S2 Physiology Unit 2 - Renal Physiology:RBF, GFR, AKI

What is the pathway of urine from the nephron to the bladder?

nephron → minor calyx → major calyx → renal pelvis → ureter → bladder if you took the cross-section of the kidney basically the major working areas going to be the renal cortex and then the renal pyramid which contains the nephron. In the middle portion of the kidney is the renal medulla, and inside these renal pyramids are going to be a whole bunch of cells that make up a Nephron. The nephron is basically what does the work for the kidney. Inside the renal pyramids, the nephron is all going to collect filtrate in a place called the collecting duct. The collecting duct is kind of like a gutter on your house where rainwater is going to come to that one spot. The collecting duct is going to take any water that the nephron hasn't reabsorbed and it's going to collect it. This is where the kidney is basically going to fine-tune things. When the kidney is fine-tuning things in the collecting duct, it can either make a very large volume of urine that is clear and very dilute or it can make a smaller volume of urine that is very dark and very concentrated. Therefore, that is kind of what the job of the collecting duct is going to be. whatever we don't reabsorb will leave that collecting duct and come into this area called the minor calyx, and then dump into the major calyx. It will then move from the major calyx into the renal pelvis and basically, at that point, we're out of the kidney tissue itself. These last areas we have just talked about are sort of like funnels that are collecting the urine and then eventually that urine will go down the ureter which is attached to the bladder.

What are the two mechanism that encompass renal intrinsic auto-regulation?

the myogenic mechanism and JGA: Tubuloglomerular feedback.

Key Points

1.Filtration is the first step of urine production. The filtrate proceeds through a 3-layered barrier that restricts large macromolecules such as albumin. The filtrate looks very similar to the plasma, but is much lower in protein. 2.3 factors determine what is filtered: the properties of the molecules, the property of the 3-layered membrane, and the forces involved in filtration. Damage to filtration barrier results in glomerular disease. 3.NFP varies mainly with hydrostatic and oncotic pressures in the glomerular capillaries. 4.Glomerular capillary pressure is determined by the relative resistances of afferent arterioles, which precede the glomerulus, and efferent arterioles, which follow it. Control of the resistances of the afferent and efferent arterioles permits independent control of glomerular filtration rate and renal blood flow. 5.Clearance expresses the rate at which a substance is removed from the plasma and excreted in the urine (renal clearance), or removed by all mechanisms combined (metabolic clearance rate), and is always quantified in units of volume per time. 6.Renal clearance of any substance is calculated by a clearance formula relating urine flow to urine and plasma concentrations. Inulin clearance is the best measure GFR because inulin is freely filtered and neither secreted nor reabsorbed. Creatinine clearance is used as practical measure of GFR. Plasma creatinine concentration is used clinically as an indicator of the GFR. 7.The kidneys receive a very large proportion of cardiac output in relation to their mass The combined blood flow through both kidneys normally accounts for 20% to 25% of total cardiac output. 8.Autoregulation of renal blood flow normally occurs between mean arterial blood pressures of 80 and 180 mm Hg and is principally due to intrinsic myogenic responses of the afferent glomerular arterioles to blood pressure changes. 9.AKI significantly reduces GFR and will result in an increase in plasma creatinine 7-10 days later. Sevoflurane represents a theoretical risk for AKI.

What two neuroendocrine influencers are considered renal specific? what does that mean?

Adenosine (ATP) and Renal Prostaglandins Renal specific means that if we took a kidney out of a person or animal we would see produce adenosine considering it is coming from the macula densa which is in the kidney. And prostaglandins also come from renal cells therefore it is confined to the kidney. All of the other neuroendocrine influencers are not renal specific and are produced elsewhere. For example, NE and Epi are produced by the medullary adrenal gland. ANG II and ADH are more systemic as well. Same with ANP. Furthermore, Both Dopamine and Vasopressin are commonly given in intensive care settings.

How does the following neuroendocrine influencer effect RBF? what is its primary effect and primary arteriole? What else should you know about it? ANG II & ADH/AVP

Agent: ANG II & ADH/AVP Primary Effect: Constriction Primary Arteriole: EA RBF: Decreases Notes: Countered in AA via NO and PG ANG II and antidiuretic hormone cause constriction of the efferent arteriole. Again this is going to lower RBF. Furthermore, the changes that happen in the afferent arteriole due to NO and prostaglandins (which we will talk about shortly) can counter some of ANG II and ADH's effects. In other words, if we are constricting the EA we will get a decrease in RBF. But, if at the same time if we dilate the AA we can help increase RBF throughout the system overall.

How does the following neuroendocrine influencer effect RBF? what is its primary effect and primary arteriole? What else should you know about it? ANP

Agent: ANP Primary Effect: Dilation Primary Arteriole: AA RBF: increases Notes: high arterial pressure ANP dilates the afferent arteriole.

How does the following neuroendocrine influencer effect RBF? what is its primary effect and primary arteriole? What stimulates its release in the kidneys and what cells release is? Adenosine (ATP)

Agent: Adenosine (ATP) Primary Effect: Constriction Primary Arteriole: AA RBF: Decreases Notes: Released by macula densa during ↑ tubular flow Adenosine (ATP) is a constrictor of the AA arteriole. It is released by the macula densa which is part of the juxtaglomerular apparatus (JGA). This is a renal-specific neuroendocrine influencer.

How does the following neuroendocrine influencer effect RBF? what is its primary effect and primary arteriole? What else should you know about it? Dopamine

Agent: Dopamine Primary Effect: Dilation Primary Arteriole: AA & EA RBF: increases Notes: ↓doses preserve renal blood flow during hemorrhage Dopamine can generally dilate the afferent and efferent arteriole.

How does the following neuroendocrine influencer effect RBF? what is its primary effect and primary arteriole? What else should you know about it? NE/Epi

Agent: NE/Epi Primary Effect: Constriction Primary Arteriole: AA RBF: decreases Notes: pain, stress, exercise, and hemorrhage. NE and Epi are going to help constrict the afferent arteriole which will help decrease RBF. We would release these catecholamines during times of pain, stress, exercise, and hemorrhage.

How does the following neuroendocrine influencer effect RBF? what is its primary effect and primary arteriole? What else should you know about it? NO

Agent: NO Primary Effect: Dilation Primary Arteriole: AA & EA RBF: Increases Notes: Sheer Stress; Helps keep GFR constant despite constrictors NO can cause dilation of the AA or EA. Where it has its effect depends on where it is most constricted. For example, if ANG II constricts the EA. As blood flows through there, it is going to create more shear force on the endothelial wall. This will cause those cells to produce NO to try to induce some vasodilation. This is why NO can have an effect on either location (AA or EA)

How does the following neuroendocrine influencer effect RBF? what is its primary effect and primary arteriole? What else should you know about it? Renal Prostaglandins

Agent: Renal Prostaglandins Primary Effect: Dilation Primary Arteriole: AA RBF: Increases Notes: Helps keep GFR constant despite constrictors Renal Prostaglandins dilate the afferent arteriole. This is a renal-specific neuroendocrine influencer that is produced by renal cells.

