The effect of ischemia/reperfusion on the kidney graft

Menke, Julia; Sollinger, Daniel; Schamberger, B.; Heemann, Uwe; Lutz, Jens

doi:10.1097/mot.0000000000000090

Cited by 87 publications

(76 citation statements)

References 76 publications

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“…This in turn may trigger innate and adaptative immune responses in the graft. 26 Activated endothelial cells might thus be involved in graft rejection and contribute to progressive graft loss. 27 Before EndMT markers can be envisioned as a routine diagnostic tool for ABMR, several points relevant to our work must be discussed, and further work is necessary.…”

Section: Discussionmentioning

confidence: 99%

Markers of Endothelial-to-Mesenchymal Transition

Xu‐Dubois

Peltier

Brochériou

et al. 2016

Journal of the American Society of Nephrology

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Antibody-mediated rejection (ABMR) is a leading cause of allograft loss. Treatment efficacy depends on accurate diagnosis at an early stage. However, sensitive and reliable markers of antibody-endothelium interaction during ABMR are not available for routine use. Using immunohistochemistry, we retrospectively studied the diagnostic value of three markers of endothelial-to-mesenchymal transition (EndMT), fascin1, vimentin, and heat shock protein 47, for ABMR in 53 renal transplant biopsy specimens, including 20 ABMR specimens, 24 cell-mediated rejection specimens, and nine normal grafts. We validated our results in an independent set of 74 unselected biopsy specimens. Endothelial cells of the peritubular capillaries in grafts with ABMR expressed fascin1, vimentin, and heat shock protein 47 strongly, whereas those from normal renal grafts did not. The level of EndMT marker expression was significantly associated with current ABMR criteria, including capillaritis, glomerulitis, peritubular capillary C4d deposition, and donor-specific antibodies. These markers allowed us to identify C4d-negative ABMR and to predict late occurrence of disease. EndMT markers were more specific than capillaritis for the diagnosis and prognosis of ABMR and predicted late (up to 4 years after biopsy) renal graft dysfunction and proteinuria. In the independent set of 74 renal graft biopsy specimens, the EndMT markers for the diagnosis of ABMR had a sensitivity of 100% and a specificity of 85%. Fascin1 expression in peritubular capillaries was also induced in a rat model of ABMR. In conclusion, EndMT markers are a sensitive and reliable diagnostic tool for detecting endothelial activation during ABMR and predicting late loss of allograft function.

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Section: Discussionmentioning

confidence: 99%

Markers of Endothelial-to-Mesenchymal Transition

Xu‐Dubois

Peltier

Brochériou

et al. 2016

Journal of the American Society of Nephrology

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“…A higher incidence of DGF has been associated with the use of allografts from older extended criteria donors (ECD, age >60, or >50 with two of the following: a history of high blood pressure, a creatinine ≥1.5, or death resulting from a stroke), donation after cardiac death donors (DCD) and increased allograft biological age (Mallon, Summers, Bradley, & Pettigrew, 2015; McGuinness et al, 2016; Menke, Sollinger, Schamberger, Heemann, & Lutz, 2014; Mundt, Yard, Kramer, Benck, & Schnulle, 2015; Schroppel & Legendre, 2014). The extent to which donor and recipient‐related characteristics influence the magnitude of IRI and/or DGF occurrence, beyond accepted clinical risk factors for DGF, remains to be proven (Menke et al, 2014; Mundt et al, 2015; Schroppel & Legendre, 2014), particularly in the context of allograft repair, or regeneration pathways, activated in response to IRI.…”

Section: Introductionmentioning

confidence: 99%

“…The extent to which donor and recipient‐related characteristics influence the magnitude of IRI and/or DGF occurrence, beyond accepted clinical risk factors for DGF, remains to be proven (Menke et al, 2014; Mundt et al, 2015; Schroppel & Legendre, 2014), particularly in the context of allograft repair, or regeneration pathways, activated in response to IRI. Increased demand for organ donation, coupled with increasing chronological age and associated comorbidities in the donor population, has necessitated the use of organs that have been previously deemed as marginal for clinical use (Morrissey & Monaco, 2014; Nagaraja et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

A molecular signature for delayed graft function

et al. 2018

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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.

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“…Ischemia/reperfusion (I/R) can occur following renal surgery or transplantation, often resulting in acute kidney injury, chronic renal failure and kidney transplantation failure (1,2). It has been demonstrated that inflammation and apoptosis serve crucial functions in I/R-induced renal injury (3), therefore the development of effective drugs to prevent inflammation and apoptosis in I/R-induced renal injury is required.…”

Section: Introductionmentioning

confidence: 99%

Gypenoside attenuates renal ischemia/reperfusion injury in mice by inhibition of ERK signaling

Zhu

et al. 2016

Experimental and Therapeutic Medicine

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Abstract. Gynostemma pentaphyllum is a traditional Chinese medicine reported to possess a wide range of health benefits. As the major component of G. pentaphyllum, gypenoside (GP) displays various anti-inflammatory and anti-oxidant properties. However, it is unclear whether GP can protect against ischemia/reperfusion (I/R)-induced renal injury, and the underlying molecular mechanisms associated with this process remain unknown. In the present study, a renal

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The effect of ischemia/reperfusion on the kidney graft

Abstract: It is of particular importance in kidney transplantation to understand the underlying mechanisms and effects of ischemia/reperfusion on the graft as this knowledge also opens strategies to prevent or treat ischemia/reperfusion injury after transplantation in order to improve graft outcome.

Cited by 87 publications

References 76 publications

Markers of Endothelial-to-Mesenchymal Transition

Markers of Endothelial-to-Mesenchymal Transition

A molecular signature for delayed graft function

Gypenoside attenuates renal ischemia/reperfusion injury in mice by inhibition of ERK signaling

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