July 12, 2019

A kidney surgeon who fixes the plumbing

By Conor McKechnie and Dodi Axelson

A kidney surgeon who fixes the plumbing

The list of people needing kidney transplants is tragically long, and donor lists are desperately short. Conor and Dodi find scientists who are coming up with alternative solutions to this problem. Some enable transplantation of less-than-perfect organs, and others dream of 3D printing important organs.

DODI : It's 5 o'clock somewhere, Conor, and I'm going to tell you about an occasion that I recently had to sit down in a faraway pub and sip at a freshly-poured Guinness and have a chat with Mr. Tim Brown.

DR. TIM BROWN : Hi, I’m Tim Brown. I'm a kidney transplant surgeon. I live in Belfast and I work at the Belfast City Hospital. And I’ve got the luckiest…I'm the luckiest man in the world to be able to do what I do.

CONOR : Mr. Brown or Dr. Brown, How should I be addressing this surgeon?

TB : I don't mind, you can call me Tim (…). I don't really care about these things, so yeah absolutely. Call me whatever you like.

CONOR : Okay. So what did you chat about with Tim?

DODI : We talked about something that matters to more people than you can imagine. We talked about organ transplants -- specifically kidneys.

CONOR : Okay. And that's what matters in this episode.

CONOR  & DODI : I'm CONOR and I'm DODI and this is Discovery Matters.

DODI : Tim is a smiling man who loves his job. and it might seem strange that Tim loves his job after you hear how often he deals with death or with near-death. In the UK,  there are about eight thousand people on the waiting list for a kidney.

TB : …and there are currently around 3000 donors a year in the UK so clearly there's a huge gap between supply and demand. The really scary statistic is three people in the UK every day die waiting for an organ.

HENRIK NITTMAR : You're right there is a shortage of donor organs of course. I mean in any given year there are hundreds of thousands of patients on the waiting list for an organ and maybe worldwide 80,000 receive an organ transplant.

CONOR : Wait. Who's this?

HN : My name is Henrik Nittmar. I'm the CEO of Corline Biomedical.

DODI : Yeah. Sorry. We're gonna leave Tim back in the pub in Belfast for a few minutes and we're gonna hear more from Henrik, the new guy, because they're involved in the same fight. We're going to come back to Tim. But right now – Henrik, we're going to hear what he's doing.

HN : We're trying to better the outcome of transplantations -- kidney transplantation specifically-- by improving organ quality into that kind of surgery.

DODI : And unlike Tim, Henrik is not a surgeon. He's a businessman. He's the CEO.

HN : I'm a PhD in innovation management so I drive the development of the product rather than the science. The perspective that you bring to a company like this should be complementary and I definitely bring a complementary perspective to the kind of hard science, clinical science that you normally meet. So, I think we do kind of feed into each other's perspectives.

DODI : Now Conor, you know how we ask all of our guests on Discovery Matters to explain stuff to regular Joes? Henrik gave us a pretty good analogy.

HN : …I could use the metaphor of a house.

We're trying to improve on the plumbing of the house. If you have a leakage in the plumbing, that will lead to immediate consequences: kind of a water leakage or something like that but also downstream - maybe a rotting wooden structure or something in the house. And the same goes for a kidney. That is, if you have plumbing then it is the vasculature that's in that kidney. If you have an injured vascular bed that will lead to immediate effects during transplantation in terms of coagulation and immune reaction problems, and also downstream, that will lead to poor over a functioning graft or a transplant.

If you look at maybe three to five years out.  We are repairing the plumbing, we are mending the leakages, we are mending the injuries in the vascular bed with a tool that we have developed. So it is very much trying to improve on the plumbing that is already there.

We not re-piping the house, we’re just repairing it and making it sustain the kind of pressure that the transplantation is for the patient and the organ.

DODI : And what Corline Biomedical’s technology also does is help produce better quality organs.

HN : The organ shortage, the imbalance between a need for transplantation and the donor pool leads to surgeons accepting what they call “expanded criteria” donors. Really in layman's terms that is donor organs from older donors that have a history of illness. For example hypertension or pre-diabetes or something like that. And that leads to maybe poor plumbing in those organs, if I may use that metaphor. And then they are more susceptible to the damage that occurs during transplantation which is the one we want to avoid. So we are improving on the quality of existing organs but also in the long term, giving the surgeons an opportunity to accept those organs into transplantation.

