Professor: Thomas D. DuBose, Jr., M.D., M.A.C.P.Telephone: 3-7212Office: NRC 215

I. Permselectivity of the Glomerular Capillary Membrane:

The glomerulus consists of a network of capillaries supplied by the afferent arteriole and is drained by the efferent arteriole. The barrier to filtration is depicted in figure 2 and consists of the endothelial lining of the capillary loop, the glomerular basement membrane and the slit diaphragm of the podocytes. The glomerular barrier is highly specialized because of two characteristics: 1) the effective pore size excludes molecules larger than 42 A. 2) because the slit diaphragm and podocytes are negatively charged (glycoprotein composition), substances in the blood with an effective molecular radius in the range of 20-42 A is selectively filtered: cationic molecules are filtered more readily than anionic molecules. Therefore, charge is an important and unique component of the permselective properties of the GBM. The glomerular ultrafiltrate that enters Bowman’s Space is an ultrafiltrate of plasma and contains no RBCs or albumin or other proteins.

Minimum Learning Objectives

Upon completion of this section, you should be able to:

1. Define verbally, conceptually and mathematically the terms clearance, glomerular filtration rate, hydraulic conductivity.

2. Use the renal clearance concept to define tubular secretion and reabsorption.

3. Explain the use of inulin and creatinine clearances to measure GFR, and how increases in blood creatinine relate to a decrease in renal function.

4. Acquire a working knowledge of the application of clinically applied formulae for estimation of GFR (eGFR) and how stratification of eGFR is used to define the clinical stages of chronic kidney disease.

5. Explain how changes in afferent and efferent arteriolar resistance regulate renal blood flow and GFR.

6. Describe the determinants of the autoregulation of renal blood flow and GFR.

7. Describe the operational components of tubuloglomerular feedback.

Clinical Correlation: Loss of Permselectivity Properties of GBM

Minimal Change Nephropathy is characterized by fusion of the foot processes, loss of charge in the basement membrane and filtration slits, and loss of the permselective properties of the GBM. The clinical finding in this disorder is proteinuria, often on the order of greater than 3.5 Gm/day (clinical definition: nephrotic syndrome includes the features of proteinuria > 3.5 Gm/day, edema and a low serum albumin).

Clinical Correlation: Hematuria of glomerular origin

When RBCs and casts of RBCs of glomerular origin are seen in the urine sediment by microscopic examination, disease of the glomerular capillary is confirmed and is denoted as a “nephritic” sediment or syndrome.

II. GLOMERULAR FILTRATION

Glomerular filtration is the process that separates the aqueous phase of plasma from the large proteins and formed elements. Like most capillaries, the glomerular capillaries are relatively impermeable to large proteins, so the filtrate is relatively free of protein and absent cellular components such as erythrocytes. The concentration of most ions and small molecules in the glomerular filtrate mirrors that in the plasma except for drugs and substances bound in the circulation to plasma proteins. About 20% of the blood plasma that flows through the glomeruli is filtered, accounting for a glomerular filtration rate (GFR) in an adult human of about 125 ml/min or 180 L/day.

As in other capillaries, the flow across the capillary membrane is governed by the Starling forces of hydraulic and oncotic pressures as well as the intrinsic permeability of the membrane surface. This latter factor is called the hydraulic conductivity, or ultrafiltration coefficient (Kf). The Kf of the glomerular capillary is 100-200 times greater than that in muscle or other tissues so this helps account for the very high water permeability of these capillaries. In addition, the pressure in the glomerular capillaries is higher than in systemic capillaries since it is interposed between two arterioles that provide resistance. The hydraulic pressure in the glomerular capillaries is about 50-60 mmHg while that in peripheral muscle averages only 10 mmHg or 20.

There is also a structural difference between the glomerular capillaries and others throughout the body, since in the kidney there are three layers instead of the usual two. The capillary has an endothelium that is punctuated by fenestrations, a basement membrane, and then a layer of epithelial cells known as podocytes. Each of these three layers contributes to the filtration barrier since natural or induced diseases in which molecular components of these membranes are perturbed results in a loss of the permselective properties of this barrier and leakiness to larger molecules such as protein.

