MRI Assessment of Myocardial Fibrosis Associated With Monocyte Phenotype in End Stage Renal Failure

Firstly, this study aims to understand how cardiac fibrosis mediated by inflammatory microvascular disease evolves during advanced chronic kidney disease and end stage renal failure and importantly how this changes with commencement on renal replacement therapy (haemodialysis and peritoneal dialysis) using sequential cardiac MRI imaging. This method of imaging is non-invasive, provides significantly more data than echocardiography, is reproducible and accurate, has been validated in numerous studies and does not involve exposure to ionising radiation.

Secondly, this study aims to examine the changes in monocyte subsets and biochemical profile in peripheral blood prior to, during and after commencement on renal replacement therapy.

The investigators hypothesis would be that renal failure causes alteration in monocyte subset phenotype resulting in increased circulating inflammatory monocytes (human CD14high CD16high), initiating pro-inflammatory cytokine expression and thereby accelerating inflammatory cardiovascular disease and development of myocardial fibrosis.

There is significant excess of cardiac mortality in patients with end stage renal failure (ESRF) - 15 to 20% relative increased risk of cardiac death compared to the normal population. 20-30% of patients on renal replacement therapy (RRT) die from a cardiac cause (UK Renal Registry Data, 2016). However, only 30% have macrovascular disease at the time of autopsy. There is therefore a significant component of cardiac morbidity and mortality in this population that is mediated by microvascular disease and cardiac fibrosis. This includes abnormal myocardial remodelling, increased ventricular stiffness and ventricular hypertrophy, with development of arrhythmia and cardiac failure as well as increased atherosclerotic disease burden. Renal replacement therapy in itself also induces a pro-inflammatory response in patients increasing cardiac risk and there is poor understanding as to how to mediate this risk.

There is a lack of evidence in how to manage both patients and the RRT process to minimise the risk of patients developing cardiac disease. The mechanisms underlying this enhanced risk are not fully understood nor explained by traditional cardiovascular risk factors. The investigators propose to study the mechanism by which this might be mediated.

The investigators have previously reported alterations in monocyte subset populations in CKD patients that importantly predict CVD events. Furthermore, the investigators have shown that dyslipidaemia influences monocyte/macrophage phenotypes. The investigators propose an important interaction exists between chronic inflammation in the uraemic state, dyslipidaemia and the formation of deleterious monocyte/macrophage phenotypes that accelerates atherosclerosis. Cardiac MRI has been used in recent years to accurately assess the degree of cardiac fibrosis in end stage renal failure.

This clinical study builds on previous clinical and non-clinical studies at Imperial College London by unifying basic science, animal models and imaging studies into the clinical context of end stage renal failure. Increased understanding of the changes in cardiac function related to development of end stage renal failure and commencement on renal replacement therapy will provide significant and novel opportunities to optimise the management of patients in the pre-dialysis setting and prevent cardiovascular complications caused by long term renal replacement therapy.

This clinical observational study will involve the recruitment of 30 participants from general nephrology services at Imperial College Healthcare NHS Trust at CKD stage 4/5 with progressive decline in renal function (anticipated start on renal replacement therapy within 6 months). Participants will be divided into two cohorts of haemodialysis and peritoneal dialysis to enable comparison between the renal replacement modalities. As part of participants recruitment they will undergo comprehensive medical assessment and will remain under the follow-up of the renal team at frequent intervals.

Enrolled participants will undergo cardiac MRI imaging at three time points - First when initially recruited at CKD4/5, second at the point of commencement on renal replacement therapy (\~6 months) and third after a further 6 months on renal replacement therapy. MRI results will be analysed at these time points for development of fibrotic and function change.

In partnership with MRI imaging patients will have blood samples collected at the same time intervals for analysis of blood count, biochemical markers, monocyte and lipid phenotypes.

Eligibility Criteria:
Inclusion Criteria:

1. Patients with a diagnosis of Chronic Kidney Disease stage 4 and above
2. Patients with a progressive decline in renal function with a expectation to require future renal replacement therapy or currently on renal replacement therapy (Haemodialysis or Peritoneal Dialysis)
3. Exclusion of macrovascular cardiac disease within the last 3 years
4. Access for haemodialysis planned via tunnelled central venous catheter

Exclusion Criteria:

1. Age under eighteen
2. Patients with a diagnosis of Diabetes Mellitus
3. Untreated macrovascular cardiac disease or Acute Coronary syndrome within 6 months of recruitment
4. Previous or current treatment with immunosuppressive/modulatory therapy
5. Current Malignancy
6. Current use of Metformin
7. Pregnancy
8. Contraindication to MRI Imaging
9. Patients lacking capacity or unable to consent and non-English language speakers
10. Immediate modality switch after commencement on renal replacement therapy i.e. transplantation
11. Plan for treatment centre change/move outside of Imperial College Healthcare NHS Trust following commencement on renal replacement therapy
12. Patients currently participating in an active CTIMP trial