Transplant research

 

Funding Research in new Transplant Technologies

Transplantation is a successful way to treat people whose own organs stop working but to prevent rejection transplant recipients have to take potent immunosuppressive drugs for the rest of their lives. Appropriate combinations of these drugs can be effective, but this requires life-long administration and results in suppression of the entire immune system non-specifically, including in some cases, the development and function of cells that have the potential to control rejection.

As a result, transplant recipients have an increased risk of cancer and infection, suffer from side-effects associated with the drug therapy and require on-going, intensive clinical management.

Understanding how the immune system is controlled when it responds to a transplant, and promoting the development and function of cells that can prevent rejection selectively hold the key to reducing the unwanted side-effects of immunosuppression.

Oxford Transplant Centres programme of research focuses on how, when and where specialised cells that can control transplant rejection work and what stops them from working.

The key areas that OTC are currently investigating include:

  • Strategies for the induction of tolerance using biological therapeutic agents.
  • The mechanisms of tolerance particularly the role of regulatory T cells and their therapeutic potential.
  • The impact of the immune system on cells and tissues generated from stem cells and tissue scaffolds
  • The translation of laboratory findings to clinical transplantation through the development and validation of biomarkers for monitoring the immune status of transplant recipients
  • Using T cells as a cell therapy for controlling rejection.

The results we obtain will also help develop new treatments for people who have autoimmune diseases, are allergic or have cancer, where controlling the immune system selectively is also critically important.

Kathryn Wood

http://www.nds.ox.ac.uk/research/trig



The Quality in Organ Donation (QUOD) Programme

A bio-resource aiming to improve the quality of donated organs for transplantation

In recent years the transplant community has faced challenges regarding the quality of organs available for transplantation, leading to uncertainty and sometimes discard of valuable organs. QUOD (Quality in Organ Donation) is a National Consortium funded by NHS Blood and Transplant, which started in 2012 and whose aim is to improve the quality of organs by providing biological samples from deceased organ donors for the transplant research community.  Recently, the Medical Research council awarded QUOD additional funding to further extend its remit.>

QUOD has established a central bio-resource of blood, urine and tissues from DBD (Donation after brain death) and DCD (Donation after circulatory death) donors, collected nationally by transplant professionals throughout the organ donation process. All UK retrieval teams and academic transplant centres are involved in sample collection as well as the SNODs (Specialist Nurses in Organ Donation), who also obtain specific QUOD consent/authorisation from the donors’ relatives.

In addition, QUOD has access to comprehensive donor and recipient data from NHSBT which are invaluable for research studies and multivariate analyses. Samples are used to analyse pathways involved in organ injury and repair and to identify novel bio-makers. Interventions performed in the donor and ex-vivo, during organ preservation, will be correlated with organ outcomes in the recipient. Biological samples, stored in a central biobank, are accessible to researchers to allow analysis and gain better understanding of how we can assess the viability of a donor organ, match it to the right recipient and increase the numbers of transplantable donor organs.

For more information please visit the QUOD website:

www.quod.org.uk 

 

 

 

COPE Consortium

The COPE Consortium is funded by a European Commission FP7 Award, and is the official organ preservation task force of the European Society for Organ Transplantation (ESOT). The Consortium brings together academic institutions, clinical and scientific experts and SMEs from across Europe to work together on advancing organ preservation techniques and is being led by Professor Rutger Ploeg in Oxford.

The COPE Consortium aims to advance and develop organ preservation technologies by performing clinical and translational studies with on-going experimental refinement. Through testing the quality and safety, increasing the efficiency and refining preservation strategies we aim to bring technologies from the bench to the bedside.

Focusing on four clinical trials across Europe the Consortium will be working on improving preservation and reconditioning strategies for kidney and liver organs procured for transplantation. By exploiting collaborations between industry and academic institutions we aim to introduce organ preservation technologies that will increase the number and quality of grafts used for transplantation.

The four strategic objectives of the programme are:

  1. To test in clinical trials a number of novel clinical approaches to repairing and preserving high-risk donor organs.
  2. To investigate in experimental models a number of novel scientific approaches to organ repair and regeneration.
  3. To develop new objective methods to measure and predict the viability and outcome of donated organs.
  4. To develop an integrated network of academic clinicians and scientists in Europe that, in collaboration with SMEs and ESOT, will develop and implement new medical therapies and devices in organ transplantation.