Figure 1 Figure 2

Glomerular filtration is a special case because the filtered fluid enters the tubule lumen rather than re-entering the glomerular capillaries. The essential features of the process are shown in Figure 3:

1. The top line is glomerular capillary hydrostatic pressure (PGC); equal to approximately 55 mmHg (depending upon species). In contrast to the peripheral capillary bed, PGC does not decrease significantly along the length of the glomerular capillary. This is because the glomerular capillary is positioned between two high resistances (afferent and efferent arterioles).

2. Hydrostatic pressure in Bowman’s space (PBS) is 15 mmHg, so net PGC is 5515 or 40 mmHg.

3. Plasma oncotic pressure is 22 mmHg at the beginning of the capillary. Therefore, the net ultrafiltration pressure is about 18 mmHg at the beginning of the capillary (shaded).

4. Colloid osmotic pressure increases along the length of the capillary as water and electrolytes are filtered and removed (thereby increasing protein concentration). Note that ultrafiltration pressure declines in glomerular capillaries mainly because plasma oncotic pressure rises, not because of a decrease in intracapillary hydrostatic pressure, as in systemic capillaries.

5. The single nephron glomerular filtration rate can therefore be described as:

a. SNGFR = Kf ([PG – PBS] – COP)

Figure 3

To summarize, the unique differences between glomerular capillaries and peripheral capillaries are as follows:1. Glomerular capillaries have a high hydraulic conductivity.

2. Glomerular capillaries are located between two high resistances, which minimize the pressure drop along the length of the capillary, and are highly regulated. Pressure is higher than in other capillary beds.

I. FORCES GOVERNING PERITUBULAR CAPILLARY REABSORPTION OF FILTRATE

In order for fluid to be reabsorbed, as in the venular end of the peripheral capillary, hydrostatic pressure must fall below that of oncotic pressure. This situation occurs in the postglomerular, peritubular circulation of the kidney, those capillaries which surround the renal tubules. However, before considering peritubular capillary circulation, let us consider the overall problem facing peritubular capillaries.

Figure 4 and subsequent diagrams show the following structures contained in a unit nephron:

1. afferent arteriole2. glomerular capillary3. efferent arteriole4. peritubular capillary. Notice that blood perfusing peritubular capillaries is post

glomerular.5. Proximal convoluted tubule – initial segment (S1)

In the illustration in Figure 4:1. Afferent glomerular capillary flow (QA) is 600 ml/min (QA is equal to renal plasma

flow, RPF).2. Glomerular filtration rate (GFR) is 120 ml/min or about 180 L/day

Figure 4

These approximate normal values for humansGiven the quantities shown in the figure:3. Efferent glomerular plasma flow (QE) is 480 ml/min4. The ratio of GFR to QA (filtration fraction, FF) is 0.25. Tubular reabsorption of filtrate is 99.5% of amount filtered6. The volume of urine excreted is only 0.5% of the volume of fluid filtered7. Therefore, peritubular capillaries must reabsorb 99.5% of the fluid filtered through

glomeruli. This is intuitively clear because the huge volume of fluid filtered at the glomerulus would quickly deplete the body of water if reabsorption were not extensive and efficient. The process of water reabsorption into the peritubular

capillaries from the renal interstitial compartment involves the same forces already outlined which govern fluid movements in all capillaries. The process by which glomerular filtrate passes across the cells of renal tubular epithelium involves different forces, which will be discussed in a later section.

Figure 5 illustrates the profile of forces that govern fluid uptake by the peritubular capillaries. Fluid movement is from interstitium into capillary, the reverse of glomerular filtration. As we saw in the previous diagram, these capillaries are post glomerular in derivation; i.e., the blood has passed through the glomerulus and efferent arteriole. Therefore, at the beginning of the peritubular capillary, colloid osmotic (oncotic) pressure is higher than in the systemic circulation, and is approximately the same as at the end of the glomerular capillary or about 40 mmHg. The line shown in this diagram is the net colloid osmotic pressure, which is the difference between the intracapillary colloid osmotic pressure and the interstitial colloid osmotic pressure. Interstitial colloid osmotic pressure is due to a small amount of lymph protein in the interstitial fluid and averages about 7mmHg. Net colloid osmotic pressure falls along the length of the capillary as protein-free fluid is absorbed from the interstitium back into the capillary.

