solid organ transplant

Question 1

pre-transplant immunologic evaluation and management - ABO and MHC

Answer 1

ABO blood group determination
major histocompatibility complex (MHC)
-an association of genes that play an important role in immune recognition and response
-referred to as HLA complex - antigen presenting structures for T cells, HLA Class I and II molecules
-HLA typing - HLA compatibility is assessed by the number of HLA mismatches (or matches) of the donor

Question 2

pre-transplant immunologic evaluation and management - determination of PRA and cross-match

Answer 2

PRA (panel reactive antibodies):
-quantified as percentage of the panel to which the patient has developed antibody, varies from 0-100% and may change over time, higher PRA = increased sensitization to histocompatibility antigens
cross match:
-negative result must be obtained prior to transplant, testing the transplant recipient’s serum against donor T cells to determine if there is preformed anti-HLA class I antibody

Question 3

allograft rejection

Answer 3

immune response causing inflammation and direct tissue destruction - ultimately can lead to loss of graft function
acute cellular rejective - infiltration of the allograft by lymphocytes and other inflammatory cells
antibody mediated rejection (AMR) - morphologic evidence of acute tissue injury, circulating donor-specified antibodies, immunological evidence of an antibody-mediated process
cellular and antibody-mediated processes may coexist

Question 4

rejection pathophysiology

Answer 4

hyperacute rejection: occus within minutes to hours after transplant, mediated by preformed circulating antibodies
acute rejection: occurs within days to months after transplant, mediated by host T-lymphocytes
chronic rejection: occurs over months to years after transplant, both cell-mediated and humoral processes appear to be involved, progressive decline in organ function

Question 5

three signal model of alloimmune responses

Answer 5

alloimmune response involved both naive and memory lymphocytes
signal 1: antigen on the surface of dendritic cells interacts with T-cell receptors through the CD3 complex
signal 2: co-stimulation when CD 80/86 on the surface of dendritic cells interacts with CD 28 on T cells
Signal 3: only after both signal 1 and 2 occur - the “target of rapamycin” pathyway is activated resulting in cell proliferation - also requires nucleotide synthesis

Question 6

induction therapy definition

Answer 6

intense prophylactic therapy at the time of transplantation

Question 7

maintenance therapy definition

Answer 7

chronic immunosuppression; less potent than induction

Question 8

rescue therapy definition

Answer 8

intense therapy utilized in response to a rejection episode

Question 9

classes of induction immunosuppressive agents

Answer 9

polyclonal antibodies - rabbit antithymocyte globulin (thymoglobulin); horse antithymocyte globulin (ATGAM)
monoclonal antibodies - alemtuzumab
IL-2a receptor antagonists - basiliximab

Question 10

antithymocyte globulin

Answer 10

indication: induction and/or rejection therapy
composed of polyclonal IgG against human T-lymphcytes derived from horses (ATGAM) or rabbits (thymoglobulin)
reduces the number of circulating T-lymphocytes and ultimately affects cell-mediated and humoral immunity
dosing considerations:
-1-1.5 mg/kg/day (thymoglobulin)
-10-15 mg/kg/day (ATGAM)
-duration depends on indication and patient tolerance
adverse effects: leukopenia and thrombocytopenia (dose limiting), fever and chills (premedicate), pruritis, erythma, rash, tachycardia, hypotension, serum sickness (rare)
monitoring: WBC, ALC, platelets, BP, HR, temp

Question 11

alemtuzumab

Answer 11

indication: off-label use in SOT as induction therapy and refractory rejection therapy
humanized anti-CD52 monoclonal antibody - CD52 cell surface glycoprotein located on T and B lymphocytes, NK cells and less densely on monocytes and macrophages
antibody-dependent cellular cytotoxicity - profound depletion of T cells and to a lesser degree B cells and monocytes
dosing: 30 mg IV/SQ x 1 dose or 20 mg x 2 doses
adverse effects: neutropenia, thrombocytopenia, pancytopenia, fatigue, HA, dizziness, insomnia, hypotension, supraventricular tachycardia, rash, urticaria, pruritis, infusion related (premedicate): chills, rigors, fever
monitor: WBC, platelets, ALC, BP, HR

