Nephrotoxicity

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Nephrotoxicity
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Kidney Physiology

• Nephron
• 3 divisions
• Glomerulus
• Vascular elements
• Tubules
• Glomerulus
• Filtration
• Endothelial cells
• Pores
• Decreased GFR
• ? afferent arteriolar blood flow
• ? surface area for filtration

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Kidney Physiology

• Proximal tubule
• Reabsorption
• Transport systems
• Organic anions and cations
• Loop of Henle
• Distal tubule and collecting duct
• Macula densa
• Alter GFR

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Assessment of Nephrotoxicity

• Urinalysis
• Volume, pH
• Glucose
• Proteins
• Cells
• Blood chemistry
• Blood urea nitrogen
• Creatinine
• Histopathology

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Pathophysiologic Responses

• Acute renal failure
• Decline in GFR
• Azotemia
• Chronic renal failure
• Adaptive responses
• Compensatory increases in single nephron GFR
• Metallothionein induction
• Stress protein induction

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Susceptibility to Injury

• Receives 20-25 cardiac output
• Concentration of urine
• Transporters
• Sensitivity to vasoconstrictors
• Biotransformation
• CP450
• Cysteine-conjugate b-lyase

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Site of Injury

• Glomerular injury
• Renal vasoconstriction
• Injury to endothelial cells
• Circulating immune complexes
• Proximal tubule injury
• Most common site of injury
• Ischemic injury
• Reactive electrophiles
• Distal tubule/collecting duct injury
• Impaired concentrating ability

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Heavy Metals

• Cadmium
• Sources
• Occurs in nature with zinc and lead
• Occupational
• Smelting, electroplating, galvanizing
• Distributes first to liver
• Induces synthesis of metallothionein
• Cd-MT complex stored in liver OR
• Cd-MT complex distributes to kidney
• Accumulates in lysosomes
• Damages proximal tubules

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Mercury

• Mechanism of action
• Binds to variety of enzyme systems
• Nonspecific cell injury or death
• Sulfhydryl groups
• Interferes with cellular metabolism and function
• Inhibits active transport mechanisms
• Diuretic
• Accumulates in kidney
• Proximal tubule necrosis
• Half-life 70 days

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Lead

• Mechanism
• Decreased mitochondrial respiration and
  phosphorylation
• Damage to proximal tubular cells
• Acute reversible
• Chronic irreversible
• Interstitial nephropathy

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Halogenated Hydrocarbons

• Chloroform, tetrafluoroethylene, bromobenzene
• Reactive metabolites
• Renal CP450
• Cysteine conjugate b-lyase
• Proximal tubule damage

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Drugs

• Aminoglycoside antibiotics
• Taken up by lysosomes
• Proximal tubule damage
• Amphotericin B
• Binds to membrane phospholipids
• Damage to glomerulus and proximal tubule
• NSAIDS
• Vasoconstriction
• Decreased GFR