Clinically it's impractical to measure GFR by Kf or NFP, therefore what can we use instead? what is the equation?

Clinically it's impractical to measure GFR by Kf or NFP! The problem is we can't measure the Kf in a human very easily nor the NFP. So why did we just learn all of this? It is because this is the mental model for how to think about how the kidney works. But, considering is it hard to measure these things safely and affordably, we instead use a guesstimate of these values to get the GFR. This guesstimate comes down to clearance. looking at the image of the first tube. Let's say we have a molecule of creatinine (which is one of our markers for clearance and is a waste product that we have to get rid of principally through the kidney through filtration). Clearance does not refer to creatinine itself being removed but rather the volume of plasma that contained the creatinine that was excreted. For example, if someone asked you to clear your desk, the clearance would not be our laptops and personal belongings being removed but rather it is the space that those items occupied on the desk. Looking at the second tube, the reason it is showing certain volumes of plasma clear while other volumes of plasma are not clear is that we do not clear the entire renal blood flow. The kidney will get about a liter per minute but we are going to take a fraction of that and actually filter it. The whole liter is not filtered. Looking at the third tube, over time the creatinine would eventually redistribute in the blood. So clearance is a volume rate. It is how many mL of blood did we filter and how long did it take us to filter that. Typically we look at clearance in two different ways - mL/min or L/day. Therefore, if we wanted to determine what a pts clearance rate was, we would only need two pieces of information - what the concentration of creatinine was in their urine [U] and then we would want to collect their urine for 24 hours to determine what their urinary volume [UV] is. This will tell us the excretion of creatinine. If we know this we only need one more piece of information to determine clearance which is the plasma creatinine levels after 24 hours [P]. So we take the urinary excretion and divide that by the plasma concentration of creatine which will tell us the pts clearance. Clearance represents how much of a substance can be removed from a certain amount of plasma volume in a given amount of time. We can use it to estimate GFR! THERE WILL BE A CLEARANCE CALCULATION QUESTION ON THE EXAM AND/OR QUIZ!!!!

What are the unique pressure attributes of the glomerulus, peritubular capillaries, and vasa recta? Why do these pressure attributes occur and why are they important?

High pressure in the Afferent Arterial to the Glomerulus = filtration (Hydrostatic Pressure > Oncotic Pressure). Lower pressure in the efferent arterial and peritubular capillaries. = Reabsorption of fluid. The Vasa Recta provide a "counter-current" with an altered osmotic gradient for exchange (more to come in PPT 8). We are now going to talk about this weird series of capillary beds that run into one another. As blood flow is coming into the glomerulus (our first capillary bed which is in charge of filtration), it will have a higher hydrostatic pressure than in other capillary space. This high hydrostatic pressure is important considering it is the pressure that is principally going to help drive the filtration of plasma into the proximal tubule. Therefore, when we talked about the glamorous filtration rate, the principal driver is going to be the glomerular hydrostatic pressure. The blood that is not filtered into the glomerulus will exit via the efferent arteriole where it will make its way into the peritubular capillaries. This blood will have high oncotic pressure which is the sucking force of proteins. This is going to pull water into the peritubular capillary beds. How do we get this high oncotic pressure in the peritubular capillary beds? What's causing this? When we filter at the glomerulus we are pulling plasma out of the blood and dumping it into the proximal tubule, but leaving proteins behind. As a result, the blood that exits the glomerulus and enters the peritubular capillaries has a higher concentration of proteins, as we have just removed plasma from the blood. Therefore, we use the high hydrostatic pressure at the glomerulus to promote filtration and move the plasma into the tubules so it can become filtrate, and then we are concentrating those proteins that are left behind in the blood to develop the high oncotic pressure in the peritubular capillaries. Why do we want a high oncotic pressure in the peritubular cap? It allows us to pull water into the peritubular capillary bed. As we move down towards the vasa recta, it is basically a much lower pressure system bc the flow through it is very slow. In this area, we rely on the counter-currents. We are basically going to reabsorb salt from the ascending LOH and reabsorb water from the descending LOH.

What occurs during Tubuloglomerular Feedback (TGF) when there is low tubule flow?

If there is low tubular flow, the amount of sodium chloride that is coming past the macular densa is going to decrease. Therefore, they will not be able to take up enough sodium chloride to depolarize the cell. As a result, there will be no calcium influx which allows the JGA cells to produce renin which leads to ANG II production and EA constriction. Which will increases the PGC and GFR. Furthermore, if there is no depolarization the macula densa cells are also not going to release adenosine. The key thing to remember about TGF is that it is apart of renal autoregulation. If we took the kidney out or even an individual nephron, this control mechanism would still be in place. If we increased tubular flow we would see a decrease in PGC and GFR. If we decreased tubular flow we would see an increase in PGC and GFR. Every single nephron can individually control its GFR based on the tubular flow. When we are looking at GFR from a pts standpoint, we are looking at the average of all of those nephrons working together. THERE WILL BE UP DOWN ARROW QUESTIONS ON THE EXAM OVER THIS NC AND THE LAST. KNOW IT ALL!!!! TGF - Each nephrons distal tubules (downstream), can communicate with the arterials of the glomerulus (upstream) to alter the GFR. When Na+ in the distal tubules is high, we lower GFR. When Na+ in the distal tubules is low, we raise the GFR. This helps keep GFR and Na+ delivery in the nephron constant, which helps us maintain ECFV.

SOOO how would a constricted efferent arteriole affect RBF, PGC, and GFR? why would our body do this? what about if we vasodilated the efferent arteriole?

If we only constrict the efferent arteriole, our renal plasma flow (renal blood flow) will have a harder time escaping out of the kidney thus decreasing the renal plasma flow. Our glomerular hydrostatic pressure is going to build up and thus increase due to the back pressure created by the constricted EA which we can see in the graph. When looking at the graph, you can see that the percent change in the RPF vs the percent change in the PGC is kind of similar. If you only vasoconstrict a little bit, GFR will go up some. BUT, if you continue to constrict the EA the GFR will kind of come back down to normal. When we constrict the EA what we are trying to do is maintain the GFR in the face of low renal blood flow. Which makes sense. Furthermore, if we look at the opposite relationship we can see that if we vasodilate the EA - blood flow will have an easier time coming into the EA so RPF will increase, the glomerular hydrostatic pressure will fall, and thus, the GFR will tend to decline.

How can you determine how much of a substance is excreted? what is the equation?

If you wanted to know how much of a substance is excreted, you would first have to determine how much of that substance was filtered into the nephron. This can be calculated by using the filtered load equation which is the plasma concentration of any substance x the GFR. The plasma concentration of this substance can be anything as long as it is freely filterable meaning it has to move across the membrane as easily as water does. Sodium, potassium, chloride, glucose, amino acids, bicarb, and phosphate are all substances that are freely filterable. Therefore, you have to calculate the filtered load in order to figure out how much of a substance has been filtered. You then would subtract any reabsorption and add any secretion. The number you obtain from this will give you the amount that was excreted. If there is a question asking you to calculate the excretion of sodium or potassium for example, it come down to this relationship. You just need to calculate the filtered load, subtract what was reabsorbed, and add what was secreted. This will give you what has been excreted.

