Renal Filtration
The structure of the glomerulus is shown in Figure 32a. The walls
of the afferent arteriole are
associated with granular cells that produce renin (Chapter 35);
there are numerous sympathetic nerve endings. The tuft of glomerular
capillaries is surrounded by Bowman’s capsule, the inner surface of
which and the capillaries are covered by specialized epithelial cells (podocytes;
see below). The glomerulus is interspersed with mesangial cells which
are phagocytic (engulf large molecules) and contractile;
contraction may limit the filtration area and alter filtration. Mesangial cells
are also found between the capsule and macula densa (extraglomerular
mesangial cells; Fig. 32a).
Glomerular filtration
Plasma is filtered in the
glomerulus by ultrafiltration (i.e. works at the molecular level), and
filtrate passes into the proximal tubule. The glomerular filtration rate (GFR)
is ∼125 mL/min in humans. The renal
plasma flow is ∼600 mL/min, so that the proportion of plasma
that filters into the nephron (filtration
fraction) is ∼20%. Fluid and solutes have to pass three filtration barriers (Fig. 32b):
1 The glomerular
capillary endothelium, which is approximately 50 times more permeable than
in most tissues because it is fenestrated with small (70 nm) pores
(Chapter 23).
2 A
specialized capillary basement membrane containing nega tively charged
glycoproteins, which is thought to be the main site of ultrafiltration.
3 Modified
epithelial cells (podocytes) with long extensions (primary processes)
that engulf the capillaries and have numerous footlike processes (pedicels)
directly contacting the basement membrane. The regular gaps between pedicles
are called filtration slits, and restrict large molecules. Podocytes
maintain the basement membrane and, like mesangial cells, may be phagocytic and
partially contractile.
The permeability of the filtration
barrier is dependent on the molecular size. Substances with molecular weights
of <7000 Da pass freely, but larger molecules are increasingly restricted up
to 70 000 Da, above which
filtration is insignificant (Fig. 32c). Negatively charged molecules are
further restricted as they are repelled by negative charges in the basement
membrane. Thus, albumin (∼69 000 Da), which is also negatively charged,
is filtered in minute quantities, whereas small molecules such as ions,
glucose, amino acids and urea pass the filter without hindrance. This means
that the glomerular filtrate is almost protein free, but otherwise has an
identical composition to plasma.
Factors determining the
glomerular filtration rate
GFR is dependent on the difference
between the hydrostatic and oncotic (colloidal osmotic, due to
proteins) pressures in the glomerular capillaries and Bowman’s capsule, as
determined by Starling’s equation (Chapter 23). The glomerular capillary
pressure (Pc) is greater than that elsewhere (∼48 mmHg) because of the
unique arrangement of afferent and efferent arterioles, and low afferent but
high efferent resistances. As the pressure in Bowman’s capsule (PB) is ∼10 mmHg,
the net hydrostatic force driving filtration is (Pc – PB) or ∼35 mmHg.
This is opposed by the oncotic
pressure of capillary plasma (πc; ∼25 mmHg);
the filtrate oncotic
pressure is essentially
zero (no protein). Thus, GFR ∝
(Pc – PB) – πc (Fig. 32d). It should be noted that, because the filtration fraction is
appreciable (∼20%) and proteins are not
filtered, the plasma protein concentration and thus πc will rise as blood traverses the glomerulus, reducing (but
not abolishing) filtration. In peritubular capillaries, where the
hydrostatic pressure is very low, this increase in πc promotes reabsorption
(Fig. 32d).
GFR is therefore strongly dependent
on the relative resistance of afferent and efferent arterioles, which is
influenced by sympathetic tone and other vasoactive agents. GFR is constant over
a wide range of blood pressure (90–200 mmHg) because of the autoregulation of
renal blood flow (Fig. 32e; Chapter 24). Renal disease, circulating and local
vasoconstrictors, and sympathetic activation all reduce GFR, although
angiotensin II preferentially constricts efferent arterioles, and thus
increases GFR (Chapter 35).
Measurement of the glomerular
filtration rate and the concept of clearance
If substance X is freely filtered
and neither reabsorbed nor secreted in the nephron, the amount appearing in the
urine per minute must equal the amount filtered per minute. Thus, if the plasma
concentra tion of X is Cp and the urine concentration is Cu, and the volume of
urine passed per minute is V, then Cp × GFR = Cu × V, or GFR = (Cu ×
V)/Cp.
Creatinine, which is steadily released from skeletal
muscle, is often used for clinical measurements of GFR because it is freely
filtered and not reabsorbed; there is a little secretion, but this introduces
only a small error, except when plasma creatinine or GFR is abnormally low.
More accurate measurements are made by infusing the polysaccharide inulin,
which is neither reabsorbed nor secreted.
This is known as a clearance
method. The term clearance can be confusing, as it does not refer to
what actually happens but is merely a way of looking at how the kidney deals
with a substance. It is defined as the volume of plasma that would need to be
completely cleared of a substance per minute in order to produce the amount
found in the urine, or: clearance
= (Cu × V)/Cp (i.e. the same equation as above).
Thus, the clearance of inulin is
equal to GFR. If a substance is reabsorbed
in the nephron, its clearance will be less than the GFR and, if it is secreted,
it will be greater than the GFR. Some substances that are normally completely
reabsorbed have zero clearance until the reabsorption mechanism becomes
saturated (e.g. glucose; Chapter 33). The renal plasma flow (RPF) can be
measured in a similar fashion by infusing para-aminohippuric acid (PAH)
which at low concentrations is completely removed from renal blood by both
filtration and secretion, so that none remains in the venous outflow. The
amount appearing in the urine must therefore equal the amount entering the
kidney, and thus the clearance of PAH is equal to RPF. The filtration
fraction (GFR/RPF; see above) can therefore be estimated from inulin
clearance/PAH clearance. The
renal blood flow
is equal to
RPF/ (1 – haematocrit).
