Presenter: Neil, Dalton, , United Kingdom
Authors: Neil Dalton
An overview of biomarkers of renal ischaemia reperfusion injury
R Neil Dalton
King’s College London
WellChild Laboratory, Evelina Children’s Hospital, London
Renal ischaemia is characterised by reduced cellular oxidative phosphorylation that results in increasing NADH accumulation and ATP depletion. The basic biochemical processes maintaining cellular viability slow down, cellular apoptosis increases, and loss of kidney function is the inevitable consequence. However, the kidney and other organs have an innate ability to survive acute ischaemic episodes though reperfusion is also associated with significant adverse events.
The cellular turmoil and compromised kidney functions associated with renal ischaemia reperfusion injury provides an opportunity to investigate a vast array of potential biomarkers for diagnosing renal ischaemia reperfusion injury, determining the magnitude of the ischaemic insult, monitoring the response to reperfusion, assessing the benefit of therapeutic interventions, and providing prognostic information on renal function outcomes.
The list of potential biomarker targets is extensive and includes markers of cellular redox and energy status, DNA damage, protein modification, mRNA transcription and protein synthesis, antigen expression and immune response, tissue damage and apoptosis, and glomerular and proximal tubular function. Despite the range of possibilities and extensive research literature relatively few potential biomarkers have survived translation into clinical practice.
The reabsorption of low molecular weight proteins in proximal renal tubules is both highly efficient and energy dependent. Consequently, even modest renal ischaemia results in rapid increases in the concentrations of low molecular weight proteins of several orders of magnitude. Urine retinol binding protein(RBP)/creatinine ratio has been shown, post renal transplantation, to correlate with graft cold ischaemia time and to reflect the relative ischaemia associated with cadaveric, live related donor, and remote ischaemic pre-conditioned grafts. Proposed new biomarkers, for example neutrophil gelatinase-associated lipocalin (NGAL) and kidney injury molecule-1 (KIM-1) have not proved as sensitive or specific as RBP. NGAL is synthesised in response to anoxia and, therefore, there is a lag phase for production that, in addition, may be compromised by the degree of ischaemic insult. Urine KIM-1 is simply a marker of kidney tissue damage and has not been shown to be any better than the classical proximal tubublar tissue injury marker, urinary N-acetyl-b-D-glucosaminidase (NAG) activity.
Creatinine, though constantly criticised, remains the plasma biomarker that provides the best information on the impact of ischaemia reperfusion injury on the kidney. Post renal transplantation, the rate of “normalisation” of plasma creatinine, analogous to RBP, has been shown to correlate with graft cold ischaemia time and to reflect the relative ischaemia associated with cadaveric, live related donor, and remote ischaemic pre-conditioned grafts. Clinically more important are the data demonstrating that plasma creatinine measured one year post-transplantation is prognostic of the long-term graft survival. Newer plasma biomarkers, for example cystatin C and symmetric dimethylarginine, are yet to be fully validated in this context.
There is substantial potential for the discovery of new biomarkers of renal ischaemia reperfusion injury and the translation into clinical practice is both intellectually exciting and regulatory demanding. The key is to accurately identify perceived clinical needs, understand the biochemistry and physiology of a potential biomarker, and then rigorously validate on appropriate biobank patient material.
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