CN2: Organ Transplantation Flashcards
1
Q
What is an example of autograft?
A
Skin graft from one part of the body to another
No transplant rejection
2
Q
What is the tissue transplant from the same species?
A
Homograft
3
Q
What is the tissue transplant from different species?
A
Xenograft
4
Q
What are the organs that can be transplanted to humans?
A
- Skin appendages
- Bone
- BM
- Liver
- Kidney
- Heart
- Lungs
- Pancreas
- Spleen
5
Q
What is to determine probable compatibility of donor and recipient?
A
Mendelian mode of inheriting MHC Ag
6
Q
Each individual has how many MHC Ag that is inherited from the mother and one from the father?
A
Diploid (has 2 sets)
example: mother with sets AB and father has sets CD, their offspring may have AC, AD, BC, or BD; therefore probabilities are:
- 25% having the same 2 sets
- 50% having only one set
the same implications:
- there’s a 25% probability of finding the most compatible donor among ones’ own sibling
- the monozygote twin is the best possible donor
- there’s a 50% chance that 2 siblings share one set of MHC Ags
- a parent and child share only one set of MHC Ags
7
Q
Define transplant rejection
A
The immunological response to incompatibility in a transplanted organ.
8
Q
How much is the probability of finding the most compatible donor among ones’ own siblings?
A
25%
9
Q
What is the best possible donor?
A
Monozygote twin
10
Q
How much is the chance that 2 siblings share one set of MHC Ag?
A
50%
11
Q
How many MHC Ag does a parent and child share?
A
One set
12
Q
What are the different mechanisms of rejection?
A
- T cell-mediated reactions
a. Direct pathway
b. Indirect - Ab mediated
a. Hyperacute rejection
b. Acute Ab-mediated rejection
13
Q
MHC Ag on cell-surface of APC of donor organ:
A
Direct pathway
14
Q
Class II Ag recognized by CD4+ T cell to:
direct pathway
A
Cytokines produced to induct macrophages and lymphocytes as effector cells
15
Q
Class I Ag recognized by CD8+ T cell to:
direct pathway
A
Activate cytotoxic T cells as killer cells
16
Q
Recipient T cells recognize alloAg from donor only when presented by the host’s own antigen-presenting cell (APC)
A
Indirect pathway
17
Q
What involves preformed Ab (in previously sensitized individual)?
A
Hyperacute rejection
18
Q
- occurs within minutes of transplantation
- Ag-Ab rxn at lvl of vascular endothelium
A
Hyperacute rejection
19
Q
Type of rejection in a recipient not previously sensitized cause of injury:
A
Acute Ab-mediated rejection
20
Q
- complement-dependent cytotoxicity
- Ab-dependent cell-mediated cytolysis
- deposition of Ag-Ab complexes graft vasculature is initial target, an immunologic vasculitis
A
Acute Ab-mediated rejection
21
Q
Rejection reactions are classified as:
A
Hyperacute, acute, and chronic
22
Q
What rejection occurs within minutes or hours after transplantation and can be recognized by the surgeon just after the graft vasculature is anastomosed to the recipient’s?
A
Hyperacute rejection
23
Q
In contrast to a nonrejecting kidney graft, which rapidly regains a normal pink coloration and normal tissue turgor and promptly excretes urine;
a hyper-acutely rejecting kidney becomes:
A
Cyanotic
Mottled
Flaccid
May excrete a mere few dps of bloody urine
24
Q
Immunoglobulin and complement are deposited in the vessel wall, and electron microscopy discloses early endothelial injury together with fibrin-platelet thrombi.
A
Early lesions point to Ag-Ab rxn at the level of vascular endothelium
subsequently, these changes become diffuse and intense, the glomeruli undergo thrombotic occlusion of the capillaries, and fibrinoid necrosis occurs in arterial walls. the kidney cortex then undergoes outright infarction (necrosis), and such nonfxning kidneys have to be removed.
25
As the changes become diffuse and intense, the glomeruli undergo what?
Thrombotic occlusion of capillaries
26
Where does *fibrinoid* necrosis occur?
Arterial walls
27
What may occur **within days** of transplantation in the untreated recipient or **may appear suddenly months or even years later**, after immunosuppression has been employed and terminated?
Acute rejection
28
What is a combined process in wc both cellular and humoral tissue injuries contribute?
## Footnote
In any one patient, one or the other mechanism may predominate.
Acute graft rejection
29
Histologically, what is humoral rejection associated with?
Vasculitis
30
Histologically, what is cellular rejection marked by?
Interstitial mononuclear cell infiltrate
31
What is most commonly seen within the **initial months** after transplantation and is heralded by an elevation of serum creatinine lvls followed by clinical signs of renal failure?
Acute *cellular* rejection
32
Histological appearance of acute *cellular* rejection:
* extensive interstitial mononuclear infiltration
* edema
* mild interstitial hemorrhage
33
What staining reveals CD4 & 8, and these cells express markers of activated T cells s/a alpha chain of the IL-2 receptor?
