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Nephrology Boards: Transplantation > Immunosuppression > Flashcards

Immunosuppression Flashcards

1
Q

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

A

T-cell activation requires three signals

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2
Q

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.

A

Signal 2 is a non–antigen-specific costimulatory signal provided by the engagement of B7 on the surface of APC with CD28 on T cell.

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3
Q

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.

A

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.

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4
Q

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.

A

Lymphocyte proliferation requires the synthesis of purine and pyrimidine nucleotides.

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5
Q

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

A

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

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6
Q

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.

A

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

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7
Q

Agents targeting both signals 1 and 2

A

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

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8
Q

Agents targeting both signals 1 and 2

A

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.

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9
Q

Agents targeting both signals 1 and 2

A

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

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10
Q

Agents targeting signal 2

A

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.

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11
Q

Agents targeting signal 3

A

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.

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12
Q

Agents targeting signal 3

A

mTOR inhibitors: sirolimus and everolimus

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13
Q

Agents targeting signal 3

A

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.

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14
Q

Lymphocyte-depleting agents

A

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.

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15
Q

Lymphocyte-depleting agents

A

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.

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16
Q

Lymphocyte-depleting agents

A

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.

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17
Q

Lymphocyte-depleting agents

A

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.

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18
Q

Lymphocyte-depleting agents

A

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.

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19
Q

Antimetabolites

A

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.

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20
Q

Antimetabolites

A

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.

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21
Q

Antimetabolites

A

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.

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22
Q

Antimetabolites

A

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.

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23
Q

Azathioprine (AZA)

A

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.

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24
Q

Corticosteroid

A

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

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25
Q

A standard immunosuppressive protocol consists of induction and maintenance immunosuppression

A

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.

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26
Q

Induction therapy

A

Lymphocyte-depleting or non–lymphocyte- depleting agent

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27
Q

Standard triple-maintenance immunosuppression

  1. Calcineurin inhibitor
  2. Adjunctive agent
  3. Corticosteroids
A
  1. Cyclosporine or tacrolimus
  2. Mycophenolic acid derivatives, sirolimus (or everolimus), or azathioprine.
  3. Maintenance dose: prednisone 5 mg daily
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28
Q

Supplementary agents

A

Nondihydropyridine calcium channel blockers

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29
Q

Infection prophylaxis

A

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

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30
Q

Induction therapy

A

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

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31
Q

Induction therapy

A

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

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32
Q

Induction therapy

A

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

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33
Q

Induction therapy

A

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.

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34
Q

Lymphocyte-depleting agents:
Thymoglobulin
Alemtuzumab

A

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

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35
Q

Lymphocyte-depleting agents:
Thymoglobulin
Alemtuzumab

A

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.

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36
Q

Thymoglobulin vs basiliximab induction

A

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)

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37
Q

Thymoglobulin vs basiliximab induction

A

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

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38
Q

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

A

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

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39
Q

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

A

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.

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40
Q

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.

A

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

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41
Q

Side Effect Profiles of Cyclosporine and Tacrolimus

A

Both cause Nephrotoxicity

CSA > Tac

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42
Q

Side Effect Profiles of Cyclosporine and Tacrolimus

A

Both cause Hypertension and sodium retention

CSA > Tac

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43
Q

Side Effect Profiles of Cyclosporine and Tacrolimus

A

Both cause Hyperlipidemia

CSA > Tac

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44
Q

Side Effect Profiles of Cyclosporine and Tacrolimus

A

Both cause Diabetes mellitus

Tac > CSA

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45
Q

Side Effect Profiles of Cyclosporine and Tacrolimus

A

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

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46
Q

Side Effect Profiles of Cyclosporine and Tacrolimus

A

Both cause Thrombotic microangiopathy

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47
Q

Side Effect Profiles of Cyclosporine and Tacrolimus

A

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

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48
Q

Side Effect Profiles of Cyclosporine and Tacrolimus

A

Both cause Hyperkalemia

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49
Q

Side Effect Profiles of Cyclosporine and Tacrolimus

A

Both cause Hypomagnesemia

50
Q

Side Effect Profiles of Cyclosporine and Tacrolimus

A

Both cause Hyperchloremic acidosis

51
Q

Side Effect Profiles of Cyclosporine and Tacrolimus

A

Both cause Hyperuricemia, gout

CSA > Tac

52
Q

Side Effect Profiles of Cyclosporine and Tacrolimus

A

Cyclosporine causes

Hirsutism and Gingival hyperplasia

53
Q

Side Effect Profiles of Cyclosporine and Tacrolimus

A

Tacrolimus causes

Pancreatitis and Alopecia

54
Q

Side Effect Profiles of Mycophenolate Mofetil and Mycophenolate Sodium

Mycophenolate mofetil (MMF) CellCept

A

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

55
Q

Side Effect Profiles of Mycophenolate Mofetil and Mycophenolate Sodium

Mycophenolate mofetil (MMF) CellCept

A

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

56
Q

Side Effect Profiles of Mycophenolate Mofetil and Mycophenolate Sodium

Mycophenolate mofetil (MMF) CellCept

A

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

57
Q

Side Effect Profiles of Mycophenolate Mofetil and Mycophenolate Sodium

Mycophenolate sodium (enteric-coated MPA derivative formulation) Myfortic

A

Potentially less gastrointestinal toxicity compared with CellCept

58
Q

Side Effect Profiles of Mycophenolate Mofetil and Mycophenolate Sodium

Mycophenolate sodium (enteric-coated MPA derivative formulation) Myfortic

A

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

59
Q

Side Effect Profiles of Mycophenolate Mofetil and Mycophenolate Sodium

Mycophenolate sodium (enteric-coated MPA derivative formulation) Myfortic

A

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

60
Q

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

A

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.

