We would like to highlight world class research undertaken by members of the ANZSN. The following is an excellent example of where our researchers are making important contributions to medicine and science. Congratulations to all the team involved in making these seminal discoveries.
This Nature publication led by Prof Richard Kitching’s team, uses kidney disease to answer a fundamental question in autoimmune disease. We have not known, in any autoimmune disease, why some HLA alleles protect from the risk of disease. Although Goodpasture's disease is rare, it has a number of characteristics that make it an ideal model autoimmune disease to use to address fundamental questions as to the nature of loss of tolerance and the cause of autoimmune diseases. Of course, autoimmune diseases are not only prominent causes of kidney disease, but also include many other diseases that affect approximately 7% of the population.
Critical contributions were made by a number of students, clinician scientists and scientists in the research team who are members of the ANZSN, especially Dr Joshua Ooi, the joint first author.
Commentary in Nature Reviews Nephrology and Nature Reviews Rheumatology (July 2017) quotes Prof Kitching as saying:
"The basis of the loss of immunological tolerance in most autoimmune diseases lies in the inheritance of HLA alleles that modulate the risk of autoimmunity.In this study we used Goodpasture's disease to address two long-standing questions — what is the basis of HLA-mediated protection in autoimmune disease and how does a protective allele mitigate the excess risk conferred by a susceptibility allele?. These findings provide a structural and mechanistic basis for understanding HLA-mediated susceptibility and protection in autoimmune disease"
The paper substantially progresses our understanding of autoimmune disease. It provides a platform for further advances, emphasises the importance and potential therapeutic roles for peptide specific regulatory T cells in autoimmune diseases, which may serve as specific therapies for these diseases which are difficult to treat effectively.
This is a link to the articles (non-downloadable or printable). The citation is below:
Nature. 2017 May 11;545(7653):243-247. doi: 10.1038/nature22329. Epub 2017 May 3.Dominant protection from HLA-linked autoimmunity by antigen-specific regulatory T cells.Ooi JD, Petersen J, Tan YH,Huynh M, Willett ZJ, Ramarathinam SH, Eggenhuizen PJ, Loh KL, Watson KA,Gan PY, Alikhan MA,Dudek NL, Handel A, Hudson BG, Fugger L,Power DA, Holt SG, Coates PT, Gregersen JW, Purcell AW,Holdsworth SR, La Gruta NL, Reid HH, Rossjohn J,Kitching AR.
The KidGen Collaborative
The KidGenCollaborative is an Australian-based consortium of clinicians, genetic counsellors, genetic diagnosticians and researchers. As a group, we are focusedon providing adefinitive diagnosis to patients with inherited forms of kidneydisease in a supportive patient setting.Throughthe KidGen multidisciplinary clinics, currently operating in 14 public hospitals across Australia,we are working to provide equitable access to genomic technology for Australian families. At the same time, we are working to betterunderstand these diseases in the hope of developing new treatments.
We also operate as the Renal Genetics Rare Disease Flagship of Australian Genomics, and are undertaking the following projects:
KidGen Clinics Network
-Currently there are 13 Multidisciplinary Renal Genetics Clinics operating around Australia in QLD, NSW, Vic, SA and WA, with a further 2 clinics currently in planning-stage in NT and Tasmania. The clinics bring together adult nephrologists, paediatric nephrologists, clinicalgeneticists, and genetic counsellors to see patientsand families affected by inherited kidney disease. Within these clinics a variety of services are offered, including but not limited to diagnostic advice, treatment advice, genetic counselling, diagnostic genetic/genomic testing and potential participation in research projects. These are clinical service clinics but are the subject of outcome and health economic research (see below) and are also a key interface to enable engagement and participation in multiple other facets ofclinical, translational and basic science research.
