St Peter’s Trust Research groups
The Prostate Research Group in UCL is going from strength to strength. It is currently led by Professor Mark Emberton and Mr Hashim Ahmed with about 20 research staff. Over the last 3 years they have conducted almost 20 phase I and II clinical studies, having recruited almost 1,000 men to these trials over the last 4 years. An achievement which places this group at the forefront of the North-East Cancer Network’s trial recruitment numbers. Their grant income now totals approximately £12M in active grants from various sources.
Innovative research has also continued. They are evaluating new ways of diagnosing prostate cancer using urine and blood biomarkers, multi-parametric MRI and multi-parametric ultrasound as devices that might transform the diagnostic pathway for men with a suspicion of prostate cancer or those already diagnosed with it. They have led on the development of a new image-fusion device called SmartTarget undertaken with the engineering faculty at UCL as an example of bench to bedside commercialisation.
Their major project area – the minimally-invasive treatment of prostate cancer - has also seen substantial growth and they have led the field in focal therapy using high intensity focused ultrasound (HIFU) and cryotherapy with over 600 men treated focally over the last 5 years. The early and medium term results are very encouraging and other centres are now starting to adopt it in Harlow, Southampton and Basingstoke. A wide range other new treatments are also being assessed - such as irreversible electroporation, radio frequency ablation, magnetic nanoparticles, water vapour and injectable toxins that aim to target just the cancer tissue.
Prostate cancer - Assessment of the feasibility and acceptability of a new clinical trial design. More than 40,000 men are diagnosed with prostate cancer every year in the UK. There are several different treatments available but much uncertainty as to which might be best, so more evidence is needed through comparison of outcomes in comparable cases. Randomised controlled clinical trials are often used to compare treatments (in drug trials for example), where neither the patient nor the doctor knows which patient is receiving what. But where surgery is involved it is almost impossible to use such trials or to recruit to them, and surgeons and their patients often have strong - but sometimes misplaced - ideas of what works. It is very important to obtain unbiased information as to the best surgical procedure to employ in any given case, and the researchers therefore propose to test a new trial design which, if successful, could change the entire way randomised clinical trials are run in surgical specialties.
Much of this was achieved through the seed-corn funding provided by St Peters Trust.
Prostate research publications (Ahmed HU & Emberton M): 2015-2006. (PDF)
As a result of major technological advances in science over the last forty years it has become possible to discover how our bodies are regulated at the level of the different microscopically small cells that make up our various tissues and organs, and which hold our genetic material. The cell is the smallest functional unit that can operate more or less independently in any organism, and a human being is made up of millions of cells. Research at the cellular level has been funded by St Peter's Trust for many years, and important findings have been reported by the scientists and clinicians the Trust has supported - in diseases such as diabetes, renal stones, complications of renal failure, bladder malfunction and prostatic cancer.
A new disorder discovered. Prof. Robert Kleta and his research group at UCL Medical School and Great Ormond Street Hospital for Sick Children, London, have a particular interest and research expertise in the genetic causes of kidney diseases, especially those rarer inherited diseases that affect the function of the kidney epithelial (tubular) cells and which often first come to light in early childhood. Such studies require powerful computers with special software, because many thousands of gene sequence variations from the affected families have to be analysed and compared with the data held in the large genome databases that are now available. Funding provided by the Trust and the Grocer’s Charity have made 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 new 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 each to suffer from several different and very debilitating diseases that were not previously thought to be linked. It has been named the EAST syndrome, due to the presence in these children of Epilepsy, Ataxia, Sensineural deafness and renal Tubulopathy. The significance of this finding has been recognised internationally and the results have been published in a leading American medical journal.
Genetic research publications (Robert Kleta et al.): 2015-2010 (PDF)
Investigation of inherited kidney diseases. Dr. Daniel Gale and his team were provided with essential laboratory equipment used for storing and growing cells, as well as for amplifying genes and detecting proteins in patients with kidney disease. The research has proceeded well, and in 25 out of 60 families with previously unexplained inherited kidney disease the gene responsible has now been identified. This has allowed a firm diagnosis to be made for these patients and for genetic testing to be performed in other family members to find out if they have the same disease.
Another new disorder discovered. The researchers are now studying a new change in a gene identified in one of the families that they think causes a problem breaking down certain types of fatty acids. Work being done at the moment aims to find out how this problem causes kidney disease and if it can be corrected. Future work aims to find the gene changes responsible for disease in the remaining families and to understand how these changes cause kidney problems.
100,000 Genome Initiative. The Centre for Nephrology and Royal Free Hospital are now participating in the world-leading 100,000 Genome Initiative supported by the UK government. UK wide leadership for interpretation of data from renal patients in this ambitious project will by provided by the Centre. The aim will be to continue to translate findings from genetic research into clinical practice.
