Dr Zein Amro – Western Sydney University
Heard Family Early Career Research Grant
Revisiting AQP water channels in cystogenesis: potential novel therapeutic targeting of AQP1 for ADPKD treatment
Autosomal dominant polycystic kidney disease (ADPKD) is an inherited condition in which fluid-filled cysts grow in the kidneys that eventually causes kidney failure. It is caused by faults in two genes that normally help kidney cells control how fluid moves in and out. When these genes do not work properly, kidney cells grow too quickly and pump excess fluid into cysts, making them larger over time.
Water enters cysts through special protein channels called aquaporins (AQPs). Several aquaporins, including AQP1, AQP2 and AQP3, are found in the kidney and are linked to cyst growth, although the roles of some are still not fully understood. AQP1 appears to act differently as the disease progresses, helping fluid enter cysts early on and later influencing signals that control cell growth.
This study will track aquaporin changes during cyst growth and test new drugs targeting AQP1 to see if cyst formation can be reduced.
Prof Sharon Ricardo – Monash University
Mitochondrial Restoration as a Therapeutic Strategy for PKD
Polycystic kidney disease (PKD) causes progressive kidney damage due to stress and injury in the cells lining kidney tubules, leading to cyst growth and kidney failure. Current treatments slow disease progression but do not repair damaged cells. Increasing evidence shows that mitochondria, the structures that generate energy within cells, are impaired in PKD, with reduced energy production and disrupted metabolic pathways contributing to epithelial dysfunction.
We have developed human PKD tubuloid cystogenesis assays to test an innovative approach that delivers healthy human mitochondria into PKD kidney epithelium. These mitochondria are clinically approved and fluorescently labelled, allowing us to track their uptake and function. We will determine whether introducing healthy mitochondria improves cellular energy production, restores epithelial structure, and reduces cyst-like changes. By focusing on repairing cellular function rather than simply slowing damage, this work aims to establish a new therapeutic direction to improve outcomes for people living with PKD.
Dr Amali Mallawaarachchi – Garvan Institute of Medical Research
Investigating spatial and regulatory relationships between PKD1 and its pseudogenes
We aim to use new DNA sequencing technologies to look for unique drivers of genetic variation in the main gene (PKD1) that causes Autosomal Dominant Polycystic Kidney Disease (ADPKD). The PKD1 gene has 6 gene copies, called pseudogenes. Pseudogenes can sometimes drive mutation in their parent gene through ‘gene conversion’. This happens when two similar gene regions meet, and some of the genetic information from the pseudogene is passed onto the parent gene, resulting in a variant or mutation in the parent gene. For this to happen the two gene regions need to physically come together. There is currently no evidence that PKD1 and its pseudogenes ‘meet’.
We will use DNA sequencing techniques that preserve the spatial information within the DNA, to understand if the pseudogenes and PKD1 meet. This has never been performed and will provide new insights into what drives genetic variation in ADPKD. If found to be a significant driver of variation, it could highlight an avenue for a treatment.
Prof Jacqueline Phillips – Macquarie University
Targeting Upstream Modulators of TGF-β to Limit Renal Fibrosis in Polycystic Kidney Disease
In polycystic kidney disease (PKD), kidney function gets worse as scar tissue builds up. A protein called transforming growth factor-β (TGF-β) helps drive this scarring and is overactive in PKD. Blocking TGF-β can reduce scarring, but it can also cause side effects, including more inflammation. Instead of blocking TGF-β directly, we are studying two molecules that control it. One is Klotho, which helps turn TGF-β off and is reduced in PKD kidneys. The other is transglutaminase 2 (TG2), which helps turn TGF-β on and may be increased in PKD kidneys.
We want to test whether increasing Klotho or blocking TG2 can reduce TGF-β activity, lower kidney scarring, and protect kidney function in people with PKD.
Dr Sumudu Gangoda – Macquarie University
Early Career Research Grant
From DNA Damage to Arterial Stiffness: Targeting DNA-Damage-Response Signalling to Attenuate Vascular Smooth Muscle Cell Calcification in Polycystic Kidney Disease
Cardiovascular disease (CVD) is the biggest killer amongst Polycystic Kidney Disease (PKD) patients. Tackling CVD-risk factors is crucial in combatting PKD.