The HIDDEN Study
The HIDDEN study is a nationwide study aiming to identify the prevalance of genetic kidney disease amongst Australia's End Stage Renal Failure (ESRF) population. The study will perform Whole Genome Sequencing in ESRF patients who are less than 50yo and who have no clearly identified cause for their renal disease. Preliminary data suggests that a proportion of this undiagnosed group have hidden genetic disease. This would be valuable to identify in order to provide diagnostic clarity, assess at-risk family members and potentially provide access to treatment for the extended family. This valuable study is currently being developed and not currently funded.
Renal Genetics Clinic & Genomics Outcome Evaluation
We anticipate recruiting approximately 500 patients to the Renal Genetics Rare Disease Flagship of Australian Genomics, and plan to evaluate the outcomes of genomic testing in terms of diagnostic and clinical utility, and cost effectiveness. We will also evaluate the patient experience of multidisciplinary Renal Genetics clinics, as well as patient understanding of genomic testing, and patient views on data sharing.
Research Genomics Project
This project seeks to identify novel or very rare genetic aetiologies for diagnostically refractory instances of inherited kidney disease. Initially applying whole exome and now whole genome sequencing with pedigree-guided comprehensive bioinformatic analysis using a custom in-house developed pipeline and interface, a total of 32 families have been analysed to date with a diagnostic finding having occurred in 14 families (44%) to date with a candidate novel genetic finding in a further 6 families. Eight further families have been enrolled and are awaiting genomic sequencing/analysis, and another 8 families are currently undergoing recruitment.
- This project is significant as it provides an avenue to potentially secure a diagnosis when all others have been exhausted for families with inherited kidney disease. The applicability of this is expanding as the current recruitment sites in QLD, NSW and Vic and being joined by others in Vic, SA, WA and NT over the coming months. This project is currently supported via an NHMRC Project Grant (2016-2019).
Functional Genomics Project
Using iPSC-lines derived from patients we are able to recreate and model their specific disease in the laboratory by turning these iPSC into kidney organoids.We have the capability to correct the mutation found in the patients genome in order to interrogate their disease further, dissecting the disease mechanism and aiding in the development of new therapies.
The ARRK Registry is a database and website being developed for patients with rare and genetic kidney disease. The website provides information written by specialists about general and more specific aspects of these conditions. In addition it provide links to further useful information for patients and their families.The ARRK database provides a platform for researchers to study these specific diseases. Kidney health teams in local hospitals around the country will be able approach patients and ask for written consent to be included and then input their clinical data onto a secure database for analysis by the research teams. Where possible, the analysis (but not sensitive personal information) will be shared with international researchers to maximise the research opportunity.
Symposium, Meet-the-Scientists and Educational Events
The KidGen group runs a number of educational events including an annual Renal Genetics Symposium (78 attendees in 2016) and an interactive Renal Genetics workshop (planned 30 attendees in December 2017). KidGen is also active in patient engagement contributing blog posts to AJKD and NephJC and recently hosting a successful "Meet the Scientists" evening with 55 attendees (movie available to download on website).
Furthermore the group maintains a busy twitter account (@kidgenaustralia) and website (www.kidgen.org.au) which provides patient information about the group's research and events (150 - 200 unique visitors per week). The KidGen group has developed an innovative approach to facilitating research consent using whiteboard animations which they have also adapted for use by other flagships.
The Affordable Dialysis Project
by Prof JF Knight, Professorial Fellow at The George Institute for Global Health, Sydney
The Affordable Dialysis Project had its seeds in a paper published by the George Institute for Global Health in the Lancet in March 2015 (1) which addressed two simple questions – how many people in the world are receiving treatment for end stage kidney disease – and how many are missing out? The answer to the first question was that 2.618 million people around the world were receiving renal replacement therapy in 2010, the most recent year for which figures were available. The number of patients dying each year to lack of access to dialysis was dependent upon the modeling tools used; and was estimated as between 4·902 million (95% CI 4·438–5·431 million) in a conservative model and 9·701 million (8·544–11·021 million) in a high estimate model. Overwhelmingly, these patients are dying because the health system in their country is unable to provide dialysis at a cost they can afford. A forward projection showed that the numbers are expected to increase, and that most of the growth would be in the developing world. For more information please click here.