 

www.nds.ox.ac.uk/research/cope

 

 

Vascular Access Innovations

I inserted Europe’s first HeRO graft in 2013 and currently have the greatest European experience with over 30 HeRO implantations to date. The HeRO (Haemodialyis Reliable Outflow) device is the only fully subcutaneous (under the skin) device available to continually provide renal failure patients with dialysis in the face of underlying stenotic (narrowing) or occlusions in the main veins in the chest that normally need to be patent if conventional fistulae / grafts for dialysis will work. 

I have the largest international series of the Flixene early cannulation graft for dialysis. These grafts can be inserted into a patient and used within hours of surgery for dialysis thus avoiding the need for dialysis lines and long in-patient stays.

I recently introduced the Surfacer Inside Out Catheter System, this enables patients who have completely occluded their central veins around the heart region, and who would have otherwise ended up with sub optimal lines in their groins, to be able to have a procedure that takes an hour and I can come from within the vein around the heart straight out onto the skin and then bring a line back in. We have just done 3 successful cases and have more pending. 

Finally, this week we became the 3rd centre to trial a novel technique to create fistulas for dialysis without doing surgery. This technique is called Endo AVF and is a radiological procedure that creates the fistula through two small punctures. The early results of this technology are very exciting and appear to be superior to the conventional surgical technique. 

Mr James A Gilbert BM BS, MA (Ed), FRCS (Gen Surg)

Consultant Transplant & Vascular Access Surgeon

Vascular Access Lead

 

 

 

 

3C Study

CAMPATH, Calcineurin inhibitor reduction and Chronic allograft nephropathy trial.

The study is called 3C. It aims to test new ways to improve kidney transplants and make them more effective.

Kidney transplantation is a very good treatment for people whose kidneys no longer function sufficiently to keep them alive. Unfortunately, kidney transplant function inevitably declines over time. On average, after about 10 years the transplant “fails” and the recipient either receives another transplant or returns to dialysis.

The aim of 3C is to test two ways to prevent this failure – and help transplant patients now and in the future live longer with better quality of lives. All people who receive a kidney transplant need drugs to prevent their body from “rejecting” the new kidney. Standard medications to prevent rejection may also cause long-term damage to the kidney. The 3C Study is testing two new treatments which might avoid this long-term damage. No one knows which of the two treatments, if any, are better than existing medication.

The treatments being tested relate to immediate treatment after transplant, and long-term care, starting about six months after transplant. The immediate treatment is referred to as ‘induction treatment’ and the longer term care as ‘maintenance treatment’.

We do not know which method of treatments, or combinations of treatment, is best. Patients will be put into different treatment groups, selected by chance (randomly), like the toss of a coin. At the end of the study scientists will analyse which treatment produces the best result. It may be that there is no clear cut answer.

At the time of transplant (‘induction’ treatment)

A patient will be allocated a treatment group at the time of the transplant operation. A computer will decide by chance (like the flicking of a coin) which induction treatment they will receive. This will either be:

  • Standard treatment: basiliximab followed by standard medications. These will include steroids for at least 3 months, after which time they may be stopped if the doctor wishes to do so.
  • New treatment: CAMPATH treatment followed by lower doses of standard medications.
  • Patients treated with CAMPATH will not need steroids.

Six months later (‘maintenance’ treatment)

Once again, the long-term treatment will be chosen at random by a computer. This will either be:

  • Standard maintenance treatment; or
  • New treatment: the patient will be switched to the new drug being tested. This new drug is called sirolimus (Rapamune).

The Principle Investigator for this study is Professor Peter Friend, Professor of Transplantation at the University of Oxford, Consultant Transplant Surgeon and Director of the Oxford Transplant Centre.

Normothermic Liver Perfusion

European liver perfusion trial

The global shortage of livers for transplantation has necessitated the use of increasingly marginal organs. Normothermic machine perfusion (NMP) of the liver is a technique of organ preservation in which the liver is perfused with oxygenated blood, medications and nutrients at normal body temperature in order to preserve it in a physiological functioning state. Previous animal work has suggested that this could improve the quality of organs and so potentially enable more marginal livers to be transplanted successfully. The trial is the first multinational randomized controlled trial to compare the efficacy of normothermic machine perfusion with conventional static cold storage in human liver transplantation.

