L2 Fill Renal Blood Flow Filtration and Clearance 2013 _mf Edited

Renal Blood Flow, Filtration and Clearance (Dr. Fill)

RENAL PHYSIOLOGY LECTURE #2

RENAL BLOOD FLOW, FILTRATION AND CLEARANCE

Michael Fill, PhD Department of Molecular Biophysics and Physiology [email protected] 312-942-6434

Resource Material:

1. These Lecture Notes 2. Suggested Readings

a. Principles of Physiology, 4th Ed., Berne & Levy, Chapters 36-40 b. Vander’s Renal Physiology, 5th or 6th Edition

Learning Objectives:

1) Define renal blood flow (RBF), renal plasma flow (RPF) and glomerular filteration rate (GFR) and give normal values of each.

2) Describe the forces (hydrostatic & oncontic pressures) and factors (hydraulic permeability & surface area) that determine the rate at which the glomerular filtrate is formed.

3) Define the terms net filtration pressure (NFP) and filtration coefficient. 4) Describe autoregulation of RBF (and GFR) and two mechanisms of autoregulation

(myogenic & tubuloglomerular feedback). 5) Define the term clearance and list what information is needed to calculate the clearance

of a solute also be able to calculate clearance if given the needed information. 6) Describe why clearance of inulin or creatinine can be used to access GFR. This includes

explaining why inulin clearance is more accurate as well as why creatinine clearance is more practical (although less accurate).

7) Describe why clearance of para-aminohippurate (PAH) can be used to access RPF.


Some Key Words:

Autoregulation BUN Clearance Creatinine Filtration Coefficient Filtration Driving Force Filtration Fraction Glomerular Filtration Rate (GFR) Inulin Juxtaglomerular Apparatus Macula Densa PAH Renal Blood Flow (RBF) Renal Plasma Flow (RPF) Tubuloglomerular Feedback

I. Filtration of Water and Some Solutes Far Exceeds Their Excretion Approximately 180 L of fluid per day enter the nephrons in an average adult. This amount of fluid weighs roughly 2.5 times the typical weight of an average adult human body. It is about 4 times the total amount of water in the average adult body (or ~50 times the typical volume of plasma). The point is that a huge amount of fluid is filtered. Of course, most of the filtrate is water and usually most of the urine produced is water. Typical urine flow per day is very roughly about 1.5 L (but this will vary with fluid intake). Since water is not secreted, this means that ~99% of filtered water is reabsorbed. Table 2.1 lists the typical values involved in the renal handling of water and a few other important solutes (for a normal individual). Note that large amounts of these substances are filtered and then nearly all of it is subsequently reabsorbed (i.e. not excreted).


TABLE 2.1

Think of filtration as the kidney’s default mode of handling solutes. Any substance that is just filtered (not reabsorbed or secreted) will be excreted in precisely the amount that is filtered. If the substance is not water, then it will end up concentrated in urine (relative to plasma) because of the extensive water reabsorption along the renal tubules. The advantage of filtration is that no specific transport system is needed for something to be eliminated from the body - just allow it to be filtered and do not reabsorb it. The disadvantage of essentially nonselective filtration is that the body must expend considerable energy to reabsorb filtered substances that it needs to retain. Table 2.1 lists some filtered substances (including water) that are almost completely (~99%) reabsorbed into the peritubular capillaries. This “filtered then almost completely reabsorbed” scenario is certainly not the case for all solutes. Indeed, different substances are handled very differently by nephrons. II. Glomerular Filtration and Renal Blood Flow 1. Numbers/Values Associated with Filtration The values below are those for a normal healthy adult.

Renal Blood Flow or RBF ≈ 1.1 L/min (This is typically 20-25% of cardiac output.)

Renal Plasma Flow or RPF ≈ 625 ml/min (RPF = RBF x (1 – hematocrit)….. For a hematocrit of ~0.43, the RPF can be calculated RBFx0.57 (or 1.1x0.57).

