Molecular assessment of disease states in kidney transplant biopsy samples

Abstract

Progress in renal transplantation requires improved understanding and assessment of rejection and injury. Study of the relationship between gene expression and clinical phenotypes in kidney transplant biopsy samples has led to the development of a system that enables diagnoses of specific disease states on the basis of messenger RNA levels in the biopsy sample. Using this system we have defined the molecular landscape of T cell-mediated rejection (TCMR), antibody-mediated rejection (ABMR), acute kidney injury (AKI), and tubular atrophy and interstitial fibrosis. TCMR and ABMR share IFNγ-mediated effects and TCMR has emerged as a cognate T cell-antigen presenting cell process in the interstitium, whereas ABMR is a natural-killer-cell-mediated process that occurs in the microcirculation. The specific features of these different processes have led to the creation of classifiers to test for TCMR and ABMR, and revealed that ABMR is the principal cause of kidney transplant deterioration. The molecular changes associated with renal injury are often more extensive than suggested by histology and indicate that the progression to graft failure is caused by continuing nephron injury, rather than fibrogenesis. In summary, advances in the molecular assessment of disease states in biopsy samples has improved understanding of specific processes involved in kidney graft outcomes.

The Banff 2015 Kidney Meeting Report: Current Challenges in Rejection Classification and Prospects for Adopting Molecular Pathology

“…In contrast, there is considerable heterogeneity among published studies with regard to how the molecular phenotype has been assessed and applied as a potential diagnostic and/or predictive tool 46. Over the last decade, transplant biopsies, blood, and urine have been studied comprehensively, primarily using transcriptomics, and have led to novel insights into the molecular phenotypes of organ transplants 47, 48, 49, 50, 51, 52, 53. Current ongoing studies—for example, the INTERCOM studies 47, 48—are assessing a molecular microscope approach in real time for examining kidney allograft biopsies and comparing the gene expression classifiers and diagnosis to the current gold standard histopathology.…”

Assessing rejection-related disease in kidney transplant biopsies based on archetypal analysis of molecular phenotypes

“…Our previous studies have been based on such classifiers comparing rejection vs. nonrejection phenotypes (10)(11)(12)(13)(14). However, we have subsequently found that methods that combine multiple classifiers provide better estimates than single classifiers (15), implying that a new method is needed to assemble the input from multiple classifiers into a single probabilistic assessment. (27), only MMF (5), no IS treatment (244).…”

The Effect of Cortex/Medulla Proportions on Molecular Diagnoses in Kidney Transplant Biopsies: Rejection and Injury Can Be Assessed in Medulla

“…We recently developed a system for translating gene expression measurements into diagnostic assessment: the molecular microscope diagnostic system (MMDx) (1). Like histology, a molecular biopsy assessment system requires consideration of the effect of sample adequacy.…”