That is how we try to increase the pool of organs. So we are using a very well-known pharmaceutical agent that is called Heparin. It has been in use for more than a hundred years and daily, even today it's used in all kind of surgical operations to avoid blood clotting when doing surgical operations. And that is a very good pharmaceutical agent and well known for its functionality and its benefits. It has a drawback: if you over-administer it, if you give the patient too much there is a very, very high risk of that patient bleeding to death, actually.

So you definitely need to avoid higher concentrations systemically. So the way we do that is to try to modify surfaces, attaching that molecule to surfaces where we want to have it and then avoiding the systemic administration. So we're trying to modify surfaces: that is the basis of the technology.

CONOR : So if we go back to Henrik’s metaphor of a house and repairing the pipes in the house, getting the plumbing sorted out instead of improving all the pipes everywhere. Corline Biomedical looks for the specific joint where there is an issue and that is the place that gets the repairs.

HN : Exactly.

So based on that Heparin technology  we have designed and manufactured a large molecule, a macro molecular conjugate of Heparin and that has the function to … actually when it's flushed through the kidney. So we just flush it through the kidney, the pipes - the piping, the vasculature and it finds those sites that are injured and actually adheres to those sites and sits on those when the patient’s blood, the patient, receives the organ. And when that blood is flushed over those sites, it doesn't recognize those sites as injured anymore, they’re mended pipings or pipes.

DODI : And what's important to note is that this is all just the beginning for Henrik and Corline Biomedical.

HN : We have just started our phase 1 trial, which is done in Uppsala and at the Karolinska Institute in Stockholm. And so we started that recruitment and the plan is to report that study end of this year and then going further on to development in phase 2 and 3 studies.

CONOR : So what is Henrik’s vision though? For example, like in a hypothetical situation after a motorcycle accident and there's a kidney available for someone who's been on a list for five years. What would Corline’s innovation actually do?

HN : Our vision is that this technology  could be used to prevent the injury that is sustained during the transportation that we're trying to avoid. In clinical terms it's called DGF (delayed graft function) and that is defined by the patient actually going back to dialysis during the first seven days after transplantation. So it's a kind of, you could say failure because you want to avoid having dialysis sessions after being transplanted. So our vision is to completely avoid those DGFs to occur at all. And our secondary vision is to lower the rate significantly. And in the terms of the motorcycle accident you are referring to, one might say that we want to add this preventive technology  to avoid that DGF, no matter  what type of recipient you present to that organ, so you have a possibility to avoid all those injuries that you would otherwise sustain.

CONOR : So it sounds like we're back in the pub with you, your Guinness and Tim Brown.

DODI : We are indeed. And we're just getting started. So Tim was telling me that the alternative to organ donation of course is to be put on dialysis but this is really no form of guarantee.

TB : So the mortality rate on dialysis is really high. The mortality rate after a kidney transplant is much lower. So a kidney transplant, as soon as I take the clamps off, doubles your life expectancy compared to being on dialysis. So what you’ve got to remember is that we're comparing mortality of a transplant with mortality on what the alternative is - and that's dialysis, which is not a good thing.

I always say to people, dialysis keeps you alive but it's not very good for you. If you can get a transplant then that's by far and away the best thing, that's the gold standard treatment.

CONOR : So there's no need to say, there's a really serious situation with all the transplants and organ donations needed. And that question of supply and demand.

DODI : Yeah. But Tim is trying something new to improve this very question of supply and demand.

TB : So in Belfast, we've looked at our waiting list and we've said, well OK, we've got five or six years with 350 people on the waiting list and I thought, my goodness, how do we address this problem? Because we have a huge gap between supply and demand. So the first thing that we did was we concentrated on our living donor program. Dr AE Courtney who's a nephrologist in Belfast headed up a phenomenal quality improvement type project to increase her living donation rate. So when she started we were doing six living donor transplants a year and last year we did 77.

Humans are like jet airplanes. We can fly around with one engine, if you apply the kidney analogy  - so we don't need both. And we can get away, get around with one very adequately but we have to make sure that there are stringent checks in place before we allow people to go on and donate. So the first thing is we concentrated on looking at the donors. We increased our donor rate to the extent that our donor rate is now 43 per million which is the highest rate of living donation anywhere on the planet which is something we’re hugely proud of.

