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Tubular Atrophy and Low Netrin-1 Gene Expression Are Associated With Delayed Kidney Allograft Function

Wohlfahrtova, Mariana1,2; Brabcova, Irena2; Zelezny, Filip3; Balaz, Peter4; Janousek, Libor4; Honsova, Eva5; Lodererova, Alena5; Wohlfahrt, Peter1; Viklicky, Ondrej1,2,6

doi: 10.1097/TP.0b013e3182a95d04
Clinical and Translational Research

Background: Delayed graft function (DGF) caused by ischemia/reperfusion injury (I/RI) negatively influences the outcome of kidney transplantation. This prospective single-center study characterized the intrarenal transcriptome during I/RI as a means of identifying genes associated with DGF development.

Methods: Characterization of the intrarenal transcription profile associated with I/RI was carried out on three sequential graft biopsies from respective allografts before and during transplantation. The intragraft expression of 92 candidate genes was measured using quantitative real-time reverse transcriptase polymerase chain reaction (2−ΔΔCt) in delayed (n=9) and primary function allografts (n=26).

Results: Cold storage was not associated with significant changes to the expression profile of the target gene transcripts; however, up-regulation of 16 genes associated with enhanced activation of innate and adaptive immune responses and apoptosis was observed after reperfusion. Multivariate logistic regression analysis revealed that higher tubular atrophy scores (ct) together with a lower expression of Netrin-1 might predict DGF development (training area under the receiver operating curve=0.89, cross-validated area under the receiver operating curve=0.81).

Conclusions: Poor baseline tubular cell quality (defined by a higher rate of tubular atrophy) combined with the reduced potential of apoptotic survival factors represented by decreased Netrin-1 gene expression were associated with delayed kidney graft function.

Supplemental digital content is available in the article.

1 Department of Nephrology, Transplant Center, Institute for Clinical and Experimental Medicine, Prague, Czech Republic.

2 Transplant Laboratory, Transplant Center, Institute for Clinical and Experimental Medicine, Prague, Czech Republic.

3 Department of Cybernetics, Faculty of Electrical Engineering, Czech Technical University, Prague, Czech Republic.

4 Department of Transplant Surgery, Transplant Center, Institute for Clinical and Experimental Medicine, Prague, Czech Republic.

5 Clinical and Transplant Pathology Department, Transplant Center, Institute for Clinical and Experimental Medicine, Prague, Czech Republic.

6 Address correspondence to: Ondrej Viklicky, M.D., Ph.D., Department of Nephrology, Transplant Center, Institute for Clinical and Experimental Medicine, Videnska 1958/9, 14021 Prague, Czech Republic.

This work was supported by grants given to O.V. from Internal Grant Agency of the Ministry of Health of the Czech Republic NS10516-3/2009, NT11227-5/2010, and MZO 00023001 and by grant from the Grant Agency of the Czech Republic P301/11/1568. F.Z. was supported by the Czech Science Foundation project P202/12/2032.

The authors declare no conflicts of interest.

E-mail: ondrej.viklicky@ikem.cz

M.W. contributed to the hypothesis forming, data collection, expression and statistical data analysis and article writing. I.B. contributed to the expression data analysis. F.Z. contributed to the statistical data analysis. P.B. and L.J. contributed to the data collection. E.H. contributed to the histological evaluation of samples. A.L. contributed to the immunohistological evaluation of samples. P.W. contributed to the data analysis. O.V. contributed to the hypothesis forming, grant funding, results interpretation, and article writing.

Part of the work was presented at the American Transplant Congress 2012 in Boston.

Supplemental digital content (SDC) is available for this article. Direct URL citations appear in the printed text, and links to the digital files are provided in the HTML text of this article on the journal’s Web site (www.transplantjournal.com).

Received 15 April 2013. Revision requested 9 May 2013.

Accepted 15 August 2013.

Accepted October 3, 2013

© 2014 by Lippincott Williams & Wilkins