Question 12

basiliximab

Answer 12

indication: induction therapy
recombinant, chimeric (murine/human) monoclonal antibodies (IgG1) against CD25
bind to the a subunit of the IL-2R - comp inhibits IL-2-mediated activation of lymphocytes
dosing: 20 mg IVPB intra-op and POD 4
well tolerated; minimal adverse effects

Question 13

choosing an induction agents

Answer 13

lymphocyte depleting therapy is more commonly used: thymoglobulin, alemtuzumab; especially for patients with high immunologic risk
basiliximab is reserved for some patient specific factors - history of malignancy, high infection risk, immunocompromised, advanced age

Question 14

classes of maintenance immunosuppressive agents

Answer 14

calcineurin inhibitors: cyclosporin, tacrolimus
m-TOR inhibitors: sirolimus, everolimus
antimetabolite: azathioprine, mycophenolate mofetil, mycophenolate sodium
corticosteroids: methylprednisolone, prednisone, dexamethasone
selective T-cell costimulation blocker: belatacept

Question 15

calcineurin inhibitors

Answer 15

cornerstone of immunosuppression: improves transplant survival, reducing hospitalization and reducing patient morbidity
cyclosporine, tacrolimus
induces immunosuppression by inhibiting the first phase of T-cell activation - blocks the synthesis of proinflammatory cytokines, inhibition of calcineurin phosphatase and subsequent T-cell activation

Question 16

cyclosporine

Answer 16

oral and IV
nonmodified - poor and erratic bioavailability
microemulsion formulation - improved bioavailability
metabolism: 3A4 and P-glycoprotein; inhibitors of both 3A4 and p-glycoprotein increase cyclosporine bioavailability
elimination half-life is highly variable (10-40 hours) - prolonged in hepatic disease or disorders of biliary excretion
intersubject variability of cyclosporine exposure (AUC) ranges from 20-50%
modified formulation has increased AUC and Cmax compared to non-modified
dosing: 5-10 mg/kg/day (given BID)
IV conversion is 3:1 (90 mg PO = 30 mg IV) ** - infused q12h
12 hour trough ranges ~100-400 mcg/ml
adverse effects*: HTN, hypercholesteolemia and hypertriglyceridemi, gingival hyperplasia, hirsutism

Question 17

tacrolimus

Answer 17

oral or parenteral
metabolism mainly via the hepatic P450 3A family - inhibitors may increase
t1/2 = 12-18 h
PO dosing: 0.1-0.15 mg/kg/day (divided BID)
conversion to IV ~5:1 - infused over 24 hours
goal 12 hour trough ranges ~5-15 mcg/ml
once-daily ER formulation - approved for KIDNEY*** transplant rejection
t1/2 ~30-40 hours
dose: 0.15 mg/kg PO QD (on an empty stomach) in the morning
Astagraf: not interchangeable with IR; Envarsus: approved for conversion from IR
AE: neurotox (HA, insomnia, tremor, dizziness), hyperglycemia, diabetes

Question 18

calcineurin inhibitors drug interactions

Answer 18

P450 inducers - decrease cyclo/tacro levels
-phenytoin, carbamazepine, phenobarbital, rifampin
P450 inhibitors - increase cyclo/tacro levels
-erythromycin, clarithyromycin, azole AFs, diltiaze,, verapamil, ritonavir, grapefruit juice

Question 19

mTOR inhibitor

Answer 19

sirolimus is an analog of tacrolimus
everolimus is an analog of sirolimus
MOA: inhibits the second phase of T-cell activation and ultimately T-cell proliferation; no end organ toxicites
acts synergistically w other immunosuppressants - cyclo/tacro or CSs

