MOLECULAR SIZE, ELECTRICAL CHARGE, AND SHAPE DETERMINE THE FILTERABILITY OF SOLUTES ACROSS THE GLOMERULAR FILTRATION BARRIER

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1 MOLECULAR SIZE, ELECTRICAL CHARGE, AND SHAPE DETERMINE THE FILTERABILITY OF SOLUTES ACROSS THE GLOMERULAR FILTRATION BARRIER The glomerular filtration barrier consists of three elements: (1) endothelial cells, (2) the glomerular basement membrane, and (3) epithelial podocytes (Figure). The latter two layers are covered with negative charges.

2 Table 33-2 summarizes the permselectivity of the glomerular barrier for different solutes, as estimated by the ratio of solute concentration in the ultrafiltrate versus the plasma (UFx/Px). The ratio UFx/Px, also known as the sieving coefficient for the solute X (i.e. concentration in ultrafiltrate divided by mean of concentrations in pre and post filter blood) depends on molecular weight and effective molecular radius. Investigators have used two approaches to estimate UFx/Px. The first, which is valid for all solutes, is the micropuncture technique. Sampling fluid from Bowman s space yields a direct measurement of UFx, from which we can compute UFx/Px. The second approach, which is only valid for solutes that the kidney neither absorbs nor secretes, is to compute the clearance ratio, the ratio of the clearances of X (Cx) and inulin (Cin). Substances of low molecular weight (less than 5500 Da) and small effective molecular radius such as water, urea, glucose, and inulin appear in the filtrate in the same concentration as in plasma (UFx/Px equals 1). In these instances, there is no sieving of the contents of the fluid moving through the glomerular pores, so that the water moving through the filtration slits by convection carries the solutes with it. As a result, the concentration of the solute in the filtrate is the same as in bulk plasma. The situation is different for substances with a molecular weight that is above approximately 14 kda, such as lysozyme. Larger and larger macromolecules are increasingly restricted from passage, so that only traces of plasma albumin (69 kda) are normally present in the glomerular filtrate. In addition to molecular weight and radius, electrical charge also makes a major contribution to the permselectivity of the glomerular barrier. Figure 334A is a plot of

3 the clearance ratio for uncharged, positively charged, and negatively charged dextran molecules of varying molecular size. Figure 334A Two conclusions can be drawn from these data. First, neutral dextrans below an effective molecular radius of 2 nm pass readily across the glomerular barrier. For dextrans with a larger radius, the clearance ratio decreases with an increase in molecular size, so that passage ceases when the radius exceeds 4.2 nm. Second, anionic dextrans (i.e., dextran sulfates) are restricted from filtration, whereas cationic dextrans (i.e., diethylaminoethyl dextrans) pass more readily into the filtrate. For negatively charged dextrans, the relationship between charge and filterability is characterized by a left shift of the curve relating molecular size to clearance ratio, whereas the opposite is true for positively charged dextrans. The previously discussed results suggest that the glomerular filtration barrier carries a net negative charge that restricts the movement of anions but enhances the movement of cations. In experimental glomerulonephritis, in which the glomerular barrier loses its negative charge, the permeability of the barrier to negatively charged macromolecules is enhanced. Figure 334B compares clearance ratios of dextran sulfate in normal rats and in rats with nephrotoxic serum nephritis.

4 Figure 334B Clearance ratios of dextran sulfate are uniformly greater in the animals with nephritis. Thus, the disease process destroys negative charges in the filtration barrier and accelerates the passage of negatively charged dextrans. Because albumin is also negatively charged at physiological ph, loss of negative charge in the glomerular barrier probably contributes in an important way to the development of albuminuria in the early stages of renal diseases such as glomerulonephritis. Finally, the shape of macromolecules also affects the permselectivity of the glomerular barrier. Rigid or globular molecules have lower clearance ratios (i.e., sieving coefficients) than molecules of a similar which are highly deformable. RENAL BLOOD FLOW Renal blood flow (RBF) is approximately 1 liter /min out of the total cardiac output of 5 liters/min. Normalized for weight, this blood flow amounts to approximately 350 ml/min for each 100 g of tissue, which is sevenfold higher than the normalized blood flow to the brain. Renal plasma flow (RPF) is [Equation 33-5]: Given a hematocrit of 0.40, the normal RPF is approximately 600 ml/min. Equation 33-6: RPF = GFR / FF Because the normal GFR is approximately 125 ml/min and the normal RPF is approximately 600 ml/min, the normal (filtration fraction) FF is approximately 0.2. Because GFR saturates at high values of RPF, FF is greater at low plasma flows than it is at high plasma flows.

