̽��ֱ�� of Cambridge - Andrew Bradley

Wash cycle: making organs fit for transplantation

cjb250 — Wed, 20 Jul 2016 08:25:59 +0000

In a room in the Department of Surgery, a kidney sits inside a chamber connected to tubes and monitors. Solutions and gases are pumping through it and urine is coming out.

In fact, the chamber in itself is not particularly special – it’s an off-the-shelf machine used for cardiac bypass surgery in children: it’s how it has been adapted and the new uses it has found that make it so significant. This machine is able to rejuvenate kidneys deemed not fit for transplant, making them fit and healthy again – and suitable for a recipient.

Professor Andrew Bradley, Head of the Department of Surgery, is quick to point out that it is his team at Addenbrooke’s Hospital, part of Cambridge ̽��ֱ�� Hospitals – particularly Professor Mike Nicholson and Dr Sarah Hosgood – who should take all the credit for this machine, which they refer to as an organ perfusion system.

There is a chronic shortage of suitable organs for transplant and something needs to be done. To help address the problem, in December 2015, Wales became the first country in the UK to make organ donation an ‘opt-out’ system – in other words, doctors would remove the organs from deceased individuals and provide them for use in sick patients unless the individual had explicitly refused consent before their death.

Unfortunately, not every donated organ is suitable for transplant – in the case of kidneys, for example, around 15% are deemed unsuitable. This can be for a variety of reasons, including the age of the donor, their disease history and the length of time the organ has been in cold storage.

“Grading organs is not an exact science – it’s a mixture of factors about the circumstance in which it became available, its storage and how it looks to a trained eye,” says Nicholson. “This isn’t good enough, particularly if it means we’re losing some potentially suitable organs.”

What if there was a way of taking these organs and assessing them systematically? And to take it a step further, could some of them even be rejuvenated? Before coming to Cambridge, Nicholson and Hosgood developed a system while at the ̽��ֱ�� of Leicester that effectively recirculates essential nutrients through the kidney, bringing it back to life.

“We use a combination of red blood cells, a priming solution, nutrients, protective agents and oxygen,” explains Hosgood. “We pump this through the kidney while maintaining a temperature close to our body temperature. It mimics being in the body.”

As the perfusion solution is being circulated, the kidney will begin to function and produce urine. By analysing the contents of this urine and monitoring blood flow, doctors can see how the kidney is performing and whether it might make a viable transplant organ. After just a 60-minute perfusion, the kidneys are resuscitated and are potentially ready for transplantation.

This is no longer just an experiment: since moving to Cambridge, with funding from Kidney Research UK and the National Institute for Health Research, the team has been able to take kidneys rejected from other transplant centres, resuscitate and assess them, then transplant them. In December last year, two individuals on the organ transplant waiting list received the perfect Christmas present courtesy of the Cambridge team: a new kidney.

So far, the team has taken five discarded kidneys and managed to rescue three. “We’re hoping to process another hundred over the next four years,” says Hosgood, who is also working with centres in Newcastle, Edinburgh and at Guy’s Hospital in London, in the hope of replicating their success.

̽��ֱ��current kit, which was not purpose-built for organ perfusion, is bulkier and clumsier than ideal, so the team is currently fundraising to help design a dedicated machine, in collaboration with colleagues from the Department of Engineering. “It’s not very mobile, so we couldn’t use it to help resuscitate organs in transit to other centres.”

Nicholson and Hosgood’s success has spurred on other colleagues. Professor Chris Watson describes himself as “piggybacking” on their work to develop a technique for perfusing livers. ̽��ֱ��situation for liver transplants is even more serious than it is for kidneys: as many as one in five patients on the waiting list will die before a liver becomes available.

So far, his team has taken 12 livers, all but one of which had been rejected by other centres, and successfully resuscitated and transplanted them using a system that builds on the pioneering work of his two colleagues.

“There’s a scene in the Woody Allen film Sleeper where Allen’s character stumbles across a 200-year-old Volkswagen Beetle and manages to start it first time,” he says. “ ̽��ֱ��liver is like that. You take it out of cold storage and expect it to start first time. By first assessing it on our machine, we can be more confident it will work first time.”

In some ways, this has proved more of a challenge than it did for kidneys, he adds. “With kidneys, you can put them in the machine for an hour, resuscitate them and then transplant them. If it doesn’t work immediately, the patient stays on dialysis until it picks up. With a liver, it takes longer to analyse and resuscitate the organ, and if it doesn’t work it’s a disaster for the patient.”

