Research Groups
Research that is unlocking the doors to new cures and treatments.
The Trust has fully funded, or contributed to the funding of, many significant achievements in the past 30 years, firstly at the St Peter’s Hospitals and the Institute of Urology & Nephrology and latterly at UCL Medical School and its associated hospitals. These successes have been due to the foresight of the clinicians and scientists who have built up teams of colleagues to develop an increasingly detailed knowledge of the urinary tract and how it works in conjunction with the other systems within the body, in order to apply this knowledge to finding cures for the diseases that affect so many people.
OUR RESEARCH GROUPS PAST AND PRESENT
Cell membrane research and the London Epithelial Group
The research group originally set up by Prof. Robert Unwin in the Department of Medicine and Institute of Urology at UCL received initial and ongoing support from the Trust to help it establish a research programme in renal tubular physiology and pathophysiology (still a rare area of research in the UK, where much of the renal research is focused on the kidney glomerulus). With the arrival of Prof. Robert Kleta to take up the new Potter Chair of Nephrology at UCL this research group has expanded to become the London Epithelial Group (LEG). Other senior members of the group include Dr. Edward Debnam, Dr. Brian King, Dr. David Shirley and Prof. Kaila Srai. This has been a joint initiative between Medicine (Nephrology) and Physiology at UCL.
Epithelial cells within the kidney tubules are specialised cells involved in the movement of various ions, small molecules and water from one side to the other. For example, into and out of the urine as it is formed in the kidney, and from digested food into the blood along the gastrointestinal tract. LEG research investigates how these processes occur and what controls them. The research groups led by Prof. Unwin are studying in great detail the way in which the thousands of tiny tubules in the kidney work, what triggers their various functions and the process by which the wrong signals get sent and disease results.
Current research is focused on:
Peptides (the ‘building blocks’ of proteins) and their role in kidney function.
The composition of urine in health and disease and the recognition of markers (‘fingerprints’) for different kidney disorders.
The role of hormones within the kidney in health and disease. Polycystic kidney disease and the possible role of a newly identified hormone and receptor system in the formation and increase in size of these cysts.
Renal and intestinal glucose transport and uptake and how they link diabetes and kidney disease.
The role of cell sensors and signals in the kidney tubules which regulate the flow of fluid and balance of chemicals retained or removed.
Rare kidney disorders can help understand and treat more common kidney diseases.
Prof. Robert Kleta moved from the USA National Institutes of Health to the UK in 2007. His particular interest and research expertise, is in the genetic causes of kidney diseases, especially those rarer inherited diseases that affect the function of the kidney epithelial (tubular) cells. This requires identification, collection and study of families with a particular inherited kidney disease. For example, Prof. Kleta’s group found the gene responsible for Hartnup disorder, an inherited disease first described in London (and at UCL) about 50 years ago. Many of these rare disorders first come to light in early childhood and, as a trained paediatric nephrologist, Prof. Kleta has established important clinical and research links with the Hospital for Sick Children at Great Ormond Street in London. This connection makes it possible to investigate a wide variety of genetic diseases affecting the kidney. But such studies require powerful computers with special software, because many thousands of gene sequence variations have to be analysed and compared with the data held in the large genome databases that are now available. The funding provided by the Trust will make it possible for simultaneous sequencing of very large quantities of DNA; screening up to 50 genes of interest without difficulty.
Prof. Kleta has already used the technology to complete a collaborative study which reported a finding of major importance where a combination of basic and clinical research across disciplines has identified a mutation on a single gene -KCNJ10 - inherited by certain children that can cause them to have multiple different diseases that were not previously thought to be linked. It has been named the EAST syndrome, due to the present in these children of epilepsy, ataxia, sensineural deafness and renal tubulopathy.
Cell sensors and signals
Dr. Brian King is a physiologist working with Prof. Unwin at UCL whose early studies on the eye of the Drosophila fruit fly led him, by a somewhat circuitous route, to his current research on the kidney. He is interested in the complex interactions that occur at the cellular level among the different hormones, receptors, enzymes and other signalling proteins that control cell function(s). The Trust is funding a three year PhD studentship to be supervised by Dr. King for a pioneering project on molecular flow sensors in the kidney. The research proposal describes how the molecule ATP (adenosine triphosphate) which is an energy source found in abundance in all cells, can act as a signal from one cell to another. The mechanism of release of ATP has proved very difficult to explain until the recent discovery of molecular triggers that can sense a range of stimuli, such as light, heat, cold, touch and pressure, and also harmful chemical that ‘activate’ its release. These triggers could be TRP (transient receptor potential) channels, which are present on kidney cells. Loss of, or damage to, TRP channels is also know to be a cause of some kidney diseases. To gain a better understanding of these processes is the subject of this research.
