DNA Hypermethylation Caused by Ischemia in Kidney Transplants Predicts Future Chronic Injury to the Allograft.

L. Heylen,^1,2,3,4 B. Thienpont,^3,4 M. Naesens,^1,2 J. Depreeuw,^3,4 P. Busschaert,^3,4 D. Kuypers,^1,2 I. Jochmans,^2,5 D. Monbaliu,^2,5 J. Pirenne,^2,5 D. Lambrechts,^3,4 B. Sprangers.^1,2

¹Nephrology, University Hospitals Leuven, Leuven, Belgium
²Microbiology and Immunology, KU Leuven, Leuven, Belgium
³Oncology, KU Leuven, Leuven, Belgium
⁴VIB, Leuven, Belgium
⁵Abdominal Transplant Surgery, University Hospitals Leuven, Leuven, Belgium

Meeting: 2017 American Transplant Congress

Abstract number: B118

Keywords: Fibrosis, Genomics, Ischemia, Kidney transplantation

Session Information

Session Name: Poster Session B: Ischemic Injury and Organ Preservation Session II

Session Type: Poster Session

Date: Sunday, April 30, 2017

Session Time: 6:00pm-7:00pm

Presentation Time: 6:00pm-7:00pm

Location: Hall D1

Study Purpose: DNA demethylation results from hydroxymethylation and is inhibited by hypoxia. We investigated whether ischemia during kidney transplantation induces DNA methylation changes of the transplant and whether these changes are involved in future chronic injury.

Methods: Genome-wide DNA methylation levels were measured in 3 cohorts of brain-dead donor kidney transplant biopsies: 1) both at procurement in the donor (before ischemia) and after ischemia and reperfusion (n=2×13), using Illumina EPIC BeadChips, 2) at implantation (i.e. after cold ischemia time) (n=82), using Illumina EPIC BeadChips, 3) after implantation and reperfusion (n=46), with the Illumina 450K BeadChips. In the first paired cohort, DNA hydroxymethylation levels were measured by TAB-chip using EPIC BeadChips.

Results: In the paired cohort, DNA methylation levels increased after ischemia, both overall (P<0.001 for all transplant pairs), in individual CpG's and on CpG island level (binomial test P<0.001 for both). This was accompanied by a loss in hydroxymethylation (P<0.001 for all transplant pairs). In most CpG's showing ischemia-induced hypermethylation (82%), hydroxymethylation decreased. In the implantation cohort, cold ischemia time mostly associated with hypermethylation of CpG's and CpG islands, adjusted for donor gender and age (binomial test P<0.001 for both). The CpG's in the islands that were significantly hypermethylated (FDR P<0.05) following ischemia in both cohorts associated with future chronic injury of the graft (as defined by the CADI score at 12 months) adjusted for donor age and gender, while CpG's in other islands were less associated (chi square P<0.001). This was confirmed in the third post-reperfusion cohort (chi-square P<0.001).

Conclusion: Ischemia during transplantation reduces DNA hydroxymethylation and induces DNA hypermethylation in the kidney transplant. These DNA methylation changes are associated with future chronic injury to the graft.

CITATION INFORMATION: Heylen L, Thienpont B, Naesens M, Depreeuw J, Busschaert P, Kuypers D, Jochmans I, Monbaliu D, Pirenne J, Lambrechts D, Sprangers B. DNA Hypermethylation Caused by Ischemia in Kidney Transplants Predicts Future Chronic Injury to the Allograft. Am J Transplant. 2017;17 (suppl 3).

To cite this abstract in AMA style:

Heylen L, Thienpont 4B, Naesens M, Depreeuw J, Busschaert P, Kuypers D, Jochmans I, Monbaliu D, Pirenne J, Lambrechts D, Sprangers B. DNA Hypermethylation Caused by Ischemia in Kidney Transplants Predicts Future Chronic Injury to the Allograft. [abstract]. Am J Transplant. 2017; 17 (suppl 3). https://atcmeetingabstracts.com/abstract/dna-hypermethylation-caused-by-ischemia-in-kidney-transplants-predicts-future-chronic-injury-to-the-allograft/. Accessed November 21, 2024.

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