Over many decades, progress in the treatment of acute rejection markedly improved the short-term success of kidney allografts, such that graft survival in the first year after transplantation now exceeds 90% [1]. However, improvement rates have decelerated. Data from 135 kidney transplant centers in 21 European countries (187,787 individual transplantations) indicate that the improvement of graft survival has slowed significantly since 2000, even when considering the increased age of donors and recipients [1]. Initiatives to further improve graft survival rates are therefore needed, but the nature of such initiatives is an important point for discussion.

Certainly, several pharmaceutical regimens have been developed, such as efficacious and relatively well-tolerated immunosuppressants, which have enabled very good short-term outcomes to be achieved in patients (and with an acceptable risk of graft rejection). However, the ensuing misconception is that all major hurdles in transplantation have been overcome [2, 3]. Good short-term outcomes that are observed in transplantation recipients do not always translate into satisfactory long-term graft functioning or patient-survival rates [4, 5]. Lack of long-term success creates difficulty in defining suitable surrogate endpoints for clinical trials, which is problematic for ongoing research and could discourage academic/commercial investment in kidney transplantation [3].

Consequently, while clinical progress in kidney transplantation is slowing down, rates of allograft loss continue to be unacceptably high. The extensive negative impact that this has on patient health and well-being—as well as the high long-term health-associated cost burden [6]—clearly indicates a need for novel, effective management strategies, tested according to endpoints that suit current practice and regulations. In addition, there are no approved surrogate markers for long-term graft failure in kidney transplantation, necessitating long-term interventional studies as an urgent priority.

Innovations in kidney transplantation often focus on the prevention and treatment of acute allograft rejection [7]. While current immunosuppressive regimens have reduced the incidence of rejection in low-risk organ recipients [8], many patients have a high immunological risk and could benefit from better preventive and therapeutic options than those available [9]. Stratification of patients and allografts according to immunological risk, however, is not standardized.

Released in 2008, the European Medicines Agency (EMA) guideline (CHMP/EWP/263148/06) [10] provides guidance on the conduct of clinical studies for solid organ transplantation (not specific for kidney transplantation) by defining treatment goals, study designs, outcome measures, and data analyses for new immunosuppressive therapies developed to prevent and treat allograft rejection. The guideline [10] defines the primary efficacy endpoint for novel immunosuppressants in solid organ transplantation (not specific for kidney transplantation) as a composite of four outcomes:

• Patient death

Components of the composite endpoint could be omitted for several reasons, such as if there is limited sensitivity/specificity for available biomarkers, or limited consensus about the importance of individual risk factors or cut-off values. Factors such as previous early graft loss (because of immunological factors), re-transplantation, human leukocyte antigen (HLA) mismatch, and presence of HLA antibodies are often taken into consideration, depending on the type of transplantation. The guideline also notes that best attempts should be undertaken to define the recipient’s immunological risk at baseline, using categories such as “low/medium/high” or “elevated/non-elevated.” Finally, CHMP/EWP/263148/06 notes that transplantation outcome is also influenced by surgery and comorbidity [10]. Therefore, reasonably validated scales for assessment of global transplantation risk are important and should be reflected in the target population of clinical studies.

Not only has clinical organ transplantation changed markedly since the publication of CHMP/EWP/263148/06 [10]; the transplant community now observes signs of substantial decline in the rate of clinical innovation in this field. Consequently, ESOT—the umbrella organization under which all European transplant activities are organized—sought to understand whether updating guidelines on clinical trial endpoints might help to encourage kidney transplantation research, since potentially outdated or unclear definitions of risk groups and markers of success or failure might limit investment or innovation in transplantation medicine.

The project that ultimately resulted in the Broad Scientific Advice request and the present special issue began in May 2016, when the European Medicines Agency responded positively to ESOT’s request to begin interactions relating to the overall topic. Within ESOT, the project was coordinated from its inception by Professor Maarten Naesens of KU Leuven, Belgium, with contributions by an international group of experts. This panel of volunteers included nephrologists, surgeons, transplant pathologists, epidemiologists, immunologists, and researchers (Box 1). The key events in the development process were:

• September 26, 2017: First workshop meeting at ESOT Barcelona to outline the project, define the core questions, and appoint working group leaders

In June 2020, ESOT presented an extended form of the articles and supporting materials in this special issue to the EMA as one document, as part of the package to request Broad Scientific Advice from CHMP. Following constructive responses from the EMA, this special issue is published to communicate outcomes and extend discussions among the wider kidney transplant community. Ultimately, it is hoped that endpoints suitable for future clinical trials and better consensus on risk stratification are developed and agreed globally, thereby increasing the quality of future research and evidence, and advancing the practical management of kidney transplantation, particularly for long-term outcomes.