Kidney stones
Dr. W.G. (Bill) Robertson is an international expert on the biochemistry of kidney stones. He joined the Institute of Urology & Nephrology and St. Peter’s Hospitals in 1997 and continues to work with the urologists and nephrologists at UCL Medical School and its associated hospitals. He has built up a data base of approximately 2000 patients with renal stones- all analysed by diet diaries and blood and urine collections. Significant discoveries have been made relating to the causes of stone formation, its relationship to diabetes and hypertension and certain painful and life-threatening kidney disorders.
The research funded by the Trust has included:
Pattern recognition studies on risk factors in urinary stone formation - studying the relationship between stone formation, diabetes and hypertension which is probably largely due to our so-called ‘bad western diet’ which contains too much salt and sugar.
A study which sought to define the roles of oxalate (and the compounds that are metabolised to form oxalate in the body) in calcium oxalate stone formation. Also to define how much oxalate derives from various sources such as dietary intake of oxalate (it is present in most fruit, vegetables and cereals), the metabolic production of oxalate within the body, and possible genetic differences between stone formers and non-stone formers.
A study of the physico-chemical factors influencing calcium oxalate crystallisation in the urinary tract, with particular reference to patients suffering from Primary Hyperoxaluria. The study aimed to define the chemical properties of urine that cause crystallisation, with the hope of offering sufferers more comprehensive advice on life-style, and the development of new drugs. The results were novel and received with great interest by the scientific community.
Dr. Robertson has also worked with Dr. John Hothersall and his research group in the Stone Cell Pathology Unit at UCL which has studied the effects of calcium oxalate crystals (the basis of kidney stones) on certain proteins that protect the kidney and a possible mechanism for preventing this. Dr. Wildman and Prof. Unwin are studying the consequences for the kidney of a ‘fat food diet’ - its possible effects on kidney acid handling and the related risk of stone disease. Prof. Kleta, with the London Kidney Stone Research Consortium, is studying the genetic basis of renal stone disease. There is a family history of kidney stones in up to half of all the patients diagnosed with this condition, but so far little progress in understanding the background to this. The Consortium has access to a comprehensive database of kidney stone patients and funding from the Trust is helping to provide the technology to enable them to carry out a wide-ranging genetic study. The prevalence of kidney stones has increased in most countries over the past century and while such stones are perhaps not life-threatening they can cause significant pain and cost to affected individuals and to society. Up to 50% of patients have a family history of kidney stones but there has been little progress in understanding the genetic causes. Prof. Kleta and his colleagues have access to a comprehensive database of kidney stone patients are in an ideal position, now that the technology is available at reasonable cost, to carry out a wide-ranging 3-year genetic study.
Dr. G. Rumsby and Prof. J. Masters have been studying the effect of hyperoxaluria on gene expression in the kidney. Hyperoxaluria arises from a defect in the enzymes that control oxalate metabolism and large amounts of oxalate accumulate within the patient’s body, particularly in the kidneys and urine where it combines with calcium and causes the formation of multiple stones. This can lead to damage of the kidney and renal failure. In many cases the disorder results from a genetic defect that manifests itself in childhood. This project aimed to increase the understanding of the progression of oxalate-induced renal disease through the culture of cells shed into the urine of patients with hyperoxaluria to see if they could be used as an indirect non-invasive, means of studying the kidney in these patients.
(NB there is a Hyperoxaluria Foundation if we wished to make a link to it)
Mr. J.E.A. Wickham, Consultant Urologist at the St. Peter’s Hospitals, led a team in the 1980’s which was responsible for the introduction to the UK of an endoscopic surgical technique for kidney stone removal, and subsequent refinement of the system. This equipment is now widely used in the NHS and provides a safe and minimally invasive alternative to major surgery, with a rapid recovery time.
Kidney failure - blood composition and high blood pressure
Dr. A.M. Joekes was a Consultant Nephrologist at the St. Peter’s Hospital and a founding member of the Trust. In the early 1980’s he and Dr. J.S. Pryor made the discovery that anaemia due to defective red blood cell production can be caused by a damaged kidney’s inability to produce the hormone erythropoietin (EPO). This led to the successful production of a synthetic version of EPO.
