Transplant example presentation

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Transplant example presentation

  1. 1. Case Presentation Joseph M Brandel, MD SUNY Downstate Medical Center Transplant Division Friday, December 3, 2004
  2. 2. Case Presentation
  3. 3. Case Presentation Labs:
  4. 4. Case Presentation Blood and tissue typing: ABO HLA A A B B DR DR Donor O+ 26 32 X 58 1 13 Recipient B+ 29 74 41 72 8 13 T-cell crossmatch (-) Flow cytometry T cell (-) B cell (+)
  5. 5. Case Presentation Pre- and intraoperative induction immuno- suppression given Oral tacrolimus Intravenous methylprednisolone Intravenous thymoglobulin
  6. 6. Case Presentation Right laparoscopic donor nephrectomy performed Kidney iced and delivered to recipient’s OR Venous and arterial anastomoses performed
  7. 7. Case Presentation Right laparoscopic donor nephrectomy performed Kidney iced and delivered to recipient’s OR Venous and arterial anastomoses performed
  8. 8. Case Presentation Right laparoscopic donor nephrectomy performed Kidney iced and delivered to recipient’s OR Venous and arterial anastomoses performed
  9. 9. Case Presentation Right laparoscopic donor nephrectomy performed Kidney iced and delivered to recipient’s OR Venous and arterial anastomoses performed
  10. 10. Case Presentation Anastomoses inspected No technical error identified Intraoperative biopsy sent for frozen section Thrombosis and acute inflammation of glomeruli, consistent with antibody mediated rejection
  11. 11. Case Presentation Postoperatively Patient given full therapy against cell- and antibody-mediated immunity Tacrolimus Mycophenolate mofetil Methylprednisolone Thymoglobulin Rituximab Plasmapheresis Patient remained anuric POD #2: Returned to OR for transplant nephrectomy Discharged home three days after nephrectomy
  12. 12. Acute Renal Allograft Rejection
  13. 13. Definition A process by which the immune system of the recipient of a transplant attacks the transplanted organ or tissue This is the normal response of the healthy human immune system, which can distinguish foreign tissues and attempts to destroy them
  14. 14. Definition Hyperacute rejection: Mediated by preformed antibodies that bind to endothelium and subsequently activate complement Rapid thrombotic occlusion of the vasculature of the transplanted allograft Occurs within minutes to hours after host blood vessels are anastomosed to donor vessels Mediated predominantly by IgG antibodies directed toward foreign protein molecules, such as MHC molecules Result from prior exposure to alloantigens from blood transfusions, pregnancy, or previous transplantation
  15. 15. Definition Acute rejection developing after the first 5-7 post-transplant days is generally a manifestation of cell- mediated immune injury Necrosis of parenchymal cells caused by infiltration of T cells and macrophages
  16. 16. Definition Chronic rejection: Fibrosis and scarring in transplanted organ Multifactorial etiology, not strictly immunologic Inflammation, ischemia, and other processes play a role Episodes of acute rejection are significant risk factors
  17. 17. History Ancient Greeks: Imagination fuelled by concept of xenotransplantation Old Testament: "A new heart also I will give you, and a new spirit will be put within you; and I will take Chimera away the stony heart out of your flesh, and I will give you a heart of flesh“1 1 Ezekiel 36:26
  18. 18. History Autotransplantation well- established 2nd century BC: Sushruta pioneered skin grafting for rhinoplasty Virtually all allografts failed Attempts at transplantation from slave to master (“sympathetic nose”)
  19. 19. History 1596: Gaspare Tagliacozzi identified essence of difficulty: "The singular character of the individual entirely dissuades us from attempting this work on another person. For such is the force and power of individuality, that if any one should believe that he could achieve even the least part of the operation, we consider him plainly superstitious and badly grounded in physical science".
