Term
|
Definition
treatment of end-stage organ disease;
Improve survival & QOL;
More cost-effective (vs. dialysis) |
|
|
Term
|
Definition
| universal donor blood type |
|
|
Term
|
Definition
| universal recipient blood type |
|
|
Term
|
Definition
|
|
Term
|
Definition
most important HLA classes;
Outcomes improved when degree of HLA matching increases; |
|
|
Term
| Panel Reactive Antibodies (PRA) |
|
Definition
testing transplant recipient's serum against a reference panel of lymphocytes that express the population spectrum of HLA phenotypes;
The higher # = increased sensitization fo histocompatibility antigens --> MORE LIKELY to experience REJECTION |
|
|
Term
| Causes of High PRA (sensitization) |
|
Definition
pregnancy;
multiple blood transfusions;
prior transplantation;
ventricular assist devices |
|
|
Term
|
Definition
| MUST be obtained prior to transplantation; use flow cytometry |
|
|
Term
|
Definition
1) Antigen-presenting cells (dendritic cells) migrate through tissue to lymphoid organs (spleen & lymph nodes) to present donor Ag to T cells;
- Ag on surface of dendritic cells trigger T-cell receptors & synapse formation;
Signal transduced through: **CD3 Complex** |
|
|
Term
|
Definition
CD80 (B7-1O & CD86 (B7-2) on antigen-presenting cell engage CD28 on T cell;
Without 2nd signal, T cell becomes INACTIVE |
|
|
Term
|
Definition
Activate 3 signal transducation pathways:
1) **Calcium-calcineurin pathway**
2) RAS-mitogen-activated protein (MAP) kinase pathway
3) Nuclear factor-B pathway |
|
|
Term
| Signal 3 (Trigger for Cell Proliferation) |
|
Definition
| IL-2 & other cytokines including IL-15 ACTIVATE molecular-target-of-rapamycin (mTOR) pathway --> initiates cell cycle |
|
|
Term
|
Definition
occurs within min to hrs;
mediated by preformed circulating Abs against HLA Class I molecules, ABO blood group Ags, or endothelial Ags of arteries;
VERY RARE if cross match is NEGATIVE;
Results in graft loss |
|
|
Term
| Acute T-cell Mediated Rejection |
|
Definition
most common during 1st 3 months after transplant;
mediated by alloreactive lymphocytes;
leads to increased inflammation;
graded from mild to severe; |
|
|
Term
| Acute Antibody-Mediated Rejection |
|
Definition
rejection resulting from documented circulating anti-donor Abs;
may occur w/ T-cellmediated rejection; |
|
|
Term
|
Definition
occurs over months to years;
T-cell &/or Ab mediated;
Progressive decline of: renal fcn, HTN, & proteinuria;
MOST COMMON CAUSE of graft loss in the late post-transplant period |
|
|
Term
| Goals of Immunosuppressive Therapy |
|
Definition
Balance therapy in terms of graft & pt survival;
Individualize therapy;
Combination therapy:
- maximize immunosuppression
- minimize side effects
- higher doses of immunosuppressants used early post-transplant to prevent acute rejection
- doses tapered post-transplant to help minimize adverse effects |
|
|
Term
| Immunosuppressive Regimens |
|
Definition
1) Induction Therapy
2) Maintenance Therapy
3) Rescue Therapy |
|
|
Term
|
Definition
| antithymocyte globulin - ATGAM [equine] & Thymoglobulin [rabbit] |
|
|
Term
|
Definition
polyclonal Abs;
MoA: polyclonoal IgG against human T-lymphocytes, reduces # of circulating T-lymphocytes, eliminates pre-activated, non-cycling memory lymphocytes;
Indication: INDUCTION &/or REJECTION therapy;
ADRs:
- LEUKOPENIA, THROMBOCYTOPENIA (dose limiting) --> decrease dose by 50% if WBC is 2000-3000 &/or Plt 50,000-75,000;
D/C therapy if WBC <= 2,000 &/or Plt <= 50,000;
PREMEDICATION REQUIRED: diphenhydramine, APAP, +/- corticosteroid;
Monitor:
- Absolute lymphocyte count, CD3 count, CBC, LFTs, SCr; |
|
|
Term
|
Definition
| polyclonal antibody that REQUIRES a test dose to be given before administration: risk of anaphylaxis/hypersensitivity; |
|
|
Term
|
Definition
IL-2 receptor antagonists (daclizumab [Zenapex], basiliximab [Simulect]);
Muromonab-CD3 (OKT3);
Alemtuzumab (Campath-1H);
Rituximab (Rituxan);
IVIG - intravenous Immune Globulin |
|
|
Term
| daclizumab [Zenapax], basiliximab [Simulect] |
|
Definition
IL-2 receptor antagonists;