Prof. G.H. Neild was appointed to the St Peter’s Trust Chair of Nephrology in 1990 and held the post until 2003. During his tenure the Trust funded many significant research projects led by Prof. Neild, including:
The discovery that platelets which activate clotting normally (following injury) can cause thickening of the blood, slowing its flow and damaging the kidney’s filtration system, which leads to high blood pressure and eventual kidney failure. As a result, the use of ACE inhibitor drugs was shown to alleviate these effects.
Discovery of the mechanism whereby Cyclosporin, an anti-rejection drug, commonly used in transplantation, was damaging the kidney.
The finding that abnormal platelet activity in the blood can cause the dangerous condition of pre-eclampsia in some pregnancies - leading to ways to diagnose and treat this.
Dr. P. Foxall worked with Prof. Neild from 1998 - 2002 and held a Senior Research Fellowship funded by a major donation made to the St Peter’s Trust for this purpose. Her specialist area of research was in nuclear magnetic resonance spectroscopy (NMR) which was applied to visualise various biological fluids and the investigation of perturbed metabolic processes involved in diseases of the urinary tract. These studies demonstrated the power of this new (but unfortunately very expensive) technology to provide a non-invasive method for recognising patterns of injury that were characteristic and therefore specifically diagnostic of individual diseases.
Bladder research
Prof. C.J. Fry is an internationally renowned physiologist, who held a joint appointment at the Institute of Urology & Nephrology and the Department of Physiology, UCL, from the early 1990’s until 2008. A number of his projects were initiated with funding from the Trust and went on to attract major grants from the Wellcome Trust, Research Councils and Pharmaceutical Research Foundations. His main research interest lies in the study of human smooth muscle, such as that occurring in the bladder. Correct functioning of the nerve impulses that control bladder emptying is most important, as impairment can result in lack of control (incontinence), too much control (retention), or frequency. The main causes of bladder problems are infection, tumours, stones, or impairment of the bladder’s nerve supply through disease or injury. With Dr. C. Wu and others in their research group Prof. Fry undertook studies of the detrusor smooth muscle in the bladder wall, and its nerve supply, to gain insights at a cellular level about the processes taking place. The results have paved the way for the potential development of drugs targeted to specific bladder functions, without having major effects on other functions.
Dr D. Wood, with Prof. C.J. Fry and Dr. P. Foxall have worked on a means of reimplanting cell cultures grown from the host and attached to a suitable support matrix as a potential treatment for severe cases of incontinence or retention. The study aimed to establish which functional properties are retained by the smooth muscle cell cultures to make them useful both as a potential bladder implant with contractile properties and also as a biological system model. Whilst many questions remained to be answered it was shown that the cells eventually produced did retain a great deal of functional capacity when cultured for implantation and it is hoped that the work can be taken forward by other researchers already involved in implant production as a tissue/cell model.
Dr. R. Khasriya and Dr. R. Lunawat, who are members of the research group headed by Prof. J. Malone-Lee of the Department of Medicine, Archway Campus, UCL, have discovered evidence of chronic, low-grade inflammation in the urine of some 70% of patients suffering from an overactive bladder. Data is being collected from cells shed in the urine of patients with this condition, to try and identify causes of the inflammation and to develop appropriate treatments.
Prof. M. Craggs, a Physiologist specialising in the operation of the body’s nerve systems, has worked for many years with Prof. A.R. Mundy, Professor of Urology and Consultant Urologist at UCL Hospital Trust, and Prof. C.J. Fry on bladder function and the means of restoring bladder control. In particular this research has involved the development of artificial sphincters and associated devices to provide continence and controlled voiding. In recent years associated projects have been addressed, and these have been supported by the Trust. Prof. Craggs’ research is now concentrated on helping patients with urological problems related to spinal cord injury. In a current project funded by the Trust he and his research group are undertaking a pilot study on the risk and possible causal link in spinal cord injury of urinary stone and osteoporosis.
New ways of treating prostate disease
Mr. M. Emberton is a Reader in Urology at UCL Medical School and Consultant Urologist at UCL Hospitals Trust. He has a particular interest in the treatment of diseases of the bladder and prostate, and in studies of the occurrence of these diseases in the population (Epidemiology). The Trust is supporting his research into assessing the effects of High Intensity Focussed Ultrasound (HIFU), or an alternative treatment known as Photodynamic Therapy, using photosensitising drugs activated by laser in the treatment of prostate cancer. Preliminary results show that cancerous tissue is destroyed quickly, accurately and effectively with far fewer side effects than those occurring after conventional open surgery. Mr. Hashim Uddin Ahmed has recently been awarded a Medical Research Council Clinical Research Training Fellowship to continue this research with Mr. Emberton.