This investigator-initiated, multinational, open-label, randomised controlled trial was sponsored by the University of Oxford and funded through COPE. The seven trial sites included four UK transplant centres (Addenbrooke’s Hospital, Cambridge; King’s College Hospital, London; Queen Elizabeth Hospital, Birmingham; Royal Free Hospital, London) and University Hospital, Essen, Germany; University Hospitals, Leuven, Belgium; and Hospital Clinic, Barcelona, Spain.

Livers from adult donors after neurological (DBD) and cardiovascular (DCD) certification of death were randomly assigned to NMP or SCS. The trial was powered (90%) to show a 33% difference in the primary endpoint, peak AST (a clinically accepted biomarker for graft and patient survival). Secondary endpoints included: organ utilisation; preservation time; reperfusion haemodynamics; early allograft dysfunction (EAD); hospital stay; cholangiopathy seen on MRCP; graft and patient survival.

Between 26th June 2014 and 8th March 2016, 222 livers were successfully transplanted as part of this trial, (121 NMP and 101 SCS). It is hoped that the full results will be published shortly.

David Nasralla

 

Novel strategies to enhance fatty livers for transplantation

Liver transplantation has become a victim of its own success and 20% of patients on the UK waiting list die without a liver transplant. Steatotic (fatty) livers derive particularly poor outcomes when transplanted and a result a large number are discarded. With the global obesity epidemic, an increasing number of steatotic livers in the donor pool is inevitable and identifying methods to salvage these livers is of great importance.

Normothermic machine perfusion (NMP) is a novel preservation technique which maintains the liver in a fully functioning state outside the body; providing it with oxygen and nutrition at normal body temperature. This facilitates extended preservation times, functional liver assessment and the potential for liver-directed therapeutic interventions.

At the Oxford Transplant Centre, Professor Friend’s liver perfusion group are performing perfusion studies of steatotic human livers which have been deemed too high risk for transplantation. By perfusing the livers for 48 hours with de-fatting agents and other adjuncts, the group hope to gain an understanding of NMP’s potential in the enhanced preservation and de-fatting of steatotic livers. If successful, this will increase the number of livers available for transplantation and take significant steps to abolish waiting list deaths.

Carlo Ceresa

ONE Study – Reference Group

After organ transplantation one of the most important problems that can occur is that the body may reject the transplanted organ because of the powerful reaction of the body’s immune system. In order to prevent rejection the patient has to take a number of different drugs for the lifetime of the transplanted organ. These drugs can have side-effects and some patients will still experience rejection episodes in spite of taking the drugs. In recent years we have found out that as well as cells that can damage a transplant, the body makes other cells that control the rejection response. We hope that it may be possible to use these cells grown in the laboratory under very carefully controlled conditions as a new treatment to prevent transplant rejection.

The Reference Group study will involve small volumes of blood and urine being taken at standard clinic visits for extra laboratory tests. 12 weeks following transplantation a sample of kidney tissue (a transplant biopsy) will be taken to look for any signs of transplant rejection.

Chief Investigator is Professor Peter Friend and the Principle Investigator is Dr Paul Harden. This study is being carried out by an EU/USA collaborative group.

Sentinel Skin Flaps study

One of the main causes of medium term pancreas graft failure is rejection. In many cases we are currently not able to detect rejection early enough to prevent it causing irreversible damage. This is due to a lack of sensitive or specific tests for pancreas graft dysfunction and rejection. We have noticed from our intestinal transplant programme that transplanted skin will often reject before other organs and it is also easily diagnosed by a rash and painless biopsy.

We are setting up a study that will investigate the use of a small donor-derived skin flap that will be transplanted onto the forearm of a patient at the same time as pancreas transplantation. This small patch of skin will then act as a constant visual ‘barometer’ of possible rejection in the pancreas. We hope this will enable much earlier diagnosis and treatment of rejection and thereby significantly improve graft survival for our patients.

