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

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

Author information

1
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.

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 CYP3A5*1 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 CYP3A5*1 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.

PMID:
27926596
DOI:
10.1097/TP.0000000000001584
[Indexed for MEDLINE]

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