Now that the team has successfully revived and transplanted kidneys and livers, this is by no means the end of the story. There is still much work to be done to further improve the organ – and hence improve the function and prolong survival, says Hosgood.

Once transplanted, organs face a battle with the body’s immune system, which recognises its new occupant as a foreign body. This is one reason why the perfusion system uses only red blood cells, not white – to do so would risk an inflammatory response that could damage the organ.

“Of course, as soon as you transplant the kidney, it will face a similar inflammatory response, but by then it should be in an improved state and able to cope better with what the body throws at it,” she explains. ̽��ֱ��Department is in the process of recruiting 400 patients for a randomised controlled trial to test this technology.

̽��ֱ��perfusion system also enables therapies to be given directly to the kidney. This ensures optimal delivery of the treatment to the targeted organ and avoids any side effects in the patient. One promising avenue of research, in collaboration with Professor Jordan Pober at Yale ̽��ֱ�� (USA), is the use of nanoparticles that target the endothelial cells in the lining of the kidney. These cells play an important role in the inflammatory response after transplantation. “ ̽��ֱ��delivery of nanoparticles in this way may reduce damage to the organ after transplantation,” she adds.

̽��ֱ��shortage of suitable organs is not going away. Not even a UK-wide ‘opt-out’ system is likely to completely eradicate the problem. If anything, the crisis is likely to get worse – the flipside of good news stories such as fewer road traffic fatalities and better medicines that reduce the number of young people dying early. ̽��ֱ��team recognises that the system alone is not the answer, but it brings a new relevance to the old adage “waste not, want not”.

There’s a nationwide shortage of suitable organs for transplanting – but what if some of those organs deemed ‘unsuitable’ could be rejuvenated? Researchers at Addenbrooke’s Hospital have managed just that – and last year gave two patients an unexpected Christmas present.

Grading organs is not an exact science – it’s a mixture of factors about the circumstance in which it became available, its storage and how it looks to a trained eye. This isn’t good enough, particularly if it means we’re losing some potentially suitable organs.

Mike Nicholson

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̽��ֱ�� of Cambridge to establish two new Blood and Transplant Research Units

sjr81 — Fri, 14 Nov 2014 15:07:08 +0000

Cambridge has received funding for two units under the £12.1 million scheme. ̽��ֱ��Units will be centres of excellence in human experimental medicine related to blood and transplantation and will have a strong focus on translation. They will support the delivery of objectives and functions of NHS Blood and Transplant, by creating an environment where world-class research, focused on the organisation’s needs, can thrive, and will provide high quality research evidence to inform decision making at NHS Blood and Transplant.

Speaking about the partnership funding awards, Dr Lorna Williamson, Medical and Research Director at NHS Blood and Transplant, said: "I am delighted that the Department of Health, through the NIHR, continues to recognise the importance of blood and transplantation research. This funding supports ambitious experimental research projects that will inform future clinical practice for services that NHS Blood and Transplant provides to the NHS and beyond."

Professor Andrew Bradley, Head of the Department of Surgery at the ̽��ֱ�� of Cambridge, in partnership with Professor Andrew Fisher from Newcastle ̽��ֱ��, will establish a unit focused on organ donation and transplantation. ̽��ֱ��Cambridge/Newcastle unit will focus on understanding how to improve the quality of organs prior to donation and will develop and evaluate novel approaches and technologies that increase the availability of suitable donor organs for transplantation, while improving graft survival.

Professor John Danesh from the Cambridge Institute of Public Health will lead a unit focused on donor health and genomics, a new area of research for NHS Blood and Transplant. ̽��ֱ��Unit will address major questions about the health of blood donors and produce evidence-based strategies to enhance donor safety while ensuring sustainability of blood supply.

̽��ֱ��Units will be based at Addenbrooke’s Hospital, part of the Cambridge ̽��ֱ�� Hospitals Partnership, and located within the Cambridge Biomedical Campus, the centrepiece of the largest biotech cluster outside the United States.

Professor Bradley said: “Blood and transplantation research is vital to improving the quality, safety and availability of donation and transplantation. These two new NIHR units will play an important role in this area and inform NHS policy and practice in the future. They will further add to and capitalise on continuing growth of the Cambridge Biomedical Campus.”

Professor Dame Sally C Davies FRS FMedSci, Chief Medical Officer and Chief Scientific Adviser at the Department of Health, said: “ ̽��ֱ��NHS and its patients rely on an efficient supply of blood and organ donations and, increasingly, stem cells and genomics. We want researchers to explore how to improve the quality and effectiveness of these donations, therapies and technologies. ̽��ֱ��NIHR Blood and Transplant Research Units will involve NHSBT in partnerships with leading university teams so that we can accelerate and translate advances in research into benefits for donors and patients.”

