Immunosuppression

Question 1

The first step in the alloimmune response involves the recognition of transplant antigens (alloantigens) by recipient T cells.

Answer 1

T-cell activation requires three signals

Signal 1 is initiated by the binding of the alloantigen on the surface of antigen-presenting cell (APC) to the T-cell receptor (TCR)–CD3 complex.

Question 2

These dual signals (ie, signals 1 and 2) activate the intracellular pathways that trigger T cells to activate interleukin-2 (IL-2) and other growth-promoting. cytokines.

Answer 2

If a TCR is triggered without the accompanying costimulatory signal 2, then the T cell is driven into an anergic state in which it is both inactivated and refractory to later activation even in the presence of all necessary activation elements.

Question 3

Signal 3, engagement of IL-2 to its receptor activates the mammalian target of rapamycin (mTOR) pathway to provide signal 3, which leads to cell proliferation.

Answer 3

Lymphocyte proliferation requires the synthesis of purine and pyrimidine nucleotides.

Question 4

T cells also express cytotoxic T-lymphocyte antigen-4 (CTLA-4), a cell surface molecule that is homologous to CD28.

Answer 4

The binding of B7 to CTLA-4 produces an inhibitory signal that inhibits T-cell proliferation and terminates the immune response.

Question 5

Calcineurin is a phosphatase that dephosphorylates and facilitates the translocation of nuclear factor of activated T cells (NFAT) (and other nuclear factors) to the nucleus.

Answer 5

Inhibition of calcineurin impairs the expression of IL-2 (and other growth-promoting cytokines) thereby reducing the proliferation of T cells.

Question 6

Agents targeting both signals 1 and 2

Answer 6

Cyclosporine and tacrolimus are termed calcineurin inhibitors (CNIs) due to their common mechanism of action.

Question 7

Agents targeting both signals 1 and 2

Answer 7

Calcineurin is a phosphatase that dephosphorylates and facilitates the translocation of the nuclear factor of activated T cells (NFAT) (and other nuclear factors) to the nucleus. Once translocated into the nucleus, NFAT promotes the translation of specific genes, including that of the growth promoting cytokine IL-2. Inhibition of calcineurin impairs the expression of IL-2 (and other growth-promoting cytokines), thereby reducing the proliferation of T cells.

Question 8

Agents targeting both signals 1 and 2

Answer 8

Inhibition of calcineurin impairs the expression of IL-2 (and other growth-promoting cytokines), thereby reducing the proliferation of T cells.

Question 9

Agents targeting signal 2

Answer 9

Belatacept (Nulojix) is a humanized fusion protein, composed of CTLA-4 fused with the Fc domain of human immunoglobulin G1 (CTLA-4Ig). Belatacept binds to B7 with high affinity and inhibits the costimulatory pathway.

Question 10

Agents targeting signal 3

Answer 10

Basiliximab is a humanized monoclonal antibody that targets against the α chain of the IL-2 receptor (also known as anti–interleukin-2 receptor [anti–IL-2R] or anti-CD25 antibody), blocking IL-2–mediated responses.

Question 11

Agents targeting signal 3

Answer 11

mTOR inhibitors: sirolimus and everolimus

Question 12

Agents targeting signal 3

Answer 12

The mTOR is a key regulatory kinase in the cell division process. Its inhibition reduces cytokine-dependent cellular proliferation at the G1 to S phase of the cell division cycle.

Question 13

Lymphocyte-depleting agents

Answer 13

Thymoglobulin is a polyclonal antibody preparation made by immunization of rabbits with human lymphoid tissue. The purified immunosuppressive product contains cytotoxic antibodies directed against a variety of T-cell markers.

Question 14

Lymphocyte-depleting agents

Answer 14

Thymoglobulin causes lymphocyte depletion through various mechanisms, including (1) complement-mediated lysis of lymphocytes, (2) lymphocyte uptake by the reticuloendothelial system, and (3) masking lymphocyte cell surface receptors.

