Determining Optimal Immunosuppression and Kidney Allocation Strategies for Mitigating Risks from Epstein-Barr Virus in Kidney Transplant Centers

Epstein-Barr Virus (EBV)-seronegative kidney transplant recipients of EBV-seropositive donor organs (EBV D+/R-) carry an extremely high risk of developing cancers such as post-transplant lymphoproliferative disorder (PTLD) due to donor-derived EBV infection. Currently, there is no cure or approved vaccine for EBV. The objectives of this proposal are to identify the effect of immunosuppression on the development of PTLD and EBV infection and to evaluate the impact of optimizing the kidney allocation system to reduce complications from EBV infection. The central hypothesis is that immunosuppression modifies the risk of PTLD and EBV infection among kidney transplant recipients, and prioritizing EBV-seronegative kidneys for EBV-seronegative recipients can reduce the incidence of PTLD with acceptable tradeoffs to waiting time and access to transplantation. The central hypothesis will be tested by pursuing three specific aims: 1) Determine if modifiable risk factors such as immunosuppression modifies the effect of EBV D+/R- serostatus on the incidence of PTLD, 2) determine the relationship between immunosuppression on EBV infection and viral kinetics among EBV D+/R- kidney transplant recipients, and 3) evaluate the effect of prioritizing transplantation of kidneys from EBV-seronegative donors into seronegative recipients on access to transplantation. The proposed research will establish a consortium of eight large-volume kidney transplant centers to establish a validated and granular dataset of EBV D+/R- kidney transplant recipients. For Aim 1, transplant centers in the consortium will submit validated data on EBV-serostatus, immunosuppression, and PTLD outcomes. For Aim 2, transplant centers in the consortium will adhere to EBV DNA surveillance guidelines from the American Society of Transplantation and collect longitudinal data on EBV DNA levels in blood. For Aim 3, the proposal will use simulation-allocation modeling to identify the effect of changing the kidney allocation system to prioritize the transplantation of EBV-seronegative kidneys into EBV-seronegative recipients. The proposed research will advance the field through innovation in data validation and clinical phenotyping of EBV infection and PTLD, utilize latent class analyses to identify discrete EBV infection trajectories, test the effect of changing the kidney allocation system to reduce the risk of cancer on equity, and employ a multipronged dissemination strategy. In summary, this proposal aims to identify therapeutic strategies, such as optimizing immunosuppression, identifying EBV infection trajectories, and changing the allocation system to reduce the risk of cancer for EBV D+/R- kidney transplant recipients. Project Number: 1R01AI191110-01 | Fiscal Year: 2025 | NIH Institute/Center: National Institute of Allergy and Infectious Diseases (NIAID) | Principal Investigator: Vishnu Potluri | Institution: UNIVERSITY OF PENNSYLVANIA, PHILADELPHIA, PA | Award Amount: $644,770 | Activity Code: R01 | Study Section: Population based Research in Infectious Disease Study Section[PRID] View on NIH RePORTER: https://reporter.nih.gov/project-details/1R01AI19111001