title: Molecular pathogenesis of post-transplant acute kidney injury: assessment of whole-genome mRNA and miRNA profiles.
abstract: Acute kidney injury (AKI) affects roughly 25% of all recipients of deceased donor organs. The prevention of post-transplant AKI is still an unmet clinical need. We prospectively collected zero-hour, indication as well as protocol kidney biopsies from 166 allografts between 2011 and 2013. In this cohort eight cases with AKI and ten matched allografts without pathology serving as control group were identified with a follow-up biopsy within the first twelve days after engraftment. For this set the zero-hour and follow-up biopsies were subjected to genome wide microRNA and mRNA profiling and analysis, followed by validation in independent expression profiles of 42 AKI and 21 protocol biopsies for strictly controlling the false discovery rate. Follow-up biopsies of AKI allografts compared to time-matched protocol biopsies, further baseline adjustment for zero-hour biopsy expression level and validation in independent datasets, revealed a molecular AKI signature holding 20 mRNAs and two miRNAs (miR-182-5p and miR-21-3p). Next to several established biomarkers such as lipocalin-2 also novel candidates of interest were identified in the signature. In further experimental evaluation the elevated transcript expression level of the secretory leukocyte peptidase inhibitor (SLPI) in AKI allografts was confirmed in plasma and urine on the protein level (p<0.001 and p = 0.003, respectively). miR-182-5p was identified as a molecular regulator of post-transplant AKI, strongly correlated with global gene expression changes during AKI. In summary, we identified an AKI-specific molecular signature providing the ground for novel biomarkers and target candidates such as SLPI and miR-182-5p in addressing AKI.
authors.affiliation: Department of Nephrology and Dialysis, Medical University Vienna, Vienna, Austria; Department of Nephrology and Transplantation, KH Elisabethinen, Linz, Austria.
authors.forename: Julia
authors.initials: J
authors.lastname: Wilflingseder
authors.affiliation: Department of Nephrology and Transplantation, KH Elisabethinen, Linz, Austria.
authors.forename: Judith
authors.initials: J
authors.lastname: Sunzenauer
authors.affiliation: Department of Transplantation and Surgery, Semmelweis University, Budapest, Hungary.
authors.forename: Eva
authors.initials: E
authors.lastname: Toronyi
authors.affiliation: emergentec biodevelopment GmbH, Vienna, Austria.
authors.forename: Andreas
authors.initials: A
authors.lastname: Heinzel
authors.affiliation: Department of Nephrology and Dialysis, Medical University Vienna, Vienna, Austria; Department of Nephrology and Transplantation, KH Elisabethinen, Linz, Austria.
authors.forename: Alexander
authors.initials: A
authors.lastname: Kainz
authors.affiliation: emergentec biodevelopment GmbH, Vienna, Austria.
authors.forename: Bernd
authors.initials: B
authors.lastname: Mayer
authors.affiliation: emergentec biodevelopment GmbH, Vienna, Austria.
authors.forename: Paul
authors.initials: P
authors.lastname: Perco
authors.affiliation: Department of Transplantation and Surgery, Semmelweis University, Budapest, Hungary.
authors.forename: Gábor
authors.initials: G
authors.lastname: Telkes
authors.affiliation: Department of Transplantation and Surgery, Semmelweis University, Budapest, Hungary.
authors.forename: Robert M
authors.initials: RM
authors.lastname: Langer
authors.affiliation: Department of Nephrology and Dialysis, Medical University Vienna, Vienna, Austria; Department of Nephrology and Transplantation, KH Elisabethinen, Linz, Austria.
authors.forename: Rainer
authors.initials: R
authors.lastname: Oberbauer
mesh_terms: D058186:Acute Kidney Injury / Q000097:blood / Q000209:etiology* / Q000235:genetics* / Q000652:urine; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D019540:Area Under Curve; D015415:Biomarkers / Q000097:blood / Q000652:urine; D016022:Case-Control Studies; D030541:Databases, Genetic; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D020869:Gene Expression Profiling; D015894:Genome, Human; D006801:Humans; D016030:Kidney Transplantation / Q000009:adverse effects*; D008297:Male; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D008875:Middle Aged; D010641:Phenotype; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015203:Reproducibility of Results; D053481:Secretory Leukocyte Peptidase Inhibitor / Q000378:metabolism; D014019:Tissue Donors; D055815:Young Adult
chemical_list: D015415:Biomarkers; D035683:MicroRNAs; D012333:RNA, Messenger; C506814:SLPI protein, human; D053481:Secretory Leukocyte Peptidase Inhibitor
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