5 The dependence of GFR on plasma flow through the glomerular capillaries is similar to the dependence of alveolar O2 and CO2 transport on pulmonary blood flow. INCREASED GLOMERULAR PLASMA FLOW LEADS TO AN INCREASE IN GFR At low glomerular plasma flow, filtration equilibrium occurs halfway down the capillary. At higher plasma flow (i.e., normal for humans), the profile of net ultrafiltration forces (PUF) along the glomerular capillary stretches out considerably to the right so that the point of equilibrium would be reached at a site actually beyond the end of the capillary. Failure to reach equilibrium (filtration disequilibrium) occurs because the increased delivery of plasma to the capillary outstrips the ability of the filtration apparatus to remove fluid and simultaneously increase capillary oncotic pressure. As a result, rises more slowly along the length of the capillary. The shift of filtration equilibrium toward the efferent arteriole has two important consequences. First, as one progresses along the capillary, PUF (and hence filtration) remains greater. Second, filtration occurs along a greater stretch of the glomerular capillary, thereby increasing the useful surface area for filtration. Thus, the end of the capillary that is wasted at low plasma flow rates really is in reserve to contribute at higher rates. A further increase in plasma flow stretches out the profile even more, so that PUF is even higher at each point along the capillary (see Fig.336C) Figure 336C Single-nephron glomerular filtration rate (SNGFR) is the sum of individual filtration events along the capillary. Thus, SNGFR is proportional to the yellow area that represents the product of PUF and effective (i.e., non-wasted) length along the capillary. Because the yellow areas progressively increase from Figure 336A to Figure 336C, SNGFR increases with glomerular plasma flow. However, this increase is not linear. Compared with the normal situation, the GFR summed for both kidneys increases only moderately with increasing RPF, but decreases greatly with decreasing RPF (see Fig. 336D). The relationship between GFR and RPF also defines a parameter known as the

6 filtration fraction (FF), which is the volume of filtrate that forms from a given volume of plasma entering the glomeruli: Figure 336D The hydrostatic pressure in the glomerular capillary favors glomerular ultrafiltration, (whereas the oncotic pressures in the capillary and the hydrostatic pressure in bowman space oppose it as is the case for filtration in other capillary beds glomerular ultrafiltration depends on the product of the ultrafiltration coefficient (kf ) and net starling forces. Figure 335A provides a schematic overview of the driving forces affecting ultrafiltration. PGC is the hydrostatic pressure in the glomerular capillary, which favors ultrafiltration. PBS is the hydrostatic pressure in Bowman s space, which opposes ultrafiltration. is the oncotic pressure in the glomerular capillary, which opposes ultra-filtration. Finally, is the oncotic pressure of the filtrate in Bowman s space, which favors ultrafiltration. Thus, tw oforces favor filtration (PGC and ), and two oppose it (PBS and ).

7 The net driving force favoring ultrafiltration (PUF) at any point along the glomerular capillaries is the difference between the hydrostatic pressure difference and the oncotic pressure difference between the capillary and Bowman s space. Thus, the glomerular filtration rate is proportional to the net hydrostatic force (PGC - PBS) minus the net oncotic force. The first term of the hydrostatic pressure difference is the pressure in the capillary lumen (PGC). As we will see later, the unique arrangement in which afferent and efferent arterioles flank the glomerular capillary keep PGC at approximately 50 mm Hg, a value that is twice as high as in most other capillaries. Moreover, direct measurements of pressure in rodents show that PGC decays very little between the afferent and efferent ends of glomerular capillaries. The second term of the hydrostatic pressure difference is the hydrostatic pressure in Bowman s space (PBS). This pressure is approximately 10 mm Hg, and does not vary along the capillary. As far as the oncotic driving forces are concerned, the first term is the oncotic pressure in Bowman s space ( ), which is very small. The oncotic pressure in the glomerular capillary ( ) starts off at 25 mm Hg at the beginning of the capillary. As a consequence of the continuous production of a protein-free glomerular filtrate, the oncotic pressure of the fluid left behind in the glomerular capillary progressively rises along the capillary. Compares the two forces favoring ultrafiltration (PGC and ) with the two forces opposing ultrafil-tration (PBS and ) and shows how they vary along the glomerular capillary. The rapid increase in the oncotic pressure of capillary blood ( ) is the major reason why the forces favoring and opposing filtration may balance each other at a point some distance before the end of the glomerular capillary. Beyond this point, PUF is zero and the system is said to be in filtration equilibrium (i.e., no further filtration) Equation 33-4 GFR = Kf [(P GC P BS ) (π GC π BS )] P GC : glomerular hydrostatic pressure P BS : Bowman's capsule hydrostatic pressure π GC : glomerular capillary colloid osmotic pressure π BS : Bowman's capsule osmotic pressure

8 Kf in Equation 33-4 is the product of the hydraulic conductivity of the capillary (Lp) and the effective surface area available for filtration (Sf). We use Kf because it is experimentally difficult to assign values to either Lp or Sf. Whereas PUF is of similar order of magnitude in glomerular and systemic capillaries, the value of Kf of the glomerular filtration barrier exceeds by more than an order of magnitude the Kf of all other systemic capillary beds combined. This difference in Kf values underlies the tremendous difference in filtration, approximately 180 liters /day in the kidneys (which receive approximately 20% of the cardiac output) com-pared with approximately 20 liters /day in the combined arteriolar ends of capillary beds in the rest of the body (which receive the other 80%). Of course, approximately 17 liters/day is reabsorbed at the venular end of these systemic capillaries owing to Starling forces, so that the net formation of lymph is approximately 3 liters /day. Alterations in the glomerular capillary surface area owing to changes in mesangialcell contractility can produce substantial changes in the Sf component of Kf. These cells respond to extrarenal hormones such as systemically circulating angiotensin II, arginine vasopressin, and parathyroid hormone. Mesangial cells also produce several vasoactive agents, such as prostaglandins and angiotensin II.