The UCL Centre for Nephrology is unusual in having a wide breadth of clinical and research expertise (applied epithelial physiology and pathophysiology, renal genetics and cell biology, immunology and inflammation, mineral metabolism, cardiovascular disease, and modalities of renal replacement therapy and conservative management) applied to kidney research, clinical care, and training.
The Centre for Nephrology is part of the UCL Division of Medicine and is within the Transplantation and Immunology theme of the UCL Academic Health Sciences Centre (UCL Partners). This theme includes active renal, liver (including islet cell) and bone marrow transplant programmes, as well as plans for face and laryngeal transplantation. The Centre became a large, single, clinical service and academic unit in 2006 when renal services at the Middlesex, University College, and Royal Free hospitals merged. As a result, our Centre is formally linked with the clinical Nephrology service at the Royal Free Hospital. We have significant internal collaborations and strong links with other UCL research departments, including physiology, biochemistry, genetics, virology, rheumatology, infectious diseases, immunology, and clinical pharmacology.
The prevalence and incidence of chronic kidney disease (CKD) is increasing for many reasons - greater public awareness, an ageing population, more advanced and complicated surgery carried out in older patients, and fewer deaths from infection, heart attacks, and some forms of cancer. CKD is recognised to be a silent epidemic with numbers expected to increase year on year. Many patients will have a ‘routine blood test’ at their GP’s surgery, usually including measurement of their blood creatinine level to screen for reduced kidney function; this method is relatively insensitive and better methods are needed to detect and treat kidney disease earlier and thereby reduce the high costs of dialysis treatment and kidney transplantation, and lessen impact on quality of life. The following summary of our key research themes and activities demonstrates our comprehensive clinical and basic research, which forms the foundation of our clinical and research training programmes.
CKD and cardiovascular disease (CVD) risk
Professor David Wheeler
People with CKD have a shortened life expectancy despite treatment with dialysis and kidney transplantation. Many people with CKD die prematurely of CVD and reducing CVD risk is essential for improving survival. The association between CVD and kidney function has been clearly defined in epidemiological studies in which we have participated, including the Chronic Renal Impairment in Birmingham (CRIB) and London Arterial Calcification, Kidney and Bone Outcomes (LACKABO) cohort studies. The Study of Heart and Renal Protection (SHARP), a trial in which we took a leading role, confirmed the benefits of lipid-lowering therapy in the CKD population. The mechanisms by which reduced kidney function increases CVD risk, particularly with respect to non-atherosclerotic disease, are still poorly understood. Our recent work has focused on the abnormal calcification of blood vessels, a phenomenon which is common in CKD. Arterial calcification may be worsened by calcium- and vitamin D-based treatments aimed at controlling over-activity of the parathyroid glands (which normally regulate mineral metabolism and bone turnover). Our ongoing research is aimed at identifying therapeutic approaches that reduce atherosclerotic cardiovascular complications of CKD.
CKD and progressive fibrosis
Dr Jill Norman
Following kidney injury or disease, damage can be repaired and organ function restored. However, in some cases the normal healing response fails and scarring continues causing CKD. Progressive scarring replaces normal kidney tissue with non-functional fibrotic tissue and kidney function is lost. Ultimately, this can lead to kidney failure and the need for dialysis or kidney transplantation. Therapies that can retard or halt progressive scarring are limited and there is a need for novel therapeutic strategies. The key to this is understanding the basic mechanisms underlying fibrosis. Our work focuses on the biology of kidney fibroblasts, since in CKD the number of fibroblasts increases and the cells become activated to produce large amounts of fibrous tissue. Gene profiling and proteomic approaches are used to identify differences in normal and CKD-derived fibroblasts. Mechanistic studies explore how altered gene expression is regulated and how changes alter fibroblast behaviour and function, as well as fibroblast interactions with other renal cell types. We are also trying to identify biomarkers in blood and urine predictive of fibrosis and to define key molecular targets for therapy, as well as to test novel anti-fibrotic agents.
Lipids, the kidney, and vascular injury
Dr Xiong-Zhong Ruan
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.
Acute kidney inflammation
Professor Alan Salama, Dr John Connolly, Dr Aine Burns
We are interested in inflammatory renal disease, which can affect different parts of the kidney, specifically the glomeruli or the tubules and lead to rapidly declining kidney function.
Each year around a thousand people in the UK develop vasculitis, an inflammation of small blood vessels. When it affects the kidneys, this form of glomerulonephritis is one of the commonest causes of kidney failure requiring dialysis or transplantation. It is often sudden in onset and sometimes associated with bleeding from the lung, frequently affecting those who were otherwise well. Our research aims to find ways to control this inflammation without disabling the body’s immune system that normally protects against infection and cancer. Vasculitis is rare and the diagnosis can be missed, and even following diagnosis it may also relapse, so we are trying to find better disease markers for earlier detection, to monitor its progress, and to predict earlier relapses. Finally, we are investigating rare cases of patients who have switched off their disease to understand if we can define a marker that helps us predict when we can stop immunosuppressive therapy. To better understand the outcomes of patients outside of clinical trials, we have established a UK registry of all affected vasculitis patients, which is expanding and will allow us to define demographics more clearly.