Immunoperoxides
34
Glomerular and peritubular capillaries contain large numbers of mononuclear cells that may invade the tubules causing what?
Focal tubular damage
35
CD8 might also injure vascular endothelial cells causing what?
Endothelitis
36
What is important bcs in the absence of an accompanying arteritis, px promptly respond to immunosuppressive therapy?
Recognition of cellular rejection
37
What is a widely used immunosuppressive drug which is **nephrotoxic** hence histologic changes resulting from it may be superimposed?
Cyclosporine
38
What is mediated primarily by anti-donor Ab, hence is manifested mainly by damage to the BV?
Acute *humoral* rejection (rejection vasculitis)
39
Acute humoral rejection (rejection vasculitis) may take the form of necrotizing vasculitis with:
- Endothelial cell necrosis
- Neutrophilic infiltration
- Deposition of Ig
- Complement
- Fibrin
- Thrombosis
| lesions are associated with extensive necrosis of the renal parenchyma
## Footnote
in many cases, the vasculitis is less acute and is characterized by marked thickening of the intima by proliferating fibroblasts, myocytes, and foamy macrophages
40
What may happen when there is the narrowing of arterioles?
May cause infarction or renal cortical atrophy
41
What are c/b cytokines that cause growth of vascular smooth muscles?
Proliferative vascular lesions mimic arteriosclerotic thickening
42
What is an important cause of graft failure?
| since acute rejection has been ctrlled by immunosuppressives
Chronic rejection
43
Px with chronic rejection present clinically w a progressive rise in what?
Serum creatinine over a pd of 4-6 mos
44
What is dominated by **vascular changes, interstitial fibrosis, and tubular atrophy w loss of renal parenchyma**?
Chronic rejection
45
What is consist of **dense, obliterative intimal fibrosis**, principally in the **cortical arteries**?
Vascular changes
46
The vascular lesions result in what?
- renal ischemia manifested by glomerular loss
- interstitial fibrosis and tubular atrophy
- shrinkage of the renal parenchyma
47
The glomeruli may show duplication of basement membranes; this appearance is sometimes called what?
Chronic transplant glomerulopathy
48
Chronically rejecting kidneys usually have **mononuclear cell infiltrate** containing large numbers of what?
- Plasma cells
- Numerous eosinophils
49
What are the major targets of transplant rejection?
HLA Antigens
## Footnote
minimizing the HLA disparity between the donor and the recipient would be expected to improve graft survival
50
HLA and transplants examples:
- Related donor kidney transplants, a beneficial effect of matching for HLA class I is observed
- Cadaver renal transplants, matching for HLA class I Ags (HLA-A and HLA-B) has at best a modest effect on graft acceptance
- Additional matching for class II Ag (HLA-DR) results in a definite improvement in graft survival
## Footnote
However, even HLA-matched unrelated donors are likely to difer from the host at one or more minor histocompatibility Ag. These antigens are formed by peptides derived from polymorphic proteins other than those encoded in the HLA complex. They evoke a weak or slower rejection reaction that, nevertheless, necessitateds the use of immunosuppression.
51
Except in the case of identical twins, who are obviously matched for all possible histocompatibility Ags, what is a practical necessity in all other donor-recipient combinations?
Immunosuppresive Therapy
52
What is the mainstay of immunosuppression?
Cyclosporine
53
What works by blocking activation of a transcription factor called nuclear factor of activated T cells, which is required for transcription of cytokine gene (IL-2)?
Cyclosporine
54
What is used to treat rejections which **inhibits leukocyte development from BM precursors**?
Azathioprine
55
What is used to treat rejections which can **block inflammation**?
Steroids
56
What are used to treat rejections which can **inhibit lymphocyte proliferation**?
Rapamycin
Mycophenolate mofetil
57
What blocks the activation and may opsonize and help to eliminate the cells?
Monoclonal anti-T-cell Ab
## Footnote
e.g., monoclonal anti-CD3 and Ab against IL-2 receptor a chain, which block T-cell activation and may opsonize and help to eliminate the cells
58
What are used to dampen the immune response in organ transplantation and autoimmune dse?
Immunosuppressive drugs
59
In transplantation, the major classes of drugs used today are:
1) glucocorticoids
2) calcineurin inhibitors
3) anti proliferative/anti metabolic agents
## Footnote
These drugs have met with a high degree of clinical success in treating conditions such as acute immune rejection of organ transplants and severe autoimmune diseases. However, such therapies require lifelong use and nonspecifically suppress the entire immune system, exposing px to considerably higher risks of infection and cancer.
60
What can be nephrotoxic and diabetogenic?
Calcineurin inhibitors and steroids
## Footnote
these are of limited usefulness in a variety of clinical setting
61
What are important adjunt therapies and provide a unique opportunity to selectively target specific immune-reactive cells and thus promote more specific tx?
