News

Registries Identify Risk Factors for Onset of Dialysis in ARPKD

Patient data collected through registries has been used to evaluate important outcomes in patients with Autosomal Recessive PKD (ARPKD), highlighting the importance of registries to determine best practice for patients and to inform research.

ARegPKD is an international registry that aims to gather the largest collection of detailed longitudinal data on clinical ARPKD courses worldwide, in order to contribute to the fight against this life-threatening disorder(1). Comprehensive prenatal, perinatal, and postnatal information was captured from 385 patients from ARegPKD and analysed for potential risk markers for dialysis during the first year of life. Identifying these risk factors may be helpful in prenatal parental counselling in cases of suspected ARPKD(2).
 
Conducting studies in rare diseases such as ARPKD and paediatric ADPKD are by nature difficult for many reasons. Registries can help determine optimal management plans and are an important aspect in the path forward for PKD. In the research of rare disease, patient registries have been described as the best tool to close the gap between research and therapeutics(3).

References
1. https://www.aregpkd.org/index.php?id=about_arpkd
2. Risk Factors for Early Dialysis Dependency in Autosomal Recessive Polycystic Kidney Disease. Burgmaier, KathrinRanguelov, Nadejda et al. The Journal of Pediatrics, Volume 199, 22 – 28.e6
3. EURODIS NORD CORD, Joint Declaration of 10 Key Principles for Rare Disease Patient Registries

The pledge we were hoping for

PKDA was a signatory last year on a call to the Federal Government to make dialysis more accessible for indigenous patients.

Representing PKDA at the meeting, Helen and Robert heard from experts and indigenous patients that the pressures of undergoing long-term dialysis far from home, away from their families and cultural commitments, can be so great for some Indigenous patients that they would rather die. Patients said that many people were dying a lonely death in cities and towns because of the poor accessibility of treatment centres in remote communities.

Helen expressed her shock and disappointment: “It’s a renal emergency. Why is it happening, and why has it existed for so long?”

Now, the Government has pledged to spend $57.8 million for dialysis in remote communities to help Indigenous patients stay at home.

Helen and Robert said of the Indigenous Patients Voices Forum at the time “it’s been an amazing privilege to be here, especially today, and to hear all of your stories. They’re so powerful and so moving, and I think it takes tremendous courage to stand up and speak from the heart as so many people have done.”

It was the voices, hard work and determination of these strong people and communities, their carers and their supporters that has led to this great outcome, a step towards equitable outcomes for all kidney patients.

What will the 2018 Health Budget mean for us?

As the 2018 Budget was announced we welcomed the new investment into health. A few words stood out to us from the Health Budget: Rare, genetic and chronic.

To us Rare genetic and chronic = PKD. So, we put together a wish list of what we hope the 2018 health Budget could mean for PKD.

“The Government will deliver $6 billion in record funding for Australia’s health and medical research sector, including $3.5 billion for the National Health and Medical Research Council, $2 billion in disbursements from the Medical Research Future Fund and $500 million from the Biomedical Translation Fund.”

Dr Gopala Rangan (the chair of our SAB) is the lead investigator of the PREVENT-ADPKD clinical trial which is funded by NHMRC.

Click here to read the full article.

New clinical trial using water to treat polycystic kidney disease

The new trial, using water to treat PKD, known as PREVENT-ADPKD is led by Dr Annette Wong, Carly Mannix, Professor David Harris and Dr Gopi Rangan at the Westmead Hospital and the Westmead Institute for Medical Research. 

The trial will investigate whether drinking the right amount of water can prevent adult polycystic kidney disease (ADPKD) progressing to kidney failure.

“A positive study result will show that water is a cheap, safe and effective treatment,” Dr Rangan explained. 

Click here to read more.

Story originally published by the Westmead Institute for Medical Research, republished on our website with their permission. Photo: Dr Gopi Rangan and his team from the Westmead Institute and the Westmead Hospital from Westmead Medical Research Foundation

PKDA seed grant helped fund the establishment of the new genetic test to diagnose ADPKD, now available in Australia


Dr Amali Mallawaarachchi, a genomics researcher in the ‘Genomics and Epigenetics’ Division at the Garvan Institute of Medical Research, was awarded one of PKD Australia’s four enabling grants last year.

The aim was to develop a new test that uses whole genome sequencing (WGS) to diagnose autosomal dominant polycystic kidney disease (ADPKD). Sequencing genes to determine a causative mutation in ADPKD is difficult using traditional gene sequencing methods.

