Patricia Campbell, MBChB
Dr. Campbell is a Professor in the Division of Nephrology and Transplant at the University of Alberta and Medical Director of the Histocompatibility Laboratory at University of Alberta Hospitals. Her main areas of interest include sensitization post-transplantation and antibody mediated rejection.
Competitors for the Transplantation Region
What is a Pathogenic Donor Specific Antibody (DSA)?
The term pathogenic means the potential to cause disease. Are all DSA harmful to the graft? Or do they all have the potential to cause harm? Not all DSA crossed at the time of transplant will result in antibody mediated rejection (ABMR), but when ABMR develops the outcomes are inferior.
The challenge has been to predict which recipients will develop a memory response when exposed to HLA mismatches that they have previously been sensitized to. Ideally, it is preferable if a donor can be found to which there is no pre-transplant DSA. However, for sensitized recipients, a DSA-negative donor may be difficult to find or significantly delay the time to transplant.
Characteristics of DSA that are associated with a greater risk of developing ABMR have been a subject of many studies. These include, but are not restricted to; antibody titre, ability to bind complement, IgG subclass locus, and antigen expression on tissue. In addition, the mode of sensitization may impact the risk of a memory response and risk for ABMR.
Loupy et al reported the significance of C1q-positive antibodies detected post-transplantation in predicting a poor outcome but the group at the highest risk were C1q-negative pre-transplant and became C1q-positive post-transplant, so the value of this assay pre-transplant as a predicator of risk is limited. Titre is strongly correlated with C1q-positivity and the risk for AMR is greater if the titre is greater or the crossmatch is CDC-positive versus Flow XM-positive or DSA-positive by luminex single antigen bead only.
Post-transplantation, the presence of DSA is associated with the risk of AMR and early graft loss but DSA may be detected in a graft that appears to have normal function. However, a biopsy frequently shows evidence of ABMR; therefore, without pathology, the significance of DSA in serum cannot be determined and may be overlooked.
Although characteristics such as complement binding in sera are associated with a shorter time to graft loss and C4d staining, C1q-negative DSA can also impact graft outcomes.
Impact of immunosuppression or lack of it likely influences the impact of DSA but is difficult to measure. It is also challenging to correlate outcomes based on DSA measurement at one time point. Frequent monitoring of DSA shows that the titres can vary over time and, as de novo DSA is associated with non-adherence, it is likely that non-adherence continues to occur in many recipients after the diagnosis of ABMR. Weibe et al showed that when adjusting for non-adherence and clinical phenotype, C1q status and DSA titre were not independent predictors of graft loss.
Therefore, trying to predict DSA risk based on antibody characteristics is challenging. To quote H. Gebel, “If an antibody is detected it must be respected.”
– Post written by Patricia Campbell
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