Physiology 5th Ed.

GLOMERULAR FILTRATION

Glomerular filtration is the first step in the formation of urine. As the renal blood flow enters the glomerular capillaries, a portion of that blood is filtered into Bowman’s space, the first part of the nephron. The fluid that is filtered is similar to interstitial fluid and is called an ultrafiltrate. The ultrafiltrate contains water and all of the small solutes of blood, but it does not contain proteins and blood cells. The forces responsible for glomerular filtration are similar to the forces that operate in systemic capillaries—the Starling forces (see Chapter 4). There are differences, however, in the characteristics and surface area of the glomerular capillary barrier, making the glomerular filtration rates much higher than the filtration rates across systemic capillaries.

Characteristics of the Glomerular Filtration Barrier

The physical characteristics of the glomerular capillary wall determine both the rate of glomerular filtration and the characteristics of the glomerular filtrate. These characteristics determine what is filtered andhow much is filtered into Bowman’s space.

Layers of the Glomerular Capillary

Figure 6-9 shows the key features of a glomerular capillary at approximately 30,000 times magnification. Beginning with the capillary lumen and moving toward Bowman’s space, the three layers, discussed in the following sections, constitute the glomerular capillary wall.

image

Figure 6–9 Structure of the glomerular capillary wall.

ENDOTHELIUM

The endothelial cell layer has pores 70 to 100 nanometers (nm) in diameter. Because these pores are relatively large, fluid, dissolved solutes, and plasma proteins all are filtered across this layer of the glomerular capillary barrier. On the other hand, the pores are not so large that blood cells can be filtered.

BASEMENT MEMBRANE

The basement membrane has three layers. The lamina rara interna is fused to the endothelium; the lamina densa is located in the middle of the basement membrane; and the lamina rara externa is fused to the epithelial cell layer. The multilayered basement membrane does not permit filtration of plasma proteins and, therefore, constitutes the most significant barrier of the glomerular capillary.

EPITHELIUM

The epithelial cell layer consists of specialized cells called podocytes, which are attached to the basement membrane by foot processes. Between the foot processes are filtration slits, 25 to 60 nm in diameter, which are bridged by thin diaphragms. Because of the relatively small size of the filtration slits, the epithelial layer (in addition to the basement membrane) also is considered an important barrier to filtration.

Negative Charge on the Glomerular Capillary Barrier

In addition to the size barriers to filtration imposed by the various pores and slits, another feature of the glomerular barrier is the presence of negatively charged glycoproteins. These fixed negative charges are present on the endothelium, on the lamina rara interna and externa of the basement membrane, on the podocytes and foot processes, and on the filtration slits of the epithelium. A consequence of these fixed negative charges is that they add an electrostatic component to filtration. Positively charged solutes will be attracted to the negative charges on the barrier and be more readily filtered; negatively charged solutes will be repelled from the negative charges on the barrier and be less readily filtered.

For small solutes such as Na+, K+, Cl, or HCO3, the effect of charge on filtration of the solute is not important. Regardless of their charge, small solutes are freely filtered across the glomerular barrier. However, for large solutes such as plasma proteins, the charge does affect filtration because the molecular diameters of these larger solutes are similar to the diameters of the pores and slits. For example, at physiologic pH, plasma proteins have a net negative charge, and they will be restricted from filtration by their molecular size and by the negative charges lining the glomerular barrier. In certain glomerular diseases, the negative charges on the barrier are removed, resulting in increased filtration of plasma proteins and proteinuria.

As an aside, the effect of charge on filtration of large solutes was demonstrated in rats by measuring the filtration rate of a series of dextran molecules of different sizes (molecular radii) and with different net charges. For a given molecular radius, there was a neutral dextran, a negatively charged (anionic) dextran, and a positively charged (cationic) dextran. At any molecular radius, cationic dextran was most filterable, anionic dextran was least filterable, and neutral dextran was in the middle. The cations were attracted to the negative charges on the pores, the anions were repelled, and the neutral molecules were unaffected.

Starling Forces Across Glomerular Capillaries

As in systemic capillaries, the pressures that drive fluid movement across the glomerular capillary wall are the Starling pressures, or Starling forces. Theoretically, there are four Starling pressures: two hydrostatic pressures (one in capillary blood and one in interstitial fluid) and two oncotic pressures (one in capillary blood and one in interstitial fluid). When applying these pressures to glomerular capillaries, there is one small modification: The oncotic pressure of Bowman’s space, which is analogous to interstitial fluid, is considered to be zero because filtration of protein is negligible.

