Sixty-two applications were received by the deadline (44 Research Projects; 18 Innovation) and following full external review of ALL applications via the full Research Grants Committee (RGC) and External Referees, 32 applications were short-listed for discussion, based upon scientific merit, at the May RGC meeting (20 research projects and 12 Innovation). Following the meeting the committee made a recommendation to fund 15 awards (9 research projects and 6 innovation) which were subsequently endorsed by the Board of Trustees as follows:
Success rate: 24%
IN6 2010 Professor Isky Gordon, Institute of Child Health, £39,712 over 18 months
Reproducibility and accuracy of absolute renal perfusion measurements using Arterial Spin Labelling with Magnetic Resonance Imaging.
Measurement of blood flow to the kidney without injections, contrast agents or chemicals
The research will establish if it is possible to measure the blood flow to the kidney in a totally non-invasive way without any injections or radiation, using a new magnetic resonance imaging technique.
Virtually all diseases that affect the kidney, affect the blood flow to the kidney significantly. Certain therapies, such as anti-cancer drugs, cause kidney damage. Reliable and reproducible measurement of kidney blood flow could enable us to monitor any kidney damage and could thus influence treatment.
Patients who have undergone kidney transplantation are monitored regularly for evidence of dysfunction of the transplanted kidney, and accurate measurement of renal blood flow may provide a new sensitive tool for the clinician.
RP19/2010 Dr Albert Ong, University of Sheffield, £179,995 over 3 years
Structure-function analysis of the polycystin-1PLAT domain.
Investigating the structure and function of PLAT, the most evolutionarily conserved domain of the PKD1 protein, polycystin-1
PKD1 is the gene that is affected by mutations in 90% of patients with autosomal dominant polycystic kidney disease. The PKD1 protein, polycystin-1, is a large and complex protein which has proved difficult to study. In this project, we will study one part of the protein, called the PLAT domain. PLAT is the most evolutionarily conserved domain of polycystin-1 and thus likely to be critical for its function. By determining the detailed structure of PLAT, we will gain new insights into how the polycystin-1 protein controls and transmits signals into the cell and how this is altered in human disease.
RP18/2010 Dr Andrew Salmon, University of Bristol, £119,999 over 2 years
VEGF 165b: developing a new treatment for proteinuria renal disease.
VEGF165b as a new treatment for kidney diseases in which protein leaks into the urine (proteinuria)
Diabetes causes filters inside kidneys (glomeruli) to leak protein into the urine (proteinuria): this is the UK’s leading cause of kidney failure. Kidneys produce an inhibitory molecule (VEGF165b) that reduces proteinuria.
We plan to test whether (and how) VEGF165b can reduce proteinuria and prevent long-term damage in an animal model of diabetic kidney disease. We will also test whether VEGF165b levels fall in human kidney diseases, and whether VEGF165b treatment can alter the leakiness of diseased human glomeruli. VEGF165b is being developed as a treatment for cancer: this project will show whether VEGF165b could be used to treat kidney disease.
RP27/2010 Professor Ken Farrington, Lister Hospital, £54,381 over 6 months
Development of methods to measure energy expenditure in chronic kidney disease.
How should we measure energy needs in patients with chronic kidney disease?
The major task of the kidneys is to remove waste products. The more energy the body expends, the higher the food requirements and the greater the waste which accumulates. We know very little about energy needs and nutritional requirements in kidney patients, and how these factors affect the need for dialysis. Simple tools are needed. We will measure energy requirements in patients with kidney disease using a very accurate method called the “doubly labelled water technique”. We will compare these with less costly measurements including those obtained using a device which measures oxygen content of air breathed out. We will also measure physical activity levels with questionnaires. This research will allow us to determine whether simple methods can provide a good estimate of energy needs in kidney patients.
RP9/2010 (IN) Dr Jill Norman, University College of London, £36,029 over 12 months
The role of Dimethylarginine Dimethlyaminohydrolase 1 (DDHA1) in profibrotic responses of renal tubular epithelial cells.
A study to establish whether an enzyme, Dimethylarginine Dimethylhydrolase 1, contributes to kidney scarring and organ failure.
Following initial injury, kidney function tends to decline inexorably with many CKD patients requiring renal replacement therapy. Our recent research has identified an enzyme, Dimethylarginine Dimethylaminohydrolase (DDAH) 1, which is found in the kidney and which appears to be closely linked to the decline in kidney function. We believe that this enzyme may promote the formation of scar tissue (fibrosis) in the kidney, leading to organ failure. The proposed project will use cultured kidney cells to investigate the role of DDAH1 in fibrosis to determine whether inhibition of the enzyme may be a new treatment strategy to preserve kidney function.
