Using Molecular Phenotyping to Guide Improvements in the Histologic Diagnosis of T Cell–Mediated Rejection

Abstract

Recognition that some lesions typical of T cellmediated rejection (TCMR) also occur in antibodymediated rejection requires revision of the histologic TCMR definition. To guide this process, we assessed the relative importance of various lesions and the performance of new histology diagnostic algorithms, using molecular TCMR scores as histology-independent estimates of true TCMR. In 703 indication biopsies, random forest analysis and logistic regression indicated that interstitial infiltrate (i-lesions) and tubulitis (t-lesions) were the key histologic predictors of molecular TCMR, with arteritis (v-lesions) having less importance. Histology predicted molecular TCMR more accurately when diagnoses were assigned by strictly applying the Banff rules to the lesion scores and redefining isolated v-lesion TCMR. This improved prediction from area under the curve (AUC) 0.70 with existing rules to AUC 0.80. Further improvements were achieved by introducing more categories to reflect inflammation (AUC 0.84), by summing the lesion scores (AUC 0.85) and by logistic regression (AUC 0.90). We concluded that histologic assessment of TCMR can be improved by placing more emphasis on i-and t-lesions and incorporating new algorithms for diagnosis. Nevertheless, some discrepancies between histologic and molecular diagnoses persist, partially due to the inherent nonspecificity of i-and t-lesions, and molecular methods will be required to help resolve these cases.

B Cell Receptor Genes Associated With Tolerance Identify a Cohort of Immunosuppressed Patients With Improved Renal Allograft Graft Function

“…Interestingly induction with alemtuzumab was not associated with a reduced frequency of the two gene “signature”. Finally, and consistent with a recent report our data indicate that the signature is less common in recipients receiving prednisone (18). In the broad context we interpret these results as further demonstration that the choice of immunosuppressive agents may influence the expression of immune response genes related specifically to B cells as well perhaps as B cell numbers and the B cell repertoire.…”

Molecular assessment of disease states in kidney transplant biopsy samples

“…The presence of vlesions in biopsy samples with ABMR is uncommon (represent ing <10% of samples with ABMR), and of little diag nostic value given their greater frequency in TCMR. Second, the use of lesion scores in a regression model gives a better estimate of molecular TCMR than does current histology practices based on dichotomous lesion cutoffs 105 , suggesting that the current lesion score cutoffs could be discarded. Regression equa tion scores should not be dichotomized, but should be used probabilistically.…”

“…• Molecular disturbance associated with inflammation and/or injury is stereotyped: molecules 'travel in herds' 65 • ABMR is frequently C4d negative 5,53 • ABMR is the main cause of renal transplant loss 5,46 • Some but not all TCMR, ABMR and graft loss is due to non-adherence 47 • The molecular landscape of TCMR has identified a potential role of checkpoints and T-cell exhaustion 66 • TCMR occurring >10 years after transplantation is rare despite the persistence of ABMR 46 • A molecular classifier for TCMR has been developed 17 • The molecular landscape of ABMR has identified a potential role of natural killer cells and CD16a 67 , and has revealed similar mechanisms in kidney and heart transplants 112 • TCMR and ABMR share mechanisms, particularly related to IFNγ-mediated effects 83 • Donor age is a risk factor in early ABMR 6 • A molecular classifier for ABMR has been developed 55,100 • The molecular landscape of AKI in transplantation has been defined 54 • The molecular landscape of TA/IF has identified a new model for response to wounding and fibrosis progression 68 • Transcripts associated with immunoglobulins 90 and mast cells 91 are associated with TA/IF • A TCMR-like process is often present in polyoma virus nephropathy 17 • TCMR is rarely present in biopsy samples with isolated intimal arteritis (identified by v-lesions) with no interstitial inflammation 10,83 • Regression equations using actual lesion scores improves histologic prediction 105 • ABMR can be diagnosed at times without knowing that donor-specific antigen is positive 7 • ABMR is heterogeneous, with various phenotypes (peritubular capillaritis and glomerulitis, chronic glomerulopathy, or both) 78 • FOXP3 expression is associated with inflammation but not with favourable outcomes 117 • A molecular risk classifier predicts progression more accurately than does conventional histological features 42 • Collagen synthesis does not cause TA/IF; rather this feature simply reflects wound repair 68 • TCMR does not programme late graft loss 46 • Molecular changes that occur in AKI can continue and be found in kidney biopsy samples with progressive TA/IF 68,88 ABMR, antibody-mediated rejection; AKI, acute kidney injury; MMDx, molecular microscope diagnostic system; TA/IF, tubular atrophy and interstitial fibrosis; TCMR, T-cell-mediated rejection.…”

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“…[18][19][20] It is possible that the incorporation of molecular tests with the light microscopical features in Banff classification will help eliminate this diagnostic category in the future. [18][19][20] The important point in this study is that these borderline changes represent early forms of rejection, rather than some other nonrejection pathologic lesions. There is a need, therefore, for more objective criteria to differentiate borderline rejection from nonrejection borderline lymphocytic infiltrates.…”