The second thing we did, was we concentrated on what we call extended criteria, deceased donors so the patients are the donors that ordinarily wouldn't have become donors. We're now concentrating on taking the higher risk organs and transplanting them in, because a higher risk transplant is still probably better than life on dialysis, the mortality rate on dialysis. So by increasing our cadaveric transplant rate in association with increasing our living donor rate. What we've done is we've managed to get our waiting list from 350 down to around 120. And what we've done also is reduce our waiting time, so waiting time is also related to your mortality on the waiting list.

The longer you wait the more likely you are to die even with the transplant. So our waiting times come from five years to two years on average. So we're very, very proud of what we've achieved in Belfast just with a little bit of hard graft and increasing the risk.

DODI : And although Tim and his team in Belfast can boast of the best statistics, internationally they're not alone in celebrating their numbers!

TB : Organ donation rate, I'm pleased to say is going up in the States, it's going up in the UK, it's going up all over Europe. We've got some fantastic success stories in Spain, Croatia and Portugal. They're achieving the world's best cadaveric organ donation rates. And they've achieved this by making sure their societies are fully signed up to the concept of organ donation. I think it's one of those gifts that society should really get behind: that organ donation shouldn't be a debate. Whenever you're approached, it should be yeah absolutely why would you not. So as a result, organ donation rate is going up across the world which is great news but it's going up very slowly and that is good news but it's no consolation to somebody who's dying on the waiting list currently for want of another organ.

DODI : Tim told me of a specific example of a kidney transplant that showed the possible future of science and it's … you got to check this out. It's all based around 3D printing.

TB : In order to try and increase the likelihood of success, we took a complex situation where a daughter needed a kidney from her father and her father in actual fact had a small tumor in the kidney. And ordinarily this wouldn't be a transplantable situation, obviously we wouldn't want to transplant a kidney with a tumor in it -- but what we were able to do because this girl desperately needed an organ.

What we were able to do was take the risk after discussion with the family they were happy to carry on with the risk and so we got a 3D printed model exact replica of the kidney containing the tumor that allowed me to plan a procedure precisely to the last millimeter, which allowed me to excise the tumor, repair the kidney and then transplant it in. And as a result we have a young mother who's walking around today and she has got a normal life expectancy compared to being on dialysis and waiting to die.

CONOR : So look, I've been really excited about 3D printing and regenerative medicine ever since I saw them print Mila Jovovich in the Fifth Element back in, what 1997 or something like that.

(Audio segment of movie, The Fifth Element)

Reconstruction: complete. Told you, perfect!

CONOR : So. I was kind of surprised to see the first application being something in surgical planning rather than actually printing organs. But this is really taking things a step in the direction that we've been imagining for a long time. So look, another hypothetical here: what if that young mother Tim had helped save, what if her daughter maybe in the future one day might need a transplant of her own. Are we going to get to the stage where we could actually use 3D printing technology  not just to plan surgery but to actually print her the organ that she needs?

 Are we going to get to that or is that just in my sci-fi brain somewhere?

DODI : So I wondered that too. And it seems like Tim has been thinking the same thing too. In fact that's on his Christmas list.

TB : That's exactly what I want on my Santa Claus list. I want to be able to go to a shelf and use her specific DNA to be able to print off an organ so that I'm able to transplant it into her without the need for immunosuppression, before she ever ends up on dialysis. That would be my holy grail.

However I think probably in the future people like me will be a thing of the past and transplant surgeons will not be required because the tissue engineers and the cell biologists will have stem cell technology  down to a tee. So that instead of me having to replace their organs what they may be able to do is to inject some sort of cell or elixir, if you like, into the organ that will repair the broken organ without me needing to put in a new one. I think that's probably where we should be heading.

Personalized healthcare so we use the patient's own cells to redesign themselves I think would be the Holy Grail. And I would be sorry to be a thing of the past because I love what I do. But you know what? If it's all about the patient and the patient doesn't want the transplant if they don't have to have one.

CONOR : Okay so look we're all over the place here. We seem to have to go through from a whole scale. We're in a drastically desperate situation. He's got this vision for 3D organ printing and maybe in an ideal world he'd like to be completely unemployed. This is like getting whiplash in this conversation.

DODI : It is.

TB : I'm gonna go and cry in my beer in a minute. So yeah, absolutely

CONOR : So maybe we need to do every episode of Discovery Matters in a pub but this was really the alcoholic one.

DODI : Ha-Ha!

CONOR : Tune in next time for a more sober episode of Discovery Matters.

DODI : Thanks for listening. Bye for now.

Our executive producer is Andrea Kilin. Discovery Matters is produced in collaboration with Soundtelling. Production and music by Thomas H.