We performed orthogonal technology comparisons of concurrent peripheral blood and biopsy tissue samples from 69 kidney transplant recipients, who underwent a comprehensive algorithm-driven clinical phenotyping. The sample cohort included patients with normal protocol biopsies and stable transplant function (TX, n=25), subclinical acute rejection (subAR, n=23), and clinical acute rejection (cAR, n=21). Comparisons between microarray and RNA sequencing (RNA-seq) signatures were performed, demonstrating a strong correlation between the blood and tissue compartments for both technology platforms. A number of shared differentially expressed genes and pathways between subAR and cAR in both platforms strongly suggest that these two clinical phenotypes form a continuum of alloimmune activation. SubAR is associated with fewer or less expressed genes than cAR in blood, whereas in biopsy tissues, this clinical phenotype demonstrates a more robust molecular signature for both platforms. The discovery work done in this study confirms a clear ability to detect gene expression profiles for TX, subAR and cAR in both blood and biopsy tissue, yielding equivalent predictive performance, that is agnostic to either technology or platform. Our data also provide strong biologic insights into the molecular mechanisms underlying these signatures, underscoring their logistical potential as molecular diagnostics to improve clinical outcomes following kidney transplantation.
Background: Significant challenges exist to detecting kidney injury early in patients with kidney transplants. The current standard of care includes monitoring serum creatinine levels and immunosuppressive drug levels, both of which are poor early predictors of kidney graft damage. Protocol (surveillance) biopsies provide an accurate assessment of the transplanted kidney but are expensive, invasive, risking infection and bleeding and even graft loss, such that they are unsuited for frequent monitoring.
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