Why would a patient with Immune Checkpoint Inhibitor (ICI)-induced myocarditis and acute interstitial nephritis develop hyperuricemia?

Causes of Hyperuricemia in a Patient with ICI-induced Myocarditis and Acute Interstitial Nephritis

Hyperuricemia in a patient with ICI-induced myocarditis and acute interstitial nephritis primarily results from acute kidney injury due to the interstitial nephritis, which impairs uric acid excretion.

Pathophysiological Mechanisms

Primary Mechanism: Acute Interstitial Nephritis (AIN)

• ICI-induced AIN is the most common histopathologic lesion in ICI-associated renal toxicity, occurring in 80-90% of cases 1
• The inflammatory process in the renal interstitium directly impairs tubular function, reducing uric acid secretion and excretion
• Median onset of ICI-related renal toxicity is 14 weeks but can range from 6.5-21 weeks 1

Contributing Factors

1. Renal Tubular Dysfunction:

   • Acute tubular injury is reported in 29% of ICI-related nephritis cases, often in combination with other pathologies 1
   • Tubular damage impairs uric acid secretion and reabsorption mechanisms

2. Concurrent Medication Use:

   • Risk factors for ICI-AIN include concomitant use of:
     • Proton pump inhibitors (PPIs)
     • Non-steroidal anti-inflammatory drugs (NSAIDs)
     • Antibiotics 1, 2
   • These medications can worsen renal function and independently contribute to hyperuricemia

3. Tumor Lysis-Like Phenomenon:

   • Rapid destruction of tumor cells following effective ICI therapy can release intracellular contents including purines
   • These purines are metabolized to uric acid, potentially overwhelming already compromised renal excretion

4. Myocarditis-Related Factors:

   • ICI-induced myocarditis frequently co-occurs with myositis 1, 3
   • Muscle breakdown in myositis releases purines that are metabolized to uric acid
   • Cardiac dysfunction may reduce renal perfusion, further impairing uric acid excretion

Clinical Considerations

Diagnostic Approach

• Monitor serum creatinine weekly during ICI treatment 4
• Evaluate for sterile pyuria (≥5 WBCs/hpf) and eosinophilia (≥500 cells per mL) 4
• Diagnostic criteria for ICI-related nephritis include:
  • Definite: Kidney biopsy-confirmed diagnosis
  • Probable: Sustained creatinine increase ≥50% on consecutive tests, absence of alternative etiology, AND sterile pyuria or eosinophilia
  • Possible: Creatinine increase ≥50% not readily attributable to other causes 4

Management Implications

• Temporarily hold ICI therapy for Grade 1 toxicity (creatinine increase >0.3 mg/dL; 1.5-2.0× baseline) 4
• For Grade 2-4 toxicity, consider permanent discontinuation of ICI therapy 4
• Administer corticosteroids based on severity:
  • Grade 2: Prednisone 0.5-1 mg/kg/day
  • Grade 3-4: Prednisone 1-2 mg/kg/day 4
• Monitor and manage electrolyte disturbances which commonly accompany ICI-related renal toxicity 4

Prevention and Monitoring

• Consider discontinuing PPIs, NSAIDs, and other nephrotoxic medications during ICI therapy 2, 5
• Complete renal recovery is seen in 63% of patients who discontinue PPIs at the time of AKI 5
• Monitor uric acid levels along with renal function tests during ICI therapy
• Early intervention with corticosteroids is crucial for renal recovery 5

Key Takeaways

1. Hyperuricemia in this clinical scenario primarily results from impaired renal excretion due to ICI-induced AIN
2. Early recognition and prompt management of ICI-related nephritis is essential to prevent complications
3. Discontinuation of concurrent nephrotoxic medications significantly improves outcomes
4. Multiorgan immune-related adverse events (myocarditis, nephritis) frequently co-occur and should be managed aggressively