In terms of renal blood flow - what are the 8 steps for the pathway of blood through the kidney? How much blood in L/min does the kidney receive? why?

In terms of renal blood flow, the first major branch is going to be the arcuate artery. The arcuate artery will branch out and give rise to the interlobular artery. Blood then flows to the afferent arteriole. Blood in the afferent arteriole will then flow into the glomerulus. This blood is coming "away" from the body and into the kidney. Today we are going to spend a lot of time talking about 3,4, and 5. from the afferent arteriole blood will flow into the glomerulus which is a modified capillary bed. Blood that is not filtered into the kidney will exit the glomerulus via efferent arteriole. At that point, the blood leaving via the EA is going to take a longer route, but it will eventually end up back in the body. The efferent arteriole moves into the peritubular capillaries. Therefore, this is a weird system. we have an afferent arteriole that goes through a capillary and then into basically a venule (efferent arteriole) so we would expect there to be a vein next, but in reality, it goes into another capillary bed which is the peritubular capillary which is an unusual anatomical arrangement. The point of the peritubular capillary bed is to provide our proximal and distal convoluted tubules blood flow. The most important for you guys in terms of blood loss during surgery is going to be the proximal tubule. This is because this is where we are going to reabsorb lots of blood (and salts, glucose, and bicarb), but bc of this we have a lot of metabolic activity in the proximal tubule cells as it takes lots of energy to reabsorb things. Therefore, the peritubular capillary bed serves as the oxygen supply for those regions so that they can continue with their metabolic activity. Therefore if we have a significant hemorrhage or we are restricting blood flow by clapping the afferent arteriole, the proximal tubule can become ischemic very quickly leading to the death of those cells which can lead to acute kidney injury and further problems. If we kill those cells they do not grow back. therefore, this pt is now going to lose lots of K, Na, Cl, water, glucose, and bicarb, leading to more issues. The peritubular capillaries move into a structure known as the vasa recta. Blood will be traveling downward down the vasa recta, are once we get to the venous side, the blood will travel to the interlobular vein and arcuate vein. The blood in the vasa recta run it was is called a counter-current system. it is coming down in one direction and up in another direction. We also have a counter-current within our loop of Henle. These two currents run in opposite directions. This plays a very important role in the absorption of water. The small fist sized kidney is only 0.5% of the body mass and gets 20% of the Q. RBF= 5L/min *20% RBF = 1L/min Each of the kidneys sits right below the rib cage, they are about the size of a fist. This is only about 0.5% of our total body mass but it receives 20% of our CO. The resting blood volume for an average male is about 5L/min therefore if we take 20% of that we get 1L/min which is what the kidneys are receiving. Why does such a small organ get such a large amount of blood flow? because it has to filter the blood. therefore the best way to filter a lot of blood is to give it lots of blood flow. The majority of the blood flow to the kidney is NOT for metabolism but rather filtration.

Renal Clearance: Plasma Cr inversely related to GFR!

LISTEN TO THIS PART. 58:22 Doublings in plasma Cr represent large reductions in GFR. For example: A -50% reduction in GFR from 125 to 62.5 mL/min induces a 100% increase in plasma Cr from 1 to 2 mg/dL. are this is this is base and my wife an app on a phone the phone with Lee Boyles Law the other if it's almost but these and for having sex before I forget don't memorize these right this is basically going to be the equation that's going to show up on your lab report and if you don't have it there's it's like my wife has an app on the phone with like Boyle's Law and all those pulmonary formulas you learn yeah there's a scroll that should know it's almost going to make these apps right so you got to know the equation but these are just the right example prediction equations that are more commonly used particularly in this area Krishna bhajans all the one thing I will say is that in studies were they made adjustments for African-American race remove look back in time at those they seem to be pretty underpowered and what you can see prepare for this this is a modification of diet and renal disease that was the study this equation but was double out then it's basically increasing their GI bar to make it look more normal guess who has very high rates of chronic kidney disease African Americans so now I question that has the column if we were very under-powered is this a good idea or we actually delaying care to patients that we think are in CKD one but they're really into KDs free because of the mistake in the prediction equation song only be a little bit wary of his kind of remember these are always guesstimate the decent guesstimate across the big population most of the time they work out but they're not perfect so I'm normal GFR is going to be 125 miles per minute you should know that number it's like knowing 120 over 80 or a blood glucose between 8200 mg / DL is normal eye normal GFR is 125 ml per minute corresponding creatine mother would be 1 mg / DL so if you have 1 mg / DL you don't have an abnormal amount of muscle mass or massive loss of muscle mass you have all your limbs we would expect that 1 mg / DL your gfrp 125 as the go forward goes down stated differently as the kidneys fail when you lose nephrons your ability to filter creatinine also goes down so if we go from 1 mg DL up to 2 we've cut our go 4 1/2 most people lose track of this after prom with something that's only a mg / DL when you're like. Well from 1 to 2 well yeah 1 mg doesn't sound like a lot but you've doubled your creatinine right we have a 100% increase in it doesn't look that bad but when you look at it in terms of relative terms and turns out change its really bad cuz your kidneys are functioning half as well as we would expect them to do small changes in the plasma creatinine box braids big changes in the dfr okay so one of money you get to the practice problems this idea is going to come back and it will help you understand hopefully as we get rid of nephrons why this this number actually double cracked is where there's going to be a moment of time where are production rate in our excretion rate are not equal which is what is normally the case when those two things on couple that's what's going to the wildest of basically increase in direct proportion to the number of nephrons is what makes it a useful marker okay if it didn't do that I wouldn't tell us anything about you how far any questions so far about go far inulin creatinine and renal clearance of these substances I

What does net filtration pressure determine? How do we calculate the net filtration pressure (NFP)?

Looking at our net filtration pressures. Net Filtration pressure (NFP) determines filtration When we look inside the glomerulus we have our hydrostatic pressure in the glomerular capillary (PGC) which is pushing out. We also have the oncotic pressure inside of the Bowman's space (πBS) The capillary bed of the golumularus is encapsulated by this structure called Bowman's space. Normally we should not have very much oncotic pressure here as we should not be filtering proteins across into the Bowman's space in any meaningful amount. Therefore, this number should be pretty small. We also have the oncotic pressure that is developing in the glomerular capillaries (ΠGC) As we push more fluid out due to the hydrostatic pressure of the glomerular capillary, the oncotic pressure of the glomerular capillaries is going to increase. You would expect this number to be higher over in the efferent arteriole when compared to the afferent arteriole considering as we filter more, the plasma is going to get more concentrated. And lastly, we have the hydrostatic pressure in the Bowman's space (PBS). We are filtering fluid out into this space, therefore, some of that fluid is going to exert pressure back towards the glomerulus capillaries. Using the equation in the image you can calculate the net filtration pressure. The NFP in the image would be 15mmHg. This is the pressure driving filtration and is pushing outwards. PGC is the biggest driving force for filtration. Normally, high PGC is the major driving force of filtration. If you increase PGC, you increase filtration.