Glomerular Filtration Rate or GFR ≈ 125 ml/min

Urine flow rate ≈ 1 ml/min (This is less than < 1% of GFR.) As you all know from experience, urine flow rate can vary a great deal from the ‘typical’ value given above. Moreover, all of the above values can vary with body size. Generally, smaller individuals have smaller values.

Substance, units Amount Filtered

Amount Excreted

Amount Reabsorbed

% of filtered load reabsorbed

H2OL/day 180 ∼1.5 178.5 99.2%

Na mM/day 25000 150 24850 99.4% Cl mM/day 20000 150 19850 99.3% HCO3 mM/day 4500 ∼2 4498 >99.9% Glucose mM/day 800 ∼0.5 799.5 >99.9%


Another definition you should be familiar with is filtration fraction.

Filtration Fraction = GFR/RPF ≈ 0.2 Because freely filtered substances enter Bowman’s space along with water, this means that ~20% of all freely filtered solutes (Na, K, glucose, etc.) present in the plasma enter Bowman’s space. Another point, RBF far exceeds what is needed to service the kidney’s own metabolic needs. This means RBF may vary dramatically without compromising kidney cell viability. In other words, RBF can be modulated in response to other physiological needs without kidney cells paying a metabolic price. 2. Filtration Driving Force

The glomerulus has both afferent and efferent arterioles. The renal circulation traverses two capillary beds in series, the glomerular capillaries then the peritubular capillaries. Most capillaries in the body (as you may recall from the Cardiovascular lectures), have a net filtration of fluid at their arterial end and net reabsorption at the venous end. This is not the case in the glomerular capillaries. Fluid is filtered into Bowman’s capsule along the entire length of the glomerular capillaries. Figure 2.1 compares filtration in skeletal muscle and glomerular capillaries to illustrate this point.

FIGURE 2.1 (adapted from Sherwood, Human Physiol., 5th edition, Brooks/Cole, 2004)

First, note that the average hydrostatic pressure (averaged over entire X-axis) in the

skeletal capillaries is ~25 mm Hg and average hydrostatic pressure in the glomerular capillaries (PGC) is ~55 mm Hg. This higher pressure arises from the fact that the afferent arterial diameter


is usually larger than that of the efferent arteriole. Second, note that the hydrostatic pressure in skeletal capillaries changes with distance, while hydrostatic pressure in the glomerular capillaries is essentially constant. This is because there is relatively high resistance in skeletal capillaries so pressure falls substantially with distance. There is relatively low resistance in glomerular capillaries so it does not. The reason is that the glomerulus has many (30-50) parallel capillary loops which make resistance to blood flow very low. Third, note that the colloid oncotic pressure (COP) becomes greater with distance along the glomerular capillaries (see sloping line in Figure 2.1, part B). The COP changes with distance along the glomerular capillaries because a large volume of water (~20%) filters out concentrating the proteins/solutes left behind. Remember, fluid is filtered into Bowman’s capsule all along the entire length of the glomerular capillaries. Hydrostatic pressure in Bowman’s space (PBS) is also shown. Figure 2.2 summarizes the forces driving glomerular filtration. FIGURE 2.2 (adapted from Sherwood, Human Physiol., 5th edition, Brooks/Cole, 2004)

Net Filtration Pressure (NFP) equals, NFP = PGC – (πGC + PBS) where, PGC is average glomerular capillary hydrostatic pressure. πGC is average plasma oncotic

(or colloid osmotic) pressure PBS is average hydrostatic Pressure in Bowman’s space As shown in Figure 2.2, average typical values of these parameters are: PGC ≈ 55 mm Hg πGC ≈ 30 mm Hg PBS ≈ 15 mm Hg Thus, plugging these values into the equation shows that average NFP = 55

– (30 + 15) or 10 mm Hg.


