Can phenytoin contribute to Acute Kidney Injury (AKI)?

Phenytoin's Contribution to Acute Kidney Injury (AKI)

Yes, phenytoin can contribute to acute kidney injury through multiple mechanisms, including direct tubular toxicity and formation of metabolite crystals in the urinary tract. While not among the most common nephrotoxic medications, evidence indicates phenytoin has potential nephrotoxic effects that should be monitored, especially in high-risk patients.

Mechanisms of Phenytoin-Induced Kidney Injury

Phenytoin can affect kidney function through several pathways:

1. Direct tubular injury:

   • Phenytoin has been associated with increased markers of renal glomerular and tubular injury, including elevated urinary N-acetyl-beta-D-glucosaminidase (U-NAG/UCr) and urinary malondialdehyde to creatinine (MDA/Cr) ratios 1
   • These markers suggest phenytoin may cause subclinical kidney damage with chronic use

2. Metabolite crystal formation:

   • Case reports document kidney stones composed of phenytoin metabolites (5-(para-hydroxyphenyl)-5-phenylhydantoin) 2
   • These metabolite stones can cause obstruction leading to hydronephrosis and kidney injury

3. Oxidative stress:

   • Similar to other antiepileptic drugs, phenytoin may induce oxidative stress in renal tissue 1

Risk Factors for Phenytoin-Associated AKI

The risk of developing AKI while on phenytoin increases with:

• Pre-existing chronic kidney disease
• Advanced age
• Concurrent use of other nephrotoxic medications
• Critical illness requiring ICU care
• Prolonged therapy duration
• High serum drug levels, particularly elevated free phenytoin levels 2

Monitoring Recommendations

For patients on phenytoin therapy:

• Monitor kidney function regularly, especially in high-risk patients
• Pay particular attention to patients receiving multiple nephrotoxic drugs, as the "nephrotoxic burden" significantly increases AKI risk 3
• Consider monitoring free phenytoin levels in patients with kidney dysfunction, as protein binding may be altered 4
• Watch for symptoms of urolithiasis in patients on long-term therapy 2

Management Considerations

When managing patients on phenytoin with potential kidney concerns:

• Follow the principle that "patients should receive potentially nephrotoxic medications only if needed and only for as long as needed" 5
• Consider dose adjustments in patients with developing AKI
• In patients with renal failure, be aware that phenytoin protein binding may be substantially reduced, potentially affecting drug levels 4
• For patients requiring continuous hemofiltration, higher daily doses of phenytoin may be needed as the drug can be removed through this process 4

Important Caveats

• Do not withhold phenytoin in life-threatening conditions (status epilepticus) due to concerns about AKI 5
• The nephrotoxic potential of phenytoin should be balanced against its therapeutic benefits
• Patients on multiple antiepileptic drugs or with severe disabilities may be at higher risk and warrant closer monitoring 1

While phenytoin is not among the most commonly recognized nephrotoxic drugs, clinicians should maintain awareness of its potential to contribute to kidney injury, especially in vulnerable patients or those with multiple risk factors for AKI.