RENAL TRANSPLANTATION IN CHILDHOOD

1. RENAL TRANSPLANTATION IN CHILDHOOD Lynne P. Yao, M.D. INOVA Fairfax Hospital for Children Fairfax, VA

2. Overview • Review basic transplantation immunology • Review immunosuppressive agents used in children • Review clinical renal transplantation outcomes in children • Review specific complications of renal transplantation in children • Review the role of the general pediatrician in the care of a child with a renal transplant • Review future directions in renal transplantation

4. Historical perspectives • 1902: First experimental kidney transplantation by Emerich Ullmann • 1933: First human kidney transplant by Voronoy • 1950-53: First functioning human kidney transplant (2 centers) • 1961: Azathioprine first used successfully • 1962: First use of tissue matching to select a donor • 1963: Prednisolone and Azathioprine combination produced longer graft survival • 1972: Successful transplantation into a 9 month-old girl • 1978: First clinical use of cyclosporine A

5. Transplant immunology • ABO group matching • Blood group mismatches result in hyperacute rejection in most cases • ABO incompatible donor protocols underway in children • Human Leukocyte Antigen (HLA) matching • Panel Reactive Antibodies (PRA) and Crossmatching • Rejection • an immune response raised by the recipient against foreign (donor) alloantigens • allograft rejection is a coordinated event

6. HLA (Human Leukocyte Antigen) matching • HLA system is divided into 2 classes • Class I: HLA-A, HLA-B, HLA-C • Expressed on most cell surfaces • Class II: HLA-DR, HLA-DP, HLA-DQ • Expressed predominantly on antigen presenting cells • HLA-A, HLA-B, HLA-DR most important in clinical transplantation • HLA genes located on short arm of chromosome 6 • HLA antigens are inherited in a Mendelian fashion as codominant alleles

7. Example of HLA matching HLA locus A B DR Mother 3/29 13/44 5/7 Father 2/1 8/42 4/3 Patient 3/18/445/3 • Result: Patient is a 3/6 antigen match with each parent (haplotype match) • Haplotype matching improves graft survival because minor (unidentified) HLA loci are also matched

8. Crossmatching • Used to detect presence of preformed HLA antibodies against donor tissues • Lymphocytes from donor are incubated with recipient serum, complement added, and cell lysis is detected • Positive crossmatch is associated with high risk for hyperacute rejection • Prevents development of hyperacute rejection

9. Panel reactive antibodies (PRA) • PRA • Used to assess likelihood of positive crossmatch • Lymphocytes from a “representative” panel of donors are incubated with serum from patient • Expressed as a percentage of panel cells showing activity • High PRA levels are associated with greater likelihood of positive crossmatch • Major risk factors for high PRA are prior blood transfusion, pregnancy, and prior transplant

10. T lymphocyte activation from Arakelov, Lakkis, Semin. Nephrol., 20:2, 2000

11. CD4 and CD8 interactions CD4 and B cell interactions Other CD4 interactions Interactions mediated by CD40 costimulatory pathway (from Arakelov, Lakkis, Semin. Nephrol., 20:2, 2000)

12. Stimulation of IL-2 production after T cell activation From Semin. Nephrol., 20:2, 2000

14. The “paradigms” of transplant immunosuppression • The Proliferation Paradigm • drugs that prevent immune cell proliferation prevent rejection • Prednisone, Azathioprine, Mycophenolate Mofetil • The Depletion Paradigm • drugs that decrease immune cell numbers prevent rejection • polyclonal and monoclonal antibodies • The Cytokine Paradigm • drugs that modify cytokine production prevent rejection • Calcineurin inhibitors, Prednisone, IL-2R monoclonal antibodies

16. need slide of cell cycle

17. Break slide

18. Pediatric Renal Transplantation • NAPRTCS (North American Pediatric Renal Transplant Cooperative Study) • Voluntary, collaborative effort • 150 participating centers in US, Canada, Mexico, and Costa Rica • Registry for pediatric renal transplants since 1987 • Registry for ESRD since 1992 • Registry for chronic renal insufficiency since 1995

19. Characteristics of Pediatric Dialysis Patients Number Percent From Neu, Pediatr. Nephrol., 17:2002

21. NAPRTCS registry 1987-1999 Number Percent

23. Age at transplantation Age Number Percent

24. Cadaveric donor Living related donor Patient survival by age at primary transplantation

25. Graft survival by bi-annual cohort

26. Cadaveric donor Living related donor Primary graft survival by age at time of transplantation

27. Causes of graft failure in primary transplant Number Percent

28. Risk factors for chronic rejection Relative risk increase p-value

29. % Rejection Time to first rejection episode

30. Risk factors for acute rejection Characteristics Living donor Cadaver donor RR p-value RR p-value From McDonald, Amer. J. Transplan., 1:2001

31. Time in years Cadaveric donor Living related donor Primary graft survival by race

32. Significant complications • Growth failure • Infection • Posttransplant lymphoproliferative disorder (PTLD) • Diabetes mellitus