Figure 5

Peritubular capillary hydrostatic pressure HP is low, since these capillaries lie beyond the high resistance in the efferent arteriole, averages around 11 mmHg, and is balanced by a positive hydrostatic pressure in the renal interstitium equal to 6.5 mmHg. Therefore, net hydrostatic pressure across the peritubular capillary wall is 4.5 mmHg.

The shaded area between these lines for net colloid osmotic pressure and net HP represents the net driving force for uptake of fluid from renal interstitium to capillary. It is the difference between net colloid osmotic pressure favoring reabsorption and net hydrostatic pressure retarding it.

There is a net driving force of about 30 mmHg moving fluid from the interstitial compartment into the capillary at the beginning of the capillary. This driving force declines to about 15 mmHg at the venular end of the capillary.

Summary:

The renal tubule transports a large amount of fluid into the interstitial compartment which must be returned to the circulation via peritubular capillaries. Therefore, peritubular capillaries must reabsorb a large amount of fluid from the interstitial space. This process is facilitated by two features of the renal circulation that cause conditions in the peritubular capillaries to be similar to the venular end of peripheral capillaries.

1. Peritubular capillary hydrostatic pressure is low because it lies beyond a high resistance in the efferent arteriole.

2. Colloid osmotic pressure of peritubular capillary blood is high because the blood is postglomerular. In other words, as blood flows through glomerular capillaries, protein-free fluid is removed from blood and passes into the tubule. During passage down the tubule, most of the fluid is transported out of the tubules and into the interstitial fluid compartment, where it is returned to the circulation via the peritubular capillaries. The volume of this large fluid turnover is approximately equivalent to the GFR, which in normal man is 120 ml/min, about 2% of the cardiac output. This unique feature of the renal vascular bed provides a considerable flexibility to the kidney in the formation of urine, as we shall see.

II. CLEARANCE CONCEPT

To consider a method for measurement of the glomerular filtration rate (GFR), we need to appreciate the most important single tool in the overall assessment of renal function; i.e., the clearance concept which is illustrated in Figure 6.

The kidney removes certain substances from blood and excretes them in urine. Therefore, blood is cleared of these substances. The clearance concept allows one to calculate the volume of blood cleared of a given substance per unit time.

Measurement of GFR is a special case of the clearance technique. It is performed by measuring the clearance of a substance filtered by the glomerulus, but is neither reabsorbed nor secreted by the tubule. The prototype of such a substance is the complex polysaccharide, inulin.

In Figure 6, Z is such a substance. The concentration of Z in plasma (PZ) is 10 mg/ml. If the GFR is 120 ml/min, the amount of Z filtered (or filtered load of Z) is 120 x 10 or 1200 mg/min.

Figure 6

As fluid passes down the tubule, water is reabsorbed, but not Z. Therefore, the amount of Z excreted is exactly the same as the amount filtered. Remember that

Amount = Volume x Concentration

The amount of Z excreted is UZV; the amount filtered is GFR x PZ. Therefore, these two quantities are equal, as shown by equation 1 in Figure 6. Solving equation 1 for GFR gives equation 2. GFR equals excretion rate of Z (UZV) divided by plasma concentration (PZ). The units are in ml/min. The parameters of this equation are easily measured.

Equation 2 is a clearance equation, which is written in a general form in equation 3. Equation 3 is valid for any substance cleared from blood by the kidney. The clearance of any substance is equal to the excretion rate of the substance divided by the plasma level of the substance.

These calculations are illustrated in Figure 7. Clearance of any substance Z is equal to excretion rate divided by plasma concentration. Units are ml/min.

CLEARANCE (C)Clearance of substance Z

UZVC = ——

PZ

UZ = Urine concentration of Z (mg/ml)PZ = Plasma concentration of Z (mg/ml)V = Urine flow (ml/min)

C = mg/ml x ml/min mg/ml

C = (ml/min)

Clearance = Volume of Plasma Completely “Cleared” of Z per Unit Time.

Figure 7

Clearance in ml/min is the volume of plasma completely cleared of substance Z per unit time. Volume in this expression is a virtual volume, not a real volume, since the kidney cannot completely remove any substance from a partial volume of a well-mixed solution such as plasma. However, the net physiologic effect with regard to any substance cleared by the kidney is as though a subfraction of plasma were completely cleared of the substance per unit of time.