3. Filtration Coefficient Glomular filtration rate (GFR) will of course depend on NFP but it will also depend on the hydraulic permeability of the glomerular capillaries as well as their surface area. The filtration coefficient (Kf) is the product of capillary hydraulic permeability (i.e. permeability to water) and capillary surface area. The Kf, GFR and NFP are related as follows,

GFR = Kf x NFP

In glomerular capillaries, hydraulic permeability and surface area are large compared to most other capillaries in the body. The hydraulic permeability is bigger because of the endothelial fenestrations of the glomerular capillaries. The surface area is bigger because of the extensive branching/looping of the glomerular capillaries. Consequently, the Kf of glomerular capillaries is high. This combined with a NFP that favors filtration along the entire length of the glomerular capillaries assures a high degree of fluid filtration at the glomerulus. Glomerular filtration amounts to roughly 180 L/day in a normal individual. Net filtration from all other capillaries in the body only amounts to only a few liters per day. The point here is that glomerular capillaries are specialized for filtration. These capillaries are different than those in other parts of the body. The magnitude of fluid filtered in the glomerular capillaries is huge. No reabsorption occurs in glomerular capillaries. The peritubular capillaries are the site of, and are specialized for, reabsorption.

4. Factors that can Influence GFR

From the discussion above, it should be clear that anything that alters NFP or Kf

will alter GFR (filtration). To illustrate this, some examples are given below:

A urinary tract obstruction can increase the hydrostatic pressure in Bowman’s space (PBS). This could occur if there is kidney stone blocking a ureter. Building pressure up stream of the blockage may be transmitted up to the nephrons and Bowman’s capsule. The resulting increase in PBC would oppose filtration.

An alteration in mean arterial pressure (MAP) can change the hydrostatic pressure in

the glomerular capillaries (PGC) and thus of course would alter GFR. For example, increased MAP would increase GFR (all else being equal, which it isn’t). A MAP-induced change in GFR may be limited by autoregulation (see below).

A renal artery stenosis (abnormal narrowing) can reduce PGC and thereby reduce GFR

in the affected kidney.

A reduction in the number of functional nephrons (perhaps due to disease) may result in a reduced Kf and thus reduce GFR. Each kidney contains ~1 million nephrons. Loss of half the nephrons in one kidney would substantially reduce the total surface area of glomerular capillary available for filtration. Remember that Kf is proportional to the surface area over which filtration occurs. Loss of nephrons reduces Kf which translates into reduced GFR.


The role of the sympathetic nervous system in renal function will be described in more

detail later. Mesangial cells sit between capillary loops in the glomerulus. These cells act as phagocytes and remove trapped material from the glomerulus. However, these cells also contain myofilaments and contract in response to simulation, much like vascular smooth muscle cells. Thus, sympathetic activation can reduce both PGC (via arteriole vasoconstriction) and Kf (via mesangial cell contraction which closes down some glomerular capillary loops). These actions, individually or combined, would lead to a reduced GFR.

Loss of plasma proteins (perhaps due to starvation or renal disease) will reduce the

plasma oncotic pressure and, by itself, will increase GFR (since plasma oncotic pressure opposes filtration).

5. Autoregulation of GFR and RBF Interestingly, RBF (and GFR) can remain relatively constant even when arterial blood pressure changes because of renal autoregulation. This autoregulation is an intrinsic property of the kidney and even occurs in kidneys that are isolated, denervated and perfused with blood in a lab. Figure 2.3 illustrates renal autoregulation showing RBF and GFR as a function of mean arterial blood pressure (MAP) over a wide range of pressures. Normal MAP (as you should recall from the cardiovascular lectures) is typically in the range of 80-180 mm Hg. In Figure 2.3, GFR and RBF values are normalized to 100% of normal so both can be seen easily on the same plot (remember, normal GFR is ~125 ml/min & normal RBF is ~1.1 L/min). Note that GFR and RBF (in the absence of extrinsic influences such as the effects of the sympathetic nervous system) are maintained essentially constant over the 80-180 range of MAPs. Autoregulation fails at the extremes of MAP. For example, autoregulation fails when MAP falls significantly (below 80 mm Hg) and this will lead to a decrease in GFR. The mechanism of autoregulation (see paragraphs below) does not depend on innervation of the kidneys or on circulating hormones. It is an intrinsic property of the kidney. It is very important, however, to recognize that it can be over-ridden by extrinsic signals to the kidneys. These extrinsic signals include the actions of the sympathetic nervous system and circulating angiotensin II. Details concerning these extrinsic signals will be considered later on. Here, our focus is on intrinsic renal autoregulation.

