Kidney Transplant Rejection – Diagnosis & Treatment Notes

Learning Objectives

• Diagnose and treat both acute cellular (T-cell–mediated) and acute antibody-mediated rejection (AMR) in kidney transplant recipients.
• Estimate an individual patient’s risk of rejection.
• Follow a systematic diagnostic work-up for suspected rejection.
• Distinguish histologic, clinical, and biomarker features of each rejection type.
• Select therapy tailored to the rejection phenotype and its severity.

Epidemiology & Risk Stratification

• Virtually every non-identical kidney recipient is at risk because of allo-HLA differences.
  • Incidence of any rejection episode within 1–2 yr: 25\%-35\%.
  • Identical‐twin grafts are the rare exception (no alloimmune injury).
• Population-level predictors (limited precision for individuals):
  • Degree of HLA mismatch (esp. class II epitope load).
  • Potency of induction (e.g.
  • Thymoglobulin > basiliximab > none).
  • Adherence to maintenance immunosuppression.
  • History of sensitization (pre-formed DSA).
  • Episodes of over-immunosuppression reduction (e.g. BK, CMV management).

Temporal Spectrum of Alloimmune Injury

• Early peri-transplant inflammation: brain-death cytokines, ischemia–reperfusion, CN-inhibitor toxicity, delayed graft function.
• T-cell–mediated injury develops first in most non-sensitized recipients → can be subclinical or clinical.
  • Subclinical = histologic inflammation without decreased eGFR; detected only by protocol biopsy or emerging biomarkers.
• Unchecked T-cell injury recruits B cells ➔ de novo DSA ➔ acute & chronic AMR ➔ transplant glomerulopathy ➔ graft loss (most common cause after death-with-function).

Decline in Clinical Rejection Rates

• Introduction of tacrolimus + mycophenolate, plus potent induction, has reduced 1-yr clinical acute rejection to single digits, yet subclinical rejection persists in \approx25\% of grafts in first 2 yr.

Modern Biomarkers

• Limit: none replace histology for grading severity & guiding therapy.

Histopathology Essentials (Banff 2019-21)

• T-cell-mediated rejection (TCMR)
  • Tubulitis (t): lymphocytes breaching tubular BM.
  • Interstitial inflammation (i).
  • Vasculitis (v) in grades ≥ iib: intimal arteritis.
• Antibody-mediated rejection (AMR)
  • Microvascular inflammation: glomerulitis (g) & peritubular capillaritis (ptc) with PMNs/mononuclear cells.
  • C4d positivity in peritubular capillaries (immunostain) ± DSA.
  • Chronic active lesions: transplant glomerulopathy, arterial intimal fibrosis with multilamination.

Therapeutic Principles

A. T-Cell–Mediated Rejection (TCMR)

1. Borderline & Banff 1A
   • High-dose steroids: methyl-pred 3{-}5\;\text{mg kg}^{-1}\times3{-}5\text{ d} (IV or PO) → oral taper ⩾ 2 wk.
   • Optimize baseline IS (tacro trough \approx7{-}10\,\text{ng mL}^{-1}, adequate MPA, ± steroid).
2. Banff 1B, 2A, 2B, 3 (severe)
   • Steroid pulse PLUS lymphocyte depletion:
     • rATG 4.5{-}10\;\text{mg kg}^{-1} total (e.g. 1.5\;\text{mg kg}^{-1}\,\text{IV daily}\times3{-}7).
     • Alemtuzumab (off-label) alternative.
   • Premedicate with steroids, acetaminophen, antihistamine.
   • Re-start/continue CMV, PJP, fungal & GI prophylaxis.
   • Consider lower total dose if extensive chronic fibrosis (e.g. >50\% IF/TA)

B. Antibody-Mediated Rejection (AMR)

Goal = interrupt antibody → complement → endothelial injury axis.

Typical regimen (severe acute AMR)

1. PLEX + low-dose IVIG every other day × 5–10 sessions (titer-guided).
2. Methyl-pred pulse concurrently.
3. Consolidation rituximab 1–2 doses post-PLEX.
4. Consider proteasome inhibitor or complement blocker in refractory/high-risk cases.

C. Mixed Rejection

• Treat TCMR component first (steroids ± ATG) ➔ begin PLEX/IVIG after final ATG dose (otherwise ATG removed by PLEX).

Practical Algorithm (Adapted)

1. Trigger = unexplained AKI, new proteinuria, +DSA, or abnormal biomarker.
2. Rule out non-immune causes (⩽ 48 h):
   • Drug nephrotoxicity (e.g. calcineurin levels).
   • Dehydration / hemodynamics.
   • Obstruction (US/CT).
   • Infections: BK viremia, CMV, UTI.
3. DSA testing (HLA ± non-HLA) and biopsy whenever feasible (low morbidity).
4. If cannot biopsy (anticoagulation, anatomy):
   • Empiric steroids.
   • Monitor response; if persistent AKI or +DSA → consider PLEX ± ATG.
5. Biopsy-guided therapy
   a. Pure TCMR → steroid ± ATG protocol above.
   b. Pure AMR → PLEX/IVIG/steroid ± rituximab etc.
   c. Mixed → sequential or combined as noted.
6. Post-treatment care
   • Reinforce adherence; optimize maintenance IS.
   • Infection & malignancy surveillance.
   • Follow biomarkers, creatinine, and DSA titers.

Dosing & Numerical Pearls

• Steroid pulse: 3{-}5\;\text{mg kg}^{-1}\text{/dose} IV × 3{-}5.
• rATG total: 6\;\text{mg kg}^{-1} (induction benchmark) but 4.5{-}10\;\text{mg kg}^{-1} flexibility.
• PLEX frequency: every 48 h; rounds = antibody strength (low:5, high:10).
• IVIG after each PLEX: 100\;\text{mg kg}^{-1} to avoid rebound; optional high-dose 2\;\text{g kg}^{-1} at end.
• Rituximab: single dose 375\;\text{mg m}^{-2}, repeat in 1–2 wk if needed.

Ethical & Practical Considerations

• Balance benefit vs toxicity: infections, PTLD, malignancy, cytopenias.
• “Make the punishment fit the crime”—avoid over-treatment in scarred grafts with limited salvage potential.
• Ensure precision diagnosis (biopsy + DSA + biomarkers) before aggressive therapy.
• Long-term focus: adherence counseling, prevent chronic rejection progression.

Take-Home Messages

• Histology remains the gold standard; biomarkers are adjunctive, not substitutes.
• Subclinical rejection is common; surveillance strategies (protocol biopsy, cfDNA, GEP) can detect otherwise silent injury.
• Differentiate T-cell vs antibody-mediated rejection—therapies target distinct immune mechanisms.
• Combine anti-inflammatory, depleting, and antibody-modulating therapies rationally, matching severity and chronicity.
• Continuous reassessment post-therapy (clinical, serologic, histologic) is key to optimizing long-term graft survival.