Download - Transplant example presentation
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Case Presentation
Joseph M Brandel, MDSUNY Downstate Medical CenterTransplant DivisionFriday, December 3, 2004
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Case Presentation
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Case Presentation
Labs:
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Case Presentation
Blood and tissue typing:
T-cell crossmatch (-)Flow cytometry
T cell (-)B cell (+)
13158X3226O+DonorDRDRBBAA
13872417429B+Recipient
HLAABO
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Case Presentation
Pre- and intraoperativeinduction immuno-suppression given
Oral tacrolimusIntravenous methylprednisoloneIntravenous thymoglobulin
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Case Presentation
Right laparoscopic donor nephrectomy performedKidney iced and delivered to recipient’s ORVenous and arterial anastomosesperformed
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Case Presentation
Right laparoscopic donor nephrectomy performedKidney iced and delivered to recipient’s ORVenous and arterial anastomosesperformed
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Case Presentation
Right laparoscopic donor nephrectomy performedKidney iced and delivered to recipient’s ORVenous and arterial anastomosesperformed
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Case Presentation
Right laparoscopic donor nephrectomy performedKidney iced and delivered to recipient’s ORVenous and arterial anastomosesperformed
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Case Presentation
Anastomosesinspected
No technical error identified
Intraoperative biopsy sent for frozen section
Thrombosis and acute inflammation of glomeruli, consistent with antibody mediated rejection
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Case PresentationPostoperatively
Patient given full therapy against cell-and antibody-mediated immunity
TacrolimusMycophenolate mofetilMethylprednisoloneThymoglobulinRituximabPlasmapheresis
Patient remained anuricPOD #2: Returned to OR for transplant nephrectomy
Discharged home three days after nephrectomy
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Acute Renal Allograft Rejection
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Definition
A process by which the immune system of the recipient of a transplantattacks the transplanted organ or tissueThis is the normal response of the healthy human immune system, which can distinguish foreign tissues and attempts to destroy them
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DefinitionHyperacute rejection: Mediated by preformed antibodies that bind to endothelium and subsequently activate complement
Rapid thrombotic occlusion of the vasculature of the transplanted allograftOccurs within minutes to hours after host blood vessels are anastomosed to donor vesselsMediated predominantly by IgGantibodies directed toward foreign protein molecules, such as MHC moleculesResult from prior exposure to alloantigens from blood transfusions, pregnancy, or previous transplantation
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Definition
Acute rejectiondeveloping after the first 5-7 post-transplant days is generally a manifestation of cell-mediated immune injury
Necrosis of parenchymalcells caused by infiltration of T cells and macrophages
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Definition
Chronic rejection: Fibrosis and scarring in transplanted organ
Multifactorial etiology, not strictly immunologicInflammation, ischemia, and other processes play a roleEpisodes of acute rejection are significant risk factors
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History
Ancient Greeks: Imagination fuelled by concept of xenotransplantationOld Testament: "A new heart also I will give you, and a new spirit will be put within you; and I will take away the stony heart out of your flesh, and I will give you a heart of flesh“1
1 Ezekiel 36:26
Chimera
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HistoryAutotransplantation well-established
2nd century BC: Sushrutapioneered skin grafting for rhinoplasty
Virtually all allografts failedAttempts at transplantation from slave to master (“sympathetic nose”)
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History1596: Gaspare Tagliacozziidentified 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".