RP45/2010 Professor Bruce Hendry, Kings College London, £75,427 over 3 years
Targeting Ras GTPase in a mouse model of autosomal dominant polycystic kidney disease.
New strategies for treating Autosomal Dominant Polycystic Kidney Disease.
Autosomal dominant polycystic kidney disease.
(ADPKD) is one of the commonest life-threatening inherited diseases, affecting approximately 12.5 million people worldwide. It is caused by an abnormal cell growth resulting in multiple cysts in both kidneys. There is currently no cure, and most people with ADPKD develop kidney failure and require dialysis or transplantation. We propose to study a novel strategy for treatment that targets the initial development of cysts in the kidneys.
IN1/2010 Dr Qihe Xu, Kings College London, £40,000 over 12 months
Retonoic acid in collecting ducts: what are its target genes?
Vitamin A target genes in the kidney
Vitamin A is necessary for normal kidney development, but its functions in the kidney after birth are unclear. We have found that vitamin A activation occurs selectively in a specific segment of the renal tubule, the collecting duct. We will examine the gene expression profiles of this tubule segment in the absence and presence of activated vitamin A and/or its inhibitors. Using high-throughput assays, we will try to answer 2 keys questions: ‘Why do kidneys still need vitamin A after birth?’ and ‘What could this mean for the role of vitamin A in normal and abnormal kidney function?’
RP28/2010 Dr Nigel Brunskill, University of Leicester, £172,446 over 3 years
CD36: A key receptor mediating the effects of proteinuria, complement and acidosis in progression of CKD.
Why protein leakage into urine leads to worsening of kidney disease
Once kidney damage starts, it frequently worsens, leading to irreparable damage. Initial damage allows proteins from blood to leak into (and damage) parts of the kidney (the tubules) which these proteins would not normally reach. These proteins then leak into the urine. It has recently been shown that neutralising acid in the kidney by giving patients sodium bicarbonate (“baking soda”) slows down this damage. This project aims to show that some of these leaking proteins are so-called complement proteins (which normally serve to destroy invading micro-organisms) but are activated inappropriately when they reach acidic parts of the kidney, leading ultimately to kidney failure.
IN14/2010 Professor Mike Nicholson, Leicester General Hospital, £36,922 over 12 months
Normothermic preservation in kidney transplantation.
Warm preservation of kidneys
Traditionally organs are stored by using low temperatures to reduce metabolism and requirement for oxygen (Hypothermic preservation). However, under these conditions some damage occurs. The longer an organ is stored cold the more injury it suffers. This reduces the function of the kidney after transplantation.
There is a clear need to develop new technologies to improve kidney transplantation. Preserving the kidney by warming it with oxygenated blood (Normothermic Preservation) after it has been stored cold may allow the reversal of the harmful effects of hypothermic preservation. This may better prepare the organ for transplantation and improve function post transplant.
IN10/2010 Dr David Kluth, University of Edinburgh, £18,300 over 12 months
Macrophage regulation of endotheline-1 haemodynamic responses.
A novel understanding of blood pressure control.
Hypertension is an important cause and consequence of chronic kidney disease (CKD). It is a major risk factor for diseases such as strokes and heart attacks. Endothelin-1 (ET-1) is a protein which raises blood pressure and is elevated in CKD. We have discovered that white blood cells (macrophages) take up ET-1 and may have an important role in controlling hypertension caused by ET-1. We aim to find out how macrophages take up ET-1 and what happens to hypertension when they are removed from mice. This innovation grant will provide a new insight into the control and treatment of hypertension.
RP11/2010 Dr David Kluth, University of Edinburgh, £130,662 over 2 years
Macrophage cell therapy in renal ischaemia-reperfusion injury.
Cell therapy for acute renal failure
Acute renal failure (ARF) is common problem for patients in hospital. It is mostly due to reduced blood flow to the kidney and many patients require dialysis. We have no specific treatment. Such episodes of ARF also increase the long-term incidence of chronic kidney disease, especially in the elderly. We have shown that specialised white blood cells (macrophages) from a mouse can be modified to express a protective gene called heme-oxygenase-1 (HO-1). When these cells are injected into a mouse with ARF they are able to maintain blood flow in the kidney and improve kidney function. We now aim to show that we can also alter human macrophages and determine whether this early benefit leads to more rapid recovery of the kidney and less long-term damage. Cell therapy is a potential treatment in ARF.
