Solid Organ Transplantation in Singapore

Transcription

1 Solid Organ Transplantation in Singapore Prof A Vathsala Head, Division of Nephrology Director, Adult Transplantation Department of Medicine National University Hospital 1960 Timeline of Transplantation in Singapore First Cornea Transplant August First Cadaveric Renal Transplant July Medical Therapy, Education and May 1973 Research Act First Living - Related Renal Transplant July First Bone Marrow Transplant July Human Organ Transplant act June 1987 First Pediatric Renal Transplant February First Bone Transplant June First Cardiac Transplant July First Liver Transplant September First Spousal Renal Transplant March First Skin Transplant March 1998 Interpretation Act June 1998 First Lung Transplant November Human Organ Transplant Act, Amendment January (Non-medical causes) Human Organ Transplant Act, Amendment January (Muslims)

2 Renal Transplantation in Singapore Schema for Management of Renal Failure in Singapore CRF / ESRF Patient Severe Heart Disease Cerebrovascular Disease Malignancy Yes High Dependency Dialysis No Live Donor Available No Dialysis Live Donor Available No Cadaveric Transplant Waiting List Yes Yes Yes Preemptive Live Donor Transplant Live Donor Transplant Cadaveric Transplant

3 Spousal Donation UNOS Renal Transplant Registry 1765 spousal transplants 5 year graft survival of 75% vs. - 74% for parent donor grafts - 62% for cadaver donor grafts Potential increase in spousal transplants by 15% assuming - 50% married, 65% have ABO compatible spouse - 50% dropout rate after initial screening Percent graft survival Donor relation N HL Spouse 1, Living unrelated HLA-1D Sibling 4, Sibling 8, Parent 6, Cadaver 86, Time, years post-transplant Gjertson DW & Cecka MJ, KI 2000 Spousal Donation: Compliance Eat your medicines sweetheart (or else, I take my kidney back) Yes, of course Sweetheart!

4 Live Donor Renal Transplantation in Singapore Deceased Donor Renal Transplantation in Singapore 4.7/yr pre HOTA 42/yr post HOTA HOTA HOTA a

5 Year End Prevalence of ESRD by Type of Renal Replacement Therapy Singapore Renal Registry, Preliminary Report 2006 Number of Patients Waiting for a Deceased Donor Renal Transplantation in Singapore

6 Eligibility for Cadaveric Renal Transplantation in Singapore Age:- Paediatric 4-16 years - Adult years ESRD due to primary renal disease Special inclusion criteria Systemic Lupus Erythematosus Diabetes Mellitus Exclusion Criteria Ischaemic heart disease Cerebrovascular and peripheral vascular disease Malignancy Active liver disease Hepatitis B surface Antigen +, e Antigen + HIV seropositivity Mental retardation India Commercialisation in Transplantation China Pakistan

7 Prevalent Renal Transplant Population, 2006 Deceased Donor Living Donor Transplants 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% Overseas Hospital National University Hospital Singapore General Hospital Year Transplants 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% Overseas Hospital Raffles Hospital Mount Elizabeth Hospital Gleneagles Hospital National University Hospital Singapore General Hospital Year Outcome of Commercial Transplantation for Transplants Returning to Singapore General Hospital, Live Donor Commercial SGH Number yr Patient Survival 88.4% 95.2% 10-yr Graft Survival 65.6% 82.7% Hepatitis B or C 38.7% 7.7% Deceased Donor Number yr Patient Survival 81.4% 86.2% 10-yr Graft Survival 64.2% 71.4% Hepatitis B or C 36% 13.5%