2. Ischaemia and acute tubular injury
Following ischaemia, certain drug therapies, or contrast agents there is an inflammatory response in the kidney which leads to acute tubular injury. We have found that the level of a protein, the mannose receptor, influences kidney damage in this context and are developing novel ways to block this particular molecule, with a view to developing a strategy for preventative treatment of patients at high risk of acute tubular injury.
Genetics of kidney disease
Dr Daniel Gale
Daniel Gale specialises in genetic kidney disease and runs a clinic caring for patients and families with familial kidney problems - of either a known cause (such as polycystic kidney disease, kidney cancer syndromes, Alport disease and thin basement membrane nephropathy) or an unknown cause. Where possible, patients are offered the opportunity to participate in research, clinical trials, and registries.
Using laboratory tools including linkage mapping, next generation sequencing and other techniques, we have identified the molecular defects responsible for two novel human genetic diseases: HIF2α erythrocytosis, which results from a defect in cellular oxygen sensing; and CFHR5 nephropathy, which results from a defect of complement alternative pathway regulation and which is endemic in Cyprus.
Ongoing projects aim, firstly, to understand the pathophysiology of these diseases and in particular the role of the complement system in kidney disease, secondly, to develop approaches to the treatment of genetic kidney diseases, and, thirdly, to investigate other families with unexplained inherited kidney diseases in order to uncover the genes responsible.
Renal genetics in paediatric and adult nephrology
Professor Robert Kleta, Prof Detlef Bockenhauer, Dr Riko Klootwijk, Dr Horia Stanescu, Dr Anselm Zdebik
Genetics is revolutionising medicine. Better and cheaper genetic technologies enable us to quickly understand genetic components of kidney disease, and to study individual families with unknown kidney disorders, and unrelated individuals with apparently similar kidney problems. Recent work from our group, in collaboration with colleagues throughout the UK and abroad, includes the elucidation of a rare, but highly informative, kidney disorder also affecting the brain (epilepsy and incoordination) and hearing - EAST syndrome; establishing the genetic basis of premature arterial calcification in adults; clarification of the genetic components contributing to idiopathic membranous nephropathy, another common form of glomerulonephritis.
Polycystic kidney disease (PKD)
Professor Patricia Wilson
Autosomal Dominant Polycystic Kidney Disease (ADPKD) is the most common genetic cause of CKD affecting approximately 60,000 patients in the United Kingdom and approximately 12 million worldwide. Kidney cysts develop and close off from developing renal tubules and continue to expand and enlarge due to excessive epithelial cell proliferation and apical fluid secretion over many years. Our translational research is focused on: 1) The identification and evaluation of potential therapeutic drug targets, including EGFR/ErbB1/ErbB2 and PDGF, to slow down cystic expansion and fibrotic accumulation associated with progressive renal functional decline in ADPKD and 2) The identification and characterization of specific urinary and blood exosomal and biomarker profiles to improve prognosis by predicting rates of disease progression and to monitor responses to tailored therapies.
Glucose and phosphate transport
Dr Joanne Marks, Professor Robert Unwin, Dr Ted Debnam
Glucose transport across renal and intestinal cells contributes to body glucose balance and is markedly altered in diabetes mellitus (DM). We aim to elucidate the mechanisms leading to altered intestinal and renal glucose transport in DM. DM accounts for almost 30% of patients developing advanced CKD, so defining the role of altered glucose transport in DM and the relationship to its major renal complication is likely to be important. The intestine and kidneys are also involved in the regulation of body phosphate balance, which has been linked to premature CVD and vascular calcification in CKD. Phosphate overload occurs in CKD. In the absence of adequate excretion by the kidneys to prevent this, absorption by the intestine becomes an important therapeutic target. We are investigating the mechanisms of phosphate absorption by the intestine and how they are regulated, particularly by a group of novel hormones called phosphatonins; one in particular, FGF-23, has also been implicated in vascular calcification.
Dr Mark Harber, Dr Gareth Jones, Mr Ben Lindsey, Dr Henry Stephens
We have an ongoing prospective programme of immune monitoring post-transplant with the aim of identifying markers of over-and under-immunosuppression in advance of viral reactivation or rejection. We also have keen interests in cytomegalovirus (CMV) post-transplant and trialling vaccination against CMV in the transplant setting. Further research is directed at the biology of urosepsis in the post-transplant setting, in particular looking for early diagnostic markers, predictors of risk, and the role of the innate immune system in urosepsis.
We have been involved with the development of the REPAIR study, a multicentre, multinational RCT of ischaemia reperfusion pre-conditioning in live donor transplantation. This study is MRC/NIH-funded and by the end of 2011 recruited over 200 donor/recipient pairs.