A third unit is due to open at UCL ( ̽��ֱ�� College London), led by Dr Karl Peggs and focused on Stem Cells and Immunotherapies.

̽��ֱ�� ̽��ֱ�� of Cambridge has received £7.9 million from the National Institute for Health Research (NIHR) to fund Blood and Transplant Research Units. Each Unit is a partnership between ̽��ֱ�� researchers and NHS Blood and Transplant, and will begin in October 2015.

Blood and transplantation research is vital to improving the quality, safety and availability of donation and transplantation.

Andrew Bradley

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Research hopes to increase available donor kidneys

bjb42 — Thu, 19 Aug 2010 00:00:00 +0000

̽��ֱ�� ̽��ֱ�� of Cambridge researchers hope their findings, published today in the journal ̽��ֱ��Lancet, will increase the use of kidneys from cardiac-death donors (kidneys which were previously viewed by some as inferior) and possibly reform how these kidneys are allocated - thereby increasing the fairness of kidney distribution as well as the likelihood of a successful transplant.

There are currently over 7000 patients waiting for a kidney transplant. Unfortunately, because of the dire lack of donation organs, almost 10 per cent of these patients die every year while waiting for a healthy kidney.

Since the 1970s, the majority of recovered organs for transplantations were from 'brain-dead' donors, patients who had suffered massive, irreversible brain injuries and needed artificial life support to stay alive. However, over the last decade there has been a reduction of these types of donors as a result of better care of patients with acute head injuries and fewer deaths from traffic accidents.

Because of the shortfall of organs, doctors have begun to use kidneys from cardiac-death donors - individuals who have suffered devastating and irreversible injuries and who have then suffered from a 'controlled' cardiac arrest (when medical support is gradually removed and the heart stops beating as a result of the injuries sustained). As these types of deaths are much more prevalent, donor organs from these patients are much more readily available.

Unfortunately, although the number of these types of transplants has increased dramatically - since 2000 they have risen from 3 to 32 per cent - there is still reluctance to adopt the use of these kidneys by some transplant specialists because of concerns about the quality of the organs. This new research, however, addresses these concerns, finding that kidneys from cardiac-death donors are of similar quality to those from brain-dead donors.

̽��ֱ��scientists examined data from 9134 kidneys transplants which were conducted in 23 centres; 8289 of the kidneys were donated after brain death and 845 after controlled cardiac death. They found no difference in survival rates or kidney function of recipients for up to five years after transplantation. ( ̽��ֱ��researchers did not have the data to explore the success rates beyond five years but indicate that there is no reason to suspect longer-term transplant outcomes would be different.) ̽��ֱ��scientists did find that some factors decreased the success rate of cardiac-death transplantations: increasing age of donor and recipient, repeat transplantation, and organs kept cold but without blood supply for longer than 12 hours.

Lead author of the paper, Professor Andrew Bradley of the Department of Surgery at the ̽��ֱ�� of Cambridge, said: "Cardiac-death donors represent an extremely important and overlooked source of high-quality donor kidneys and have the potential to increase markedly the number of kidney transplants performed in the UK."

Currently, kidneys donated by 'brain-dead' donors are allocated according to a national points-based system, ensuring equal access to donor kidneys irrespective of geographical location of those on the waiting list. Because of the absence of adequate information regarding kidneys from cardiac-death donors, however, they are instead allocated locally according to the policy of individual transplant centres, an arguably less effective way of distribution as it unlikely to secure the best candidate for receiving the kidney.

Dr Dominic Summers, one of the authors of the paper, added: "What we have shown, for the first time, is that cardiac-death donor kidneys last as long and work as well as brain-death donor kidneys, and should be regarded as comparable. In view of our findings, we recommend that cardiac-death kidneys be allocated in a similar way as brain-death kidneys, ensuring better tissue matches and favouring those who have waited longest.

"Cardiac-death donor kidneys currently make up only a third of deceased donor kidney transplants, but hopefully this paper will provide the evidence and impetus to greatly expand the national programme, and improve the national organ donation rates."

Donor kidneys from individuals who have recently died from cardiac arrest perform just as well in recipients as kidneys from traditional 'brain-dead' donors, scientists have found.

Cardiac-death donors represent an extremely important and overlooked source of high-quality donor kidneys and have the potential to increase markedly the number of kidney transplants performed in the UK.

Professor Andrew Bradley

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