What is the auto-regulation rage for the kidneys? why is there an auto-regulation rage and what would happen if it didn't exist? What occurs we fall below or above this range?

Looking at the top graph we can see that as renal blood flow increase, GFR will also increase. And then we get to a point where we are trying to maintain those two things. But at some point if we started pushing a whole lot of RBF through the kidney, it would start to uncouple with the GFR. In other words, if is very easy for the blood to move in and out, we wouldn't get a massive increase in GFR. The plateau in the middle is a protective range that YOU SHOULD KNOW which is MAP of 80-180mmHg A normal MAP is around 93 mmHg which is a BP of 120/80. Therefore, we have this range where we can have lower blood pressure than normal or pretty high blood pressures (of like 240/260) before we would start to see RBF and GFR uncouple pretty significantly. The benefit to this is that it allows us to maintain a constant GFR, despite massive changes in the mean arterial pressure. One of the reasons they called hypertension the silent diseases, is that if auto-regulation did not exist and you had hypertension, your urinary volume would significantly increase. This is because filtration is driving by hydrostatic pressure. If your MAP increased, by definition, your capillary hydrostatic pressure would also increase. This would cause the kidneys to filter more which would increase urinary volume. The most important thing to know about the bottom graph is that this relationship does not happen considering we have mechanisms to protect against it such as autoregulation. If this relationship did occur, you would lose so much of your extracellular fluid volume that you would basically be dead in a few hours. Therefore, we want to keep the GFR and RBF fairly constant at all times which allows us to also scan the blood at a pretty constant rate. If a pt had very significantly untreated hypertension and a very high MAP above 180, then we would see the RBF start to increase through the system which can lead to damage to the glomerulus. Once that area is damaged, it will start to heal and become all sclerotic, leading to a kidney that does not filter very well. We can also look at the opposite end of the scenario such as a pt with a MAP below 80 mmHg, which is something we are very likely to see in surgery or with a significant hemorrhage. These both can lead to renal ischemia. If a pt is losing blood due to surgery or a hemorrhage, this is going to decrease the RBF which will decrease the GFR. Renal ischemia has a large impact on the proximal tubular cells.

What is neuroendocrine regulation? what is intrinsic auto-regulation?

Neuroendocrine Regulation - Vasoconstrictors vs dilators. - Can be impaired during disease (i.e.: hypertension) There are vasoconstrictors and vasodilators that can constrict the AA and EA. Right now we are talking about how this system should normally work, but it is important to keep in mind that this can change depending on different diseases. For example, pts can have hypertension bc they produce more ANGII than they should or they have conn's syndrome where they produce too much aldosterone. In these cases, neuroendocrine regulation does not work as well as we would expect. "Intrinsic Autoregulation" of RBF - Occurs independent of renal nerves, circulating hormones, and metabolism (seen in isolated kidneys perfused in vitro) i. Myogenic ii. JGA: Tubuloglomerular feedback The other part that plays a role in the protective mechanisms of the kidneys is the intrinsic autoregulation of RBF. what this means is there are things going on in the kidney-specific only to the kidneys. For example, if we take a kidney out of the lab mouse, intrinsic autoregulation would still occur but neuroendocrine regulation would not. There are two different mechanisms that fall under intrinsic autoregulation - the myogenic mechanism and JGA: Tubuloglomerular feedback. We will go more in-depth about both but basically, the myogenic mechanism comes down to the fact that if you stretch a smooth muscle it will want to contract. Tubuloglomerular feedback occurs at the juxtaglomerular apparatus. Between the thick ascending limb and the start of the distal convoluted tubule, we have a region that is really close to the glomerulus. This region is the juxtaglomerulus which is known as the juxtaglomerular apparatus. It is basically a part of the nephron that is near the glomerulus. Without these two mechanisms (neuroendocrine regulation and intrinsic autoregulation) a 25% increase in BP (from 100 to 125 mmHg) would cause a 25% increase in GFR (from 180 to 225 L/d). Hypertension would lead to a large amounts of filtration and a high workload on the kidney to reabsorb salts.

What is a normal GFR for both of the kidneys in mL/min? L/day? how much is urinated out in L/day? how many times a day can the kidneys filter the plasma?

Norms that are handy to know: •GFR of both kidneys = 125 ml/min = 180 L/day Which means the plasma volume (PV) = 3 L = filtered 60 x's/d ~99% volume filtered (GFR) is reabsorbed If you look at both kidneys we know that a typical GFR is 125 mL/min which is roughly 180 L/day (about 5 gallons). This is the amount of blood that is actually going to get filtered. This is a crazy amount of fluid. Out of that 180 L/day we only urinate out about 1-2L/day. This might seem like an extreme inefficiency, but if we look at the plasma volume (PV) this means we can filter our blood about 60 times per day. Therefore, we get to turn over the blood several times to make adjustments but the only downside to this is that it takes time. We have short-term control mechanisms for HR and BP and then the kidneys are always considered longer-term considering it takes them all day to look through everything that's in the plasma and compensated appropriately.

What is the average CO? how do we calculate renal fraction and what is a normal renal fraction? how much blood do the kidneys receive in mL/min? about about in mL/min/g? what is a filtration fraction? how is it calculated? about can we determine a normal FF using the information we know? what is a normal FF?

Renal Blood Flow (RBF) - Cardiac Output (CO) = 5-6 L/min - Renal Fraction (RBF/CO) = 20% - 5-6 L*20% = 1000 -1200 ml/min - ≈ 300 g Kidney - ≈ 3.5 ml/min/g (<0.5% Bodyweight) -vs- Tissue Blood Flow •Brain = 0.5 ml/min/g •Sk.M (max ex) = 1.0 ml/min/g Filtration Fraction (FF) - %Plasma filtered into the Renal Tubules - FF = GFR/Renal Plasma Flow (RPF) - FF = 125 mL/min ÷ 600 mL/min =20% We know that the CO is about 5-6 L/min which is our resting blood volume. If we take our renal fraction (which is the renal blood flow divided by CO) we can see that our kidneys are getting about 1000-1200 mL/min. Each kidney is only 300 grams. To just kind of put this idea of metabolic hyperemia in the some context, we are getting about 3.5 mL/min/per gram of tissue weight for the kidneys. Your brain during its most active moments only gets 0.5 mL/min/gram of tissue. And your skeletal muscle during the most extreme workouts is only getting 1 mL/min/g. Therefore, the kidney's input is remarkably higher. The kidney only needs about 1 mL/min/g to run its transporters but the rest is basically there for filtration. The filtration fraction is basically what percent of this total blood flow are we actually going to filter. The renal fraction is basically saying - what percent of the cardiac output do we get? and from that 20% how much are we actually going to filter. So the filtration fraction equation is the GFR divided by the renal plasma flow. What's the difference between renal blood flow and renal plasma flow? It basically comes down to the difference between blood and plasma. The plasma is only about 50% of the volume of whole blood. The other 50% would be pack RBC and a little white buffy coat WBC. Therefore, when looking at the FF, what we can do is take 50% of 1200 mL/min which is 600 mL/min. We know our GFR is 125 mL/min. Therefore, if we have a normal healthy person with 6 L of cardiac output and the kidney is getting 1200 mL/min of blood flow, half of that blood flow should be plasma. If we divide our 125 mL/min by 600 mL/min we get 20%. In other words, we are getting 20% of the cardiac output, and from that volume, we are going to filter 20% of it. This kind of links back to the idea of clearance. Back on NC 15 where we talked about how we have some volumes of plasma that are cleared and other volumes that weren't. Why is this the case? it is because we do not filter all of the renal blood flow. This is what we just proved. We only filter a fraction of it which is about 20%.

