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Molecular diagnostics identifies risks for graft dysfunction despite borderline histologic changes

P. Hrubá, I. Brabcová, F. Gueler, Z. Krejčík, V. Stránecký, E. Svobodová, J. Malušková, W. Gwinner, E. Honsová, A. Lodererová, R. Oberbauer, R. Zachoval, O. Viklický,

. 2015 ; 88 (4) : 785-795. [pub] 20150715

Language English Country United States

Document type Journal Article, Multicenter Study, Observational Study, Research Support, Non-U.S. Gov't, Validation Study

Persistent link   https://www.medvik.cz/link/bmc16028367

Grant support
NT11227 MZ0 CEP Register
NT14102 MZ0 CEP Register

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.

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$a The significance of borderline changes in kidney allograft biopsies is widely debated. To help resolve this, we studied differences in intrarenal gene expression patterns between early clinical and 3-month protocol biopsies, all of which had borderline histologic changes. The gene expression profiles in training set of patients by microarray analysis and data were validated in a larger cohort using RT-qPCR. There was greater expression of immunity- and inflammation-related genes in the early clinical biopsies compared to the 3-month protocol biopsies with borderline changes. In early clinically manifested borderline changes, graft deterioration within 24 months due to chronic rejection was associated with increased activation of immune, defense, and inflammatory processes. Regression modeling identified higher donor age and expression of macrophage receptor CLEC5A as risk factors for progression. In the 3-month protocol biopsies with borderline changes, graft dysfunction was associated with increased expression of fibrinogen complex transcripts. The discrimination power of fibrinogen was confirmed by cross-validation on two independent cohorts. Thus, our study highlights variations in gene expression between clinical and subclinical borderline changes despite similar histological findings. The data also support a recommendation for frequent patient monitoring, especially in those with borderline changes who received grafts from older donors.
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$a Gueler, Faikah $u Department of Nephrology, Hannover Medical School, Hannover, Germany.
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$a Krejčík, Zdeněk $u Institute of Hematology and Blood Transfusion, Prague, Czech Republic.
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$a Stránecký, Viktor $u Institute of Inherited Metabolic Disorders, 1st Faculty of Medicine Charles University and General Faculty Hospital, Prague, Czech Republic. $7 xx0128943
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$a Svobodová, Eva $u Department of Immunogenetics, Institute for Clinical and Experimental Medicine, Prague, Czech Republic.
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$a Gwinner, Wilfried $u Department of Nephrology, Hannover Medical School, Hannover, Germany.
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