RP33/2010 Dr William Newman, St Mary’s Hospital, £177,587 over 3 years
Uro-facial syndrome (UFS): a novel genetic model to understand human renal tract function and malformation.
Genetics of bladder dysfunction leading to kidney problems.
Urofacial syndrome is an inherited condition, which results in incomplete emptying of the bladder and subsequent kidney damage. We have found one gene that causes this condition. We now want to find out if this gene is responsible for other forms of bladder dysfunction and for reflux disease. At present, we do not know how many children have changes in the identified gene or what the gene does. This study will try to answer these questions and provide important information so that children will bladder problems get the correct explanation for their problems and optimum treatment.
RP42/2010 Dr Richard Coward, Southmead Hospital, £136,068 over 2 years
The role of insulin like growth factors in podocyte and glomerular function.
Insulin like growth factors and kidney function
An important role of the kidney is to act as a sieve and prevent protein leaking into the urine. A filter called the glomerular filtration barrier, of which a cell called the podocyte is extremely important, achieves this. We have found that two hormones called IGF1 and IGF2 are very important for keeping the podocyte and ultimately the kidney healthy. We now intend to study the role of these hormones in kidney disease. We hope it will lead to new treatments to prevent the loss of protein into the urine and ultimately reduce the number of people developing kidney failure.
RP2/2010 (IN) Dr Lesley Rees, Great Ormond Street Hospital, £9,600 over 18 months
Evolution of mineral and bone disorder in early CKD: the role of FGF23 and vitamin D.
Insights into the evolution of mineral and bone disorder in chronic kidney disease in children.
Vitamin D deficiency is common in children with chronic kidney disease (CKD) and begins early in its course.
Low vitamin D levels lead to release of parathyroid hormone (PTH). PTH leaches calcium and phosphate from the bones and deposits them in the blood vessels, causing hardening of the arteries and risk of cardiovascular disease.
We are, therefore, running a randomised trial of nutritional vitamin D supplements to see if we can prevent high
PTH levels. Recently a new factor, FGF23, has been identified to also play a role from the earliest stages of development of CKD. We therefore wish to find out more about this hormone by measuring it in the samples that we are already taking during our ongoing vitamin D study. We hope that a better understanding of the evolution of the processes causing mineral and bone disorders will enable the future development of new and more targeted therapies to prevent bone and cardiovascular disease.
RP8/2010 Dr Jill Norman, University College of London, £173,264 over 3 years
The role of fibrosis in progression of Autosomal Dominant Polycystic Kidney Disease (ADPKD).
Understanding the relationship between progressive scarring and loss of kidney function in human
Autosomal Dominant Polycystic Kidney Disease (ADPKD).
ADPKD is a common genetic kidney disease which frequently leads to renal failure. Both kidneys progressively enlarge due to expansion of cysts surrounded by variable amounts of scar tissue (fibrosis) produced by fibroblast cells. Fibrosis is thought to accelerate decline in kidney function but how or why this happens in ADPKD is unknown. Cultures of fibroblasts from normal and ADPKD kidneys, human kidney samples and a model of ADPKD will be used to investigate differences in fibroblast behaviour and identify molecules driving fibrosis. Understanding how fibrosis develops should lead to therapies to slow progression and delay the need for dialysis.
RP29/2010 Professor Tim Goodship, University of Newcastle, £137,742 over 2 years
Complement susceptibility factors in idiopathic membranoproliferative glomerulonephritis (MPGN)
Multiple genetic and autoimmune factors predisposing to membranoproliferative glomerulonephritis
Membranoproliferative glomerulonephritis (MPGN) is a progressive cause of kidney failure from which recovery is unusual and often requires long term dialysis. The pivotal role of the complement system in MPGN has been recognised for some time. Complement is an ancient defence system which coats both foreign cells (such as bacteria and viruses) and our own cells (including those of the kidney) with a substance called C3. This substance will eventually lead to the destruction of bacteria and viruses by damaging the cell wall. If our own cells are not protected against C3 they can suffer a similar fate. This is why we have a series of regulators which inactivate C3. We have in pilot studies found that patients with MPGN have mutations in C3 and antibodies against a regulator called factor H. In this study we wish to examine whether MPGN patients have mutations in other complement genes and antibodies against other complement proteins. There are now specific agents to treat both complement and antibody associated diseases. This opens up other possible avenues for the treatment of MPGN.
