Episode 56      17 min 26 sec
Farewell To Dialysis?

Associate Professor Darren Kelly discusses his research into antifibrotic agents and how they may herald the end of conventional dialysis treatment. With host Dr Shane Huntington.

"If an organ undergoes trauma it often fibroses to try to protect the organ or maintain its integrity, but it’s when this aberrant scarring occurs that it excessively causes the deletion of cells or the loss of cell function. " - Assoc Prof Darren Kelly




           



Darren Kelly
Darren Kelly

Darren Kelly is Associate Professor at the University of Melbourne, is the Director of Biomedical Research in the Department of Medicine at St Vincent’s Hospital, Melbourne.  He is recognised expert in progressing pre-clinical novel interventions and in developing experimental models of renal and cardiac disease. Darren has published more than 100 manuscripts, with most in high quality journal such as PNAS, Diabetes and American Journal of Pathology.  In particular, many of these manuscripts have led to translational research that has had a direct impact on human disease.  Assoc Prof Kelly has previously received major grants and fellowships from the NH&MRC and Juvenile Diabetes Research Foundation (JDRF) International. Assoc Prof Kelly is also CEO of Fibrotech Therapeutics, a member of the Australian Inst of Company Directors, and a Fellow of the American Society of Nephrology.

Credits

Host: Dr Shane Huntington
Producers: Kelvin Param, Eric Van Bemmel and Dr Shane Huntington
Audio Engineer: Craig McArthur
Theme Music performed by Sergio Ercole. Mr Ercole is represented by the Musicians' Agency, Faculty of Music
Voiceover: Paul Richiardi

Series Creators: Eric van Bemmel and Kelvin Param

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Farewell to Dialysis?

VOICEOVER
Welcome To Melbourne University Up Close, a fortnightly podcast of research, personalities, and cultural offerings of the University of Melbourne, Australia. Up Close is available on the web at upclose.unimeld.edu.au. That’s upclose.u-n-i-m-e-l-b.edu.au.

SHANE HUNTINGTON
Hello and welcome to Up Close, coming to you from Melbourne University, Australia. I’m Dr Shane Huntington. In Australia and New Zealand there are about 6,000 people on dialysis as a result of renal or kidney disease. Being hooked up to a dialysis machine for four or five hours a day three times a week with this routine going on indefinitely is extremely stressful for the patients and their families. While all these patients hope to receive a kidney transplant, the reality is only a small portion of the dialysis patients we have will ever become recipients. One common cause of renal disease is called fibrosis.

Our guest today is Professor Darren Kelly from the Department of Medicine in the Bio21 Institute here at the University of Melbourne, Australia. Darren will discuss the nature and causes of fibrosis, particularly as it occurs in the kidney, and will give us an insight into the groundbreaking research he’s been leading in the development of anti fibrosis drugs. The success that Professor Kelly has had thus far, for the first time, offers a ray of hope for many dialysis patients around the world.
Welcome to Up Close, Darren.

DARREN KELLY
Thanks a lot, Shane.

SHANE HUNTINGTON
I’d firstly like to ask what fibrosis actually is.

DARREN KELLY
Well you actually have fibrosis following trauma or injury. So a little bit like when you have a surgical wound and the fibrosis that causes wound healing to repair back together. When it occurs in organs like the kidney and the heart as a response to injury from something like diabetes this aberrant fibrosis then stops the organ from functioning normally.

SHANE HUNTINGTON
Is fibrosis one of those things that affects different parts of the body in different ways?

DARREN KELLY
It seems to be a pretty similar response in most of the organs actually, so hence the reason our concept is to develop anti fibrotics that may work in other organs. We’re focusing at the moment on the kidney but there certainly is potential for other treatments in other organs.

SHANE HUNTINGTON
Let’s talk about the kidney. As an expert in this area, what do they actually do for us, and how do they go about that?

DARREN KELLY
The kidneys are obviously the filtering units that clean up our blood and play a really vital role in maintaining our health and wellbeing. So if you affect the kidneys in any way, say for from diabetes or chronic illnesses, then you obviously build up waste products in the kidney and require dialysis to basically clean up the blood.

SHANE HUNTINGTON
In the kidneys when we have this fibrosis scenario the structure of the kidney I can imagine is being modified in some way. Can you tell us a bit more about what’s actually happening there?

DARREN KELLY
As I was saying, a little bit like wound healing on the skin following a surgical incision, that’s what happens to the kidney as well. It undergoes this fibrotic process where you get scarring which, if you think about it, then stops the kidney from functioning because you’re obliterating cells that normally have a specific role.

SHANE HUNTINGTON
When we talk about scarring, we’ve all got scars somewhere on our body and they look a little bit different but it’s not dead tissue, is it? It’s doing something?

DARREN KELLY
It’s basically a structural thing, fibrosis or scarring. It’s really holding the skin or the organ together. If an organ undergoes trauma it often fibroses to try to protect the organ or maintain its integrity, but it’s when this aberrant scarring occurs that it excessively causes the deletion of cells or the loss of cell function.