8 Renal Transplantation at NUH Number of Transplants Year of Transplant Adult Live Donor Adult Deceased Donor Peds Live Donor Peds Deceased Donor 1. ANTIGEN RECOGNITION 2. ANTIGEN SIGNAL TRANSDUCTION 4. MITOSIS 3. CYTOKINE SIGNAL TRANSDUCTION CD2 LFA-3 ANTIGEN PRESENTING CELL T LYMPHOCYTE P LFA-1 ICAM-1 p88 NFAT MHC I/II CD4/8 Calcineurin B 1 Ca +2 p19 p59 NUCLEUS RNA 4 NFAT-P IL-2 DNA Promoter 600 bp AG T C R Calmodulin A FKBP CD3 Cyclophilin/ FKBP Tyrosine Kinase p56 lck Induction Anti lymphocyte preparations Calcineurin inhibitors Purine synthesis inhibitors/antagonists Corticosteroids IL2 receptor antagonists TOR inhibitors Maintenance Calcineurin inhibitors Purine synthesis inhibitors/antagonists Corticosteroids TOR inhibitors

9 Standard Immunosuppressive Protocol post Renal Transplantation iv IL2Receptor Antagonists / iv Polyclonal / Monoclonal Ab oral Azathioprine/Mycophenolate iv Steroids - oral Steroids LIVE TX ALL TX Calcineurin Inhibitor: Cyclosporine / FK506 D- 3 D- 2 D- 1 POD 1 POD 3 Transplant Immunosuppressive Protocol post Renal Transplantation 3 rd Drug: Azathioprine/Mycophenolate iv HYDROCORTISONE 1 g/day PREDNISOLONE 30 mg/day p.o. CYCLOSPORINE 8 mg/kg/day CYCLOSPORINE LEVELS POD 1 POD 2 POD 3 POD 4 Transplant

10 The Very High Risk Recipient Cross Match Positive: Stratify based on crossmatch Cyclosporine/Tacrolimus and Mycophenolate (Day -14) Plasma exchange (Day -10) + CMV Hyperimmune Ig Pre op cross match (Proceed with transplant if negative) Thymoglobulin (Day -1) IV Ig High dose (Day -1) Blood Group Incompatible Rituximab (Day -30) Tacrolimus and Mycophenolate (Day -14) Glycosorb adsorption (Day -10) Pre op ABO titer (Proceed with transplant if low titer) Thymoglobulin (Day -1) IV Ig High dose (Day -1) Is there a need to tailor therapy in renal transplantation? Differences in outcomes between patients Impact of risk factors Graft function and survival Patient survival Toxicity of therapy Immune (infections, malignancies) Non Immune (nephrotoxicity, hyperlipidemia, osteoporosis) Adaptation to immunosuppression

11 Prophylaxis Antibacterial Ceftriaxone 1 g stat on call to OT Longer duration for DD (till cultures back) PCP: Trimethoprim Sulphamethoxazole 480 mg ON Pentamidine inhalation monthly for 6 months in sulpha allergic CMV: D+R- D+R+/D-R+ & Antilymphs D+R+/D-R+ & 2of 3 (IL2r/MP/MPA) R+ & 2of 3 Valacylclovir IV GanC till off dialysis +PO Valganc IV GanC till off dialysis +PO Valganc Valacylclovir X 1 month Risk Factors in Renal Transplantation PreTransplant Source of allograft (Live vs. Cadaveric) Immunologic Re-transplants Sensitised HLA Mismatch Non Immunologic Donor age Cold Ischaemia Time Post Transplant Delayed Graft Function Acute rejection

12 Non-Immunologic Toxicities of Therapy Calcineurin Inhibitors Nephrotoxicity Cyclosporine Hypertension Ectodermal: Hypertrichosis, gingival hyperplasia Tacrolimus Diabetes mellitus Sirolimus Hyperlipidemia Corticosteroids Diabetes Osteoporosis Cataracts Hyperlipidemia Mycophenolate Leukopenia GI side effects Azathioprine Myelotoxicity Hepatotoxicity Adaptation Post Transplantation Pre Adaptation Period (eg. < 6 months) Inflammation is frequent Acute rejection is frequent Choice of IS is critical Emphasis is on efficacy Outcomes are immune related Evidence for choice of IS is good Post Adaptation Period (eg. > 6 months) Inflammation is variable, declines Acute rejection is rare Is choice of IS critical? Emphasis is on risk reduction Outcomes are mostly non immune related Evidence for choice of IS is not good