MoA: chimeric monoclonal Abs against CD25, binds to alpha-subunit of IL-2R (present only on activated & non-resting T cells);
D: saturates on IL-2R for ~90 days;
B: saturates on IL-2R for ~36 days;
ADRs: VERY WELL TOLERATED |
|
|
Term
|
Definition
MoA: murine monoclonal Ab binds to CD3 Ag of T cells causing inhibition of all T cell functions, leading to T cell depletion; inhibits Signal 1;
Indication: REJECTION therapy
Premedicate with: diphenhydramine + APAP +/- corticosteroid --> prevent cytokine release syndrome;
C/I: Pts w/ human-mouse Ab titers >= 1:1000 --> SHOULD NOT receive this med;
ADRs:
- CYTOKINE RELEASE SYNDROME: higher fever, chills, hypo- or HTN, angina, tachycardia, dyspnea, wheezing, N/V/D, HA, tremor;
Monitoring:
- Absolute CD3 count, Plasma drug levels (>=800 ng/mL by ELISA), CBC, baseline CXR (pulmonary edema), LFTs, SCr |
|
|
Term
|
Definition
MoA: humanized anti-CD53 monoclonal Ab, Ab-dependent cellular cytotoxicity --> profound depletion of T cells (mainly), some B cells & monocytes;
Indication: OFF-LABEL as INDUCTION & REFRACTORY REJECTION therapy;
Pre-med required: Diphenhydramine + APAP +/- corticosteroids;
ADRs:
- H: neutropneia, thrombocytopenia, pancytopenia; CNS: fatigue, HA, dizziness, insomnia; CV: hypotension, supraventricular tachycardia; R: dyspnea; Derm: rash, urticaria, pruritus; GI: N/V/D; ID: infection; Infusion: chills, rigors, fever;
Monitor:
- CBC w/ diff., Absolute Lymphocyte count |
|
|
Term
|
Definition
MoA: anti-CD20 chimeric monoclonal AB binds to CD20 Ag on B lymphocytes -> cell lysis due to complement-dependent cytotoxicity & Ab-dependent cellular cytotoxicity; causes rapid & sustained depletion of circulating & tissue-based B cells;
Indication: OFF-LABEL in DESENSITIZATION PROTOCOLS & in Tx of Ab-mediated Rejection;
Premedicate: diphenhydramine + APAP +/- corticosteroid;
ADRs:
- BBW: first dose "INFUSION REACTION COMPLEX": cytokine relase syndrome -> severe pulmonary & CV-related events w/in 24 hrs of infusion (hypoxia, pulmonary infiltrates, ARDS, MI, v.fib, cardiogenic shock);
- Other infusion-related rxns;
- lymphopenia, leukopenia, thrombocytopenia, anemia, supraventricular tachycardia, rash, pruritus, abd pain, N/V, diaphoresis;
Monitor:
- CBC w/ diff., EKG |
|
|
Term
| Intravenous Immune Globulin (IVIG) |
|
Definition
MoA: heterogenous human IgG w/ trace amounts of IgA & IgM derived form pooled human plasma; inhibits T-cell activation & induces B-cell apoptosis;
Indication: OFF-LABEL use in DESENSITIZATION PROTOCOLS;
ADRs:
- infusion-related side effects (fever, chills, flushing, HA, myalgia, hypotension);
- ARF, osmotic nephrosis;
- thromboembolism;
- N/V;
- hemolysis, hemolytic anemia;
Monitor:
- Pts predisposed to ARF should receive SUCROSE-FREE formula |
|
|
Term
|
Definition
| cyclosporine (Sandimmune, Neoral, Gengraf); tacrolimus (Prograf) |
|
|
Term
| cyclosporine (Sandimmune, Neoral, Gengraf) |
|
Definition
**Cornerstone of therapy**
MoA: inhibits 1st phase of T-cell activation -> reduced circulating levels of T-cell activators; binds to cyclophilin --> binds to & inhibits phosphatase activity of calcineurin -> prevents IL-2 gene trasncription -> inhibits T cell IL-2 production;
Modified formulations (N, G) are NOT bioequivalent to non-modified formulation (S);
Bioavailbility IMPROVED with MODIFIED formulation (N, G)--> microemulsion;
Metabolism: Substrate & Inhibitor of CYP3A4 & PGP;
IV:PO conversion rate: 1:3
TDM: 12-hr trough levels (C0) vs. 2-hr post-dose levels (C2) [200-400 ng/mL];
Avoid high fat meals;
Administer consistently w/ regard to meals & time;
ADRs:
- NEPHROTOXICITY
- NEUROTOXICITY (< than Tacrolimus);
- HTN (> than TAC)
- gingival hyperplasia
- hirsutism |
|
|
Term
|
Definition
**Cornerstone of therapy**
MoA: inhibits 1st phase of T-cell activation -> reduced circulating levels of T-cell activators; binds to immunophilin FK binding protein 12 --> binds to & inhibits phosphatase activity of calcineurin -> prevents IL-2 gene trasncription -> inhibits T cell IL-2 production;
Poor & Variable Oral Bioavailability (~17-22%);