Question 20

sirolimus

Answer 20

KIDNEY** transplant - not liver
PO as tablet or soln - difference in bioavailability
3A4 and P-glycoprotein - same DIs as calcineurin inhibitors
dose initiated at 2 mg daily; target trough ~6-12 mcg/ml
AEs: edema, hyperlipidema, hypertriglyceridemia, mouth ulcers, hypertension, abnormal/impaird wound healing, anemia, hepatic artery thrombosis, interstitial pneumonitis

Question 21

everolimus

Answer 21

approved for kidney and liver transplant rejection prophylaxis
MOA: binds to FK506 binding protein and the complex binds to and inhibits mTOR; inhibits antigenic and interleukin (IL-2 and IL-15) stimulated activation and proliferation or T and B lymphocytes
PO - availability decreases with food
metabolized by 3A4 and p-glycoprotein - drug interactions
starting dose is 0.75-1 mg PO BID - monitor levels q4-5 days upon initiation; goal trough level is 3-8 mcg/ml
AEs: angioedema, hyperlipid, hypertriglycerid, impaired wound healing, mouth ulcers, arthralgia, diarrhea, non-infectious pneumonitis, kidney arterial and venous thrombosis, derm reactions

Question 22

mTOR inihibitors role in therapy

Answer 22

adjunct agents with various roles
replace calcineurin inhibitors in patients with CI toxicity (nephro)
in combination with CI’s to use lower levels of both
replace mycophenolic acid in patients with intolerable AEs
newer protocols use in place of CI’s
steroid free protocols

Question 23

azathioprine

Answer 23

MOA: purine analog, converted to 6-mercaptopurine, metabolite is incorporated into nucleic acids, leading to inhibition of RNA and DNA synthesis, thus inhibiting immune cell proliferation
dose: 1-3 mg/kg/day; no routine level monitoring
AEs: leukopenia, thrombocytopenia, macrolytic anemia, nausea, vom, abd pain, alopecia, pancreatitis, hepatotoxicity, malignancy, infection; lack of specificity and potential for inhibiting replication in other highly proliferative tissues such as bone marrow and gut
DIs: allopurinol (reduce AZA to 1/4 of original dose)

Question 24

mycophenolic acid

Answer 24

most commonly used adjunct agent; usually used in combo w tacrolimus or cyclosporine
MOA: inhibits the de novo pathway of purine synthesis (selective for lymphocytes; limit progression of activated T and B cells
metabolism: immediately hydrolyzed to form free MPA, the active compound; most of the free MPA is conjugated in the liver by glucuronyl transferase
mofetil: immediate release; typical dose 500-1000 mg PO BID; PO or IV (1:1 conversion)
sodium: EC, DR; typical dose 360-720 mg PO* BID
therapeutically equivalent and interchangable; MMF 250 = sodium 180
t1/2 ~ 13-18 hours
routine monitoring is not recommended
drug interaction: aluminum/magnesium antacids, cholestyramine, myelosuppressive drugs including ganciclovir, valganciclovir, sirolimus
AEs: GI event esp abd pain, anorexia, constipation, diarrhea, dyspepsia, NV; hematologic and lymphatic AEs (agranulocytosis, leukopenia, neutropenia, pancytopenia, polycythemia and thrombocytopenia); preg category D