Hardening of arteries associated with the deposition of calcium and phosphorus within vascular walls is a major CVD-risk factor seen in association with poor kidney function in PKD. A key feature of this process is a transformation of the vascular smooth muscle cells into bone-like-cells. We are examining if this process is driven by an abnormal response to damage in the vascular tissue. This response process, called the DNA-damage-response (DDR) triggers a molecular switch for cell repair. Our hypothesis is that this does not occur properly in vascular tissue of PKD patients, resulting in increased mineral deposits and hardening of artery walls. We will use vascular cells isolated from rats with PKD to explore the DDR-pathways.
Our findings would open new ways to combat a serious complication of PKD.
A/Prof Sonia Saad – Kolling Institute of Medical Research, Royal North Shore Hospital & The University of Sydney
Utilising Serum 8-OHdG as a Biomarker to Assess Autosomal Dominant Polycystic Kidney Disease Progression
Current tests to monitor risk of progression in ADPKD, such as assessment of kidney and cyst volume with MRI scanning, are limited. This project aims to explore whether measuring levels of 8-hydroxy-2′-deoxyguanosine (“8-OHdG”) in the blood could help predict how quickly ADPKD will worsen.
We hypothesise patients with higher blood 8-OHdG levels may indicate more rapid progression of disease. We plan to measure 8-OHdG levels from blood samples of patients with ADPKD across different timepoints to assess (1) whether 8-OHdG is associated with disease progression and (2) whether it can identify which patients will have fast progressing disease. Current health markers such as kidney function tests and the effect of different treatments prescribed for ADPKD patients will be examined and taken into consideration before confirming our data.
If successful, our research could identify high-risk patients with ADPKD earlier for them to receive intensive treatments to slow down disease progression.
A/Prof Kelly Lambert – University of Wollongong
Validation of a Non-Invasive tool to Measure biomarkers of fruit and vegetable intake in people with kidney disease: The ANIMATE Study
Diet is of great interest to people with PKD. Healthy dietary patterns high in fruits, vegetables, legumes, nuts, and wholegrains are important for the health of people with kidney disease. Devices that can measure markers of a healthy diet exist. However, we do not know if they can be used accurately or reliably in people with kidney disease.
We hope to determine if these devices can be used. This knowledge can then be used in future studies to measure the healthiness of a person’s diet, as well as to track improvements over time as a result of diet changes. This knowledge is important as we know that a healthy diet can slow down the progression of kidney disease and help manage other chronic conditions.
Dr David Tunnicliffe – The University of Sydney
Co-Designing Knowledge Translation Tools to Enhance Shared Decision-Making in ADPKD Management
The publication of guidelines for managing ADPKD, including new recommendations on tolvaptan and dietary changes like increased water intake and ketogenic diets, could greatly benefit the ADPKD community. However, if these guidelines are not effectively communicated, people may not use evidence-based treatments and could be misled by ineffective products.
Our project aims to create tools that help patients and doctors make informed decisions based on these guidelines. We will refine existing resources through focus groups with patients and test their usability and acceptability with surveys with people who have ADPKD. By involving patients in the development process, we ensure the tools are user-friendly and meet their needs. This project will also strengthen partnerships with clinical trial networks in Australia, ensuring that future research is effectively translated into clinical practice to support shared decision-making in ADPKD care.
Dr Mardiana Lee – Austin Health Department of Nephrology
Bob Peters Memorial Early Career Research Grant
Treating Polycystic Kidney Disease with the Novel AMPK Activator ATX-304.
Many therapies targeting different pathways in ADPKD have been studied with limited success. Tolvaptan, the only currently approved treatment for ADPKD, has modest effects in slowing cyst growth and decline in kidney function. Its use is limited by side effects and the potential risk of liver injury. All cells generate energy from glucose or fat to grow. These cellular processes are tightly controlled. Recent research has shown that ADPKD cells generate energy from glucose or fat differently from normal kidney cells. We have access to a new medication, ATX-304, which can increase energy levels in cells and has shown promising results in other kidney diseases. Many ADPKD patients live with CKD and face a daunting future of progression towards kidney failure. Understanding the role of AMPK and metabolic changes in ADPKD will generate a new hope of improved treatment and better outcomes for ADPKD patients. If successful, ATX-304 may become a new treatment for ADPKD patients.