SHANE HUNTINGTON
In the case of renal fibrosis - we’re talking about the kidneys here - what sort of symptoms can a person expect to be experiencing when this starts to occur?

DARREN KELLY
To be honest most of the symptoms would not be noticed very early on if fibrosis did occur. It’s when it really gets into the later stages where you do require dialysis that obviously you’d have noticeable changes.

SHANE HUNTINGTON
What sort of changes?

DARREN KELLY
Things like oedema and just general feeling of unwellness and nausea. Feeling quite sick, actually.

SHANE HUNTINGTON
Presumably if the toxins continue to build up you’ll actually die from that?

DARREN KELLY
Correct.

SHANE HUNTINGTON
At the moment, the treatment being primarily dialysis, can we be on that permanently? Can that just continue on, or is a process that over time fails?

DARREN KELLY
Dialysis is usually instigated when kidney function is at the very end, so it’s sort of a last resort to keep someone alive long enough so they can get a kidney transplant. So at that particular stage the disease is quite advanced.

SHANE HUNTINGTON
I’m guessing we have an almost oversupply of kidney function, and I ask that question because I know people can donate a kidney. What percentage of our total kidney function can we get away with?

DARREN KELLY
That’s an interesting point. We do have an excess of kidney function, and hence you really need to lose more than 80 per cent of your kidney function before you require dialysis so it’s a significant amount of kidney loss.

SHANE HUNTINGTON
In many cases our bodies are designed in certain ways and it makes sense. Does it make sense for us to have such a redundancy of kidney functions?

DARREN KELLY
I wouldn’t say it’s a redundancy of kidney function because with age you progressively lose nephrons, or kidney function and viability, so it’s sort of a backup supply that, depending on how long you live or how rapidly your kidney function declines, is a necessary backup of kidney function.

SHANE HUNTINGTON
In Australia we have a relatively good - relatively good - medical system compared to many countries in the world. How common is renal fibrosis here?

DARREN KELLY
Renal fibrosis is the leading cause of kidney failure and it’s very common.

SHANE HUNTINGTON
What are some of the causes of renal fibrosis?
DARREN KELLY
The main cause is diabetes. High glucose contributes to loss of kidney function. High blood pressure is another factor that’s involved in kidney failure. There’s a lot of unknown causes as well, that are associated with chronic renal disease. It could be virally instigated or chemically induced.

SHANE HUNTINGTON
The reason for this interview, we have to be truthful, is because of the incredible work you’ve been doing in anti fibrotic agents. Tell me a bit about what’s happening there. Why did you choose renal fibrosis as the area you wanted to focus on?

DARREN KELLY
We’ve been working in the area of renal fibrosis for a number of years, our research group with Professor Richard Gilbert and also Professor Henry Krum from Monash University. We’ve been focusing on fibrosis in particular in the kidney and also on the heart. It’s an area that we’ve worked on for 15 or more years now. We’ve been looking at testing the pharmaceutical industry’s compounds against fibrosis, and the way this current project got underway was one of those sorts of serendipitous moments where I was talking to someone at Bio21 Institute in Melbourne. We started talking about a series of anti fibrotic compounds that we’d been using in some of our animal models, and how we could potentially develop them or improve their actual anti fibrotic activity, and the project just snowballed from there.

SHANE HUNTINGTON
The drug that you guys are working on must somehow halt the fibrosis mechanism. Tell us about what’s happening in the process itself with fibrosis? Is it just terminating, is it just being reduced, how effective is the drug?

DARREN KELLY
Our drug is looking inhibiting fibrosis. One of the questions is whether it can actually reverse fibrosis - we haven’t looked at that. We’ve shown in our animal models that it can inhibit fibrosis and the way that it inhibits the fibrosis is probably associated by blocking certain cellular mechanisms that are triggered off by these injurious responses like high glucose from diabetes, and high blood pressure. So inhibiting those downstream pathways and more centrally looking at inhibiting some of the specific growth factor pathways, like transforming growth factor beta, which is thought to be one of the central growth factors involved in the development of fibrosis.

SHANE HUNTINGTON
The drug you’ve chosen is one many I assume. Were there a number of candidates you tried before you got to this one?

DARREN KELLY
There actually are no anti fibrotics available on the market at the moment, and the drug that we’ve developed is an analogue of a compound that we’ve been working on for some years now called Tranilast. Tranilast is widely available in Japan, and Professor Richard Gilbert and I had been looking at this drug a number of years ago in some of our animal models looking at kidney and heart failure, and showing that it had this profound anti fibrotic effect. And interestingly, the reason it wasn’t picked up and taken into clinical development is that it’s off patent and doesn’t really have a potential market as such. So the compound we’ve developed is based on basically that core structure, and we’ve developed it further so we think we can get better anti fibrotic activity and less toxicity in the long term.    

SHANE HUNTINGTON
You’re listening to Melbourne University Up Close. I’m Dr Shane Huntington and we’re speaking with Professor Darren Kelly about fibrosis.
You mentioned the use of animal models. What sort of effect is happening on the overall organism when they take this drug? Is it repairing scar tissue in any other way, or limiting it in other parts of the body? Or is it really focused in on the kidneys?

