title: Orthogonal Comparison of Molecular Signatures of Kidney Transplants With Subclinical and Clinical Acute Rejection: Equivalent Performance Is Agnostic to Both Technology and Platform.
abstract: We performed orthogonal technology comparisons of concurrent peripheral blood and biopsy tissue samples from 69 kidney transplant recipients who underwent comprehensive algorithm-driven clinical phenotyping. The sample cohort included patients with normal protocol biopsies and stable transplant (sTx) function (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 and demonstrated 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 sTx, subAR, and cAR in both blood and biopsy tissue, yielding equivalent predictive performance that is agnostic to both technology and platform. Our data also provide strong biological insights into the molecular mechanisms underlying these signatures, underscoring their logistical potential as molecular diagnostics to improve clinical outcomes following kidney transplantation.
authors.affiliation: Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA.
authors.forename: S M
authors.initials: SM
authors.lastname: Kurian
authors.affiliation: Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA.
authors.forename: E
authors.initials: E
authors.lastname: Velazquez
authors.affiliation: Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA.
authors.forename: R
authors.initials: R
authors.lastname: Thompson
authors.affiliation: Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA.
authors.forename: T
authors.initials: T
authors.lastname: Whisenant
authors.affiliation: Transplant Genomics Inc., Mansfield, MA.
authors.forename: S
authors.initials: S
authors.lastname: Rose
authors.affiliation: Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA.
authors.forename: N
authors.initials: N
authors.lastname: Riley
authors.affiliation: Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA.
authors.forename: F
authors.initials: F
authors.lastname: Harrison
authors.affiliation: Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA.
authors.forename: T
authors.initials: T
authors.lastname: Gelbart
authors.affiliation: Comprehensive Transplant Center, Feinberg School of Medicine, Northwestern University, Chicago, IL.
authors.forename: J J
authors.identifier: http://orcid.org/0000-0002-9344-9928
authors.initials: JJ
authors.lastname: Friedewald
authors.affiliation: Comprehensive Transplant Center, Feinberg School of Medicine, Northwestern University, Chicago, IL.
authors.forename: J
authors.initials: J
authors.lastname: Charette
authors.affiliation: Comprehensive Transplant Center, Feinberg School of Medicine, Northwestern University, Chicago, IL.
authors.forename: S
authors.initials: S
authors.lastname: Brietigam
authors.affiliation: Comprehensive Transplant Center, Feinberg School of Medicine, Northwestern University, Chicago, IL.
authors.forename: J
authors.initials: J
authors.lastname: Peysakhovich
authors.affiliation: Transplant Genomics Inc., Mansfield, MA.|Comprehensive Transplant Center, Feinberg School of Medicine, Northwestern University, Chicago, IL.
authors.forename: M R
authors.initials: MR
authors.lastname: First
authors.affiliation: Comprehensive Transplant Center, Feinberg School of Medicine, Northwestern University, Chicago, IL.
authors.forename: M M
authors.identifier: http://orcid.org/0000-0001-9333-463X
authors.initials: MM
authors.lastname: Abecassis
authors.affiliation: Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA.
authors.forename: D R
authors.initials: DR
authors.lastname: Salomon
mesh_terms: D000328:Adult; D000368:Aged; D015415:Biomarkers / Q000378:metabolism*; D016022:Case-Control Studies; D005260:Female; D005500:Follow-Up Studies; D020869:Gene Expression Profiling; D006084:Graft Rejection / Q000097:blood / Q000175:diagnosis* / Q000453:epidemiology / Q000235:genetics; D006085:Graft Survival; D059014:High-Throughput Nucleotide Sequencing / Q000379:methods*; D006801:Humans; D007676:Kidney Failure, Chronic / Q000235:genetics* / Q000601:surgery; D016030:Kidney Transplantation / Q000009:adverse effects*; D008297:Male; D008875:Middle Aged; D015995:Prevalence; D011379:Prognosis; D011446:Prospective Studies; D055815:Young Adult
chemical_list: D015415:Biomarkers
keywords: clinical research/practice; diagnostic techniques and imaging; genomics; kidney (allograft) function/dysfunction; kidney transplantation/nephrology; microarray/gene array; rejection: acute; translational research/science