Question 15

Lymphocyte-depleting agents

Answer 15

Thymoglobulin use can result in prolonged lymphopenia, and the CD4+ helper T-lymphocyte subsets may be suppressed for several years. Such prolonged immunosuppressive effect may prevent rejection recurrence.

Question 16

Lymphocyte-depleting agents

Answer 16

Thymoglobulin can also cause rapid expansion of the subset of T cells that express CD4+CD25+ and FOXP3+ also known as regulatory T cells (Tregs). Tregs are different from helper T cells in that their presence may limit antigraft immunity. High levels of Tregs increase the chance of reversal of acute rejection.

Question 17

Lymphocyte-depleting agents

Answer 17

Alemtuzumab is a humanized monoclonal antibody targeting against CD52 on the surface of both B and T lymphocytes leading to a rapid and profound depletion of peripheral and central lymphoid cells.

Question 18

Antimetabolites

Answer 18

Mycophenolic acid (MPA) derivatives (mycophenolate mofetil [MMF], mycophenolate sodium) MMF (CellCept) is a prodrug that must be hydrolyzed to the active agent—MPA— in the gastric acidic milieu.

Question 19

Antimetabolites

Answer 19

MPA is a reversible inhibitor of the enzyme inosine monophosphate dehydrogenase (a rate-limiting enzyme in the de novo synthesis of purines). Depletion of guanosine nucleotides by MPA has a relatively selective antiproliferative effect on lymphocytes due to their reliance on the de novo pathway of nucleotide synthesis.

Question 20

Antimetabolites

Answer 20

Mycophenolate sodium (Myfortic) is an enteric-coated formulation of MPA that dissolves at pH >5.5. Therefore, unlike MMF, mycophenolate sodium bypasses the acidic milieu of the stomach and is absorbed in the intestines.

Question 21

Antimetabolites

Answer 21

The use of antacids or proton pump inhibitors (PPIs) can reduce the dissolution of MMF by increasing gastric pH. In contrast, the bioavailability of mycophenolate sodium is not affected by antacids or PPIs.

Question 22

Azathioprine (AZA)

Answer 22

AZA is a precursor of 6-mercaptopurine. AZA inhibits DNA replication and subsequent T-cell proliferation. MMF/mycophenolate sodium has largely replaced AZA due to its greater efficacy in reducing acute rejection.

Question 23

Corticosteroid

Answer 23

Key component of all immunosuppressive regimens Modulates inflammatory mediators Blocks interleukin-1 (IL-1) and IL-2 production, thereby suppressing the early phase of the immune response

Question 24

A standard immunosuppressive protocol consists of induction and maintenance immunosuppression

Answer 24

All kidney transplant recipients also receive prophylactic therapy with an antibiotic, antiviral and antifungal agent, and a nondihydropyridine calcium channel blocker to boost CNI or mTOR inhibitor levels.

Question 25

Induction therapy

Answer 25

Lymphocyte-depleting or non–lymphocyte- depleting agent

Question 26

Standard triple-maintenance immunosuppression 1. Calcineurin inhibitor 2. Adjunctive agent 3. Corticosteroids

Answer 26

1. Cyclosporine or tacrolimus 2. Mycophenolic acid derivatives, sirolimus (or everolimus), or azathioprine. 3. Maintenance dose: prednisone 5 mg daily

Question 27

Supplementary agents

Answer 27

Nondihydropyridine calcium channel blockers

Question 28

Infection prophylaxis

Answer 28

PJP (trimethoprim and sulfamethoxazole, dapsone, atovaquone), CMV (acyclovir, valganciclovir), antifungals (nystatin, fluconazole)

Question 29

Induction therapy

Answer 29

Induction therapy can be classified into lymphocyte-depleting and non–lymphocyte-depleting agents. The choice of one induction agent over the other is generally based on each individual immunologic risk factors or anticipated delayed graft function (DGF) or both

Question 30

Induction therapy

Answer 30

In the presence of anticipated DGF due to donor acute tubular necrosis (ATN), it is important to maintain adequate immunosuppression.

