In France, a team of researchers, doctors and engineers are developing software to improve kidney transplant patient's follow-up
Six university hospitals. Three leading companies in the IT and medical sectors. Hundreds of volunteers. Thousands of data points...
These few figures show the scale of KTD-innov, a public-private consortium aiming to gain a better understanding of kidney transplants and then develop diagnostic and prediction software for use by doctors and patients alike. How do the researchers involved work, and what phase of the project are they in today?
Magali Giral (professor of nephrology and director of clinical research at Nantes University Hospital) was kind enough to answer our questions.
The KTD-innov* project continues to advance in the development of an activity diagnostic system and of the kidney graft rejection stage. To achieve this goal, a new partner joined the consortium at the end of 2020: Sebia, a leader in protein separation techniques applied to in vitro diagnostics. Interview on the new markers with Pierre Sonigo, Director of Research & Development, and the research team.
Some of the main objectives of the KTD-innov project are to improve the graft rejection follow-up processes in order to perfect kidney transplantation and consequently promote patient comfort. This is why researchers are now aiming to find new reliable biomarkers to predict transplant rejection. The analysis of the transcriptomic signature appears to be a promising avenue for a personalized monitoring of kidney transplant patients. The focus is on this technique developed within the project.
The American Transplant Congress (ATC) is a major annual event for experts of organ transplantation. The 2020 edition was initially planned to take place in Philadelphia, US. Following the recommendation from the World Health Organization (WHO, national and local administrations regarding the Covid-19 outbreak, the in-person event was cancelled. It is replaced by a 3-day virtual congress starting on 30th May 2020. Sessions and presentations are broadcasted on an online platform.
The theme chosen for this year is “The Science of Tomorrow Starts Today”. The discussions cover the latest research in organ transplantation.
Members of KTD-innov partners attend the event. All their presentations are available on the program of the ATC 2020 online.
Many advances have been made in the field of transplantation over the decades, but monitoring of patients after transplantation still faces challenges. This is why the KTD-innov project aims to develop a graft rejection prediction system that provides a probability of individual risks. Since the first transplant experiments at the beginning of the 20th century, what are the challenges of kidney transplantation today? Answer in figures
Kidney transplantation, A French story since the 19th century
In the history of medicine, the chapter dedicated to organ transplantation began at the end of the 19th century. Kidney transplantation plays an important role because it is the most performed organ transplantation in the world.
It was in Lyon that the pioneers of transplantation performed the first transplantations: Dr. Alexis Carrel, first of all, who in 1908 succeeded in the first kidney transplant in animals and demonstrated the effectiveness of cold to preserve organs; Dr. Mathieu Jaloubay, then, who experimented with the first kidney transplants in humans.
France will continue to play a major role in the field of kidney transplantation with the discovery of the compatibility of organs, thanks to the work of Doctors Dausset and Hamburger, of the Saint-Louis and Necker hospitals in 1962, and the establishment of bioethics laws in 1994 which place the well-being of the patient at the centre of medical research.
Since 1959, France has carried out nearly 90,000 kidney transplant operations, making kidney transplantation a treatment of choice for chronic kidney failure (CKD).
82,000 people with End Stage Renal Disease (ESRD) in France
There are two options when the disease reaches a terminal stage (End Stage Renal Disease - ESRD). The most common is hemodialysis. Today, this blood filtering technique remains constraining, as the patient must be dialysed over a period of 4 hours, 3 times a week.
The alternative for people with ESRD is a kidney transplant. The French High Authority for Health (HAS) considers transplantation to offer a better quality of life compared to dialysis. In fact, transplantation makes it possible to restore almost normal kidney activity while maintaining a lifestyle close to "normality".
More than €6,400: the monthly cost of End Stage Renal Disease (ESRD)
While dialysis can cost up to €7,200 per month, the cost of a kidney transplant is between €6,400 and €6,800. Kidney transplantation therefore represents a much more economical alternative to dialysis, with nearly €25 million saved on healthcare costs for all patients in France in 2018.
More than 3,500 kidney transplants performed each year in France
There were 3,567 new transplant patients in 2018, according to the French Biomedicine Agency, which is 215 fewer than in 2017, showing a decrease of the renal transplant activity of 11% in 2018. However, the growth rate of the number of people on the waiting list increases from year to year, with 19,625 patients waiting for a transplant in 2018, including 5,269 new patients on the waiting list, compared to 4,557 new patients in 2013. But the situation is improving as the number of transplants carried out in 2019 has risen to 3,641 operations.
1 graft available for 5 people on the waiting list
In 2018, for each available kidney, more than 5 people were on the waiting list. The HAS also estimates that only 31% of patients will receive a transplant in the first year after being placed on the list of potential recipients. Up to 15% will have to wait more than 5 years.
How can the shortage of organs for transplantation be tackled to ensure patients' comfort and chances of getting better?
