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).
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).