High incidence of post-transplant lymphoproliferative disorder in Epstein-Barr virus-seronegative kidney recipients

1. In this retrospective cohort study, individuals who were Epstein-Barr virus-seronegative had higher rates of post-transplant lymphoproliferative disorder than their seropositive counterparts following transplant with seropositive donor kidneys.

2. The incidence of post-transplant lymphoproliferative disorder in seronegative recipients was found to be five to ten times higher than previously reported.

Evidence Rating Level: 2 (Good)

Study Rundown: Solid organ transplantation requires lifelong immunosuppression which renders the recipient susceptible to malignancy. Post-transplant lymphoproliferative disorder (PTLD) is one such form of cancer and is highly associated with Epstein-Barr virus (EBV) due to suppression of EBV-specific cytotoxic T cell response in these individuals. EBV-associated PTLD is associated with high morbidity and mortality. Among kidney transplant recipients, those who are EBV seronegative and receive a kidney from an EBV-seropositive donor have the highest risk of developing PTLD, with a recent study reporting an absolute incidence of 2.5% in this population. However, 90% of organ donors are EBV seropositive and thus, most EBV-seronegative candidates continue to receive kidneys from EBV-seropositive donors. Many studies of PTLD are limited by single-center populations in the United States (U.S.) and there is a paucity of data on the effects of the EBV donor-positive/recipient-negative (D+/R-) serostatus on graft loss and mortality. Hence, this retrospective study aimed to investigate the cumulative incidence of PTLD in EBV D+/R- kidney recipients and the effects of EBV D+/R- status on graft and patient survival at 2 large transplant centers in the U.S. Overall, EBV D+/R- kidney recipients had a higher cumulative incidence of PTLD than their EBV donor-positive/recipient-positive (D+/R+) counterparts. Moreover, EBV D+/R- individuals had higher rates of EBV DNAemia and all-cause graft failure. Mortality was also noted to be higher in the EBV-seronegative recipient group, but this was not statistically significant. The study was limited by a relatively short follow-up period as well as a lack of standard protocols in monitoring EBV DNAemia across centers.

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Relevant Reading: Epstein-Barr virus-positive posttransplant lymphoproliferative disease after solid organ transplantation: pathogenesis, clinical manifestations, diagnosis, and management

In-Depth [retrospective cohort]: This multicenter retrospective cohort study investigated the cumulative incidence of PTLD among EBV D+/R- kidney recipients and the impact of EBV D+/R- serostatus on graft loss and mortality. Adults who underwent renal transplant at the Hospital of the University of Pennsylvania and the University of Pittsburgh Medical Center between January 1, 2010 and June 30, 2022 were screened. Individuals with multi-organ or prior transplants, EBV donor-negative/recipient-negative (D-/R-) individuals, and recipients who had a history of hepatitis B, hepatitis C, or human immunodeficiency virus (HIV) were excluded. The primary outcome was biopsy-proven PTLD. The secondary outcomes encompassed EBV DNAemia, defined as 2 consecutive tests with detectable and quantifiable EBV loads, all-cause graft loss, and survival at 3 years following transplant. Multivariable matching was used to match each EBV D+/R- recipient to 3 EBV D+/R+ recipients. In total, 104 EBV D+/R- recipients were matched to 312 EBV D+/R+ recipients. The mean age in the matched cohort was 42 years (standard deviation, 17.1 years) and the median follow-up time was 1,095 days (interquartile range [IQR], 730.8 to 1,095 days). PTLD occurred in 23 (22.1%) EBV D+/R- recipients at a median of 202 days (IQR, 118 to 317 days) following transplantation, while no EBV D+/R+ recipients developed PTLD. EBV DNAemia occurred in 50 (48.1%) EBV D+/R- recipients with a median time of 198 days (IQR, 110 to 282 days) after transplantation versus 5 (1.6%) EBV D+/R+ recipients. EBV D+/R- recipients had higher all-cause graft failure with a hazard ratio of 2.21 compared to EBV D+/R+ recipients (95% confidence interval, 1.06 to 4.63; p=0.035). Mortality was also higher among EBV D+/R- individuals but this was not statistically significant (hazard ratio, 2.19 [95% CI, 0.94 to 5.13]; p=0.071). In summary, this study demonstrated that EBV D+/R- kidney recipients had a significantly higher incidence of PTLD within 3 years of transplantation compared to their EBV D+/R+ counterparts.

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