A Multi-Omics approach to understanding cardiovascular risk in patients with End-Stage Kidney Disease

Background.

End-stage Kidney failure, also known as End-Stage Kidney Disease (ESKD), is the final, irreversible stage of chronic kidney disease (CKD), where kidney function has worsened to the point that the kidneys can no longer function independently. In 2009, an estimated 7,000 extra strokes and 12,000 extra myocardial infarctions per year were due to CKD in the UK, costing the NHS over £170 million. However, it is cardiovascular complications rather than impaired renal function that are the leading cause of death in ESKD. This is due to CKD/ESKD being a chronic systemic proinflammatory state contributing to vascular and myocardial remodelling, atherosclerosis, vascular calcification and senescence, cardiac fibrosis, valve calcification and complex dyslipidaemia. Also, in CKD, due to uraemia, there is disruption of the microbiome and gut barrier function that allows translocation of endotoxin and bacterial metabolites to the systemic circulation, contributing to inflammation associated cardiovascular disease. In this respect, CKD mimics accelerated ageing of the cardiovascular system. As a result, these patients are at increased risk of developing heart failure, irregular heart rhythms (arrhythmias) and sudden heart death.

Circulating blood cardiac biomarkers provide an insight into various aspects of cardiovascular health including injury, inflammation, and fibrosis. There are several promising new cardiovascular biomarkers (soluble suppression of tumorigenesis-2 (ST-2), galectin-3, and Cardiac myosin-binding protein C (cMyC)), but their role in risk stratification in ESKD is yet unknown. In ESKD, lipid dynamics are also altered with an upregulation of small, dense, low-density lipoprotein (LDL) particles that remain in the circulation for longer and are capable of inducing inflammation. High-density lipoprotein (HDL) also becomes dysfunctional, with impaired maturation, altered molecular composition, depressed anti-oxidant/anti-inflammatory functions, and clearance of triglyceride-rich lipoproteins. Together, along with microbiome dysregulation contribute to cardiovascular disease in ESKD.

Therefore by measuring cardiac biomarkers, HDL-particle number and function and microbiome composition, could aid in early detection of heart disease/damage in patient with ESKD.

Aim and Objectives

1.    To identify metabolomic and genomic patterns associated with cardiovascular disease in ESKD.

2.    Assess the utility of putative metabolomic and genomic pattern in predicting deterioration in cardiac function and incidence major adverse cardiac events (MACE) in patients with ESKD.

3.    Determine the utility of existing and new cardiac biomarkers in predicting deterioration in cardiac function and incident MACE in patients with ESKD.

4.    To characterise the microbiome in patients with ESKD and its association with incident MACE.

Methods

Blood samples and clinical data will be obtained from dialysis patients at Royal Liverpool University Hospital to conduct proteomics, mass-spectrometry based metabolomics and microbiome assessment. We will use a targeted approach to understand the function of the current biomarkers listed above but also a global approach to identify new biomarkers. Students will gain experience in phlebotomy, SWATH based mass spectrometry that will be used to analyse patient serum samples, metabolomic analysis and large-scale data handling. Proteomic analysis using tools such as DAVID and Reactome will be used to evaluate global changes and biomarker release. Validation of biomarkers and differential expressed proteins will establish skills including cell culture, western blotting, immunofluorescence and ELISA. The student will also gain some experience of genomic analysis (Amplification of genomic DNA analysed by 16S ribosomal RNA gene sequencing).

Applicant Information

The successful applicant should have an interest in renal, cardiovascular disease and biomarkers and hold a minimum of a 2:1 in a science or health-related subject.

The successful applicant will be trained during the PhD in both bench and bedside skills, which are essential for a clinical research career. The successful candidate will assist with collecting and processing blood samples for analysis, undertake laboratory work, data processing and analysis and the preparation of abstracts and papers for publication. In addition, the successful candidate will benefit from working in a multi-disciplinary team of clinicians and scientists at the Liverpool Centre for Cardiovascular Science with expertise in clinical practice, appraising literature (systematic review), laboratory methods and analysis, database skills and statistical skills.

Furthermore, all postgraduate students undertake the Post Graduate Rsearcher (PGR) Development Programme which aims to enhance their skills for a successful research experience and career. They are required to maintain an online record of their progress and record their personal and professional development throughout their research degree. The Liverpool Centre for Cardiovascular Science holds monthly research group meetings where students are given opportunities to present their research.

The Institute of Life Course and Medical Science is fully committed to promoting gender equality in all activities. In recruitment we emphasize the supportive nature of the working environment and the flexible family support that the University provides. The Institute holds a silver Athena SWAN award in recognition of on-going commitment to ensuring that the Athena SWAN principles are embedded in its activities and strategic initiatives.

For any enquiries please contact: Dr Anirudh Rao (Anirudh.Rao@liverpoolft.nhs.uk)

Application is by CV and covering letter.  The covering letter must detail your interest in the studentship, related experience and training and suitability for the position.  Applications should be sent to Dr Anirudh Rao (Anirudh.Rao@liverpoolft.nhs.uk).