Question 31

Induction therapy

Answer 31

It has been suggested that endothelial injury upregulates and exposes donor histocompatibility antigens, adhesion molecules, and costimulatory molecules, heightening the risk for acute rejection.

Question 32

Induction therapy

Answer 32

Induction therapy with lymphocyte-depleting agent and delayed introduction of CNI may avoid the additive injury associated with CNI nephrotoxicity (due to afferent arteriolar vasoconstriction) while reducing the risk of allograft rejection at the time of heightened immunogenicity.

Question 33

Lymphocyte-depleting agents: Thymoglobulin Alemtuzumab

Answer 33

Non–lymphocyte-depleting agents: Basiliximab Daclizumab - No longer commercially available in the U.S.

Question 34

Lymphocyte-depleting agents: Thymoglobulin Alemtuzumab

Answer 34

Lymphocyte-depleting agents can cause first-dose reaction or cytokine release syndrome including chills, fever, arthralgia, and rarely serum sickness. Alemtuzumab is used at a small number of transplant centers in the United States.

Question 35

Thymoglobulin vs basiliximab induction

Answer 35

Thymoglobulin: commonly used in high immunologic risk patients (eg, highly sensitized or re-allograft transplant recipient, DSA positive) or anticipated delayed graft function to avoid early exposure to cyclosporine or tacrolimus (nephrotoxic)

Question 36

Thymoglobulin vs basiliximab induction

Answer 36

Basiliximab: commonly used in low to moderate immunologic risk transplant recipients

Question 37

Maintenance immunosuppression is used to sustain a therapeutic net state of immunosuppression in order to prevent rejection.

Answer 37

A standard maintenance immunosuppressive regimen consists of triple drug therapy: CNI (cyclosporine or tacrolimus) + adjunctive agent + corticosteroid.

Question 38

CNI: The choice of tacrolimus over Cyclosporine A (CSA) or vice versa is generally based on the potential adverse effects of these agents

Answer 38

Tacrolimus is the preferred agent for women and pediatric patients due to the cosmetic side effects of CSA such as hirsutism or hypertrichosis and gingival hyperplasia.

Question 39

Cyclosporine is less diabetogenic than tacrolimus, and it may be the preferred agent for patients at risk for posttransplantation diabetes mellitus (PTDM) such as those with a strong family history of diabetes or African American race, particularly those with concomitant hepatitis C infection.

Answer 39

Tacrolimus-treated patients with tremors or hair loss can be switched over to CSA.

Question 40

Side Effect Profiles of Cyclosporine and Tacrolimus

Answer 40

Both cause Nephrotoxicity CSA \> Tac

Question 41

Side Effect Profiles of Cyclosporine and Tacrolimus

Answer 41

Both cause Hypertension and sodium retention CSA \> Tac

Question 42

Side Effect Profiles of Cyclosporine and Tacrolimus

Answer 42

Both cause Hyperlipidemia CSA \> Tac

Question 43

Side Effect Profiles of Cyclosporine and Tacrolimus

Answer 43

Both cause Diabetes mellitus Tac \> CSA

Question 44

Side Effect Profiles of Cyclosporine and Tacrolimus

Answer 44

Both cause Neurotoxicity (headache, tremors, confusion, paresthesia) Tac \> CSA

Question 45

Side Effect Profiles of Cyclosporine and Tacrolimus

Answer 45

Both cause Thrombotic microangiopathy

Question 46

Side Effect Profiles of Cyclosporine and Tacrolimus

Answer 46

Both cause Gastrointestinal side effects (hepatotoxicity approximately 4% first month, dose related)

