Can Keytruda (pembrolizumab) cause impaired renal function?

Impact of Keytruda (Pembrolizumab) on Renal Function

Yes, Keytruda (pembrolizumab) can cause immune-mediated nephritis and renal dysfunction in some patients, with an incidence rate of approximately 0.3% based on FDA data. 1

Mechanism and Incidence of Renal Toxicity

Pembrolizumab can affect the kidneys through immune-mediated mechanisms, primarily causing:

• Immune-mediated nephritis: Occurs in 0.3% (9/2799) of patients receiving pembrolizumab, including Grade 4 (<0.1%), Grade 3 (0.1%), and Grade 2 (0.1%) adverse reactions 1
• Acute interstitial nephritis (AIN): The most common histological finding in patients with pembrolizumab-related kidney injury 2
• Acute tubular injury (ATI): Another common histological finding 2
• Minimal change disease (MCD): Less common but reported in some patients 2

The overall incidence of clinically significant renal toxicity is approximately 1.77% according to a case series study 2, though the FDA label reports a lower rate of 0.3% for immune-mediated nephritis specifically 1.

Risk Factors and Onset

Renal toxicity from pembrolizumab can occur at any time during treatment:

• Median time to onset is approximately 9 months after treatment initiation (range 1-24 months) 2
• Risk may be increased when pembrolizumab is combined with other potentially nephrotoxic agents 3
• Pre-existing renal dysfunction does not appear to be a strong contraindication, but may require closer monitoring 4

Clinical Presentation

Renal toxicity from pembrolizumab typically presents as:

• Acute kidney injury (most common) 2
• Proteinuria (less common) 2
• Elevated serum creatinine levels 5
• Usually asymptomatic until significant renal dysfunction occurs

Management of Pembrolizumab-Induced Renal Toxicity

When renal toxicity is suspected:

1. Discontinuation of pembrolizumab: The FDA label recommends withholding pembrolizumab for moderate (Grade 2) nephritis and permanently discontinuing for severe (Grade 3-4) nephritis 1

2. Corticosteroid therapy: Systemic corticosteroids are required in 89% of patients with immune-mediated nephritis 1

   • Typically high-dose corticosteroids initially, followed by a gradual taper

3. Monitoring renal function: Regular monitoring of serum creatinine and estimated glomerular filtration rate (eGFR) is essential during treatment 2

4. Kidney biopsy: May be necessary to confirm the diagnosis and determine the specific type of renal injury 2

Prognosis and Recovery

The prognosis for pembrolizumab-induced renal toxicity varies:

• Approximately 56% of patients with immune-mediated nephritis experience complete resolution 1
• All patients who were temporarily withheld from pembrolizumab and then reinitiated after symptom improvement did not experience recurrence of nephritis 1
• Early identification and prompt treatment improve outcomes 5
• Some patients may develop severe renal failure requiring dialysis 2

Special Considerations

• Combination therapy: When pembrolizumab is combined with other potentially nephrotoxic agents, the risk of renal toxicity may increase 3
• Neoadjuvant setting: In the neoadjuvant setting before radical cystectomy for bladder cancer, pembrolizumab appears to have minimal impact on renal function 4
• Recurrence risk: Reintroduction of pembrolizumab after a renal adverse event may result in more severe recurrence of nephritis 2

Monitoring Recommendations

For patients receiving pembrolizumab:

• Baseline renal function assessment before initiating therapy
• Regular monitoring of serum creatinine and eGFR during treatment
• More frequent monitoring in patients with risk factors for renal dysfunction
• Immediate assessment of renal function if symptoms suggestive of nephritis develop
• Early consultation with nephrology for significant changes in renal function

Common Pitfalls

1. Delayed recognition: Early identification of increased serum creatinine is crucial for preventing progression to severe renal dysfunction 5

2. Misattribution: Renal toxicity may be incorrectly attributed to other concurrent medications when pembrolizumab is the actual cause 3

3. Inadequate monitoring: Failure to regularly monitor renal function may lead to delayed diagnosis and treatment

4. Underestimating severity: What appears to be mild nephritis can progress to severe renal dysfunction if not properly managed

5. Premature rechallenge: Reintroducing pembrolizumab too soon after a renal adverse event may lead to more severe recurrence 2