A molecular signature for delayed graft function

Abstract

Chronic kidney disease and associated comorbidities (diabetes, cardiovascular diseases) manifest with an accelerated ageing phenotype, leading ultimately to organ failure and renal replacement therapy. This process can be modulated by epigenetic and environmental factors which promote loss of physiological function and resilience to stress earlier, linking biological age with adverse outcomes post‐transplantation including delayed graft function (DGF). The molecular features underpinning this have yet to be fully elucidated. We have determined a molecular signature for loss of resilience and impaired physiological function, via a synchronous genome, transcriptome and proteome snapshot, using human renal allografts as a source of healthy tissue as an in vivo model of ageing in humans. This comprises 42 specific transcripts, related through IFNγ signalling, which in allografts displaying clinically impaired physiological function (DGF) exhibited a greater magnitude of change in transcriptional amplitude and elevated expression of noncoding RNAs and pseudogenes, consistent with increased allostatic load. This was accompanied by increased DNA methylation within the promoter and intragenic regions of the DGF panel in preperfusion allografts with immediate graft function. Pathway analysis indicated that an inability to sufficiently resolve inflammatory responses was enabled by decreased resilience to stress and resulted in impaired physiological function in biologically older allografts. Cross‐comparison with publically available data sets for renal pathologies identified significant transcriptional commonality for over 20 DGF transcripts. Our data are clinically relevant and important, as they provide a clear molecular signature for the burden of “wear and tear” within the kidney and thus age‐related physiological capability and resilience.

Metabolic Flexibility and Innate Immunity in Renal Ischemia Reperfusion Injury: The Fine Balance Between Adaptive Repair and Tissue Degeneration

“…It seemed that cellular stress and restoration of physiological homeostasis (i.e., regeneration) was exacerbated in patients who developed DGF. At the protein level, DGF and perfusion status were associated with a state of cellular senescence (163). Altogether, the data from this study put PRR signaling, cell death and survival signaling, cellular stress and fitness, an exacerbated regenerative response, and cellular senescence at the center stage in the development of human IRI, and the authors suggest that these events probably occur independently of (minor) genetic differences in PRR.…”

Assessment of Organ Quality in Kidney Transplantation by Molecular Analysis and Why It May Not Have Been Achieved, Yet

“…A majority of studies focused on DGF as a surrogate marker for organ quality and early outcome (46)(47)(48)(49)(50)(51)(52). They largely confirm the earlier findings that DGF is usually better predicted with molecular changes than histology or clinical scores at time of transplantation (46,(49)(50)(51)(52).…”

“…Consequently a number of studies focused on molecular markers for biological age as parameters for organ quality (50)(51)(52). In particular increased expression of CDKN2A associated with graft function, probably better reflecting the allostatic load of "wear and tear" of an organ and its resilience to cope with the peri-and post-transplant stressors (50-52).…”

Inflammaging and Complement System: A Link Between Acute Kidney Injury and Chronic Graft Damage

“…During transplantation, several stressors such as IRI, cold ischemia, and acute rejection can induce aberrant DNA methylation changes with serious implications for graft outcomes and acceleration of renal aging (198) (Figure 2). A great body of evidence recently provided the epigenomic, transcriptomic, and proteomic signature that characterize the biological older allografts (199)(200)(201)(202) and the CKD methylation patterns (203,204). Comparable results showing the importance of epigenetic modifications in AKI-to-CKD progression were obtained by rat and mice model of IRI, CKD, and premature renal aging.…”