Question 47

Side Effect Profiles of Cyclosporine and Tacrolimus

Answer 47

Both cause Hyperkalemia

Question 48

Side Effect Profiles of Cyclosporine and Tacrolimus

Answer 48

Both cause Hypomagnesemia

Question 49

Side Effect Profiles of Cyclosporine and Tacrolimus

Answer 49

Both cause Hyperchloremic acidosis

Question 50

Side Effect Profiles of Cyclosporine and Tacrolimus

Answer 50

Both cause Hyperuricemia, gout CSA \> Tac

Question 51

Side Effect Profiles of Cyclosporine and Tacrolimus

Answer 51

Cyclosporine causes Hirsutism and Gingival hyperplasia

Question 52

Side Effect Profiles of Cyclosporine and Tacrolimus

Answer 52

Tacrolimus causes Pancreatitis and Alopecia

Question 53

Side Effect Profiles of Mycophenolate Mofetil and Mycophenolate Sodium Mycophenolate mofetil (MMF) CellCept

Answer 53

Diarrhea, nausea, vomiting, abdominal pain, flatulence, dyspepsia

Question 54

Side Effect Profiles of Mycophenolate Mofetil and Mycophenolate Sodium Mycophenolate mofetil (MMF) CellCept

Answer 54

Hematologic effects: leukopenia, leukocytosis (less commonly seen than leukopenia), anemia, thrombocytopenia

Question 55

Side Effect Profiles of Mycophenolate Mofetil and Mycophenolate Sodium Mycophenolate mofetil (MMF) CellCept

Answer 55

Comments: More than 2 g/d is usually not well tolerated.

Question 56

Side Effect Profiles of Mycophenolate Mofetil and Mycophenolate Sodium Mycophenolate sodium (enteric-coated MPA derivative formulation) Myfortic

Answer 56

Potentially less gastrointestinal toxicity compared with CellCept

Question 57

Side Effect Profiles of Mycophenolate Mofetil and Mycophenolate Sodium Mycophenolate sodium (enteric-coated MPA derivative formulation) Myfortic

Answer 57

Hematologic effects: leukopenia, leukocytosis (less commonly seen than leukopenia), anemia, thrombocytopenia

Question 58

Side Effect Profiles of Mycophenolate Mofetil and Mycophenolate Sodium Mycophenolate sodium (enteric-coated MPA derivative formulation) Myfortic

Answer 58

Comments: Myfortic 180 mg = CellCept 250 mg (similar efficacy)

Question 59

Adjunctive agent: The MPA derivative MMF (or the enteric-coated mycophenolic sodium salt formulation) is the most commonly used adjunctive agent.

Answer 59

AZA, sirolimus, or everolimus is generally used in place of MPA derivatives for special indications. AZA Safe in pregnancy (recommended dose 1 mg/kg). Unlike AZA, MPA derivatives must be discontinued in anticipation of pregnancy.

Question 60

Sirolimus or everolimus (mTOR inhibitors) Must be discontinued in anticipation of pregnancy.

Answer 60

Must be discontinued in anticipation of pregnancy. Potential beneficial effect in patients with history of malignancy, particularly skin cancer, renal cell carcinoma, or Kaposi sarcoma.

Question 61

Sirolimus or everolimus (mTOR inhibitors) Must be discontinued in anticipation of pregnancy.

Answer 61

Its use in posttransplant lymphoproliferative disorder (PTLD) has inconsistently been shown to be beneficial. Not recommended in the early postoperative period (may impair wound healing and delay recovery of ATN).

