So haemodialysis is this treatment which is the original type of dialysis, where it takes blood out of your circulation, puts it through a machine, puts it back into your body having filtered off a lot of the waste materials. It needs to be done usually at least three times a week. Probably takes at least four hours. Although interestingly, some people are deliberately doing much – either much longer treatments, or more frequent treatments, and that seems to make them feel better. Get them up to a better level of performance and, and health. So that, that treatment – as I say – it’s been around for a long time, but it’s been gradually refined. And many people have lived on dialysis for decades, if they need to do. The other kind of dialysis that came along a bit later is peritoneal dialysis, where you have a tube in your tummy, and you join it to bags of fluid that wash in and out of there, and do the same kind of job of removing waste materials but in a kind of more continuous gradual way than haemodialysis. There are different ways of doing this. In CAPD you put bags in there and change them, several times a day. Many people now have an overnight machine that automatically does the exchanges for them during the night. And peritoneal dialysis is a really good treatment for young people, or for people who want to travel, or for people who, for whom going to a renal unit three times a week to do dialysis is a, a burden. Which is actually almost everybody [laugh]. One of the difficulties with peritoneal dialysis is that it doesn’t – it doesn’t seem to give people decades of treatment in the same way as haemodialysis does. But it’s a particularly good treatment for people who are heading towards a transplant, or between two treatments, and so on. And it’s a treatment that many people with Alport syndrome would want to have at some time.

Just in very broad principles, people with kidney disease, they’re going to face a lifetime of having kidney disease. And some of the problems are going to be related to their kidneys, but we know that patients with kidney disease are also more likely to get heart disease. Perhaps because of the high blood pressure, and so on. So the general advice about eating healthy and living healthy is particularly important to patients with kidney disease. So early in kidney disease, the best advice is just to follow good healthy living and eating advice. There aren’t any particular restrictions that you should be placing on kidney patients at that time, with just two exceptions. So, one is – and it’s not really an exception – it’s particularly important for kidney patients not to eat too much salt. Because it your kidney function isn’t as good, your kidneys struggle to get rid of it, and it causes high blood pressure. But actually that’s general advice to the population. It’s maybe, it’s maybe just more important that kidney patients should follow it. There’s a lot of talk on the internet and everywhere about what you should do with protein. And in the past we used to recommend that people should restrict the amount of protein they eat, and eat low protein diets. We’ve actually gone off that quite a lot, because with modern treatments for blood pressure and ACE inhibitors, it looks like diet makes very little, if any – or low protein makes very little, if any, difference to what happens. And there’s a real risk that people on very low protein diets actually end up malnourished and ill. So we’ve, we’ve moved away from that. On the other hand, you should definitely avoid very high protein intake. And that’s not often a problem with normal diets in the UK. Maybe it’s more of an issue in North America, where you’re having moose steaks three times a day. But it does, it – it does arise with people going to the gym, and being told to take protein supplements for sport and so on. Patients with kidney disease should not do that. That’s the only other specific bit of advice, beyond healthy living.

One of the difficulties with – it’s a genetic disease. So the obvious thing is to think well can we do gene therapy for it? Gene therapy is now becoming possible for some genetic diseases, but they tend to be diseases where the, the trouble is easy to get at. So diseases in the bone marrow are the ones that have been subjected to the first successful gene therapy treatments. The cells in the kidney that produce the GBM, the filtration membrane which is abnormal in Alports are really difficult to get to. The kidney is a really complex structure. And these cells are tucked way, way inside it. Many years ago there was an attempt to do gene therapy in pigs, actually. With the intention of trying to treat Alport syndrome. And they got part of the way there. It looks really hard. It seems quite unlikely that we can – in the next few years – go in there and correct the gene defect in those cells. On the other hand, there may be ways to alter the proteins that they produce. But I think it’s gonna take quite a bit more work to be sure that we can do that safely and effectively. And so that’s probably a little bit further off than I know many people would hope.

And what about sort of bionic kidneys, and that sort of development?