  20. 20. History: The tumor specialists 1912: In his book “Heteroplastische und Homoplastische Transplantation” Georg Schöne formulated rules on “Transplantationsimmunität” based on contemporary research: Heteroplastic (xenogeneic) transplants invariably fail Homoplastic (allogeneic) transplants usually fail Autografts are almost always successful There is an initial take of a first allograft which is then followed by rejection Second grafts undergo accelerated rejection if recipient has previously rejected a graft from the same donor or, if recipient has been preimmunized with material from tumor donor Graft success is more likely when donor and recipient have a closer "blood relationship"
  21. 21. History Sir Peter Medawar at Glasgow Infirmary published “The Fate of Skin Homografts in Man” The destruction of foreign epidermis is brought about by a mechanism of active immunization “The accelerated regression of second-set homografts argues for the existence of a systemic immune state” “The inflammation has in all likelihood the character of a local anaphylaxis… yet, the reaction is atypical; for the lymphocyte takes the place of the polymorph in the ‘classical picture’”
  22. 22. History 1933: Yu Yu Voronoy of the Soviet Union performed the first human-to-human kidney transplant 1954: Joseph E. Murray performed the first successful kidney transplant Donor and recipient identical twins
  23. 23. History Early attempts at immunosuppression Whole-body X-irradiation Nitrogen mustard 6-mercaptopurine 1957: George Hitchings and Gertrude Elion modify 6-MP to produce azathioprine 1963: Thomas Starzl observed that large doses of corticosteroids can reverse rejection episodes and stabilize allograft function
  24. 24. Pathophysiology
  25. 25. Pathophysiology – Immune cascade T lymphocytes are incapable of recognizing soluble antigen Professional antigen presenting cell must phagocytose foreign cell Presents antigen on surface in conjunction with class II major histocompatibility complex Activated APC produces IL-1, augmenting T cell response
  26. 26. Pathophysiology – Immune cascade
  27. 27. Pathophysiology – Immune cascade Antigen binding induces a conformational change in the TCR complex TCR complex is phosphorylated and coupled via a G-binding protein to phospholipase C The activation of phospholipase C results in production of inositol 1,4,5-triphosphate (IP3) Intracellular [Ca2+] increases Nuclear factor of activated T cells (NFAT) is activated by dephosphorylation Production of mRNA for IL-2
  28. 28. Pathophysiology – Immune cascade
  29. 29. Immunosupressants Steroids Purine analogs Azathioprine Calcineurin inhibitors Cyclosporine Tacrolimus Other T lymphocyte inhibitors Mycophenolate mofetil Sirolimus Antibodies Polyclonal Monoclonal
  30. 30. Immunosupressants: Glucocorticoids Pivotal role in treatment of acute rejection episodes and maintenance since early days of transplantation Suppress interleukin-2 production and Inhibit lymphocyte activation and both monocyte and neutrophil migration Also modulate humoral immunity by regulating T-cell activation of B cells At high doses directly inhibit B-cell activation and proliferation Worsen cardiovascular risk profiles Post-transplant diabetes Hypertension Hyperlipidemia Weight gain Bone loss, cataracts, growth retardation Steroid-sparing and steroid-minimizing regimens described1 1 Borrows R, Loucaidou M, Van Tromp J, et al. Steroid sparing with tacrolimus and mycophenolate mofetil in renal transplantation. Am J Transplant 2004;4:1845-1851
  31. 31. Immunosupressants: Purine analogs Azathioprine Made organ transplantation across non-identical individuals a clinical reality When ribosylated, competitively inhibits nucleotide synthesis Side effects relate to antimetabolite activity Bone marrow suppression Liver toxicity
  32. 32. Immunosupressants: Calcineurin inhibitors Cyclosporine Extracted from Tolypocladium inflatum Introduction in 1983 was a landmark development, ending the “azathioprine era” Selective T cell inhibition No myelosuppression Nephrotoxic Unpredictable bioavailability Tacrolimus Extracted from Streptomyces tsukubaensis Mechanism of action and side effect profile resemble cyclosporine’s Increased incidence of PTDM Levels must be monitored
  33. 33. Immunosupressants: Other lymphocyte inhibitors Mycophenolate mofetil Blocks lymphocyte proliferation by inhibiting inosine monophosphate dehydrogenate Aspart of multidrug regimen significantly reduced incidence of biopsy-proven rejection during the first 12 months aftertransplant, leading to a 50% decrease in loss of renal allografts Leukopenia Gastrointestinal upset (diarrhea) Sirolimus Close structural analogue of tacrolimus, binds to FKBP Inhibits transduction of signals from the IL-2R to the nucleus Acts synergistically with cyclosporine Not significantly nephrotoxic Halloran P, Mathew T, Tomlanovich S, Groth C, Hooftman L, Barker C. Mycophenolate mofetil in renal allograft recipients. Transplantation 1997;63:39
