Direct Determinants of GFR

Variation in GFR is a crucial determinant of renal function.
Everything else being equal, a higher GFR means greater excretion of salt and water. Regulation of the GFR is straightforward in terms of physical principles but very complex functionally because there are so many regulated variables. The rate of filtration in any of the body’s capillaries, including the glomeruli, is determined by the hydraulic permeability of the capillaries, their surface area, and the net filtration pressure (NFP) acting across them.

Rate of filtration 5 hydraulic permeability × surface area × NFP

Because it is difficult to estimate the area of a capillary bed, a parameter called the filtration coefficient (Kf ) is used to denote the product of the hydraulic permeability and the area. The net filtration pressure is the algebraic sum of the hydrostatic pressures and the osmotic pressures resulting from protein—the oncotic or colloid osmotic pressures —on the 2 sides of the capillary wall. There are 4 pressures to contend with: 2 hydrostatic pressures and 2 oncotic pressures. These are referred to as Starling forces, named after the physiologist who first described them. Applying this to the glomerular capillaries:

NFP = (PGC - πGC) - (PBC - πBC),

where PGC is glomerular capillary hydraulic pressure, πBC is oncotic pressure of fluid in Bowman’s capsule, PBC is hydraulic pressure in Bowman’s capsule, and πGC is oncotic pressure in glomerular capillary plasma.
Because there is normally little protein in Bowman’s capsule, πBC may be taken as zero and not considered in our analysis. Accordingly, the overall equation for GFR becomes

GFR = Kf (PGC − PBC − πGC).

Net filtration pressure in the renal corpuscle equals glomerular-capillary hydraulic pressure (PGC) minus Bowman’s capsule hydraulic pressure (PBC) minus glomerularcapillaryoncotic pressure (πGC).

Estimated forces involved in glomerular filtration in humans (these are the same values shown in Table 2–1). Net filtration pressure (NFP) = PGC − πGC − PBC.

Note that the hydraulic pressure changes only slightly along the glomeruli; this is because the very large total cross-sectional area of the glomeruli collectively provides only a small resistance to flow. Importantly, note that the oncotic pressure in the glomerular capillaries does change substantially along the length of the glomeruli. Water is moving out of the vascular space and leaving protein behind, thereby raising protein concentration and, hence, the oncotic pressure of the unfiltered plasma remaining in the glomerular capillaries. Mainly because of this large increase in oncotic pressure, the net filtration pressure decreases from the beginning of the glomerular capillaries to the end. The average net filtration pressure over the whole length of the glomerulus is about 17 mm Hg. This average net filtration pressure is higher than found in most nonrenal capillary beds. Along with a high value for Kf , it accounts for the enormous filtration of 180 L of fluid/ day (compared with 3 L/day or so in all other capillary beds combined).
As we have noted, the GFR is not fixed but shows marked fluctuations in differing physiological states and in disease. If all other factors remain constant, any change in Kf , PGC, PBC, or πGC will alter GFR. However, “all other factors” do not always remain constant, and so other simultaneous events may oppose the effect of any one factor. To grasp this situation, it is essential to see how a change in any one factor affects GFR under the assumption that all other factors are held constant.
Table 2–2 presents a summary of these factors. It provides, in essence, a checklist to review when trying to understand how diseases or vasoactive chemical messengers and drugs change GFR. In this regard, it should be noted that the major



cause of decreased GFR in renal disease is not any change in these parameters within individual nephrons but rather simply a decrease in the number of functioning nephrons.

Kf
Changes in Kf can be caused by glomerular disease and drugs, but this variable is also subject to normal physiological control by a variety of chemical messengers. The details are still not completely clear, but these messengers cause contraction of glomerular mesangial cells. Such contraction may restrict flow through some of the capillary loops, effectively reducing the area available for filtration and, hence, Kf. This decrease in Kf will tend to lower GFR.

