title: Molecular diagnostics identifies risks for graft dysfunction despite borderline histologic changes.
abstract: The significance of borderline changes in kidney allograft biopsies is widely debated. To help resolve this, we studied differences in intrarenal gene expression patterns between early clinical and 3-month protocol biopsies, all of which had borderline histologic changes. The gene expression profiles in training set of patients by microarray analysis and data were validated in a larger cohort using RT-qPCR. There was greater expression of immunity- and inflammation-related genes in the early clinical biopsies compared to the 3-month protocol biopsies with borderline changes. In early clinically manifested borderline changes, graft deterioration within 24 months due to chronic rejection was associated with increased activation of immune, defense, and inflammatory processes. Regression modeling identified higher donor age and expression of macrophage receptor CLEC5A as risk factors for progression. In the 3-month protocol biopsies with borderline changes, graft dysfunction was associated with increased expression of fibrinogen complex transcripts. The discrimination power of fibrinogen was confirmed by cross-validation on two independent cohorts. Thus, our study highlights variations in gene expression between clinical and subclinical borderline changes despite similar histological findings. The data also support a recommendation for frequent patient monitoring, especially in those with borderline changes who received grafts from older donors.
authors.affiliation: Transplant Laboratory, Institute for Clinical and Experimental Medicine, Prague, Czech Republic.
authors.forename: Petra
authors.initials: P
authors.lastname: Hrubá
authors.affiliation: Transplant Laboratory, Institute for Clinical and Experimental Medicine, Prague, Czech Republic.
authors.forename: Irena
authors.initials: I
authors.lastname: Brabcová
authors.affiliation: Department of Nephrology, Hannover Medical School, Hannover, Germany.
authors.forename: Faikah
authors.initials: F
authors.lastname: Gueler
authors.affiliation: Institute of Hematology and Blood Transfusion, Prague, Czech Republic.
authors.forename: Zdeněk
authors.initials: Z
authors.lastname: Krejčík
authors.affiliation: Institute of Inherited Metabolic Disorders, 1st Faculty of Medicine Charles University and General Faculty Hospital, Prague, Czech Republic.
authors.forename: Viktor
authors.initials: V
authors.lastname: Stránecký
authors.affiliation: Department of Immunogenetics, Institute for Clinical and Experimental Medicine, Prague, Czech Republic.
authors.forename: Eva
authors.initials: E
authors.lastname: Svobodová
authors.affiliation: Department of Clinical and Transplant Pathology, Institute for Clinical and Experimental Medicine, Prague, Czech Republic.
authors.forename: Jana
authors.initials: J
authors.lastname: Malušková
authors.affiliation: Department of Nephrology, Hannover Medical School, Hannover, Germany.
authors.forename: Wilfried
authors.initials: W
authors.lastname: Gwinner
authors.affiliation: Department of Clinical and Transplant Pathology, Institute for Clinical and Experimental Medicine, Prague, Czech Republic.
authors.forename: Eva
authors.initials: E
authors.lastname: Honsová
authors.affiliation: Department of Clinical and Transplant Pathology, Institute for Clinical and Experimental Medicine, Prague, Czech Republic.
authors.forename: Alena
authors.initials: A
authors.lastname: Lodererová
authors.affiliation: Department of Nephrology and Dialysis, Medical University Vienna, Vienna, Austria.
authors.forename: Rainer
authors.initials: R
authors.lastname: Oberbauer
authors.affiliation: Department of Urology, Thomayer's Hospital, Prague, Czech Republic.
authors.forename: Roman
authors.initials: R
authors.lastname: Zachoval
authors.affiliation: Transplant Laboratory, Institute for Clinical and Experimental Medicine, Prague, Czech Republic.|Department of Nephrology, Institute for Clinical and Experimental Medicine, Prague, Czech Republic.|Biomedical Centre, Faculty of Medicine in Plzen, Charles University in Prague, Plzen, Czech Republic.
authors.forename: Ondřej
authors.initials: O
authors.lastname: Viklický
mesh_terms: D000328:Adult; D000368:Aged; D058070:Asymptomatic Diseases; D001706:Biopsy; D042241:Early Diagnosis; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D005819:Genetic Markers; D020022:Genetic Predisposition to Disease; D006084:Graft Rejection / Q000235:genetics* / Q000473:pathology* / Q000503:physiopathology; D006801:Humans; D007668:Kidney / Q000473:pathology* / Q000503:physiopathology; D016030:Kidney Transplantation / Q000009:adverse effects*; D008297:Male; D008875:Middle Aged; D025202:Molecular Diagnostic Techniques; D020411:Oligonucleotide Array Sequence Analysis; D010641:Phenotype; D016133:Polymerase Chain Reaction; D011237:Predictive Value of Tests; D015203:Reproducibility of Results; D012189:Retrospective Studies; D018570:Risk Assessment; D012307:Risk Factors; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D005819:Genetic Markers