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

Abstract

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.

Keywords: chronic allograft failure; kidney transplantation; rejection; survival.

Graphical abstract

Figure 1.

Patient flow.

Figure 2.

Graft and patient survival were worse in those who experienced rejection in the first 6 months post-transplant, particularly for those who experienced AMR. P<0.001 for all graphs.

Figure 3.

Graft losses and death from most causes were increased in those who experienced rejection. The figure shows the adjusted associations between rejection in the first 6 months post-transplant and subsequent cause-specific graft loss and cause-specific death. All models are adjusted for patient and donor characteristics, baseline immunologic risk, transplant era, and delayed graft function.

Figure 4.

Associations between rejection and outcomes were similar across different rejection subtypes. The figure shows the adjusted associations between different subtypes of rejection and subsequent outcomes. All models are adjusted for patient and donor characteristics, baseline immunologic risk, transplant era, and delayed graft function and as described in the text.

Figure 5.

Rejection without complete resolution, or with an antibody-mediated component, was associated with more graft loss from chronic allograft nephropathy. The figure shows the adjusted associations between rejection in the first 6 months post-transplant and subsequent outcomes, stratified by (A) whether the rejection completely resolved (defined as the return of graft function to prerejection levels or better) and (B) whether AMR was present or not. P values are for the differences in subhazard ratios between resolving and nonresolving rejection.

Figure 6.

Kidney function was worse in those who experienced rejection, especially rejection that didn't completely resolve. The figure shows the eGFR in those with and without rejection in the first 6 months post-transplant: (A) any AR versus not, and (B) AMR versus AR excluding AMR versus no AR, and (C) treatment responsive (return to within 10% of baseline serum creatinine) versus not. eGFR was only calculated in those patients with functioning grafts at each timepoint. P<0.001 for all comparisons apart from panel 3C rejection with versus without AMR (P=0.88).