13 Financial Support for Renal Transplantation 3 M s Medisave - Hospital expenses, Monthly deductions for immunosuppressive drugs ($300/month) Medishield - Monthly deductions for immunosuppressive drugs ($200/month, lifetime limit) Medifund - for the needy Government subsidy for immunosuppressive drugs For subsidised patients in restructured hospitals For Singaporeans and Permanent Residents Life of the kidney 50% subsidy for Cyclosporine since ~ % subsidy for FK506, Mycophenolate Subsidy for Valganciclovir for CMV prophylaxis % Distribution of Bacterial Infections by Site of Involvement 31.6% % 10.5% % 1.4% 1.4% 1.4% 1.4% 1.4% 1.4% UTI Septicemia Pneumonia Skin Abscess Cholecystitis Colitis Sinusitis Tenosynovitis Brain Abscess Traumatic Sinusitis Wound Infection

14 CMV Infection and Disease in MMF Treated Recipients: SGH Experience 3 fold increased risk of CMV infection in the MMF group (p=0.022) No of Pts (9.2%) 11 (28.9%) CMV Infection CMV Disease 7 (18.4%) 6 fold increased risk of CMV disease in the MMF group (p=0.024) (3.1%) AZA MMF T Kee, A Vathsala. Asian Colloquium, Pattaya, Thailand, Feb 2003 MPA Pharmacokinetic Profiles PK Parameter C 0 (mg/l) C max (mg/l) AUC ss 0-12 (mg.h/l) T max (h) CL oral (L/h) Yau WP, Vathsala A, Lou HX, Chan E. NDT 2007; 22 (12):3638

15 Is a Standard Fixed Dose of Mycophenolate Mofetil Ideal for all Patients? In our study population, the observed MPA AUC ss,0-12 dose-normalized to 1g MMF was comparatively higher than that reported in the Western population and that proposed by the roundtable discussion on TDM of MPA. The observed correlation between drug exposure and body weight-adjusted MMF dose suggests that MMF could be better dosed based on body weight, rather than a fixed dose regimen, especially in populations with a wide variation in body weight. To attain an average total MPA AUC ss, we propose that patients may be empirically at 12 mg/kg twice daily. of 45 mg h/l, initially dosed ss,0-12 of Yau WP, Vathsala A, Lou HX, Chan E. NDT 2007; 22 (12):3638 Free MPA C max, normalized by TBW-adjusted MMF dose, according to UGT1A9-440T>C/-331C>T genotypes in Asian RTxR receiving CsA-MMF-Prednisolone immunosuppression Free MPA Cmax (mg/l) normalized by MMF dose (mg/kg) ( ) ( ) wt/m (n=7) m/m (n=42) UGT1A9-440T>C/-331C>T p = 0.010, Mann-Whitney test

16 Biologicals as Immunosuppressants Lymphocyte depletion Polyclonal antilymphocyte antibodies Rabbit: ATG, Thymoglobulin Monoclonal antibodies T Lymphocytes Alemtuzumab B Lymphocytes Rituximab Modulation of specific receptors Anti-CD3 (OKT3) Blocking of receptors/ligands Anti-CD25 (IL2 Receptor) Antibodies Basiliximab Daclizumab B7 mediated co-stimulation Polyclonal Anti-lymphocyte Antibodies Thymocyte Lymphocyte Lymphoblast lines

17 Lymphocyte Depleting Antibodies Number CD2/CD3 Lymhocytes ATG Days The antibodies bind to a variety of human lymphocyte receptors Macrophages bind to the antibody-lymphocyte complex and remove lymphocytes by opsonization. Apoptosis and complement-dependent lysis are other mechanisms of T cell depletion. Thus, deplete lymphocytes and cause profound immunosuppression Other effects: hypersensitivity reactions Association of Antibody Induction with Short and Long Term Cause Specific Mortality in Renal Transplant Recipients USRDS database, ,707 primary transplants Polyclonal ab or OKT3 use in 1/3 of patients Cumulative Risk of Infection Related Death Cumulative Risk of Cancer Related Death Meier-Kreiesche et al. JASN :769

18 Solid Organ Transplantation in Singapore Liver Transplantation in Singapore