To take the example of the preceding figure, inulin (substance Z) clearance is 120 ml/min. This means that the net physiologic effect of renal function is to remove all inulin that would have been contained in 120 ml of plasma each minute. As mentioned earlier, this same concept applies to any substance cleared by the kidney, which includes almost every substance present in plasma water.

The normal inulin clearance (GFR) in adult humans between the ages of 20 and 50 is 122 ± 13 ml/min. The GFR in males tends to be higher than females, and it usually declines with age in both sexes. The identity of inulin clearance and GFR as shown in the previous diagram depends on certain assumptions, the most important of which is that the amount of inulin filtered is equal to the amount excreted. A drawback to the routine clinical use of inulin clearance to measure GFR is that a sterile solution must be infused at a constant rate and accurately times urine collections made. Blood must be sampled to ensure steady state. Nevertheless, it remains the “gold standard.”

Creatinine, an endogenous metabolite, is a useful as a marker of GFR, becaue the plasma level is relatively constant and does not have to be infused. Creatinine is excreted mostly, but not totally, by glomerular filtration so that its clearance approximates that of inulin. Therefore, for a clinical estimate of GFR, the endogenous creatinine clearance may be used.

Because creatinine is produced endogenously at a relatively constant rate unless big changes in muscle metabolism occur, the plasma or serum level of creatinine can also be used as an index of renal function. If GFR is reduced by 50% with constant production, serum creatinine will double. Thus, it serves as an easy clinical marker of kidney function. Since in the clinical setting a 24 hour collection is often used, it is not surprising that the accuracy of the Ccr depends on whether all urine is collected appropriately. The error rate is high and therefore this test is

used less often. Figure 8 illustrates the reverse hyperbolic relationship between serum creatinine and GFR. Note that the major limitation of the serum creatinine is its insensitivity to small changes in GFR in the range of 50-100 mL/min.

Figure 8

Because of collection errors and inconvenience, one nomogram for estimating GFR just from the serum creatinine concentration, age, sex, and weight, is known as the Cockcroft-Gault formula:

GFR (males) = (140 – age in yr) x lean BW in kg——————————————Serum creat in mg/dl x 72

GFR (females) = value for males x 0.85

In our hospital and in most clinical reference laboratories used by physician offices throughout the US, the plasma or serum creatinine can be used to calculate an estimated GFR or eGFR, using the MDRD study equation (see below). Every serum creatinine measured in clinical practices of WFBH is accompanied by an automated calculation of eGFR. While only accurate for calculation of GFR < 60 mL/min, and only applicable for adults, the eGFR calculated in this way is much more accurate than relying on a Pcr alone, and has been shown to help the clinician detect kidney disease at an earlier stage. The MDRD equation helps the clinician recognize clinical kidney disease before the Pcr increases significantly. Note in figure 8 that the Pcr may not increase until the GFR is less than 70 mL/min in many patients.

MDRD Formula for eGFR:

GFR (ml/min/1.73m2) = 186 x (Pcr)-1.154 x (Age) -0.203 x (0.742 if female) x (1.210 if African American)

The equation requires 4 variables: • plasma creatinine • age • sex • African American or not

Occasionally a radioactively tagged compound is used to estimate GFR by its clearance. Some examples are 131I-iothalamate, 51Cr-EDTA, or 99mTcDTPA.

Another serum marker, cystatin C, is available as an index of kidney function, and is being used with increasing frequency in the US. The plasma cystatin C concentration may correlate more closely with GFR than the plasma creatinine concentration. In multiple studies, plasma [cystatin C] was more sensitive in identifying mild reductions in kidney function than creatinine. Using the clearance of radioactive iothalamate as the standard for GFR, cystatin C levels increase at GFR levels of approximately 90 mL/min per 1.73 m2, while the plasma creatinine increases when measured GFR is approximately 70 mL/min per 1.73 m2. A GFR estimating equation is also available for the plasma cystatin C and is more accurate at eGFRs above 60 mL/m as opposed to the eGFR from the creatinine based MDRD equation, which is not reliable at eGFRs above 60 mL/m. Estimating equations other than the MDRD equation may be used for either the plasma cystatin C or creatinine, e.g., the eGFR Epi equation, but the latter, although more accurate for clinical trials, is beyond the scope of this course.

Note that the clearance of inulin, and other substances neither secreted nor reabsorbed by the tubules, is not affected by urine flow rate. That is because the excretion rate of inulin is independent of tubular reabsorption of water. However, the concentration of inulin in the urine will vary inversely, of course, with the urine volume.