Question 62

Side Effect Profiles of Mammalian Target of Rapamycin Inhibitors (Sirolimus and Everolimus)

Answer 62

Delayed recovery of acute tubular necrosis Impaired wound healing Increased risk of lymphocele formation

Question 63

Side Effect Profiles of Mammalian Target of Rapamycin Inhibitors (Sirolimus and Everolimus)

Answer 63

May potentiate calcineurin inhibitor (CNI) nephrotoxicity Oral ulcers Diabetogenic

Question 64

Side Effect Profiles of Mammalian Target of Rapamycin Inhibitors (Sirolimus and Everolimus)

Answer 64

Proteinuria Dyslipidemia (↑ cholesterol, ↑↑ triglyceride) Peripheral edema

Question 65

Side Effect Profiles of Mammalian Target of Rapamycin Inhibitors (Sirolimus and Everolimus)

Answer 65

Pulmonary toxicity Thrombotic microangiopathy Others: acne, rash, anemia, thrombocytopenia, ↓ testosterone

Question 66

Side Effect Profiles of Mammalian Target of Rapamycin Inhibitors (Sirolimus and Everolimus)

Answer 66

Not recommended in the early postoperative period Not recommended in patients with preexisting proteinuria ≥500 mg/d (Practice may differ among centers.) (mTOR) inhibitors.

Question 67

Side Effect Profiles of Mammalian Target of Rapamycin Inhibitors (Sirolimus and Everolimus)

Answer 67

CNI target level should be lowered when used in combination with mammalian target of rapamycin

Question 68

Sirolimus or everolimus (mTOR inhibitors)

Answer 68

CNI to mTOR inhibitor switch should only be done after graft function is stable.

Question 69

Sirolimus or everolimus (mTOR inhibitors)

Answer 69

CNI to sirolimus: Concurrent administration is required due to the long half-life of sirolimus. Reduce CNI dose by 50% and initiate sirolimus at 2 mg/d. Loading doses may be used. Monitor dosing via therapeutic drug monitoring (TDM) with dosing adjustments made at 7- to 14-day intervals. CNI dosing can be discontinued when sirolimus troughs are \>60% of goal.

Question 70

Sirolimus or everolimus (mTOR inhibitors)

Answer 70

CNI to everolimus: concurrent administration not required due to shorter half-life of everolimus. The evening dose of CNI can be omitted and everolimus can be started the next morning. Typical starting dose is 0.75 mg twice daily.

Question 71

Sirolimus or everolimus (mTOR inhibitors)

Answer 71

If major surgery is planned, consider mTOR inhibitor to CNI switch 1 to 2 weeks prior to surgery. For emergent surgery, mTOR inhibitors can be discontinued in the immediate postoperative period and be replaced with CNI.

Question 72

Two-hour cyclosporine peak level must be drawn within 15 minutes of 2 hours post drug (also known as C2 level).

Answer 72

C2 level has been suggested to correlate better with drug exposure and clinical events than trough level.

Question 73

Steroid withdrawal (CNI + MPA derivatives dual therapy)

Answer 73

Safe in low immunologic risk patients at short-term follow-up (Long-term graft function and the risk of chronic rejection have not been thoroughly evaluated.)

Question 74

Belatacept in CNI-free protocol

Answer 74

May be considered in low-immunologic risk patients with biopsy-documented CNI toxicity or CNI-induced thrombotic microangiopathy and absence of acute rejection

Question 75

Belatacept in CNI-free protocol Typically used in combination with basiliximab induction, MPA derivatives, and corticosteroid: belatacept + MPA derivatives + corticosteroid

Answer 75

U.S. Food and Drug Administration (FDA) black box warning: Belatacept is contraindicated in Epstein-Barr virus (EBV)-naive kidney transplant recipients due to increased risk of PTLD predominantly involving the central nervous system.

Question 76

Belatacept in CNI-free protocol

Answer 76

Adverse effects: anemia, diarrhea, urinary tract infection, peripheral edema, constipation, hypertension, pyrexia, graft dysfunction, cough, nausea, vomiting, headache, hypo- and hyperkalemia, leukopenia, progressive multifocal leukoencephalopathy (PML)

Question 77

Side effect profiles

Answer 77

AZA: bone marrow suppression, gastrointestinal (GI) upset, skin rashes, hepatotoxicity.

