What are nephrotoxic drugs?

Nephrotoxic Drugs: Classification and Mechanisms

Nephrotoxic drugs are medications that can cause kidney dysfunction or injury through various mechanisms, including direct tubular toxicity, crystal formation, immune-mediated injury, and hemodynamic alterations affecting kidney perfusion. 1

Classification of Nephrotoxic Drugs

Nephrotoxic drugs can be classified into two major categories based on their mechanisms of action:

1. Drugs Causing Kidney Dysfunction (Hemodynamic Effects)

• Medications that lead to systemic hypotension (systemic arterial vasodilation) 1
• Drugs that alter intraglomerular hemodynamics (afferent arteriole constriction, efferent arteriole dilation) 1
• These agents decrease renal perfusion pressure, which if sustained or severe, can lead to ischemic injury 1

2. Drugs Causing Direct Kidney Injury (Structural Damage)

• Medications that cause glomerular or tubular cell injury triggered by filtered toxins 1
• Drugs causing tubular obstruction 1
• Agents inducing endothelial dysfunction 1
• Medications triggering allergic reactions in the kidney 1

Common Nephrotoxic Drugs

Antimicrobials

• Aminoglycosides (gentamicin, tobramycin): Cause direct tubular toxicity, with risk increasing with higher peak (>12 mcg/mL) and trough (>2 mcg/mL) concentrations 2, 3, 4
• Other antibiotics: Can cause acute interstitial nephritis, acute tubular necrosis, and crystal deposition 4, 5

Analgesics and Anti-inflammatory Drugs

• NSAIDs including COX-2 inhibitors: Particularly harmful in patients with pre-existing kidney insufficiency or diminished kidney blood flow 1, 6
• Acetaminophen is preferred for non-inflammatory pain in patients with kidney dysfunction 1

Cardiovascular Medications

• Angiotensin-converting enzyme (ACE) inhibitors: May cause functional changes in GFR, though some are actually renoprotective in certain conditions 1, 6

Contrast Media

• Intravenous or intra-arterial contrast dye: Particularly nephrotoxic in patients with pre-existing kidney dysfunction, especially diabetic nephropathy 1, 6

Other Nephrotoxic Agents

• Chemotherapeutic agents (cisplatin) 3, 7
• Calcineurin inhibitors 1
• Diuretics (ethacrynic acid, furosemide): Can enhance aminoglycoside toxicity when administered intravenously 2

Risk Factors for Drug-Induced Nephrotoxicity

• Pre-existing chronic kidney disease 4, 8
• Advanced age 2, 4
• Dehydration or volume depletion 2
• Diabetes mellitus 1, 6
• Concurrent use of multiple nephrotoxic medications 2, 4
• Hypercalcemia 1

Prevention and Monitoring Strategies

• Patients should receive potentially nephrotoxic medications only when needed and for the shortest duration possible 1
• Kidney function must be monitored in patients exposed to nephrotoxic agents 1
• For aminoglycosides, monitor serum concentrations to avoid peak levels above 12 mcg/mL and trough levels above 2 mcg/mL 2, 3
• Ensure adequate hydration, especially when administering contrast media 1
• Consider N-acetylcysteine before contrast studies in high-risk patients 1
• Avoid combining multiple nephrotoxic agents when possible 2, 4

Important Caveats

• Some drugs that may cause a rise in serum creatinine (like ACE inhibitors or SGLT2 inhibitors) can actually be renoprotective in certain conditions such as diabetic nephropathy 1
• Potentially nephrotoxic agents should not be withheld in life-threatening conditions due to concern for AKI, including IV contrast when necessary 1
• The risk-benefit ratio must be carefully considered, especially in critically ill patients 4, 5
• Novel kidney-specific biomarkers (cystatin C, KIM-1) may allow earlier detection of kidney injury than traditional markers like creatinine 5