Long-Term Outcomes after Acute Rejection in Kidney Transplant Recipients: An ANZDATA Analysis

Significance Statement Declining rates of acute rejection (AR) and the very high rate of 1-year graft survival among patients with AR has led some clinicians and researchers to reconsider the importance of AR as a primary outcome in clinical trials or in patients. The authors examine the association of AR within 6 months of kidney transplant with long-term outcomes of transplant recipients, using data from the Australia and New Zealand Dialysis and Transplant (ANZDATA) Registry between 1997 and 2017. Recipients with early AR were more likely to experience graft loss attributed to chronic allograft nephropathy (hazard ratio [HR], 1.39; 95% confidence interval [95% CI], 1.23 to 1.56) and recurrent AR (HR, 1.85; 95% CI, 1.39 to 2.46). Recipients with early AR were also more likely to die from cardiovascular disease (HR, 1.30; 95% CI, 1.11 to 1.53) or cancer (HR, 1.35; 95% CI, 1.12 to 1.64). AR therefore remains an important short-term outcome in kidney transplantation with significant long-term effects. Background Declining rates of acute rejection (AR) and the high rate of 1-year graft survival among patients with AR have prompted re-examination of AR as an outcome in the clinic and in trials. Yet AR and its treatment may directly or indirectly affect longer-term outcomes for kidney transplant recipients. Methods To understand the long-term effect of AR on outcomes, we analyzed data from the Australia and New Zealand Dialysis and Transplant Registry, including 13,614 recipients of a primary kidney-only transplant between 1997 and 2017 with at least 6 months of graft function. The associations between AR within 6 months post-transplant and subsequent cause-specific graft loss and death were determined using Cox models adjusted for baseline donor, recipient, and transplant characteristics. Results AR occurred in 2906 recipients (21.4%) and was associated with graft loss attributed to chronic allograft nephropathy (hazard ratio [HR], 1.39; 95% confidence interval [95% CI], 1.23 to 1.56) and recurrent AR beyond month 6 (HR, 1.85; 95% CI, 1.39 to 2.46). Early AR was also associated with death with a functioning graft (HR, 1.22; 95% CI, 1.08 to 1.36), and with death due to cardiovascular disease (HR, 1.30; 95% CI, 1.11 to 1.53) and cancer (HR, 1.35; 95% CI, 1.12 to 1.64). Sensitivity analyses restricted to subgroups with either biopsy-proven, antibody-mediated, or vascular rejection, or stratified by treatment response produced similar results. Conclusions AR is associated with increased risks of longer-term graft failure and death, particularly death from cardiovascular disease and cancer. The results suggest AR remains an important short-term outcome to monitor in kidney transplantation and clinical trials.