Urinary C-peptide study

This study is investigating whether a urine test can help to monitor how well the transplanted pancreas is functioning. It is hoped that this could also be developed into a simple test that could even be sent from home. If we can identify poor pancreas graft function then it may be possible to investigate and treat the causes earlier than is currently possible. This study is a collaboration between the Oxford Transplant Centre, Oxford Centre for Diabetes Endocrinology and Metabolism, and Prof Hattersley’s group at the University of Exeter.

Intestinal Transplantation

Quality of Life and Outcomes

Over the past few years we have been collecting quality of life data to understand how an intestinal transplant impacts on our patients. We have used three different questionnaires to record this including both generic, that have the advantage of being applicable across many different conditions, and condition specific questionnaires, allowing us compare patients with the same condition. From the generic ones, we have found that following intestinal transplant patients overall score with life rises from an average of 40% (+/- 21%) to 73% (+/- 7%), with an improvement in move around, to do everyday activities including caring for themselves and their pain or discomfort levels. In addition, from the disease specific questionnaire there were marked improvement in ability to travel, body image, concerns regarding their health and the future and the ability to eat food again. This is incredibly exciting to see the improvement that intestinal transplant brings. We are continuing to collect data and our aim in the next few years is to develop a short patient centred questionnaire that reflects what patients feel are important questions for us to ask them.

Centre for Evidence in Transplantation

The Centre for Evidence in Transplantation (CET) (www.transplantevidence.com) was established at the beginning of 2005 by Professor Sir Peter Morris with the aim of providing a source of high quality evidence-based information on all aspects of solid organ transplantation. The Centre is devoted to evaluating the quality of evidence in organ transplantation (kidney, heart, lung, pancreas, liver, etc.) and defines gaps in our knowledge in these different areas. The CET has offices and staff within the Clinical Effectiveness Unit at the Royal College of Surgeons of England, and at the Oxford Transplant Centre.

The CET has been involved in a number of projects since its establishment, one of which is the development and maintenance of the Transplant Library (www.transplantlibrary.com). The Transplant Library is an electronic library of all RCTs in solid organ transplantation, including congress abstracts, from 1970 to the present and more recently includes systematic reviews that are regarded as of reasonable quality, and clinical practice guidelines. We have also recently added invited expert commentaries to key articles and the ability for users to comment on and discuss articles on the site. To promote the Transplant Library CET produces the Transplant Trial Watch, a monthly overview of RCTs that were recently added to the Transplant Library. The Trial Watch includes a summary of the RCT, critical commentary written by CET and critical appraisal.

The Centre has also carried out and is carrying out a large number of systematic reviews and meta-analyses in all aspects of solid organ transplantation. Many of these have been published in peer reviewed journals and are well cited. The CET staff have expertise in literature searching, risk of bias assessment and meta-analysis, including handling missing data, mixed effects analysis and network meta-analysis.

More recently, the CET has been involved in the design and reporting of clinical trials in transplantation, including the management and design of the Consortium for Organ Preservation in Europe (COPE) clinical trials in partnership with the Surgical Interventional Trials Unit (SITU).

The CET also has an agreement with the European Society for Organ Transplantation (ESOT) that we will become the Knowledge Centre for ESOT and would offer advice on the design of RCTs and systematic reviews, as well as provide assistance with the reporting of RCTs and systematic reviews. Trials that were methodologically sound in design will be given ESOT/CET accreditation.

www.transplantevidence.com

www.transplantlibrary.com

www.nds.ox.ac.uk/research/centre-for-evidence-in-transplantation

Transplant Immunology

The Transplant Immunology and Immunogenetics Laboratory provides consultant-lead specialist regional services for clinical transplantation within the Oxford Transplant Centre and for haematopoietic stem cell transplants performed within the OUH. Currently these services include HLA typing to the DNA sequence level, antibody screening and specification and crossmatching.  The laboratory provides a 24-hour on-call service for transplantation and post-transplant monitoring.  Immunogenetics services are also provided to clinicians to define disease susceptibility genes as an aid to patient diagnosis and treatment. The laboratory is accredited by the UK Accreditation Service (UKAS) and the European Federation for Immunogenetics (EFI). Referrals are received from within the OUH and externally from Primary Care Trusts and other Trusts and Institutions.  In order to maintain the highest standards of the services in a continually developing field, the laboratory supports research and development in histocompatibility and immunogenetics testing and in the broader field of clinical transplantation.