Development, integration and application of existing and novel spectroscopic techniques to urine, other biofluids and tissue analysis. The research will develop and explore three advanced spectroscope techniques to analyse urine and other biological fluid samples collected in order to identify and characterise rare renal diseases for genetic analysis, since a gene defect is likely to underlie the majority of such diseases. A renal bio-analytical research group will result, and use the information gained from the project to help develop non-invasive diagnostic criteria for clinical screening and potentially provide new insights into renal disease mechanisms. Prof. R. Unwin, with Dr. P. Cutillas, Senior Lecturer at Queen Mary, University of London Centre for Haemato-Oncology. The grant will provide half the costs of a PhD studentship jointly held between UCL and QMC / Barts Hospital under the UCL Partners arrangements.
The kidney filtering system and factors influencing its function. The main purpose of the kidney is to filter the blood circulating through the body and to remove the toxic waste products of metabolism - allowing filtration and formation of urine but preventing leakage of blood cells, proteins and larger molecules. The structure in the kidney that provides this ‘sieve’ within each of the kidney nephrons is called the glomerulus. A disease such as diabetes can damage the specialised cells of this complex filter and the barrier function is lost. The hallmark of such diseases is protein leaking into the urine and this can indicate progressive kidney failure. Diabetes remains the commonest cause of kidney failure worldwide, but other aspects are also being investigated:-
Dr. A. Hall, Dr. C. Peppiatt-Wildman, Prof. M. Duchen.
Many widely used medicines have toxic side effects in the kidney and in most cases the underlying mechanisms of damage remain poorly understood. The team has developed a new imaging-based research method that allows the effects of harmful agents to be studied in detail. Combined with experimental electrophysiology the effects of two drugs that commonly cause kidney disease will be investigated, together with possible ways of protecting against such harm.
Dr. Rob Blaber, together with Dr. Jill Norman and Dr. John Connolly in the Centre for Nephrology at UCL have been studying a growth factor present in the body, known as the Vascular Endothelial Growth Factor (VEGF). This is an entity whose effects on the kidney are very complex but vitally important for the maintenance of kidney filtration function. Efforts to inhibit the action of VEGF, for example in treating cancer, or to use it as a treatment of some medical conditions by attempting to grow new blood vessels, have both resulted in kidney damage and leak of protein in the urine. The goal of this project has been to understand how VEGF operates, and the following discoveries have been made:-
The group has demonstrated the unique signalling pathways inside cells that control the effects of VEGF and have identified these pathways as potential targets for drug development to treat kidney damage.
They have successfully established the culture of glomerular cells in the laboratory and their response to VEGF. Excitingly, they have developed a means of stimulating these cells to form blood vessels in culture. This assay method is being used to examine how kidney blood vessel growth is regulated and work is underway to establish a system in which cells grow together, producing a kidney glomerulus in culture. If successful this would be the first such experiment.
Podocytes are branching cells that surround the tiny blood vessels in the kidney and prevent leakage of protein from the great amount of blood filtered by the kidney each day. Over recent years there has been much interest in these cells as many genetic forms of kidney disease have been found to be due to inherited defects in podocyte proteins, and damage to them is also thought to be central to kidney disease resulting from diabetes. The group has now cultured and characterised podocyte cells in the laboratory and is examining how they function.
This work has been funded by St. Peter’s Trust and the Eranda Foundation and is being presented at international nephrological meetings and prepared for publication.
Dr. J. Marks, Dr. T. Debnam and Dr. L. Mossa-Al Hashimi studied the interaction between the small intestine and kidneys to investigate the function and identity of enteric phosphatonins. There is evidence that imbalance of phosphate regulation in the body increases the risk of hardening of the arteries and heart disease. Such phosphate toxicity is known to occur in patients with kidney disease but it has recently been suggested that eating foods high in phosphate (e.g. processed foods) can also produce vascular calcification in healthy individuals. In 2007 a ‘communication’ between the small intestine and kidneys to maintain phosphate balance was reported whereby upon ingestion of a phosphate-rich meal the intestine signals to the kidney to adjust its rate of phosphate reabsorption to rapidly eliminate any excess phosphate from the body.
The research funded by the Trust was undertaken to confirm whether or not different regions of the intestine release such a factor(s) and to establish the molecular identity of the factor. Their work refuted this hypothesis but the methods developed to investigate this question have led to new discoveries regarding the role of the gut in the regulation of other minerals and nutrients, including glucose handling. The resulting discoveries have been presented by Dr. Mossa-Al Hashimi at the Physiological Society and will form part of a full publication. The techniques are also being used by a PhD student (supervised by Dr. Marks) who is investigating how polyphenols affect intestinal glucose transport and whether these antioxidants can be used to treat diabetes-induced hyperglycaemia and hypertension.