Our tissue typing service is provided by the Anthony Nolan Laboratories, which has a group dedicated to human leukocyte antigen (HLA) typing, HLA antibody identification, and cross-matching for the renal, liver and islet cell transplant programmes of the RFH. This group has a research and development programme focusing on HLA and natural killer cell receptor genes, and acts as a resource for immunogenetic surveillance of transplant recipients, as well as patients with autoimmune, malignant and infectious diseases, and population genetics at UCL.
Dialysis (haemodiafiltration/haemodialysis/peritoneal dialysis)
Dr Jenny Cross, Dr Andrew Davenport
We currently have a range of projects from assessing the relationship between body composition, energy expenditure and dialysis dosing for both peritoneal and haemodialysis patients, to investigation of role of sodium balance and volume status during haemodialysis and changes in blood pressure, and divalent ion balance during haemodialysis and haemodiafiltration. In addition, we have two new series of studies designed to investigate the potential role of newer surrogates for dialysis adequacy plus cardiovascular risk factors in haemodialysis patients.
Acute kidney injury (AKI)
Dr Andrew Davenport, Dr Chris Laing
The Royal Free Hospital is the central hub of the North London Acute Kidney Injury Network. We are currently involved in a number of clinical projects including biomarker studies in decompensated cirrhosis and post-cardiac surgery and epidemiological and clinical studies in management of patients with AKI.
CKD: Conservative management and end of life care
Dr Aine Burns, Dr Aisling O'Riordan
The Royal Free NHS Trust was one of the first units in the country to introduce a formal conservative care programme as an alternative to dialysis for patients who chose not to dialyse often because of old age and high co-morbidity. The multi-disciplinary group has an active clinical research programme in this area and has contributed to both national and international recommendations surrounding end of life care. Much of the research work is conducted in collaboration with the Marie Curie Care Centre at UCL.
Proteomics in systems biology, medical therapeutics and medical aetiology
Professor Jasminka Godovac-Zimmermann
Cellular systems offer an unparalleled ability to control, manipulate and experiment with complex living systems. We address the influence of diversity (protein form and/or function), quantity (abundance), space (subcellular spatial distribution) and time (dynamic responses) at the cellular level using high throughput, quantitative mass spectrometry based proteomics.
Our current applications include several areas of investigation in cancer and the genetic theory of viral infection: (A) Complex, dynamic spatial organisation of subcellular biology in relationship to the energetic/integrative functions of mitochondria, nuclear-mitochondrial coordination and the nature of their role in cancer and other diseases. (B) The complexity of form and subcellular distribution of proteins and pathways that relate the cell cycle and metabolic status of cancer cells. (C) Proteomics methods for detection/analysis of functional networks across human populations with genetic variability in determining susceptibility to, consequences of, and potential diagnostic/therapeutic approaches in viral infections. We have established high throughput proteomics methods that can address at least some of the complexity of protein spatio-temporal distribution/flux in cells.
Our large-scale proteomics investigations of protein abundance, subcellular distribution and temporal response to hormonal stimulation, oxidative stress, viral infection and endocytotic processes, suggest that extensive subcellular dispersion of the constituent proteins of core cellular functions is a fundamental characteristic of cells that may be consistent with requirements for robustness in complex systems and is vital to various disease conditions. Several specific sets of proteins and their pathways have a potential for future medical diagnostic and therapeutic applications.
Renal stone disease
Dr Shabbir Moochhala, Professor Robert Unwin
We are interested in finding new ways to treat kidney stone disease as the more common forms are becoming increasingly problematic in the UK and worldwide. We are participating in clinical trials into pharmacological treatment for certain calcium stone formers. Some families have a very strong family history of stone formation and we are looking for genetic causes in these families or using our large DNA biobank to look for patterns in larger groups (collaborations with Renal Genetics group). We recognise that collecting urine over 24 hours is inconvenient for patients, so we are now trialling new portable infra-red technology to quickly and accurately obtain biochemical data for urine and stones in collaboration with UCL Structural and Molecular Biology.
Chronic UTI Group
Dr Jennifer Rohn
Urinary Tract infection (UTI) is the most common infectious disease in
women and in the elderly. As such, it wreaks an enormous economic and
healthcare burden. The Chronic UTI group focuses primarily on the
microbial diversity and host/pathogen interactions of recalcitrant and
recurrent urinary tract infection in human cells and tissues. We have a
particular interest in how chronic/recurrent UTI differs from
uncomplicated acute UTI. We are also investigating how protected
bacterial reservoirs might facilitate recurrence and antibiotic
resistance. Our research encompasses microbiology, molecular cell
biology, immunology, tissue engineering, metagenomics, high-resolution
imaging and biofilm biology. We work closely with clinicians to study
the causative bacteria in patient populations, including renal
transplant recipients and the chronically infected elderly. We also
collaborate with engineers to develop novel therapeutics and diagnostic
tools with an emphasis on circumventing antibiotic resistance.