There are two basic mechanisms of intrinsic renal autoregulation. These are: 1. myogenic

2. tubuloglomerular feedback The myogenic mechanism is one that is common to many arterioles and has already been described in the cardiovascular lectures. When arterioles are stretched due to increased blood pressure, they tend to contract and thereby increase their resistance to flow. Although the exact mechanism is uncertain, it is proposed that stretch of the arterial wall “somehow” depolarizes the smooth muscle cells in the wall. This activates voltage-dependent Ca channels resulting in an influx of Ca into the cell. The resulting rise in intracellular Ca triggers contraction. Reduced stretch (at lower blood pressure) “somehow” hyperpolarizes the smooth muscle cells, reduces Ca


entry and promotes relaxation. In the kidney, this myogenic mechanism is less important than the tubulogomerular feedback described below. FIGURE 2.3 (made by Dr. Fill)

The tubuloglomerular feedback mechanism of renal autoregulation was described briefly in the previous lecture. In general, this is a negative-feedback system that stabilizes RBF and GFR. It is associated with the juxtaglomerular apparatus (JGA) which is shown (again here) in Figure 2.4. The JGA consists of a juxtaposition of the distal tubule and the arterioles that control the blood supply at the glomerulus where the tubular fluid (inside that particular distal tubule) first formed. The JGA has one type of specialized cell that make up the macula densa and another type called granular cells. These are labeled in Figure 2.4. Briefly, tubular fluid composition in the distal tubule is sensed by the macula densa (which is part of the distal tubule wall). This generates a signal that ultimately leads to vasoconstriction of the afferent arteriole and decreased GFR.

FIGURE 2.4 (adapted from Sherwood, Human Physiol., 5th edition, Brooks/Cole, 2004)


The details of the tubuloglomerular feedback mechanism are still not entirely known. It is known that an increase in blood pressure (MAP) will increase the hydrostatic pressure in the glomerular capillaries (PGC). This will increase GFR and ultimately increase the flow of tubular fluid through the nephron. Increased flow through the distal tubule is sensed by the macula densa. It is thought that the increased delivery of NaCl due to the increased flow is involved in the “sensing”. The precise “sensing” mechanism is still a bit of a mystery. In any event, increased flow in the distal tubule is “sensed” by the macula densa and this triggers the release of a vasoconstrictor molecule (from the macula densa cells). This molecule then diffuses locally around the JGA and ultimately causes the vasoconstriction of the afferent arteriole. There is some evidence (still inconclusive evidence) that the local vasoconstrictor is perhaps ATP (or possibly adensine). A simplified summary of local tubulogomerular feedback is illustrated in Figure 2.5. Note that granular cells are not involved in the local tubulogomerular feedback. Later you will learn that the granular cells secrete renin. This renin leaves the kidney and promotes production of angiotensin II. Angiotensin II is a potent vasoconstrictor (system-wide) but it is not part of the local tubulogomerular feedback mechanism.

FIGURE 2.5 (adapted from Rhoades & Tanner, 2003)

In Figure 2.5, autoregulation by both the myogenic and tubuloglomerular (TG) pathways are shown. Both pathways result in afferent arteriolar constriction. Remember the TG pathway plays the bigger role in renal autoregulation. Also remember that extrinsic signals (i.e. coming from outside the kidney) like sympathetic inputs and/or circulating angiotensin II can override the intrinsic auotoregulation in the kidney.


SUMMARY POINTS: Glomerular Filtration & Renal Blood Flow

1. More than 99% of filtered water is reabsorbed. This “filter then reabsorb almost

all” paradigm also applies to certain other solutes like Na, Cl, HCO3 and glucose.