Monoclonal and polyclonal antibody preparations directed at reactive T cells
62
What are being used to target growth factor pathways, substantially limiting clonal expansion and thus promoting tolerance?
**Sirolimus** and **anti-CD25 (IL-2 receptor) Ab** (***basiliximab***, ***daclizumab***)
63
What are the 5 general principles of organ transplant therapy?
1) careful px prep and selection of best available ABO-compatible HLA match for organ donation
2) a multititered approach to immunosuppressive drug therapy (several agents are used simultaneously, each of which is directed at a different molecular target within the allograft response. Synergistic effects are obtained through application of the various agents at a relatively low doses, thereby limiting specific toxicities while maximizing the immunosuppressive effect)
3) greater immunosuppression
4) careful investigation of each episode of transplant dysfxn (eval for rejection, drug toxicity, infxn; they can co-exist)
5) redxn or withdrawal of a therapeutic agent when toxicity exceeds its benefit
64
To gain early engraftment and/or to treat established rejection than maintain immunosuppression in the long term:
## Footnote
therefore, intensive induction and lower-dose maintenance drug protocols are employed
Greater immunosuppression
65
Response elements in DNA (regulate gene transcription)
Glucocorticoids
66
T-cell receptor complex (blocks Ag recognition)
Muromonab-CD3
67
Calcineurin (inhibits phosphatase activity)
Cyclosporine and Tacrolimus
68
DNA (false nucleotide incorporation)
Azathioprine
69
Inosine monophosphate dehydrogenase (inhibits activity)
Mycophenolate mofetil
70
IL-2 receptor (block IL-2-mediated T cell activation)
Daclizumab, Basiliximab
71
Protein kinase involved in cell-cycle progression (mTOR) (inhibits activity)
Sirolimus
72
What are used as induction therapy in the immediate post transplantation period?
- Muromonab-CD3
- Anti-CD25 monoclonal Ab
- Polyclonal anti-lymophocyte Ab
73
These tx enables initial engraftment without the use of high doses of nephrotoxic calcineurin inhibitors:
Muromonab-CD3
Anti-CD25 monoclonal Ab
Polyclonal antilymophocyte Ab
## Footnote
such protocols reduce the incidence of early rejection and appear to be particularly beneficial for patients, pediatric recipients, or African Americans
74
What are directed at a discrete site in T cell activation?
- Calcineurin inhibitor
- Steroids
- Mycophenolate mofetil
## Footnote
- typical therapy
- also basic immunosuppressive protocol used in most transplant center involves the use of multiple drugs simultaneously
75
What is a purine metabolism inhibitor?
Mycophenolate mofetil
76
What are effective in preventing acute cellular rejection but not as effective in blocking T cells that already are activated, and are not very effective against established, acute rejection or for total prevention of chronic rejection?
Low doses of prednisone, calcineurin inhibitors, purine-metabolism inhibitors, or sirolimus
77
Agents directed against activated T cells
- Glucocorticoids in high doses (pulse therapy)
- Polyclonal antilymophocyte Ab
- Muromonab-CD3
78
Steroids lyse and induce the redistribution of lymphocytes = rapid, transient decrease in peripheral blood lymphocyte cts
For long term effects to occur: they bind to receptors inside cells, then receptors OR glucocorticoid-induced CHON bind to DNA = transcription
## Footnote
additonally, glucocorticoid-receptor complexes increase IkB expression, thereby curtailing activation of NFkB, which results in increased apoptosis of activated cells.
Of central importance is the downregulation of important proinflammatory cytokines s/a IL-1 and IL-6.
T cells are inhibited from making IL-2 and proliferating. The activation of cytotoxic T lymphocytes is inhibited. Netro and monocytes display poor chemotaxis and decreased lysosomal enx release.
Therefore, glucocorticoids have broad antiinflammatory effects on cellular immunity. In contrast, they have relatively little effect on humoral immunity.
Adrenocortical steroids MOA
79
Central impt: down-regulation of proinflammatory cytokines (IL-6, IL-1)
Adrenocortical steroids
80
What are commonly used in combination with other immunosuppressive agents both prevent and treat transplant rejection?
Glucocorticoids
81
What are used to reverse acute transplant rejection and acute exacerbations of selected autoimmune disorders?
High doses of IV methylprednisone sodium succinate (SOLUMEDROL, A-METHAPRED) (pulses)
82
What are efficacious for tx of GVHD in BM transplantation?
Glucocorticoids
83
What are routinely used to treat RA, SLE, systemic dermatomyositis, psoriasis, asthma, allergic dis, inflammatory bowel dse, inflammatory ophthalmic dses, autoimmune hema dis, and acute exacerbations of multiple sclerosis?
