PRINCIPLES OF TOXICOLOGY

142 NEPHROTOXICITY: TOXIC RESPONSES OF THE KIDNEY
gas causes massive hemolysis of red blood cells, which results in hemoglobinuria and associated renal
failure (see Chapter 4 for a general listing of hemolytic agents, methemoglobin formers, etc.).
Heroin overdosage can result in a prolonged pressure on dependent muscles and a lysis of the
muscle cell, leading to a release of myoglobin into the blood. Heroin may also cause some direct lysis
of the muscle cells. The result can be myoglobinuria and ultimately acute renal failure. Aniline dyes
are another group of chemicals that have been shown to release methemoglobin, with an associated
renal failure.
Therapeutic Agents
Table 6.4 lists a number of therapeutic agents known to cause nephrotoxicity. Acetaminophen is
oxidized by the microsomal P450 oxygenase system in the renal cortex to a toxic metabolite. The
microsomal P450 oxygenase system of the kidney is similar to that of the liver (see Chapter 5).
Cephalosporadine reaches high toxic concentrations in the nephron because the organic ion
transport system of the proximal tubule secretes it into the tubule. The nephrotoxicity of cephalosporadine
can be diminished by compounds that compete with the organic anion secretion system in the
proximal tubule, such as probenicid. The resulting decrease in tubular concentration of cephalosporidine
in tubular fluid results in elimination of toxicity.
Other therapeutic agents can, in certain individuals, elicit a nephrotoxicity by an allergic type of
reaction. However, such nephrotoxicities are usually only rarely encountered.
6.4 SUMMARY
TABLE 6.4 Therapeutic Agents Known to Cause Nephrotoxicity
Acetaminophen (analgesic)
Aminoglycoside antibiotics
Amphotericin B (antibiotic)
Cephalosporadine (antibiotic)
Colistimethate (antibiotic)
Gentamycin
Kanamycin
Neomycin
Polymyxin B (antibiotic)
Streptomycin
Tetracyclines (particularly outdated formulations) (antibiotics)
The kidney performs a number of functions essential for the maintenance of life:
• Elimination of waste products (particularly nitrogen-containing wastes from the metabolism
of proteins) from the blood
• Regulation of acid-base balance, extracellular volume, and electrolyte balance
Toxic agents that disrupt these key functions can be life-threatening.
The kidney is a highly metabolic organ sensitive to deprivation of oxygen, and any agent that
significantly impedes renal flow will cause two adverse sequelae; acute renal failure that can result in
death:
• First, less blood plasma will reach the kidney, resulting in a decrease in removal of blood
wastes with a resulting increase of wastes in the blood (i.e., uremia).