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.
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
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.
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.
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
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
).
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 ×[(PGC ― PBS) ― (πGC ― πBS)]
PGC : glomerular hydrostatic pressure
PBS : Bowman's capsule hydrostatic pressure
πGC : glomerular capillary colloid osmotic pressure
πBS : Bowman's capsule osmotic pressure
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.