Starling Equation

Fluid movement across the glomerular capillary wall is glomerular filtration. It is driven by the Starling pressures across the wall and, with the assumption that the oncotic pressure of Bowman’s space is zero, is described by the Starling equation:

image

where

GFR

= Glomerular filtration rate (mL/min)

Kf

= Hydraulic conductance (mL/min • mm Hg)

 

or

 

Filtration coefficient (mL/min • mm Hg)

PGC

= Hydrostatic pressure in glomerular

capillary (mm Hg)

PBS

= Hydrostatic pressure in Bowman’s space (mm Hg)

πGC

= Oncotic pressure in glomerular capillary (mm Hg)

Each of the following parameters in the Starling equation is described as it applies to glomerular capillaries:

image Kf, filtration coefficient, is the water permeability or hydraulic conductance of the glomerular capillary wall. The two factors that contribute to Kf are the water permeability per unit of surface area and the total surface area. Kffor glomerular capillaries is more than 100-fold that for systemic capillaries (e.g., skeletal muscle capillaries) because of the combination of a higher total surface area and a higher intrinsic water permeability of the barrier. The consequence of this extremely high Kf is that much more fluid is filtered from glomerular capillaries than from other capillaries (i.e., GFR is 180 L/day).

image PGChydrostatic pressure in glomerular capillaries, is a force favoring filtration. When compared with systemic capillaries, PGC is relatively high (45 mm Hg). In systemic capillaries, hydrostatic pressure falls along the length of the capillary; in glomerular capillaries, it remains constant along the entire length.

image PBShydrostatic pressure in Bowman’s space, is a force opposing filtration. The origin of this pressure (10 mm Hg) is the fluid present in the lumen of the nephron.

image πGConcotic pressure in glomerular capillaries, is another force opposing filtration. πGC is determined by the protein concentration of glomerular capillary blood. πGCdoes not remain constant along the capillary length; rather, it progressively increases as fluid is filtered out of the capillary. πGC eventually increases to the point where net ultrafiltration pressure becomes zero and glomerular filtration stops (called filtration equilibrium).

In words, glomerular filtration rate is the product of Kf and the net ultrafiltration pressure. The net ultrafiltration pressure, the driving force, is the algebraic sum of the three Starling pressures (omitting the oncotic pressure in Bowman’s space). For glomerular capillaries, the net ultrafiltration pressure always favors filtration, so the direction of fluid movement is always out of the capillaries. The greater the net pressure, the higher the rate of glomerular filtration.

Figure 6-10 is a pictorial presentation of the three Starling pressures, each of which is represented by an arrow. The direction of the arrow indicates whether the pressure favors filtration out of the capillary or absorption into the capillary. The size of the arrow indicates the relative magnitude of the pressure. The numerical value of the pressure (in mm Hg) has a plus sign if the pressure favors filtration and a minus sign if the pressure favors absorption. The net ultrafiltration pressure, which is the driving force, is the algebraic sum of the three pressures.

image

Figure 6–10 Starling forces across the glomerular capillaries. A, Net filtration; B, filtration equilibrium. Arrows show the direction of the Starling pressures; numbers are the magnitude of the pressure (mm Hg); + signs show pressures that favor filtration; − signs show pressures that oppose filtration. PGC, Hydrostatic pressure in the glomerular capillary; PBS, hydrostatic pressure in Bowman’s space; πGC, oncotic pressure in the glomerular capillary.

Figure 6-10A shows the profile of the Starling pressures at the beginning of the glomerular capillary. At the beginning of the glomerular capillary, blood has just come from the afferent arteriole and no filtration has yet occurred. The sum of the three Starling pressures, or the net ultrafiltration pressure, is +16 mm Hg; thus, the net ultrafiltration pressure strongly favors filtration.

Figure 6-10B shows the three Starling pressures at the end of the glomerular capillary. At this point, the blood has been extensively filtered and is about to leave the glomerular capillary to enter the efferent arteriole. The sum of the three Starling pressures now is zero. Because net ultrafiltration is zero, no filtration can occur, a point called filtration equilibrium. Conveniently, filtration equilibrium normally occurs at the end of the glomerular capillary.

An important question to ask is What causes filtration equilibrium to occur? Stated differently, Which Starling pressure has changed to make the net ultrafiltration pressure zero? To answer this question, compare the Starling pressures at the beginning of the glomerular capillary with those at the end of the capillary. The only pressure that changes is πGC, the oncotic pressure of glomerular capillary blood. As fluid is filtered out of the glomerular capillary, protein is left behind and the protein concentration and πGC increase. By the end of the glomerular capillary, πGC has increased to the point where the net ultrafiltration pressure becomes zero. (A related point is that this blood leaving the glomerular capillaries will become peritubular capillary blood. The peritubular capillary blood will, therefore, have a high oncotic pressure [πc], which becomes a driving force for reabsorption in the proximal tubule of the nephron.) There is no decrease in PGC along the length of the glomerular capillaries, as occurs in systemic capillaries. The difference for glomerular capillaries is the presence of a second set of arterioles, the efferent arterioles. Constriction of efferent arterioles prevents the decline in PGC that would otherwise occur as fluid is filtered out along the length of the glomerular capillaries.