The clearance of urea, however, is affected by urine flow, because urea can be reabsorbed from the tubules and is affected by the rate of water reabsorption in the collecting ducts which affects the concentration gradient for diffusion of urea in the tubule and the contact time for back-diffusion. In this way, the ratio of creatinine to urea concentration in the blood can serve as a rough clinical index of fluid filtration and reabsorption such as in dehydration or kidney failure.

Figure 9

Note: try to understand fluid and solute movement in the renal tubules. These processes as summarized above are diagramed conceptually in Figure 9.

Figure 10 considers the clearance of a substance that is filtered and reabsorbed by the tubules.

Figure 10

In this example consider a substance (A) for which 80% of the filtered load is reabsorbed by the tubules. GFR is the same as in Figure 6, 120 ml/min. The plasma level of substance A is 10 mg/ml. Therefore, the filtered load is 1200 mg/min. Since 80% is reabsorbed, 960 mg/min is reabsorbed, and 240 mg/min excreted. Therefore, the clearance of A is 240 ÷ 10 or 24 ml/min.

Note that the clearance of A can be measured without knowing GFR. However, one cannot calculate the amount of A reabsorbed by the tubules without knowing the GFR since it is necessary to calculate the filtered load.

Figure 10 illustrates the relationships among the various types of substances handled by the kidney and serves to summarize the preceding discussion.

The clearance of a substance filtered and reabsorbed (A) will always be less than the clearance of inulin. The clearance of a substance filtered and secreted, but not reabsorbed, is greater than the clearance of inulin.

The kidneys, which constitute only 0.5% of the total body weight, receive approximately 25% of the cardiac output. The total renal blood flow per gram of tissue is one of the highest in the body. As we have seen in the previous section, plasma water is filtered from the blood through glomeruli and returned to the blood by tubular reabsorption. Thus, the kidney is unique in having a large blood flow and a high fluid turnover within the organ itself.

III. MEASUREMENT OF TOTAL RENAL BLOOD FLOW

Total renal blood flow in humans (both kidneys) is approximately 1100 ml/min. There are basically two ways to measure total renal blood flow:

1. Electromagnetic (EM) or Doppler flow probe . The most accurate measurement of renal blood flow is obtained by these devices. The EM probe is a device which senses the electrical changes produced by blood as it flows through a vessel and with proper calibration can measure flow very precisely, but attaching a flow probe to a renal artery is obviously restricts its use to animal studies. The pulsed Doppler device measures the shift in ultrasound echo produced by flowing blood, and modifications of Doppler technology allow transcutaneous measurements. We have an excellent Vascular Laboratory at WFBH using the latter technique for evaluation of RBF and comparison of left and right RA values. Such a technique is very helpful to exclude the diagnosis or renal artery stenosis.

2. Clearance of a flow dependent substance . The second method for estimating total blood flow involves use of the indirect Fick method, which you have previously encountered in lectures on other circulatory beds.

Consumption (mg/min)Flow (ml/min) = ——————————

(A-V) (mg/ml)

This approach is based on two assumptions:

1. Some substances are removed from blood by the kidney in amounts, which are directly related to blood flow. That is, the more of the substance delivered to the kidney, the more is removed, and vice versa. There are a number of substances, which fit this criterion. The most convenient marker for measuring RBF is an organic acid extensively secreted by the renal tubules such as para-aminohippurate (PAH).

2. The amount of the substance removed by the kidney can be accurately measured.

The kidney is an ideal organ for application of this technique since substances removed from blood by the kidney are excreted into the urine. Thus, the amount of substances removed or extracted by the kidney can be easily measured by collecting urine.

The Fick principle states that the amount of a substance extracted by the kidney is equal to the flow times the difference between the arterial and the venous concentration of the substance. It should be pointed out here that this refers to renal plasma flow and not total renal blood flow, since we will be working with markers that are dissolved in plasma only, and not whole blood. This will become clearer in the subsequent discussion. When we rearrange this to determine flow, we make the convenient substitution to which I already alluded; i.e., that the amount extracted (filtered + secreted) is equal to the amount excreted in urine. This gives the relationship in which flow is equal to urinary excretion of the marker divided by the A-V difference. Since it is not easy to obtain renal venous blood, we can apply one more trick that will bypass the necessity to measure the renal venous concentration.

