What are examples of nephrotoxic drugs and how can their risk be mitigated?

Nephrotoxic Drugs: Examples and Risk Mitigation

Major Nephrotoxic Drug Categories

The most clinically significant nephrotoxic drugs include aminoglycosides, NSAIDs, vancomycin, platinum-based chemotherapy, calcineurin inhibitors, contrast media, and the "triple whammy" combination of NSAIDs + diuretics + ACE inhibitors/ARBs, which more than doubles acute kidney injury risk. 1

Antibiotics

• Aminoglycosides (gentamicin, tobramycin) cause direct tubular toxicity and increase AKI odds by 53%, with risk compounding when combined with other nephrotoxins 1, 2, 3

  • Peak concentrations should not exceed 12 mcg/mL and trough levels should remain below 2 mcg/mL 2, 3
  • Nephrotoxicity typically develops after 10 days of treatment and is usually reversible upon discontinuation 4

• Vancomycin causes nephrotoxicity particularly at prolonged peak concentrations above 12 mcg/mL and trough levels above 2 mcg/mL 1

  • Risk increases substantially when combined with other nephrotoxic agents or in patients with pre-existing renal impairment 5

NSAIDs and Cardiovascular Drugs

• All NSAIDs, including COX-2 inhibitors, cause afferent arteriole constriction and renovasoconstriction, precipitating AKI especially in patients with pre-existing kidney insufficiency or diminished kidney blood flow 1, 6

• ACE inhibitors and ARBs alter intraglomerular hemodynamics through efferent arteriole dilation, decreasing renal perfusion pressure 1, 6

  • Despite causing functional GFR changes, these agents can be renoprotective in diabetic nephropathy 6

• The "triple whammy" combination (NSAIDs + diuretics + ACE inhibitors/ARBs) more than doubles AKI risk, with 25% of non-critically ill patients developing AKI when receiving three or more nephrotoxins 1, 6

Chemotherapeutic Agents

• Cisplatin has preferential nephrotoxicity through direct tubular injury 1
• Methotrexate causes crystalline nephropathy through intratubular crystal deposition and obstruction 1, 6
• Tyrosine kinase inhibitors and BRAF inhibitors cause tubulointerstitial injury and AKI 1
• Proteasome inhibitors may be associated with thrombotic microangiopathy 1
• Immune checkpoint inhibitors cause AKI primarily through acute interstitial nephritis and acute tubular injury 1

Immunosuppressants and Other Agents

• Calcineurin inhibitors (cyclosporin, tacrolimus) cause direct nephrotoxicity through afferent arteriole vasoconstriction, likely mediated by the sympathetic system 1, 4

  • Nephrotoxicity is dose-dependent and generally reversible, though irreversibility has been reported with long-term use 4

• Amphotericin B causes renal insufficiency in 80% of treated patients, with risk increasing as cumulative dose exceeds 5g 4

• IV or intra-arterial contrast media cause nephrotoxicity especially in patients with pre-existing kidney dysfunction such as diabetic nephropathy 1, 6

  • Risk ranges from 0.6% in patients with normal renal function to 100% in patients with serum creatinine above 400 µmol/L 4

High-Risk Drug Combinations

• Macrolide antibiotics + statins increase AKI risk from rhabdomyolysis due to impaired statin clearance via CYP3A4 inhibition 1, 6

• Furosemide enhances nephrotoxicity of other drugs like cisplatin 5

  • Potent diuretics (ethacrynic acid, furosemide) should be avoided with aminoglycosides as they may cause ototoxicity themselves and enhance aminoglycoside toxicity by altering antibiotic concentrations in serum and tissue 2

• Escalating from two to three nephrotoxic medications more than doubles AKI risk 1, 6

• Nephrotoxic chemotherapy should not be administered on the same day as intravenous bisphosphonates to reduce the risk of renal toxicity 7

Risk Factors for Drug-Induced Nephrotoxicity

• Pre-existing chronic kidney disease significantly increases vulnerability 1, 6
• Diabetes mellitus increases risk of drug-induced nephrotoxicity 1, 6
• Previous history of AKI elevates risk 1
• Advanced age and volume depletion increase patient risk of toxicity 2, 3
• Hypercalcemia increases nephrotoxicity risk 1, 6

Risk Mitigation Strategies

Medication Selection and Timing

• Administer potentially nephrotoxic medications only when needed and for the shortest duration possible 7, 1, 6

• Use less nephrotoxic alternatives: acetaminophen for non-inflammatory pain instead of NSAIDs 1, 6

  • Consider low-dose opiates or short courses of corticosteroids for inflammatory conditions 6

• Avoid NSAIDs entirely in patients with pre-existing kidney insufficiency or diminished kidney blood flow 1, 6

• Potentially nephrotoxic agents should not be withheld in life-threatening conditions due to concern for AKI, including IV contrast 7

Monitoring Requirements

• Monitor kidney function (serum creatinine, BUN, creatinine clearance) in all patients exposed to nephrotoxic agents 7, 1, 6

  • Urine should be examined for decreased specific gravity, increased protein excretion, and presence of cells or casts 2

• Monitor serum aminoglycoside concentrations when feasible to ensure adequate levels and avoid potentially toxic levels 2, 3

  • Dosage should be adjusted so that prolonged peak levels above 12 mcg/mL are avoided 2, 3
  • Trough concentrations should be adjusted so that levels above 2 mcg/mL are avoided 2, 3

• Serial audiograms should be obtained in patients old enough to be tested, particularly high-risk patients receiving aminoglycosides 2

Preventive Measures

• Ensure adequate hydration, especially when administering contrast media or other high-risk agents 1, 6

  • Sodium loading may prevent much of the nephrotoxicity associated with amphotericin B 4

• Consider N-acetylcysteine before contrast studies in high-risk patients 1, 6

• Avoid concurrent or sequential use of multiple nephrotoxic drugs whenever possible 7, 2, 3

• Continue nephrotoxin avoidance throughout the persistent phase of AKD, and exercise caution when initiating nephrotoxins during the recovery phase to prevent re-injury 6

Patient Education

• Educate patients to avoid over-the-counter NSAIDs during UTI episodes and other high-risk situations 1

• Instruct patients to consult before taking new medications, particularly decongestants, antivirals, antibiotics, and herbal products 1, 6

• Patients should be instructed to recognize and report signs and symptoms indicating key adverse events, including evidence of ototoxicity (dizziness, vertigo, tinnitus, roaring in ears, hearing loss) or nephrotoxicity 7, 2

Critical Pitfalls to Avoid

• Do not assume diabetes mellitus alone greatly increases radiocontrast nephrotoxicity risk—the primary risk factor is pre-existing renal dysfunction 4

• Evidence of ototoxicity or nephrotoxicity requires dosage adjustment or discontinuance of aminoglycosides, as changes in renal and eighth cranial nerve function may not become manifest until soon after completion of therapy 2

• Acute interstitial nephritis is usually self-limiting, but some evidence suggests steroids may promote recovery 4