PGC
Hydrostatic pressure in the glomerular capillaries (PGC) is the most complex of the variables in the basic filtration equation because it is itself influenced by so many factors. We can help depict the situation by using the analogy of a leaking garden hose. If pressure feeding the hose (pressure in the pipes leading to the faucet) goes up or down, this directly affects pressure in the hose and, hence, the rate of leak. Resistances in the hose also affect the leak. If we kink the hose upstream from the leak, pressure at the region of leak falls, and less water leaks out. However, if we kink the hose beyond the leak, this raises pressure at the region of leak and increases leak rate. These same principles apply to PGC and GFR. First, a change in renal arterial pressure will cause a change in PGC in the same direction. If resistances remain constant, PGC will rise and fall as renal artery pressure rises and falls. This is a crucial point because a major regulator of renal function is arterial blood pressure. Second, changes in the resistance of the afferent and efferent arterioles have opposite effects on PGC. An increase in resistance upstream from the glomerulus in the afferent arteriole (like kinking the hose above the leak) will lower PGC, whereas an increase in resistance downstream from the glomerulus in the efferent arteriole (like kinking the hose beyond the leak) will increase PGC. In contrast, a decrease in afferent resistance (RA) (resulting from afferent arteriolar dilation) will tend to raise PGC. Similarly, a decrease in efferent resistance (RE) (caused by efferent arteriolar dilation) tends to lower PGC. It should also be clear that when RA and RE both change simultaneously in the same direction (ie, both increase or decrease), they exert opposing effects on PGC.
It is possible for both resistances to rise by the same fraction, with the result that there is no effect on PGC (even though, in this case, RBF would fall). In contrast, when they change in different directions, they cause additive effects on PGC (and can have no effect on RBF). The real significance of this is that the kidney can regulate PGC and, hence, GFR independently of RBF. The effect of changes in RA and RE.

PBC
Changes in this variable generally are of very minor physiological importance. The major pathological cause of increased hydraulic pressure in Bowman’s capsule is obstruction anywhere along the tubule or in the external portions of the urinary system (eg, the ureter). The effect of such an occlusion is to increase the tubular pressure everywhere proximal to the occlusion, all the way back to Bowman’s capsule. The result is to decrease GFR.

Effects of afferent- and/or efferent-arteriolar constriction on glomerular capillary pressure (PGC) and renal blood flow (RBF). The RBF changes reflect changes in total renal arteriolar resistance, the location of the change being irrelevant. In contrast, the changes in PGC are reflected in which set of arterioles the altered resistance occurs. Pure afferent constriction lowers both PGC and RBF, whereas pure efferent constriction raises PGC and lowers RBF. Simultaneous constriction of both afferent and efferent arterioles has counteracting effects on PGC but additive effects on RBF; the effect on PGC may be a small increase, small decrease, or no change. Vasodilation of only 1 set of arterioles would have effects on PGC and RBF opposite those shown in parts B and C. Vasodilation of both sets would cause little or no change in PGC, the same result as constriction of both sets but would cause a large increase in RBF. Constriction of 1 set of arterioles and dilation of the other would have maximal effects on PGC but little effect on RBF.

πGC
Oncotic pressure in the plasma at the very beginning of the glomerular capillaries is, of course, simply the oncotic pressure of systemic arterial plasma. Accordingly, a decrease in arterial plasma protein concentration, as occurs, eg, in liver disease, will lower arterial oncotic pressure and tend to increase GFR, whereas increased arterial oncotic pressure will tend to reduce GFR.
However, now recall that πGC is identical to arterial oncotic pressure only at the very beginning of the glomerular capillaries; πGC then progressively increases along the glomerular capillaries as protein-free fluid filters out of the capillary, concentrating the protein left behind. This means that net filtration pressure and, hence, filtration progressively decrease along the capillary length. Accordingly, anything that causes a steeper rise in πGC will tend to lower average net filtration pressure and hence GFR.
This steep increase in oncotic pressure tends to occur when RPF is low. It should not be hard to visualize that the filtration of a given volume of fluid from a small total volume of plasma flowing through the glomeruli will cause the protein left behind to become more concentrated than if the total volume of plasma were large. In other words, a low RPF, all other factors remaining constant, will cause the πGC to rise more steeply and reach a final value at the end of the glomerular capillaries that is higher than normal. This increase in average πGC along the capillaries lowers average net filtration pressure and, hence, GFR. Conversely, a high RPF, all other factors remaining constant, will cause πGC to rise less steeply and reach a final value at the end of the capillaries that is less than normal, which will increase the GFR.
Another way of thinking about this is in terms of filtration fraction: the ratio GFR/RPF. The increase in πGC along the glomerular capillaries is directly proportional to the filtration fraction (ie, the more volume that is filtered from plasma, the higher is the rise in πGC). Therefore, if you know that filtration fraction has changed, you can be certain that there has also been a proportional change in πGC and that this has played a role in altering GFR.