In: Veterinary Toxicology, V. Beasley (Ed.

)
Publisher: International Veterinary Information Service (www.ivis.org), Ithaca, New York, USA.

Introduction to the Toxicology of the Urinary System (9-Aug-1999)

V. Beasley
Department of Veterinary Biosciences, College of Veterinary Medicine, University of Illinois at Urbana-Champaign, Urbana, IL, USA.

Chapter Sections
Major Functions of the Urinary System
Major Clinical Effects of Kidney Failure
Sites and Mechanisms of Action of Urinary Tract Toxicants
Specific Nephrotoxic Substances and Their Primary Effects

Introduction to the Toxicology of the Urinary System

1. Major Functions of the Urinary System

z Elimination of waste products from the body
z Regulation of the volume of the extracellular fluid
z Control of electrolyte concentrations in the extracellular fluid
z (e.g. Na+, K+, Ca++, Cl-)
z Control of acid base status (pH)
z Production of hormones
z Erythropoietin (stimulates red blood cell production - bone marrow)
z Vitamin D3 [kidney hydroxylates (addition of an -OH group) to activate]
z Renin
z With a decline in blood pressure, the kidney secretes renin which is an enzyme that acts on a plasma globulin to
produce angiotensin. Angiotensins include a potent vasoconstrictor. Angiotensins also stimulate aldosterone
secretion from the adrenal glands. Aldosterone increases sodium retention, which attracts water to the
extracellular fluid, thereby expanding the plasma volume and thus, increasing the blood pressure.
z Vasoactive prostanoids and kinins

2. Major Clinical Effects of Kidney Failure

z Increased concentrations of waste products in the body
z (e.g. increased blood urea nitrogen, increased serum creatinine)
z People and other animals may appear weak, vomit, develop an odor to the breath, oral ulceration
z With severe acute renal failure, renal shutdown (absence of urine production) may occur
z With chronic renal failure, increased urine production (decreased concentrating ability) and associated thirst may occur
z Dilute urine (low specific gravity) often containing amino acids, protein and sometimes glucose.
z Potential anemia with chronic renal failure

3. Sites and Mechanisms of Action of Urinary Tract Toxicants

z Sites of action may include (epithelial cells &/or basement membranes of):
z Glomeruli (e.g. doxorubicin; aminonucleoside of puromycin)
z Renal tubular epithelial cells (often proximal tubules are involved) (e.g. ethylene glycol toxicosis)
z Collecting ducts (e.g. phenylbutazone toxicosis - renal papillary necrosis)
z Lower urinary tract [e.g. carcinogenesis from toxins in Pteridium (= bracken fern)]
z Toxic effects on cells range from imperceptible to necrosis
z Reactive oxygen species
z Reactive oxygen species and their generation: all can produce lipid peroxidation
z Are often produced by neutrophils (often involved in glomerular nephritis - e.g. phorbol ester toxicosis;
bacterial infections)
z Generated by reperfusion injury (e.g. after relief of circulatory shock - caused by any of the following:
hemorrhage, sudden cardiac failure, acute anaphylaxis, bacterial toxins, other toxic chemicals that affect the gut,
 heart, vasculature)
z Superoxide anion (O-)= the free radical produced when oxygen accepts one electron
z May diffuse through the cell, but cannot readily cross membranes
z Often reacts within membranes
z Hydrogen peroxide (H2O2) = a reactive neutral molecule produced when oxygen accepts two electrons
z Readily crosses membranes
z Superoxide anion reduces Fe+3 to Fe+2, and Fe+2 reduces H2O2 to the hydroxyl radical (• OH).
z Extremely reactive, reacts before diffuses or crosses membranes
z Reacts in cytosol
z Effects of reactive oxygen species:
z Induction of a chain reaction resulting in propagation of lipid peroxidation (altered membrane fluidity and
permeability)
z Decomposition of lipid peroxides is catalyzed by transitional metals; but this forms alkoxy and peroxy
free radicals that propagate the reaction
z Inactivation of cellular enzymes by directly oxidizing critical -SH or -NH2 groups - results in altered enzyme
activity
z Depolymerization of polysaccharides
z Induction of breaks in DNA
z Production of toxic breakdown products from lipids including:
z Hydroxylated fatty acids
z Alkanals
z Alkenals
z Altered calcium homeostasis
z Extracellular Ca++: intracellular Ca++ is normally 10,000:1
z Proximal renal tubules normally reabsorb 60 - 70% of filtered Ca++
z Must avoid elevated intracellular free Ca++ to avoid:
z Activation of calcium-dependent phospholipases
z Degrade cellular organelles
z Degrade plasma membrane phospholipids altering function
z Uncouple oxidative phosphorylation
z Cause marked disorganization of the cytoskeleton
z Cause apoptosis &/or necrosis
z Causes of elevated intracellular Ca++:
z Reperfusion injury (lack of ATP to pump Ca++ out of cells)
z Mercuric chloride (one factor in the toxicosis)
z Gentamicin (antibiotic) (one factor in the toxicosis)
z Glomerular effects of urinary toxicants
z May complex with, alter permeability of, or partially occlude renal glomerular capillaries
z Altered permeability may result in an increased loss of protein
z Tubular effects of urinary toxicants
z A number of toxicants damage the proximal renal tubular epithelial cells
z Some nephrotoxicants damage the basement membrane making effective regeneration (healing) less likely
z A few nephrotoxicants may precipitate in and thereby block the renal tubules
z Vascular effects of urinary toxicants
z Vasospasms or swelling in kidney may greatly impede renal blood flow
z Reduced renal perfusion is a common complicating factor in a number of forms of toxicant-induced kidney failure