Prof. J. Masters is a physiologist who has undertaken much significant research, initially at the Institute of Urology & Nephrology and subsequently at UCL Medical School after the merger. His main research interest is the way in which cancers develop in the urinary tract and the use of novel drug treatments to cure such cancers. Most of his project funding is derived from the main cancer charities, the prostate cancer charities and the National Institutes of Health in America. However, the St Peter’s Trust has contributed funding towards:
Discovery of a change in a particular gene in the prostate gland that allows cancer to spread through mutations in its signalling mechanism. Monoclonal antibodies are being developed to counteract this. A patent was awarded for this work.
The creation of a ‘gene profile’ for the three zones of the normal prostate gland, which can be used in recognising patterns of diseaes in the prostate. The genes and signalling pathways revealed help to explain differences in disease susceptibility between the zones, and should lead to earlier and more accurate diagnoses.
Dr. Hide Yamamoto is working with Prof. Masters on the isolation from patients’ tissue of the prostate cancer stem cells that are responsible for the growth and spread of the cancer; with the aim of identifying therapeutic targets to inhibit them.
Mr. J.E.A.Wickham, Consultant Urologist, led a team in the 1980’s that invented and attempted to produce a robotic device to standardise, and make safer and quicker, the procedure of resection of the prostate to relieve urinary outflow obstruction - one of the most frequently performed urological operations. Much successful development was achieved but the robotic device could not be completed at the time with the funds available. The work has recently been taken up again at Imperial College, London, (collaborators in the original project) and is now close to clinical application.
(NB there is probably a media news link to the clinical implementation of this work - if we wish to find it - as the team at Imperial is under the direction of Lord Darzi!)
Reconstructive surgery of the lower urinary tract in children
A distinguished succession of Consultant Urologists has held joint appointments between the St. Peter’s Hospitals and The Hospital for Sick Children, Great Ormond Street - Sir David Innes Williams, Mr. P.G. Ransley, Mr. P. Duffy Much of their expert surgical work has involved reconstructing the lower urinary tract for children born with the devastating congenital abnormality known as bladder exstrophy/epispadias, which affects approximately one in 30,000 live births. In addition to refining the surgical procedures over the years, associated research has also been undertaken and, with financial help from the Trust, Mr. P.G. Ransley identified the importance of testing urinary flow dynamics before, during and after reconstructive surgery of the bladder and urethra in children - thus minimising the number of operations and improving their effectiveness.
Prof. C.R.J. Woodhouse, Professor of Urology at UCL Medical School and Consultant Urologist at UCL Hospitals and the Royal Marsden Hospital, has specialised in the treatment of urological conditions of patients in their adolescence and young adulthood. This has become an increasingly important area of work as the patients undergoing urological surgery have survived through childhood and into their teenage years. The Trust has funded Prof. Woodhouse to undertake the first substantial assessment of the views in adulthood of the female patients who had surgery in infancy to correct congenital abnormalities of the genitalia, in order to help parents decide on the best treatment for their child.
Funding has also been granted to Prof. Woodhouse and Mr. Ivan Meng Hoh to study abnormal pressures in dysfunctional bladders which can lead to renal failure in children, including those with spina bifida. The aim of the research is to identify a ‘safe’ threshold between volume and pressure so that appropriate action can be taken for individual patients to avoid the possibility of the kidneys being affected.
Mr. D. Wood (for whom the Trust provided the funds to achieve his PhD at UCL on tissue culture for potential bladder cell reimplantation) has been appointed Consultant Urologist in the Department of Paediatric and Adolescent Urology , UCLH. With financial support from the Trust he is now working with Great Ormond Street Hospital for Sick Children on the development of a database for the long term follow-up through adolescence and adult life of complex congenital urological conditions originally treated in childhood. Once existing information has been combined and structured the intention is to start prospective data collection on a wide range of outcomes affecting these patients, and to explore the possibility of creating a national database.
Improving catheters and stents
Mr. H.N. Whitfield and Mr. S. Choong, Urological surgeons at St. Peter’s Hospital, have, in conjunction with Prof. Fry’s research group, discovered the processes by which catheters and stents, inserted to improve drainage in treatments of urinary tract disease, become encrusted and unusable. Development of a mathematical model which will enable various inhibitors to be tried in the composition of the devices has resulted.