Question 78

Drug-drug Interactions

Answer 78

AZA Avoid concurrent use of xanthine oxidase (XO) inhibitors because XO inhibitors inhibit the metabolism of AZA. Commonly used XO inhibitors that should be avoided with the use of AZA: allopurinol, febuxostat Additive bone marrow suppression when used with ganciclovir

Question 79

Drug-drug Interactions

Answer 79

MPA derivatives Antacids/cholestyramine decrease absorption. Acyclovir decreases excretion. CSA prevents enterohepatic recycling of MPA, which decreases the area under the concentration-time curve (AUC) of MPA.

Question 80

Nursing and dietary considerations Cyclosporine and tacrolimus

Answer 80

Can be used during pregnancy, but mothers should not breastfeed in the postpartum period. Take on an empty stomach

Question 81

Nursing and dietary considerations Cyclosporine and tacrolimus

Answer 81

Cyclosporine oral to IV conversion: IV dose is one-third of total oral daily dose. Administer in divided doses every 12 hours over 4 hours or as continuous infusion.

Question 82

Nursing and dietary considerations Cyclosporine and tacrolimus

Answer 82

Tacrolimus oral to IV conversion: IV dose is one-third of total oral daily dose. Administer only as a continuous infusion.

Question 83

Nursing and dietary considerations AZA

Answer 83

Can be used during pregnancy, but mothers should not breastfeed in the postpartum period.

Question 84

Nursing and dietary considerations MPA derivatives

Answer 84

Avoid pregnancy while taking MPA derivatives (increased risk of first trimester pregnancy loss and congenital malformation).

Question 85

Drug-Drug and Drug-Food Interactions Drugs that increase CNI level by inhibition of CYP3A or by competition for its pathways

Answer 85

Calcium channel blockers: diltiazem, verapamil \> nicardipine Changing the dose of these drugs is equivalent to changing CNI dosage. Brand vs generic names and immediate vs delayed-release formulations of diltiazem may have different effects on CNI levels. Nifedipine, amlodipine, isradipine, and felodipine have minimal effects on CNI drug levels.

Question 86

Drug-Drug and Drug-Food Interactions Drugs that increase CNI level by inhibition of CYP3A or by competition for its pathways

Answer 86

The “azole” antifungals: fluconazole, ketoconazole, itraconazole, voriconazole, posaconazole, isavuconazole The “azole” antifungals markedly increase CNI levels. Great care must be taken when starting and stopping these drugs. The absorption of ketoconazole and itraconazole requires acidic gastric contents. The use of proton pump inhibitors/H2 blockers may reduce CNI-absorption, hence blood levels.

Question 87

Drug-Drug and Drug-Food Interactions Drugs that increase CNI level by inhibition of CYP3A or by competition for its pathways

Answer 87

Antibiotics: erythromycin \> other macrolide antibiotics (clarithromycin, josamycin, ponsinomycin) Azithromycin (conflicting reports): A short course can generally be given without the need for CNI-level monitoring.

Question 88

Drug-Drug and Drug-Food Interactions Drugs that increase CNI level by inhibition of CYP3A or by competition for its pathways

Answer 88

Antiretroviral agents: essentially all currently available protease inhibitors (eg, ritonavir, ritonavir/lopinavir combination therapy aka Kaletra, darunavir, indinavir/ritonavir, saquinavir, atazanavir, amprenavir) Immunosuppressive management in HIV patients requires close collaboration with infectious disease specialist due to multiple drug-drug interactions.

Question 89

Drug-Drug and Drug-Food Interactions Drugs that decrease CNI level by induction of CYP3A activity

Answer 89

Antituberculous drugs: rifampin \> rifabutin Rifampin markedly reduces CNI levels, and its use should be avoided if possible. Pyrazinamide and ethambutol may reduce drug levels. Their use requires drug monitoring. Isoniazid (INH) can be used with careful drug level monitoring.