Why do I need to know this stuff?

Reversible decreases in renal blood flow, glomerular filtration rate, urinary flow, and sodium excretion occur during both neuraxial and general anesthesia. Acute kidney injury is less likely to occur if adequate intravascular volume and normal blood pressure are maintained. The endocrine response to surgery and anesthesia is at least partly responsible for the transient fluid retention often seen postoperatively. Today we are going to talk about how the kidney filters the blood, how it controls how much blood flow it gets, how it increases or decreases that filtration, and then two clinically relevant topics which are chronic kidney disease and acute kidney injury. The reason knowing this stuff is so important is because it comes down to controlling the extracellular fluid, which is the kidney's job. For example, if we are monitoring heart rate and blood pressure starts to plummet, it is usually due to a volume issue in surgery. Therefore, we're going to have to understand the renal effects that our competitions are going to have.

What is the meaning of filtration? reabsorption? secretion? excretion?

So we have our afferent arteriole where blood is coming into the kidney. it travels to the glomerular capillary bed where filtration happens. The glomerulus is filtering the blood that enters by pulling out plasma and dumping it into the proximal tubule where it will become filtrate. Reabsorption is the movement of water and solutes from the nephron tubule back into circulation. In other words, the filtrate that is now in the tubular lumen will move from the apical side of the tubular lumen, into the cytoplasm, and then across the basolateral side into the interstitial fluid. Once it is in the interstitial fluid, we can reabsorb that fluid back into the peritubular capillaries or sometimes the vasa recta. Therefore, reabsorption is basically taking something that was in the tubular lumen and bringing it back to the vascular space. Secretion is the opposite direction of reabsorption. It is the movement of water and solutes from the circulation into the nephron tubule. In other words, secretion is taking something that's in the extracellular fluid (either in the plasma or the interstitial fluid) and moving it from the basolateral side of the cell into the cytoplasm and then across the apical side of the cell into the tubular lumen. The general rule of thumb is that the kidney is going to secrete things to excrete them. Therefore, the last thing is excretion, which is basically what we are going to lose to the urine.

What is the myogenic mechanism and how does it effect auto-regulation?

The Myogenic mechanism is basically trying to dampen the effects of every single heartbeat by vasodilating and constricting the AA. During every single heartbeat, the systolic pressure opens afferent arteriole. This creates stretch causing the afferent arteriole to want to contract. By this point, we are in diastole. What this is doing is protecting the kidney against pulse pressure. Looking at the image we can see the breakdown of this process. We get an increase in our BP during systole. This is basically transmitted to the afferent arteriole which stretches the wall of the afferent arteriole. There are stretch receptors in the wall of the AA that will open voltage-gated calcium channels. This allows calcium to be released. When you release calcium into any muscle tissue including smooth muscle it is going to contract. Therefore, we get contraction of the AA which is what is driving the vasoconstriction. But, this vasoconstriction is coming at a point where our BP is heading towards diastole. Therefore, when we have a high pulse pressure, we are stretching the AA open. How is that going to affect the pressure against the vasculature wall in the AA? this will increase the tension on the walls therefore they constrict due to stretch. At this occurs the pressure between those walls is going to be going down as we will then be in diastole. So when the BP is falling towards diastole we are starting to contract the AA. Therefore, instead of having this huge systolic pulse and low diastole pulse over and over in the glomerulus, the afferent arteriole helps to normalize the pressure differences to maintain GFR by stretching open when the pressure is high and contracting when the pressure is low. This helps keep the pressure inside of the glomerulus pretty constant and thus GFR. If the pressure is constant, the renal blood flow will be constant, and thus the GFR will be constant. The AA is trying to dampen the effects of every single heartbeat. The simple explanation of the myogenic mechanism is if you stretch the vascular wall of a blood vessel, it will have a reflexive contraction. This reflexive contraction is an intrinsic property of smooth muscle.

Why is inulin the gold standard for measuring GFR? how is this done?

The best standard to perform the clearance procedure with is inulin. We take a pt and Infuse inulin into them, allow them to achieve steady-state plasma concentration (let the blood begin to circulate and spread the inulin from the venous side evenly to the arteriole side), and then we will collect urine for 24 hours and then do a blood draw. we will then plug everything into the clearance equation. Why is inulin used and considered the gold standard of GFR? Inulin is ideal because it is: •non-toxic and infusible •freely filterable by the kidney •not reabsorbed, secreted, metabolized, synthesized or stored in any way. •unable to alter GFR Therefore, the clearance of inulin is equal to the GFR! •CInulin = GFR Inulin is a Prebiotic fiber therefore it is not normally absorbed by cells anywhere in the body including the GI system. It is also not toxic, very easily infusible, and has a sieving coefficient of 1 hence it is freely filterable and does not alter the filtration (GFR) bc again it is freely filterable. It's not reabsorbed, secreted, or metabolized. And it is also not synthesized by the body nor does it get stored anywhere in any way. Therefore, we just do the clearance procedure and plug our numbers into the clearance equation. The clearance of inulin is going to equal the GFR. we can do basically the exact same thing for creatinine.

What does the glomerular filtrate look like compared to plasma? are electrolyte concentrations that same or different between the two?

The glomerular filtrate is going to look basically just like the plasma except for two major things. The first is that lower levels of protein are going to make it across and the other thing is cells are not going to make it across. So if you had basically plasma with 98% of the proteins removed and all of the cells remove that's what the filtrate is. But your sodium, potassium, chloride, bicarb, glucose, urea, and creatinine all are freely filterable. Therefore, they should be present in the same concentration in both areas as water is going to move at the same rate as these substances.

what is a sieving coefficient? what are the 4 substances that have a sieving coefficient of 1? The smaller the sieving coefficient the easier or harder it is to filter? How does charge affect the sieving coefficient?