2. The typical values of glomerular filtration rate (GFR), renal blood flow (RBF), renal plasma flow (RPF) and filtration fraction (FF) are: GFR ≈ 125 ml/min RBF ≈ 1.1 L/min RPF ≈ 625 ml/min where RPF = RBF x (1 – hematocrit) FF ≈ 0.2 where FF = GFR/RPF 3. Net filtration pressure (NFP) is a function of hydrostatic and oncotic pressure

differences in the glomerular capillaries and Bowman’s space. The product of NFP and the filtration coefficient (Kf) defines GFR. The Kf in turn is defined by glomerular capillary hydrostatic permeability and surface area. Any disturbance or change in any of these factors (i.e. pressures, capillary permeability, capillary surface area) will affect GFR. Examples of such disturbances include: a urinary tract obstruction, changes in MAP, sympathetic nervous system activity and changes plasma protein concentration.

4. Renal autoregulation allows RBF (and GFR) to remain relatively constant even when arterial blood pressure changes (within certain limits). This autoregulation is an intrinsic property of the kidney. There are two basic mechanisms of intrinsic renal autoregulation. These two mechanisms are myogenic and tubuloglomerular feedback. III. Renal Clearance The plasma leaving the kidney through the renal veins lacks the substances that were left behind (in the kidney) to be eventually eliminated in the urine. In other words, the kidneys literally clears (or cleans) these substances from the plasma that flows through them. Renal clearance of any substance is defined as the volume of plasma cleared of that substance by the kidneys per minute. Clearance can be calculated and is often used to evaluate how well the


kidneys are working. To help you understand this concept, it is often useful to keep the units of clearance (ml/min) in mind. Clearance units are volume per time. Clearance is not the amount of the substance removed but instead the volume of plasma from which it was removed. 1. Calculation of Clearance Intuitively, what goes in must come out. Substances enter the kidney in plasma and exit either in the outgoing plasma or in the urine. It is also logical that the amount of a substance excreted in the urine must have been contained in “some” volume of plasma. The goal here is to calculate this “virtual” plasma volume. Consider substance X and a patient sitting in the hospital waiting room generating urine for the last hour. To determine the clearance of X (CX), we need to know how much X was excreted in the patient’s urine. If this patient has a urine flow rate (V) of 50 ml per hour and their urine X concentration (UX) is 0.6 mg/ml, then the amount of X excreted is UX x V (0.6 mg/ml times 50 ml/hr) or 30 mg/hr. Analogous to above, the amount of substance X in “cleared plasma” can be expressed as a product of plasma volume per unit time (i.e. CX) and plasma X concentration (PX). This can be expressed as PX x CX. The amount in cleared plasma must equal amount excreted in urine (in must equal out). In other words, PX x CX must be equal to 30 mg/hr in our example (i.e. UX x V). PX x CX = UX x V (amount X in = (amount X excreted cleared plasma) in urine) Some straightforward algebra and we have a convenient way to calculate the clearance of X.

PV x UC

X

XX =

This formula is convenient because UX, PX and V can be measured in the lab. In our example above, assume that PX equals 0.1 mg/ml. If we plug all the values in, then we can calculate that CX is 300 ml/hr (i.e. 30 mg/hour divided by 0.1 mg/ml). The clearances of a few “special” substances have proven to be very useful in estimating crucial renal parameters such as GFR (glomerular filtration rate) and RPF (renal plasma flow). Thus, clearance (of these substances) represents important diagnostic tools in probing renal function. 2. Clearance of Inulin Inulin is a polysaccharide that is freely filtered but not reabsorbed or secreted. This means that all the inulin that enters the nephron by filtration will be excreted in the urine. Thus, the volume of plasma cleared of inulin per unit time is the same as the glomerular filtration rate (GFR). Indeed, inulin clearance is the “gold standard” way to measure GFR. The factors that make inulin clearance ideal for measuring GFR are,


1. Inulin is freely filtered. 2. Inulin is neither reabsorbed nor secreted. The nephron tubules have no inulin

transporters and inulin can not diffuse out of the tubules so all that is filtered will be excreted.