  34. 34. Induction of immunosuppression Prior to 1992: Vast majority (92%) of transplant recipients received no induction with antilymphocyte preparations By 2001 59% of recipients received induction Antilymphocyte induction agents: Muromonab-CD3 (OKT3) predominant immunosuppressive agent used for induction OKT3 through 1995 Basiliximab In 2001, 26% of the 13,109 transplants for which Daclizumab information is available used basiliximab (Simulect) Thymoglobulin and 15% used daclizumab (Zenapax) Rabbit antithymocyte globulin (Thymoglobulin) was used in 18% of transplants in 2001 OKT3 use has dropped to <1% of transplants Heldermana JH, Bennett WM, Cibrikc DM, Kaufmand DB, Kleine A, Takemotof SK. Immunosuppression: practice and trends. Am J Transplant 2003; 3 (Suppl. 4): 41–52
  35. 35. Mechanism of action of immunosupressants
  36. 36. Statistics Allograft survival, patient survival, and rates of acute rejection in the first 12 months after transplantation are excellent and continue to improve For recipients of a first cadaveric kidney in the United States, current 1-year patient and graft survival probabilities are about 95% and 88%, respectively For recipients of a first living donor kidney, current 1-year patient and graft survival probabilities are 98% and 94%, respectively US Renal Data System. USRDS 2002 Annual Data Report: Atlas of End-Stage Renal Disease in the United States. Bethesda, Md: National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases; 2002
  37. 37. Statistics Acute rejection episode decreases 1- year graft survival by 20% and shortens half-life by four years Rates of acute rejection in the first 6 months have decreased to less than 20% due to improvements in: Crossmatching tests (pretransplantation in vitro assays to detect donor antibodies to recipient HLA antigens) Immunosuppressive regimens antimicrobial prophylaxis overall surgical and medical care Gjertson DW. Impact of delayed graft function and acute rejection on kidney graft survival. Clin Transpl. 2000:467- 480
  38. 38. Pretransplant evaluation Physical exam Chest x-ray Complete medical and surgical history Electrocardiogram Ultrasound with Doppler examination Blood tests Pulmonary function test Viral testing - hepatitis, CMV, EBV, HIV
  39. 39. Pretransplant evaluation Histocompatibility Laboratory Tests Blood Typing Tissue Typing Crossmatch Testing Panel Reactive Antibody (PRA)
  40. 40. Diagnosis of rejection Clinical signs: Malaise Fever Oliguria Hypertension Graft tenderness Diagnosis hinges on serial creatinine measurements Elevation of 20% over baseline triggers further evaluation Rule out non-immunologic causes Ultrasonography Renal scanning Percutaneous biopsy Fisher JS, Woodle ES, Thistlethwaite JR Jr: Kidney transplantation: Graft monitoring and immunosuppression. World J Surg 2002(26):185-193
  41. 41. Diagnosis of rejection Banff criteria Interpretation of renal biopsy specimens for diagnosing rejection have been greatly facilitated and standardized Based on scores for glomerular, vascular, interstitial, and tubular lesions Has been shown to have clinical relevance when predicting rejection reversal and may prove useful for choosing first-line therapy of rejection episodes 1 Solez K, Arelsen RA, Benedictsson H, et al. International standardization of criteria for the histiologic diagnosis of renal allograft rejection: the Banff working classification of kidney transplant pathology. Kidney Int 1993(44):411 2 Gaber LW, Moore LW, Alloway RR, et al. Correlation between Banff classification, acute renal rejection scores and reversal of rejection. Kidney Int 1996(49):481
  42. 42. Diagnosis of rejection Banff criteria Grade 1: Moderate interstitial mononuclear inflammation affecting 25-50% of the sampled parenchyma
  43. 43. Diagnosis of rejection Banff criteria Grade 2: Moderate interstitial mononuclear infiltrate involving 26-50% of the renal parenchyma
  44. 44. Diagnosis of rejection Banff criteria Grade 3: severe transmural arteritis and/or transmural fibrinoid change and necrosis of smooth muscle cells