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Funding Research in new Transplant Technologies

Transplantation is a successful way to treat people whose own organs stop working but to prevent rejection transplant recipients have to take potent immunosuppressive drugs for the rest of their lives. Appropriate combinations of these drugs can be effective, but this requires life-long administration and results in suppression of the entire immune system non-specifically, including in some cases, the development and function of cells that have the potential to control rejection.

As a result, transplant recipients have an increased risk of cancer and infection, suffer from side-effects associated with the drug therapy and require on-going, intensive clinical management.

Understanding how the immune system is controlled when it responds to a transplant, and promoting the development and function of cells that can prevent rejection selectively hold the key to reducing the unwanted side-effects of immunosuppression.

Oxford Transplant Centres programme of research focuses on how, when and where specialised cells that can control transplant rejection work and what stops them from working.

The key areas that OTC are currently investigating include:

  • Strategies for the induction of tolerance using biological therapeutic agents.
  • The mechanisms of tolerance particularly the role of regulatory T cells and their therapeutic potential.
  • The impact of the immune system on cells and tissues generated from stem cells and tissue scaffolds
  • The translation of laboratory findings to clinical transplantation through the development and validation of biomarkers for monitoring the immune status of transplant recipients
  • Using T cells as a cell therapy for controlling rejection.

The results we obtain will also help develop new treatments for people who have autoimmune diseases, are allergic or have cancer, where controlling the immune system selectively is also critically important.

Kathryn Wood

http://www.nds.ox.ac.uk/research/trig



The Quality in Organ Donation (QUOD) Programme

A bio-resource aiming to improve the quality of donated organs for transplantation

In recent years the transplant community has faced challenges regarding the quality of organs available for transplantation, leading to uncertainty and sometimes discard of valuable organs. QUOD (Quality in Organ Donation) is a National Consortium funded by NHS Blood and Transplant, which started in 2012 and whose aim is to improve the quality of organs by providing biological samples from deceased organ donors for the transplant research community.  Recently, the Medical Research council awarded QUOD additional funding to further extend its remit.>

QUOD has established a central bio-resource of blood, urine and tissues from DBD (Donation after brain death) and DCD (Donation after circulatory death) donors, collected nationally by transplant professionals throughout the organ donation process. All UK retrieval teams and academic transplant centres are involved in sample collection as well as the SNODs (Specialist Nurses in Organ Donation), who also obtain specific QUOD consent/authorisation from the donors’ relatives.

In addition, QUOD has access to comprehensive donor and recipient data from NHSBT which are invaluable for research studies and multivariate analyses. Samples are used to analyse pathways involved in organ injury and repair and to identify novel bio-makers. Interventions performed in the donor and ex-vivo, during organ preservation, will be correlated with organ outcomes in the recipient. Biological samples, stored in a central biobank, are accessible to researchers to allow analysis and gain better understanding of how we can assess the viability of a donor organ, match it to the right recipient and increase the numbers of transplantable donor organs.

For more information please visit the QUOD website:

www.quod.org.uk 

 

 

 

COPE Consortium

The COPE Consortium is funded by a European Commission FP7 Award, and is the official organ preservation task force of the European Society for Organ Transplantation (ESOT). The Consortium brings together academic institutions, clinical and scientific experts and SMEs from across Europe to work together on advancing organ preservation techniques and is being led by Professor Rutger Ploeg in Oxford.

The COPE Consortium aims to advance and develop organ preservation technologies by performing clinical and translational studies with on-going experimental refinement. Through testing the quality and safety, increasing the efficiency and refining preservation strategies we aim to bring technologies from the bench to the bedside.

Focusing on four clinical trials across Europe the Consortium will be working on improving preservation and reconditioning strategies for kidney and liver organs procured for transplantation. By exploiting collaborations between industry and academic institutions we aim to introduce organ preservation technologies that will increase the number and quality of grafts used for transplantation.

The four strategic objectives of the programme are:

  1. To test in clinical trials a number of novel clinical approaches to repairing and preserving high-risk donor organs.
  2. To investigate in experimental models a number of novel scientific approaches to organ repair and regeneration.
  3. To develop new objective methods to measure and predict the viability and outcome of donated organs.
  4. To develop an integrated network of academic clinicians and scientists in Europe that, in collaboration with SMEs and ESOT, will develop and implement new medical therapies and devices in organ transplantation.

