How does colistin cause Acute Tubular Necrosis (ATN)?

Mechanism of Colistin-Induced Acute Tubular Necrosis (ATN)

Colistin primarily causes acute tubular necrosis (ATN) by increasing tubular epithelial cell membrane permeability, leading to cation, anion, and water influx that results in cell swelling and eventual cell lysis. 1

Primary Mechanisms of Nephrotoxicity

• Colistin disrupts the cell membrane of renal tubular cells by increasing membrane permeability, which allows excessive influx of water and electrolytes, causing cell swelling and ultimately cell lysis 1
• Oxidative stress and inflammatory pathways are also involved in colistin-induced nephrotoxicity 1
• Colistin accumulates in renal tubular cells due to specific renal handling mechanisms, leading to high concentrations in kidney tissue 2
• Cell cycle arrest has been identified as an early molecular event in colistin nephrotoxicity, with altered expression of genes involved in cell cycle proliferation 3

Clinical Manifestations of Colistin Nephrotoxicity

• Acute kidney injury (AKI) occurs in up to 59.2% of patients receiving colistin therapy 4
• Acute tubular necrosis is the most common kidney lesion associated with colistin use 5
• Renal replacement therapy may be required in approximately 50.8% of patients who develop colistin-induced AKI 4
• Signs of impaired renal function include diminishing urine output, rising BUN and serum creatinine, and decreased creatinine clearance 6

Risk Factors for Colistin-Induced ATN

• Dose and duration of colistin therapy are significant factors, with higher doses increasing nephrotoxicity risk 1
• Co-administration of other nephrotoxic drugs significantly increases the risk of ATN 1, 4
• Patient-related factors that increase risk include:
  • Advanced age 1, 4
  • Hypoalbuminemia 1, 4
  • Hyperbilirubinemia 1
  • Use of vasopressors 4
  • Use of diuretics 4
  • Pre-existing renal impairment 4

Prevention and Monitoring

• A loading dose of 9 MU (5 mg/kg) of colistin followed by a maintenance dose of 4.5 MU twice daily is recommended for critically ill patients with normal renal function 5, 7
• Renal function should be closely monitored during colistin therapy 5, 6
• Dose adjustment is necessary for patients with impaired renal function 8, 6
• Therapy with colistin should be discontinued immediately if signs of impaired renal function occur 6
• Consider alternative antibiotics when available, as newer β-lactam/β-lactamase inhibitors may have lower nephrotoxicity risk 5

Biomarkers for Early Detection

• Urinary neutrophil gelatinase-associated lipocalin (NGAL) has been studied as an early biomarker for colistin-induced AKI, though its predictive capacity may be limited in patients with urinary tract infections 9
• Early detection is crucial as colistin nephrotoxicity is generally reversible following discontinuation of the antibiotic 1

Comparative Nephrotoxicity

• Emerging data suggest significantly higher rates of AKI in patients treated with colistimethate (prodrug of colistin) compared to patients treated with polymyxin B 2
• This difference may be due to variations in pharmacokinetics and renal handling mechanisms between the two drugs 2

Understanding the mechanism of colistin-induced ATN is essential for appropriate clinical management and development of strategies to prevent this serious adverse effect while treating multidrug-resistant gram-negative infections.