3. There are no enzymes in the tubules that break down or synthesize inulin. The concept of inulin clearance is illustrated graphically in Figure 2.5A. Inulin containing plasma is filtered. The plasma (not the inulin) is reabsorbed. Thus, the volume of plasma filtered was “cleared” of inulin. This is why inulin clearance can be used as a measure of GFR.

FIGURE 2.5A (adapted from Sherwood, Human Physiology 5th Edition, 2004)

In order to calculate inulin clearance (CINULIN) and thus GFR, you will need to know the plasma and urine inulin concentrations (PINULIN & UINULIN) as well as urine flow rate (V). However, inulin will need to be infused into the patient because it is not a naturally occurring substance in the body. At this point, you may be inclined to think that clearance of a substance can never be greater than GFR (or CINULIN). If so, then you would be wrong. Clearance can be greater than CINULIN and a great example is the clearance of PAH (para-aminohippurate) described next. But first, let’s consider why clearance may vary. Why clearance of a substance may vary is illustrated in Figure 2.5B. Clearance will be greater than GFR (or CINULIN) if the substance is filtered and also secreted (right panel). Clearance will be smaller if the substance is filtered and


then reabsorbed (left panel). Reabsorption (R) Secretion (S) Reducing Clearance Increasing Clearance

FIGURE 2.5B (adapted from Sherwood, Human Physiology 5th Edition, 2004) 3. Clearance of PAH Para-aminohippurate (PAH) is a freely filtered small organic anion that happens to be robustly secreted into the proximal tubule of the nephron. Its secretion can saturate. In other words, there is a maximum rate at which PAH can be secreted into the tubule (i.e. there is a transport maximum or TM). This concept of TM will be discussed more later. Like inulin, exogenous PAH must be infused into the patient. Robust PAH secretion results in nearly all (~90%) of the PAH in the plasma entering the kidney being excreted in the urine. Such a high value can not be reached simply by filtration alone because only ~20% of the plasma is filtered (recall filtration fraction = GFR/RPF = 0.2 usually). So, secretion must be involved here. The 90% value means that PAH clearance (CPAH) approaches RPF. Indeed, CPAH is often used to access RPF. The RPF estimated in this way is sometimes called the “effective renal plasma flow” (ERPF) to indicate that it is a slight underestimate of the true RPF.


The concept of PAH clearance is graphically presented in Figure 2.6 below.

FIGURE 2.6 (adapted from Berne & Levy, Physiology 4th Edition, 1998)

Two different situations are presented in Figure 2.6. Note that plasma PAH is double in part B of the figure. The RPF and GFR are the same but PAH clearance is not. Why? The PAH clearance in part A is a relatively good estimate of RPF because all the non-filtered PAH is secreted (i.e. all PAH in plasma entering the system ends up in the urine). In part B, the PAH secretion mechanism reaches its transport maximum (TM) and some non-filtered PAH escapes (33% in this case). Thus, not all PAH in plasma entering the system ends up in the urine. Consequently, PAH clearance in this particular situation is not such a good an estimate of RPF. The point is that PAH clearance predictions of RPF are best when the PAH secretion mechanism is not saturated (i.e. when its working below its TM). For practice, you may want to use the numbers given in Figure 2.6 and calculate CPAH, RPF and GFR for yourself. In this example (Figure 2.6 part A), GFR and RPF are 100 and 700 ml/min, respectively.