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History: The tumor specialists1912: In his book “Heteroplastische und Homoplastische Transplantation” Georg Schöneformulated 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"
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HistorySir 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’”
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History
1933: Yu Yu Voronoy of the Soviet Union performed the first human-to-human kidney transplant1954: Joseph E. Murray performed the first successful kidney transplant
Donor and recipient identical twins
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HistoryEarly attempts at immunosuppression
Whole-body X-irradiationNitrogen mustard6-mercaptopurine
1957: George Hitchings and Gertrude Elion modify 6-MP to produce azathioprine1963: Thomas Starzl observed that large doses of corticosteroids can reverse rejection episodes and stabilize allograft function
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Pathophysiology
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Pathophysiology – Immune cascade
T lymphocytes are incapable of recognizing soluble antigen
Professional antigen presenting cell must phagocytose foreign cellPresents antigen on surface in conjunction with class II major histocompatibility complexActivated APC produces IL-1, augmenting T cell response
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Pathophysiology – Immune cascade
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Pathophysiology – Immune cascade
Antigen binding induces a conformational change in the TCR complexTCR complex is phosphorylatedand coupled via a G-binding protein to phospholipase CThe activation of phospholipaseC results in production of inositol1,4,5-triphosphate (IP3)Intracellular [Ca2+] increasesNuclear factor of activated T cells (NFAT) is activated by dephosphorylationProduction of mRNA for IL-2
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Pathophysiology – Immune cascade
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Immunosupressants
SteroidsPurine analogs
AzathioprineCalcineurin inhibitors
CyclosporineTacrolimus
Other T lymphocyte inhibitorsMycophenolate mofetilSirolimus
AntibodiesPolyclonalMonoclonal
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Immunosupressants: GlucocorticoidsPivotal 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 profilesPost-transplant diabetesHypertensionHyperlipidemiaWeight gain
Bone loss, cataracts, growth retardationSteroid-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
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Immunosupressants: Purineanalogs
AzathioprineMade organ transplantation across non-identical individuals a clinical realityWhen ribosylated, competitively inhibits nucleotide synthesisSide effects relate to antimetabolite activity
Bone marrow suppressionLiver toxicity
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Immunosupressants: Calcineurin inhibitors
CyclosporineExtracted from Tolypocladium inflatumIntroduction in 1983 was a landmark development, ending the “azathioprine era”Selective T cell inhibitionNo myelosuppressionNephrotoxicUnpredictable bioavailability
TacrolimusExtracted from Streptomyces tsukubaensisMechanism of action and side effect profile resemble cyclosporine’sIncreased incidence of PTDMLevels must be monitored
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Immunosupressants: Other lymphocyte inhibitors
Mycophenolate mofetilBlocks lymphocyte proliferation by inhibiting inosinemonophosphate dehydrogenateAspart 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 allograftsLeukopeniaGastrointestinal upset (diarrhea)
SirolimusClose structural analogue of tacrolimus, binds to FKBPInhibits 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
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Induction of immunosuppression
Prior to 1992: Vast majority (92%) of transplant recipients received no induction with antilymphocyte preparationsBy 2001 59% of recipients received inductionMuromonab-CD3 (OKT3) predominant immunosuppressive agent used for induction through 1995In 2001, 26% of the 13,109 transplants for which information is available used basiliximab (Simulect) and 15% used daclizumab (Zenapax)Rabbit antithymocyte globulin (Thymoglobulin) was used in 18% of transplants in 2001OKT3 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
Antilymphocyte induction agents:OKT3
BasiliximabDaclizumab
Thymoglobulin
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Mechanism of action of immunosupressants
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StatisticsAllograft survival, patient survival, and rates of acute rejection in the first 12 months after transplantation are excellent and continue to improveFor recipients of a first cadaveric kidney in the United States, current 1-year patient and graft survival probabilities are about 95% and 88%, respectivelyFor 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
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StatisticsAcute rejection episode decreases 1-year graft survival by 20% and shortens half-life by four yearsRates 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 regimensantimicrobial prophylaxisoverall surgical and medical care
