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)(1996)(1997)(1998)(1999)(2000)(2001)(2002)(2003)(2004)(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 ¼ 0.88, p < 0.0000001). In the validation set, MT-1 expression was also significantly associated with steroid resistance (p ¼ 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 antiinflammatory effect of the glucocorticoid receptor.

Inflammatory macrophage–associated 3-gene signature predicts subclinical allograft injury and graft survival

“…The data sets comprised 1,697 biopsy samples from renal (11 data sets, 1,571 samples), cardiac (3 data sets, 94 samples), and lung transplants (1 data set, 32 samples; Table 1). Four of these data sets included only protocol biopsies (7,(17)(18)(19)(20), six included only for-cause biopsies (21)(22)(23)(24)(25)(26), and five included both protocol and for-cause biopsies (7,(27)(28)(29). We curated each data set to identify allograft biopsies from AR and stable (STA) patients.…”

Beneficial Immune Effects of Myeloid-Related Proteins in Kidney Transplant Rejection

“…Gene expression profiles were analyzed for 36 AR biopsy samples using Illumina HumanRef‐8 v3.0 BeadChips (Illumina, San Diego, CA) and Illumina GenomeStudio software . Samples had an RNA quality index >8.…”

Ex vivo perfusion induces a time- and perfusate-dependent molecular repair response in explanted porcine lungs

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