Dr Yan Wang – Monash Biomedicine Discovery Institute, Monash University
Early Career Research Grant
AT2 Receptor: A novel target for ADPKD.
The initial inflammation in ADPKD patients is associated with cyst growth, and uncontrolled inflammation leads to tissue scarring (fibrosis) while aging. The scar tissue/ fibrosis formation is directly associated with the progression of kidney failure in ADPKD. Therefore, targeting inflammation and fibrosis could be an effective therapy for attenuating ADPKD progression, although there are few current treatments targeting these mechanisms. Our lab has recently designed and synthesised a number of ligands that stimulate a cell surface binding site, or protein, which are called AT2 receptors (AT2R).
Importantly, AT2R are often upregulated in renal disease, but this has not been studied for ADPKD. We have previously reported that novel AT2R stimulating drugs that we have developed can inhibit kidney inflammation and fibrosis in models of chronic kidney disease.
However, the expression and function of AT2R stimulation in ADPKD is unknown. This study will be the first to examine the levels of AT2R in ADPKD, which may represent a biomarker for ADPKD as well as being a target for drug action. Moreover, we will determine if AT2R stimulating drugs can inhibit three features involved in the progression of ADPKD: inflammation, fibrosis and cyst growth, which all impact on the progression to kidney failure in ADPKD patients. Thus, this study will provide the first evidence for the therapeutic strategy of stimulating (upregulated) AT2R to slow ADPKD progression and provide potential novel therapies for ADPKD.
Dr Thomas Forbes – Royal Children’s Hospital / Murdoch Children’s Hospital
Clinical and health economic impact of preconception screening for autosomal recessive polycystic kidney disease (ARPKD).
In autosomal recessive polycystic kidney disease (ARPKD), an affected child inherits two copies of an abnormal PKHD1 gene, one from each unaffected parent (who is a ‘carrier’). There is no publicly funded test to determine carrier status for PKHD1 gene mutations (aka ‘variants’) for parents planning a pregnancy. On the 1st November 2023, the Australian Government commenced Medicare-rebated, preconception carrier screening (PCS), for three genetic diseases: cystic fibrosis, spinal muscular atrophy and Fragile X Syndrome.
These diseases were chosen because of their high frequency in the population and/or high severity of illness for the child. ARPKD/PKHD1 is not currently included on this list. We hypothesise that the cost of medical care for ARPKD patients is greater than the cost of adding PKHD1 screening to the current Medicare-funded PCS program. We will perform a health economic analysis of PCS for ARPKD, comparing the modelled cost of screening to the audited cost of medical care for the disease in our hospital. This work will be informed by broad ranging stakeholder engagement with patients, charities, researchers, clinicians and policy-makers. This holistic and multidisciplinary analysis will provide new information on how best to deliver this PCS health service with the interests of all stakeholders represented, from patient to policy-maker.
Professor Sharon Ricardo – Kidney Therapeutics and Stem Cell Laboratory, Monash University
Examining Pax2-driven mitochondrial-ferroptosis in PKD cystogenesis.
This research investigates the mechanisms behind cyst formation and growth in polycystic kidney disease (PKD). While progress has been made in elucidating the genetic underpinnings of PKD, there are remaining gaps in our understanding of how cysts form and worsen over time, with the aim of identifying therapeutic interventions to attenuate cyst growth. In PKD, cyst growth occurs due to an imbalance between cell proliferation (division) and cell death. Recent studies have implicated ferroptosis, a form of cell death triggered by excess iron, in the development of PKD. We hypothesise that the protein Pax2, along with mitochondria (the cell’s energy powerhouses), may contribute to ferroptosis and cyst formation in PKD. This study aims to elucidate the involvement and mechanism/s of the role of Pax2 and mitochondria in ferroptosis and cyst development in PKD, with the goal of identifying potential therapeutic targets to prevent and/or slow this process.
Professor Judith Savige – Medicine (Melbourne Health and Northern Health), Royal Melbourne Hospital, University of Melbourne
Estimated prevalence of different genetic forms of Polycystic Kidney Disease.
