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Research

Centre for Kidney Research

Clinical Research

Group Leader
Dr Jonathan Craig
Head of Clinical Research, Centre for Kidney Research
Phone: 9845 3432
Email: jonc@chw.edu.au

Laboratory Research

Group Leader
Dr Stephen Alexander
Head of Laboratory Research, Centre for Kidney Research
Phone: 02 9845 3430
Email: stephena@chw.edu.au

See also: the website of the Centre for Kidney Research for more details and contact information.

Clinical Research

Current research program

There are a number of research groupings within the Centre for Kidney Research (CKR) Clinical Group, including groups of national and international standing. We aim to bring the most up to date research methods available to bear on questions of the cause, the treatment and the prevention of diseases of the kidneys and urinary tract in childhood and in adults. Because we are based in a clinical environment, we seek to ask questions which are clinically important and to provide answers which are of value to clinicians. We also believe that we have an obligation to teach others about renal disease in childhood, and to contribute to the national and international kidney disease research communities.

Aboriginal Health

ARDAC (Antecedents of Renal Disease in Aboriginal Children)
Studies in remote Aboriginal communities, with large number of adults with kidney failure, have detected high numbers of children with blood and protein in their urine. We do not know if Aboriginal children in the southern states, where about 50% of Aboriginal children live, are more likely to have early markers of kidney disease compared with non-Aboriginal children. This study is now in its 6 year and involves over 2000 children from over 100 schools around NSW.

SEARCH (Study of Environment on Aboriginal Resilience and Child Health)
SEARCH is a collaboration between a number of organisations, including the Coalition for Research to Improve Aboriginal Health (comprising the Aboriginal Health and Medical Research Council and the Sax Institute), NSW Department of Health, the University of Sydney and six Aboriginal Medical Services across New South Wales. The SEARCH program aims:

  • To describe and investigate the causes of health and illness in Aboriginal children with a focus on healthy environments and selected child health problems by a cross sectional study of 800 families in urban and large regional centres and a prospective cohort study of the 800 families over 5 years
  • To determine whether a community appointed health broker in (i) a randomised trial focussed on otitis media and (ii) a feasibility trial of housing improvement is an effective, sustainable agent for improving the environment and health of aboriginal children and their families.

Cancer and Kidney Disease

Cancer is a major cause of morbidity and mortality in the chronic kidney disease (CKD) population. Large observational studies have consistently shown, on average, a two to three fold increased risk of cancer among kidney transplant recipients. Previous studies have also reported an excess risk of 20-50% for all cancers among people both with early stage CKD and on dialysis. Screening, which detects early stage disease and allows curative treatment is effective in reducing cancer-specific mortality in the general population. In the CKD population, the benefits and harms of screening is uncertain. The focus of our research will explore the various aspects of cancer risk, screening, prognosis and treatment effectiveness of cancers such that policy makers and health professionals will be informed about the most appropriate screening and management strategies in the CKD populations. Current research projects include:

  • Postal survey evaluating cancer screening practices among nephrologists in Australia and New Zealand
  • Evaluation of the cost-effectiveness of breast, colorectal and cervical cancer screening in the CKD population using decision analytical modelling
  • Evaluation of the incidence of cancers in the pre-dialysis population
  • Assessing the prognosis and treatment effectiveness of cancers in the CKD population

CARI Guidelines (Caring for Australasians with Renal Impairment)

The editorial base for the national guidelines on Kidney Disease is based at the CKR. Broadly this involves producing the guidelines and implementation research.

CARI Guidelines
The CARI Guidelines is an evidence-based project that commenced in 1999. The two bodies assuming responsibility for the CARI Guidelines are the Council of the Australian and New Zealand Society of Nephrology (ANZSN) and the Board of Kidney Health Australia (KHA). The CARI Organisation consists of a Steering Committee, the Guidelines Editorial Office and 26 Guideline groups. The CARI Guidelines also works in conjunction with the NHMRC Health Advisory Committee and the Cochrane Renal Group. The aim of the CARI Guidelines is to improve the health care and outcomes of paediatric and adult patients with kidney disease by helping clinicians and health care workers to adhere to evidence-based medical practice. By the end of 2007, a total of 20 major Practice Guidelines had been researched and written, with 5 Supplements published in the journal Nephrology. Existing guidelines cover the areas of Chronic Kidney Disease; Dialysis and Transplantation. Guideline recommendations are based on Level I and II evidence according to the NHMRC evidence classification system. The updating and revision of all guidelines is scheduled to occur every 3 years. Current and previous research projects within CARI include both quantitative and qualitative research projects.

