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Molecular Patterns Discriminate Accommodation and Subclinical Antibody-mediated Rejection in Kidney Transplantation

Hruba, Petra, PhD1; Krejcik, Zdenek, PhD2; Stranecky, Viktor, PhD3; Maluskova, Jana, MD4; Slatinska, Janka, MD5; Gueler, Faikah, MD, PhD6; Gwinner, Wilfried, MD, PhD6; Bräsen, Jan Hinrich, MD, PhD7; Wohlfahrtova, Mariana, MD, PhD5; Parikova, Alena, MD, PhD5; Osickova, Klara, MD5; Fronek, Jiri, MD, PhD8; Seda, Ondrej, MD, PhD9; Prefertusova, Lucie, MSc4; Honsova, Eva, MD, PhD4; Viklicky, Ondrej, MD, PhD1,5

doi: 10.1097/TP.0000000000002604
Original Basic Science—General
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Background. Accommodation in ABO-incompatible (ABOi) transplantation and subclinical antibody-mediated rejection in HLA-incompatible (HLAi) transplantation share several morphological similarities. Because the clinical long-term outcomes differ, we hypothesized different molecular processes involved in ABOi transplantation and subclinical antibody-mediated rejection.

Methods. Using Illumina Human HT-12 v4 Expression BeadChips, the whole transcriptome was evaluated based on 3-month protocol C4d+ biopsies in otherwise stable ABOi and HLAi kidney grafts, as well as in C4d-negative HLA-compatible grafts exhibiting normal histological findings. Top differently regulated genes were further validated using real-time quantitative polymerase chain reaction in another patient cohort and complement regulatory proteins by immunohistochemistry.

Results. In the case of genes involved in immune response–related biological processes, ABOi and HLAi cohorts had similar transcriptomic profiles to C4d-negative controls. The majority of deregulated genes in the ABOi and HLAi groups consisted of metallothioneins and epithelial transporter genes. Increased expression of epithelial transporters (SLC4A1, SLC4A9, SLC17A3, SLC12A3, and SLC30A2) and class 1 metallothioneins (MT1F, MT1G, and MT1X) in HLAi transplantation was validated by real-time quantitative polymerase chain reaction. In comparison to controls, both incompatible cohorts were characterized by the upregulation of intrarenal complement regulatory genes. CD46 and CD59 transcripts were increased in the ABOi cohort, whereas CD46 solely in HLAi group, and CD59 protein expression was similar in both incompatible groups.

Conclusions. Several epithelial transporters and metallothioneins discriminate subclinical antibody-mediated rejection in HLAi transplantation from accommodation in ABOi transplantation, which suggest different involved downstream mechanisms and increased risk of injury in HLAi settings. Metallothioneins with their antioxidative properties may help to attenuate the inflammation response induced by donor-specific anti-HLA antibody binding.

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

2 Department of Genomics, Institute of Hematology and Blood Transfusion, Prague, Czech Republic.

3 Research Unit for Rare Diseases, Department of Pediatrics and Adolescent Medicine, First Faculty of Medicine, Charles University, Prague, Czech Republic.

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

5 Department of Nephrology, Institute for Clinical and Experimental Medicine, Prague, Czech Republic.

6 Department of Nephrology, Hannover Medical School, Hannover, Germany.

7 Department of Pathology, Hannover Medical School, Hannover, Germany.

8 Transplant Surgery Department, Institute for Clinical and Experimental Medicine, Prague, Czech Republic.

9 Institute of Biology and Medical Genetics, First Faculty of Medicine, Charles University and General Teaching Hospital, Prague, Czech Republic.

Received 29 June 2018. Revision received 6 December 2018.

Accepted 6 December 2018.

The authors declare no conflicts of interest.

This work was supported by the Grant Agency of the Ministry of Health of the Czech Republic (grant 15-26865A).

O.V. contributed to the design of the study. O.V., P.H., and M.W. participated in the writing of the manuscript. P.H., Z.K., F.G., W.G., J.H.B., J.S., K.O., J.F., A.P., J.M., L.P., and E.H. participated in the performance of the research. V.S., P.H., and O.S. participated in data analysis.

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).

Correspondence: Ondrej Viklicky, MD, PhD, Department of Nephrology, Transplant Center, Institute for Clinical and Experimental Medicine, Videnska 1958/9, 14021 Prague, Czech Republic. (ondrej.viklicky@ikem.cz).

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