85% of kidney transplants come from deceased donorS
The main source of organs comes from donations from deceased patients. In 2018, there were 1,881 brain-dead organ donors. The vast majority (93%) of these people donated at least one kidney. In 2006, organ donation became available for people who died from cardiac arrest. Today, thanks to this measure, 8% of grafts come from people who have died from heart failure.
Living donors make up 15% of donations. The French Biomedicine Agency considers this number to be low and due to the reluctance of patients to put their family and friends at risk as well as a lack of knowledge about how donors are medically monitored. Yet these donors are in better health than the general population, due to the clinicians' demands on donor monitoring.
Half the number of unallocated grafts in France than in the US
60% of transplants are kidney transplants
A 2018 study by the French Biomedicine Agency recorded 3,567 kidney transplants, 1,325 liver transplants and 450 heart transplants in one year. Despite the state of organ shortage, kidney remains the most widely transplanted organ.
On average, a kidney transplant survives 12.4 years
Today, the HAS measures graft survival time at 12.4 years, on average, after which the graft stops functioning properly. The patient must then undergo a new transplant or return to dialysis. The graft survival rate has been stable since 2010. In 2015, 1,032 transplant patients had to return to the waiting list of transplant candidates.
Graft failure is due, among other reasons, to immunological mechanisms leading to graft loss, and the field of transplantation still lacks robust assessments of immunological monitoring. It is a major issue for adapting treatment and increasing graft survival.
The KTD-innov project focuses on this issue, with the goal of developing a system for predicting rejection and providing a probability of individual risk of rejection. It will use a precision diagnostic system providing information regarding the activity and stage of the disease.
The KTD-innov consortium annual meeting took place on the 7th of February. The project partners came from different regions of France and met to review the project’s progress and up-coming steps.
The first news of this meeting: a significant milestone in the KTD-innov research project has just been reached with the recruitment of more than 800 kidney transplant patients in transplant centres in Bordeaux, Lyon, Montpellier, Nantes, Paris and Toulouse. The recruitment target has been met thanks to the patient volunteers who agreed to take part in this study. These patients will be monitored within the framework of the project for 12 months following their transplantation.
The next milestone is the collection and analysis of blood, urine and biopsy samples. The annual meeting was an opportunity to review overall coordination between the transplant centres - where samples are collected - and the analytical platforms.
This collaborative research project allows for the implementation of standardised collection processes between the different centres, thereby improving the quality of the samples and thus the quality of the analytical results.
In the meantime, over the past two years, the scientists involved in this French research project have been working to improve the analysis methods and the technical know-how of their teams. They have already optimised their ability to process samples, as well as the quality of the results that are and will be produced.
In the coming months, the researchers involved in the KTD-innov study will face many challenges. In particular, the compilation of analytical data from the samples in compliance with the existing regulations. With the integration of data collected from previous studies, the final database will contain monitoring information from more than 5,000 kidney transplants.
By 2022, the objective to be achieved is the development of an algorithm to use this database for research purposes. The design of a visual interface is also planned to compare the status of one transplant patient to another. The long-term goal is to deploy this algorithm to physicians as a diagnostic system to predict rejection of the kidney transplant.
Patients: the first link in the medical research chain
Both in Toulouse and at other research centres, the KTD-innov study could not succeed without close patient collaboration. Their involvement means researchers can obtain valuable data aimed at better understanding kidney transplant rejection and improving patient care and post-transplant monitoring.
As a recruitment centre for KTD-innov, Toulouse University Hospital's role is to establish this partnership with transplant patients. Prof. Kamar's team at Toulouse University Hospital provides information and collects samples from volunteer patients who are recruited when being cared for at the hospital. Although the samples are mostly among the usual necessary ones taken to monitor transplant patients and donors, a few extra samples are taken to provide data required for and specific to the study. All samples are sent to the analytical laboratories partnering with the KTD-innov project.
The Organ Transplant Unit (UTO) at Toulouse's Rangueil Hospital, coordinated by Prof. Kamar, is the only one in France to gather for adult kidney, pancreas, liver, lung and heart transplant departments all in one place. The Transplant Unit monitors almost 1500 patients and performed 293 grafts in 2016, making it one of the French leaders in the transplant field.
This expertise in transplant patient care and monitoring makes Prof. Kamar's service a key asset for the KTD-innov project. Toulouse's Rangueil Hospital is thus the 3rd center in terms of patients inclusions in the study.
A collaborative network serving patients and research
Toulouse University Hospital is part of the KTD-innov consortium that involves 9 partners (2 industrial and 7 hospitals and academic centres) involved in the KTD-innov study. Some partners are recruiting centres like Toulouse University Hospital and others are analysis platforms with the equipment required to extract the desired data from the samples collected: the presence of certain proteins and antibodies, plus transcriptomic data.
This collaborative drive between public and private stakeholders in multidisciplinary teams reflects French healthcare players' determination to improve care for patients who have received a kidney transplant.
