Solid Organ Transplantation - Basic Concepts

Solid Organ
Transplantation – Basic
Concepts
Bassem Almalki B.Sc.Pharm, PharmD, BCPS
Assistant Professor & Solid Organ Transplant Clinical Pharmacist
Learning Outcomes
• Review basic concepts of solid organ transplantation
• Describe immune response to allograft and review T cell
activation
• Discuss ways to estimate rejection risk
• Consider strategies to attenuate the immune response
Allografts For
Transplantation
• Thoracic organs
• Heart transplant
• Lung transplant
• Abdominal organs
• Liver transplant
• Small bowel
transplant
• Kidney transplant
• Pancreas transplant
Image source:
http://wexnermedical.osu.edu/~/media/Images/WexnerMedical/Global/Modu
les/Global/FeaturedPageListingCallout/Patient-Care/Healthcare-
Services/Transplant/OrganTransplant.png?mw=1382
Indications For Organ
Transplantation
Chronic heart failure, Coronary artery disease, Arrhythmias, Congenital disease
Chronic obstructive pulmonary disease, Idiopathic pulmonary fibrosis, Cystic

fibrosis, Idiopathic pulmonary arterial hypertension
Hepatitis B and C, Alcohol/Drug toxicity, Hepatocellular carcinoma, Fatty liver

disease, Autoimmune, Biliary disease
Diabetes, Hypertension, Lupus, Polycystic kidney disease, Infections, Drug

toxicities
Diabetes
Crohn’s, Trauma, Thrombosis, Tumors

Transplantation Surgery
• Orthotopic heart, lung, liver, small bowel
• Not all transplants are done in situ
• Kidney
https://www.youtube.com/watch?v=zPXphpl7gco
• Pancreas
• Living vs cadaveric (deceased) donation
Image source: http://www.webmd.com/lung/lung-transplant

Image source: http://tpis.upmc.com/changeBody.cfm?url=/tpis/EN/E00002n.jsp
What Are Benefits of
Transplantation?
• Prolongs life, minimizes morbidity of end stage disease
• Improves quality of life in most patients
• Socioeconomic benefits
• Ongoing disability vs. return to work
• Renal transplant = freedom from dialysis
• Ongoing hemodialysis ~$90,000/year
• Maintaining kidney transplant under $15,000/year
• Pancreas transplant = freedom from insulin and diabetic complications
Transplantation – The Most
Regulated Field of Medicine
• United Network for Organ Sharing (UNOS)
• Saudi Center for Organ Transplantation
Organ Shortage
• In USA, 121859 people awaiting transplantation
• Renal transplant 81%
• Liver transplant 12%
• In 2014, 29533 transplants were performed

• 23715 from deceased donors
• 5818 from living donors
• Patients wait months to many years to receive life-sustaining

transplants
• Renal transplant median ~ 4.7 years
• Lung, liver, pancreas median ~ 1-2 years
• Heart median ~ 6 months
Immune Response To
Allograft & T-cell
Activation
Immune Response To Allograft
• Adaptive immune system activation results in rejection

• CD4+ T helper cell (Th) and APC
• CD8+ T cytotoxic cell (Tc) and APC
• B cell and antibody producing plasma cell
• T cell activation by APC is essential first step
• T cell activation/proliferation requires three distinct signals

• Signal 1 or Antigenic signal
• Signal 2 or Co-stimulatory signal
• Signal 3 or Cytokine signal
Halloran PF. New England Journal of Medicine.351.26 (2004): 2715-2729.

