PRINCIPLES OF TOXICOLOGY

Metabolism of Vitamin D The kidney also plays a key role in the metabolism of vitamin D, thus
performing a vital function in the hormonal regulation of calcium in the body. Vitamin D3 (cholecalciferol)
is relatively inactive. The liver hydroxylates vitamin D3 to 25-hydroxycalciferol, and then, the
kidney hydroxylates the 25-hydroxycalciferol to 1,25-dihydroxycalciferol, the most potent active form
of vitamin D. The kidney is also the key to the metabolism of parathyroid hormone, another hormone
important to calcium regulation. If the kidney is damaged, thereby disrupting its role in vitamin D and
parathyroid hormone metabolism, the development of a renal osteodystrophy can occur, which is
characterized by skeletal disease and hyperplasia of the parathyroid gland.
6.2 FUNCTIONAL MEASUREMENTS TO EVALUATE KIDNEY INJURY
From the preceding paragraphs it should be clear that the kidney plays an essential role in maintaining
a number of vital body functions. Therefore, if a disruption of normal kidney function is caused by the
action of a toxic agent, a number of serious sequelae can occur besides a disruption in blood waste
elimination. However, for clinical purposes, alterations in the excretion of wastes are the principal
endpoints for determining the action of nephrotoxicants. Nevertheless, it must be remembered that
changes in the other functions may also be present, even if they are not conveniently or routinely
measured as toxic endpoints.
Determining the excretion rate of certain drugs from the kidney is a useful clinical procedure for
diagnosing the functional status of the kidney. This rate of elimination in the urine is the net result of
three renal processes:
• Glomerular filtration
• Tubular reabsorption
• Tubular secretion
6.2 FUNCTIONAL MEASUREMENTS TO EVALUATE KIDNEY INJURY 135
The rates of glomerular filtration and tubular secretion are dependent on the concentration of the drug
in the plasma, and the rate of reabsorption by the tubules is dependent on the concentration of drug in
the urine.
The Glomerular Filtration Rate
The glomerular filtration rate (GFR) can be measured in intact animals and humans by measuring both
the excretion and plasma levels of those chemicals that are freely filtered through the glomeruli and
neither secreted nor reabsorbed by the kidney tubules. The substance used should ideally be one that
is freely filtered, not metabolized, not stored in the kidney, and not protein bound. Inulin, a polymer
of fructose with a molecular weight of 5200 daltons, meets these criteria. For measuring the glomerular
filtration rate the inulin is allowed to equilibrate within the body, and then accurately timed urine
specimens and plasma samples are collected.
The following general formula is used to determine the clearance in this procedure:
Ua × V
= Cl
where Ua = concentration of substance a per milliliter urine
V = urine volume excreted per unit time
Pa = concentration of substance a per milliliter of plasma
Cl = clearance of substance per unit of time
Pa
For clearance of inulin (in), the following values can be used to demonstrate a sample calculation:
Uin = 31 mg/mL