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Molecular assessment of disease states in kidney transplant biopsy samples

Key Points

  • Unmet needs in renal transplantation include not just accurate diagnosis but understanding and reclassifying of disease states, which requires molecular studies of biopsy samples

  • Benefits of molecular analysis over histology include the potential for centralized objective assessment of rejection and injury, identification of mechanisms and druggable targets and better prediction of outcomes

  • Conventional diagnostic classes guide the mapping of the molecular landscape of disease entities, and the creation of molecular classifiers, which in turn can be used to guide diagnosis

  • The molecular phenotype provides an opportunity to recalibrate the conventional histologic classifications

  • The molecular phenotype of disease states can only be reliably assessed as a centralized test as it relies on rigorous reproducible measurement, quantification and normalization

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.

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Figure 1: Pathogenesis based transcript (PBT) scores reveal large-scale molecular disturbances in biopsy samples with different disease diagnoses.
Figure 2: Emerging models of antibody-mediated rejection (ABMR) and T cell-mediated rejection (TCMR) mechanisms.
Figure 3: Time-dependent effects on disease states after transplantation.
Figure 4: The relationship between the time-dependent changes in the expression of immunoglobulin, mast cell, acute kidney injury (AKI), and fibrillar collagen transcripts and the progression of tubular atrophy and interstitial fibrosis (TA/IF).
Figure 5: The nephron-centric model of renal transplant fibrosis based on the injury-related molecular events observed in biopsy samples in the first year post-transplantation.
Figure 6: Schematic of an analysis of a new biopsy sample in relation to a reference set of samples from indication biopsies.

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P.F.H. researched data for article. All authors made substantial contributions to discussing the article's content, writing the article and reviewing or editing the article before submission.

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Correspondence to Philip F. Halloran.

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Competing interests

P.F.H. holds shares in Transcriptome Sciences Inc., a company with an interest in molecular diagnostics in transplantation, and has received research support from Transcriptome Sciences Inc., Roche Molecular Systems, Hoffmann-La Roche Canada Ltd., the Roche Organ Transplant Research Foundation, Novartis Pharma AG, and Astellas. The other authors declare no competing interests.

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DATABASES

Alberta Transplant Applied Genomics Centre Gene Lists

Ingenuity Pathway Analysis

Kyoto Encyclopedia of Genes and Genomes pathways

Broad Institute gene sets

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Halloran, P., Famulski, K. & Reeve, J. Molecular assessment of disease states in kidney transplant biopsy samples. Nat Rev Nephrol 12, 534–548 (2016). https://doi.org/10.1038/nrneph.2016.85

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