title: Increased metallothionein expression reflects steroid resistance in renal allograft recipients.
abstract: Steroid-refractory acute rejection is a risk factor for inferior renal allograft outcome. We aimed to gain insight into the mechanisms underlying steroid resistance by identifying novel molecular markers of steroid-refractory acute rejection. Eighty-three kidney transplant recipients (1995-2005), who were treated with methylprednisolone during a first acute rejection episode, were included in this study. Gene expression patterns were investigated in a discovery cohort of 36 acute rejection biopsies, and verified in a validation cohort of 47 acute rejection biopsies. In the discovery set, expression of metallothioneins (MT) was significantly (p < 0.000001) associated with decreased response to steroid treatment. Multivariate analysis resulted in a predictive model containing MT-1 as an independent covariate (AUC = 0.88, p < 0.0000001). In the validation set, MT-1 expression was also significantly associated with steroid resistance (p = 0.029). Metallothionein expression was detected in macrophages and tubular epithelial cells. Parallel to the findings in patients, in vitro experiments of peripheral blood mononuclear cells from 11 donors showed that nonresponse to methylprednisolone treatment is related to highly elevated MT levels. High expression of metallothioneins in renal allografts is associated with resistance to steroid treatment. Metallothioneins regulate intracellular concentrations of zinc, through which they may diminish the zinc-requiring anti-inflammatory effect of the glucocorticoid receptor.
authors.affiliation: Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, the Netherlands. n.v.rekers@lumc.nl
authors.forename: N V
authors.initials: NV
authors.lastname: Rekers
authors.forename: I M
authors.initials: IM
authors.lastname: Bajema
authors.forename: M J K
authors.initials: MJ
authors.lastname: Mallat
authors.forename: J D H
authors.initials: JD
authors.lastname: Anholts
authors.forename: Y J H
authors.initials: YJ
authors.lastname: de Vaal
authors.forename: M
authors.initials: M
authors.lastname: Zandbergen
authors.forename: G W
authors.initials: GW
authors.lastname: Haasnoot
authors.forename: E W
authors.initials: EW
authors.lastname: van Zwet
authors.forename: J W
authors.initials: JW
authors.lastname: de Fijter
authors.forename: F H J
authors.initials: FH
authors.lastname: Claas
authors.forename: M
authors.initials: M
authors.lastname: Eikmans
mesh_terms: D000893:Anti-Inflammatory Agents / Q000008:administration & dosage / Q000009:adverse effects; D015415:Biomarkers / Q000378:metabolism; D016022:Case-Control Studies; D041322:Chromosomes, Human, Y; D015331:Cohort Studies; D004351:Drug Resistance / Q000235:genetics*; D005260:Female; D020869:Gene Expression Profiling; D006084:Graft Rejection / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D007124:Immunoenzyme Techniques; D017403:In Situ Hybridization; D007676:Kidney Failure, Chronic / Q000235:genetics / Q000628:therapy*; D016030:Kidney Transplantation / Q000009:adverse effects*; D008297:Male; D008668:Metallothionein / Q000235:genetics* / Q000378:metabolism; D008775:Methylprednisolone / Q000008:administration & dosage / Q000009:adverse effects*; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D000893:Anti-Inflammatory Agents; D015415:Biomarkers; D012333:RNA, Messenger; D008668:Metallothionein; D008775:Methylprednisolone
keywords: Acute allograft rejection; biopsy specimen; gene expression; immunohistochemistry; kidney transplantation; steroid refractory rejection