A 2-fold Approach to Polyoma Virus (BK) Nephropathy in Kidney Transplants: Distinguishing Direct Virus Effects From Cognate T Cell–mediated Inflammation

Halloran, Philip F.; Madill‐Thomsen, Katelynn S.; Böhmig, Georg A.; Myślak, Marek; Gupta, Gaurav; Kumar, Dhiren; Viklický, Ondřej; Perkowska‐Ptasińska, Agnieszka; Famulski, Konrad S.

doi:10.1097/tp.0000000000003884

Cited by 15 publications

(14 citation statements)

References 41 publications

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“…BKN often develops a TCMR-like process as ISD minimization continues, directed at alloantigens, BK antigens, or both. 9 Hyalinosis of the glomerular afferent arteriole, a marker for CNI exposure, is less than expected in TCMR biopsies, consistent with underimmunosuppression as a risk for TCMR. 10 , 11 Although TCMR becomes uncommon after 5 to 10 y, unlike AMR, 12 late TCMR (usually defined as after 1 y posttransplant) is associated with worse outcomes.…”

Section: Introductionmentioning

confidence: 80%

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

Madill‐Thomsen¹,

Böhmig²,

Bromberg³

et al. 2023

Transplantation

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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.

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Section: Introductionmentioning

confidence: 80%

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

Madill‐Thomsen¹,

Böhmig²,

Bromberg³

et al. 2023

Transplantation

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“…Molecular diagnoses shows strong agreement with histology, albeit with some discrepancies, 21,22 in part due to the intrinsic variability in histology, 23 for example, in TCMR. 24,25 Some discrepancies reflect diagnostic conventions: for example, BK virus nephropathy often has molecular TCMR-like changes due to cognate T cell responses against virus or alloantigens, 26 but the histologic convention is to not diagnose TCMR in BK virus nephropathy, despite typical lesions. 26 All biopsy assessments-molecular or histologic-can be affected by sampling error, and have potential for error around boundaries of diagnostic classes.…”

mentioning

confidence: 99%

The Trifecta Study: Comparing Plasma Levels of Donor-derived Cell-Free DNA with the Molecular Phenotype of Kidney Transplant Biopsies

Halloran¹,

Reeve²,

Madill‐Thomsen³

et al. 2022

JASN

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BackgroundThe relationship between the donor-derived cell-free DNA fraction (dd-cfDNA[%]) in plasma in kidney transplant recipients at time of indication biopsy and gene expression in the biopsied allograft has not been defined.MethodsIn the prospective, multicenter Trifecta study, we collected tissue from 300 biopsies from 289 kidney transplant recipients to compare genome-wide gene expression in biopsies with dd-cfDNA(%) in corresponding plasma samples drawn just before biopsy. Rejection was assessed with the microarray-based Molecular Microscope Diagnostic System using automatically assigned rejection archetypes and molecular report sign-outs, and histology assessments that followed Banff guidelines.ResultsThe median time of biopsy post-transplantation was 455 days (5 days to 32 years), with a case mix similar to that of previous studies: 180 (60%) no rejection, 89 (30%) antibody-mediated rejection (ABMR), and 31 (10%) T cell–mediated rejection (TCMR) and mixed. In genome-wide mRNA measurements, all 20 top probe sets correlating with dd-cfDNA(%) were previously annotated for association with ABMR and all types of rejection, either natural killer (NK) cell–expressed (e.g., GNLY, CCL4, TRDC, and S1PR5) or IFN-γ–inducible (e.g., PLA1A, IDO1, CXCL11, and WARS). Among gene set and classifier scores, dd-cfDNA(%) correlated very strongly with ABMR and all types of rejection, reasonably strongly with active TCMR, and weakly with inactive TCMR, kidney injury, and atrophy fibrosis. Active ABMR, mixed, and active TCMR had the highest dd-cfDNA(%), whereas dd-cfDNA(%) was lower in late-stage ABMR and less-active TCMR. By multivariate random forests and logistic regression, molecular rejection variables predicted dd-cfDNA(%) better than histologic variables.ConclusionsThe dd-cfDNA(%) at time of indication biopsy strongly correlates with active molecular rejection and has the potential to reduce unnecessary biopsies.Clinical Trial registration number:NCT04239703

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“…The ability of this classifier to predict TCMR after resolution of BKVN has also not been formally interrogated. Most recently, MMDx has incorporated a BKVN probability classifier into its diagnostic system 40 . Its expected clinical value is limited by the fact that it was derived from training sets containing TCMR and BKVN biopsies with unknown proportions of both diseases.…”

Section: Distinction Between Tcmr and Bkv Nephropathymentioning

confidence: 99%

The MMDx^®diagnostic system: A critical re‐appraisal of its knowledge gaps and a call for rigorous validation studies

Randhawa

2022

Clinical Transplantation

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A 2-fold Approach to Polyoma Virus (BK) Nephropathy in Kidney Transplants: Distinguishing Direct Virus Effects From Cognate T Cell–mediated Inflammation

Abstract: Supplemental Digital Content is available in the text.

Cited by 15 publications

References 41 publications

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

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

The Trifecta Study: Comparing Plasma Levels of Donor-derived Cell-Free DNA with the Molecular Phenotype of Kidney Transplant Biopsies

The MMDx^®diagnostic system: A critical re‐appraisal of its knowledge gaps and a call for rigorous validation studies

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A 2-fold Approach to Polyoma Virus (BK) Nephropathy in Kidney Transplants: Distinguishing Direct Virus Effects From Cognate T Cell–mediated Inflammation

Abstract: Supplemental Digital Content is available in the text.

Cited by 15 publications

References 41 publications

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

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

The Trifecta Study: Comparing Plasma Levels of Donor-derived Cell-Free DNA with the Molecular Phenotype of Kidney Transplant Biopsies

The MMDx®diagnostic system: A critical re‐appraisal of its knowledge gaps and a call for rigorous validation studies

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The MMDx^®diagnostic system: A critical re‐appraisal of its knowledge gaps and a call for rigorous validation studies