The example given in Figure 2.6 (part A) is idealized (i.e. 100% non-filtered PAH is secreted). In reality, there will always be some PAH in the renal venous blood even at very low plasma PAH values. The reason is related to kidney circulatory anatomy. The PAH secretory mechanism is in the proximal tubule and PAH in the peritubular capillaries surrounding the proximal tubule is secreted. However, some PAH containing plamsa goes to capillaries that perfuse other regions of the nephron (e.g. vasa recta). PAH in this plasma is not secreted and escapes back into the systemic circulation. Typically, this amounts to 10% of the PAH explaining the “nearly all 90%” value given above, This is why CPAH underestimates true RPF. If CPAH estimates RPF, then CPAH can be also be used to estimate RBF (renal blood flow). Recall that, RPF = RBF x (1 – hematocrit) re-arranging, RBF = RPF / (1 – hematocrit) If the hematocrit is ~0.43, then (1-hemetocrit) = 0.57 CPAH is not usually performed in clinical situations. Measurements of CINULIN are more common especially if accurate measures of GFR are required. For routine assessment of renal function (and GFR), however, creatinine clearance (CCREATININE) is often used (see below). 4. Clearance of Creatinine CINULULI is the “gold standard” for clinical GFR determinations. Unfortunately, inulin is not a naturally occurring substance in the body. Thus, a CINULULI measurement requires administration of inulin into the blood at a rate that will keep its concentration in the plasma constant throughout the measurement period. This can be rather cumbersome and rarely pleasant for the patient. Measurement of CCREATININE is a practical alternative. Creatinine is the end product of creatine metabolism and is continuously dumped into the blood by skeletal muscle. Skeletal muscle creatinine production is constant and the rate of creatinine appearance in the blood is proportional to a person’s muscle mass (which is typically constant on the time frame needed here). Creatinine is freely filtered and not reabsorbed (i.e. just like inulin). A small amount (10-20%) is secreted by the proximal tubule and this makes it a non-ideal inulin substitute that will slightly overestimate GFR (by 10-20%). However, this degree of error is often acceptable when a quick GFR assessment is desired. Indeed, CCREATININE is the most common method used for routine GFR assessments. In practice, however, it is far more common to simply measure plasma creatinine concentration (PCREATININE) and then use this value alone as an indicator of GFR. This is possible because there is a nice inverse correlation between PCREATININE and GFR. This correlation is shown in Figure 2.7.


FIGURE 2.7 (adapted from Berne & Levy, Physiology 4th Edition, 1998)

Normal PCREATININE is 1 mg/dl and (from the plot above) normal GFR is ~125 ml/min (as expected). Suppose one day GFR suddenly falls to 50% normal. The plot above indicates that PCREATININE will approximately double. A common question is the following. If there is a persistent 50% GFR reduction, then why doesn’t PCREATININE just continue to rise? Why does it stabilize at approximately double? The reason is that the amount of creatinine excreted in the urine is the same at (100% GFR & 1 mg/dl creatinine) as it is at (50% GFR & 2 mg/dl). This is the level of creatinine excretion that equals the creatinine production in the body. This is the balance concept. A substance is in balance when its input and output match.

In the example above, a single PCREATININE measurement is used as a reasonable indicator of GFR. As noted, this method is not completely accurate because some creatinine is secreted. In many cases, a person’s normal PCREATININE is unknown before a renal crisis arises. However, an abnormally high PCREATININE is always a red flag and suggests that there may be a renal problem. Occasionally, plasma urea level (BUN or blood urea nitrogen) may also serve as an indicator of GFR. This is, however, even less accurate than the PCREATININE method.


SUMMARY POINTS: Renal Clearance

1. The formula to calculate clearance of a solute is….

PV x UC

X

XX =

where, CX is clearance of X (volume per unit time) UX is urine X concentration (amount per unit volume) V is urine volume (volume per unit time) PX is the plasma X concentration (amount per unit volume) 2. In words (instead of a formula), clearance of a particular substance (X) is

the volume of plasma from which X is totally removed by the kidney per minute.

3. The clearance of inulin can accurately measure GFR. Inulin, however, is not

a naturally occurring substance in the body and thus measuring inulin clearance can be clinically cumbersome.

4. The clearance of creatinine can also be used to assess GFR. Creatinine is

naturally occurring in the body and thus creatinine clearance is the more common method used for routine GFR assessments. However, it is less accurate than inulin clearance. Creatinine clearance over estimates GFR.