Implementation research
A number of research projects have been undertaken to evaluate barriers to the implementation of evidence into routine clinical practice. The current major focus of research concerns the use of central venous catheters and fistulas in new cases of end-stage kidney disease.

Haemodialysis for end stage kidney disease (ESKD) requires permanent access to the blood circulation. The preferred choice of access is the native arteriovenous fistula (AVF), followed by an arteriovenous graft (AVG) with the least preferred choice being a central venous catheter. Patients commencing haemodialysis with a graft or catheter in situ have been shown to be at an increased risk of death (all-cause and infectious mortality) compared with those with an AVF in place. In Australia, the intervention rates for grafts and catheters are 6 times those for AVFs. The vascular access implementation project involves a controlled before and after study to measure the change in the number of new haemodialysis patients starting dialysis with a functioning native arteriovenous fistula. The CARI guidelines on "Timing of Access Formation" and "Choice of Type of Access" will be actively implemented because both are key steps in the adequate preparation of an individual for chronic haemodialysis. Initial baseline data for the 16 units who registered their interest in taking part in the project was performed using data collected by the Australia and New Zealand Dialysis and Transplant registry (ANZDATA). Eight renal units from Australia and New Zealand have been selected. An introductory face to face meeting was held in Feb 2008, to explain to all participating units how the project will run and their role and responsibilities. The units will work together with the CARI Guidelines Project Officer to establish protocols and procedures that can be employed to improve the timing of vascular access formation and increase the number of patients who begin haemodialysis with a functioning native arteriovenous fistula. A process map of current practice for each unit is being developed and their barriers to improved practice will be identified. An implementation plan will be developed for each unit to help them overcome blocks to better practice. The project is expected to run for 2.5 years.

Paediatric Kidney Disease

PRIVENT (Prevention of Recurrent urinary tract Infection in children with Vesicoureteric reflux and Normal renal tracts Trial)
Incontinence Research

The incontinence research group at the Centre for Kidney Research is involved with research in the areas of nocturnal enuresis and daytime incontinence.

The OUTCOMES study concerns two very common and important health problems in childhood, daytime wetting and urinary tract infections (UTI) in children. The aims of this population based cohort study are to determine the natural history of daytime wetting over a 1 year follow up period, the frequency of and risk factors for persistent daytime wetting and urinary tract infections.

We are currently conducting research on:

  • The effects of the anticholinergic drug oxybutynin on the functional bladder capacity of children with daytime incontinence (cohort of 100 children)
  • The accuracy of parental reporting of daytime incontinence in the diagnosis of monosymptomatic nocturnal enuresis (cohort of 1000 children)
  • A cohort study on response to bell and pad alarm training and need for re-training.

CRG (Cochrane Renal Group)
The world wide editorial base of the Cochrane Renal Group is based at the CKR, and is responsible for the development and dissemination of systematic reviews in the areas of kidney disease and kidney transplantation. The Cochrane Renal Group has had a major impact on the incorporation of clinical epidemiology and evidence-based medicine into mainstream nephrology worldwide, both directly and indirectly, including partnerships with guidelines groups (European, American, Australia-New Zealand, International), professional societies (International Society of Nephrology, Australia-New Zealand Society of Nephrology), advocacy groups (National Kidney Foundation of the US, Kidney Health Australia), and journals (Journal of the American Society of Nephrology, Kidney International, American Journal of Kidney Disease).

STEP (Screening and Test Evaluation Program)

FEVER Study (Febrile Evaluation of children in the Emergency Room)
The first phase of this study was to evaluate the relative diagnostic accuracy of clinical judgement versus a statistical algorithm for the detection of serious bacterial illness in over 14,000 children under 5 years of age presenting with a febrile illness to the Emergency Department. The second phase, which is currently underway is a cluster randomised trial to determine whether the algorithm-based decision support tool improves outcomes for these children.

Towards consumer-centered care and research: understanding patient and caregiver experiences and perspective in chronic kidney disease.