Glucocorticoids
84
Glucocorticoids limit allergic rxns that occur w other immunosuppressive agents and are used in transplant recipients to block first-dose cytokine storm by tx with:
Muromonab-CD3
85
Extensive use of steroids has resulted in disabling and life-threatening adverse effects s/a:
* growth retardation
* avascular necrosis of bone
* osteopenia
* inc risk of infxn
* poor wound healing
* cataracts
* hyperglycemia
* HPN
86
What target intracellular signaling pathways induced as a consequence of T cell receptor activation?
Calcineurin inhibitors, cyclosporine, tacrolimus
| most effective immunosuppressive drugs in routine clinical use
87
Most effective immunosuppressive drugs in routine clinical use:
Calcineurin inhibitors, cyclosporine, tacrolimus
| inhibit normal T cell signal transduction
88
Cyclosporine and tacrolimus do not act per se as immunosuppressive agents. Instead, they "gain fxn" after binding to cyclophilin or FKBP-12, resulting to subsequent interaction w calcineurin to:
Block activity of this phosphatase
89
What is required for movement of a component of the nuclear factor of activated T lymphocytes (NFAT) into nucleus?
Calcineurin-catalyzed dephosphorylation
90
What is required for induction of a number of cytokine genes including that for IL-2, a prototypic T cell growth and differentiation factor?
NFAT (nuclear factor of activated T lymphocytes)
91
- cyclic polypeptide 11 AA
- produced as metabolite of fungus sp Beauveria nivea
- lipophilic and highly hydrophobic, so must be solubilized for clinical administration
## Footnote
of note: all amide nitrogens are either hydrogen bonded or methylated, the single D-amino acid is at position 8, the methyl amide between residues 9 and 10 is in the cis configuration, and all other methyl moieties are in the trans form.
Cyclosporine (cyclosporine A)
92
- Cyclosporine inhibits Ag-triggered signal transduction in T lymphocytes, blunting expression of many lymphokines (IL-2 and anti-apoptotic proteins)
- Cyclosporine forms a complex w cyclophilin (complex binds to calcineurin, inhibiting Ca2+-stimulated dephosphorylation of cytosolic component of NFAT. NFAT translocates to the nucleus where it complexes with nuclear components required for complete T-cell activation, including transactivation of IL-2 and other lymphokine genes.
- Calcineurin enzymatic activity is inhibited frollowing physical interaction w the cyclosporine/cyclophilin complex.
- Results: blockade of NFAT dephosphorylation; thus, the cytoplasmic component of NFAT doesn't enter the nucleus, gene transcription isn't activated, and T lympho fail to respond to specific Agnic stimulation.
## Footnote
Cyclosporine supress some humoral immunity but most effective against T cell-dependent immune mechanisms s/a those underlying transplant rejection and some forms of autoimmunity.
Cyclosporine MOA
## Footnote
Cyclosporine also increases expression of transforming growth factor B (TGF-B), a potent inhibitor of IL-stimulated T-cell proliferation and generation of cytotoxic T lymphocytes (CTL)
93
What is a cytoplasmic receptor protein present in target cells?
Cyclophilin
94
This complex binds to calcineurin, inhibiting Ca 2+ stimulated dephosphorylation of the cytosolic component of NFAT:
Cyclosporine-cyclophilin complex
95
Cyclosporine increases expression of what?
Transforming growth factor B
96
What is a potent inhibitor of IL-2 stimulated T cell proliferation and generation of cytotoxic T lymphocytes?
Transforming growth factor B
97
Disposition and Pharmakokinetics of Cyclosporine
- IV or orally
- IV (SANDIMMUNE) as ethanol -polyxyethylated castor oil vehicle --> diluted in 0.9% NaCl or 5% dextrose
- Oral - soft gel capsule 20-50% bioavailability
- NEORAL - more uniform & slightly inc bioavailability
98
Terminal half life of cyclosporine
5-18 hrs
99
After IV infusion, clearance is approx what in adult recipients of renal transplants?
5-7 mL/min per kg
100
Following oral administration of cyclosporine (as NEORAL), the time to peak blood conc is:
1.5 to 2 hrs
101
How many % of cyclosporine is excreted unchanged in urine?
0.1%
102
Cyclosporine is extensively metabolized in the liver by what enz system to a lesser degree by GI tract and kidneys?
Cytochrome-P459 3A (CYP3A)
103
Where are Cyclosporine and its metabolites excreted?
## Footnote
clinical indications for cyclo: kidney, heart, liver, other organ transplantation; RA and psoriasis
- Principally: thru bile into the feces
- Approx. 6% being excreted in the urine
- Also in human milk
## Footnote
in hepatic dysfxn, dosage adjustments are required
no necessary adjustments for dialysis or renal failure px
104
What is generally recognized as the agent that ushered in the modern era of organ transplantation, increasing the rates of early engraftment, extending graft survival for kidneys, and making cardiac and liver translpant possible?
Cyclosporine
## Footnote
usually used in combination w other agents, esp glucocorticoids and either azathrioprine or mycophenolate mofetil, and most recently sirolimus.