Question 90

Drug-Drug and Drug-Food Interactions Drugs that decrease CNI level by induction of CYP3A activity

Answer 90

Anticonvulsants: barbiturates \> phenytoin \> carbamazepine Oxcarbazepine (Trileptal) may decrease cyclosporine level. Gabapentin (Neurontin) and levetiracetam (Keppra) and other drugs in this category do not appear to have significant drug interactions.

Question 91

Drug-Drug and Drug-Food Interactions Drugs that decrease CNI level by induction of CYP3A activity

Answer 91

Corticosteroids Discontinuation of steroid therapy may result in an increase in tacrolimus level by up to 25%.

Question 92

Drug-Drug and Drug-Food Interactions Drugs that decrease CNI level by induction of CYP3A activity

Answer 92

Antidepressant herbal preparation: Hypericum perforatum (St. John’s wort)

Question 93

Drug-Drug and Drug-Food Interactions Drugs or food that increase the absorption of CNIs

Answer 93

Grapefruit, pomegranate, star fruit (also inhibits CYP3A) Metoclopramide The effect of grapefruit juice may vary widely among brands and is concentration, dose, and preparation dependent.

Question 94

Drug-Drug and Drug-Food Interactions Drugs or food that decrease the absorption of CNIs

Answer 94

GoLYTELY, sevelamer, olestra, cholestyramine

Question 95

Drug-Drug and Drug-Food Interactions Nephrotoxic drugs or drugs that may potentiate CNI toxicity

Answer 95

mTOR inhibitors, NSAIDs, tenofovir, amphotericin, aminoglycosides, ACE inhibitors, ARBs CNI target levels should be lowered when used in combination therapy with mTOR inhibitors. Amphotericin and aminoglycoside-associated nephrotoxicity may occur earlier than anticipated when used with CNI therapy.

Question 96

Drug-Drug and Drug-Food Interactions Cholesterol-lowering agents

Answer 96

Cyclosporine has an inhibitory effect on CYP3A and P-glycoprotein. The concomitant use of cyclosporine and statins can result in a several-fold increase in statin blood level and an increased risk for myopathy and rhabdomyolysis and acute kidney injury.