This is a series of projects, using qualitative research methods, to improve the quality of care delivered to children (and adults) with chronic disease. It includes:

  • Parental perspectives on caring for a child with chronic kidney disease
  • Patient priorities for health research: focus group study of patients with chronic kidney disease
  • An analysis of media coverage of prevention and early detection of chronic kidney disease in Australia
  • Patient perspectives on living with chronic kidney disease: focus group study

Major achievements in last 10 years

The CKR has an internationally recognized reputation in the discipline of clinical epidemiology, applied to nephrology and paediatrics. Historically, nephrology has been strong in basic science but weak in clinical and population health research which this group has sought to resolve. Highlights include:

  • The Cochrane Renal Group has produced the completion of about 55 published meta-analyses in the area of kidney disease, and the training of dozens of researchers in meta-analytic methods worldwide. These have directly impacted clinical practice through our contribution to many guidelines groups (European Best Practice Guidelines, CARI, and KDIGO), and through other means. Very recently, following the publication of a meta-analysis in the Lancet (February 2007), one of our PhD students and the head of CKR were invited to publish an editorial which questioned normalization of haemoglobin targets in chronic kidney disease patients, which has been widely advocated. Shortly after, the FDA issued a black box warning advising against normalization of haemoglobin levels because of increased all-cause and cardiovascular mortality, consistent with our editorial and a previously published meta-analysis.
  • As the NHRMC Centre of Clinical Research Excellence in Kidney Disease, we have been able to provide infrastructure to young clinical researchers in Australia, and to develop a national network of clinician-scientists in kidney disease. Eight PhD scholarships have been provided, and 13 awards to subsidise clinical epidemiology training for promising clinical researchers have been made. With the success in obtaining a Capacity Building in Population Health Research NHRMC grant this year, this collaboration can be extended both at an investigator level, but also in the provision of post-doctoral support to 10 researchers. A critical mass of clinical researchers in kidney disease now exists in Australia, and our impact is being felt internationally.
  • 21 of our publications have been cited more than ≥ 20 times (h-index), and fifteen of our publications have been co-published with positive editorials. We have been invited to write editorials for the Lancet, and for most of the major nephrology journals (American Journal of Kidney Disease, Journal of the American Society of Nephrology, and Nephrology, Dialysis and Transplantation). Overall, our publications have been cited nearly 1000 times, about 8 times on average, and with the current number of citations per year increasing sharply is now around 350.

Key publications with comments on their significance

  1. Strippoli GFM, Craig JC, Schena FP. The number, quality and coverage of randomized controlled trials in nephrology. Journal of the American Society of Nephrology 2004; 15: 411-419 (with editorial)
    First study to show the poor trial basis of many interventions used in nephrology
  2. McDonald S, Craig JC. Long-term survival of children with end-stage renal disease. New England Journal of Medicine 2004; 350(26): 2654-2662 (Perspective on p2637)
    Widely quoted study describing prognosis for children with ESKD
  3. Caldwell P, Butow P, Murphy S, Craig JC. Clinical trials involving children. Lancet 2004; 364: 803-11 (with editorial)
    Widely quoted study describing the therapeutic orphan status of children and proposed solutions
  4. Hodson E, Jones CA, Webster A, Strippoli G, Barclary PG, Kable K, Vimalachandra D, Craig JC. Antiviral medications to prevent cytomegalovirus disease and early death in recipients of solid-organ transplants: a systematic review of randomised controlled trials. Lancet 2005; 365(9477): 2105-2115
    Definitive study describing the improvements in survival with prophylactic antiviral medication to solid organ transplant recipients
  5. Strippoli GFM, Tognoni G, Navaneethan SD, Nicolucci A, Craig JC. Haemoglobin targets: we were wrong, time to move on. Invited editorial Lancet 2007; 369(9559): 346-350