This is due to six ‘pseudogenes’ –  which are non-functional genes, almost identical in DNA sequence to the causative genes. Dr Mallawaarachchi and a team of clinicians and scientists trialled WGS and found it more detailed and accurate than current testing. This has led to the establishment of a genetic test for Australian ADPKD families. More accessible genetic testing will allow patients to be diagnosed sooner, allow families to better inform their family planning decisions, help to predict prognosis and allow better selection of living kidney donors for kidney transplantation.

In the long term, improved genetic testing will accelerate our understanding of the underlying cause of ADPKD – an important step in finding a cure. To read Dr Mallawaarachchi final report please see here.

Tolvaptan is being considered for inclusion on the Australian Pharmaceutical Benefits Scheme. Have your say!

Our bodies depend on a hormone called vasopressin to regulate fluid balance. When our bodies are not hydrated more of the hormone, vasopressin is produced. High vasopressin levels (which occur when we don’t get enough fluid) have been linked to cyst growth in ADPKD. Drinking more fluid can reduce vasopressin levels and may slow the progression of ADPKD.

Tolvaptan is a selective vasopressin type 2 receptor inhibitor and blocks vasopressin’s actions at the cellular level. Results from the Phase 3 REPRISE trial of tolvaptan, which was conducted in 21 countries for treatment of ADPKD were announced late last year by Otsuka Pharmaceutical (Otsuka).

In the REPRISE trial, Tolvaptan reduced the rate of decline of kidney function by 35 percent over a 12-month period, compared to the placebo. These results built upon their previous trial, known as TEMPO 3:4. The REPRISE trial focused on ADPKD patients with more severe kidney disease than those in the TEMPO 3:4 trial. To summarise the TEMPO 3:4 trial, Tolvaptan, when given over a period of 3 years, slowed the increase in total kidney volume and the decline in kidney function (as measured by glomerular filtration rate). Key safety findings were generally consistent in both the REPRISE and TEMPO 3:4 trial.

In these two trials patients who received tolvaptan had a higher frequency of adverse events such as excessive thirst, increased urine production and urination during the night. Furthermore, Tolvaptan led to more instances of increased liver-enzyme levels, which resolved after the discontinuation of the drug. Those who received placebo had higher frequencies of adverse events related to ADPKD, such as kidney pain, haematuria (blood in the urine), urinary tract infection and back pain.

The Australian PBS listing application for Tolvaptan will be reviewed at the March 2018 meeting of the Pharmaceutical Benefits Advisory Committee (PBAC). As part of the review process, the PBAC welcomes input from patients and their families, carers, members of the public, health professionals and members of consumer interest groups. These submissions provide accounts of how the medication under consideration will impact the lives of individuals.

To complete the consumer input form, please go to the PBAC online submission form. Or you may write a letter to the PBAC at the following addresses:

Mail: PBAC Secretariat MDP 952, Department of Health and Ageing GPO Box 9848 Canberra ACT 2601
Email: CommentsPBAC@health.gov.au
Facsimile: (02) 6289 4175

The Outcomes of the PBAC meeting will be available on the PBS website six (6) weeks after the meeting. Public submissions for medicines being considered at the March 2018 meeting will be received up until the deadline date of 7 February 2018.

Sources: 1: Torres, V. E. et al. Tolvaptan in patients with autosomal dominant polycystic kidney disease. N. Engl. J. Med. 367, 2407–2418 (2012). 2: Torres, V. E. et al. Tolvaptan in later-stage autosomal dominant polycystic kidney disease. N. Engl. J. Med. 377, 1930–1942 (2017) 3: van Gastel M, D, A, Torres V, E, Polycystic Kidney Disease and the Vasopressin Pathway. Ann Nutr Metab 2017;70(suppl 1):43-50

PKD Australia has been busy this year!

PKDA has presented Public Patient Seminars in both Perth and Darwin and has represented and raised awareness for PKD at a number of conferences. We are grateful to have received many generous donations, including a bequest in memory of Audrey Florence Wright, which will fund kidney research. PKDA will fund a number of research grants, including two up to the value of AUD $80,000 and one for USD $160,000, in partnership with US PKD Foundation. We have also said farewell to our General Manager, Sarah, who has been such an integral part of PKDA for the past few years. With her departure, we are thrilled to welcome Charmaine Green (PhD) to the PKDA family. Another very warm welcome must also be extended to Dr. Deborah Lewis who has recently joined the PKDA Scientific Advisory Board. Read more in our Musings from the Chair.

