Endothelial transcripts uncover a previously unknown phenotype: C4d-negative antibody-mediated rejection

Curr Opin Organ Transplant. 2010 Feb;15(1):42-8. doi: 10.1097/MOT.0b013e3283352a50.


Purpose of review: In the last decade, there has been a growing recognition of alloantibody responses in organ transplantation, but phenotypes related to antibody-mediated rejection (ABMR) remain incompletely defined. This article reviews recent molecular studies in kidney allograft tissues that decipher molecular burden and mechanisms of ABMR, leading to discovery of a new phenotype: 'C4d-negative ABMR'.

Recent findings: High endothelial gene expression in kidney transplant biopsies with anti-human leukocyte antigen alloantibody indicates active antibody-mediated damage and poor graft survival, defining a previously unknown group of C4d-negative ABMR. C4d-negative ABMR is characterized by high intragraft endothelial gene expression, alloantibodies, histology of chronic ABMR (less frequently acute ABMR), and poor outcomes. Thus, endothelial molecular phenotype in biopsies with circulating antibody detects degree of active graft injury, and many of these transcripts reflect endothelial activation. C4d-negative ABMR is twice as common as C4d-positive ABMR. Recognition of this new phenotype reveals ABMR (C4d positive or negative) as the most common cause of late kidney transplant loss.

Summary: C4d staining, although very useful, is insensitive for detecting ABMR. Measuring endothelial gene expression in biopsies from kidneys with alloantibody is a sensitive and specific method to diagnose ABMR and predict graft outcomes.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Biomarkers / metabolism
  • Biopsy
  • Complement C4b / analysis*
  • Endothelial Cells / immunology*
  • Endothelial Cells / metabolism
  • Gene Expression Profiling
  • Gene Expression Regulation
  • Graft Rejection / genetics
  • Graft Rejection / immunology*
  • Graft Rejection / metabolism
  • Graft Rejection / pathology
  • HLA Antigens / immunology
  • Humans
  • Immunity, Humoral* / genetics
  • Immunohistochemistry
  • Isoantibodies / blood
  • Kidney / blood supply
  • Kidney / immunology*
  • Kidney / pathology
  • Kidney Transplantation / adverse effects*
  • Microvessels / immunology
  • Oligonucleotide Array Sequence Analysis
  • Peptide Fragments / analysis*
  • Phenotype
  • Predictive Value of Tests
  • RNA, Messenger / metabolism*
  • Transplantation, Homologous
  • Treatment Outcome


  • Biomarkers
  • HLA Antigens
  • Isoantibodies
  • Peptide Fragments
  • RNA, Messenger
  • Complement C4b
  • complement C4d