Past SPT achievements and putting the results of research into practice
The Trust has fully funded, or contributed to the funding of, many significant achievements in the past 45 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 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. The following research projects undertaken in the years up to 2010 have provided the basis for the innovative work continuing today. Important work that is still supported by the Trust.
Dr. W.G. (Bill) Robertson, an international expert on the biochemistry of kidney stones, joined the Institute of Urology & Nephrology and St. Peter’s Hospitals in 1997. He 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 objective 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 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. Stones might be prevented by promoting these proteins. Dr. Wildman and Professor Robert Unwin went on to study the consequences for the kidney of a ‘fat food diet’ - its possible effects on kidney acid handling and the related risk of stone disease.
The data base started by Bill Robertson is still used even though Bill has retired. Professor Robert Kleta, with the London Kidney Stone Research Consortium, is studying the genetic basis of renal stone disease. The prevalence of kidney stones has increased in most countries over the past century and while most of them are not life-threatening they can cause significant pain and cost to affected individuals and to society. 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 has been made in understanding the genetic causes. Funding from the Trust helped to provide the technology which is being used to carry out a wide-ranging three-year genetic study in patients in the database.
Dr. Gill Rumsby and Professor John Masters studied 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. 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.
Impact on patient management:
- The risk of any particular patient who has a stone subsequently forming another one can be assessed.
- A dietary programme to reduce the risk of stone formation can be tailored to the risk factors of individual patients.
In the 1980s there was a revolution in the surgical management of stones in the kidney and ureter (the tube that takes urine from the kidney to the bladder). The late John Wickham, Consultant Urologist at the St. Peter’s Hospitals, had long held the view that the standard operation that involved making an incision about 15 to 20cm long to remove a stone that might be only 5 to 15mm in diameter was ridiculous. He led a team which developed techniques for making an incision about 15mm in long and removing the stone with the aid of a telescope (endoscopic removal).
Working with Mr Ron Miller, several modalities were developed to fragment larger stones so that they too could be removed through these small incisions. 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.
The other revolution in stone treatment was developed in Germany. A machine was devised that fired a shock wave through the skin to fragment stones in the kidney or ureter (the shock wave lithotripter). John Wickham raised funding to buy the first such machine for the UK.
Impact on patient management:
- It is almost never necessary to do a major open operation to remove a stone.
- Most stones can be fragmented by a modern lithotripter without even the need of an anaesthetic.
- Stones that are not suitable for lithotripter treatment can be removed by one of several endoscopic approaches.
- For very complex stones, both types of treatment can be combined to avoid major open surgery.
Kidney failure - blood composition and high blood pressure
The late 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.
Professor Guy 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 Professor 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. This can be prevented by angiotensin converting enzyme (ACE) inhibitors.
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. Peta 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.
Impact on patient management:
- Patients in renal failure can have their anaemia corrected with erythropoietin (EPO).
- The progression of renal failure in many patients can slowed with the use of ACE inhibitor drugs.
- Modification of drug regimes used to prevent the rejection of transplanted kidneys reduces the damage due to cyclosporin
Professor Chris 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 Professor 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.
One of the most sought after, but elusive, research objectives is to grow cells from patients in the laboratory to make functioning organs which could then be transplanted back into the patient. Mr Dan Wood, with Professor Chris Fry and Dr. Peta Foxall have worked on a means of doing this for severe cases of bladder malfunction, either incontinence or retention. They established what functional properties could be retained by cultured cells and how they could be attached to a supporting. Many questions remained to be answered and it is hoped that the work can be taken forward by other researchers already involved in implant production as a tissue/cell model.