33. Growth failure • Growth fails to improve after renal transplantation in several studies • Improvement in growth occurs only in the younger age groups (age 0-5 years) • Long term steroid therapy is implicated • Change to alternate day dosing of prednisone has shown to improve growth • Growth hormone improves growth • Growth hormone not associated with increased risk of rejection or significant graft • Theoretical risk of malignancy

34. Infectious complications • Bacterial • Generally more likely in early posttransplant period • Viral • CMV and other Herpes viruses • CMV infections relative common and symptoms may be severe • CMV infection may increase risk of chronic rejection • EBV • Infection can produce spectrum of disease • Varicella • Risk significantly decreased with immunization pretransplant

35. PTLD • Malignancy associated with polyclonal expansion of B cells associated with rise in EBV titers • Incidence of PTLD in pediatric renal transplants is 1.2% overall • Incidence has increased slightly • Increased incidence with use of tacrolimus, white race, and cadaver donor • Treatment generally involves reduction in immunosuppression dose and antiviral agents

36. Posttransplant diabetes mellitus (PTDM) • Occurs in small number (2.6%) of pediatric renal transplant patients • Higher risk groups • African American race • Use of tacrolimus • No differences based on overweight, presence of specific HLA antigens, family history, or prednisone dose • Increased incidence of acute rejection in PTDM group

37. Role of general pediatrician • Growth and development • Surveillance for infection • Immunizations • Live virus vaccines can be given if prednisone dose is low • Influenza vaccine and pneumococcal vaccine are recommended • Awareness of potential drug interactions • drugs that increase activity of CYP450 will increase metabolism of calcineurin inhibitors • Tegretol, Dilantin, INH, Phenobarbital, Rifampin • drugs that compete for metabolism by CYP450 will decrease the metabolism of calcineurin inhibitors • Cimetidine, ketoconazole, erythromycin, diltiazem

38. Future directions • Steroid withdrawal or steroid avoidance protocols • Designer immunosuppression • Tolerance • Xenotransplantation

39. Transplant tolerance • A state where the immune system does not respond to a specific antigen: A Way to Peace • Strategies to induce tolerance • CD28 and CD40L blockade • CTLA4 and FasL blockade • Studies in nonhuman primates are promising • No data on long term effects, or long term graft function

40. Xenotransplantation

41. Xenotransplantation • The need: 12,000 renal transplants were performed, but 42,000 patients remained on waiting lists • The solution: xenotransplantation • Major obstacles: hyperacute rejection, delayed xenograft function, and “xenoses” • Search for the suitable species

42. Last slide

43. Kidney allocation and distribution • 1984: US Congress passes National Organ Transplant Act (NOTA) • NOTA provides for the establishment and operation of an Organ Procurement and Transplantation Network (OPTN) • 1986: United Network of Organ Sharing (UNOS) was awarded the contract to develop OPTN • US is divided into regions each with a separate Organ Procurement Organization (OPO) • Washington Regional Transplant Consortium (WRTC) is the Washington metropolitan area OPO

44. Allocation of cadaveric kidneys UNOS scoring system

45. % Graft survival Time in years Cadaveric donor Living related donor Primary graft survival by use of induction antibody

46. Time in years Cadaveric donor Living related donor Primary graft survival by number of transfusions

47. Prednisone • First immunosuppressive agent used • Several immunosuppressive effects • inhibit gene transcription of several cytokines ( IL-1, IL-2, IL-6, IF-g, TNF-a) by binding to 5’ glucocorticoid response areas of DNA • produces lympholysis by direct effects on lymphocyte membrane • causes sequestration of circulating T cells • antagonizes neutrophil and monocyte chemotaxis

48. Prednisone • Side effects • Cardiovascular: hypertension • ID: infection and delayed wound healing • GI: peptic ulcer disease, pancreatitis • Endocrine: hyperglycemia, growth failure, obesity, hyperlipidemia • Ortho: osteoporosis, aseptic necrosis • Ophtho: cataracts • Derm: acne, hypertrichosis • Psych: psychosis, pseudotumor cerebri

49. Azathioprine • History • Derivative of 6-MP but can be given orally • First drug widely used for maintenance immunosuppression • Immunosuppressive effects • metabolized to 6-thioinosinic acid and is incorporated into strands of DNA and RNA and causes chromosome breaks • 6-thioinosinic inhibits purine (adenine and guanine) synthesis from inosine • Side effects • Hematologic: bone marrow suppression, megaloblastic anemia • Derm: alopecia • GI: hepatic dysfunction

50. Mycophenolate Mofetil • History • semi-synthetic derivative of mycophenolic acid produced by fungus Penicillium • approved by the FDA in 1995 for use in rejection prophylaxis in renal transplantation • Immunosuppressive effects • irreversible inhibitor of inosine monophosphate dehydrogenase (IMPDH) that converts IMP to GMP • prevents de novo synthesis of GMP from IMP. GMP is essential nucleoside for purine synthesis • lymophcytes use de novo synthesis of purines exclusively • Side effects • GI: diarrhea, GI discomfort, GI bleeding (12%) • Cardiovascular: hypertension • Hematologic: leukopenia, thrombocytopenia • ID: increased risk of CMV infection (10%) • none developed PTLD