Key Takeaways

• Provides an objective assessment of the effectiveness of desensitization treatments
• Recommends the use of serial dilutions
• Linking cPRA reduction to antibody titer is a reliable approach to simplify complex antibody data
• Provides a mean to determine a suitable endpoint for clinical trials.

Introduction

There are a significant number of wait-list patients with cPRA >99.9% who, despite receiving higher priority in the organ allocation system, still experience markedly lower rates of transplantation. Often, the only credible option for these patients is to undergo desensitization therapy. The use of cPRA provides a means for assessing the efficacy of desensitization therapy but is hindered by the fact that it is usually predicted on the MFI readout of single antigen bead assays, which at best provides only semi-quantitative measurements.

Data Analysis

This study used serial dilution analysis to determine the point at which cPRA could be reduced below 98%, a value previously shown to significantly increase probability of transplant. From this, it was possible to stratify patients according to the ease with which cPRA could be brought below 98% with serial dilution. It was observed that some patients show a steady and rapid decline in cPRA in consecutive diluted samples, therefore indicating an increased likelihood that desensitization would reach a satisfactory endpoint. Conversely, other patients maintained a high cPRA value through multiple dilutions, up to 1:4096 in one instance, indicating that some patients would require a much more robust therapeutic intervention in order to make them “transplantable.”

Clinical Utility

This study has demonstrated that the simulated response to desensitization therapy is patient-specific and that dilution studies can help to identify the level of therapeutic intervention required to facilitate a successful transplant. The use of dilution testing can be costly and labor-intensive so the authors advise that the use of a single dilution point (1:64 is suggested based on the experimental data) can be a valuable guide from which to further refine the dilution protocol. This novel approach can be used as a robust endpoint for future desensitization trials, which can be readily adopted by any HLA laboratory using a range of tools already widely in use in the HLA field.