Relating Molecular T Cell–mediated Rejection Activity in Kidney Transplant Biopsies to Time and to Histologic Tubulitis and Atrophy-fibrosis

Abstract

Background. We studied the variation in molecular T cell–mediated rejection (TCMR) activity in kidney transplant indication biopsies and its relationship with histologic lesions (particularly tubulitis and atrophy-fibrosis) and time posttransplant. Methods. We examined 175 kidney transplant biopsies with molecular TCMR as defined by archetypal analysis in the INTERCOMEX study ( ClinicalTrials.gov #NCT01299168). TCMR activity was defined by a molecular classifier. Results. Archetypal analysis identified 2 TCMR classes, TCMR1 and TCMR2: TCMR1 had higher TCMR activity and more antibody-mediated rejection (“mixed”) activity and arteritis but little hyalinosis, whereas TCMR2 had less TCMR activity but more atrophy-fibrosis. TCMR1 and TCMR2 had similar levels of molecular injury and tubulitis. Both TCMR1 and TCMR2 biopsies were uncommon after 2 y posttransplant and were rare after 10 y, particularly TCMR1. Within late TCMR biopsies, TCMR classifier activity and activity molecules such as IFNG fell progressively with time, but tubulitis and molecular injury were sustained. Atrophy-fibrosis was increased in TCMR biopsies, even in the first year posttransplant, and rose with time posttransplant. TCMR1 and TCMR2 both reduced graft survival, but in random forests, the strongest determinant of survival after biopsies with TCMR was molecular injury, not TCMR activity. Conclusions. TCMR varies in intensity but is always strongly related to molecular injury and atrophy-fibrosis, which ultimately explains its effect on survival. We hypothesize, based on the reciprocal relationship with hyalinosis, that the TCMR1-TCMR2 gradient reflects calcineurin inhibitor drug underexposure, whereas the time-dependent decline in TCMR activity and frequency after the first year reflects T-cell exhaustion.

The Molecular Phenotype of Kidney Transplants: Insights From the MMDx Project

“…122,123 Banff 2017 revised this classification. 121–124 We recently confirmed that tubulitis is a robust feature of TCMR even in late biopsies with atrophy-fibrosis, 108 but the atrophy-fibrosis can make it difficult to score tubulitis.…”

“…FIGURE 15. Various relationships between molecular, histological, and clinical variables and graft survival postbiopsy 108,114. (A) Survival shown per archetype group in 1679 biopsies.…”

Distinct Molecular Processes Mediate Donor-derived Cell-free DNA Release From Kidney Transplants in Different Disease States

“…Some TCMR2 biopsies had low dd-cfDNA, possibly because TCMR2 is less intense and has more fibrosis than TCMR1. 27 Among injury archetype groupings, 28,29 dd-cfDNA was highest in molecular AKI (mAKI; P < 0.0001; Figure 3C). Removing biopsies diagnosed as rejection from the injury archetype set resulted in lower dd-cfDNA in all groups.…”

“…Biopsies were diagnosed by their MMDx signouts and automated archetypal assignments of rejection and injury. 17,[23][24][25][26][27][28][29] Biopsies with no molecular rejection taken within 6-wk posttransplant were classified as no-rejection-clinical AKI (cAKI), and the remaining NR biopsies were classified as Normal. A group of "pristine" biopsies was classified as NRNI based on intersection of MMDx Normal and archetypal no injury in the whole population (SDC, http://links.lww.com/TP/C935).…”

“…Estimated host cfDNA quantity, and dd-cfDNA quantity and fraction, over time posttransplant were analyzed with binscatter regression. 30,31 Differences in mean plasma dd-cfDNA among MMDx subgroups, rejection archetypes, and injury archetypes [27][28][29] with and without biopsies diagnoses as MMDx rejection were assessed by ANOVA followed by post-hoc tests with all pairwise contrasts. The probability of MMDx rejection given the corresponding quantity and fraction dd-cfDNA was assessed by logistic regression.…”