Yes. Dialysis hasn’t changed much, so haemodialysis as it was invented fifty years ago – more than fifty years ago. Or, fifty years ago it was used for people with chronic kidney disease. It’s, it’s pretty much the same. And a lot of people have wondered whether you could make it much smarter. Peritoneal dialysis is in a way smarter, it takes place inside your body, there’s much less artificial stuff going on. But it, it hasn’t lived out its vision as a, as a permanent treatment. It’s a really good treatment for a time for many, many people. The concept of the artificial kidney that you might make in a box and put inside people and then never see. There are some experiments going on around that now. My prediction is that there’s going to be an awful lot more research needed before that becomes much better and safer than the treatments we have now. And let’s not forget, they’re doing a really good job. They’re keeping, in the UK, well we have – I think we have sixty thousand people alive with dialysis and transplantation, and about half of them are on dialysis. So these treatments are doing really well. These new things coming along will have to prove themselves to be really safe and manageable, and work in the long term, for them to take the place of these others. Of course we all hope that these things that make dialysis simpler and easier to cope with will come along. But I don’t think we’re quite there with them yet.

So I think most, most people know a little bit about dialysis and transplantation, nowadays. They, they were both invented interestingly around about the same time, in the 1960s. So there are some people alive now with both, who’ve been on dialysis and had transplants for more than fifty years. It’s, it’s quite – quite an amazing medical success story. Interestingly, dialysis seems quite similar to treatments that were around in the 1960s, although peritoneal dialysis came along later. But it has improved a lot. So although it’s haemodialysis, which is the one that washes your blood through a machine, it’s a big burden on anybody. But many – particularly young people who don’t have other serious illnesses, lead a very, a very good life on it. On the other hand, most people want a transplant. Because a transplant restores you completely to normal health. I guess sometimes people reckon they lead really good lives on dialysis and it’s only when the transplant comes on that they suddenly discover they have much more energy. Transplantation has become much, much more successful in the last fifty years. Progressively so. So, most patients with Alport syndrome are transplanted now. And most of them do really well for a long time. I think the, the worry for a young person heading towards kidney failure is that they’re often told that a transplant won’t last forever. Which is often true. And they may need to experience dialysis and more than one transplant in a lifetime. So I guess that just makes it particularly important that they get a good transplant, and look after it well. But they do really well with transplants, and lead completely normal lives, essentially.

There’s never a disease you would wish to have, is there. So The good thing, that there is a lot of good news about Alport syndrome. We’re able to slow it down now, and we never thought we would be able to do that as soon as it’s proving that we are. And the treatments for patients who do get kidney failure have improved no end in my lifetime, they’re so much better than they were. So the great majority of people with Alports – even if they develop kidney failure – are leading really healthy, good lives. And that, that’s a fantastic change. I, I think we , we did a quick look, and there are nearly five hundred people transplanted or on dialysis with Alports – all, great majority transplant in the UK now. And of course fifty years ago there were none. But it’s an extraordinary change. We will continue to make huge changes in the future. Those treatments will continue to get better. And it looks as if we’re going to increasingly be able to slow down the rate at which people get kidney failure. So hopefully more people will be out there, not needing dialysis and transplantation. So yes, you wouldn’t wish it on anybody. But if you have it, the outlook is much better than it was. And we can really now offer things that, that make a difference. And that’s a huge step forward.

It’s useful. It’s useful. There are some families who, where the pattern of disease obviously seems to be quite severe. So the hearing loss comes on quite early, and the kidney disease comes on quite early. Nowadays we can quite often track that down to a severe mutation. And in other families, the disease tends to be quite mild. The difficulty is that for any individual person, they cannot be sure that they’re going to follow the family pattern. So although they may be – if you come from a family with severe disease, although you’re more likely to get severe disease, there are some lucky people in those families who get very mild disease. And vice versa. There are some people in families that tend to be mild, who get very early disease. And we often can’t fully explain yet why we see that amount of variation.

