What should be done for a patient with a history of kidney transplant who was exposed to one dose of pembrolizumab (pembrolizumab) without prior consultation with the transplant team?

Management of Kidney Transplant Patient After One Dose of Pembrolizumab

Immediately discontinue pembrolizumab and do not administer the second dose, as PD-1 pathway blockers carry near-universal risk of renal allograft rejection in transplant recipients. 1

Immediate Actions Required

Urgent Transplant Nephrology Consultation

• Contact the transplant team immediately to establish joint management, as this is a high-risk scenario requiring multidisciplinary input from the renal transplant nephrology team 1
• The risk of renal allograft rejection with PD-1 pathway blockers approaches near-universal rates, significantly higher than with anti-CTLA-4 antibodies 1

Baseline Assessment and Monitoring Protocol

• Measure serum creatinine immediately and compare to baseline pre-pembrolizumab values 1
• Obtain complete metabolic panel including electrolytes, as acute kidney injury from checkpoint inhibitors can present with electrolyte disturbances 1
• Check urinalysis for proteinuria, hematuria, and cellular casts 2
• Measure calcineurin inhibitor (CNI) trough levels immediately, as any change in patient status may affect immunosuppressant concentrations 1

Intensive Monitoring Schedule

Renal Function Surveillance

• Check serum creatinine every 2-3 days for the first 2 weeks, then weekly for 4-6 weeks, as immune-related renal toxicity typically occurs at a median of 91 days (range 21-245 days) after checkpoint inhibitor initiation 1, 3
• Monitor for any elevation in creatinine, as early identification may help establish effective treatment before irreversible damage occurs 3
• Continue daily to every-other-day creatinine monitoring until stable, following KDIGO recommendations for transplant recipients with medication changes 1

Immunosuppression Management

• Maintain current immunosuppressive regimen at therapeutic levels unless rejection occurs 1
• Check CNI trough levels every 2-3 days initially, then weekly, as recommended whenever there is a change in medication or patient status 1
• Do not reduce immunosuppression prophylactically, as this would increase rejection risk 1

Signs of Rejection to Monitor

Clinical Indicators

• Rising serum creatinine (any increase >0.3 mg/dL from baseline warrants immediate evaluation) 1
• New-onset proteinuria or worsening of existing proteinuria 2
• Microscopic hematuria 2
• Fluid retention, edema of face/extremities, sudden weight gain 1
• Decreased urine output 1
• Abdominal or pelvic pain 1

Laboratory Monitoring

• Serum creatinine every 2-3 days initially 1
• Urinalysis weekly for first month 1
• CNI levels every 2-3 days initially 1
• Complete metabolic panel to assess for electrolyte disturbances 1

Management of Suspected Rejection

Diagnostic Approach

• Obtain kidney allograft biopsy immediately if creatinine rises or other signs of rejection appear, as KDIGO recommends biopsy before treating acute rejection unless it will substantially delay treatment 1
• Rule out other causes: dehydration, urinary tract infection, nephrotoxic medications, recent IV contrast 1
• Pathology typically reveals acute tubulointerstitial nephritis in checkpoint inhibitor-related nephritis, though T cell-mediated rejection is expected in transplant recipients 1, 3

Treatment of Confirmed Rejection

• Initiate high-dose corticosteroids (methylprednisolone) as first-line treatment for acute cellular rejection 1, 4
• Consider lymphocyte-depleting antibodies for steroid-refractory rejection 1
• One case report demonstrated successful reversal of acute cellular rejection with methylprednisolone, followed by conversion to sirolimus-based immunosuppression 4

Critical Pitfalls to Avoid

Do Not Resume Pembrolizumab

• Pembrolizumab must remain permanently discontinued in this transplant recipient 1, 5
• Case reports document both graft rejection and treatment failure when pembrolizumab is used in renal transplant recipients 5
• Even with aggressive immunosuppression adjustments, the risk of graft loss remains extremely high 1

Do Not Delay Transplant Team Involvement

• The median time to rejection can be as early as 21 days after checkpoint inhibitor initiation 1, 3
• Some patients require hemodialysis despite treatment, and recovery of renal function is not guaranteed even with corticosteroids 1, 3
• Two of 13 patients in one series remained on hemodialysis permanently after checkpoint inhibitor-induced nephritis 1

Do Not Assume Stability After Initial Period

• Immune-related adverse events can occur at any point during or even after completion of therapy 1
• Continue intensive monitoring for at least 3-6 months post-exposure 1

Long-Term Considerations

If Graft Function Remains Stable

• Transition to standard post-transplant monitoring schedule after 3 months of stability 1
• Continue serum creatinine monitoring every 2-3 months long-term 1
• Maintain therapeutic immunosuppression indefinitely 1

If Rejection Occurs and Graft is Lost

• One case report documented successful kidney retransplantation 4.5 years after pembrolizumab-induced graft rejection, with the second allograft functioning well at 10.5 months 6
• This suggests retransplantation may be feasible in the future if the cancer remains in remission 6