DARREN KELLY
It’s not focused on the kidneys. The effect, as we’ve talked about, we’ve seen after a heart attack in animals we can prevent some of the scarring that occurs after a heart attack as I’ve said with diabetic kidney disease, but other chronic kidney disease as well. So we have different models that can be used to assess the fibrosis in different organs.

SHANE HUNTINGTON
The heart attack one is very interesting to me because presumably that scar tissue formation is very rapid. So would you have to have it in your system at the time, or would it be something you would immediately administer to a patient after that event?

DARREN KELLY
Well the heart attack is an interesting one because really the scar tissue forms after the heart attack to try to hold the ventricle in place, or to stop the heart from bursting or causing an aneurism. It’s the progressive scarring that occurs months and years later that actually then stops the heart from working, so a certain amount of natural repair process is required to preserve cardiac function but it’s that scar tissue that forms years and beyond that actually causes heart failure. So that’s the sort of pathological fibrosis that we’re aiming to target.

SHANE HUNTINGTON
I’d like to congratulate you on being successful in getting about three million Australian dollars out of the US government for progressing this research. This is something that’s rather uncommon for Australian researchers, and it’s indicative of just how good some of this work is. Give us an idea of the reasoning behind them funding this from the US?

DARREN KELLY
This is a grant that was awarded to Fibrotech Therapeutics in collaboration with my colleagues Richard Gilbert and Henry Krum, and also Spencer Williams at Bio21 Institute in Melbourne. This grant is called a rapid access to interventional development grant from the National Institute of Health in the United States. The grant is given to basically accelerate the whole preclinical development of drugs and try to get them to the market or into patients more quickly. So it is a unique opportunity and we’re very fortunate to have received this grant from the United States. It’s one of the first of its kind that’s been given out in Australia for type one diabetes.

SHANE HUNTINGTON
Let’s talk a bit about that development phase because I’m sure a lot of our listeners, including me, are not too aware of the sheer amount of work involved. You’ve done some of the testing in I assume mice or rats. What’s the next step and how far do we have to go?

DARREN KELLY
The next step for us is basically to do a formal preclinical or nonclinical data package that we can submit to the FDA for approval to then potentially go out and do clinical trials within the next 18 months or so. So that’s what we’re doing at the moment, we’re just starting our formal preclinical program and hopefully by early 2010 we’ll be able to go into the first clinical trials looking at the safety of the compound in people.

SHANE HUNTINGTON
What sort of timeframe are we talking until it’s actually available to be utilised?

DARREN KELLY
Realistically, probably about five years to get this compound to market which is a lot shorter than some of the other drug development programs and hopefully our grant from the US will accelerate that as well.

SHANE HUNTINGTON
I’m sure there are good reasons for the use of the animal model being the mouse in this case. Why do we choose the mouse, and how confident are we that the results will translate across to humans?

DARREN KELLY
The model we’re actually using, in particular with the diabetic kidney diseases, is a rat model. We have been using this rat model for some 10 or 15 years now to predict a number of clinical trials, and as I said earlier we have worked with the pharmaceutical industry quite closely over the last 10 or 15 years using their drugs and testing them in our animal models to see whether they will have potential clinical efficacy. And so far we’ve been able to predict with 100 per cent accuracy the outcomes of clinical trials. So we’re actually quite confident that our animal data will translate into something that has clinical significance.

SHANE HUNTINGTON
We talked about heart attacks and about kidneys - what other potential applications in the body does this sort of drug have?

DARREN KELLY
It potentially has applications for a number of diseases associated with fibrosis. There was a quote that up to 45 per cent of mortality can be associated with fibrosis, and that quote is actually quite true. There is a significant proportion of diseases that are associated with fibrosis. If we look at the chronic kidney diseases, heart, liver, lung, they’re just a few examples of significant conditions that are associated with fibrosis. So although we don’t have data on these conditions at the moment we are hopeful that there may be benefit in some other organs.

SHANE HUNTINGTON
Professor Darren Kelly from the Department of Medicine in the Bio21 Institute at the University of Melbourne, Australia, thank you for being our guest on Up Close today.

DARREN KELLY
Thanks Shane.

SHANE HUNTINGTON
Relevant links, a full transcript and more information on this episode can be found on our website at upclose.unimelb.edu.au. We also invite you to leave your comments or feedback on this or any episode of Up Close. Simply click on the ‘add new comment’ link at the bottom of the episode page. Melbourne University Up Close is brought to you by the Marketing and Communications Division in association with Asia Institute of the University of Melbourne, Australia. Our producers for this episode were Kelvin Param and Eric van Bemmel, audio recording by Craig McArthur, theme music performed by Sergio Ercole.  Melbourne University Up Close is created by Eric van Bemmel and Kelvin Param. I’m Dr Shane Huntington. Until next time, goodbye.

VOICEOVER
You’ve been listening to Melbourne University Up Close, a fortnightly podcast of research, personalities and cultural offerings of the University of Melbourne, Australia. Up Close is available on the web at upclose.unimelb.edu.au, that’s upclose.u-n-i-m-e-l-b.edu.au. Copyright 2009 University of Melbourne.


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