• Activated CD4+ Th produces cytokines that will attract,

activate and proliferate many other leukocytes (T cells, B
cells, macrophages, neutrophils, etc.)
• Activated CD8+ Tc cells directly damage antigen source
• Activated B cells differentiate into Ab producing plasma

cells that directly damage antigen source
Rejection Timing Transplant
How Can We Estimate
Rejection Risk?
Rejection Risk Differs by Organ
Type
• Organs that are very rich in lymphoid tissue carry
higher risk of rejection as higher population of
APCs transplanted with organ
• Lung/small bowel>>heart>kidney/pancreas>>liver
Rejection Risk Depends on Previous
Exposure to Foreign Ag: ABO
• Blood group antigens (ABO)
• Ab to blood group antigens are naturally occurring
• Blood group mismatch is an absolute contraindication
for deceased donor transplants
• Due to severe organ shortage, may be overcome in case
of living kidney donor
What Happens if I Transplant an Organ
When There Are Pre-Formed Ab?
Hyperacute, antibody mediated rejection
Antibody Mediated Rejection
Rejection Risk Depends on Previous
Exposure to Foreign Ag: HLA
• Human leukocyte antigens (HLA) are cell surface proteins
• Function:
• Help our immune system distinguish self from non-self
• Exist on surface of APC and are used to present Ag to T cells
• Every human has 6 distinct sets of HLA protein
• MHC I: HLA-A, HLA-B, HLA-C
• MHC II: HLA-DP, HLA-DQ, HLA-DR
• We genetically express two alleles for each HLA protein
• Identical twins have 6/6 matched HLA protein set
• Non-identical siblings carry 25% chance for 6/6 match
• Preformed donor-specific HLA Ab (DSA) are associated with graft failure
in kidney, heart, lung and liver transplantation  absolute
contraindication for deceased donor transplants
Panel Reactive Antibody (PRA)
Screen
• Estimates the rejection risk and determines wait time on list
• For waitlisted patients, evaluated every three to six months
• Measures the amount of pre-formed HLA Ab in potential recipient vs.

random pool of HLA from general population
• Patients with high PRA (>30%) are often referred to as “sensitized”

Crossmatch (XM) Test
• Donor-specific HLA Ab test; two types
• Standard XM is qualitative
• Flow XM is quantitative – measures degree of Ab activity but not
specific for which Ab present
• Done before every transplant by mixing the lymphocytes of the

recipient with the blood of the identified donor
• Positive XM means patient has preformed HLA Ab against identified

donor  poor outcomes expected
• Deceased donor transplant is canceled a n d organ moves to the
next person on the list
• Due to severe organ shortage, may be overcome in case of living
kidney donor
Rejection Timing
Principles of
Immunosuppression
Strategies of Immunosuppression
• Desensitization
• Induction
• Maintenance
• Rejection
Basics
• Unifying goal of all IMS therapies is to block T cell
activation and prefoliation
• Prevent cellular rejection
• Prevent humoral rejection
• Improve graft survival
• Improve patient survival
• Maintain good quality of life
Basics
• Immunosuppression is achieved by:
• Depletion of lymphocytes
• Diversion of lymphocyte traffic
• Blocking of lymphocyte proliferation and response
• Combination of mechanisms yields best outcomes
• Induction + maintenance
• 3 maintenance drugs
Seeking The Perfect Balance
Strategies For
Immunosuppression:
Desensitization
Desensitization
• Goal: To allow highly sensitized patients to be transplanted by
reducing preformed Ab to acceptable level
• Patients with high PRA on the deceased donor waiting list
• ABO incompatible living donor kidney transplants
• Positive crossmatch living donor kidney transplants
• Mechanisms:
• Removal of Ab producing cells (mechanical or pharmacologic)
• Physical removal of pre-formed antibodies
• Neutralizing complement activity
Desensitization
•Classic Therapies
• Plasmapheresis (PP)
• Intravenous immunoglobulin (IVIG)
• Splenectomy
• Rituximab (Rituxan®)
•Novel Agents
• Bortezomib (Velcade®)
• Eculizumab (Soliris®)
Plasmapheresis
• Mechanical removal of antibodies 3-6 times per week
• KEY: ALL antibodies are removed with the plasma
• PROBLEM: other protein and clotting factors are also

removed
Plasmapheresis
IVIG: Pharmacology
• Generally used AFTER plasmapheresis
• IVIG is derived from plasma of random donors, several different

