Proteomic identification and validation of novel biomarkers for monitoring the early phase of renal transplantation

Lead Research Organisation: University of Leeds
Department Name: Leeds Institute of Molecular Medicine

Abstract

The number of people being diagnosed with kidney failure is increasing. The treatments for the most severe forms when the kidneys fail completely are dialysis or a kidney transplant. Transplantation is associated with a better quality of life, greater survival, and is cheaper, saving the NHS more than £490 million per year. However, transplanted kidneys don‘t always work immediately, or they may be rejected. The most common way of finding out that there is a problem is by measuring levels of a substance (creatinine) in the blood and then taking a small piece (biopsy) of the kidney tissue but this has risks, is unpleasant for the patient and may be done too late when too much damage has happened. This project is aimed at finding better biomarkers, that is substances (proteins) which can be measured in a blood or urine sample and give us earlier information about whether the kidney is working properly, and if it isn‘t, help us decide quickly what is going wrong. This would enable us to treat the patient in the best way and prevent loss or misfunctioning of the transplanted kidney, both in the short and longer term.

Technical Summary

Aims: To identify and validate potential biomarkers for important complications in the early phase after renal transplantation, focusing particularly on delayed graft function (DGF) and acute rejection (AR).

Specific objectives: 1)To use proteomic approach(es) to identify candidate diagnostic or prognostic biomarkers for AR, or DGF subtypes, using current serum banks and prospectively collected urine, plasma, and transplant perfusates; 2)To validate and assess their clinical utility in further independent prospective samples (including core biopsies); 3)To investigate findings of mechanistic relevance for potential targeting or increasing understanding of underlying pathogenesis.

Methodology and study design: An existing bank of serum samples collected serially following renal transplantation (n=258) will be used for the discovery phase with a proposed collection of serum, plasma, urine and archival tissue forming an independent validation set (urine and perfusate samples will also be used for discovery), with clinical data. Selected samples from 5 groups will form the main focus: DGF (AR or acute tubular necrosis) vs immediate graft function (no complications or AR or acute tubular necrosis). The complementary approaches of 2D-DIGE, SELDI and for a limited number of samples, nano-LC-MS/MS with 8-plex iTRAQ labelling will be used to compare samples longitudinally within patients and cross-sectionally between patient groups. Potentially discriminatory proteins or profiles will be identified, confirmed and validated in an independent test set - following development of single analyte or multiplex ELISAs or immuno-MS (depending on protein/peptide). Immunohistochemical analysis of the core biopsies will be used to examine protein expression/source. Potentially useful markers would ultimately be taken forward in long-term validation studies under the auspices of UKCRN and with the involvement of clinical assay companies. Selected markers which provide information of possible biological/mechanistic relevance would also be pursued further using suitable cell-based systems.

Scientific and medical opportunities: The excellent improvements in patient health and long term outcomes made possible by renal transplantation can be forestalled by complications in the early post-transplant period. These include DGF and AR. Biomarkers which allow detection of these complications as early as possible, as well as differentiation between subtypes of DGF, would facilitate early treatment of these complications and so reduce their impact on both the patient and the transplant. This translational research project has the potential to deliver clinically useful biomarkers (potentially transferable to other forms of acute kidney injury), and may also provide new targets for intervention by providing mechanistic insight into the underlying pathogenesis.
 
Description Innovate UK
Amount £736,881 (GBP)
Organisation Innovate UK 
Sector Public
Country United Kingdom
Start 01/2018 
End 12/2020
 
Description Yorkshire Kidney Research Fund
Amount £14,480 (GBP)
Organisation Yorkshire Kidney Research Fund 
Sector Charity/Non Profit
Country United Kingdom
Start 10/2011 
End 02/2012
 
Title Aminocylase-1 as a novel biomarker in delayed graft function after renal transplantation 
Description Measurement of ACY-1 by ELISA in human serum in ischaemia reperfusion injury, specifically in Delayed Graft Function after renal transplantation 
IP Reference GB1211229.8 
Protection Patent granted
Year Protection Granted 2015
Licensed No
Impact N/A
 
Title Biochip for measuring early post renal transplant biomarkers including ACY-1 
Description Earlier diagnosis of delayed graft function after renal transplantation, potentially leading to reduced hospital stay in some cases. Simultaneous risk stratification in donation after brain death grafts allowing focused intervention in the longer term care of the transplant patient who is most at risk of return to dialysis. Most recent funder Innovate UK. Next step requires a multi-centre clinical trial (not yet funded) 
Type Diagnostic Tool - Non-Imaging
Current Stage Of Development Refinement. Clinical
Year Development Stage Completed 2019
Development Status Actively seeking support
Impact Nil of note 
 
Description Article in Yorkshire Kidney Research Fund Newsletter 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Primary Audience Participants in your research and patient groups
Results and Impact Article detailing the research for patients to read

N/A
Year(s) Of Engagement Activity 2009