Subclinical Rejection Phenotypes at 1 Year Post-Transplant and Outcome of Kidney Allografts

Abstract

Kidney allograft rejection can occur in clinically stable patients, but long-term significance is unknown. We determined whether early recognition of subclinical rejection has long-term consequences for kidney allograft survival in an observational prospective cohort study of 1307 consecutive nonselected patients who underwent ABO-compatible, complement-dependent cytotoxicity-negative crossmatch kidney transplantation in Paris (2000-2010). Participants underwent prospective screening biopsies at 1 year post-transplant, with concurrent evaluations of graft complement deposition and circulating anti-HLA antibodies. The main analysis included 1001 patients. Three distinct groups of patients were identified at the 1-year screening: 727 (73%) patients without rejection, 132 (13%) patients with subclinical T cell-mediated rejection (TCMR), and 142 (14%) patients with subclinical antibody-mediated rejection (ABMR). Patients with subclinical ABMR had the poorest graft survival at 8 years post-transplant (56%) compared with subclinical TCMR (88%) and nonrejection (90%) groups (P<0.001). In a multivariate Cox model, subclinical ABMR at 1 year was independently associated with a 3.5-fold increase in graft loss (95% confidence interval, 2.1 to 5.7) along with eGFR and proteinuria (P<0.001). Subclinical ABMR was associated with more rapid progression to transplant glomerulopathy. Of patients with subclinical TCMR at 1 year, only those who further developed de novo donor-specific antibodies and transplant glomerulopathy showed higher risk of graft loss compared with patients without rejection. Our findings suggest that subclinical TCMR and subclinical ABMR have distinct effects on long-term graft loss. Subclinical ABMR detected at the 1-year screening biopsy carries a prognostic value independent of initial donor-specific antibody status, previous immunologic events, current eGFR, and proteinuria.

Keywords: allograft function; allograft loss; renal medicine; translational research; transplant rejection.

Figure 1.

Distinct allograft injury phenotypes in 1 year screening kidney allograft biopsies. Graft injury phenotype in screening allograft biopsies performed at 1 year post-transplant (n=1001). Results are given as Banff scores for each lesion. Bars represent SEMs.

Figure 2.

Distinct kidney allograft function course according to the 1 year screening kidney allograft biopsies phenotype. Long-term kidney allograft function according to 1-year subclinical rejection profile. The evolution of eGFR in 1001 patients on the basis of assessment of 4.511 longitudinal eGFRs is shown. We evaluated the long-term course of eGFR in three groups of patients by using a linear mixed model starting from 1 year post-transplant to the last available eGFR; 905 eGFR measurements taken at 3 months post-transplant are also shown. Bars represent SDs.

Figure 3.

Distinct time frame of progression of transplant glomerulopathy lesions according to the 1 year screening kidney allograft biopsies phenotype. Conditional probability of occurrence of transplant glomerulopathy lesions in three groups of patients. The conditional probability plot integrates all biopsies for cause taken after 1 year (n=316) and assesses the cg Banff score of each biopsy. Note that, for three groups, the probability of developing cg lesions after 1 year is conditional on having a biopsy for cause performed after 1 year. This does not represent the overall or absolute probability of developing transplant glomerulopathy (cg) lesions after 1 year.

Figure 4.

Long-term allograft survival according to the one-year biopsy phenotype. (A) Graft survival probability, according to the rejection profile: subclinical ABMR, subclinical TCMR, or no rejection. (B) Risk of kidney allograft loss according to eGFR and the presence of subclinical ABMR. GFR was estimated by the Modification of Diet in Renal Disease formula. Relative risks (RRs) and 95% CIs are 1.8 (0.2 to 15.6), 4.2 (2.2 to 8.2), and 2.5 (1.1 to 5.3).