INTERCOMEX Trial Summary
Insights derived from this project have changed the understanding of mechanisms of rejection and the classification of transplant diseases
The MMDx-Kidney system was developed in ongoing kidney transplant biopsy studies beginning in 2005. Insights derived from this project have changed the understanding of mechanisms of rejection and the classification of transplant diseases (see Appendix).MMDx-Kidney studies the pattern of transcript expression in kidney tissue associated with TCMR, ABMR, acute kidney injury (AKI) and chronic parenchymal damage (atrophy-fibrosis) (5-7), revising the conventionally defined disease classes. Classifier algorithms based on a large reference set (currently >2400 biopsies) are used to generate probability scores for each sample’s diagnoses. The percent cortex in the biopsy is estimated, although Molecular Microscope® can read medulla.
TCMR has been characterized in MMDx as cognate T cell-antigen presenting cell engagement in the interstitium (8), and ABMR as an NK cell (natural killer cell)-mediated process triggered by donor-specific antibody binding to the microcirculation (9). Both share IFNG effects, which are more intense in TCMR (10). ABMR has the complexity of different stages: early-stage, fully-developed, and late-stage (11). The molecular changes associated with renal injury are often more extensive than suggested by histology (7) and indicate that progression to graft failure is caused by continuing nephron injury, rather than autonomous fibrogenesis (5). Injury also induces IFNG effects (10;12). The INTERCOMEX studies are now driving toward a new classification of the disease states in biopsies using a method called cluster analysis (13).
Have Greater Confidence in Managing Your Patient
The clinician-leaders in our trials indicate that when there is agreement between histology and the MMDx, the MMDx report gives them greater confidence in managing the patient. When the two systems disagree, they have more faith in the MMDx than in local histology assessment (1). Another advantage of MMDx is that it can read medulla and small samples, unlike histology (14), reducing the risk of an “inadequate” or “sub-optimal” biopsy sample and the need for another biopsy.
The Molecular Microscope® system generates an automatic report which is then transmitted to the clinician. Biopsy processing time is usually in one to two business days plus transit time. Only molecular measurements and time of the biopsy post-transplant are used. The report uses the microarray measurements of the level of expression of selected genes or gene set measurements to assess the probability of TCMR and ABMR as well as the extent of acute and chronic injury. The possibility that recent non-adherence or underimmunosuppression has triggered rejection is raised by certain phenotypes (e.g. late-onset TCMR) and by the arteriolar hyalinosis (ah) classifiers (15;16). We are iteratively refining the molecular diagnosis of TCMR and ABMR, and developing a new disease classification system.
The current report format is shown below for two different biopsies, one with TCMR and one with ABMR. This page shows the key findings (Global Disturbance (inflammation), acute kidney injury and atrophy-fibrosis scores and different rejection classifier scores) as well as the overall molecular interpretation. The relationship of the new biopsy to its nearest molecular neighbors in the Reference Set estimates future graft survival. Many other classifiers (page 2 of the reports – not shown for simplicity) are also run to establish details of ABMR. For example, these estimate the probability of microcirculation inflammation (ptc- and g-changes) and glomerular double contours (cg) as an estimate of late-stage ABMR. These are high in the biopsy shown, indicating that this biopsy has fully-developed ABMR. The net result of all of these measurements is integrated by a novel method called archetype analysis, a form of cluster analysis (13).