5. The clearance of para-aminohippurate (PAH) is a measure of RPF. The RPF

estimated in this way is sometimes called the “effective renal plasma flow” (ERPF), to indicate that it is a slight underestimate of the true RPF.

6. Clearance will be equal to GFR if the substance is filtered but not

reabsorbed or secreted. Clearance will be greater than GFR if the substance is filtered and also secreted. Clearance will be smaller than GFR if the substance is filtered and then reabsorbed.


RENAL PHYSIOLOGY LECTURE #2 QUIZ Note that this and other Renal Physiology quizzes are simply provided to you to help you self-test your understanding of each lecture. These questions are not intended to reflect the style or level of difficulty of questions on the Block Exam. True/False Questions: 1. Approximately 99% of filtered water is normally reabsorbed by the nephrons. 2. For a solute that is only filtered (not reabsorbed or secreted), the amount of that

substance excreted in the urine will exactly equal the amount filtered. 3. For a solute that is only filtered (not reabsorbed or secreted), the concentration of that

substance will be higher in the urine than it is in the plasma. 4. Approximately 50% of filtered glucose is normally reabsorbed. 5. Clearance of PAH is a useful measure for estimating renal plasma flow. 6. The normal value for glomerular filtration rate and urine flow rate is about 125 ml/min. 7. Like most capillaries in the body, filtration of fluid occurs initially and then some fluid is

reabsorbed later along the length of the glomerular capillaries. 8. Autoregulation of GFR and RPF is most effective when mean arterial pressure (MAP) is

less than 60 mm Hg. Multiple Choice Questions: 9. Which of the following best describes the relation between Excretion (E), Filtration (F),

Reabsorption (R), and Secretion (S):

a. E = F + R + S b. E = F + R – S c. E = F – R + S d. E = F – R – S e. F = R – S – E


10. Which of the following is normally more concentrated in urine than in plasma:

a. Creatinine b. Glucose c. Plasma proteins d. Blood cells e. none of the above

11. Which of the following is/are involved in the autoregulation of GFR and when MAP

changes:

a. a myogenic response of afferent arteriole b. release of a vasoconstrictor substance from cells in the juxtaglomerular apparatus c. increased sympathetic nervous system output to the kidneys d. a and b only are correct e. a, b and c are all correct

12. Clearance of inulin is

a. independent of the number of working nephrons present b. calculated using the numerical value of RPF c. a reasonably good measure of GFR d. slightly overestimates RPF e. slightly underestimates RBF

Answers: 1. T 6. F 11. d 2. T 7. F 12. c 3. T 8. F 4. F 9. c 5. T 10. a


Normal Plasma & Urine Values

Substance Plasma (blood) Urine Units Ammonium 0 average 30-50 average mEq/L Anion Gap 13 (10-16) mEq/L Bicarbonate 24 (22-26 arterial) mEq/L Calcium 4.5-5.5 5-12 mEq/L Chloride 100 (98-106) 50-130 mEq/L Creatinine 1.2 (0.5-1.5) 6.5-23 mg/100mL Glucose 80 (70-100, fasting) 0 mg/100mL Hematocrit (Hct) 45 (40-50) % Magnesium 2 2-18 mEq/L Osmolality 287 (280-295) 500-800 mOsm/Kg H2O PCO2 (arterial) 40 (37-43, arterial) mmHg pH 7.4 (Average arterial) 5-7 Phosphate 2-3 mEq/100mL Potassium 4.5 (3.5-5.5) 20-70 mEq/L Protein (total) 7 (6-8) 0 g/100mL Sodium 140 (136-146) 50-130 mEq/L Specific Gravity 1.018 (1.001-1.030) Titratable Acid 10-40 mEq/L Urea Nitrogen (BUN) 12 (9-18) mg/100mL

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L2 Fill Renal Blood Flow Filtration and Clearance 2013 _mf Edited