Disappearance of T Cell-Mediated Rejection Despite Continued Antibody-Mediated Rejection in Late Kidney Transplant Recipients

Abstract

The prevalent renal transplant population presents an opportunity to observe the adaptive changes in the alloimmune response over time, but such studies have been limited by uncertainties in the conventional biopsy diagnosis of T cell-mediated rejection (TCMR) and antibody-mediated rejection (ABMR). To circumvent these limitations, we used microarrays and conventional methods to investigate rejection in 703 unselected biopsies taken 3 days to 35 years post-transplant from North American and European centers. Using conventional methods, we diagnosed rejection in 205 biopsy specimens (28%): 67 pure TCMR, 110 pure ABMR, and 28 mixed (89 designated borderline). Using microarrays, we diagnosed rejection in 228 biopsy specimens (32%): 76 pure TCMR, 124 pure ABMR, and 28 mixed (no borderline). Molecular assessment confirmed most conventional diagnoses (agreement was 90% for TCMR and 83% for ABMR) but revealed some errors, particularly in mixed rejection, and improved prediction of failure. ABMR was strongly associated with increased graft loss, but TCMR was not. ABMR became common in biopsy specimens obtained >1 year post-transplant and continued to appear in all subsequent intervals. TCMR was common early but progressively disappeared over time. In 108 biopsy specimens obtained 10.2-35 years post-transplant, TCMR defined by molecular and conventional features was never observed. We conclude that the main cause of kidney transplant failure is ABMR, which can present even decades after transplantation. In contrast, TCMR disappears by 10 years post-transplant, implying that a state of partial adaptive tolerance emerges over time in the kidney transplant population.

Keywords: T cells; antibody; graft rejection; kidney transplant; microarrays.

Copyright © 2015 by the American Society of Nephrology.

Figures

Figure 1.

Relationship of biopsy findings to subsequent graft survival. Kaplan–Meier curves for 3-year survival postbiopsy for 564 kidneys with one random biopsy per kidney and censoring death with function at 3 years (n is the total number of kidneys, F is failure, and vertical ticks indicate censoring). The total number of patients at risk at various times postbiopsy was 564 at day of biopsy, 498 at day 200, 435 at day 400, 342 at day 600, 273 at day 800, and 241 at day 1000. (A) Conventional diagnosis showing P values compared with relatively normal biopsies. (B) Molecular diagnosis split by ABMR and TCMR scores in pure ABMR (positive ABMR score and negative TCMR score), pure TCMR (positive TCMR score and negative ABMR score), and mixed (both positive). (C) Survival in groups divided by rising ABMR score. (D) ABMR score combined with the conventional diagnosis of ABMR/mixed versus no ABMR.

Figure 2.

Relationship between time of the biopsy post-transplant and biopsy findings. Distribution of TCMR and ABMR scores and conventional diagnoses in 703 biopsies by the time of the biopsy post-transplant. Each biopsy is represented by a symbol colored by conventional diagnosis. (A) TCMR scores on a log scale. (B) TCMR scores on a linear scale. (C) ABMR scores on a log scale. (D) ABMR scores on a linear scale. The intermediate time period (years 1–5) is shaded to separate early (first 1 year) from late (after 5 years). The time periods are further divided into intervals: early at day 7 and 6 months and late at 10 years.