 

www.nds.ox.ac.uk/research/cope

 

 

Vascular Access Innovations

I inserted Europe’s first HeRO graft in 2013 and currently have the greatest European experience with over 30 HeRO implantations to date. The HeRO (Haemodialyis Reliable Outflow) device is the only fully subcutaneous (under the skin) device available to continually provide renal failure patients with dialysis in the face of underlying stenotic (narrowing) or occlusions in the main veins in the chest that normally need to be patent if conventional fistulae / grafts for dialysis will work. 

I have the largest international series of the Flixene early cannulation graft for dialysis. These grafts can be inserted into a patient and used within hours of surgery for dialysis thus avoiding the need for dialysis lines and long in-patient stays.

I recently introduced the Surfacer Inside Out Catheter System, this enables patients who have completely occluded their central veins around the heart region, and who would have otherwise ended up with sub optimal lines in their groins, to be able to have a procedure that takes an hour and I can come from within the vein around the heart straight out onto the skin and then bring a line back in. We have just done 3 successful cases and have more pending. 

Finally, this week we became the 3rd centre to trial a novel technique to create fistulas for dialysis without doing surgery. This technique is called Endo AVF and is a radiological procedure that creates the fistula through two small punctures. The early results of this technology are very exciting and appear to be superior to the conventional surgical technique. 

Mr James A Gilbert BM BS, MA (Ed), FRCS (Gen Surg)

Consultant Transplant & Vascular Access Surgeon

Vascular Access Lead

 

 

 

 

3C Study

CAMPATH, Calcineurin inhibitor reduction and Chronic allograft nephropathy trial.

The study is called 3C. It aims to test new ways to improve kidney transplants and make them more effective.

Kidney transplantation is a very good treatment for people whose kidneys no longer function sufficiently to keep them alive. Unfortunately, kidney transplant function inevitably declines over time. On average, after about 10 years the transplant “fails” and the recipient either receives another transplant or returns to dialysis.

The aim of 3C is to test two ways to prevent this failure – and help transplant patients now and in the future live longer with better quality of lives. All people who receive a kidney transplant need drugs to prevent their body from “rejecting” the new kidney. Standard medications to prevent rejection may also cause long-term damage to the kidney. The 3C Study is testing two new treatments which might avoid this long-term damage. No one knows which of the two treatments, if any, are better than existing medication.

The treatments being tested relate to immediate treatment after transplant, and long-term care, starting about six months after transplant. The immediate treatment is referred to as ‘induction treatment’ and the longer term care as ‘maintenance treatment’.

We do not know which method of treatments, or combinations of treatment, is best. Patients will be put into different treatment groups, selected by chance (randomly), like the toss of a coin. At the end of the study scientists will analyse which treatment produces the best result. It may be that there is no clear cut answer.

At the time of transplant (‘induction’ treatment)

A patient will be allocated a treatment group at the time of the transplant operation. A computer will decide by chance (like the flicking of a coin) which induction treatment they will receive. This will either be:

  • Standard treatment: basiliximab followed by standard medications. These will include steroids for at least 3 months, after which time they may be stopped if the doctor wishes to do so.
  • New treatment: CAMPATH treatment followed by lower doses of standard medications.
  • Patients treated with CAMPATH will not need steroids.

Six months later (‘maintenance’ treatment)

Once again, the long-term treatment will be chosen at random by a computer. This will either be:

  • Standard maintenance treatment; or
  • New treatment: the patient will be switched to the new drug being tested. This new drug is called sirolimus (Rapamune).

The Principle Investigator for this study is Professor Peter Friend, Professor of Transplantation at the University of Oxford, Consultant Transplant Surgeon and Director of the Oxford Transplant Centre.

Normothermic Liver Perfusion

European liver perfusion trial

The global shortage of livers for transplantation has necessitated the use of increasingly marginal organs. Normothermic machine perfusion (NMP) of the liver is a technique of organ preservation in which the liver is perfused with oxygenated blood, medications and nutrients at normal body temperature in order to preserve it in a physiological functioning state. Previous animal work has suggested that this could improve the quality of organs and so potentially enable more marginal livers to be transplanted successfully. The trial is the first multinational randomized controlled trial to compare the efficacy of normothermic machine perfusion with conventional static cold storage in human liver transplantation.