Research Staff

Researchers

  • Dr Patrina Caldwell, B Med FRACP PhD, Staff Specialist for Incontinence, CKR
  • Ms Denise Campbell, BSc, MPH, Senior Project Officer, CARI Guidelines
  • Ms Sonia Crampton, BN, Data Manager, Fever Study
  • Dr Elisabeth Hodson, MBBS, MRCP, FRACP, Head Department of Nephrology/Centre for Kidney Research
  • Ms Sana Hamilton, BAppSc(Nursing), MPH, Research Nurse, Fever Study
  • Ms Gail Higgins, BA, DipEd, Grad Dip Lib Sci, Trials Search Coordinator, Cochrane Renal Group
  • Dr Martin Howell, BSc(Hons), PhD, Research Assistant
  • Ms Michelle Irving, MHScEd, Senior Research Officer, CARI Guidelines
  • Ms Ashisha Kallukaran, MBBS, Data Manager, Fever Study
  • Ms Marianne Kerr, , BAppSc(Nursing), BPH,Data Manager, Fever Study
  • Ms Anh Kieu, BMSc, Research Assistant, Fever Study
  • Ms Pamela Lopez-Vargas, RN, BSc., BHthSc.(T.C.M.), Project Officer, CARI Guidelines
  • Ms Alison Lowe, BSc (Hons), Research Assistant / Trial co-ordinator PRIVENT
  • Ms Ruth Mitchell, Grad Dip Lib Sci, MA (Inf), Trials Search Coordinator, Cochrane Renal Group
  • A/Prof Paul Roy, MBBS, BSc(Med), FRACP, Clinical Research, CKR
  • Ms Premala Sureshkumar, BSc, PhD, Clinical Research Fellow (NHMRC Capacity building grant in Population Health)
  • Dr Giovanni Strippoli, MBBS, MPH, PhD, Honorary Research Fellow
  • Ms Allison Tong, MPH (Hons), and B Med Sci, Research Officer, CARI
  • Dr Angela Webster, MBBS, MM (Clin Epi), PhD, MRCP(UK), Snr Research Fellow
  • Ms Gabrielle Williams, BSc (Hons) MPH, PhD, Senior Research Officer- FEVER Study
  • Ms Narelle Williams, RN BAppSc(Nursing) GradDipNurs(Surgical), Fever Study
  • Ms Rita Williams, BA, Snr Aboriginal Health Education Officer, ARDAC Study
  • Ms Narelle Willis, BSc, MSc, Coordinator, Cochrane Renal Group

PhD Candidates

  • Dr Miriam Codarini, MBBS, DipPaeds, FRACP, Clinical Research Fellow
  • Dr Nick Cross, MbChB, MM (Clin Epi), FRACP, Clinical Research Fellow
  • Dr Hasantha Gunasekera, MBBS DCH FRACP MIPH(Hons), Clinical Research Fellow
  • Dr Leigh Haysom, MBBS, FRACP, MSc (Med), MClin Epi
  • Dr David Lester-Smith, B Med Sci (Hons), BM BS, DCH, MRCP(UK), MRCPCH(UK), FRACP, MPH, Clinical Research Fellow
  • Dr Angie Morrow, MB, BCh, BAO (NUI), LRCPI, LRCSI, Clinical Research Fellow
  • Dr Yashwant Sinha, BSc(Med), MBBS(Hons), FRACP, A Mus A, LTCL, L Mus A, Clinical Research Fellow
  • Dr Germaine Wong, MBBS, MMed (Clin Epi)

Administrators

  • Sandra Puckeridge, Officer Manager, CKR
  • Tamara Borysko, Administrative Officer, PRIVENT & NHMRC Capacity building grant in Population Health
  • Leslee Edwards, Administrative Officer, Cochrane Renal Group

Research Support (2005-2008)

  • NHMRC/ARC - 5 research grants, 2 program grants, 1 capacity building grant, 1 healthy start to life grant, 1 enabling grant & 1 CCRE grant, total funding $18,334,998
  • Other Government competitive funds - 4 grants, total funding $8,177,089
  • Government non-competitive fund
  • Funds from industry - Servier $120,000 for post doc LIRICO
  • Other competitive fund - 3 grants, total funding $235,500
  • Other non-competitive fund

Laboratory Research

Current Research Programs

There are 3 research groupings within the Centre for Kidney Research (CKR) Laboratory Group.

Glomerulonephritis Research Group
This group, which includes Stephen Alexander and Yuan Min Wang studies the causes of and possible treatments for nephritis, the commonest cause of renal failure in children and adults in Australia.

It examines animal models of nephritis such as Heymann nephritis and also human forms of nephritis such as IgA nephropathy and acute crescentic GN. Our current focus of research is in T cell directed forms of immunotherapy aimed at treating renal disease.

We currently have studies aimed at DNA vaccination against pathogenic TCR Vbetas and against chemokines thought to be pathogenic. These studies are done in collaboration with Prof David Harris at Westmead hospital.

Renal Genetics Group
We are currently establishing methods of investigating genetic renal diseases in patients. We have identified a number of children with renal failure due to mutations in the WT-1 gene and hope to extend this to other diseases over the coming years. This work is principally the work of Stephen Alexander and Jeffery Fletcher.

Transplantation Research
This group led by Stephen Alexander studies rejection and tolerance in human renal transplantation - particularly the living related donor transplants (parent to child) performed regularly at the hospital - and in animal models of transplantation (skin grafts in mice). It has a particular interest in T-cell activation and T-cell receptor repertoire, and in the study of tolerance through adoptive transfer.

