What is the recommended desensitization protocol for patients with high levels of sensitization undergoing renal transplants?

Desensitization Protocols for Highly Sensitized Renal Transplant Patients

The most effective desensitization protocol for highly sensitized renal transplant patients combines plasmapheresis with intravenous immunoglobulin (IVIG), with the addition of rituximab in cases of severe sensitization. This approach has demonstrated the best outcomes for reducing donor-specific antibodies and enabling successful transplantation in patients with high panel reactive antibody (PRA) levels.

Understanding Sensitization in Renal Transplant Candidates

Sensitization occurs when patients develop anti-HLA antibodies due to:

• Previous transplantation
• Blood transfusions
• Pregnancies

Highly sensitized patients (those with high PRA levels) face significant challenges:

• Longer waiting times for compatible donors
• Increased risk of antibody-mediated rejection
• Poorer graft survival outcomes

Recommended Desensitization Protocol

First-Line Protocol

1. Plasmapheresis

   • Exchange of 1.5 plasma volumes
   • Multiple sessions (typically 3-5) based on antibody levels

2. IVIG Administration

   • Standard dose (5g) after each plasmapheresis session 1
   • Or high-dose protocol (2g/kg) in two divided doses 2

3. Immunosuppression Initiation

   • Begin with calcineurin inhibitor (preferably tacrolimus)
   • Add mycophenolate mofetil or sirolimus

For Severe Sensitization (PRA >85% or Persistent Positive Crossmatch)

1. Add Rituximab
   • 1g administered in two doses 2
   • Effectively depletes CD20+ B cells in peripheral blood
   • Particularly beneficial for patients with high Class II HLA antibodies

Monitoring Protocol

• Regular measurement of donor-specific antibodies (DSA)
• T/B cell crossmatches using solid phase flow cytometry
• Monitor for reduction in HLA antibody levels
• Repeat crossmatch testing before proceeding to transplantation

Efficacy and Outcomes

The success of desensitization varies based on:

1. Initial Sensitization Level

   • Patients with PRA >85% may have limited response to rituximab/IVIG alone 2
   • Patients with moderate sensitization (PRA 30-85%) show better response rates

2. Antibody Class

   • Class II HLA antibodies may be more resistant to desensitization
   • Combined Class I and II sensitization presents greater challenges

3. Protocol Effectiveness

   • Plasmapheresis with IVIG can achieve negative crossmatches in approximately 85% of cases 3
   • Adding rituximab improves outcomes in highly sensitized patients 4
   • Patient survival of 100% and graft survival of 88.2% have been reported with comprehensive protocols 3

Important Considerations and Pitfalls

Pitfalls to Avoid

1. Antibody Rebound

   • Monitor for transient depletion followed by antibody rebound
   • May require maintenance therapy or repeated desensitization

2. Inadequate Monitoring

   • Use both traditional and newer, more sensitive assays (ELISA, Flow Bead)
   • Flow PRA can detect clinically relevant IgG antibodies not detected by ELISA 5

3. Incomplete Desensitization

   • Verify negative crossmatch before proceeding to transplantation
   • Consider changing donors if desensitization is unsuccessful despite multiple attempts

Special Considerations

1. HLA Matching Optimization

   • Consider HLA amino acid residue matching to improve compatibility 6
   • Use historically highest PRA sera for crossmatching, not just current levels 5

2. Post-Transplant Management

   • Induction with anti-thymocyte globulin
   • Maintenance with calcineurin inhibitor, mycophenolate mofetil, and steroids
   • Close monitoring for antibody-mediated rejection

Failed Allograft Management

For patients with failed allografts returning to the waitlist:

1. Monitor CPRA every 3-6 months 5

2. Maintain appropriate immunosuppression to prevent sensitization

   • Reduce anti-metabolite by 50%
   • Maintain CNI ± low dose prednisone
   • Monitor for graft intolerance syndrome 5

3. Consider re-listing when eGFR approaches 20 5

By implementing this comprehensive desensitization protocol and careful monitoring, the likelihood of successful renal transplantation in highly sensitized patients can be significantly increased, improving their quality of life and reducing mortality compared to remaining on dialysis.