University/hospital research projects like KTD-innov are funded by the French government: something that for Prof. Kamar is "needed for promoting the excellence of French research and its applications".
From 15 to 18 September 2019 the annual event of the European Society for Organ Transplantation (ESOT) will take place in Copenhagen.
ESOT is the European umbrella organisation under which all European transplant professionals are organized. The organisation trains and supports its members through various European programmes and events, such as the 2019 event in Copenhagen.
Several members of the KTD-innov consortium are fortunate to be able to participate in this event with the EU Train-ESOT symposium on 15 September. As well as through various conferences such as that of Dr. Hannah Kaminski of the University Hospital of Bordeaux on the "effect of antithymocyte globulin on CMV infection in renal transplant recipients". And a presentation by Professor Nassim Kamar at the Novartis symposium.
To follow the various presentations of the event, go to #ESOT2019 and @KTDinnov.
On April 15, the annual meeting of the KTD-innov consortium took place. This meeting allows all the partners to meet in order to review the progress of the study.
The meeting was also an opportunity to exchange views with representatives of the National Research Agency (ANR), which funded the KTD-innov research project.
Several of the partners took part in this day-long meeting, including Sophie Brouard and Alexandre Loupy, the two project coordinators.
The success of this project depends in particular on the quantity and quality of data collected from volunteer patients. To date, more than 400 patients have accepted to be part of this study.
The objectives for the next steps have been set. New patients will be recruited throughout the coming year. And the analysis of the collected samples will soon begin, 50% of the samples should be analyzed by the end of 2019.
The researchers involved in the KTD-innov study will work to solve many challenges in the coming months. The data collected must be consolidated in a homogenized database that meets international security standards.
In the next few months, scientists involved in this French research project will try to identify patients at risk for allograft rejection. Bioinformatic tools will be used to analyze results from collected samples and data. A tool will then be provided to clinicians to assist the medical decision process in order to improve patients’ follow-up.
Collaborative and sustainable research on graft rejection in Bordeaux
The Bordeaux University Hospital's participation in the KTD-innov project was a natural collaboration between Prof. Couzi and the two co-coordinators of the project, Drs Alexandre Loupy and Sophie Brouard.
Thanks to this funding, the Bordeaux University Hospital has joined a partnership with other university hospitals, such as those in Lyon, Nantes, Toulouse, Montpellier and the APHP.
At the Bordeaux University Hospital, the team of Prof. Couzi and Prof. Merville is conducting translational research with the CNRS-UMR 5164 ImmunoConcept unit led by Dr. Julie Déchnet-Merville on cytomegalovirus infection, an infection particularly common in renal transplant patients.
Other research themes of the service include humoral rejection mediated by anti-HLA antibodies, which is at the centre of the KTD-innov study. The participation of the University Hospital of Bordeaux in the KTD-innov project will therefore help to consolidate a team of researchers thanks to stable funding for a project over several years.
Within the team at the University Hospital of Bordeaux led by Prof. Couzi and Prof. Merville, 11 people are working on the KTD-innov project, including three clinical research associates. Accompanied by several co-investigators, they are responsible for accompanying transplant patients in their voluntary participation in the KTD-innov study.
The collection of this data is essential for the progress of the research project, because it is the basis on which it is based. As in six transplant centers in France, the team of Prof. Couzi and Merville collects clinical, biological, immunological and molecular data from kidney transplant patients. These data are then anonymized before being analyzed by Inserm, Nantes University Hospital, APHP and Bio-Rad. It is by analyzing these data that researchers hope to gain a better understanding of the complex causes of renal transplant rejection.
The KTD-innov project has a great impact on the different parties involved in the research
For Prof. Couzi, the KTD-innov project has enormous benefits for patients because it offers a better definition of the diagnosis of rejection and should lead to improved patient care. Today, as life expectancy increases, the life expectancy of a transplanted kidney is only about a dozen years on average. It is therefore urgent to better diagnose the signs of rejection in order to better manage them and thus prolong the life of kidney transplants.
The project has clear societal benefits, particularly in addressing the current shortage of organ donation. More and more patients around the world need an organ transplant, but unfortunately the supply is not able to meet this increased demand. That is why this project to predict graft rejection is important, not only on a French scale but also on a global scale.
Research for patients in France and around the world
The KTD-innov project will generate knowledge in kidney transplantation that will be useful for medical professionals in the decades to come. It also has the potential to disrupt the way kidney transplants are treated in the short and long term.
The success of the project favors the financing of other large scale and high potential studies. The consortium has a "significant impact on French scientific reputation in kidney transplantation". It therefore contributes to strengthening the dynamism of research in Bordeaux, and of French research centres in general, in the field of kidney transplantation, thus strengthening their positions as major players in the world.
To elucidate the mechanisms of success or failure of a kidney transplant, KTD-innov collects, centralizes and analyses clinical, biological and immunological data from thousands of kidney transplant patients in France.