillary wall.
c. We know that the capillary walls are fairly permeable. The only thing that doesn’t cross this is the plasma
proteins.
i. We know that we have albumin and globulins in the plasma, and actually they are macromolecules so they
constitute about 6-7% of the volume of the plasma. In terms of millimolar concentration it’s something on
the order of 1-2.
ii. The importance of the presence of the colloid in the plasma is these proteins exert an osmotic effect. They
are the only thing that can exert an osmotic effect across this leaky capillary wall because they are the only
thing that’s impermeable.
iii. So these proteins are attempting to pull things into the capillary.
XII. [S12] Balance of Starling forces across capillary membranes
a. This should be a review from the cardiovascular tract.
Neuro: 2:00 - 3:00
Scribe: Brittney Wise
Monday, May 4, 2009
Proof: Laura Adams
Dr. Shafer
Introduction to Renal Structure and Function
Page 5 of 6
b. We have inside of the capillaries blood pressure. The pressure is much lower than the systemic circulation
because it’s been dropped by the resistance vessels (the arterioles).
c. We have about a +30 or +40 at the arteriole ends of the capillaries (systemic capillaries throughout the body).
d. We have a little bit of pressure in the interstitial fluid, but it tends to be slightly negative if anything. In other
words, it’s lower than atmospheric pressure in the tissues.
e. What’s tending to keep this pressure from driving fluid out of the capillaries and into the interstitial fluid (which
would cause edema) is the colloid osmotic pressure given here by the symbol “pi” that is exerted by the plasma
proteins. That osmotic effect is what tends to draw fluid into the capillaries.
f. Edema is a swelling of the interstitial fluid.
g. We have a net of about 26mm of mercury oncotic pressure or colloid osmotic pressure. Some of these proteins
do leak across the capillary wall. It’s not perfect and those proteins exert some colloid osmotic pressure out
here in the interstitial fluid. The net effect is that of about 23 that’s opposing this net hydrostatic filtration
pressure.
h. As we go toward the venous end of the capillaries the pressure is reduced just by the resistance of the capillary,
there is less hydrostatic pressure, and the colloid osmotic pressure is somewhat enhanced by the filtration of
fluid that occurs.
i. Overall along the capillary, the net effect is the hydrostatic pressure (the blood pressure) is tending to cause
fluid to ooze out into the interstitial fluid and that would cause edema.
i. The reason this normally doesn’t happen is because the proteins in the capillary blood can suck the fluid up
out of the interstitial fluid.
ii. Now this isn’t perfect. He said there was leakage of proteins out which gives you a colloid osmotic
pressure out here in the interstitial fluid and if you do the arithmetic you will find that on the average, there
is a little net pressure for filtration.
iii. Most capillaries are constantly oozing a little bit of fluid and how do you get that back? Well you have the
lymphatic system which picks up proteins that leak out of the capillaries. It picks up the excess of filtered
fluid and it returns it to the venous circulation.
j. The net result is that you can see things that would tend to favor filtration like increased blood pressure. For
example if you have an injury, inflammation, or a burn or something like that in a localized area, you might
increase filtration by opening the capillary sphincters. This is why an area that you injure turns read because you
have vasodilation, pressure is going up, the number of capillaries being perfused is going up, you have
increased pressure which will increase filtration which is what causes the swelling that you get with an injury.
k. On the other hand, capillaries might become permeable. That happens in injury. It also happens when
cytokines are released in response to irritation or inflammation. Capillaries get leaky to the proteins. They leak
out, there’s not enough colloid osmotic pressure to oppose filtration and you begin to form edema.
XIII. [S13] Volume contraction and expansion
a. Here are some examples of how we can have changes in the extracellular fluid volumes that we can call volume
contraction or volume expansion. He is going to talk about it in terms of the extracellular fluid and the
intracellular fluid. If this were a typical 70kg person there would be about 14 liters of extracellular fluid and about
28 liters of intracellular fluid. 1st he will give us a couple of examples of volume contraction.
b. By volume contraction we mean the reduction of volume in the extracellular fluid volume.
i. One possibility is a loss of isotonic extracellular fluid, for example, with diarrhea. It turns out that diarrhea
and gastric contents in vomiting are pretty nearly isotonic and they have a lot of sodium. So what you are
losing is essentially an isotonic sodium chloride solution. When this happens, what that’s going to do is
reduce the volume of the extracellular fluid by the volume of the diarrhea fluid or of the vomit that you have
lost. This will reduce its volume, but it’s not going to change its osmolality because the fluid that has been
lost is isotonic.
ii. Now on the other hand let’s suppose that somebody in the desert doesn’t have any access to water? They
are going to lose water from their plasma by sweating, respiration, humidifying the arid air that they are
taking into their lungs. So, their extracellular fluid is going to lose water and its osmolality is going to rise.
As soon as the osmolality of the extracellular fluid rises cell membranes are very permeable to water, and
water is going to go out of the intracellular compartment to the extracellular compartment so that both the
extra and intracellular fluid compartments are going to be reduced in volume. If you are losing pure water
what is going to happen to the osmolality? It is going to go up. You are losing water, solutes are more
concentrated, and because the cell membranes are very permeable to water, the intra and extracellular
fluid always have the same osmolality because water is just going to distribute quickly between the two of
them in response to any osmolality difference.
c. Let’s look at volume expansion.
i. Let’s look at someone who’s just been given a liter of isotonic saline intravenously. The saline is isotonic
so it has the same osmolality as the extracellular fluid. So what is this going to do? It’s going to stay all in
Neuro: 2:00 - 3:00
Scribe: Brittney Wise
Monday, May 4, 2009
Proof: Laura Adams
Dr. Shafer
Introduction to Renal Structure and Function
Page 6 of 6
the extracellular fluid because its sodium and chloride and they are kept outside of the cells. So it’s here in
the extracellular fluid that the extracellular volume is going to increase by the volume of the infusion and
nothing is going to happen to the intracellular fluid. Sodium and chloride aren’t going to move in, there is
no osmotic gradient, so water isn’t going to shift in or out.
ii. On the other hand, let’s see what happens to somebody who’s taken in a very salty meal and hasn’t drunk
enough water. In this situation you are adding sodium and chloride hypertonically to the extracellular fluid.
What will this do? It will increase the volume of the extracellular fluid and it will increase the osmolality. As
that osmolality increases what’s going to happen to the intracellular fluid? It is going to go from the inside
to this hypertonic compartment so that the osmolality of the intracellular fluid rises.
d. As we will find out, normally the kidney is operating to try to maintain a normal volume and composition of the
extracellular fluid but we have to realize that because of the high permeability of cell membranes, water is going
to distribute between those 2 compartments and solutes are going to move between those 2 compartments. So,
by regulating extracellular fluid the kidney is indirectly regulation intracellular fluid as well.
XIV.
[S14] Key Points
a. Just to summarize the key points. He read directly from the slide (copied for you below).
b. The role of the kidney as an excretory, endocrine, and metabolic organ – and in the maintenance of body fluid
volume – homeostasis
c. Concept of mass balance in the body, the kidney, and along the nephrons
d. Body fluid compartments – the “60, 40, 20, rule”
e. Differences in intra- and extracellular fluid compartments
f. Starling forces determine the distribution of fluid between plasma and interstitial fluid
g. Types of volume expansion and volume contraction
[End 40:45 min]