Changes in Starling Pressures

The GFR depends on the net ultrafiltration pressure, which in turn depends on the sum of the Starling pressures across the glomerular capillary wall. It should be clear, therefore, that changes in GFR can be brought about by changes in any one of the Starling pressures (Table 6-6).

Table 6–6 Effect of Changes in Starling Forces on Renal Plasma Flow, Glomerular Filtration Rate, and the Filtration Fraction

image

GFR, Glomerular filtration rate; N.C., no change; RPF, renal plasma flow.

image Changes in PGC are produced by changes in the resistance of the afferent and efferent arterioles. For reasons that will be apparent, changes in GFR occur in opposite directions, depending on which arteriole is affected. The mechanism underlying this phenomenon is shown in Figure 6-11.

image

Figure 6–11 Effects of constricting afferent (A) and efferent (B) arterioles on renal plasma flow (RPF) and glomerular filtration rate (GFR). PGC, Hydrostatic pressure in the glomerular capillary.

Figure 6-11A shows constriction of the afferent arteriole, in which afferent arteriolar resistance increases. As expected with any arteriolar constriction, RPF decreases. GFR also decreases because, as less blood flows into the glomerular capillary, PGC decreases, reducing net ultrafiltration pressure. Examples include the effects of the sympathetic nervous system and high levels of angiotensin II.

Figure 6-11B shows constriction of the efferent arteriole, in which efferent arteriolar resistance increases. The effect of arteriolar constriction on RPF is the same as with constriction of the afferent arteriole (decreases), yet the effect on GFR is opposite (increases). GFR increases because blood is restricted from leaving the glomerular capillary, causing PGC and net ultrafiltration pressure to increase. An example is the effect of low levels of angiotensin II.

The effects of angiotensin II on RPF and GFR have important implications. Angiotensin II constricts both afferent and efferent arterioles, but it preferentially constricts efferent arterioles. Thus, a low level of angiotensin II has a large constrictor effect on efferent arterioles and a small constrictor effect on afferent arterioles, leading to a decrease in RPF and an increase in GFR. A higher level of angiotensin II (as seen in response to hemorrhage) has a pronounced constrictor effect on efferent arterioles and a medium constrictor effect on afferent arterioles, leading to a decrease in RPF and a smaller decrease in GFR. Thus, with both low and high levels of angiotensin II, because of its preferential effect on efferent arterioles, the GFR is “protected” or “preserved” in the setting of vasoconstriction. Angiotensin-converting enzyme (ACEinhibitors block the production of angiotensin II and offset or eliminate its protective effect on GFR.

image Changes in πGC are produced by changes in plasma protein concentration. Thus, increases in plasma protein concentration produce increases in πGC, which decrease both the net ultrafiltration pressure and GFR. On the other hand, decreases in plasma protein concentration (e.g., nephrotic syndrome, in which large amounts of protein are lost in urine) produce decreases in πGC, which increase both net ultrafiltration pressure and GFR.

image Changes in PBS can be produced by obstructing urine flow (e.g., ureteral stone or constriction of a ureter). For example, if the ureter is constricted, urine cannot flow through that ureter to the bladder, causing urine to back up in the kidney. Consequently, hydrostatic pressure in the nephrons will increase as far back as Bowman’s space, producing an increase in PBS. An increase in PBS decreases the net ultrafiltration pressure, thereby decreasing GFR.

Measurement of Glomerular Filtration Rate

GFR is measured by the clearance of a glomerular marker. A glomerular marker has the following three characteristics: (1) It must be freely filtered across the glomerular capillaries, with no size or charge restrictions; (2) it cannot be reabsorbed or secreted by the renal tubule; and (3) when infused, it cannot alter the GFR. Thus, the properties of the ideal glomerular marker differ from those of a marker substance used to measure RPF (i.e., PAH).

Clearance of Inulin

The ideal glomerular marker is inulin, a fructose polymer with a molecular weight of approximately 5000 daltons. Inulin is not bound to plasma proteins, nor is it charged, and its molecular size is such that it is freely filtered across the glomerular capillary wall. Once filtered, inulin is completely inert in the renal tubule: It is neither reabsorbed nor secreted by the renal tubular cells. Thus, the amount of inulin filtered across the glomerular capillaries is exactly equal to the amount of inulin that is excreted in the urine.