Gjertson DW. Impact of delayed graft function and acute rejection on kidney graft survival. Clin Transpl. 2000:467-480
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Pretransplant evaluation
Physical examChest x-rayComplete medical and surgical historyElectrocardiogramUltrasound with Doppler examinationBlood testsPulmonary function test Viral testing - hepatitis, CMV, EBV, HIV
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Pretransplant evaluation
HistocompatibilityLaboratory Tests
Blood TypingTissue TypingCrossmatch TestingPanel Reactive Antibody (PRA)
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Diagnosis of rejectionClinical signs:
MalaiseFever Oliguria Hypertension Graft tenderness
Diagnosis hinges on serial creatinine measurements
Elevation of 20% over baseline triggers further evaluationRule out non-immunologic causesUltrasonographyRenal scanningPercutaneous biopsy
Fisher JS, Woodle ES, Thistlethwaite JR Jr: Kidney transplantation: Graft monitoring and immunosuppression. World J Surg 2002(26):185-193
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Diagnosis of rejectionBanff 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):4112 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
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Diagnosis of rejectionBanff criteria
Grade 1: Moderate interstitial mononuclear inflammation affecting 25-50% of the sampled parenchyma
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Diagnosis of rejectionBanff criteria
Grade 2: Moderate interstitial mononuclear infiltrate involving 26-50% of the renal parenchyma
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Diagnosis of rejectionBanff criteria
Grade 3: severe transmural arteritis and/or transmural fibrinoid change and necrosis of smooth muscle cells
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Diagnosis of rejectionBiochemical markers
Various markers reported to correlate with rejection
ß2-microglobulin1
Neopterin2
Not widely adoptedPCR amplification of messenger RNA in urinary sediment3
Perforin mRNAGranzyme 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. Immunobiology1986;173:562 Reibnegger G, Aichberger C, Fuchs D, Hausen A, et al. Posttransplant neopterinexcretion in renal allograft recipients—a reliable diagnostic aid for acute rejection and a predictive marker of long-term graft survival. Transplantation 1991;52:583 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
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Reversal of rejectionGlucocorticoids
Observation that steroids could reverse acute rejection was seminal1High 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
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Reversal of rejectionOKT3
A murine monoclonal antibody reactive with antigen-recognition complex on T cellsReverses 94% of acute rejection episodesImmunogenicToxic 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
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Reversal of rejectionThymoglobulin
Polyclonal antithymocyteantibody derived from rabbitsEfficacy appears similar to that of OKT3More favorable side effect profileMore resistant to antibody deactivationFirst line treatment for histologically severe and steroid-resistant rejection in many centers
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Reversal of rejectionTacrolimus
75% success rate in salvaging renal transplants undergoing steroid-refractory rejection1
Mycophenolate mofetil2 and sirolimus3
Similar salvage rates1 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;62:5942 Anonymous. Mycophenolate mofetil for the treatment of refractory, acute, cellular renal transplant rejection: the Mycophenolate Mofetil Renal Refractory Rejection Study Group. Transplantation 1996;61:7223 Hong JC, Kahan BD. Sirolimus rescue therapy for refractory rejection in renal transplantation. Transplantation 2001;71:1579
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Acute humoral rejection
Antibody-mediated rejection frequently undiagnosed
Lack of typical morphologic characteristics
C4d immunohistochemistryC4 is an element of the complement cascadeIts degradation product (C4d) adheres to endothelial cellsCan be detected by pathologist
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Acute humoral rejectionClassification of rejection as either “cellular” or “humoral” is flawed
Significant overlap existsTreatment 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;70:887–8942 Becker YT, Becker BN, Pirsch JD, Sollinger HW. Rituximab as treatment for refractory kidney transplant rejection. Am J Transplant 2004;4:996-1001
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Investigational therapiesLeflunomide
An orally administered antimetaboliteAction against NF-B and JAK3, key mediators in cytokine generationInhibits CMV
FTY720Reduces peripheral lymphocyte levels by causing sequestration in lymph nodes and Peyer patches
EfalizumabMonoclonal anti-CD11a antibodyBlocks 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
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Conclusions
Organ transplantation induces a fundamentally abnormal physiologic stateSteady improvement has been made in both prevention and treatment of organ rejectionThe potential for further improvement –both incremental and revolutionary – is great
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