title: Identification of the activating cytotoxicity receptor NKG2D as a senescence marker in zero-hour kidney biopsies is indicative for clinical outcome.
abstract: The definition of biological donor organ age rather than chronological age seems obvious for the establishment of a valid pre-transplant risk assessment. Therefore, we studied gene expression for candidate markers in 60 zero-hour kidney biopsies. Compared with 29 younger donors under age 55, 31 elderly donors age 55 and older had significant mRNA expression for immunoproteasome subunits (PSMB8, PSMB9 and PSMB10), HLA-DRB, and transcripts of the activating cytotoxicity receptor NKG2D. Gene expression was validated in an independent donor cohort consisting of 37 kidneys from donors 30 years and under (Group I), 75 kidneys from donors age 31-54 years (Group II) and 75 kidneys from donors age 55 and older (Group III). Significant gene induction was confirmed in kidneys from Group III for PSMB9 and PSMB10. Strikingly, transcripts of NKG2D had the significantly highest gene induction in Group III versus Group II and Group I. Similar results were obtained for CDKN2A, but not for telomere length. Both NKG2D and CDKN2A mRNA expression were significantly correlated with creatinine levels at 24 months after transplantation. Univariate regression analysis showed significant predictive power regarding graft function at 6 and 12 months for NKG2D and CDKN2A. However, only NKG2D remained significantly predictive in the multivariate model at 12 months. Thus, our results reveal novel candidate markers in aged renal allografts, which could be helpful in the assessment of organ quality.
authors.affiliation: Center of Operative Medicine, Department for Visceral, Transplant and Thoracic Surgery, Innsbruck Medical University, Austria.
authors.forename: Julia
authors.initials: J
authors.lastname: Günther
authors.affiliation: Center of Operative Medicine, Department for Visceral, Transplant and Thoracic Surgery, Innsbruck Medical University, Austria.
authors.forename: Thomas
authors.initials: T
authors.lastname: Resch
authors.affiliation: Division of Bioinformatics, Biocenter, Innsbruck Medical University.
authors.forename: Hubert
authors.initials: H
authors.lastname: Hackl
authors.affiliation: Department for General, Visceral and Transplantation Surgery, Charité-Universitätsmedizin, Berlin, Germany.
authors.forename: Arne
authors.initials: A
authors.lastname: Sattler
authors.affiliation: Center of Operative Medicine, Department for Visceral, Transplant and Thoracic Surgery, Innsbruck Medical University, Austria.
authors.forename: Susanne
authors.initials: S
authors.lastname: Ebner
authors.affiliation: Department for General, Visceral and Transplantation Surgery, Charité-Universitätsmedizin, Berlin, Germany.
authors.forename: Paul Viktor
authors.initials: PV
authors.lastname: Ritschl
authors.affiliation: Department for General, Visceral and Transplantation Surgery, Charité-Universitätsmedizin, Berlin, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Biebl
authors.affiliation: Department for General, Visceral and Transplantation Surgery, Charité-Universitätsmedizin, Berlin, Germany.
authors.forename: Robert
authors.initials: R
authors.lastname: Öllinger
authors.affiliation: Center of Operative Medicine, Department for Visceral, Transplant and Thoracic Surgery, Innsbruck Medical University, Austria.
authors.forename: Stefan
authors.initials: S
authors.lastname: Schneeberger
authors.affiliation: Department of Plastic and Reconstructive Surgery, Vascularized Composite Allotransplantation Laboratory, John Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Gerald
authors.initials: G
authors.lastname: Brandacher
authors.affiliation: Center of Operative Medicine, Department for Visceral, Transplant and Thoracic Surgery, Innsbruck Medical University, Austria.
authors.forename: Hubert
authors.initials: H
authors.lastname: Schwelberger
authors.affiliation: Institute for Pathology, Innsbruck Medical University.
authors.forename: Bettina
authors.initials: B
authors.lastname: Zelger
authors.affiliation: ZTB Zentrum für Transfusionsmedizin und Zelltherapie Berlin, HLA Tissue Typing Laboratory, Berlin, Germany.
authors.forename: Diana
authors.initials: D
authors.lastname: Stauch
authors.affiliation: Department for General, Visceral and Transplantation Surgery, Charité-Universitätsmedizin, Berlin, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Pascher
authors.affiliation: Department for General, Visceral and Transplantation Surgery, Charité-Universitätsmedizin, Berlin, Germany.
authors.forename: Johann
authors.initials: J
authors.lastname: Pratschke
authors.affiliation: Department for General, Visceral and Transplantation Surgery, Charité-Universitätsmedizin, Berlin, Germany. Electronic address: katja.kotsch@charite.de.
authors.forename: Katja
authors.initials: K
authors.lastname: Kotsch
mesh_terms: D000328:Adult; D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D001317:Austria; D001706:Biopsy; D016922:Cellular Senescence; D019941:Cyclin-Dependent Kinase Inhibitor p16; D050763:Cyclin-Dependent Kinase Inhibitor p18 / Q000235:genetics; D003546:Cysteine Endopeptidases / Q000235:genetics; D051799:Delayed Graft Function / Q000235:genetics; D046148:Donor Selection; D005260:Female; D005786:Gene Expression Regulation; D005819:Genetic Markers; D005858:Germany; D006084:Graft Rejection / Q000235:genetics; D006085:Graft Survival; D059806:HLA-DR beta-Chains / Q000235:genetics; D006801:Humans; D007668:Kidney / Q000737:chemistry* / Q000473:pathology; D016030:Kidney Transplantation / Q000009:adverse effects / Q000379:methods*; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D055655:NK Cell Lectin-Like Receptor Subfamily K / Q000235:genetics*; D011237:Predictive Value of Tests; D046988:Proteasome Endopeptidase Complex / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics; D012307:Risk Factors; D059505:Telomere Homeostasis; D013997:Time Factors; D014019:Tissue Donors; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: C000614131:CDKN2A protein, human; D019941:Cyclin-Dependent Kinase Inhibitor p16; D050763:Cyclin-Dependent Kinase Inhibitor p18; D005819:Genetic Markers; D059806:HLA-DR beta-Chains; C527085:KLRK1 protein, human; D055655:NK Cell Lectin-Like Receptor Subfamily K; D012333:RNA, Messenger; C071313:LMP-2 protein; D003546:Cysteine Endopeptidases; C077436:LMP7 protein; C098948:PSMB10 protein, human; D046988:Proteasome Endopeptidase Complex
keywords: NKG2D; kidney; senescence; zero-hour biopsy