105
Dosage is guided by:
* signs of rejection (too low a dose)
* renal or other toxicity (too high a dose)
* close monitoring of blood lvls
## Footnote
- initial dose generally is not given pretransplant bcs of concern about neurotoxicity
- especially for renal px: therapeutic algorithms have been developed to delay cyclosporine introdxn until a threshold renal fxn has been attained
106
In rheumatoid arthritis, cyclosporine is used in cases of severe dse that have ***NOT*** responded to:
Methotrexate
107
In psoriasis, ________ is indicated for the tx of adult nonimmunocompromised px w severe and disabling dse who have failed other systemic therapies.
Cyclosporine
## Footnote
because of its mechanism of action, there is a theoretical basis for the use of cyclosporine in a variety of other T-cell mediated dses
- reported to be effective in Behcet's acute ocular syndrome, endogenous uveitis, atopic dermatitis, inflammatory bowel dse, and nephrotic syndrome when standard therapies have failed.
108
What are the principal adverse reactions to cyclosporine therapy?
```
Renal dysfxn
Tremor
Hirtutism
HPN
Hyperlipidemia
Gum hyperplasia
```
## Footnote
Nephrotoxicity is limiting and occurs in the majority of px treated.
It is a major indication for cessation or modification of therapy.
Hypertension may occur in approx 50% of renal transplant and almost all cardiac transplant px.
109
Combined use of calcineurin inhibitors and glucocorticoids is what?
Diabetogenic
## Footnote
with diabetes being more frequent in patients treated with tacrolimus than in those receiving cyclosporine
110
Inhibiting CYP3A can what?
- Decrease cyclosporine metabolism
- Increase blood conc
## Footnote
- Ca channel blockers (verapamil, nicardipine)
- Antifungal agents (fluconazole, ketoconazole)
- Antibiotics (erythromycin)
- Glucocorticoids (methylprednisolone)
- HIV-protease inhibitors (indinavir)
- other drugs (allopurinol, metoclopramide)
111
Inhibit enz can decrease cyclosporine metabolism and increase bld conc:
- Ca channel blockers (verapamil, nicardipine)
- antifungal (fluconazole, ketoconazole)
- antibiotics (erythromycin)
- glucocorticoids (methylprednisone)
- HIV-protease inhibitors (indinavir)
- allopurinol, metoclopramide
112
What can block the CYP3A system and increase cyclosporine blood conc and thus should be avoided by px receiving the drug?
Grapefruit and grapefruit juice
113
Drugs that induce CYP3A activity can what?
Increase cyclosporine metabolism and decrease blood concentrations
## Footnote
- antibiotics (nafcillin and rifampin)
- anticonvulsants (phenobarbital anf phenytoin)
- other drugs (octreotide and ticlopidine)
114
What aggravates cyclosporine-induced renal dysfxn?
Sirolimus
## Footnote
interactions between cyclosporine and sirolimus have led to the recommendation that administration of the 2 drugs be separted by time
115
What increases sirolimus-induced hyperlipidemia and myelosuppression?
Cyclosporine
## Footnote
other cyclosporine-drug interactions include additive nephrotoxicity when coadministered w NSAIDs and other drugs that cause renal dysfxn; and reduced clearance of other drugs, including prednisolone, digoxin, and lovastatin
116
What is a macrolide antibiotic produced by *Streptomyces tsukabaensis*?
Tacrolimus
117
MOA: inhibits T cell activation by inhibiting calcineurin
## Footnote
- binds to an intracellular protein, FK506-binding protein-12 (FKBP-12)
Tacrolimus
118
What binds to an intracellular protein, FK506-binding protein-12 (FKBP-12), an immunophilin structurally related to cyclophilin?
Tacrolimus
## Footnote
A complex tacrolimus-FKBP-12, Ca, calmodulin, and calcineurin then forms, and calcineurin phosphatase activity is inhibited.
The inhibition of phosphatase activity prevents dephosphorylation and nuclear translocation of NFAT and leads to inhibition of T-cell activation. Although, the intracellular receptors differ, cyclosporine and tacrolimus appear to share a single common pathway of immunosuppression.
119
Tacrolimus is available for oral administration as capsules and a sterile solution for injection?
capsules: 0.5, 1 and 5mg
IV: 5mg/dL
## Footnote
Immunosuppressive activity resides primarily in the parent drug because of intersubject variability in pharmacokinetics, individualization of dosing is required for optimal therapy.
120
What is the most appropriate sampling compartment to describe tacrolimus pharmacokinetics?
Whole blood
121
- GI absorption is incomplete and variable
- food decreases both rate and extent of absorption
- plasma protein binding of tacrolimus is 75-99%, involving primarily albumin and a1-acid glycoprotein
Tacrolimus half-life is:
12 hours
122
Tacrolimus is extensively metabolized in the liver by what?
CYP3A
## Footnote
The bulk of excretion of parent drug and metabolites is in the FECES.