Until recently, the treatment for Alport syndrome was just like the treatment for any other kind of kidney failure, which was to control the blood pressure, look after general health, encourage people to lead a very healthy life, and then prepare for dialysis and transplantation if it became necessary. And then it was picked up a number of years ago, that some medicines that were used to control blood pressure seemed to be particularly useful at slowing down the disease in Alport syndrome. And these are the ACE inhibitors, which have been quite widely used in other kidney diseases where there’s protein in the urine. And it was first found in experimental animals with Alport Syndrome, that it slowed down their disease. And then Oliver Gross and his team in Germany pulled together a lot of European patients, and showed that those who’d had ACE inhibitors seemed to get much later kidney failure than those who hadn’t. So that is a really important part of treatment now.

And can you explain in sort of layman terms what ACE inhibitors are, and what they do exactly?

So they’re blood pressure medicines. One of about four of the common blood pressure treatments that we use. They all work in slightly different ways. And ACE inhibitors seem to have a particular effect in the kidney, that protects the filtering units, the glomerulus. And in patients with proteinuria, they seem to slow down the deterioration of, of, of kidney function and loss of filtration capacity. The patients who benefit are the ones who have protein in their urine, and that is usually the case in Alport syndrome.

So patients with Alport syndrome, like most other kidney diseases, are completely unaware that there’s anything happening in their kidneys until quite late on. Some of them notice – or their parents notice – blood in the urine, when they’re babies. But really you wouldn’t know anything was going on after that time, unless you did tests of urine or of kidney function. And for people with severe Alport syndrome, their kidney function gradually deteriorates. So that typically, people with severe Alports would be getting into serious kidney trouble in their late teens or twenties without treatment. Fortunately, that’s getting a bit later now. In addition to that, there are people who carry the Alport gene. And carriers is maybe not the best term, because quite a few of those people in their lifetime do get kidney disease. Maybe up to a third of them, max. So, most of them are fine. Those people may also get abnormalities of their, in their urine and kidney function, as the years go by. But on the whole are less severely affected.

And how would you diagnose somebody with Alport syndrome? What sort of tests would you conduct?

So usually – again, I’m talking about the people with severe Alport syndrome. Usually the doctors are going to suspect it, because the patients are often complaining of deafness, or someone else in the family has had a disease in which deafness was associated with kidney failure. In reality there are quite a few conditions that can cause deafness and kidney failure. But that would certainly raise suspicion. In the past, most of the diagnoses have been made by doing a kidney biopsy and examining it under the microscope. Increasingly it’s now becoming possible to do that with genetic testing. And that’s probably going to get better in the future.

So the common type of Alport syndrome that everybody- well, let’s say every medical student is supposed to know – [laugh] is, affects young men. Because it’s X-linked. Men have one X chromosome and one Y chromosome. So if they inherit an X chromosome with the Alport mutation on it, that’s their only copy. They don’t have another matching chromosome with a normal copy on it. So it’s very easy to understand why they should get severe Alport syndrome. So they would typically begin to get protein in their urine in their teens. Maybe start losing their hearing some time during their teens. And then increasingly lose their kidney function in their late teens and into their twenties. And the average age at which patients like that used to get kidney failure was in their mid to late twenties. Fortunately that’s now later, with ACE inhibitors. Now you can get exactly the same kind of, of Alport syndrome from two other genes, which aren’t on the X chromosome. So there are three genes that can cause Alport syndrome. They’re called collagen 4 – alpha 3, 4, and 5.So 5 is the one that’s on the X chromosome, and 3 and 4 aren’t. But if you have two abnormal copies of either the 3 or the 4 gene, you’ll get exactly the same thing as a, a boy with X-linked Alports. Now it’s very rare to inherit two abnormal copies of, of one of the other genes. So the majority of people that we see who are affected at a young age, are boys. But boys and girls could be equally affected by the other type. And it’s thought that it might cause up to fifteen percent of typical Alport syndrome.

So autosomal dominant means that you have one copy of the abnormal gene, but you get disease. It’s slightly controversial whether we should be calling it autosomal dominant, because many people with one abnormal copy, probably most people with one abnormal copy don’t get severe kidney disease in their lifetime. But some do. And in some families that seems to be more common. And in those families it’s sometimes been called autosomal dominant. Other people say, “Actually you should just call these people unlucky carriers.” It means the same thing. So they have one abnormal copy, and they get kidney disease. Usually much later in life. And often without the hearing loss, or at least without the severe hearing loss that patients with typical Alport syndrome get.