Recognising the prevalence of different types of ADPKD is important to alert clinicians to the likelihood of their patients being affected, to help with health service planning and funding, and to help pharmaceutical companies focus on developing treatments for the more common forms with the more severe outcomes. The published population frequencies of different forms of polycystic kidney disease are underestimates that do not take into account structural variants and pathogenic missense changes. Thus clinical estimates of ADPKD are one in 500, but genetic estimates are one in 1000 for ADPKD and the genetic estimate for HNF1B-associated nephropathy is reported to be one in 28,000 which is much too infrequent. This study will identify accurate population frequencies for different forms of Polycystic kidney disease in order to alert clinicians to the likelihood of encountering these diseases clinically. Accurate population frequencies of different forms of PKD will be useful for health service planning, and will encourage pharmaceutical companies to focus on developing treatments for more of the commonest diseases with the most severe impact.
Cara Hildreth – Macquarie University
Is stress-induced brain rewiring to blame for high vasopressin levels in people with Polycystic Kidney Disease?
Vasopressin is a hormone that is released by the brain and via its actions on the kidney, is very important in regulating the amount of water that the body retains. In people with PKD, the brain releases too much vasopressin, and instead of undertaking its normal function at the kidney and causing fluid reabsorption (i.e., increase body water), it instructs kidney cells to accumulate water and hence causes cysts. While we know that vasopressin has a damaging effect on the kidney in PKD, we do not yet understand why the brain is producing too much vasopressin. This project seeks to understand what causes the brain to produce too much vasopressin, exploring the novel idea that stress hormone induced rewiring of the brain is responsible. By exploring what rewiring occurs, we hope to identify new treatment opportunities to reduce vasopressin levels and in doing so, halt the progression of PKD.
Brooke Huuskes – La Trobe University – Centre for Cardiovascular Biology and Disease Research Department of Microbiology, Anatomy, Physiology and Pharmacology
Decoding the cystic conversation: Investigating the inflammasome pathway in polycystic kidney disease using microfluidic tubules on a chip
Polycystic kidney disease is a condition in which cells in the kidney undergo structural and functional changes. Communication between cells though complex signalling pathways is a key driver of these changes. Our study aims to investigate these pathways, focusing on the pro-inflammatory signals that contribute to cyst progression. We will use cutting edge technology to create a miniature version of the kidney, known as “tubules on a chip,” which will allow us to study these pathways in a controlled environment. Our hope is that by understanding the mechanisms behind PKD, we can identify new targets for drug therapies. In addition, this platform has the potential to be used as a tool for screening the efficacy of these therapies on human tissues. Ultimately, our work may lead to new treatment for PKD and improved outcomes for patients with this condition.
David Tunnicliffe PHD – Sydney School of Public Health, The University of Sydney, The Children’s Hospital at Westmead
Increasing the impact of living guidelines on delivery of best practice care for ADPKD: through knowledge translation with people with lived experience of disease
Numerous drugs and diets have been recently examined in clinical trials to treat autosomal dominant polycystic. However, national guidance on the use of these therapies currently needs to be available. Treatments such as tolvaptan are available to people with ADPKD at reduced costs. Still, despite limited supporting data, there are fewer regulatory oversights for dietary interventions that are marketed online. A national multidisciplinary working group are developing a living guideline with recommendations for these therapies. However, there is a clear need to ensure that these recommendations are produced into content that supports people with lived experience of ADPKD in their clinical decision-making. In our project, in partnership with people with ADPKD and caregivers, we will develop and evaluate educational resources (i.e., web applications, info sheets, video and audio content) to convey up-to-date, evidence-based recommendations on emerging therapies for managing ADPKD.
Dr Sara Holton – Senior Research Fellow, School of Nursing and Midwifery (Deakin University)
Pregnancy and childbearing for women with Polycystic Kidney Disease
Development and evaluation of a question prompt list. PKD in pregnancy is associated with a greater risk of maternal complications and requires planning and management of their condition. The aim of this study is to co-design and evaluate a question prompt list that can be used by PKD patients during consultations with their health care providers, ultimately improving outcomes for women and their babies.
Allara Zylberberg – PhD Kidney Development and Disease Laboratory, Department of Anatomy and Developmental Biology (Monash Biomedicine Discovery Institute)
Investigating the role of ciliary fission in Polycystic Kidney Disease
We have recently identified a factor critical in cyst development and demonstrated that its removal prevents cyst development in two animal models of PKD. In this study, we aim to better understand the pathogenesis of cystic disease, which may have considerable implications for identifying new ways to treat PKD in the future.