Less than 1% of administered tacrolimus is excreted unchanged in the urine.
123
What is indicated fot the prophylaxis of solid-organ allograft rejection in a manner similar to cyclosporine and as rescue therapy in px w rejection episodes despite "therapeutic" lvls of cyclosporine?
Tacrolimus
recommended dose:
- injection: 0.03-0.05mg/kg per day as a continuous infusion
recommended initial oral doses:
- 0.2mg/kg per day for adult kidney transplant px
- 0.1-0.15mg/kg per day for pediatric liver transplant px in 2 divided doses 12 hrs apart
## Footnote
these dosages are intended to acheive typical blood trough lvls in the 5-20mg/mL range; pedia px require higher doses than adults
124
Toxicity of Tacrolimus:
```
Nephrotoxic
Neurotoxic (tremor, headache, motor disturbances, seizures)
GI complaints
HPN
Hyperkalemia
Hyperglycemia
Diabetes
```
Risk: secondary tumors and opportunistic infxn
## Footnote
as with cyclosporine, nephrotoxicity is limiting
125
Tacrolimus has a negative effect on
Pancreatic islet beta cell
## Footnote
both glucose intolerance and diabetes mellitus are well-recognized complications of tacrolimus-based immunosuppression among adult solid-organ transplant recipients
126
Tacrolimus coadministration with cyclosporine results in additive or synergistic nephrotoxicity; therefore, a delay of at least ________ is required when switching a px from cyclosporine to tacrolimus.
24 hours
## Footnote
Since tacrolimus is metabolized mainly by CYP3A, the potential interactions described for cyclosporine apply for tacrolimus as well.
127
# ANTI-PROLIFERATIVE AND ANTIMETABOLIC DRUGS
What is a macrocyclic lactone produced by *Streptomyces hygroscopicus*?
Sirolimus (rapamycin; RAPAMUNE)
128
MOA: inhibits T-lympohocyte activation and proliferation downstream of the IL-2 and other T-cell growth factor receptors.
MOA of Sirolimus
129
What is a drug whose therapeutic action requires formation of a complex w the immunophilin, FKBP-12?
Sirolimus
Also cyclosporine and tacrolimus
130
What complex doesn't affect calcineurin activity, but binds to and inhibits the mammalian kinase, target of rapamycin (mTOR)?
Sirolimus-FKBP-12 complex
131
What is a key enz in cell-cycle progression?
Rapamycin (mTOR)
132
Inhibition of Mammalian kinase blocks cell cycle progression at what phase?
GJ-S Phase transition
133
What effects lasts for several months after discontinuing therapy, suggesting a tolerizing effect?
Sirolimus
## Footnote
in animal models, it inhibits transplant rejection, GVHD, and a variety of autoimmune dses
134
What is absorbed rapidly and reaches a peak bld conc within about 1 hr after a single dose in healthy subjects and within 2 hrs after multiple oral doses in renal transplant px?
Sirolimus
135
Systemic availability is approx. ___, and blood conc are proportional to does between _____.
15%; 3-12 mg/m^2
Systemic availability is approx. 15%, and blood conc are proportional to does between 3-12 mg/m^2
136
A high-fat meal decreases peak bld conc by how many %?
34%
137
How should Sirolimus be taken?
Consistently either w or w/o food and bld lvls should be monitored closely
138
What is extensively metabolized by CYP3A4 and is transported by P-glycoprotein?
Sirolimus
## Footnote
about 40% of wsirolimus in plasma is bound to protein, especially albumin. the drug partitions into formed elementsof blood, with a blood-to-plasma ratio of 38 in renal transplant px
139
The blood half-life after multiple dosing in stable renal transplant px is:
62 hrs
## Footnote
a loading dose of 3x the maintenance dose will provide nearly steady-state conc within 1 day in most px
140
Sirolimus is indicated for prophylaxis of organ transplant rejection in combination therapy with what?
A calcineurin inhibitor and glucocorticoids
141
In px experiencing or at high risk for calcineurin inhibitor-associated nephrotoxicity, sirolimus has been used with what to avoid permanent renal damage?
sirolimus with glucocorticoids and mycophenolate mofetil
142
The initial dose in px 13 y.o. or older who weigh <40kg should be adjusted based on body surface area (1mg/m2 per day) with a loading dose of:
3mg/m2
## Footnote
reduce dose by 1/3 with hepatic impairment px
143
The use of Sirolimus in renal transplant px is associated w a dose-dependent increase in:
Serum cholesterol
Triglycerides
| that may require tx
144
While immunotherapy w sirolimus per se isn't nephrotoxic, px treated w cyclosporine + sirolimus have impaired renal fxn compared to
cyclosporine + either azathioprine or placebo
| renal fxn must be monitored
145
What is a known surgical complication associated with renal transplant, and has occurred significantly often in a dose-dependent fashion in sirolimus-treated px, requiring close post-op follow-up?