Metabolized by CYP3A4; Substrate & Inhibitor of PGP;
IV:PO conversion Rate: 1:5;
TDM: 12 hr trough levels, early goal trough conc.: 8-12 ng/ml;
-easier for pts to tolerate, but poor bioavailability;
Avoid high fat meals;
ADRs:
- Nephrotoxicity
- Neurotoxicity (> than CYA)
- HTN (< than CYA)
- alopecia |
|
|
Term
|
Definition
| azathioprine (Imuran); mycophenolic acid - MPA (CellCept, Myfortic) |
|
|
Term
|
Definition
Antiproliferative agent
MoA: metabolized by 6-mercaptopurine, incorporated into nuceleic acids inhibiting DNA & RNA synthesis -> inhibiting lymphocyte proliferation;
-rarely used;
ADRs:
- leukopenia, thrombocytopneia, macrocytic anemia, N/V, abd pain, alopecia, pancreatitis, hepatotoxicity, malignancy, infection;
Drug Interactions:
- allopurinol: inhibits azathioprine metabolism, decrease dose to 1/4 of original dose;
- myelosuppressive drugs: ganciclovir, valganciclovir, sirolimus |
|
|
Term
| mycophenolic acid - MPA (CellCept, Myfortic) |
|
Definition
**Cornerstone of Therapy**
mofetil -> C: prodrug;
sodium -> M: delayed-release tab
**NOT INTERCHANGEABLE**
MoA: inhibits lymphocyte purine synthesis by reversible, noncompetitive inhibition of inosine monophosphate dehydrogenase (IMPDH) -> inhibits lymphocyte proliferation;
Highly protein bound: 98%;
Metabolism: free drug conjugated in liver by glucuronyl transferase to form active MPAG -> excreted in bile, reabsorbed in gut -> 2nd peak conc. 6-12 hrs after initial dose;
Dosing: C - 1000 mg PO BID; M - 720 mg PO BID;
TDM NOT recommended;
ADRs:
- N/V/D, abd pain, leukopenia, neutropenia, thrombocytopenia, anemia, malignancy, infection;
DDIs:
- AL/Mg-containing antacids decrease AUC
- cholestyramine decreases AUC
- myelosuppressive drugs: ganciclovir, valgancyclovir, sirolimus |
|
|
Term
| Corticosteroids - IV methylprednisolone or PO prednisone |
|
Definition
**Cornerstone of Therapy**
MoA: anti-inflammatory effect (inhibits production of PGs & leukotrienes), immunosuppressive effect (inhibits cytokine production by T cells & macrophages);
ADRs:
- hyperglycemia, HTN, hyperlipidemia, psychosis, mood swings, insomnia, photosensitivity, acne, osteoporosis, weight gain, hirsutism, Cushing's syndrome, menstrual iregularities, growth retardation, infection, GI disturbance, cataracts, impaired wound healing, leukocytosis; |
|
|
Term
|
Definition
**NOT 1st line --> used in pts who cannot use calcineurin inhibitor (cyclosporine, tacrolimus);
MoA: mTOR inhibitor -> inhibits IL-2 induced cell cycle progression of T cell;
POOR Bioavailability (Tabs > oral soln)
CYP3A4 susbtrate & PGP substrate & inhibitor;
VERY LONG HALF-LIFE: 62 hrs;
TDM: 24 hr trough levels - Goal: 6-12 ng/ml;
Once MD is adjusted, pts should continue new regimen for ~7 days before further dose adjustment;
ADRs:
- thrombocytopenia, leukopenia, ANEMIA, hyperlipidemia, IMPRAIRED WOUND HEALING, lymphedema, mouth ulcers, bone pain, diarrhea, pneumonitis (requires drug D/C);
BBWs: HEPATIC ARTERY THROMBOSIS in liver transplant pts; BRONCHIAL ANASTOMOTIC DEHISCENCE in lung transplants; |
|
|
Term
|
Definition
1) Specialized agent (IL-2 rececptor antagonist [declizumab/basiliximab] OR T-lymphocyte depleteing agent)
2) High-dose Maintenance Therapy |
|
|
Term
|
Definition
1) Triple Drug Immunosuppression: calcinuerin inhibitor (tacrolimus or cyclosporine) + antiproliferative agent (mycophenolate or azathioprine) + corticosteroids;
2) Corticosteroid withdrawal or avoidance: decrease long-term associated toxicity, avoid increasing incidence of acute rejection;
3) Calcineurin inhibitor withdrawal or avoidance: sirolimus + mycophenolate or azathioprine + corticosteroid -> improved renal fcn, higher incidence of acute rejection; |
|
|
Term
|
Definition
1) Dependent on severity, type, & prior anti-rejection therapy utilized;
2) 1st line Mild-Moderate Rejection: High-dose Corticosteroids (methylprednisolone 250-1000 mg IV x 3-5 days)
3) Moderate-Severe Rejection or Steroid-resistant Rejection: T-lymphocyte depleting therapy (thymoglobulin or OKT3);
4) Ab-Mediated Rejection:
- plasmapharesis
- IVIG therapy
- rituximab (?) |
|
|