The graph is looking at the radius of a substance. the bigger the number on the x axis the bigger the molecule is. On the Y axis we have the sieving coefficient. A sieving coefficient of 1 means that the substance is freely filterable and that it will move as easily as water would move. The smaller the sieving coefficient the hard it will be to move the substance across. the general rule, which you can see based on the graph, is if we increase the size of a substance the sieving coefficient will decrease. If we have a positive charge on a substance we would expect it to be more filterable because it's going to be more attracted to that negative charge on the glomerular membrane therefore the sieving coefficient would increase. If the substance has a negative charge it will have a harder time moving across that membrane therefore it will have a lower sieving coefficient. If we look at things like glucose, all of our electrolytes and a substance called inulin that we are going to talk about here in a little bit, these things all have the same coefficient of 1. Hence, they move across as easily as water. Myoglobin is basically the hemoglobin form for oxygen-binding that is expressed in skeletal muscles. We might see this in the plasma during a heart attack, severe muscle injury, etc. Hemoglobin is bigger than myoglobin therefore, you can see that the sieving coefficient is smaller, meaning myoglobin is more easily filtered when compared to hemoglobin. Therefore, if you have a pt showing + for hemoglobin in their urine, we would expect the hemoglobin to be blocking up the membrane, which can be a danger to clogging this entire filter. And lastly, albumin is a huge blood protein. As a result, it has the lowest sieving coefficient. What you should know for this NC is the impact of the size and charge and you should be familiar with some of these examples because that's basically where he is going to pull things from for test questions. When sizes are equal, negative charged substances have a harder time being filtered! Conversely, when sizes are equal, positively charged substances are more easily filtered! Dextrans are exogenous polysaccarides of D-glucose that can be produced in various molecular weights as well as neutral, anionic or cationic forms.

What is the renal triad of AKI? what are the 3 different means by which a pt can get AKI?

The last thing we are going to talk about is acute kidney injury (AKI). The renal triad that we are going to see in pts with AKI is they are going to have a lower GFR which is typically measured by creatinine. A lower urine output and also higher levels of blood urea nitrogen (BUN). One the exam, if you see a question with this set up you should start thinking of AKI considering this is the classic presentation. There are three different means by which we can get this acute kidney injury. 1. Pre-renal mechanism 2. intrinsic 3. Post-renal mechanisms Pre-renal mechanisms basically links to not having enough extracellular fluid volume (aka hypovolemia), having a significantly impaired cardiac output or impaired auto-regulation of the AA and EA. For example, surgery wise, if a surgeon clamps the aorta at some point, it will decrease renal perfusion, setting the pt up for AKI. Therefore, that would be a Pre-renal AKI. So anytime you are dealing with pressure, CO, RBF from the AA perspective to the EA perspective, that would be a Pre-renal injury. Therefore, it is always pretty much vascular-based. AKI can also be Intrinsic. This is basically the tubular cells themselves are injured. For example, sepsis would cause this as well as nephrotoxins such as contrast contract dye from an MRI. The dye is actually nephrotoxic in some people considering it can clog up the glomeruli and kill the cells. Compound A can also cause tubular renal cell injury. This is why we have to have a fresh gas flow rate of at least 2 L/min to minimize the risk of this occurring. This would all fall under intrinsic AKI. Post-renal AKI is caused by some sort of bladder outlet obstruction. For example, if a surgeon for some reason clamped the ureter, and now urine is back up through the kidney and nephron, it can cause damage to the glomerulus and the renal cells. The tubule would actually expand and stretch and get super leaky and could even rupture and explode. Another common cause of this would be a very enlarged prostate gland that can occur in men. If they had very severe benign prostatic hyperplasia or a tumor in the prostate that was obstructing urinary flow out of the bladder, it can cause Post-renal AKI. SOO Pre-renal AKI is basically an issue in delivering blood flow to the kidney, Intrinsic AKI is dealing with things that kill the kidney cells themselves, and Post-renal AKI is dealing with things that cause urine to back up and therefore rupture the cells in the kidney. Renal Triad of AKI: ↓GFR, ↓ urine output & ↑ BUN. Compound A, a breakdown product of sevoflurane, causes AKI in laboratory animals. Low fresh gas flow rates promote its accumulation in the anesthesia breathing circuit. Authorities recommend a fresh gas flow of at least 2 L/min with sevoflurate to minimize the risk of this theoretical problem. FOR THE EXAM make sure you know what GFR is and how to calculate it. How we can control RBF, understand what chronic kidney disease is (basically we are losing nephrons) and what that means in terms of creatinine, and then AKI.

How many nephrons does each kidney have? what occurs at the at of 40? what about at the age of 80? what happens once you have lost more then 50% of your nephrons?

The nephron is the "functional unit" of the kidney. It's what does the work of making urine to remove waste, and reabsorbing electrolytes to maintain the ECF. Losing nephrons makes it more difficult to filter the blood and maintain the ECF. The remaining nephrons adapt to compensate; however, loss of too many nephrons (>50% loss) pushes you towards kidney failure/uremia. In the picture is a general overview of each segment, we will get into the details next lecture. The nephron is basically the functional unit of the kidney. Its job is to filter our plasma by removing waste products and reabsorbing electrolytes to maintain our ECF. The waste products that are removed are eliminated in the urine. It is in charge of filtering the blood and deciding from the blood that is filtered, how much of the plasma and the things that are in that plasma we going to reabsorb versus what we are going to let go into the urine. Across the two kidneys, there are going to be about 2 million nephrons. You lose about 10% of those nephrons per decade after 40. But the good news is that if nothing else bad happens to your kidneys and you hit the age of 80 you are only down 40%. And until you have lost 50% of your nephrons, your kidneys are still in pretty good shape and can maintain the extracellular fluid. It is once you cross this 50% threshold that you start to see a decline in kidney function. Once you get under 1 million nephrons it will start to impact the kidney's ability to control things such as blood pressure, extracellular fluid, potassium levels, and calcium levels.

How do you calculate the glomerular filtration rate (GFR)? what is GFR?

The rate at which filtrate is formed by both kidneys per minute is termed the glomerular filtration rate (GFR). It is a key measure of renal health. GFR is a passive process normally driven in large part by NFP (particularly high PGC). Everything we have discussed has basically been to get us to this point which is the glomerular filtration rate (GFR). GFR is the clinical marker for renal function. It can be calculated using the equation in the image. It is essentially equal to the quality of the capillary membrane times NFP. The quality of the glomerular capillary membrane comes down to two factors. The first is hydraulic conductivity which is how easy it is to move things from the capillary side into the filtrate side. The other thing that affects the quality is surface area. The bigger the capillary bed network the more it will be able to push water across. The quality is representing the permeability of the glomerular capillary and is known as the coefficient of filtration. There are a couple of groups of people which crappy capilaries and blood vessels. The elderly, diabetics, and smokers. These would all decrease the Kf which would decrease GFR. The other major factor in determining GFR is NFP. If NFP increases and Kf stays the same the GFR will increase. Having this basic relationship in our head is a really useful way to think about a pts renal function. You just need to think about the quality of their capillary membrane and what is their NFP going to look like. If a pt has really bad hypertension their NFP is going to increase considering PGC increases. These would be the types of questions he would ask on the exam or quiz. one thing that we don't consider is the filtered molecules in this equation. we don't have any control over that kind of stuff so generally from a physiology standpoint and clinical medicine standpoint, we kind of ignore them. we know that those rules exist but we can't change them so we do not include them as part of the equation.

