Molecular Patterns Discriminate Accommodation and Subclinical Antibody-mediated Rejection in Kidney Transplantation
Language English Country United States Media print
Document type Journal Article, Multicenter Study, Observational Study, Research Support, Non-U.S. Gov't
- MeSH
- ABO Blood-Group System immunology MeSH
- Allografts immunology metabolism pathology MeSH
- Biomarkers metabolism MeSH
- Biopsy MeSH
- Adult MeSH
- HLA Antigens immunology MeSH
- Isoantibodies immunology MeSH
- Kidney immunology metabolism pathology MeSH
- Middle Aged MeSH
- Humans MeSH
- Membrane Transport Proteins metabolism MeSH
- Metallothionein metabolism MeSH
- Young Adult MeSH
- Follow-Up Studies MeSH
- Blood Group Incompatibility diagnosis immunology pathology MeSH
- Graft Survival immunology MeSH
- Graft Rejection diagnosis immunology pathology MeSH
- Retrospective Studies MeSH
- Aged MeSH
- Gene Expression Profiling MeSH
- Kidney Transplantation adverse effects MeSH
- Check Tag
- Adult MeSH
- Middle Aged MeSH
- Humans MeSH
- Young Adult MeSH
- Male MeSH
- Aged MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Multicenter Study MeSH
- Observational Study MeSH
- Research Support, Non-U.S. Gov't MeSH
- Names of Substances
- ABO Blood-Group System MeSH
- Biomarkers MeSH
- HLA Antigens MeSH
- Isoantibodies MeSH
- Membrane Transport Proteins MeSH
- Metallothionein MeSH
BACKGROUND: Accommodation in ABO-incompatible (ABOi) transplantation and subclinical antibody-mediated rejection in HLA-incompatible (HLAi) transplantation share several morphological similarities. Because the clinical long-term outcomes differ, we hypothesized different molecular processes involved in ABOi transplantation and subclinical antibody-mediated rejection. METHODS: Using Illumina Human HT-12 v4 Expression BeadChips, the whole transcriptome was evaluated based on 3-month protocol C4d+ biopsies in otherwise stable ABOi and HLAi kidney grafts, as well as in C4d-negative HLA-compatible grafts exhibiting normal histological findings. Top differently regulated genes were further validated using real-time quantitative polymerase chain reaction in another patient cohort and complement regulatory proteins by immunohistochemistry. RESULTS: In the case of genes involved in immune response-related biological processes, ABOi and HLAi cohorts had similar transcriptomic profiles to C4d-negative controls. The majority of deregulated genes in the ABOi and HLAi groups consisted of metallothioneins and epithelial transporter genes. Increased expression of epithelial transporters (SLC4A1, SLC4A9, SLC17A3, SLC12A3, and SLC30A2) and class 1 metallothioneins (MT1F, MT1G, and MT1X) in HLAi transplantation was validated by real-time quantitative polymerase chain reaction. In comparison to controls, both incompatible cohorts were characterized by the upregulation of intrarenal complement regulatory genes. CD46 and CD59 transcripts were increased in the ABOi cohort, whereas CD46 solely in HLAi group, and CD59 protein expression was similar in both incompatible groups. CONCLUSIONS: Several epithelial transporters and metallothioneins discriminate subclinical antibody-mediated rejection in HLAi transplantation from accommodation in ABOi transplantation, which suggest different involved downstream mechanisms and increased risk of injury in HLAi settings. Metallothioneins with their antioxidative properties may help to attenuate the inflammation response induced by donor-specific anti-HLA antibody binding.
Department of Genomics Institute of Hematology and Blood Transfusion Prague Czech Republic
Department of Nephrology Hannover Medical School Hannover Germany
Department of Nephrology Institute for Clinical and Experimental Medicine Prague Czech Republic
Department of Pathology Hannover Medical School Hannover Germany
Transplant Laboratory Institute for Clinical and Experimental Medicine Prague Czech Republic
Transplant Surgery Department Institute for Clinical and Experimental Medicine Prague Czech Republic
References provided by Crossref.org
Antibody-mediated rejection of renal allografts: diagnostic pitfalls and challenges