If there were a substance cleared by the kidney for which the renal venous concentration approached zero (Figure 11), it would simplify the equation. Such a substance would be one removed completely in one pass through the kidney. It turns out that substances which are secreted by the renal tubules, such as organic acids and bases, fulfill this requirement. PAH (p-aminohippurate) is such a substance.

Figure 11Accordingly, using PAH as the marker, the venous concentration approaches zero and the

venous term can be dropped from equation 4, yielding equation 5. You should recognize equation 5 as the familiar clearance equation; i.e., urinary excretion rate of PAH divided by its plasma concentration. Thus, the clearance of PAH and substances handled in a similar fashion by the kidney provides an approximation of renal plasma flow.

IV. INTRARENAL HEMODYNAMICS

Let us now consider intrarenal pressure and resistances. Intracapillary hydrostatic pressure for the anatomical components of the renal microcirculation has been measured (Figure 12).

Figure 12

As we noted earlier, hydrostatic pressure in the glomerular capillaries is approximately 60 mmHg. It is a reasonable assumption that pressure at the beginning of the afferent arteriole is similar to mean aortic pressure, or about 100 mmHg. The pressure gradient profile is shown in Figure 12, and indicates that the major resistances to blood flow in the kidney are at the afferent and efferent ends of the glomerular capillary. Recall that this anatomic arrangement of the glomerular capillary bed situated between two arteriolar resistances is very unusual and allows for the unique control of glomerular capillary pressure. Afferent resistance contributes 33-45% of the total renal resistance and the efferent resistance is 43-50% of the total. Thus, RA and RE make up about 85% of total renal vascular resistance.

Let us now examine the physiologic consequences of these pressure-resistance arrangements. First, glomerular hydrostatic pressure is maintained at a much higher level along the length of the capillary than in the other capillaries. As noted earlier, pressure in other peripheral capillaries drops from around 40 mmHg at the arteriolar end to about 10 mmHg at the venular end. Maintenance of a high pressure in the glomerular capillaries, is a major driving force for the glomerular filtration rate.

The second important consequence of this unique vascular bed is that glomerular pressure is also a function of the ratio between the afferent and efferent resistances. Since afferent and efferent resistance are in series, but can be varied independently, glomerular filtration rate can be regulated independently of systemic pressure and renal blood flow. This can be illustrated by considering the consequences of changes in resistances of RA and RE which are summarized in Figure 13.

If RA decreases, total renal vascular resistance and the ratio RA/RE decreases, and glomerular pressure increases to approach aortic pressure. This will cause a rise in both GFR and RBF. If RA increases, the converse occurs.

Figure 13

If RE decreases, the ratio RA/RE increases, glomerular pressure decreases, GFR goes down, and RBF rises. If RE increases, the converse occurs. Thus, changes in RA cause GFR and RBF to change in opposite directions.

If RA and RE both increased an equivalent amount, so that the ratio RA/RE were unchanged, RBF would decrease but glomerular pressure would remain the same and GFR would not decrease.

Mesangial cells in the glomerulus can also constrict or dilate in response to certain vasoregulatory hormones and peptides. Constriction by the mesangium lowers surface area and Kf and in this manner may also serve as a regulator of GFR.

A number of endogenous vasoactive substances regulate renal resistance. Some are listed in Table 1.

Table 1Some Regulators of Renal Arteriolar Tone

Constrictors DilatorsAndenosine BradykininAngiotensin II Nitric oxideEndothelin ProstaglandinsNorepinephrine

V. AUTOREGULATION OF GFR AND RBF

Next, we will consider the factors that affect renal resistance and control GFR and RBF.

A major determinant of flow is perfusion pressure, as shown in Figure 14. This diagram illustrates the consequences of changes in renal perfusion pressure. Renal arterial pressure is on the abscissa, and RPF and GFR and on the ordinate. Between 80 and about 200 mmHg MAP, there is almost no change in either GFR or RPF. This phenomenon is defined as autoregulation. Autoregulation is a phenomenon whereby increases or decreases in perfusion pressure cause no changes in GFR or RBF. Autoregulation is probably due to changes in RA, such that when perfusion pressure falls, vasodilation occurs in the afferent arteriole; and when perfusion pressure rises, the reverse occurs. Remember, changes in RA cause GFR and RPF to change in the same direction, so that changes in RA could account for regulation of both GFR and RPF.

