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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 non-response 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. Transcriptional profiles of 40 renal allograft biopsy samples were analyzed using Illumina HumanRef-8 v3.0 BeadChips (Illumina, San Diego, CA). Expression profiles were investigated in total RNA isolated from biopsy samples of 18 patients with steroid responsive acute rejection and 18 patients with steroid resistant acute rejection. Four biopsies, taken during acute decrease of graft function but with no histomorphologic indication of rejection, were included as controls.

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PROVIDER: S-DIXA-D-1152 | biostudies-other |

REPOSITORIES: biostudies-other

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Project description: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 non-response 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. Transcriptional profiles of 40 renal allograft biopsy samples were analyzed using Illumina HumanRef-8 v3.0 BeadChips (Illumina, San Diego, CA). Expression profiles were investigated in total RNA isolated from biopsy samples of 18 patients with steroid responsive acute rejection and 18 patients with steroid resistant acute rejection. Four biopsies, taken during acute decrease of graft function but with no histomorphologic indication of rejection, were included as controls.

Project description:BACKGROUND:Cardiovascular disease (CVD) due to atherosclerosis is a major cause of death in renal allograft recipients. Recently, C1q/TNF-? related protein-9 (CTRP9), which is a paralog of adiponectin (ADPN), has been suggested to be related to the prevention of atherosclerosis and the occurrence of CVD, but this relationship has not been confirmed in renal allograft recipients. SUBJECTS AND METHODS:The relationships among the serum CTRP9 concentration, serum ADPN concentration, and vascular calcification were investigated in 50 kidney transplantation recipients at our hospital. Calcification of the abdominal aorta was evaluated according to the aortic calcification area index (ACAI) calculated from CT images. Changes in the serum CTRP9 and ADPN fractions and ACAI were examined for 8 years. In addition, the expression of CTRP9 and ADPN and their respective receptors AdipoR1 and R2 in muscular arteries of the kidney was examined by immunofluorescence. RESULTS:In renal allograft recipients, the serum CTRP9 concentration at the start of the observation was not significant correlated with eGFR or serum high-molecular-weight (HMW)-ADPN concentration (rS = -0.009, p = 0.950; rS = -0.226, p = 0.114, respectively). However, the change in the serum CTRP9 concentration was positively correlated with the change in the serum HMW-ADPN concentration (rS = 0.315, p = 0.026) and negatively correlated with the change in ACAI (rS = -0.367, p = 0.009). Multiple regression analysis revealed that the serum HMW-ADPN concentration was a significant positive factor for the change in the serum CTRP9 concentration. Moreover, for ACAI, an increase in the serum CTRP9 concentration was an improving factor, but aging was an exacerbating factor. Furthermore, colocalization of CTRP9 and AdipoR1 was noted in the luminal side of intra-renal arterial intima. CONCLUSION:In renal allograft recipients, both CTRP9 and HMW-ADPN were suggested to prevent the progression of aortic calcification through AdipoR1.

Project description:BackgroundMycophenolic acid (MPA) is widely used as part of immunosuppressive regimens following allograft transplantation. The large pharmacokinetic (PK) and pharmacodynamic (PD) variability and narrow therapeutic range of MPA provide a potential for therapeutic drug monitoring. The objective of this pilot study was to investigate the MPA PK and PD relation in combination with belatacept (2nd generation CTLA4-Ig) or cyclosporine (CsA).MethodsSeven renal allograft recipients were randomized to either belatacept (n = 4) or cyclosporine (n = 3) based immunosuppression. Samples for MPA PK and PD evaluations were collected predose and at 1, 2 and 13 weeks posttransplant. Plasma concentrations of MPA were determined by HPLC-UV. Activity of inosine monophosphate dehydrogenase (IMPDH) and the expressions of two IMPDH isoforms were measured in CD4+ cells by HPLC-UV and real-time reverse-transcription PCR, respectively. Subsets of T cells were characterized by flow cytometry.ResultsThe MPA exposure tended to be higher among belatacept patients than in CsA patients at week 1 (P = 0.057). Further, MPA concentrations (AUC0-9 h and C0) increased with time in both groups and were higher at week 13 than at week 2 (P = 0.031, n = 6). In contrast to the postdose reductions of IMPDH activity observed early posttransplant, IMPDH activity within both treatment groups was elevated throughout the dosing interval at week 13. Transient postdose increments were also observed for IMPDH1 expression, starting at week 1. Higher MPA exposure was associated with larger elevations of IMPDH1 (r = 0.81, P = 0.023, n = 7 for MPA and IMPDH1 AUC0-9 h at week 1). The maximum IMPDH1 expression was 52 (13-177)% higher at week 13 compared to week 1 (P = 0.031, n = 6). One patient showed lower MPA exposure with time and did neither display elevations of IMPDH activity nor IMPDH1 expression. No difference was observed in T cell subsets between treatment groups.ConclusionThe significant influence of MPA on IMPDH1 expression, possibly mediated through reduced guanine nucleotide levels, could explain the elevations of IMPDH activity within dosing intervals at week 13. The present regulation of IMPDH in CD4+ cells should be considered when interpreting measurements of IMPDH inhibition.

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Increased metallothionein expression reflects steroid resistance in renal allograft recipients.

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