What is the recommended treatment for acute rejection of a kidney transplant?

Treatment of Acute Kidney Transplant Rejection

Corticosteroids are the first-line treatment for acute cellular rejection of kidney transplants, and biopsy should be performed before initiating treatment unless it would substantially delay therapy. 1

Diagnostic Approach Before Treatment

Obtain a kidney allograft biopsy before treating acute rejection to distinguish between cellular and antibody-mediated rejection, as management differs significantly. 1 The biopsy is critical because:

• Acute rejection requires increased immunosuppression, while other causes of acute kidney injury (infection, volume depletion, CNI toxicity) may require opposite management 2
• Never empirically reduce immunosuppression assuming AKI equals drug toxicity without biopsy confirmation—rejection is equally likely and requires opposite management 2
• Holding or reducing tacrolimus and mycophenolate without biopsy confirmation risks precipitating or worsening acute rejection, leading to irreversible graft damage 2

First-Line Treatment: Corticosteroids

For acute cellular rejection, initiate high-dose corticosteroids as initial therapy. 1, 3 This represents a strong recommendation (1D grade) from KDIGO guidelines. 1

• Intravenous methylprednisolone 0.5-1 g/day (total dose 2-8 g) or high-dose oral prednisone (150-600 mg/day) are effective options 4
• Approximately 70-75% of acute cellular rejection episodes respond to corticosteroid therapy alone 5, 4
• Add or restore maintenance prednisone in patients not on steroids who experience a rejection episode 1

Important Caveat on C4d-Positive Rejection

Even in C4d-positive (antibody-mediated) rejection without severe chronic changes, 75% may respond to corticosteroids alone, challenging the assumption that all antibody-mediated rejection requires aggressive plasmapheresis/IVIG therapy. 6 However, standard-of-care for acute antibody-mediated rejection typically combines plasma exchange with intravenous immunoglobulin (IVIG). 7

Second-Line Treatment: Lymphocyte-Depleting Antibodies

For steroid-resistant or recurrent acute cellular rejection, use lymphocyte-depleting antibodies or OKT3. 1, 3 This is a 2C grade recommendation. 1

• Anti-thymocyte globulin (ATG) is the primary lymphocyte-depleting agent, working through complement-dependent lysis and activation-induced apoptosis of T lymphocytes 8
• ATG dosing: 10-15 mg/kg/day for 14-21 doses, with mean peak concentrations of 727 ± 310 μg/mL 8
• Approximately 25-30% of rejection episodes are steroid-resistant and require escalation to lymphocyte-depleting therapy 5

Alternative Rescue Therapy

Tacrolimus can serve as rescue therapy for rejections refractory to both corticosteroids and polyclonal antibodies, with a 76.5% response rate in one study. 9 However, this should be considered after standard lymphocyte-depleting therapy, given the strength of guideline recommendations for ATG/OKT3. 1

Optimization of Maintenance Immunosuppression

After treating acute rejection, optimize baseline immunosuppression to prevent recurrent episodes:

• Measure CNI blood levels immediately and every other day until stable 2
• Verify therapeutic tacrolimus trough levels (typically 5-15 ng/mL in maintenance phase) 2
• Add or restore maintenance prednisone if the patient was not on steroids 1
• Consider that subtherapeutic levels may have contributed to rejection 2

Critical Monitoring During and After Treatment

Measure serum creatinine 2-3 times per week during the acute rejection treatment period. 2 This allows detection of:

• Worsening function indicating inadequate treatment 2
• New complications such as CNI toxicity 2

Perform repeat biopsy if:

• Creatinine has not returned to baseline after treatment 1
• Creatinine rises or does not stabilize within 7-10 days 2

Common Pitfalls to Avoid

• Never assume AKI equals drug toxicity without biopsy—rejection requires opposite management (increased, not decreased immunosuppression) 2
• Avoid empirically reducing immunosuppression "to protect the kidney" as this precipitates rejection and causes irreversible graft loss 2
• Do not exceed methylprednisolone total doses of 3-5 g without clear benefit, as higher doses increase steroid-related complications without improved therapeutic response 4
• Reducing immunosuppression during active rejection introduces unnecessary risk during a critical period when the graft is already under immune attack 2

Emerging Therapies for Antibody-Mediated Rejection

For refractory antibody-mediated rejection not responding to standard plasma exchange/IVIG:

• Rituximab has been used successfully as salvage therapy, particularly for CD20+ B-cell infiltrates refractory to steroids and ATG 3
• Other agents under investigation include Bortezomib, Eculizumab, and C1 inhibitors, though randomized controlled trial data remain limited 7