What is the juxtaglomerular apparatus (JGA)? what are granular cells and where are they located? what do they produce? What are macula densa cells? where are they located? what is Tubuloglomerular Feedback (TGF)? what occurs when there is high tubular flow?

The second part of autoregulation is tubuloglomerular feedback (TGF). It occurs in all 2 million nephrons at every single second of every single day. In the image, we can see our AA, EA, glomerulus, and proximal tubule. The proximal tubule would go down to the loop of Henle, up through the thick ascending limb. The thick ascending limb is a part of the distal tubule. We then can see our juxtaglomerular apparatus (JGA) which is where the tubule comes into close contact with the glomerulus. It is also important to note, that the AA has these sympathetic nerve endings which are innervating the vascular wall themselves, as well as the cells in blue which are called granular cells. They are the cells that produce renin and are sometimes referred to as JG cells. These are the juxtaglomerular cells or granule cells that are going to make up some of the JGA. Anytime we have the release of catecholamines such as NE or Epi, they are coming from those sympathetic nerve endings. Okay, so now let's look at what the idea of TGF is. This occurs in every nephron. What they are measuring is basically tubular flow. So how much fluid is coming around the loop of Henle up to the point of the macula densa cells which are in purple. So they look at the tubular fluid flow, they are examining how much sodium chloride is in that solution. They are not looking at the concentration of sodium chloride considering it can vary, but rather, how many individual molecules of sodium and chloride there are. As the macular densa cells reabsorb more sodium and chloride it will lead to depolarization of those cells. Therefore, when we have higher tubular flow, we tend to have more sodium chloride, that's going to make these cells depolarize. When they depolarize, calcium is going to enter. When calcium enters these cells, the granular cells in the AA in blue are basically told to stop producing renin which means we are not going to have any ANG II. As we have learned, ANG II causes constriction of the EA which decreases RBF. Therefore, if we stop producing ANG II we will in turn get EA dilation. In other words, we are removing the constrictor which is ANG II. The macula densa cells also produce adenosine. Therefore, they release it which will cause constriction of the AA decreasing RBF. Therefore, we get AA constriction and EA dilation considering we have gotten rid of ANG II. This in turn lowers the glomerular hydrostatic pressure (PCG) considering we have now made it harder for blood to come in (bc we constricted the AA) which will lower the GFR. What that means is if we are filtering less, there is going to be less flow eventually to the distal tubule. SOOO high tubular flow leads to high sodium chloride delivery, we lower the GFR by constricting the AA and relaxing the EA.

Question - If we constricted only the afferent arterial (AA) what would happen to: Blood Flow, Glomerular Capillary Hydrostatic Pressure (PGC), and GFR?

There is increased resistance in the afferent arteriole. This would decrease RBF, GFR, and PGC. When we are talking about renal blood flow we are talking about the movement of blood through the kidney's entire system (afferent arteriole, glomerulus, and efferent arteriole). So when talking about blood flow we are referring to the amount of blood that comes in through the AA and leaves through the EA. If we constrict the AA it is going to be harder to bring blood into the system. It is important to keep in mind that we have 2 million of these glomeruli, therefore, if blood flow is restricted, the blood is just going to go find another area that is easier to get into. Therefore, if the afferent arteriole pressure is higher than the blood pressure, it will go somewhere else in the body. When we lower the blood flow to the kidney by constricting the AA this is also going to lower the hydrostatic pressure which thus lowers the GFR. this is because the major factor in determining the GFR is the glomerular hydrostatic pressure.

Question - If we constricted only the efferent arterial (EA) what would happen to: Blood Flow, Glomerular Capillary Hydrostatic Pressure (PGC), and GFR?

There is increased resistance in the efferent arteriole. This would decrease RBF but increase both GFR and PGC. Because this maintains the PGC, it tends to maintain the GFR, despite lower RBF. If we constrict the EE it is going to be harder for blood to move through the kidney therefore, this will create a back pressure which will increase the hydrostatic pressure. This thus will increase the GFR. But in this case, RBF will decrease because it cannot exit through the efferent side very easily. But the glomerular hydrostatic pressure will increase due to the back pressure created which increases the GFR. Therefore, from these two problems, we can see that a decrease in RBF can either decrease or increase the GFR depending on which arteriole is constricted. Also, it is important to note on problems that renal blood flow and renal plasma flow are the same thing, but just keep in mind that we are only filtering plasma. In the diagram on the next NC it says renal plasma flow (RPF) you can just think of that as total renal blood flow (RBF).

SOOO how would a constricted afferent arteriole affect RBF, PGC, and GFR? what about if we vasodilated the afferent arteriole?

This diagram is basically looking at the same relationship that occurs when we constrict the afferent arteriole but graphically. The black dots on the graph are representing what would be considered normal. If we are constricting only the afferent arteriole, we can see that renal plasma flow (also known as renal blood flow) is going to decrease. This will make it harder to bring blood into the kidneys, which will make it harder to generate a higher hydrostatic pressure, therefore PGC will decrease. And because of this decrease in hydrostatic pressure, GFR will also decrease. This graph also shows you the opposite relationship. If we vasodilated the AA, we would get an increase in RBF, this would increase the hydrostatic pressure, which would increase the GFR.

How does this protective relationship occur where despite huge swings in the MAP, the GFR can remain constant? In other words, what are the two physiological mechanisms that allow for this to happen?

Two things allow this to occur: neuroendocrine regulators and intrinsic auto-regulation. Because PGC is a major driver of filtration, any increase in the MAP would increase RBF and GFR. To keep GFR constant, despite an increase in MAP from 80-180 mmHg, the kidney's use Neuroendocrine regulation and autoregulation.

What are the general functions of the segments of the nephron - the glomerulus, proximal tubule, thin descending LOH, thick ascending LOH, distal concluded tubule, and collecting duct?

We are now going to go over a general overview of the functions of each part of the nephron. Reabsorption = movement of water and solutes from the nephron tubule back into the circulation Secretion = movement of water and solutes from circulation into the nephron tubule Early nephron (major, net functions) •Glomerulus - Filters •PT - Reabs salts & drug secretion. •LOH (DL) - Reabs water! Mid to late nephron (major, net functions) •LOH (AL) - NaCl reabsorption •DCT - Adjusting salts •CD - Adjusting water The glomerulus is our filter. Blood will enter the glomerulus from the afferent arteriole. The glomerulus will then filter the plasma out of this blood and dump it into the proximal tubule. When the plasma enters the PT is it referred to as filtrate. The proximal tubule is in charge of basically reabsorbing a lot of salt and water back into circulation. There are some other things that are going to be highly reabsorbed in this area such as proteins (amino acids), glucose, and bicarb. The descending limb of the Loop of Henle is basically reabsorbing water. The thick ascending limb is basically going to be pumping out salts back into circulation, thus we are reabsorbing salts in this area. The thick ascending limb and the thin descending limb work together. As the thick ascending limb pushes out salts it will cause water to also be reabsorbed from the thin descending limb considering water follows salts. The distal convoluted tubule is fine tunning the adjustment of salts. Some of that will continue in the collecting duct. But the collecting duct's main function is fine-tuning the adjustment of water.

