供体基因型及移植肾内CYP3A5的表达反映急性肾移植排斥反应期间对类固醇治疗的反应。

Donor Genotype and Intragraft Expression of CYP3A5 Reflect the Response to Steroid Treatment During Acute Renal Allograft Rejection.

作者信息

Rekers Niels Vincent, Flaig Tanja M, Mallat Marko J K, Spruyt-Gerritse Marijke J, Zandbergen Malu, Anholts Jacqueline D H, Bajema Ingeborg M, Clahsen-van Groningen Marian C, Yang Jianxin, de Fijter Johan W, Claas Frans H J, Brakemeier Susanne, Lachmann Nils, Kreutz Reinhold, de Heer Emile, Budde Klemens, Bolbrinker Juliane, Eikmans Michael

机构信息

1 Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, the Netherlands. 2 Obesity R&D Center, Novo Nordisk Inc., Seattle, WA. 3 Institute of Clinical Pharmacology and Toxicology, Charité-Universitätsmedizin Berlin, Charité Campus Mitte, Berlin, Germany. 4 Department of Nephrology, Leiden University Medical Center, Leiden, the Netherlands. 5 Department of Pathology, Leiden University Medical Center, Leiden, the Netherlands. 6 Department of Pathology, Erasmus Medical Center, Rotterdam, the Netherlands. 7 Department of Nephrology, Charité-Universitätsmedizin Berlin, Charité Campus Mitte, Berlin, Germany. 8 HLA Laboratory, Charité-Universitätsmedizin Berlin, Charité Campus Mitte, Berlin, Germany.

出版信息

Transplantation. 2017 Sep;101(9):2017-2025. doi: 10.1097/TP.0000000000001584.

DOI:10.1097/TP.0000000000001584

PMID:27926596

Abstract

BACKGROUND

Glucocorticoid (GC)-refractory acute rejection (AR) is a risk factor for inferior renal allograft outcome. We investigated genetic predisposition to the response to steroid treatment of acute allograft rejection.

METHODS

Single nucleotide polymorphisms of genes involved in GC signaling (GR, GLCCI1) and drug metabolism and transport (CYP3A5, ABCB1, and PXR) were analyzed in kidney transplant recipients (1995-2005, Leiden cohort, n = 153) treated with methylprednisolone. Significant associations were verified in a second cohort (Berlin cohort, n = 66).

RESULTS

Patients who received a CYP3A51 allele expressing allograft had a lower risk of resistance to methylprednisolone during AR (odds ratio, 0.29; 95% confidence interval, 0.11-0.79; P = 0.016 in combined cohorts analysis). No differences were observed for GC signaling or other drug metabolism/transport-related genes. Both before transplantation (n = 69) and at time of AR (n = 88), tissue CYP3A5 mRNA expression was significantly higher in CYP3A51 allele expressing donor kidneys than in CYP3A5*3/*3 allografts (P < 0.00001). Moreover, steroid-responsive patients (n = 64) expressed significantly higher intragraft CYP3A5 mRNA levels compared to steroid-refractory patients (n = 42) in AR (P = 0.006).

CONCLUSIONS

CYP3A5 protein expression was detected in tubular epithelial cells and inflammatory cells within the grafts. Our findings show that steroid resistance during AR is associated with donor genotype and intragraft expression levels of CYP3A5.

摘要

背景

糖皮质激素（GC）难治性急性排斥反应（AR）是肾移植预后不良的一个危险因素。我们研究了急性移植排斥反应对类固醇治疗反应的遗传易感性。

方法

对接受甲基泼尼松龙治疗的肾移植受者（1995 - 2005年，莱顿队列，n = 153）进行GC信号通路相关基因（GR、GLCCI1）以及药物代谢和转运相关基因（CYP3A5、ABCB1和PXR）的单核苷酸多态性分析。在第二个队列（柏林队列，n = 66）中验证显著关联。

结果

接受表达CYP3A51等位基因同种异体移植物的患者在AR期间对甲基泼尼松龙耐药的风险较低（优势比，0.29；95%置信区间，0.11 - 0.79；联合队列分析中P = 0.016）。在GC信号通路或其他药物代谢/转运相关基因方面未观察到差异。在移植前（n = 69）和AR时（n = 88），表达CYP3A51等位基因的供体肾组织中CYP3A5 mRNA表达均显著高于CYP3A5*3/*3同种异体移植物（P < 0.000,01）。此外，在AR中，类固醇反应性患者（n = 64）的移植物内CYP3A5 mRNA水平显著高于类固醇难治性患者（n = 42）（P = 0.006）。