10-7-08 Kidney Transplant & Immunosuppression
Epidemiology (Norman)
Introduction
 Renal Replacement Therapy – 100,000 individuals develop ESRD yearly, transplantation is best RRT
 DM/HTN – Two most common factors leading to progression of ESRD, leading to ESRD epidemic
 Dialysis Mortality – 20-30% death rate in dialysis patients yearly, not as good a RRT as transplant
Transplant Demographics
 Demographics – about 70,000 patients in total, disproportionately African American, Hispanic, female
 Incidence – about 30,000 new each year, 4,500 die w/out offer, 1,500 taken off list (too sick)
 Success – about 11,000 transplants annually
Donor Sources
 Living Donors – can be Living Related (LRD) or Living Unrelated (LURD)
 Deceased Donors – must meet SCD, ECD, or DCD:
o Standard Criteria Donor (SCD) – age < 60, no kidney/vascular disease, brain death
o Extended Criteria Donor (ECD) – age > 60, or donors 50-59 w/ stroke/HTN/creatinine > 1.5
o Deceased Cardiac Death (DCD) – card. death (life support) but not brain dead; no recovery poss.
 Living Donor Selection Issues – must put donor’s health ahead of recipient, donor must be uncoerced and:
o Healthy – donor cannot have DM, HTN, active malignancies/infections/drug use
o Non-elderly – donor should be < 60 yo to maximize benefit of transplant
 Living Donor Advantages – include pre-emptive transplant, less rejection, graft function, longevity
o Pre-emptive transplantation – can transplant patient before needing dialysis, healthier
o Less Rejection, Better Graft Function/Survival – all improved in living donors
Deceased Donor Allocation
 Waiting Time – how long recipient has been waiting on list for donor, starts from referral, not ESRD event
 Matching – if antigens match better, recipient more likely to receive
 Panel Reactive Antibodies – kidney reacts to many Ig’s from blood x-fusions, need kidney before too late
 Pediatric – children given priority
 Prior Donor – individuals who have donated one of their own kidneys get a better crack at receiving donor
Recipient Selection
 In General – biased towards transplanting whenever possible, even if chances of success are slim
 Contraindications:
o CAD – severe CAD not amenable to intervention
o PVD – severe peripheral vascular disease, not amenable to intervention
o Pulmonary Disease – if too severe
o Malignancy/Infection – active tumors & infections C/I (after transplant, you immunosuppress…)
o Non-compliance – need to make sure recipient will take care of new kidney
o Obesity/malnutrition – also C/I, as transplants have limited success
Transplant Outcomes
 Patient Survival – after 1 year, survival rate above 95%
 Graft Survival – after 1 year, survival rate 95% (living donors) to about 85-90% (deceased donors)
 Transplant T1/2 – about 20 years (living donor) to about 10 years (deceased donor)
 Mortality Risk – compared to dialysis, if you can make it to day 250, you’re better off with transplant
 Post-Transplant Mortality – most often because of CV disease
 Cost – much cheaper than dialysis on year basis, once you sink cost of initial surgery
Transplant Disadvantages
 Shortage – organ shortage, long wait times for transplant
 Operation morbidities – in short term after operation, mortality/morbidity higher than dialysis
 Immunosuppression – has negative effects on CV disease, infection, malignancy, bone disease
Pancreas Transplantation
 With Kidney – in 10% of kidney transplant recipients, a pancreas transplant also done
 Indications – if in ESRD w/ Type I DM, or hypoglycemia unawareness (hard for pt. to realize hypogly.)
 Types – include SPK, PAK, PTA
o Simultaneous Pancreas & Kidney (SPK)
o Pancreas After Kidney (PAK)
o Pancreas Transplant Alone (PTA) – not too often, usually need kidneys as well
 Risks – surgical complications, infection risk, allograft rejection risk
 Benefits – offers hypoglycemia protection, freedom from DM, stabilize retinopathy/neuropathy, survival?
 Results – 1-year SPK survival is >95%, 10-year SPK survival is 67%
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Surgery and Immunology (Sung)
Kidney Transplant Surgery
 Bad Kidney – left in patient, not doing any harm, just not helping  no need to remove!