Dr Brooke Huuskes – Centre for Cardiovascular Biology and Disease Research (La Trobe University)
To generate a comprehensive cellular landscape of kidney tissue at steady state and during polycystic kidney disease using single cell RNA sequencing and spatially resolved transcriptomic.
This project will use technology called transcriptomics to compare information from healthy and diseased kidneys, ultimately leading to the discovery of new cellular pathways that cause both high blood pressure and cyst growth during PKD progression. Once identified, these pathways might be able to be targeted with new drugs that could slow the progression of PKD.
Emily Major – La Trobe University, Vic
‘The Pamela Maud Ratcliff’ PKD PhD Scholarship’ Awarded 2023
*co-funded with Australian Rotary Health
Discovering the influence of the NLRP3 inflammasome on Polycystic Kidney Disease progression
The aim of this project is to understand how the immune system contributes to the progression of Polycystic Kidney Disease (PKD). Patients with PKD commonly have high blood pressure, which can increase their risk of cardiovascular disease. More and more, research shows that the immune system and inflammation contribute to the development of high blood pressure and cyst growth in PKD. However, the exact cells that contribute to both high blood pressure and cyst growth in PKD is not fully understood. This means that the chance of developing new therapies that can slow the progression of cyst growth and target blood pressure rises is limited. This project will use technology called “transcriptomics” which can tell us information about every single cell in the kidney. This allows us to compare information from healthy and diseased kidneys, ultimately leading to the discovery of new pathways that cause both high blood pressure and cyst growth during PKD progression. Once identified, these pathways might be able to be targeted with new drugs that could slow the progression of PKD.
Supervisors: Dr Brooke Huuskes and Professor Grant Drummond
Professor Melissa Little – Murdoch Children’s Research Institute
University of Melbourne
In vitro modelling of autosomal recessive polycystic kidney disease
*co-funded with PKD Foundation US
Researchers often study genetic diseases in animals as a surrogate model for human disease. However, animals with PKHD1 mutations don’t develop kidney cysts like human ARPKD patients. PKHD1, therefore, has unique functions in humans and needs to be studied using human kidney cells. Obtaining kidney cells from paediatric ARPKD patients by kidney biopsy is impractical and unethical. Our laboratory is one of few in the world generating stem cells from patients with kidney disease and turning them into 3D mini-kidneys in a dish (called organoids). We have developed a new method to grow collecting duct (CD) cells, which are the cells that develop cysts in ARPKD. When we grow CD organoids from stem cells carrying PKHD1 mutations, they form large cysts. This represents an opportunity to study ARPKD in a human model without having to biopsy a human kidney.
This grant will allow us to compare healthy and ARPKD-patient kidney organoids to better understand how defects in PKHD1 lead to cyst formation. In the short term, this will help us to understand the function of PKHD1 and possibly also allow the testing of treatments to reduce cyst growth. To move towards drug screening, we will miniaturise our cultures using a robotic cell handling and imaging platform. This will allow us to create almost 400 kidney models on one plate the size of a cell phone. Showing we can test drugs in this way will provide the foundation for future work screening potentially thousands of potential therapies to see which works best at reducing cyst growth in the ARPKD organoids. As such, this may lead to the development of the first treatments for ARPKD. The long term hope is to be able to grow an individual patient’s kidney cells within this system and find the best treatment for their particular PKHD1 mutation. This type of ‘personalised therapeutics’ would be a world first. In the long term this approach may also be applied to other diseases of the collecting duct, including ADPKD.
Professor Ian Smyth- Monash Biomedicine Discovery Institute, Monash University
Using functional genomics to diagnose PKD
Diagnosing the genetic cause of ADPKD can be challenging because of the sometimes-subtle nature of the changes found in the PKD proteins in patients. This grant will allow us to develop a new experimental model in which to assess whether such “variants of uncertain significance” cause disease, providing diagnostic certainty to individuals affected by PKD. In the future, these models may also be useful for better understanding how PKD develops and for trialling new therapies for the disease.
