What medications can cause direct tubular injury?

Medications That Cause Direct Tubular Injury

Several classes of medications can cause direct tubular injury, with aminoglycosides, platinum-based chemotherapy agents, and certain other nephrotoxic drugs being the most common culprits. 1

Aminoglycoside Antibiotics

Aminoglycosides are among the most well-documented causes of direct tubular injury:

• Gentamicin: Causes acute tubular necrosis through direct toxicity to proximal tubular cells 2
• Tobramycin: Primarily manifests as acute tubular necrosis with signs including rising BUN and creatinine, decreased urinary output, and urinary losses of sodium, potassium, bicarbonate, magnesium, phosphate, and calcium 3

The nephrotoxicity risk with aminoglycosides increases with:

• Drug accumulation (trough levels above 2 mcg/mL)
• Excessive peak concentrations (above 12 mcg/mL)
• Total cumulative dose
• Advanced age
• Volume depletion
• Concurrent use of other nephrotoxic drugs
• Diabetes 3

Chemotherapeutic Agents

Several anticancer drugs cause direct tubular injury:

• Cisplatin: Causes cross-linking and interference with DNA replication, leading to acute tubular injury and necrosis, proximal tubulopathy, Fanconi syndrome, and electrolyte wasting 1
• Ifosfamide: Nitrogen mustard alkylating agent that causes acute tubular injury and necrosis 1
• Pemetrexed: Antifolate agent that causes acute tubular injury and necrosis 1
• Methotrexate: Causes both crystalline nephropathy and acute tubular injury 1

Bisphosphonates

• Pamidronate: Associated with moderate FPPS inhibition, causing focal segmental glomerulosclerosis and acute tubular injury 1
• Zoledronic acid: More potent FPPS inhibitor that causes acute tubular injury and necrosis 1

Targeted Therapies

• BRAF inhibitors (vemurafenib and dabrafenib): Cause acute tubular injury through inhibition of mutated BRAF V600E kinase 1
• ALK inhibitors (crizotinib): Cause acute tubular injury through inhibition of mutated anaplastic lymphoma kinase 1

Other Medications

• Radiocontrast agents: Cause direct kidney tubule toxicity 1
• Amphotericin B: Direct tubular toxin 1
• Vancomycin: Can cause acute tubular injury, particularly at high doses 4

Mechanisms of Tubular Injury

Medications can cause direct tubular injury through several mechanisms:

1. Direct cellular toxicity: Drugs like aminoglycosides and cisplatin directly damage tubular cell mitochondria and other cellular components 4

2. Transport-mediated injury: Some drugs accumulate in tubular cells through specific transporters:

   • Aminoglycosides enter via endocytosis at the apical membrane
   • Cisplatin enters via organic cation transporters at the basolateral membrane
   • Tenofovir enters via organic anion transporters 4

3. Intratubular crystal formation: Drugs like methotrexate can precipitate within tubular lumens 4

Prevention Strategies

To minimize the risk of medication-induced tubular injury:

• Use the shortest duration of therapy clinically appropriate
• Ensure adequate hydration during treatment
• Limit concurrent use of other nephrotoxic drugs
• Monitor drug levels closely (especially for aminoglycosides)
• Consider alternative less nephrotoxic medications when possible 5
• Monitor renal function, electrolytes, urine output, and urinalysis during therapy 3

Clinical Monitoring

For high-risk medications like aminoglycosides:

• Monitor serum drug concentrations to avoid toxic levels
• Check renal function before and during treatment
• Adjust dosing based on renal function
• Consider once-daily dosing regimens when appropriate 5

For patients receiving potentially nephrotoxic medications, early detection of tubular injury is crucial for preventing progression to more severe kidney damage and improving outcomes.