What is the appropriate workup and treatment for a patient suspected of kidney transplant rejection?

Workup and Treatment of Suspected Kidney Transplant Rejection

Perform an urgent kidney allograft biopsy before initiating any anti-rejection therapy, then treat biopsy-confirmed acute cellular rejection with high-dose intravenous methylprednisolone as first-line therapy. 1, 2, 3

Diagnostic Workup Algorithm

Immediate Laboratory Assessment

• Measure serum creatinine immediately and compare to baseline to quantify the degree of dysfunction 1, 3
• Check calcineurin inhibitor (CNI) trough levels urgently to distinguish between CNI toxicity and rejection, as both present with rising creatinine 1, 3
  • For tacrolimus: obtain 12-hour trough (C0), therapeutic target typically 5-15 ng/mL in early post-transplant period 1, 2
  • For cyclosporine: obtain 12-hour trough (C0), 2-hour post-dose (C2), or abbreviated AUC 1
• Estimate GFR using validated formulas (MDRD or CKD-EPI for adults, Schwartz formula for children) to quantify dysfunction severity 1, 3
• Measure urine protein excretion to assess for new-onset proteinuria suggesting antibody-mediated rejection or glomerular injury 1, 3

Imaging Studies

• Perform renal ultrasound with Doppler to exclude vascular complications, obstruction, or perinephric collections that can mimic rejection 3

Kidney Allograft Biopsy (Mandatory)

• Biopsy is required before treating acute rejection unless it will substantially delay treatment (strong recommendation, 1C evidence) 1, 2, 3
• The biopsy determines whether rejection is cellular, antibody-mediated (AMR), or mixed, which directly impacts treatment choice 2, 4
• Do not delay biopsy beyond 24-48 hours, as CNI toxicity, infection, obstruction, and recurrent disease can all mimic rejection 3
• C4d staining of peritubular capillaries should be performed to identify antibody-mediated rejection 5

Treatment Protocol for Acute Cellular Rejection

First-Line Therapy

• Administer intravenous methylprednisolone 250-1000 mg daily for 3-5 days as initial treatment for biopsy-proven acute cellular rejection (strong recommendation, 1D evidence) 1, 2, 3
• This applies regardless of which calcineurin inhibitor the patient is receiving 2

Maintenance Immunosuppression Adjustment

• Add or restore maintenance prednisone if the patient was not already on maintenance steroids, as the rejection episode indicates inadequate immunosuppression 1, 2
• Verify CNI trough levels are therapeutic, as subtherapeutic levels may have contributed to the rejection episode 2

Second-Line Therapy for Steroid-Resistant Rejection

• Use lymphocyte-depleting antibodies or OKT3 for acute cellular rejections that do not respond to corticosteroids and for recurrent acute cellular rejections 1, 2

Treatment of Subclinical and Borderline Rejection

• Treat subclinical and borderline acute rejection detected on protocol biopsies or incidentally 1

Post-Treatment Monitoring

Serum Creatinine Monitoring

• Monitor serum creatinine 2-3 times weekly during and after treatment of acute rejection 1, 3
• Perform repeat biopsy if creatinine does not return to baseline after treatment 3
• Incomplete recovery (delta creatinine >0.5 mg/dL at 6 weeks post-treatment) significantly increases risk for chronic rejection and graft loss 6

CNI Level Monitoring

• Obtain CNI levels every other day until stable therapeutic targets are reached 1, 2
• Measure levels whenever there is declining renal function that may indicate nephrotoxicity or ongoing rejection 1

Infection Surveillance

• Monitor for infection complications given increased immunosuppression 3
• Ensure appropriate antimicrobial prophylaxis: trimethoprim-sulfamethoxazole for PCP, valganciclovir if CMV high-risk 3, 4

Critical Pitfalls to Avoid

Do Not Treat Empirically Without Biopsy

• Never empirically treat for rejection without biopsy confirmation unless biopsy would cause substantial treatment delay 1, 3
• CNI toxicity, infection, obstruction, and recurrent disease can all mimic rejection clinically 3, 7

Do Not Use Rituximab as First-Line Therapy

• Rituximab is not indicated for first-line treatment of cellular rejection—this violates guideline recommendations and exposes patients to unnecessary infectious risk 3, 4
• Rituximab may have a role in antibody-mediated rejection, but only after biopsy confirmation 4, 5

Do Not Switch CNI During Active Rejection

• Changing calcineurin inhibitors during active rejection introduces unnecessary risk of unstable immunosuppression when the graft is already under immune attack 2
• Both tacrolimus and cyclosporine require 3-5 days to reach steady-state levels, creating a window of subtherapeutic immunosuppression that could worsen rejection 2
• CNI conversion may be considered after successful reversal of rejection, only in specific scenarios such as steroid-resistant rejection or documented CNI nephrotoxicity 2

Do Not Reduce Overall Immunosuppression

• Never reduce overall immunosuppression intensity during or immediately after rejection, as the rejection itself indicates the patient requires more, not less, immunosuppression 2

Recognize High-Risk Rejection Episodes

• Late acute rejection (>6 months post-transplant) carries worse prognosis than early rejection and increases risk for chronic rejection (relative risk 3.8) 6, 5
• Moderate or severe rejection episodes (relative risk 2.7) and incomplete recovery (delta creatinine >0.5 mg/dL at 6 weeks) confer greatest risk for chronic rejection and graft loss 6
• Patient noncompliance is a major contributor to late acute rejection and should be addressed through medication review and increased vigilance 8