61
Q

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

A

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.

62
Q

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

A

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).

63
Q

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

A

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

64
Q

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

A

May potentiate calcineurin inhibitor (CNI) nephrotoxicity
Oral ulcers
Diabetogenic

65
Q

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

A

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

66
Q

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

A

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

67
Q

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

A

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

68
Q

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

A

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

69
Q

Sirolimus or everolimus (mTOR inhibitors)

A

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

70
Q

Sirolimus or everolimus (mTOR inhibitors)

A

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.

71
Q

Sirolimus or everolimus (mTOR inhibitors)

A

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.

72
Q

Sirolimus or everolimus (mTOR inhibitors)

A

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.

73
Q

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

A

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

74
Q

Steroid withdrawal (CNI + MPA derivatives dual therapy)

A

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.)

75
Q

Belatacept in CNI-free protocol

A

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

76
Q

Belatacept in CNI-free protocol

Typically used in combination with basiliximab induction, MPA derivatives, and corticosteroid: belatacept + MPA derivatives + corticosteroid

A

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.

77
Q

Belatacept in CNI-free protocol

A

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)

78
Q

Side effect profiles

A

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

79
Q

Drug-drug Interactions

A

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

80
Q

Drug-drug Interactions

A

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.

81
Q

Nursing and dietary considerations

Cyclosporine and tacrolimus

A

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

Take on an empty stomach

82
Q

Nursing and dietary considerations

Cyclosporine and tacrolimus

A

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.

83
Q

Nursing and dietary considerations

Cyclosporine and tacrolimus

A

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

84
Q

Nursing and dietary considerations

AZA

A

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

85
Q

Nursing and dietary considerations

MPA derivatives

A

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

86
Q

Drug-Drug and Drug-Food Interactions

Drugs that increase CNI level by inhibition of CYP3A or by competition for its pathways

A

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.

87
Q

Drug-Drug and Drug-Food Interactions

Drugs that increase CNI level by inhibition of CYP3A or by competition for its pathways

A

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.

88
Q

Drug-Drug and Drug-Food Interactions

Drugs that increase CNI level by inhibition of CYP3A or by competition for its pathways

A

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.

89
Q

Drug-Drug and Drug-Food Interactions

Drugs that increase CNI level by inhibition of CYP3A or by competition for its pathways

A

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.

90
Q

Drug-Drug and Drug-Food Interactions

Drugs that decrease CNI level by induction of CYP3A activity

A

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.

91
Q

Drug-Drug and Drug-Food Interactions

Drugs that decrease CNI level by induction of CYP3A activity

A

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.

92
Q

Drug-Drug and Drug-Food Interactions

Drugs that decrease CNI level by induction of CYP3A activity

A

Corticosteroids

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

93
Q

Drug-Drug and Drug-Food Interactions

Drugs that decrease CNI level by induction of CYP3A activity

A

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

94
Q

Drug-Drug and Drug-Food Interactions

Drugs or food that increase the absorption of CNIs

A

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.

95
Q

Drug-Drug and Drug-Food Interactions

Drugs or food that decrease the absorption of CNIs

A

GoLYTELY, sevelamer, olestra, cholestyramine

96
Q

Drug-Drug and Drug-Food Interactions

Nephrotoxic drugs or drugs that may potentiate CNI toxicity

A

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.

97
Q

Drug-Drug and Drug-Food Interactions

Cholesterol-lowering agents

A

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.

98
Q

Drug-Drug and Drug-Food Interactions

Cholesterol-lowering agents

A 
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.
99
Q

mTOR inhibitors (sirolimus or everolimus)

A

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).

100
Q

mTOR inhibitors (sirolimus or everolimus)

A

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).

101
Q

Corticosteroid

A

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.

102
Q

Other Immunosuppressive Agents

Rituximab

A

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.

103
Q

Other Immunosuppressive Agents

Rituximab

A

Treats acute antibody-mediated rejection (ABMR)

Used in the treatment of posttransplant lymphoproliferative disease (PTLD)

104
Q

Other Immunosuppressive Agents

Rituximab

A

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

105
Q

Other Immunosuppressive Agents

Bortezomib

A

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.

106
Q

Other Immunosuppressive Agents

Bortezomib

A

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

107
Q

Other Immunosuppressive Agents

Bortezomib

A

Clinical Use:

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

108
Q

Other Immunosuppressive Agents

Bortezomib

A

Adverse effects:

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

109
Q

Eculizumab

A

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

110
Q

Eculizumab

A

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) .

111
Q

Eculizumab

A

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

112
Q

Eculizumab

A

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.

113
Q

Eculizumab

A

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.

114
Q

IVIG

A

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

115
Q

IVIG

A

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

116
Q

IVIG

A

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.

117
Q

Tocilizumab

A

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.

118
Q

Tocilizumab

A

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

119
Q

Tocilizumab

A

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

120
Q

Tocilizumab

A

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.

121
Q

Tocilizumab

A

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

Nephrology Boards: Transplantation (1 decks)

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