Dr Brooke Huuskes- Centre for Cardiovascular Biology and Disease Research, La Trobe University
The NLRP3 inflammasome in the pathogenesis of polycystic kidney disease
Patients with polycystic kidney disease (PKD) commonly have high blood pressure, which can increase their risk of cardiovascular disease. More and more research show that the immune system and inflammation contribute to the development of high blood pressure, with inflammation being a well-known to be key in driving the progression of PKD. Recently, we have shown that blocking a specific inflammatory pathway reduces blood pressure and kidney damage in animal models of high blood pressure. We suspect that this same inflammatory pathway is activated in PKD and this project will determine if blocking it with a new molecule to see if we can reduce blood pressure and stop cyst progression. Understanding this pathway may offer new therapeutic options to treat PKD.
Dr Amali Mallawaarachchi- Garvan Institute of Medical Research
Investigating Gene Conversion as a mechanism of disease in Autosomal Dominant Polycystic Kidney Disease
Autosomal Dominant Polycystic Kidney Disease (ADPKD) is the most common genetic cause of kidney disease. In ADPKD, cysts overwhelm the kidney, leading to kidney failure. There are unfortunately limited treatments for ADPKD. Remarkably for such a common disease, it is not well understood what causes cysts to develop. A clear understanding of the mechanisms of disease is essential to developing effective treatments. ADPKD is most often associated with genetic changes in the PKD1 or PKD2 gene. A relatively unique feature of ADPKD is that PKD1 has 6 associated pseudogenes. These pseudogenes are ‘copies’ of part of the original PKD1 gene and are not currently thought to have a function. The pseudogenes have an almost identical genetic sequence to PKD1. There has been limited previous studies of the pseudogenes. We hypothesise that the pseudogenes contribute to a mutation in the PKD1 gene, through ‘gene-conversion’. Through a cell’s lifetime DNA can sometimes be damaged (called DNA ‘breaks’). When these breaks occur, the cell repairs them by using a copy of the gene sequence as a template. In regions with a pseudogene, because the pseudogenes look so similar to their original gene, the body can incorrectly use the wrong template to fix the break – this is called gene conversion and leads to a mutation in the DNA. We will investigate whether this is frequently occurring in PKD1. Understanding the causes of mutation in ADPKD are essential if we want to develop treatments that disrupt these mutational mechanisms.
Professor Melissa Little – Murdoch Children’s Research Institute, University of Melbourne
Deprivation of Induced Pluripotent Stem Cells from Patients with Autosomal Recessive Polycystic Kidney Disease
Autosomal Recessive Polycystic Kidney Disease (ARPKD) is a rare (1 in 20,000 births), genetic disease that causes kidney failure in babies and children. About one quarter of babies born with ARPKD will not survive after birth. The remaining babies and older children with more mild disease will require dialysis or kidney transplantation. ARPKD also causes a progressive liver disease and some children require combined kidney and liver transplantation. The vast majority of ARPKD is caused by mutations in the gene PKHD1. The protein made by this gene is thought to interact with the proteins affected in the more common autosomal dominant polycystic kidney disease (ADPKD). However, very little is understood about why a defect in this protein causes disease or what can be used to treat this condition. To date, ARPKD has been studied using animal models, but these do not show the same severity of disease as humans.
We have developed a method to recreate human kidney tissue using stem cells made from babies with ARPKD. With support from PKD Australia, we will generate stem cells using blood samples taken from babies with ARPKD and use these to make a model of the patient’s disease in the laboratory. Ultimately, such patient models of ARPKD will be used to screen for new treatments to slow the progression of the disease.
Dr Denny Cottle – Monash Biomedicine Discovery Institute (BDI), Monash University
Screening candidate gene targets to reverse or prevent Autosomal Dominant Polycystic Kidney (ADPKD)
Autosomal Dominant Polycystic Kidney Disease (ADPKD) is the most common life threatening, inherited disease, affecting ~1 in 1000 individuals. It is characterised by development of fluid filled cysts that disrupt kidney function. Thus, patients eventually require dialysis and/or kidney transplantation. Recently, we have identified a critical factor which causes cysts and we have prevented PKD in two animal models by genetically removing it. In this application we wish to perform a screen inactivating related downstream factors to determine the best candidates for translating our findings into future therapeutics to treat ADPKD patients.
Associate Professor Andrew Mallet, Institute for Molecular Bioscience, The University of Queensland
Rab GTPase regulation in Ciliogenesis and Polycystic Kidney Disease
Rabs are a family of molecular switches that control the growth of the cilia or cell antennae that are essential for normal kidney development. Polycystic kidney disease is the result of gene mutations that cause cilia defects and malformations in the kidney that lead to renal failure. This project will investigate whether and how a subset of Rab proteins, particularly Rab13, contribute to cilia formation and kidney function under normal and disease conditions. Our findings stand to reveal these Rabs as important new cilia regulators that may open up new interventions for improving kidney formation and renal function.