 Attachment – place new kidney in pelvis off iliac artery because:
o Ureter/vascular distance – harvested kidney isn’t long enough to attach near renal artery
o Biopsy/access – pelvis much easier place to access than up in CVA
 Reflux – attach muscular tunnel to end of ureter attaching to bladder, to prevent reflux
 Surgical Complications – rare, but artery/venous occlusion, ureteral leak/stenosis, or wound inj:
o Hematoma – accumulation of blood in wound, can lead to infection if untreated
o Lymphocele – accumulation of lymph fluid near x-plant site, need to drain
Pancreas Transplant Surgery
 Bad Pancreas – also left in place, no need to remove
 Attachment – placed in similar location as kidney transplants  iliac arteries, exocrine secretion sewn into bladder or small
bowel
 Complications – problems draining exocrine; if attach to small bowel, risk of crap in peritoneum
Transplant Immunology
T-cell Development
 T-cell precursor with viable receptors migrates to thymus – where positive & negative selection occur
 Positive – T cells expressing TCRs recognizing peptides presented by self-MHC selected for
 Negative – T cells expressing TCRs binding to self peptides selected against; if this doesn’t work  autoimmune disease
 Weak interaction – key to rescuing mature CD4 thymocyte from programmed cell death
 After this selection, mature T cells leave thymus, enter 2o lymphoid organs – spleen & lymph nodes
Immune Response: Bacteria
1) APC (macrophage, B-cell) uptakes antigen thru endocytosis, lysosome degradation  surface presentation
2) Helper T-cell (CD4+) binds to an APC through MHC Class II complexes
3) If T-cell recognizes antigen on APC  differentiation & proliferation  activate B, TH, TC, APCs
Immune Resposne: Virus
1) APC (dendritic cell) degrades viral proteins in proteasomes  surface presentation
2) Cytotoxic T-cell (CD8+) binds to APC through MHC Class I complexes
3) If T-cell recognizes antigen on APC  differentiation & proliferation  activate B, TH, TC, APCs
Antigen Presenting Cells
 Dendritic cells, mphages, B cells – normal APCs
 Vascular endothelial, epithelial, parenchymal – may act ast APCs in setting of inflammation
 Antigen presentation – occurs on MHC for recognition by antigen receptors on T cells
MHC Classes I/II
 MHC Class I – have A, C, B loci  present on all nucleated cells, recognized by CD8+ TC
o Since a virus can infect any cell, makes sense that all nucleated cells have MHC Class I
o Dendritic cells, though, are the heroes in presenting & activating T C against viruses
 MHC Class II – have DR, DQ, DP loci  present only on APCs, recognized by CD4+ TH
o Since bacteria usually not intracellular, just need specialized cells to break down and present to T H
 Peptide binding region – where majority of polymorphisms are located
HLA
 Human Leukocyte Antigen (HLA) – polymorphic cell-surface molecules encoden by MHC genes
 Variety – have different A/B/C domains and DR/DQ/DP domains  gives person autoimmune identity
 Rejection – occurs when T-cells recognize HLA as foreign, rather than self
T-cell Activation
 Presentation – presentation & recognition of antigen essential for T-cell activation, but not sufficient
 Costimulation – needed for T-cell proliferation  example is B7 (B-cell) attaching to C28 (T-cell)
o Anergy – if T-cell binds, but no costimulation  no proliferation of immune response
 Autocrine Proliferation – after costimulation, T-cells become very numerous, and differentiate
T-cell Allorecognition
 Direct – a donor APC presenting a recipient self-peptide mimics self-APC presenting foreign peptide 
autoimmune response activation  transplant rejection
 Indirect – recipient APC presents a donor peptide  T-cell activation against donor peptide  rejection
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Transplant Rejection Pathology (Johnson)
Transplant Rejection
 Immune Response – transplant rejection is both cellular and humoral:
o Cellular – T-cell mediated immunity, when donor tissue presents self-peptides to T-cells
o Humoral – formation of antibodies against donor tissue
Hyperacute Rejection
 Hyperacute Rejection – recipient has a pre-formed antibody reacting against donor vascular antigen
 Prevalence – very rare, used to occur more often, when different blood types transplanted
 Timeframe – occurs minutes to hours after transplant, massive complement activation
 Results – causes thrombosis & infarction
 Histology – targets are arterioles & microvasculature – loss of blood flow, rapid rejection
Acute Rejection
 Acute Rejection – occurs with both cellular and humoral mediated tissue injury, days-years after x-plant w/ decreasing
risk over time
 Acute Cellular Rejection – cell-mediated immune injury, presents as tubular interstitial nephritis
o Cells – has mononuclear inflammatory cells (Tc, TH, macrophages, eosinophils, plasma cells)
o Histology – cell-mediated immunity, no PMNs, tubule destruction, glomeruli preserved
 Acute Vascular Rejection – mainly from anti-donor Ig’s, and CD8-mediated injury of endothelial cells
o Severity – vascular rejection implies more severe rejection
o Arteries/capillaries – endothelial cells which attacked by T c cells
o Target antigens – include AB, HLA (Class I/II), and endothelial cells
o Cells/effectors – effectors include neutrophils, platelets, and complement C4d
