Experimental Nephrology

Can you support greater patient involvement in planning renal research?

Professor Alan Salama explains some research plans at the Royal Free Kidney unit to get greater patient involvement into planning research and organising research priorities.

How one patient-doctor journey gives hope to millions who suffer UTIs

A patient who spent years of treatment in the case of a UCL academic for a chronic urinary tract infection (UTI) is now supporting his work with a £1.7m endowment.

Our work

Renal Inflammation and autoimmunity

We focus on understanding the balance between factors causing inflammatory kidney disease and the natural regulatory mechanisms that keep them in check. Defining these factors may provide better ideas of how to monitor disease, predict those who need treatment and lead to better therapeutic strategies. Our main clinical interest is in small vessel vasculitis and systemic lupus erythematosus as the important diseases in which there is dysregulated immunity. Understanding how to better treat these diseases, in which therapy can lead to significant side effects, is critical with new options becoming available. Testing new strategies and protocols as part of clinical trials is an important part of our work. Experimentally, we use animal models of ischaemia reperfusion and glomerulonephritis. We have in vitro models using cell cultures and granuloma formation to investigate the basis of the immune dysregulation.

Current Projects

Investigating the role of salt in promoting renal inflammation and the immunodeficiency state induced by salt losing nephropathies - Dr Rhys Evans with Dr Ben Walsh
Investigating the role of myeloperoxidase as a mediator of crescentic glomerulonephritis - Dr Marilina Antonelou with AstraZeneca
Investigating the role of myeloperoxidase inhibition on the accelerated atheromatous disease in lupus and vasculitis patients - with AstraZeneca
Understanding the development of granulomas in patients with ANCA vasculitis - Dr Scott Henderson with Dr Paul Frankel
Investigating urinary lymphocytes as biomarkers of disease in ANCA vasculitis - Jannis Sonnermann with Dr Adrian Schreiber
Defining the role of CTGF in mediating cryoglobulinaemic vasculitis - Dr Gayathri Rajakaruna with Prof. Roger Mason and Ionis Pharmaceuticals.

Principal Investigator

Prof. Alan Salana

Members

Rhys Evans
Scott Henderson
Marilina Antonelou
Heidy Hendra
Anuja Upadhyay
Gisele Vajgel

Lipids, the kidney, and vascular injury

Dyslipidaemia is the most common metabolic disorder at all stages of CKD and contributes to vascular injury in CKD patients. We have shown that inflammation in CKD increases cholesterol influx and reduces lipid efflux from cells, thus diverting cholesterol from the blood to the tissues. This cholesterol redistribution causes cholesterol to accumulate in the kidney and in the arterial wall, and lowers circulating cholesterol levels. This may be why CVD risk is increased in CKD, yet plasma cholesterol levels (usually directly correlated with CVD risk) are not high. Inflammatory stress, a feature of CKD, also increases intracellular cholesterol synthesis, which adds to lipid accumulation and foam cell formation (a feature of atherosclerosis) in the kidney and blood vessels. This suggests that the level of circulating cholesterol is not solely a reliable predictor of cardiovascular and renal risks in patients with CKD. We are working to identify new biomarkers in blood or cells for risk assessment and to define key molecular targets that can block the cholesterol redistribution in CKD.

Principal Investigator

Dr Xiong-Zhong Ruan

Polycystic kidney diseases (ADPKD and ARPKD)

Renal development and rare renal diseases.

Approaches

Basic cell biology of renal cyst development: e.g. mechano-sensory mechanisms
Pre-clinical evaluation of potential therapeutic drug targets e.g. ErbB family

Principal investigator

Professor Pat Wilson

Four slides of polycystic kidney demonstration. Shows the collecting tubule in slide 1, followed by ADPKD in slide 2, ARPKD in slide 3, and a PKD cyst expansion in slide 4, with arrows showing the activity

Causes, progression and complications of CKD

Ben Caplin's team aims to understand further the causes and consequences of chronic kidney disease (CKD). The group has a particular focus on endemic nephropathies in low- and middle-income countries (LMICs). Our current work includes the following.

Endemic nephropathies

Globally, most CKD occurs in the elderly, and in those with diabetes and cardiovascular disease but there is now increasing recognition of forms of progressive kidney injury which are not due to known causes, with devastating effects on the working-age populations of Central America and South Asia.

The common clinical features of this syndrome - termed CKD of undetermined cause (CKDu) - are impaired kidney function in the absence of diabetes, atherosclerotic vascular disease, evidence of primary glomerulonephritis or structural abnormality.

Finding the cause of CKDu in Central America

In collaboration with the team at the National Autonomous University of Nicaragua, Leon (UNAN-Leon), we lead a longitudinal cohort study which has recruited the (initially) unaffected young adult population of eleven communities at-risk of CKDu in Northwest Nicaragua (where the condition is termed Mesoamerican Nephropathy).

The study has reported loss of kidney function which is without parallel at a population level with almost one-in-ten young men losing over 15% of kidney function (from a normal baseline) per year. The fact that women were also affected but at lower rates suggests there may be a key occupational element to disease.

This work aims to describe the natural history and risk factors for disease and to provide a unique biobank of samples captured contemporaneously with the earliest signs of kidney decline in those affected. We are exploring several genetic and other ‘omic’ approaches in these samples, in parallel with in vitro mechanistic studies to gain insight into disease aetiology (in collaboration with Prof. Jill Norman).

International comparisons of the prevalence of CKDu

Alongside Prof. Neil Pearce at London School of Hygiene and Tropical Medicine, we have been instrumental in establishing international collaborative efforts to describe the burden of CKDu around the world (the DEGREE collaboration).

Robust estimates of the prevalence of CKDu are not only important for local health service planning, they also provide the basis for assessment of secular trends and international comparisons. This may in turn provide insight into aetiology.

UK-based CKD Studies

Ben Caplin has designed and contributes to ongoing studies on UK-based CKD.

The East and North London Diabetes Cohort Study (HEROIC)Alongside the team at Barts Health (Professor Magdi Yaqoob and Doctor Kieran McCafferty) we have conceived and designed HEROIC, an observational cohort study of those with biopsy proven diabetic kidney disease. The study, now recruiting, employs cutting-edge imaging techniques as well as collecting a range of biological samples with plans to exploit (epi)genomic, metabolomic and proteomic technologies to better understand the heterogeneity of disease and gain insight into key mechanistic pathways in the disease evolution and associated complications.

Electronic health records to better understand the consequences of CKD in the UK. Working with the team led by Professor Dorothea Nitsch at London School of Hygiene and Tropical Medicine and Professor David Wheeler at UCL, Ben Caplin co-led the analytical team delivering the Health Quality Improvement Partnership National CKD Audit in Primary Care. Although the audit is now closed, we continue to aim to use electronic health records to gain insight into the identification of those with disease as well as access, processes, variability, and outcomes of care in those with CKD.

Cardiovascular complications of CKD

The team have a long-standing interest in the cardiovascular complications of CKD. In addition to athero-occlusive disease that is seen in much of the population those with CKD exhibit stiff arteries with reduced wall elasticity containing abnormal smooth muscle cells and altered extracellular matrix.

The mechanisms underlying the arterial changes in CKD-associated CVD remain elusive. Recently, in collaboration with Prof. Stephan Beck and taking advantage of arterial material donated by transplant patients, we have examined the contribution of DNA-methylation in the cells of the arterial in the evolution of these changes.