Associate Professor Gopi Rangan, Westmead Institute for Medical Research, The University of Sydney
Effect of inorganic nitrate supplementation on systolic blood pressure in normo- and hyertensive adults with ADPKD
The aim of this project is to determine the feasibility, safety and efficacy of dietary nitrate supplementation on decreasing blood pressure in ADPKD. This project will determine if a daily dietary nitrate supplement lowers blood pressure either as monotherapy or together with conventional drug therapy, and persuade people suffering with ADPKD to make appropriate life-style changes. The study will provide data on tolerability and safety and determine if long-term nitrate supplementation clinical studies in ADPKD are required.
Dr Andrea Wise- Kidney Regeneration and Stem Cell Laboratory, Monash University
Kidney organoids from patients with Polycystic Kidney Disease
The reprogramming of adult cells to generate stem cells – namely, induced pluripotent stem cells – has advanced the study of disease modelling. Recently, there has been great excitement in the ability of iPSCs to self-assemble into three-dimensional structures that resemble mini-kidneys. These kidney organoids express markers of different kidney cell types and show great potential in many applications including disease modelling and regenerative medicine. This project will develop these “kidneys in a dish” targeted to PKD. This research will facilitate the use of kidney organoids from PKD patients, and genetically altered PKD organoids, for disease modelling, drug screening, and in the future, potential development of novel stem cell replacement therapies for this debilitating kidney disease for which there is no cure.
Dr Sayan Saravanabavan- Centre for Transplant and Renal Research, Westmead Institute for Medical Research, The University of Sydney
Role of mitochondrial genomic analysis as a prognostic biomarker in autosomal dominant polycystic kidney disease (ADPKD)
Genetic testing in ADPKD is in the early stages of development, and more sophistication is needed to help predict who is at higher risk of developing kidney failure. Energy metabolism in cells is altered in ADPKD and changes (mutations) in genes that regulate the mitochondria (the main energy producing organelle in our body which has its own genes) may worsen the severity of ADPKD. The aim of this study is to determine if mutations in mitochondrial genes affect the severity of ADPKD. The results of this study could help better identify patients who are at higher risk of developing kidney failure, and also lead to new approaches for treating ADPKD.
Dr Cara Hildreth- Department of Biomedical Sciences, Macquarie University
Is a hormone controlled by the brain driving high blood pressure in PKD?
It is well known that high blood pressure is common in people with polycystic kidney disease. Why blood pressure increases in people with polycystic kidney disease, however, is less well known. This project seeks to determine how the brain is contributing to the development of high blood pressure in polycystic kidney disease by uncovering what hormonal changes the brain is initiating that result in high blood pressure. This work has the potential to identify new treatment targets that could be used in individuals with polycystic kidney disease to lower blood pressure and reduce their risk of developing diseases associated with high blood pressure.
Assoc. Professor Andrew Mallett- Centre for Health Services Research, The University of Queensland, Australasian Kidney Trials Network
The IMPEDE-PKD Trial (Implementation of Metformin theraPy to Ease DEcline of kidney function in PKD).
There is an urgent need for treatments to slow the loss of kidney function and prevent complications in affected patients and families with ADPKD. Repurposing of existing medications is a promising way to potentially expedite this. Laboratory studies suggest Metformin, a common diabetes medication, might be one such medication.
The aim of this study is to establish a randomised clinical trial of Metformin amongst patients with ADPKD to investigate its potential to slow kidney function decline. Pre-clinical studies suggest that there are ADPKD disease pathways that can be advantageously modified by administration of Metformin. The common use of this medication, including in non-diabetic conditions such as polycystic ovarian syndrome, its relative inexpensive nature as well as its defined side effect and dosing profiles in kidney disease lend it to the conduct of a clinical trial to address this aim. If successful, this would dramatically change the prognosis for many Australians living with this condition and hoping for a future in which dialysis can be avoided.
* This Project is funded in partnership with The BEAT-CKD Program
Professor Sharon Ricardo- Kidney Regeneration and Stem Cell Laboratory, Monash University
Clinical development of a monoclonal antibody-based therapeutic targeting polycystic kidney disease.