Lymphocoele
146
Other adverse effects of Sirolimus:
- Hypokalemia or hyperkalemia
- Anemia
- Leukopenia
- Thrombocytopenia
## Footnote
as w other immunosuppressive agents, there is an increased risk of neoplasms, especially lymphomas, and infections
Prophylaxis for Pneumocystis carinii pneumonia and CMV is recommended
147
Other adverse effects of Sirolimus:
```
Hypokalemia or hyperkalemia
Anemia
Leukopenia
Thrombocytopenia
Fever
GI effects
```
Increased risk of neoplasms, lymphomas, infxns
148
Sirolimus is a substrate for cytochrome CYP3A4 and is transported by:
P-glycoprotein
## Footnote
close attention to interactions w other drugs that metabolized or transported by these proteins is required
149
Coadministration with sirolimus:
Cyclosporine and sirolimus: **separated by time**
**Dose adjustment** may be required with cyclosporine, diltiazem, or rifampin
**No adjustment** with acyclovir, digoxin, glyburide, nifedipine, norgestrel/ethinyl estadiol, prednisolone, or sulfamethoxazole/trimethoprim
150
What is a purine antimetabolite and is an imidazolyl derivative of 6-mercaptopurine?
Azathioprine (IMURAN)
151
MOA: Following exposure to nucleophiles, s/a glutathione, azathioprine is cleaved to 6-mercaptopurine then is converted to metabolites that inhibit de novo purine synthesis
Azathioprine
152
MOA: 6-thio-IMP (fraudulent nucleotide) --> 6-thio-GMP --> 6-thio-GTP which is incorporated into DNA and gene translation is inhibited
Cell proliferation is prevented, inhibiting a variety of lymphocyte fxns
Azathioprine
## Footnote
Aza is more potent than 6-mercapto, which reflect differences in drug uptake or pharmacokinetic differences in the resulting metabolites.
153
What is the half-life of azathioprine?
## Footnote
- well absorbed orally
- reaches maximum blood lvls w/in 1-2 hrs after admnistration
10 mins
154
Half-life of mercaptopurine
1 hour
155
What are moderately bound to plasma proteins and are partially dialyzable?
Azathioprine and mercaptopurine
156
Both azathioprine and mercaptopurine are rapidly removed from blood by what?
Oxidation and methylation in liver and/or erythrocytes
## Footnote
renal clearance is of little impact in biological effectiveness or toxicity, but dose redxn is practiced in px w renal failure
157
What is the strating dose for azathioprine, required to prevent organ rejectionand minimize toxicity which varies?
3-5 mg/kg per day
158
Lower initial dose of azathioprine (1mg/kg per day) is used in treating:
Rheumatoid arthritis
159
What should be monitored in azathioprine intake?
CBC & LFT
160
What is the major side effect of azathioprine?
Bone marrow suppression with:
• leukopenia (common)
• thrombocytopenia (less common)
• anemia (uncommon)
```
Other
• increased susceptibility to infxns (esp varicella, HSV)
• hepatotoxicity
• alopecia
• GI toxicity
• pancreatitis
• increased risk of neoplasia
```
161
What is an enz of major impt in catabolism of metabolites of azathioprine, and is blocked by allopurinol?
Xanthine oxidase
162
What should you do if the same px is using both azathioprine and allopurinol?
Azathioprine must be decreased to 25% - 33% of the usual dose
163
Adverse effects resulting from coadministration of azathioprine w other myelosuppression agents or angiotensin converting enzyme inhibitors include:
* leukopenia
* thrombocytopenia
* anemia as a result of myelosuppression
164
What is the 2-morpholinoethyl ester of mycophenolic acid (MPA)?
Mycophenolate mofetil
165
What is a prodrug that is rapidly hydrolyzed to the active drug, MPA (**mycophenolic acid**); and is also selective, uncompetitive, and irreversible inhibitor of inosine monophosphate dehydrogenase (IMPDH)?
Mycophenolate mofetil
| an important enz in de novo pathway of guanine nucleotide synthesis
166
What undergoes rapid and complete metabolism to MPA after oral or IV administration?
Mycophenolate mofetil
167
What does MPA do?
Selectively inhibits lymphocyte proliferation and fxns, including Ab formation, cellular adhesion, and migration
168
To what is MPA metabolized?
Inactive phenolic glucoronide, MPAG
169
What is the half-life of MPA?
16 hrs
170
Plasma conc of MPA and MPAG are usually increased in what pxs?
Renal insufficiency
171
Where is mycophenolate mofetil typically used in combination and not?
