A 32-year-old woman undergoes living-donor renal transplantation for end-stage renal disease. On postoperative day 5, she develops acute rejection with rising serum creatinine (2.8 mg/dL from baseline 1.2 mg/dL) and a renal biopsy showing interstitial infiltration with lymphocytes. She is started on high-dose intravenous methylprednisolone. However, her rejection episode does not respond after 3 days of steroid therapy. Which immunosuppressant is the next best agent to add to prevent graft loss?

Explanation

## Acute Rejection Refractory to Steroids: Management Approach **Key Point:** Steroid-refractory acute rejection requires polyclonal or monoclonal antibody therapy targeting T cells. ATG is the gold standard for this scenario. ### Pathophysiology of Steroid-Resistant Rejection Acute cellular rejection involves T-cell-mediated infiltration of the graft. While corticosteroids suppress cytokine production and reduce inflammation, they do not directly eliminate activated T lymphocytes. When high-dose IV methylprednisolone fails after 3 days, the rejection is deemed "steroid-refractory" and requires direct T-cell depletion. ### Why ATG is the Correct Choice **High-Yield:** Antithymocyte globulin (ATG) is a polyclonal antibody preparation derived from immunizing rabbits or horses with human T lymphocytes. It directly binds to and depletes circulating and tissue-resident T cells through: - Complement-dependent cytotoxicity - Antibody-dependent cellular cytotoxicity (ADCC) - Opsonization and phagocytosis ATG is the standard of care for steroid-refractory acute rejection because it achieves T-cell depletion within hours to days, reversing rejection in 60–80% of cases. ### Comparison with Other Agents | Agent | Mechanism | Indication | Onset | Efficacy in Steroid-Refractory Rejection | |-------|-----------|-----------|-------|-------------------------------------------| | **ATG** | Polyclonal T-cell depletion | Steroid-refractory acute rejection | Hours–days | 60–80% reversal | | Basiliximab | Anti-CD25 (IL-2R α-chain) | Induction prophylaxis, not treatment | Days | Poor (induction agent, not rescue) | | MMF | IMPDH inhibitor (purine synthesis) | Maintenance, not acute rejection | Weeks | Slow; inadequate as monotherapy | | Tacrolimus escalation | Calcineurin inhibitor | Maintenance; inadequate if already on CNI | Days–weeks | Insufficient for refractory disease | **Clinical Pearl:** The patient is likely already on a baseline calcineurin inhibitor (cyclosporine or tacrolimus) + MMF + prednisolone as maintenance therapy. Escalating tacrolimus alone does not address the acute T-cell infiltration; ATG provides rapid, direct T-cell depletion. **Warning:** Do not confuse basiliximab (induction agent, used prophylactically) with ATG (rescue agent, used for established rejection). Basiliximab blocks only the IL-2 receptor on activated T cells and is ineffective for acute rejection treatment. ### Mnemonic: STAR for Steroid-Refractory Rejection **S**teroid-refractory → **T**-cell depletion → **A**TG or **R**abbit ATG ### Adverse Effects of ATG to Monitor - Cytokine release syndrome (fever, chills, hypotension) - Thrombocytopenia and leukopenia - Serum sickness - Increased infection risk (CMV, opportunistic infections) - Premedication with acetaminophen, diphenhydramine, and methylprednisolone is standard. [cite:Harrison 21e Ch 283]