As people get older the bladder function often deteriorates, especially in women. The main problem is overactivity of the bladder muscle which causes frequent urination. Dr. R. Khasriya and Dr. R. Lunawat, members of the research group headed by Professor J. Malone-Lee of the Department of Medicine, Archway Campus, UCL, discovered evidence of chronic, low-grade inflammation in the urine of some 70% of patients suffering from an overactive bladder. It was found that bacteria invade the lining of the bladder wall (urothelium) and continue to exist, concealed within the cells of the tissue, causing inflammation (cystitis) even after any apparent urine infection tested by routine methods has been cleared. Although biofilm-like colonies of bacteria (biopods) were not actually found within cells in the patients in the study, the data produced from the tests pointed to undetected bacterial infection with colonisation of the cells in the bladder wall as a cause of the over active bladder. Acute/chronic cystitis was found in association with this, plus changes in the urothelium and strong symptom links to these pathologies.
Professor Mike Craggs, a Physiologist specialising in the operation of the body’s nerve systems, has worked for many years with Tony Mundy, Professor of Urology and Consultant Urologist at UCL Hospital Trust, and Chris 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. Professor Craggs’ research is now concentrated on helping patients with urological problems related to spinal cord injury. In a project funded by the Trust he and his research group undertook a pilot study on the risk and possible causal link in spinal cord injury of urinary stone and osteoporosis.
- Drugs are available that act more specifically on the muscles of the bladder so that symptom control is improved and side effects reduced.
New ways of treating prostate disease
Professor John Masters' main research interest is the way in which cancers develop in the urinary tract and the use of novel drug treatments to cure them. Most of his project funding is derived from the big cancer charities, the prostate cancer charities and the National Institutes of Health in America. However, St Peter’s Trust has contributed funding which has laid the ground for these larger grants.
- In particular the discovery of a change in a 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 diseases 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, working with Professor John Masters, studied stem cells from the prostate gland which are thought be responsible for prostate cancer development, with the aim of developing a novel stem cell-based approach to the treatment of prostate cancer. The Trust provided running costs for the project.
Stem cells are important basic cells which replenish and replace old and dying cells with new ones and ensure that a person’s organs are in good working order. Evidence from different cancers, however, has shown that they also contain their own rare ‘cancer stem cells’ which replenish the cancer and cause it to continue spreading. A cancer without cancer stem cells is similar to a tree without its roots, making it shrink and become less active. The project was started by using human tissue donated by hospital patients to study the properties of normal prostate stem cells. Methods were developed by Dr. Yamamoto for separating the minute stem cells from others in the tissue, using both lasers and magnetic fields. He has also discovered ways to grow them for prolonged periods in a specialised laboratory environment. Following this success, the same processes will be used on cancer stem cells in order to compare the behaviour of the normal cells with those from the cancerous tissue. In the long term this will proceed to investigation of various ways to target cancer stem cells using nanotechnology and novel drugs. The results have been presented at several international conferences.
The late John 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, and is now close to clinical application.
- The Trust shares any income from drug development based on patents arising from our funded research. Should this happen with Professor Masters patent, extra money would come to the Trust to fund further research.
- More accurate diagnosis of some prostate cancers can be made by identifying abnormal genes in the urine.
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 Children, Great Ormond Street(GOSH) – the late Sir David Innes Williams, Mr. P.G. Ransley, Mr. P. Duffy and most recently Peter Cuckow. 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 25,000 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.
Christopher Woodhouse, Professor of Adolescent 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 funded Professor 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 was also granted to Professor 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 was 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.
Dan 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 working with GOSH 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.
- In the past, children born with abnormal or missing bladders would have had an external bag to drain urine for their whole lives. Now they can have an internal reservoir for their urine which may be emptied by natural voiding or by intermittent self catheterisation.
- Renal failure due to abnormal bladder pressure or to over distension can be prevented or delayed by early intervention.
- Proper arrangements are made for the children to move through a transition clinic into an adolescent/adult clinic for lifelong specialist care.
Improving catheters and stents
Mr. Hugh Whitfield and Mr. Simon Choong, Urological surgeons at St. Peter’s Hospital, have, in conjunction with Professor 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.
- There is a much better understanding of the causes of catheter failure and chronic infection which has improved prophylaxis.