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Inflammation in the setting of chronic allograft dysfunction post-kidney transplant: phenotype and genotype.

ABSTRACT: Chronic allograft dysfunction (CGD) is a common outcome in kidney transplants, but its pathogenesis is unclear. We investigated the CGD phenotype and single-nucleotide polymorphisms (SNPs) associated with CGD.This prospective study enrolled 2336 transplants from seven transplant centers in North America. CGD was defined as a >25% rise in serum creatinine relative to a three-month post-transplant baseline, requiring a kidney biopsy. We genotyped 2724 SNPs in the initial 979 transplants, which form the test cohort.CGD occurred 11.2 times per 100 person-years at a median of 509 ± 387 days from the three-month baseline. CGD was independently associated with death-censored, allograft failure, in an adjusted analysis [HR=20.6 (11.8-35.8, p < 0.001)]. Among 366 transplant recipients with CGD, 91% had inflammation on biopsy scores. 94 (26%) had inflammatory changes consistent with a diagnosis of concomitant acute rejection. SNPs in FM06 and FM03, potential drug metabolism genes, were associated with CGD, after accounting for multiple testing.CGD phenotype with concomitant inflammation is associated with increased risk of allograft failure. SNPs associated with CGD in novel drug metabolism and transport genes, will be validated in subsequent transplants.

SUBMITTER: Israni AK

PROVIDER: S-EPMC3647022 | biostudies-literature | 2013 May-Jun

REPOSITORIES: biostudies-literature

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Inflammation in the setting of chronic allograft dysfunction post-kidney transplant: phenotype and genotype.

Israni Ajay K AK Leduc Robert R Jacobson Pamala A PA Wildebush Winston W Guan Weihua W Schladt David D Matas Arthur J AJ Oetting William S WS

Clinical transplantation 20130127 3

<h4>Background</h4>Chronic allograft dysfunction (CGD) is a common outcome in kidney transplants, but its pathogenesis is unclear. We investigated the CGD phenotype and single-nucleotide polymorphisms (SNPs) associated with CGD.<h4>Method</h4>This prospective study enrolled 2336 transplants from seven transplant centers in North America. CGD was defined as a >25% rise in serum creatinine relative to a three-month post-transplant baseline, requiring a kidney biopsy. We genotyped 2724 SNPs in the ...[more]

PMID: 23350966

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Project description:Background Ischemia during kidney transplant causes chronic allograft injury and adversely affects outcome, but the underlying mechanisms are incompletely understood. In tumors, oxygen shortage reduces the DNA demethylating activity of the ten-11 translocation (TET) enzymes, yielding hypermethylated genomes that promote tumor progression. We investigated whether ischemia similarly induces DNA hypermethylation in kidney transplants and contributes to chronic injury.Methods We profiled genome-wide DNA methylation in three cohorts of brain-dead donor kidney allograft biopsy specimens: a longitudinal cohort with paired biopsy specimens obtained at allograft procurement (preischemia; n=13), after implantation and reperfusion (postischemia; n=13), and at 3 or 12 months after transplant (n=5 each); a cross-sectional cohort with preimplantation biopsy specimens (n=82); and a cross-sectional cohort with postreperfusion biopsy specimens (n=46).Results Analysis of the paired preischemia and postischemia specimens revealed that methylation increased drastically in all allografts on ischemia. Hypermethylation was caused by loss of 5-hydroxymethylcytosine, the product of TET activity, and it was stable 1 year after transplant. In the preimplantation cohort, CpG hypermethylation directly correlated with ischemia time and for some CpGs, increased 2.6% per additional hour of ischemia. Hypermethylation preferentially affected and reduced the expression of genes involved in suppressing kidney injury and fibrosis. Moreover, CpG hypermethylation in preimplantation specimens predicted chronic injury, particularly fibrosis and glomerulosclerosis, 1 year after transplant. This finding was validated in the independent postreperfusion cohort, in which hypermethylation also predicted reduced allograft function 1 year after transplant, outperforming established clinical variables.Conclusions We highlight a novel epigenetic basis for ischemia-induced chronic allograft injury with biomarker potential.

Dataset Information

Inflammation in the setting of chronic allograft dysfunction post-kidney transplant: phenotype and genotype.

Publications

Inflammation in the setting of chronic allograft dysfunction post-kidney transplant: phenotype and genotype.

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