The glomerulus has a 3-layer barrier that helps promote filtration and limit what is able to cross into the nephron. What are these 3 barriers? what are the 3 things that determine what will be filtered across the glomerulus?

We are now going to look at the glomerular membrane. The glomerulus has a 3-layer barrier that helps promote filtration and limit what is able to cross into the nephron. 1.Fenestrated Capillary Endothelium 2.Glomerular basement membrane 3.Podocytes with filtration slits. A normal capillary bed just has fenestrated capillary endothelium cells. These cells have a gap or space between them therefore they are typically referred to as fenestrated. There is a physical space between each endothelium cell on the capillary side. While this is normally the only barrier in capillary beds, the glomerulus has two additional barriers. In the glomerulus, blood entering through the afferent arteriole will be pushed through these gaps outward into the Bowman's capsule where it will make its way into the proximal tubule. We also have the basement membrane in the glomerulus which has a negative charge on it. If the substance that you are trying to filter into the nephron has a negative charge on it, there will be an issue considering the two negatives will want to repel each other. This is actually a good thing because it helps prevent proteins from being filtered into the nephron and making their way into the filtrate. The third barrier in the glomerulus is a group of cells sometimes referred to as podocytes. These are also epithelial cells. Therefore, because there are three different barriers in the glomerulus capillary bed, it is able to handle a much higher pressure than a normal capillary bed would. It is important to note that the quality of this membrane can change. For example, in pts with sepsis, the bacteria that induce sepsis can make a byproduct called LPS (lipopolysaccharide). LPS can make the capillary endothelium cells swell. When this occurs, the fenestrations (the gaps) get smaller, thus making it harder to filter stuff across the glomerulus that you would normally filter across with ease. Chronic diabetics who are not good at glycemic control would also be another example. The basement membrane will thicken in these pts which makes it a lot harder for things to be filtered across the glomerulus and into the nephron. Having an understanding of the three cell layer barriers that make up the glomerulus helps us understand glomerular filtration and what can affect it. What can be filtered across this capillary bed and into the nephron depends on the 3 things listed below. 1. The glomerular filtration membrane 2. Size & charge of filtered molecules 3. Net filtration pressure What is going to filter across will depend on a couple of things. The first is the quality of our filtration membrane, which is what we just discussed. 2nd is the size and charge of the molecules that we are trying to filter, and the third thing is the driving pressure (net filtration pressure). These are the three things that are going to determine what will move across this membrane.

What are the 7 different groups of neuroendocrine influencers? which causes vasoconstriction? vasodilation?

We are now going to look at the neuroendocrine influencers. There are 7 different groups. 1. NE/Epi 2. ANGII & ADH/AVP 3. Adenosine (ATP) 4. NO 5. Renal prostaglandins 6. ANP 7. Dopamine 1, 2, and 3 are vasoconstrictor,s and 4, 5, 6, and 7 are vasodiltors. For the 7 neuroendocrine influencers, you should be familiar with the agent, its primary effect, which arteriole it is affecting, and how that would affect GFR. Test questions will target this information!!

What is the movement of plasma from the glomerulus to the collecting duct? what is the plasma called when it enters the nephron? what is the juxtaglomerular apparatus?

We are now going to take a look at the nephron. The glomerulus is the place where blood is going to be filtered. It is basically a modified capillary bed that's going to allow us to filter blood and bring plasma into the nephron. Once the plasma enters the nephron it is referred to as filtrate. We will talk a little about how those two things differ but they're basically the same thing except for two major differences. The filtrate is first going to enter the proximal tubule. It will then go down the descending loop of Henle and up the ascending loop of Henle. It will then travel into the thick ascending limb of the loop of Henle, the distal convoluted tubule, and lastly into the collecting duct. The collecting duct can be separated into the cortical collecting duct and the medullary collecting duct. In this image, we can also see the juxtaglomerular apparatus. We have our glomerulus which sits in between our afferent arteriole and efferent arteriole. Between the thick ascending limb and the start of the distal convoluted tubule, we have a region of the nephron that is really close to the glomerulus. This region is the juxtaglomerulus which is known as the juxtaglomerular apparatus. It is basically a part of the nephron that is near the glomerulus.

Why can creatinine also be used to estimate GFR? how is it done?

We can do the exact same thing that we just talked about with inulin but rather with creatinine. The advantage to using creatinine is that we do not have to infuse it considering it is produced by the muscle cells in our body. It is endogenously produced and the rate of production does not change as long as the pt isn't taking creatinine, missing limbs, or has a severe muscle-wasting disease. Therefore, the advantage to this is we can just collect the blood, measure the creatinine, and then we can plug this into the prediction equation. Again, it is endogenously produced and in a normal healthy pt it will be constant. Therefore, the rate of production and the rate of excretion should be the same. It is freely filterable and does not get reabsorbed. The only downside is we get a little bit of secretion which is what the little arrow is showing us in the image. About 10% of the total urinary creatinine will be secreted. Creatinine is most commonly used estimate of GFR because: •it's a metabolite produced by creatine phosphate metabolism (no infusion needed) •in a normal healthy person the rate of production is constant •The rate of production = rate of excretion •freely filterable by the kidney •not Reabsorbed •some small secretion into the nephron (~10%) •Tends to be balanced out by measurement error.

What is a normal GFR? what is the GFR for stage 2 CKD? stage 4? stage 5?

We use GFR as a way to stage kidney disease. Normal kidney GFR is 129-91. Once the pts GFR beings to drop under 90 they would be considered to be in stage 2 of chronic kidney disease (CKD). For the exam, you should know the following thresholds - under 90 which is stage 2 and then you should also know stage 4 which is from 30 to 15, and stage 5 which is <15 or the pt is on dialysis. It is also important to know that GFR decreases with age. You will lose about a 1mL/min/yr after the age of 40. Furthermore, with the most severe kidney disease you're basically looking at a 50% death rate every about 2 years. The lesser the stage of kidney disease the longer the 50% death rate is pushed out. In other words, the better your GFR the better your lifespan estimate will be. In terms of CKD, there is not a whole lot that can be done for the pt. If the pt manages their BP and/or diabetes (which are the two major causes of CKD) really well. And lower their blood cholesterol on top of that, the pt will still die. Most patients will die of cardiovascular disease not from kidney disease in these cases due to cardiac hypertrophy. GFR declines as a natural function of age, but in a normal healthy aging person, remaining renal function will be adequate for proper filtration. CKD is accelerated declines in GFR and the lower the GFR, the higher the mortality rate.