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MicroRNAs Differentiate Between Antibody and T-Cell Mediated Renal Allograft Rejection

van den Bosch, Thierry1; Clahsen-van Groningen, Marian C.2; Rezaee, Farhad3; Nieboer, Daan4; Steyerberg, Ewout W.4; Baan, Carla C.1; Rowshani, Ajda T.1

doi: 10.1097/

1Internal Medicine, section of Nephrology and Transplantation, Erasmus University Medical Center, Rotterdam, Netherlands; 2Pathology, Erasmus University Medical Center, Rotterdam, Netherlands; 3Gastroenterology and Hepatology, Erasmus University Medical Center, Rotterdam, Netherlands; 4Public Health, Erasmus University Medical Center, Rotterdam, Netherlands.

MicroRNAs are important immune regulators of gene and protein expression. Both circulating and intragraft expression of microRNAs have been related to renal allograft rejection. To determine the mechanisms that control cellular and antibody mediated rejection, we hypothesized that miRNA expression as (post)transcriptional regulator of gene expression could be different between rejection subtypes. In this study, we investigated microRNA tissue expression of different histopathological types of kidney allograft rejection according to Banff 2013, i.e. to analyse the differences between acute cellular rejection, and acute and chronic antibody mediated rejection. Results of such a study would help detect new biomarkers.

Microarray experiments and semi quantitative real-time reverse transcription polymerase chain reaction (QPCR) were performed using total RNA isolated from 46 fresh-frozen renal allograft biopsies showing rejection. Initial microarray analysis (miRCURY LNA™ microRNA Array platform, Exiqon) and subsequent QPCR revealed 5 microRNAs with significantly differential expression between the rejection biopsies.

Expression levels of miR-155 and miR-21 were significantly downregulated in acute antibody mediated rejection group (n = 9) compared to acute cellular rejection biopsies (n = 24) (p = <0.05) whereas miR-195 was upregulated (p = <0.05). miR-21 was significantly downregulated in chronic antibody mediated rejection group (n = 13) compared to acute antibody mediated rejection biopsies (p = <0.001). The specific cell sources in rejecting kidney biopsies are now being investigated, as miR-155 and miR-21 has been repeatedly associated with the monocyte-macrophage lineage cells.

We found significant differences in expression of miR-155, miR-21 and miRNA195 between antibody mediated and cellular rejection. Future validation studies are needed to confirm these data.

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