Estimating alloantibody levels in highly sensitized renal allograft candidates: Using serial dilutions to demonstrate a treatment effect in clinical trials

Anat R. Tambur, Carrie Schinstock, Chelsea Maguire, David Lowe, Byron Smith, Mark Stegall

Research output: Contribution to journalArticlepeer-review

Abstract

Small reductions in calculated panel-reactive antibody (cPRA) are associated with increased kidney transplantation in 100% cPRA patients. However, the high level of antibody in these patients is such that desensitization may reduce antibody but not cPRA, thus the cPRA change on undiluted serum with desensitization is an insensitive measure of effectiveness. We evaluated cPRA reduction, calculated per antibody titer, as a desensitization trial endpoint. To accomplish this, two serum samples from 20 kidney transplant candidates with cPRA ≥99.9% (100%) were obtained and serially diluted in triplicate to determine the titer of individual human leukocyte antigen (HLA) antibody specificities. CPRA was computed per dilution to identify the titer at which cPRA drops below 98%. Inter- and intra-assay variability and changes overtime were determined. The dilution needed to reach a cPRA <98% was within 1 titer for replicates from the same sample, with 90% (36/40) concordance. This indicates that only changes >2 titers can be deemed clinically meaningful. The median (IQR) titer difference was 0 (0-1) from baseline to follow-up within 12 months. The cPRA per titer also risk-stratified candidates for trial inclusion. In conclusion, determining the cPRA per titer is a reliable approach to simplify complex antibody data and an ideal endpoint for desensitization trials.

Original languageEnglish (US)
JournalAmerican Journal of Transplantation
DOIs
StateAccepted/In press - 2020

Keywords

  • alloantibody
  • clinical research / practice
  • desensitization
  • histocompatibility
  • kidney transplantation / nephrology
  • panel reactive antibody (PRA)
  • sensitization

ASJC Scopus subject areas

  • Immunology and Allergy
  • Transplantation
  • Pharmacology (medical)

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