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