Phosphate transport publications (J Marks et al.): 2015-2006 (PDF)
Exploring the role of the intestinal-renal axis and potential contribution of phosphatonins in phosphate balance in chronic kidney disease. Chronic kidney disease (CKD) is associated with increased deposition of calcium in arteries, causing them to harden. The high blood levels of phosphate that occur commonly in CKD patients may underlie this process. By exploring the regulation of phosphate by proteins called phosphatonins, which act on the kidney and gut, it is hoped to identify new therapeutic approaches to reduce premature vascular hardening and decrease the high risk of cardiovascular disease in CKD patients. Prof. R. Unwin. The Trust is contributing to the costs of a PhD studentship awarded to Grace Lee in 2013, in conjunction with Kidney Research UK.
Dr. M. Little, Ms. P. Jukes. Variability in neutorophil and antibody effector mechanisms in auto-immune small vessel vasculitis.
Dr. A. Salama, Dr. S. Henderson. Investigating granuloma formation in systemic autoimmune ANCA associated vasculitis and other granulomatous diseases. There are particular forms of inflammation that can affect the kidney and which are due to the immune system failing to clear certain infectious agents or proteins. These result in a clump of white blood cells, called a granuloma, and are typically found with tuberculosis infections and autoimmune diseases such as systemic vasculitis - inflammation of the small blood vessels which is a leading cause of acute kidney injury and thought to be associated with an antibody called ANCA. Vasculitis is difficult to diagnose, so organs may be severely affected by the time treatment is started.
The Little/Jukes study investigated the variable effect of the antibody ANCA in different patients and its importance in determining why some people develop severe vasculitis in their lungs and kidneys, while others have a mild form of the disease.
The Salama/Henderson study is trying to define the critical triggers for granuloma formation and see if it is possible to inhibit them more effectively.
KIDNEY DISEASE AND HYPERTENSION
Blood pressure is regulated by the kidneys and many renal diseases cause a sustained increase (hypertension), which in turn affects the health of the heart. Two grants have been awarded towards the purchase of core items of equipment for the Nephrology research teams to aid the study of the links between chronic kidney disease and cardiovascular impairment, such as ‘arterial stiffness’. Firstly a machine for the measurement of indicators such as arterial pulse wave velocity, for use in the Renal and Endocrine Investigation Unit (Prof. R. Unwin and his group). Secondly a telemetry suite for continuous 24 hour measurement of blood pressure changes using a laboratory model in order to understand the basic biology of hypertension and provide baseline information for clinical studies (Dr. S. Walsh and his group).
Spectroscopy equipment to develop a novel biomarker database in research on renal stones and other kidney diseases
Prof. Peter Rich reports that, thanks to the Trust, a bench top infrared ‘vibrational’ spectroscope has been installed in the kidney and urology unit at the Royal Free Hospital, and ward nurses Faith and Cameron are recording infrared spectra of patients’ urine samples. These can be obtained quickly and without need for any sample preparation. A database of urine readings related to specific clinical conditions will be built up over a three year period. More than 140 have been collected so far and spectra from patients with a variety of disease states show some promising differences. As the database is built and advanced analytical methods are applied, the researchers will look for diagnostic markers that indicate particular disease states, and the effectiveness of treatments, from this non-invasive procedure.
Dr. S.B. Walsh, Dr. A.A. Zdebik investigated the molecular regulation of the sodium chloride co-transporter NCC. Transplant patients often suffer from high blood pressure (hypertension). Recent data suggest that immunosuppressive therapy required to maintain the transplant has a side-effect on a salt transporter in the kidney so that these patients retain salt and water, leading to hypertension. By unravelling the mechanisms of this effect in the transplant patients, the aim is to understand the pathways important for blood pressure regulation and hypertension in the wider population; allowing more rational and effective treatment for this condition which affects 1.5 billion people worldwide.
Perioperative optimisation of transplant recipients. Dr. E. Stern, newly appointed Clinical Lecturer in Renal Medicine and Transplantation, was awarded a travel grant to enable him to spend a period of time at Yale School of Medicine in the USA to train in mass spectrometry and proteomics analysis techniques being developed there for new blood and urine tests to detect early kidney failure. In the protocol designed for the project (in which Dr. Stern would participate at the UCL/Royal Free Centre for Nephrology) the results from the analyses would be compared with the current standard treatment. It is hoped that proteins can be identified in the urine of kidney transplant donors and recipients which would help to predict how well a transplant would function, and consequently improve the average lifespan of kidney transplants and increase the number of kidneys available for transplantation.
Kidney Transplantation - Improvement of outcomes
Defining and manipulating immune reactions towards BK virus in renal transplant patients. Transplantation is a very successful treatment for kidney failure. However, lifelong immunosuppressant medicines to prevent rejection increase the risk of particular infections. BK virus is one such infection and, as there are no anti-viral therapies, treatment involves an adjustment of medication to enable the patient’s body to fight off the virus, which increases the risk of kidney rejection. At present doctors cannot predict who is at greatest risk, nor is it possible to do a test. This project will aim to develop novel treatments based on expanding the pool of white blood cells reactive to the BK virus.