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The future of medical innovation in transplantation
Prof B. CHARPENTIERHead of the Department of Nephrology
University Hospital of BicêtreDirector of the INSERM Unit U542
ESOT Past President
Defining transplantation:
Replacing a failing organ and ensuring a major vital function
One example:transplantation of kidney
• The most commonly transplanted organ is the kidney
• Kidney transplantation is the most effective treatment for end-stage renal disease– Improves improves patient survival– improves quality of life
• Treatment, not a cure• Transplant recipients receive life-long
maintenance immunosuppressive therapy• Transplant immunosuppressive therapy carries
significant morbidities
Unmet medical need in transplantation, as exemplified by
kidney transplantation• Calcineurin inhibitors (cyclosporine; tacrolimus)
are the cornerstone of life-long maintenance immunosuppression
• Dramatic improvements in prevention of acute rejection have, however, not been matched by gains in patient and graft survival– Need for re-transplantation for certain patients, due to
chronic allograft nephropathy• Cardiovascular death and chronic allograft
nephropathy (C.A.N.) are the leading causes of death and graft loss
• Cornerstone and adjunctive immunosuppressive agents contribute to cardiovascular and metabolic morbidities and are directly nephrotoxic
I. Speaking optimally: prevention is the first goal
Preventing the preventable:kidney, heart and liver diseases
Gains
• For the State: financial savings • For the patient: well-being• For physicians: time
I.I Prevention of Chronic Kidney Disease (CKD):
• Obesity non-HDL cholesterol• High blood pressure• Chronic infections• Smoking• Genetic diseases• Nephrolithiasis• Diabetes
I.2 Prevention of Chronic Liver Disease (CLD)
• Viral infection• Alcohol
I.3 Prevention of Ischaemic Heart Disease (IHD)
• Smoking• Non-HDL cholesterol• Exercise
II. If not preventable, then treat
Possible future alternatives to transplantation given the
context of organ shortage
II.1. regenerative medicine
• Stem cells and others: myocytes transplant for the failing heart comes of age
Stem Cell Therapy The Promise of Embryonic Stem Cells
II.2. Organ embryogenesis in vitro/in vivo
• Example: tracheal transplant
Possibility to increase organ replacement
Stem Cells In Vitro Organogenesis
II.3. artificial organs
• HD• CAPD• Artificial heart• Artificial liver
III. Transplantation as part of a treatment
Trends in transplantation
Trends in organ transplantation
• Increasingly more patients• Increasingly older recipients (new
paradigm of recipient’s death with a functioning graft)
• Increasingly older donors (new question of extended criteria donors)
• Discrepancy between the donor slope and the recipient slope leading to transplant tourism
III.1 Living related donors
• Different laws in different European countries• European coordination• National vs. regional vs. European networks• Campaigns for organ donation: interesting the
media to promote a culture of organ donation (different successes in different countries)
• “old” living related donors (LRD)• “pool exchange” donors for sensitised recipients
III.2 deceased donors
• Non heart beating donors– Controversy in Italy with the notion of brain death
• Aged donors• Perfusion machines• Expanding the donor pool • Action on family refusal
– Despite some political and societal initiatives in France, family refusal has risen from 5-10% in 1976 to roughly 40% in 2007
• Coordination– As exemplified by the Spanish experience
• Donation campaigns
III.3 Xenotransplantation
• At present, still many years away …– Humoral rejection (antibodies)– Acute rejection (immune cells)– Chronic rejection (antibodies + immune
cells)– Interspecies viral infections
III.4 in vivo/in vitro organ embryogenesis
• For example: tracheal transplantation coated with autologous epithelial cells (Barcelona, Spain)
IV. If transplantation is only part of a treatment …
… then what happens after transplantation?
IV.1 managing the side effects of immunosuppressive therapies (1)• Cardiovascular events are the first cause
of death with a functioning graft…– Vascular toxicity of steroids and Calcineurin
inhibitors – Older patients– Vascular comorbidity– Smoking– Obesity– Lack of exercise
IV.1 managing the side effects of immunosuppressive therapies (2)• Oncogenesis is also a significant problem:
– Post transplant lymphoma disorder (PTLD): role of Epstein-Barr virus (EBV, commonly called mononucleosis) under immunosuppression
– Skin cancers: role of papillomavirus + UV– Other cancers
IV.1 managing the side effects of immunosuppressive therapies (3)• Fungal infections:
– Need new therapeutic agents • Bacterial infections:
– Need new antibiotics• Viral infections:
– Vaccination?– New therapeutic agents on
• Cytomegalovirus• big DNA Epstein-Barr virus• Herpes viruses BK virus (of polyomavirus family)
IV.2 towards better immunosuppressive agents …
• Development of new biologic agents– E.g., LEA
• Development of new chemical molecules– E.g., FTY, MNA
which=> are less toxic=> are less carcinogenic=> prevent chronic allograft nephropathy (C.A.N.)=> have an improved metabolic profile (blood pressure, lipids,
diabetes, …)
But=> high cost of development (phase I -> phase IV)
IV.3 … or no need for immunosuppression at all …
• Inducing a real state of organ ‘transplantation tolerance’, without immunosuppressants
• … the goal of every physician and surgeon involved in transplantation
• … achieved by manipulating the immune system
V. Ensuring the progress we need
Calling for action
V.1 Education for transplantation: professionals and citizens
• Professionals– At national level– At European level
• For example, the ESOT pyramid of education– Accreditation
• Transplant teams• Doctors: UEMS-EBS
• Society– Education and campaigns on prevention and
on donation as early as in primary school
V.2 Research / funding
• Bench: basic research• Bedside: clinical investigation• Different from one country to another• European network:
– Example: RISET (reprogramming the immune system for the establishment of tolerance), a multinational European project financed by the EU Commission (DG RTD)
• No global action plan• Compared with US
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