Antibody-Mediated Rejection of Renal Allografts: Diagnostic Pitfalls and Challenges

Abstract

Antibody-mediated rejection (ABMR) is a major obstacle to the long-term success in kidney transplantation. Diagnosis of ABMR is determined according to the internationally recognized Banff criteria. However, a significant proportion of patients does not meet all the defined criteria, and the outcome of such cases remains poorly understood. The histology of ABMR frequently lacks sensitivity and specificity. More importantly, mixed forms of ABMR and T cell-mediated rejection as well as findings of nonspecific injury are common in clinical settings. Donor-specific anti-HLA antibodies (DSA) are detectable only in half of the ABMR cases by histology. Prognostic role of non-HLA antibodies against various endothelial proteins has been discussed. Antibody independent NK cell activation reflecting killer-cells’ inhibitory receptor incompatibility is suggested in microvascular inflammation in DSA negative patients. Molecular assessment of ABMR has been prioritized to overcome high interobserver variability and improve diagnostics in mixed forms of rejections and in DSA negative cases. Finally, donor-derived cell-free DNA detected in a recipient’s peripheral blood sample has been proposed as a noninvasive marker for diagnosis of graft rejection, and thus might serve as a liquid biopsy in the near future. Despite all achievements, diagnosing ABMR in kidney allografts remains to be a challenge in a significant number of cases.

Novel insights in the clinical management of hyperimmune patients before and after transplantation

“…Even when highly sensitized patients eventually are transplanted, they are at increased risk of antibody-mediated allograft rejection, also when the crossmatch is negative at the time of transplantation ( Novotný et al, 2021 ). This phenomenon is due to a higher alloreactivity and/or to donor-specific antibodies (DSAs) that were overlooked in the crossmatch tests or antibody screenings ( Novotný et al, 2021 ). For this reason, it is mandatory an accurate identification and monitoring of anti-HLA antibodies for all patients awaiting transplantation ( Kransdorf et al, 2017 ).…”

Chronic Active Antibody-mediated Rejection: Opportunity to Determine the Role of Interleukin-6 Blockade

“…The multiplicity of antibody-secreting cell types, leading to “humoral compensation” if any one type is knocked out, 16 and the involvement of T-cell help likely contributes to observations that targeting individual cell types has not been successful in ameliorating AMR. 17 Apparent AMR is actually frequently “mixed” and involves multiple effectors, including T cells, 18 complement, endothelial adhesion molecules, neutrophils, monocyte/macrophages, and IgG-stimulated antibody-dependent cellular cytotoxicity by natural killer cells. 19 , 20 IL-6 is implicated in T-cell activation, reducing Treg, stimulating T-follicular helper cells and germinal centers, 21 , 22 as well as driving B-cell proliferation, maturation, and class-switching.…”

Predicting Cellular Rejection of Renal Allograft Based on the Serum Proteomic Fingerprint

“…Due to these factors, it is important to develop cost-effective, minimally invasive alternatives to predict rejection processes. For all mentioned above, the routine prediction of the humoral rejection processes is based on serum analysis of the circulating antibodies [22], which may target human leukocyte antigens (HLAs), non-HLA antigens, and blood group antigens [23][24][25][26]. However, predicting T-cell-mediated rejection processes, also known as cellular rejection, using minimally invasive methods is particularly challenging.…”