This investigator-initiated, multinational, open-label, randomised controlled trial was sponsored by the University of Oxford and funded through COPE. The seven trial sites included four UK transplant centres (Addenbrooke’s Hospital, Cambridge; King’s College Hospital, London; Queen Elizabeth Hospital, Birmingham; Royal Free Hospital, London) and University Hospital, Essen, Germany; University Hospitals, Leuven, Belgium; and Hospital Clinic, Barcelona, Spain.

Livers from adult donors after neurological (DBD) and cardiovascular (DCD) certification of death were randomly assigned to NMP or SCS. The trial was powered (90%) to show a 33% difference in the primary endpoint, peak AST (a clinically accepted biomarker for graft and patient survival). Secondary endpoints included: organ utilisation; preservation time; reperfusion haemodynamics; early allograft dysfunction (EAD); hospital stay; cholangiopathy seen on MRCP; graft and patient survival.

Between 26th June 2014 and 8th March 2016, 222 livers were successfully transplanted as part of this trial, (121 NMP and 101 SCS). It is hoped that the full results will be published shortly.

David Nasralla

 

Novel strategies to enhance fatty livers for transplantation

Liver transplantation has become a victim of its own success and 20% of patients on the UK waiting list die without a liver transplant. Steatotic (fatty) livers derive particularly poor outcomes when transplanted and a result a large number are discarded. With the global obesity epidemic, an increasing number of steatotic livers in the donor pool is inevitable and identifying methods to salvage these livers is of great importance.

Normothermic machine perfusion (NMP) is a novel preservation technique which maintains the liver in a fully functioning state outside the body; providing it with oxygen and nutrition at normal body temperature. This facilitates extended preservation times, functional liver assessment and the potential for liver-directed therapeutic interventions.

At the Oxford Transplant Centre, Professor Friend’s liver perfusion group are performing perfusion studies of steatotic human livers which have been deemed too high risk for transplantation. By perfusing the livers for 48 hours with de-fatting agents and other adjuncts, the group hope to gain an understanding of NMP’s potential in the enhanced preservation and de-fatting of steatotic livers. If successful, this will increase the number of livers available for transplantation and take significant steps to abolish waiting list deaths.

Carlo Ceresa

ONE Study – Reference Group

After organ transplantation one of the most important problems that can occur is that the body may reject the transplanted organ because of the powerful reaction of the body’s immune system. In order to prevent rejection the patient has to take a number of different drugs for the lifetime of the transplanted organ. These drugs can have side-effects and some patients will still experience rejection episodes in spite of taking the drugs. In recent years we have found out that as well as cells that can damage a transplant, the body makes other cells that control the rejection response. We hope that it may be possible to use these cells grown in the laboratory under very carefully controlled conditions as a new treatment to prevent transplant rejection.

The Reference Group study will involve small volumes of blood and urine being taken at standard clinic visits for extra laboratory tests. 12 weeks following transplantation a sample of kidney tissue (a transplant biopsy) will be taken to look for any signs of transplant rejection.

Chief Investigator is Professor Peter Friend and the Principle Investigator is Dr Paul Harden. This study is being carried out by an EU/USA collaborative group.

Sentinel Skin Flaps study

One of the main causes of medium term pancreas graft failure is rejection. In many cases we are currently not able to detect rejection early enough to prevent it causing irreversible damage. This is due to a lack of sensitive or specific tests for pancreas graft dysfunction and rejection. We have noticed from our intestinal transplant programme that transplanted skin will often reject before other organs and it is also easily diagnosed by a rash and painless biopsy.

We are setting up a study that will investigate the use of a small donor-derived skin flap that will be transplanted onto the forearm of a patient at the same time as pancreas transplantation. This small patch of skin will then act as a constant visual ‘barometer’ of possible rejection in the pancreas. We hope this will enable much earlier diagnosis and treatment of rejection and thereby significantly improve graft survival for our patients.