Question 25

coricosteroids

Answer 25

used for immunosuppression in transplant patients since the 60s, the original cornerstone, tapered after transplant, some transplant centers utilize corticosteroid withdrawal or corticosteroid-free regimens
MOA: inhibits cytokine production by T cells and macrophages, blocks transcription of cytokine genes including IL 1, 2, 3, 5, TNF-a and INFg
interferes with cell migration, recognition and cytotoxic effector mechanisms
comparison:
-hydrocortisone 20 mg, relative activity: 1, 8-12 hours
-prednisone 5 mg, relative activity: 4, 12-36 hours
-methylprednisolone 4 mg, relative activity: 5, 12-36 hours
-dexamethasone 0.75 mg, relative activity: 30, 36-72 hours
adverse effects related to both average dose and cumulative duration of use
may affect many organ systems
range of severity
symptoms may or may not be present
AEs: lots; some acute, some long-term
withdrawal:
-acute adrenal insufficiency syndrome: most severe complication of steroid withdrawal, results from overly rapid withdrawal after prolonged therapy (over 2-3 weeks) has suppressed the HPA axis, may be lethal
-variation among patients regarding the degree and duration
-recovery may take weeks to months
-tapering often necessary

Question 26

belatacept

Answer 26

selective T-cell costimulation blocker
-blocks the CD 28 mediated costimulation of T lymphocytes by binding to CD80 and CD86 on APCs
-inhibits T lymphocyte proliferation and the production of the cytokines IL2, INFg, IL4, and TNFa
inhibition of cytokine production by T cells required for antigen-specific antibody production by B cells leads to reduced antibody concentrations
similar efficacy in kidney transplant recipients compared to cyclosporine - cyclo group experienced more chronic allograft nephropathy at one year, belatacept group experienced more frequent and more severe acute cellular rejection, GFR higher in belatacept group up to 5 years post transplant
contraindicated for use in liver transplant*** - increased graft loss and death
adverse reactions: post-transplant lymphoproliferative disorder (PTLD) (predominantly involves the CNS, 9-fold higher rate in those EBV seronegative or unknown, CI in EBV seronegative patients), anemia, GI complications

Question 27

classes of antibody elimination and neutralization

Answer 27

monocloncal antibodies: rituximab

neutralizing antibodies: intravenous immune globulin (IVIG)

Question 28

rituximab

Answer 28

indication: off-label use in SOT
anti-CD20 chimeric (murine/human) mAb
dosing: 375 mg/m2 IVPB (typically weekly)
AEs: first dose “infusion reaction complex”; within 24 hours of infusion, hypoxia, ARDS, vfib, cardiogenic shock, infusion should be STOPPED
premedication: acetaminophen, diphenhydramine, methylprednisolone
monitoring: BP and HR q 15 minutes x 1 hours then q 30 minutes x 2 hours then every 2 hours

Question 29

IVIG

Answer 29

indication: desensitization protocols in SOT, treatment of antibody-mediated rejection
derived from the pooled human plasma of thousands of donors
dose: depends on indication, number of infusions and concomitant therapy; 100-2000 mg/gk as cont IV infusion
AEs: infusion related (fever, chill and flushing, premedicate), HA, myalgia, back pain, hypotension, acute renal failure, renal dysfunction, hemolysis, hemolytic anemia
monitoring: vital signs prior to infusion, before an increase in rate of infusion, mid infusion, immediately post infusion

Question 30

triple drug regimen

Answer 30

most common
calcineurin inhibitor: tacro* or cyclo
antiproliferative agent: mycophenolic acid* product or AZA
CS: typically pred

Question 31

calcineurin inhibitor avoidance/minimization

Answer 31

sirolimus + mycophenolic acid or AZA + CS
everolimus + low dose tacro or cycle + CS
belatacept + mycophenolic acid + CS
improved renal fxn
increased incidence of acute rejection

Question 32

CS withdrawal or avoidance

Answer 32

goal to decrease long-term associated toxicity

CV risk, HTN, hyperlip, glucose intolerance, weight gain, growth retardation, bone loss

Question 33

cellular rejection therapy

Answer 33

first line for mild-moderate rejection: high dose CS - methylpred 250-2000 mg IV x 3-5 days
mod-severe rejection or steroid-resistant rejection: T-lymphocyte depleting therapy (thymoglobulin or alemtuzumab)

Question 34

antibody mediated rejection

Answer 34

steroids + rituximab + IVIG + bortezomib
bortezomib is not commonly used
plasmapharesis is often performed in conjunction with medications therapy