4. Specific Nephrotoxic Substances and Their Primary Effects

z Heavy metals
z Alter -SH and other groups in proteins
z End product of acute (high dose) exposure to many metals include damage to proximal tubular epithelial cells (necrosis
with loss of protein) with marked deprivation of blood flow (combination of direct cellular toxicity and ischemia)
z Lead (Pb++)
z Lead (Pb++) may not only affect -SH groups, but may also alter Ca++ homeostasis
z Lead sequestered in intranuclear inclusion bodies as a lead/protein complex
z Mercury (Minamata Bay Disease)
z Several forms of mercury were once used as diuretics
z (Elemental, inorganic, organic)
z Mercury salts are most nephrotoxic
z Breakdown of organic forms to inorganic forms seems to account for their nephrotoxicity.
z Mitochondrial enzymes are especially sensitive to Hg (potential role of Ca++ disruption yet to be thoroughly
investigated)
 z Causes glomerular and tubular injury
z Glomerular damage believed linked to a Hg-induced autoimmune reaction
z Outer proximal tubules are most sensitive
z With higher doses, injury proceeds toward the medulla
z Cadmium (Itai-Itai Disease)
z Stimulates synthesis of metallothionein to which it binds
z Metallothionein complex limits effects of Cd on some organs such as the testis
z Metallothionein complexes in kidney can lead to such high concentrations that eventually the kidney
becomes damaged
z Cause of chronic renal failure
z Multiparous women most susceptible - osteoporosis - spontaneous fractures - Itai-itai = ouch-ouch
disease.
z Ochratoxin-A (Balkan nephropathy of human beings; porcine nephropathy)
z Mycotoxin from several species of Penicillium and Aspergillus
z Selectively taken up by the kidney
z Affects rural populations of Bulgaria, Romania, and Yugoslavia
z Causes marked interstitial fibrosis, proximal tubular injury
z Also immunosuppressive
z Urinary tract carcinogen
z Residues - especially from grain, lesser amounts from kidneys and blood (blood pudding)
z Cephalosporin antibiotics
z Nephrotoxic in rats and human beings
z Actively transported from the peritubular capillary into the tubular epithelial cell, but not efficiently across into the
tubular lumen
z Damages proximal tubules
z Induces production of reactive oxygen species
z Inhibits mitochondrial energy production
z Cyclosporine
z Fungal cyclic polypeptide used to limit rejection after organ transplantation
z Renal effects are expected with the routine use of the drug
z Multiple types of lesions may develop in the kidney potentially involving the glomeruli, proximal tubules, and
vasculature.
z Interstitial fibrosis can lead to a progressive form of worsening kidney failure (fibroplasia - contraction - necrosis -
more fibroplasia - etc.)
z Paraquat
z At massive doses, paraquat damages not only the lung, but also the kidney
z Kidney damage delays the rapid renal elimination of paraquat that occurs at lower doses thereby increasing the severity
of lung damage
z Nonsteroidal anti-inflammatory drugs
z Induce "analgesic nephropathy"
z Several such drugs may cause papillary necrosis (e.g. phenylbutazone; aspirin)
z This effect is believed to be related to inhibition of prostaglandin synthesis by the non-steroidal compound) and
locally impaired blood flow
z May also affect proximal tubules, probably by an independent mechanism
z May require higher doses than those necessary to have a threshold effect in the renal papilla

References
Introduction to the Toxicology of the Urinary System
1. Hewitt WR, Goldstein RS, Hook JB. Toxic Responses of the Kidney. In: Amdur MO, Doull JD, Klaassen CD, eds. Casarette
and Doull's Toxicology, the Basic Science of Poisons, 4th Edition. New York, NY : Pergamon Press, 1991.
2. Rush GF, Hook JB. The Kidney as a Target Organ for Toxicity. In: Cohen GM, ed. Target Organ Toxicity, Vol. II. Boca
Raton, FL : CRC Press, 1986.

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