Figure 14

Because GFR and RBF are both regulated over the same pressure range, and because renal plasma flow is an important determinant of GFR, the same mechanisms appear to regulate both flows. Note that when MAP drops below the autoregulatory range, both GFR and RBF drop dramatically. Consider hypotension and acute renal failure (ARF).

Two mechanisms are responsible for autoregulation of RBF and GFR: one that responds to changes in arterial pressure and one that responds to changes in tubular flow rate.

1. Myogenic mechanisms. Variations in the distending pressure of the afferent arteriole cause an opposite response from the smooth muscle in the arteriolar wall. Thus, increases in distention pressure cause a myogenic contraction and a decrease in distention pressure causes relaxation of smooth muscle. One possible explanation for this myogenic reflex is the transmural pressure theory. According to this view, afferent arteriolar tone is determined by the transmural pressure across the arterial wall, i.e., the difference between the capillary intraluminal pressure and renal tissue interstitial pressure. Increases in transmural pressure cause vasoconstriction so that when perfusion pressure increases, intraluminal and transmural pressures increase and vasoconstriction ensues. The converse occurs when perfusion pressure decreases.

2. Tubuloglomerular feedback. This concept proposes that afferent arteriolar tone is determined by the production of a vasoconstrictor in the afferent arteriolar wall, the release of which is controlled by the macula densa cells of the distal tubule.

The macula densa (MD) is the segment of the distal convoluted tubule that contacts the afferent arteriole of its own glomerulus. The conjunction of the two structures is called the juxtaglomerular (JG) apparatus (Figure 15). An increase in NaCl delivery to the MD elicits release of a vasoconstrictor (angiotension), which causes afferent arteriolar vasoconstriction, as shown in Figure 16.

Figure 15 Figure 16

According to this paradigm an increase in renal perfusion pressure would increase GFR, causing increased delivery of NaCl to the MD. This would cause increased release of vasoconstrictors, which would then cause an increase in RA and thus decrease (or restore) PGC. Vasoactive hormones such as some of those listed in Table 1 or some drugs that block the transport-related signal at the macula densa can interrupt the myogenic and TGF pathways to change renal resistance and GFR for a given level of perfusion pressure.

Outside the context of autoregulation, a major influence on RA and probably RE is the sympathetic nervous system. Afferent arterioles are innervated by adrenergic fibers, and increases in SNS activity can clearly cause an increase in RA. However, autoregulation occurs even in denervated kidneys. Therefore, renal nerves modulate but are not solely responsible for autoregulation.

Finally, there is another potentially important regulator of renal blood flow to appreciate, the prostaglandins. Prostaglandins are a family of fatty acids produced in all blood vessels and other cells of the body, which have a wide array of biologic activities. Of interest is that prostacyclin (PGI2) is produced in renal blood vessels, especially in the cortex, and that E series prostaglandins are produced in the renal medulla. They are both potent renal vasodilators. Some prostanoids such as thromboxanes and products of cytochrome P450 are vasoconstrictors and may play a role in autoregulation and renal pathology. However, there is good evidence that prostaglandins together with renin are responsible for maintenance of the pattern of intrarenal blood flow distribution discussed earlier. The vasodilatory prostaglandins do not participate meaningfully in the maintenance of GFR under normal circumstances, but can be very important in militating against the effect of vasoconstrictors. Numerous studies have shown that the interaction of the vasoconstrictors (norepinephrine, etc.) and the vasodilatory prostaglandins help to maintain RBF and GFR in clinical circumstances such as shock and volume depletion. The ability to mitigate the effect of vasoconstrictors is significantly impaired if prostaglandin production is inhibited by drugs such as non-steroidal anti-inflammatory drugs (NSAIDS) (e.g. ibuprofen, etc.). Accordingly, vasoconstriction then proceeds unabated and acute renal failure may ensue. Since the use of NSAIDs is so common, they often play a role in the susceptibility of certain categories of patients to develop acute renal failure especially in circumstances associated with vasoconstriction, such as shock from blood loss or sepsis. Categories of patients at risk for NSAID-induced ARF include patients with preexisting CKD, diabetics, and the elderly.