  45. 45. Diagnosis of rejection Biochemical markers Various markers reported to correlate with rejection ß2-microglobulin1 Neopterin2 Not widely adopted PCR amplification of messenger RNA in urinary sediment3 Perforin mRNA Granzyme B mRNA Strong predictive value for acute rejection 1 Konig P, Spielberger M, Kathrein H, Margreiter R. Beta 2-microglobulin: a prognostic parameter for graft survival after renal transplantation. Immunobiology 1986;173:56 2 Reibnegger G, Aichberger C, Fuchs D, Hausen A, et al. Posttransplant neopterin excretion in renal allograft recipients—a reliable diagnostic aid for acute rejection and a predictive marker of long-term graft survival. Transplantation 1991;52:58 3 Li B, Hartono C, Ding R, et al. Noninvasive diagnosis of renal-allograft rejection by measurement of messenger RNA for perforin and granzyme B in urine. N Engl J Med 2001;344:947
  46. 46. Reversal of rejection Glucocorticoids Observation that steroids could reverse acute rejection was seminal1 High dose steroid administration successfully treats rejection in 75%2 First line treatment for acute rejection in most centers is pulse methylprednisolone, 500 to 1000 mg, given intravenously daily for 3 to 5 days 1 Starzl TE, Marchioro TL, Waddell WR. The reversal of rejection in human renal homografts with subsequent development of homograft tolerance. Surg Gynecol Obstet. 1963 Oct;117:385-95 2 Ortho Multicenter Study Group: A randomized trial of OKT3 monoclonal antibody for acute rejection of cadaveric renal transplants. N Engl J Med 1985, 313:337
  47. 47. Reversal of rejection OKT3 A murine monoclonal antibody reactive with antigen- recognition complex on T cells Reverses 94% of acute rejection episodes Immunogenic Toxic cytokine release syndrome Ortho Multicenter Study Group: A randomized trial of OKT3 monoclonal antibody for acute rejection of cadaveric renal transplants. N Engl J Med 1985, 313:337
  48. 48. Reversal of rejection Thymoglobulin Polyclonal antithymocyte antibody derived from rabbits Efficacy appears similar to that of OKT3 More favorable side effect profile More resistant to antibody deactivation First line treatment for histologically severe and steroid-resistant rejection in many centers
  49. 49. Reversal of rejection Tacrolimus 75% success rate in salvaging renal transplants undergoing steroid- refractory rejection1 Mycophenolate mofetil2 and sirolimus3 Similar salvage rates 1 Woodle ES, Thistlethwaite JR, Gordon JH, et al. A multicenter trial of FK506 (tacrolimus) therapy in refractory acute renal allograft rejection: a report of the Tacrolimus Kidney Transplantation Resue Study Group. Transplantation 1996;62:594 2 Anonymous. Mycophenolate mofetil for the treatment of refractory, acute, cellular renal transplant rejection: the Mycophenolate Mofetil Renal Refractory Rejection Study Group. Transplantation 1996;61:722 3 Hong JC, Kahan BD. Sirolimus rescue therapy for refractory rejection in renal transplantation. Transplantation 2001;71:1579
  50. 50. Acute humoral rejection Antibody-mediated rejection frequently undiagnosed Lack of typical morphologic characteristics C4d immunohistochemistry C4 is an element of the complement cascade Its degradation product (C4d) adheres to endothelial cells Can be detected by pathologist
  51. 51. Acute humoral rejection Classification of rejection as either “cellular” or “humoral” is flawed Significant overlap exists Treatment of humoral rejection Plasmapheresis1 Rituximab2 Monoclonal anti-CD20 antibody (found on B cells) May improve outcomes in antibody- mediated acute rejection episodes 1 Montgomery R, Zachary AA, Racusen LC et al. Plasmapheresis and intravenous immune globulin provides effective rescue therapy for refractory humoral rejection and allows kidneys to be successfully transplanted into cross-matchpositive recipients. Transplantation 2000;70:887–894 2 Becker YT, Becker BN, Pirsch JD, Sollinger HW. Rituximab as treatment for refractory kidney transplant rejection. Am J Transplant 2004;4:996-1001
  52. 52. Investigational therapies Leflunomide An orally administered antimetabolite Action against NF-B and JAK3, key mediators in cytokine generation Inhibits CMV FTY720 Reduces peripheral lymphocyte levels by causing sequestration in lymph nodes and Peyer patches Efalizumab Monoclonal anti-CD11a antibody Blocks T cell adhesion Alemtuzumab (Campath 1H) Monoclonal antibody targeting CD52 (found on all lymphocytes) Causes profound, prolonged lymphocyte depletion Tolerance induction with full immunosuppression and bone marrow transplant
  53. 53. Conclusions Organ transplantation induces a fundamentally abnormal physiologic state Steady improvement has been made in both prevention and treatment of organ rejection The potential for further improvement – both incremental and revolutionary – is great

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