We form part of the larger transplantation research group at the Western Hub, with whom, there are close collaborations. Min Hu is responsible for the human studies, and Geoff Zhang and Debbie Watson are responsible for the animal studies.

Major Achievements in last 10 years

Our group has made major discoveries on the role of regulatory T cells in kidney disease and transplantation. It has developed a number of animal models of tolerance using pruning and donor specific transfusions which have allowed us to investigate major mechanisms of tolerance.

  • The group has also been involved in identifying genetic causes of kidney disease.
  • Work on mixed chimerism.
  • Identification of the indirect pathway of allorecognition in clinical transplant patients.
  • Development of pruning of alloreactive T cells.
  • Work on models of tolerance in glomerulonephritis including identification of a novel gamma-delta regulatory subset.
  • Identification of pathogenic T cells at a molecular level in the urine of transplant patients.
  • Development of novel therapeutic strategies for T cell mediated disease.

Key Publications with comments on their significance

  1. Long-term Cardiac Allograft Survival Across a Major MHC Mismatch After "Pruning" of Alloreactive CD4 T Cells Hu M, Watson D, Zhang GY, Graf N, Wang YM, Sartor M, Howden B, Fletcher J, Alexander SI. J Immunol 2008 (May 15).This is the use of a new method of removing alloreactive T cells allowing solid organ transplantation without immunosuppression
  2. Expression of IL-2 and IL-7 receptors discriminates between human regulatory and activated T cells Seddiki N , Santner-Nanan B, Martinson, J, Zaunders J, Sasson S, Landay A, Solomon M, Selby W,. Alexander SI, Nanan R, Kelleher A, Fazekas de St Groth B. J Exp Med. 2006 Jul 10;203(7):1693-700. This is a seminal paper that defined surface markers that allow clinical separation of regulatory T cells.
  3. Wu H, Wang YM, Wang Y, Hu M, Zhang GY, Knight JF, Harris DC, Alexander SI. Depletion of gammadelta T cells exacerbates murine adriamycin nephropathy. J Am Soc Nephrol. 2007 Apr;18(4):1180-9. This paper defined a novel regulatory gamma delta T cell subset in kidney disease, it was listed as one of the top 10 publications of 2007 in renal disease at the European Nephrology Meeting.
  4. Development Of Tolerance And Complete Hematopoetic Chimerism, Without Graft Versus Host Disease, Following Fully Mismatched Cadaveric Liver Transplantation Alexander SI; Smith N; Hu M; Verran D; Shun A; Dorney S; Smith A; Webster B; Shaw PJ; Lammi A; Stormon MO. New England Journal of Medicine 2008 Jan 24;358(4):369-74. This is the first demonstration of spontaneous full chimerism allowing withdrawal of immunosuppression in a transplant patient.
  5. Wang YM , Zhang GY, Wang Y, Hu M , Wu H, Watson D, Hori S, Alexander IE., Harris DCH and Alexander SI Foxp3 transduced polyclonal regulatory T cells protect against chronic renal injury from Adriamycin . J Am Soc Nephrol. 2006 Mar;17(3):697-706. This is the first demonstration of gene therapy protecting against renal disease by the induction of a regulatory population.

Research Staff

Researchers

  • Dr Elisabeth Hodson, MBBS, MRCP, FRACP, Head Department of Nephrology/Centre for Kidney Research
  • Dr Min Hu, MD, MMed, PhD, Research Officer
  • Dr Yuan Min Wang, MD, PhD in Medicine, Senior Research Officer
  • Dr Debbie Watson, BSc (Hons), PhD
  • Dr Geoff Zhang, MD, Senior Hospital Scientist

PhD Candidate

  • Ms Tania Polhill, BSc (Hons) NHMRC funded
  • Dr Jeff Fletcher, BSc (Hons), MBBS, FRACP NHMRC funded

Administrator

  • Sandra Puckeridge, Officer Manager, CKR

Research support for group (2005-2008)

  • NHMRC/ARC - 4 project grants, 1 ARC grant total funding $1,812,030
  • Other Government competitive funds
  • Government non-competitive fund
  • Funds from industry
  • Other competitive fund - 4 grants total funding $962,592
  • Other non-competitive fund

Opportunities for Students

Postgraduate Research available at the University of Sydney.

This document was updated on Wednesday, 30 July 2008

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