## Footnote
MM - indicated for prophylaxis of transplant rejection
Combi: glucocorticoids and calcineurin inhibitor
Not: azathioprine
## Footnote
Renal transplant px: 1g oral/IV over 2 hrs BID (2g per day)
African American renal transplant px & cardiac transplant px: higher dose 1.5g BID (3g per day)
172
Principal toxicities of mycophenolate mofetil are:
* GI
* Hematologic
Also: increased incidence in some infxns (esp sepsis ass w CMV)
- diarrhea
- vomiting
- leukopenia
173
MM has no untoward effects by combbination therapy with:
- cyclosporine
- sulfamethoxazole/trimethoprim
- oral contraceptives
174
Its coadministration leads to decreased absorption of mycophenolate mofetil
Antacids containing aluminum or magnesium hydroxide
175
What should not be administered w mycophenolate mofetil bcs it will affect enterohepatic circulation?
Cholestyramine
## Footnote
decreases plasma MPA conc, probably by binding free MPA in the intestines
176
What may compete w MPAG for tubular secretion, possibly resulting in increased conc of both MPAG and antiviral agents in the blood?
## Footnote
this may be compounded in px w renal insufficiency
Acyclovir and gancyclovir
177
What is used for the tx of GVHD, RA, anticancer therapy, and psoriasis?
Methotrexate
178
What are used to treat childhood nephrotic syndrome and variety of malignancies?
Cyclophosphamide and chlorambucil
179
Tx for SLE
Cyclophosphamide
180
What is a pyrimidine synthesis inhibitor that is indicated for tx of adults w RA?
Leflunomide
## Footnote
drug that inhibits dihydroorotate dehydrogenase in the de novo pathways of pyrimidine synthesis; hepatotoxic and can cause fetal injury
181
* Encountered in transplant of immunocompetent tissue/cell or their precursors (graft) in immunologically crippled hosts (e.g BM transplant)
* immunocompetent cells of BM recognizes the host cells as foreign and mounts an immune response against them
GVHD
| the host is immunologically crippled intentionally or not
182
Occurs within days to wks after BM transplantation; prominent manifestations are those from the involvement of skin, liver, intestines; the host is at great risk of opportunistic infxn, being immunologically crippled cell-mediated delayed or cytotoxicity mechanism
Acute GVH
183
What may follow acute form or occur insidiously characterized by extensive skin injury (changes similar to systemic sclerosis); chronic liver damage with cholestatic jaundice and GIT damage causing esophageal stricture?
Chronic GVH
184
* host immune system is devastated w involution of thymus and depletion of lymphocytes in LN
* T lymphocytes are destroyed in donor BM tissue before transfusion virtually eliminates GVH
Chronic GVH
185
What reacts against allogeneic stem cells bcs the latter are lacking self-MHC class I molecules and hence fail to deliver the inhibitory signal to what?
NK cells
## Footnote
There is great interest in exploiting the ability of NK cells to kill allogeneic hematopoietic cells for treating certain acute leukemias (another ex of GVHD effect)
allogenic NK cells - will not see self-MHC molecules and will not be inhibited but will not cause GVH rxns
186
What is a frequent accompaniment of GVHD?
Immunodeficiency
187
Examples of immunodeficiency:
- result of prior tx
- myeloablative preparation for the graft
- a delay in repopulation of recipient's IS
- attack on the host's immune cells by grafted lymphocytes
188
Immunologically competent cells or their precursors are transplanted into immunologically crippled recipients and the transferred cells recognize alloAg in the host.
GVHD
189
Pathogenic Mechanism of GVHD
● Recipients of bone marrow transplants are immunodeficient
because of either their primary disease or prior treatment of the disease with drugs or irradiation.
● When such recipients receive normal bone marrow cells from allogeneic donors, the immunocompetent T cells present in the donor marrow recognize the recipients HLA antigens as foreign and react against them.
● Both CD4+ and CD8+ T cells recognize and attack the host
tissues.
● In clinical practice, GVH disease can be so severe that transplants are done only between HLA-matched donor and recipient.
● However, it is possible that with conventional HLA typing, subtle molecular differences between donor and recipient HLA molecules are not picked, and these may be enough
to trigger GVH reactions.
● For this reason, DNA sequencing methods are now being used for molecular typing of HLA alleles.
● Furthermore, HLA matching will miss minor histocompatibility differences, and these may also be
enough to induce GVH disease.
190
Skin: generalized rash leading to desquamation in some cases
Acute GVH
191
Skin: extensive injury with skin appendages destruction and fibrosis of the dermis (resembles systemic sclerosis clinically)
Chronic GVH
192
Liver: destruction of small bile ducts resulting to jaundice
Acute GVH
193
Liver: cholestatic jaundice
Chronic GVH
194
GIT: mucosal ulceration leading to bloody diarrhea
Acute GVH
195
GIT: damage to mucosa may cause esophageal strictures
Chronic GVH
196
Immune system:
profoundly immunosuppressed
CMV infxn - most important
CMV pneumonitis can be a fatal complication
Acute GVH
197
Immune system:
System devastated w involution of thymus abd depletion of lymphocyte in the LN
Recurrent and life-threatening infxns and autoimmunity
Chronic GVH