Urinary C-peptide study

This study is investigating whether a urine test can help to monitor how well the transplanted pancreas is functioning. It is hoped that this could also be developed into a simple test that could even be sent from home. If we can identify poor pancreas graft function then it may be possible to investigate and treat the causes earlier than is currently possible. This study is a collaboration between the Oxford Transplant Centre, Oxford Centre for Diabetes Endocrinology and Metabolism, and Prof Hattersley’s group at the University of Exeter.

Intestinal Transplantation

Quality of Life and Outcomes

Over the past few years we have been collecting quality of life data to understand how an intestinal transplant impacts on our patients. We have used three different questionnaires to record this including both generic, that have the advantage of being applicable across many different conditions, and condition specific questionnaires, allowing us compare patients with the same condition. From the generic ones, we have found that following intestinal transplant patients overall score with life rises from an average of 40% (+/- 21%) to 73% (+/- 7%), with an improvement in move around, to do everyday activities including caring for themselves and their pain or discomfort levels. In addition, from the disease specific questionnaire there were marked improvement in ability to travel, body image, concerns regarding their health and the future and the ability to eat food again. This is incredibly exciting to see the improvement that intestinal transplant brings. We are continuing to collect data and our aim in the next few years is to develop a short patient centred questionnaire that reflects what patients feel are important questions for us to ask them.

Centre for Evidence in Transplantation

The Centre for Evidence in Transplantation (CET) (www.transplantevidence.com) was established at the beginning of 2005 by Professor Sir Peter Morris with the aim of providing a source of high quality evidence-based information on all aspects of solid organ transplantation. The Centre is devoted to evaluating the quality of evidence in organ transplantation (kidney, heart, lung, pancreas, liver, etc.) and defines gaps in our knowledge in these different areas. The CET has offices and staff within the Clinical Effectiveness Unit at the Royal College of Surgeons of England, and at the Oxford Transplant Centre.

The CET has been involved in a number of projects since its establishment, one of which is the development and maintenance of the Transplant Library (www.transplantlibrary.com). The Transplant Library is an electronic library of all RCTs in solid organ transplantation, including congress abstracts, from 1970 to the present and more recently includes systematic reviews that are regarded as of reasonable quality, and clinical practice guidelines. We have also recently added invited expert commentaries to key articles and the ability for users to comment on and discuss articles on the site. To promote the Transplant Library CET produces the Transplant Trial Watch, a monthly overview of RCTs that were recently added to the Transplant Library. The Trial Watch includes a summary of the RCT, critical commentary written by CET and critical appraisal.

The Centre has also carried out and is carrying out a large number of systematic reviews and meta-analyses in all aspects of solid organ transplantation. Many of these have been published in peer reviewed journals and are well cited. The CET staff have expertise in literature searching, risk of bias assessment and meta-analysis, including handling missing data, mixed effects analysis and network meta-analysis.

More recently, the CET has been involved in the design and reporting of clinical trials in transplantation, including the management and design of the Consortium for Organ Preservation in Europe (COPE) clinical trials in partnership with the Surgical Interventional Trials Unit (SITU).

The CET also has an agreement with the European Society for Organ Transplantation (ESOT) that we will become the Knowledge Centre for ESOT and would offer advice on the design of RCTs and systematic reviews, as well as provide assistance with the reporting of RCTs and systematic reviews. Trials that were methodologically sound in design will be given ESOT/CET accreditation.

www.transplantevidence.com

www.transplantlibrary.com

www.nds.ox.ac.uk/research/centre-for-evidence-in-transplantation

Transplant Immunology

The Transplant Immunology and Immunogenetics Laboratory provides consultant-lead specialist regional services for clinical transplantation within the Oxford Transplant Centre and for haematopoietic stem cell transplants performed within the OUH. Currently these services include HLA typing to the DNA sequence level, antibody screening and specification and crossmatching.  The laboratory provides a 24-hour on-call service for transplantation and post-transplant monitoring.  Immunogenetics services are also provided to clinicians to define disease susceptibility genes as an aid to patient diagnosis and treatment. The laboratory is accredited by the UK Accreditation Service (UKAS) and the European Federation for Immunogenetics (EFI). Referrals are received from within the OUH and externally from Primary Care Trusts and other Trusts and Institutions.  In order to maintain the highest standards of the services in a continually developing field, the laboratory supports research and development in histocompatibility and immunogenetics testing and in the broader field of clinical transplantation.

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