There are various supportive treatments that can be used to control the symptoms of PKD, to help prevent or slow down the loss of kidney function. However, there are currently no treatment options to prevent cysts developing or reverse the process once formed. As such, there is currently no cure for PKD, where the only options to treat kidney failure are dialysis or organ transplantation.
Our recent discovery has identified a novel protein, called WISP1, that may play an important role in the formation of kidney cysts and the detrimental scarring of the kidneys that leads to reduced kidney function over time. The successful completion of these studies will unravel the role that WISP1 plays in both cyst growth and kidney scarring. Moreover, we will develop a protein that inhibits WISP1 protein production that will be used therapeutically to retard cyst growth and slow or alleviate disease progression.
Dr Gopi Rangan- Centre for Transplant and Renal Research, Westmead Institute for Medical Research, The University of Sydney
Role of DNA damage signalling in Autosomal Dominant Polycystic Kidney Disease.
This project will determine if stopping damage to the genetic coding material (called DNA) reduces the formation of kidney cysts in polycystic kidney disease.
Professor John Shine- Molecular Genetics of Inherited Kidney Disorders, Garvan Institute of Medical Research, Sydney
Identifying novel mutational mechanisms in the genetic pathogenesis of PKD.
ADPKD is the most common genetic kidney disorder – it causes cysts to develop within the kidney, which eventually destroy the normal kidney tissue and lead to renal failure in many patients. Despite how common the disease is there are still many gaps in our understanding. In many families we still cannot identify the genetic cause of their disease and there remain questions about the reason kidney cysts develop and destroy the kidney. Our project will use the latest in genetic sequencing technologies, called Whole Genome Sequencing, to identify new genetic causes of ADPKD. Understanding new mechanisms will help in better understanding this complex disease and to develop ways to slow and treat ADPKD.
* This Project is funded in partnership with the PKD Foundation USA
Dr Amali Mallawaarachchi, Garvan Institute of Medical Research, Sydney
A novel genetic test for ADPKD – A new genetic sequencing technique which has shown promising results was previously trialled and now requires testing a larger study.
Partnering with the Mayo Clinic, this grant will work to test this with patients who have been sequenced by more established methods. It is anticipated that comparing the two methods will show the new test to be more detailed and accurate and to establish it as the lead genetic test for PKD in Australia. This will result in improvements for patients and assist with understanding underlying causes and to find a cure.
To read the final report please click here.
Professor Jacqueline Phillips, Macquarie University, Sydney
Genes and cellular stress in PKD- This grant will investigate how PKD genes can cause an increase in stress signals in kidney cells that drives cell damage and progression of kidney disease.
These same processes can also be driven by the build-up of toxins in the blood that arises when kidney function declines and this project will further test if the combination of PKD mutation and toxins worsens the stress response in the cell. Determining how PKD leads to cell damage has the potential to change the way we treat patients from symptomatic to strategically targeted.
To read the final report please click here.
Dr Bo Wang, Monash University, Melbourne
The therapeutic potential of miRNA-based MAPK inhibition to slow the progression of PKD
Several therapeutic interventions have been designed specifically to inhibit cell proliferation in a variety of animal models of PKD. A cell signal–regulated kinase (MAPK) inhibitor is shown to effectively block cyst growth and kidney enlargement, and to preserve kidney function.
Recently, a unique microRNA was discovered that is important in regulation of gene expression and can slow down the over proliferation of kidney cells that lead to cyst formation. The project will investigate the mechanisms of microRNA in maintaining normal kidney cell function that will result in reduced cyst growth. The study will provide a novel target for PKD treatment with a high potential for clinical translation.
Dr Annette Wong, Westmead Institute for Medical Research, Sydney
Validation of copeptin as a prognostic molecular biomarker in patients with CKD stages 1 – 3 due to ADPKD- Predicting patients at high risk of kidney failure who therefore require medical follow-up is important however, currently there are no blood tests to provide this information.
Vasopressin is a natural hormone in the body that may cause kidney cysts to grow bigger. In the past it has been difficult to measure vasopressin but it can now can be measured easily using a test for copeptin. This project will determine if a simple blood and/or urine test for copeptin can help predict this risk in patients with early-stage ADPKD.
Grant summaries