Lab-grown mini kidneys hint at pathways leading to Polycystic Kidney Disease

Review of: Cruz, N.M., et al. “Organoid cystogenesis reveals a critical role of microenvironment in human polycystic kidney disease.” Nature Materials (2017) by Shabarni Gupta, PhD Candidate Macquarie University. http://www.nature.com/nmat/journal/vaop/ncurrent/full/nmat4994.html Polycystic kidney disease (PKD) results in the formation of fluid filled cysts that gradually displace normal kidney cells and ultimately loss of kidney function. While PKD is studied by groups across the globe, a model that is derived from cells of human origin and closely replicates the disease is yet to be established. In 2015, research led by a group of scientists in the Division of Nephrology at the University of Washington led to a paradigm shift in the way the community looked at PKD as a disease. They were able to recreate the disease in a controlled laboratory based setting using stem cell technology1, growing mini-kidneys – also termed “organoids”, from human stem cells. By deleting the two major genes causing PKD: PKD1 and PKD2, they created PKD in a petri dish. However, the fluid-filled cysts formed in the mini-kidneys did not exactly resemble the hallmarks of human PKD. A new report from the same group has now shown that if the mini-kidneys are grown in a jelly like suspension, they develop large free-floating hollow cysts, more like what is observed in clinical PKD cases.2 By changing the cellular microenvironment they were able to better mimic the conditions that allowed for diseased kidney growth. This breakthrough has allowed the researchers to begin to unveil the processes that lead to the development of cysts. For example, one study hints that mutated PKD proteins loosed their ability to properly interact with the tissue surrounding the kidney cell, resulting in a loss of cellular shape and ultimately the integrity of overall kidney structure. This exciting and innovative new model opens avenues for understanding the fundamental cues that determine the progression of PKD, and may even pave the way for the next phase of research involving the use of patient cell-derived mini-kidneys for rapid screening and personalised medicine testing. Sources: 1. Freedman, Benjamin S., et al. “Modelling kidney disease with CRISPR-mutant kidney organoids derived from human pluripotent epiblast spheroids.” Nature communications 6 (2015). 2. Cruz, N.M., et al. “Organoid cystogenesis reveals a critical role of microenvironment in human polycystic kidney disease.” Nature Materials (2017).

This is the kidney-swapping that’s revolutionising organ donations

In an exciting development, kidney transplant patients have got a new option that allows those with donors who aren’t a match to, in simple terms, swap kidneys. It’s called the Paired Kidney Exchange Programme and the ABC 7:30 Report went inside an operating theatre to see to a carefully choreographed three-way kidney swap. Watch the video here.

PKD Australia welcome the ACNC Charity Tick

PKD Australia is proud to display the Australian Charities and Not-for-profits Commission (ACNC) ‘Tick of Charity Registration’, which provides the public with reassurance the charity is transparent and accountable. For more information visit the ACNC website and view our listing on the Charity Register.

Kidney in a Dish

Murdoch Children’s Research Institute has just been awarded winner of the 2016 UNSW Eureka Prize for Scientific Research. Kidney disease affects 1 in 10 Australians, with kidney failure increasing at 6% per annum. Recognising the urgent need for new treatment options, Professor Melissa Little and Dr Minoru Takasato have recreated human kidney tissue from stem cells, opening the door to disease modelling, drug screening, and ultimately replacement organs. Polycystic Kidney Disease & Chronic Kidney Disease researchers are very excited at this wonderful award winning discovery.