o Histology – accumulation of subintimal lymphocytes & mononuclear cells; fibrinoid necrosis if severe
 Banff Criteria – ways to classify the severity of acute cellular rejection; 1A/B nonvascular, 2A/B, 3 vascular and more
severe
Chronic Allograft Nephropathy
 Chronic Allograft Nephopathy – a progressive loss of renal function over months-years
 Prevalence – most common kind of transplant rejection
 Mechanism – both immune and non-immune mechanisms at work
 Risk factors – ACR, HLA mismatch, prior sensitization, poor immunosuppression, hyperlipidemia, smoking, HTN,
calcineurin inhibitor nephrotoxicity, obesity
 Cells/effectors – include TH (CD4+), macrophages, fibroblasts
 Histology – shows vascular intimal fibrosis, interstitial fibrosis
Preventing Rejection
 Matching – need to match by blood type; good to match HLA type & crossmatch
o Blood Type – O is universal donor (no antigens on RBC), AB is universal recipient
o HLA Matching – class I (HLA A, B), class II (HLA DR)  improves chances, but not sure thing and also not
necessary with better immunosuppresants
o Lymphocytotoxic crossmatch – mix receipient serum, donor lymphocytes and complement  if rxn occurs 
incompatible  no go on x-plant
o Crossmatch – if recipient has foreign HLA antibodies (blood x-fusions), can’t x-plant this HLA
 Crossmatch – can occur from blood x-plant, previous x-plant, pregnancy
 Panel Reactive Antibody – the number of HLA types a person has antibodies against
 High PRA – means that wait will be longer for recipient to find donor  higher priority
 Immunosuppressive Drugs – primary way to prevent transplant rejection
Transplant Pharmacology (Cibrik/some pharm lady)
Immunosuppression Uses
 Induction – given immediately post-transplant to patients @ risk for acute cellular rejection
 Maintenance – all patients during lifetime of transplant
 Rejection – immunosuppressor drugs designed to fight rejection
 Tolerance – transplant where immunosuppression no longer needed (haven’t achieved yet)
Induction
 Induction – use of immunosuppression at the time of transplant
 Patients – induction necessary for patients with high rejection risk, or those with delayed graft function
o High Rejection Risk – child, African-American, multi-organ x-plant, 2nd x-plant, PRA, unrelated
o Delayed Graft Function (DGF) – need dialysis in 1st week post-x-plant, often if long ice time or old donor
 Induction Agents – Include monoclonal antibodies & polyclonal antibodies:
o Monoclonal Antibodies:
 OKT3 – binds to CD3 on T-cell receptor, clearing these lymphocytes in spleen (sick SE)
 Anti-IL2 Receptor Ig’s – bind to CD25 on IL-2 receptor (only activated T-cells) to prevent autocrine T
cell activation; only useful for induction
 Daclizumab – humanized (10% mouse – the antigen-binding site of var. reg.)
 Basiliximab – chimeric (25% mouse – the whole variable region)
o Polyclonal Antibodies (bind to more than one type of cell):
 Work by nonselectively depleting lymphocyte & platelet populartions
 Thymoglobulin (rATG) – anti-thymocyte globulin from rabbits  works best
 ATGAM (hATG) – anti-thymocyte globulin from horse
Maintenance
 Mainenence – immunosuppressive drugs give to all patients during lifetime of transplant
 Triple Therapy – include corticosteroids, anti-proliferative agents, & calcineurin inhibitors
o Corticosteroids – inhibit cytokine secretion in lymphocytes  bind promoter response elements
 Methylprednisone – IV corticosteroid
 Prednisone – oral corticosteroid
o Anti-proliferative agents – inhibit immune cell growth & replication
 Azathioprine – inhibits all purine biosynthesis (both de novo & selvage)
 Mycophenolate – inhibits only de novo purine biosynthesis (WBC only have this)
 Rapamycin/Sirolimus – prevents T-cells from “raping” & dividing, blocks G1S phase; binds to FKBP
to exert effect on TOR (yeah, that probably means nothing to most of us)
o Calcineurin inhibitors (CNIs) - inhibits IL-2 gene transcription
 Cyclosporine - works by binding cyclophillin (a calcineurin phosphatase)  no IL-2
 Tacrolimus – binds to FK binding protein, inhibits calcineurin phosphatase  no IL-2
o Cytochrome P450 – liver enzyme metabolizes many CNIs, problematic if altered function:
 Inducers (reduce cyclosporin level)– phenytoin (dilantin), carbamazapine (tegretol)
 Inhibitors (increase cyclosporin level) – grapefruit juice, macrolides
Acute Rejection
 Acute Rejection – drug treatment for acute transplant rejection, divided into humoral/cellular
 Humoral Rejection Drugs – treat against antibody responses
o Rituximab – chimeric antibody, anti-CD20 against B-cells
o Plasmapheresis – filter out all antibodies from blood
o IVIG – intravenous pooled IgG immunoglobulins… works thru many theories
 Cellular Rejection Drugs – treat against T-cell mediated responses, Tx choice depends on severity
o Methylpredisone IV – IV corticosteroid
o OKT3 – binds to CD3 on T-cell receptor, clearing these lymphocytes in spleen (sick SE)
o Thymoglobulin - anti-thymocyte globulin from rabbits
Chronic Rejection
 Chronic Allograft Nephropathy (CAN) - slow loss of renal function, both non-immune & immune
o Acute Rejection - most important risk factor for CAN
o Treatment – reduce risk factors (smoking, hyperlipemia, obesity)
o CNI – if too much or not enough calcineurin inhibitor, can have CAN
o MMF – protective against CAN