Alloimmune Risk Stratification for Kidney Transplant Rejection

Abstract

Different types of kidney transplantations are performed worldwide, including biologically diverse donor/recipient combinations, which entail distinct patient/graft outcomes. Thus, proper immunological and non-immunological risk stratification should be considered, especially for patients included in interventional randomized clinical trials. This paper was prepared by a working group within the European Society for Organ Transplantation, which submitted a Broad Scientific Advice request to the European Medicines Agency (EMA) relating to clinical trial endpoints in kidney transplantation. After collaborative interactions, the EMA sent its final response in December 2020, highlighting the following: 1) transplantations performed between human leukocyte antigen (HLA)-identical donors and recipients carry significantly lower immunological risk than those from HLA-mismatched donors; 2) for the same allogeneic molecular HLA mismatch load, kidney grafts from living donors carry significantly lower immunological risk because they are better preserved and therefore less immunogenic than grafts from deceased donors; 3) single-antigen bead testing is the gold standard to establish the repertoire of serological sensitization and is used to define the presence of a recipient’s circulating donor-specific antibodies (HLA-DSA); 4) molecular HLA mismatch analysis should help to further improve organ allocation compatibility and stratify immunological risk for primary alloimmune activation, but without consensus regarding which algorithm and cut-off to use it is difficult to integrate information into clinical practice/study design; 5) further clinical validation of other immune assays, such as those measuring anti-donor cellular memory (T/B cell ELISpot assays) and non–HLA-DSA, is needed; 6) routine clinical tests that reliably measure innate immune alloreactivity are lacking.

Utility of Routine Post Kidney Transplant Anti-HLA Antibody Screening

“…Thus, we cannot rule out that some recipients could have been considered as patients with a donor-specific cellular memory. 4 , 5 However, to ensure the completeness of such information is a complex task in practice. The definition of low immunological risk patients remains a matter of debate.…”

“… 2 , 3 Recent advances in alloimmune risk stratification before transplantation, mainly driven by highly sensitive detection of preformed anti-HLA DSAs with the Luminex single antigen technology, have allowed the identification of the highest risk scenarios for rapid loss of function. 4 , 5 After transplantation, the development of dnDSA has been strongly associated with the development of acute and chronic AMR and graft loss. 6 , 7 , 8 However, the prevention of dnDSA development after transplantation remains a major obstacle.…”

Immune Checkpoint Inhibitors in Solid Organ Transplant Recipients With Advanced Skin Cancers—Emerging Strategies for Clinical Management

“…48 Novel markers to stratify rejection risk are currently being developed, including circulating/urinary transcriptomic and HLA eplet mismatch profiling, but are not in widespread use and require validation regarding utility in guiding IS reduction. 95 If a patient experiences acute or chronic rejection, the likelihood that it can be reversed is unknown, but patients need to be aware that there is a significant risk of allograft loss. Recommendations on management of SOTRs before, during ICI therapy, and in case of allograft rejection.…”

“…48 Novel markers to stratify rejection risk are currently being developed, including circulating/urinary transcriptomic and HLA eplet mismatch profiling, but are not in widespread use and require validation regarding utility in guiding IS reduction. 95…”

BSHI and BTS UK guideline on the detection of alloantibodies in solid organ (and islet) transplantation

“…Despite the widespread use of vXM within the UK, prospective laboratory crossmatching remains a pretransplant risk assessment tool, which can provide an important risk stratification (Bestard et al, 2021(Bestard et al, , 2022Orandi et al, 2014), and assist in identifying reactivity towards denatured HLA which is thought to be clinically irrelevant (Visentin et al, 2014).…”