Dieting proves beneficial in PKD mice

Written by Conor Underwood, PhD student, Macquarie University

In 2010 there was anticipation surrounding the outcome of several clinical trials testing the effectiveness of a new class of drugs to treat PKD. These drugs, known as mTOR inhibitors because they switch-off a cellular pathway called mTOR, which is important for cyst growth, had previously shown great success in laboratory rodents. In humans, however, these drugs proved very toxic and consequently the results of these clinical trials were disappointing. Having taken this research problem back to the drawing board, scientists from the University of California Santa Barbara, headed by Thomas Weimbs, may have now come up with an alternative strategy to target the same deleterious mTOR pathway without the need for potentially toxic drugs. The premise of their approach is to take advantage of an important property of the mTOR pathway: it switches-off when cell energy stores are running low. Consequently, they thought, it might be possible to turn-off the mTOR pathway and ultimately slow cyst growth by simply reducing daily food consumption. To test their idea researchers placed mice with PKD (so called PKD1cond/cond:NesCre mice) on a 7 week diet consisting of 23% less kilojoules and assessed changes in kidney weight (which increases with cyst growth) and others signs of disease progression. What they found was striking. The kidney growth of PKD mice on the low-kilojoule diet was 3.7 times less than that of PKD mice without food restriction despite total bodyweight not being significantly affected by the diet. What’s more, food restricted PKD mice had less kidney scarring (or ‘fibrosis’) and also appeared less likely to develop renal failure. These results are truly exciting and give hope for a new treatment avenue for a disease for which there is currently no approved treatment in Australia. Nevertheless many important questions must be addressed in order to translate this research to clinical trials and following that clinical practice. The researchers themselves emphasise that it remains to be determined whether the remarkable effect that they observed in PKD mice is because of a lower energy intake as a whole or only that of certain nutrients (e.g. carbohydrates or fats). Link: http://ajprenal.physiology.org/content/early/2016/01/07/ajprenal.00551.2015 Published online Jan 13th 2016 American Journal of Physiology – Renal Physiology. A mild reduction of food intake slows disease progression in an orthologous mouse model of polycystic kidney disease. Kevin R Kipp, Mina Rezaei, Louis Lin, Elyse C Dewey, Thomas Weimbs.

What happened in Canada?

Late last year, the PKD Foundation of Canada hosted their 2nd PKD Symposium with people from the PKD medical community as well as PKD patients, their families and friends. Topics included:

  • Eating Healthy with PKD
  • Learn the Facts: The Basics of ARPKD & ADPKD
  • Understanding Living Kidney Donation
  • Update on Canadian Clinical PKD Research
  • Dealing with the Emotional Aspects of Living with a Chronic Disease

Click the button below to watch the video.Watch Video

PKD in a dish

Some New Research holds hope to Test Medications to Treat PKD Taking new PKD treatments from the bench to the bedside might be just that bit faster now after researchers from the Harvard Stem Cell Institute at Brigham and Women’s Hospital have been able to grow 3D mini-PKD kidneys in a dish. Using what are called human pluripotent stem cells (hPSCs), which are cells that under the right conditions can be made to turn into any type of cell, Joseph Bonventre and his team first showed that they could create mini 3D structures (called tubular organoids), which look and behave like kidney cells (3D mini-kidneys). They tested the 3D mini-kidneys with drugs that cause kidney damage and showed they responded in the same way as a kidney would, proving they could be used to test if a drug will harm the kidney (nephrotoxicity). They then took the cells and transplanted them into mice, to see if they would survive, and they did. Finally, and most excitingly, using a gene-editing technique called CRISPR, they introduced a mutation into either PKD1 or PKD2, and much to their surprise, found that the 3D mini-kidneys now grew large-cysts from the tubular organoids – similar to how cysts grow from kidney cells in ADPKD. Using the same CRISPR techniques, the researchers introduced a gene mutation linked to glomerulonephritis in a protein called podocalyxin, and again were able to reproduce features of the disease condition. The potential outcomes from this work are quite remarkable. Not only can researchers now reproduce PKD in a dish, but they can use the cells to rapidly test new drugs, both for their toxicity and potential to slow down or prevent cyst formation. Furthermore, it might be that the same CRISPR technique could be used to instead correct a gene mutation, rather than cause one, and in the future, healthy mini-kidneys derived from patients own cells could be used as functional transplant. Link: http://hsci.harvard.edu/news/modeling-genetic-diseases-mini-kidney-organoids And: http://www.nature.com/ncomms/2015/151023/ncomms9715/full/ncomms9715.html Published Oct 23rd 2015 Nature Communications: 6:8715 DOI: 10.1038/ncomms9715 Modelling kidney disease with CRISPR-mutant kidney organoids derived from human pluripotent epiblast spheroids Benjamin S. Freedman, Craig R. Brooks, Albert Q. Lam, Hongxia Fu, Ryuji Morizane, Vishesh Agrawal, Abdelaziz F. Saad, Michelle K. Li, Michael R. Hughes, Ryan Vander Werff, Derek T. Peters, Junjie Lu, Anna Baccei, Andrew M. Siedlecki, M. Todd Valerius, Kiran Musunuru, Kelly M. McNagny, Theodore I. Steinman, Jing Zhou, Paul H. Lerou & Joseph V. Bonventre


1 CRISPR (clustered regularly interspaced short palindromic repeats) was discovered as part of a normally occurring bacterial process that provides a type of immunity to for bacteria from foreign genetic elements. It is now used by researchers to changing the sequence of specific genes and therefore functionally inactivate them in human cell lines.