formulations (some contain maltose)
• MOA: complex but has 2 main functions

• Immune modulation
• Down-regulates antibody production (negative feedback)
• Immune replacement
• Replaces essential antibodies removed with PP
• Adverse reactions
• Infusion-related reactions (flushing, fevers, chills, arthralgia,
dyspnea)
• Maltose in some IVIG products can cause hyponatremia and can
interfere with BG readings (false high)
Rituximab: Pharmacology
• Chimeric monoclonal antibody against CD20 on surface of B cell
• MOA: Binds to CD20 on B cells  apoptosis B cell depleting agent
• Dose: 375 mg/m2 IVPB x one time only pre-operatively
• Infusion reactions:
• Hypotension, bronchospasm, mucocutaneous reactions
• Mandatory premedication with acetaminophen and diphenhydramine
• Reaction management:
• Stop infusion, restart at 50% previous rate
• If respiratory sxs persist despite stopping, hydrocortisone 100 mg IVP, epinephrine
SC
Bortezomib: Pharmacology
• Proteasome Inhibitor used for Multiple Myeloma/Mantle Cell
Lymphoma
• MOA: Inhibits 26S proteasome complex involved in protein processing
within metabolically active cells
• Plasma cells – high metabolic activity due to massive Ab production
(2k/sec)
• Proteasome inhibition  accumulation of mis-folded, damaged
protein apoptosis
• ADR
• Peripheral neuropathy in 30%, neutropenia, thrombocytopenia
Eculizumab: Pharmacology
• Humanized monoclonal Ab specific for complement factor C5
• MOA: Inhibits formation of MAC, the terminal step in complement
cascade
• ADR
• Headache, back pain, URI symptoms, nausea
•Meningococcus prevention
• Meningococcal vaccines at least 2 weeks prior to administering the
first dose
• Penicillin V 500 mg oral twice daily while on ecu and for 4 weeks
after DC eculizumab
Splenectomy
• Spleen function:
• Stores long lasting, memory B-cells
• Opsonizes encapsulated organisms
• Recycles RBCs
• Stores Plt
•Vaccination against encapsulated organisms

• Pneumococcal
• Meningococcal
• Haemophilus influenza B
Desensitization Protocol
• Plasmapheresis + IVIG
• Minimum 4 sessions pre-transplant
• Continue post-transplant
• Repeat Ab titers and transplant when reduced
• Splenectomy at time of transplant

• ABO incompatible only
• Salvage – Bortezomib/Rituximab
• Salvage – Eculizumab
Thank you!

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Solid Organ

Chronic obstructive pulmonary disease, Idiopathic pulmonary fibrosis, Cystic

Hepatitis B and C, Alcohol/Drug toxicity, Hepatocellular carcinoma, Fatty liver

Diabetes, Hypertension, Lupus, Polycystic kidney disease, Infections, Drug

Crohn’s, Trauma, Thrombosis, Tumors

Image source: http://www.webmd.com/lung/lung-transplant

• In 2014, 29533 transplants were performed

• Patients wait months to many years to receive life-sustaining

• Adaptive immune system activation results in rejection

• T cell activation/proliferation requires three distinct signals

Halloran PF. New England Journal of Medicine.351.26 (2004): 2715-2729.

• Activated CD4+ Th produces cytokines that will attract,

• Activated CD8+ Tc cells directly damage antigen source

• Activated B cells differentiate into Ab producing plasma

• For waitlisted patients, evaluated every three to six months

• Measures the amount of pre-formed HLA Ab in potential recipient vs.

• Patients with high PRA (>30%) are often referred to as “sensitized”

• Done before every transplant by mixing the lymphocytes of the

• Positive XM means patient has preformed HLA Ab against identified

• KEY: ALL antibodies are removed with the plasma

• PROBLEM: other protein and clotting factors are also

• IVIG is derived from plasma of random donors, several different

• MOA: complex but has 2 main functions

•Vaccination against encapsulated organisms

• Splenectomy at time of transplant

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