The clearance of inulin equals the GFR, as expressed in the following equation:

image

where

GFR

= Glomerular filtration rate (mL/min)

[U]inulin

= Urine concentration of inulin (mg/mL)

[P]inulin

= Plasma concentration of inulin (mg/mL)

image

= Urine flow rate (mL/min)

Cinulin

= Clearance of inulin (mL/min)

Several additional points about the use of inulin to measure GFR should be noted: (1) Inulin is not an endogenous substance and, therefore, must be infused intravenously. (2) The numerator of the fraction, [U]inulin × image, is equal to the excretion rate of inulin. (3) Changes in plasma inulin concentration do not alter GFR, although examination of the equation might lead to the opposite conclusion. For example, an increase in plasma inulin concentration (by infusing more inulin) does not decrease GFR, according to the following logic: When the plasma inulin concentration increases, the amount of inulin filtered also increases, which increases the amount of inulin excreted (i.e., [U]inulin× image). Thus, both the numerator and the denominator increase proportionately, and the calculated value of GFR is unaffected. (4) GFR (or the clearance of inulin) also is unaffected by changes in urine flow rate, although inspection of the equation might again lead to the opposite conclusion. When urine flow rate (image) increases, the urine concentration of inulin, [U]inulin, decreases proportionately by dilution. Thus, the numerator ([U]inulin × image) and the calculated value of GFR will be unaffected by such a change in urine flow rate, as illustrated in the following sample problem:

SAMPLE PROBLEM. A woman who consents to renal studies in the Clinical Research Center is infused with inulin to measure her GFR. Over the course of the measurement, her urine flow rate is intentionally varied by having her drink large amounts of water. The [P]inulin is kept constant at 1 mg/mL with an infusion. The urine flow rate and [U]inulin before and after she drinks water are as follows:

Before drinking water

After drinking water

[U]inulin = 100 mg/mL

[U]inulin = 20 mg/mL

image = 1 mL/min

    image = 5 mL/min

What is the effect of the increase in urine flow (produced by drinking water) on the woman’s GFR?

SOLUTION. Calculate the GFR from the clearance of inulin before and after the woman drank water.

image

image

Despite urine flow rate being markedly different in the two conditions, GFR was absolutely constant. As the urine flow rate increased from 1 mL/min to 5 mL/min, [U]inulin decreased (by dilution) from 100 mg/mL to 20 mg/mL (a proportional change).

Other Markers for Glomerular Filtration Rate

Inulin is the only perfect glomerular marker; no other marker is perfect. The closest substance is creatinine, which is freely filtered across the glomerular capillaries but also secreted to a small extent. Thus, the clearance of creatinine slightly overestimates the GFR. The convenience of using creatinine, however, outweighs this small error: Creatinine is an endogenous substance (inulin is not), and it need not be infused in order to measure GFR.

Both blood urea nitrogen (BUN) and serum creatinine concentration can be used to estimate GFR because both urea and creatinine are filtered across the glomerular capillaries. Thus, each substance depends on the filtration step in order to be excreted in urine. When there is a decrease in GFR (e.g., in renal failure), BUN and serum creatinine increase because they are not adequately filtered.

Volume contraction (hypovolemia) results in decreased renal perfusion and, as a consequence, decreased GFR (prerenal azotemia). In prerenal azotemia, both BUN and serum creatinine are increased due to the decrease in GFR. However, because urea is reabsorbed and creatinine is not, BUN increases more than serum creatinine; in volume contraction, there is increased proximal reabsorption of all solutes, including urea, which is responsible for the greater increase in BUN. One indicator, therefore, of volume contraction (prerenal azotemia) is an increased ratio of BUN/creatinine to more than 20. In contrast, renal failure due to renal causes (e.g., chronic renal failure) produces an increase in both BUN and serum creatinine, but it does not produce an increase in the ratio of BUN/creatinine.

Filtration Fraction

The filtration fraction expresses the relationship between the glomerular filtration rate (GFR) and renal plasma flow (RPF). The filtration fraction is given by the following equation:

image

In other words, the filtration fraction is that fraction of the RPF that is filtered across the glomerular capillaries. The value for the filtration fraction is normally about 0.20, or 20%. That is, 20% of the RPF is filtered and 80% is not filtered. The 80% of RPF that is not filtered leaves the glomerular capillaries via the efferent arterioles and becomes the peritubular capillary blood flow.

As an exercise, think about the effect of changes in filtration fraction on the protein concentration and oncotic pressure (πc) of peritubular capillary blood. If the filtration fraction were to increase (see Table 6-6), relatively more fluid would be filtered out of glomerular capillary blood, resulting in a greater than usual increase in the protein concentration of the capillary blood. Thus, increases in the filtration fraction produce increases in the protein concentration and πc of peritubular capillary blood (which has consequences for the reabsorptive mechanism in the proximal tubule that is discussed later in this chapter).