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Glomerular Filtration

Molecules smaller than 10,000 daltons are filtered at the glomerulus. Endothelial cells of glomerular capillaries and podocytes (cells that encircle the capillaries) form a leaky filtration membrane that allows the filtration of water and small solutes but prevent filtration of most plasma proteins, blood cells and platelets.

The glomerular endothelial cells have large fenestations that allow all solutes in plasma to pass but prevent filtration of blood cells and platelets. A layer of acellular material between the endothelium and the podocytes, the basal lamina, prevents filtration of large plasma proteins. Extending from each podocyte are thousands of foot-like processes (pedicels) that wrap around glomerular capillaries The spaces between pedicels (filtration slits) are covered with a thin membrane that allows passage of molecules smaller than 6-7 nm, including water, glucose, vitamins, amino acids, very small proteins, ammonia, urea and ions.

The glomerular filtration rate (GFR) is defined as:

GFR = kf NFP

were kf is the glomerular coefficient and NFP is the net filtration pressure. kf is influenced by the permeability of the filtering membrane (for example, thickening of the basement membrane will decrease kf) and the surface are available for filtration (for example, loss of glomerular surface will decrease kf). NFP is defined as:

NFP = GHP - BCP - CHP

where GHP is the glomerular hydrostatic pressure (~ 55 mmHg), BCP is the blood colloidal osmotic pressure (~ 30 mmHg) and CHP is the capsular hydrostatic pressure (~ 15 mmHg). Therefore, on average:

NFP = 55 mmHg - 30 mmHg - 15 mmHg = 10 mmHg

When the systemic blood pressure rises above normal, NFP and GFR increase very little due to regulatory mechanisms that may be intrinsic to the kidney, sympathetic or hormonal.

Intrinsic regulation operates by vasodilation or vasoconstriction of the afferent arteriole in response to blood pressure changes. Stretching (due to elevated pressure) triggers contraction of the smooth muscle in the wall of the afferent arterioles. At the same time, filtered fluids flow more rapidly along the tubules, with less time to reabsorb Na+, Cl- and water. This stimulates the release of a local vasoconstrictor from the juxtaglomerular cells (probably a prostaglandin or proteolitic enzyme ?).

With moderate sympathetic stimulation, both afferent and efferent arterioles constrict to the same degree. With greater sympathetic stimulation, like during exercise or hemorrhage, afferent vasoconstriction predominates. This reduces urine output and conserves blood volume.

Osmoreceptors at the macula densa and sympathetic stimuli will trigger secretion of renin from the juxtaglomerular cells into the blood stream. Renin clips off angiotensin I from angiotensinogen, a normal plasma protein produced by the liver. Angiotensin converting enzyme (ACE) in the lungs converts angiotensin I into angiotensin II, which affects renal physiology by causing vasoconstriction of afferent arterioles, enhancing Na+, Cl- and water reabsorption and stimulating the release of aldosterone from the adrenal cortex and antidiuretic hormone (ADH) from the pituitary.

Renal plasma clearance, Cx, is the volume of blood cleared of a substance X by the kidneys per unit time:

Cx = Ux V
           Px

where Ux is its concentration in urine and Px in plasma, and V is the urine flow rate (volume/time). Renal clearance of a solute depends on GFR, tubular reabsorption, and tubular secretion.

If a substance is filtered but neither reabsorbed nor secreted, its clearance equals its GFR. This is very nearly the case of creatinine, a product of catabolism of creatinine phosphate in skeletal muscle. Normally the blood creatinine level remains steady and its excretion in urine equals its discharge from muscle. It is easily filtered, not reabsorbed, and only slightly secreted.

An even more accurate way of measuring GFR is by giving an intravenous infusion of inulin (8-12 hrs) then measuring its concentration in urine and blood. Inulin is completely filtered and neither reabsorbed nor secreted.

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Advance Topics: Distribution/Excretion (Medical Pharmacology)
                              Clearance (Introduction to Pharmacology and Toxicology)

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