Question 97

Drug-Drug and Drug-Food Interactions Cholesterol-lowering agents

Answer 97

``` Rhabdomyolysis associated with tacrolimus and stain use is generally seen in patients on concomitant diltiazem therapy. Concomitant lovastatin (or simvastatin) and gemfibrozil therapy increases the risk of rhabdomyolysis and should be avoided. ```

Question 98

mTOR inhibitors (sirolimus or everolimus)

Answer 98

Avoid pregnancy while taking mTOR inhibitors (its use in pregnancy has been shown to be associated with increased fetal mortality, decreased fetal weights, and delayed ossification of skeletal structure).

Question 99

mTOR inhibitors (sirolimus or everolimus)

Answer 99

Use reliable contraception while on mTOR inhibitor therapy and for 3 months after discontinuation. May be taken with or without food, but take medication consistently with respect to meals (always take with food or always take on an empty stomach).

Question 100

Corticosteroid

Answer 100

Should be taken after meals or with food or milk May require increased dietary intake of pyridoxine, vitamin C, vitamin D, folate, calcium, and phosphorous May require decreased dietary intake of sodium.

Question 101

Other Immunosuppressive Agents Rituximab

Answer 101

Rituximab is a chimeric murine/human monoclonal IgG1 kappa antibody directed against the CD20 antigen on the surface of B cells. May induce naive and memory B-cell depletion. Plasma cells lack CD20 and are unaffected by rituximab.

Question 102

Other Immunosuppressive Agents Rituximab

Answer 102

Treats acute antibody-mediated rejection (ABMR) Used in the treatment of posttransplant lymphoproliferative disease (PTLD)

Question 103

Other Immunosuppressive Agents Rituximab

Answer 103

Adverse effects Fever, chills, rigors, hypotension, dizziness, myalgias, nausea/vomiting, pruritus, rash, infusion reaction, infection, asthenia, lymphopenia, angioedema

Question 104

Other Immunosuppressive Agents Bortezomib

Answer 104

Inhibits proteasomes—enzyme complexes which regulate protein homeostasis within the cells. Specifically, it reversibly inhibits chymotrypsin-like activity at the 26S proteasome, leading to activation of signaling cascades, cell-cycle arrest, and apoptosis.

Question 105

Other Immunosuppressive Agents Bortezomib

Answer 105

Reduces donor-specific antibody (DSA) production by plasma cells

Question 106

Other Immunosuppressive Agents Bortezomib

Answer 106

Clinical Use: Treatment of acute ABMR where intravenous immunoglobulin (IVIG) and/or rituximab therapy have failed.

Question 107

Other Immunosuppressive Agents Bortezomib

Answer 107

Adverse effects: Thrombocytopenia, neutropenia, anemia, peripheral neuropathy, fever, hypotension, nephrotoxicity, thrombotic microangiopathy.

Question 108

Eculizumab

Answer 108

Eculizumab is a humanized monoclonal antibody that targets the complement protein C5.

Question 109

Eculizumab

Answer 109

Inhibits terminal complement (binds to C5, preventing cleavage of C5 into C5a and C5b, and the formation of C5b and membrane attack complex C5b-9) .

Question 110

Eculizumab

Answer 110

Protects endothelium from injury caused by existing antibodies Clinical Use; Atypical Hemolytic Uremic Syndrome

Question 111

Eculizumab

Answer 111

Adverse effects: Increased risk of meningococcal infections Meningococcal vaccination: Both MenACWY vaccine and the full series of MenB vaccine should be administered at least 2 weeks prior to eculizumab, with a booster dose of MenACWY vaccine every 5 years, for the duration of eculizumab therapy.

Question 112

Eculizumab

Answer 112

Adverse effects: If vaccination is given \< 2 weeks prior to first dose, must start prophylactic antibiotic therapy (penicillin G \> ampicillin \> 3rd generation cephalosporin \> macrolide \> or fluoroquinolone, in order of preference) and continue for 2 weeks.

Question 113

IVIG

Answer 113

Pooled human gamma globulin preparations from thousands of blood donors Only sucrose-free preparations should be used to prevent osmotic nephrosis.

Question 114

IVIG

Answer 114

Potential mechanisms of action: Anti-idiotypic antibodies (inhibits anti-HLA antibody) Produces long-term suppression or elimination of anti–human leukocyte antigen (anti-HLA) reactive T and B cells Induces apoptosis of B cells Downregulates antibody production by plasma cell Inhibits complement-mediated damage Inhibits cytokine signaling pathway and alloimmunization via blockade of TCR Immune modulation

Question 115

IVIG

Answer 115

Clinical use To reduce high levels of preformed anti-HLA antibodies in sensitized patients. To facilitate living donor transplant in the face of a positive crossmatch or ABO incompatibility. Treatment of ABMR.

Question 116

Tocilizumab

Answer 116

IL-6 is a critical cytokine that mediates numerous inflammatory and immunomodulatory pathways, including regulation of T-cell differentiation and B-cell progression to antibody-producing plasma cells.

Question 117

Tocilizumab

Answer 117

Emerging data indicate that IL-6 plays a role in the mediation of cell-mediated rejection, ABMR, and chronic allograft vasculopathy.

Question 118

Tocilizumab

Answer 118

IL-6 neutralization delayed onset of acute cell-mediated rejection and prolonged graft survival.

Question 119

Tocilizumab

Answer 119

Tocilizumab is an IgG1 humanized monoclonal antibody specific for IL-6 receptor. It binds soluble as well as membrane-bound IL-6 receptors, hindering IL-6 from exerting its proinflammatory effects.

Question 120

Tocilizumab

Answer 120

Tocilizumab was developed to treat autoimmune diseases such as rheumatoid arthritis. Clinical studies evaluating the safety and efficacy of tocilizumab in desensitization protocols and ABMR