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.