Ch 8 - Kidney Transplant (Pham) Flashcards
T/F ABO blood group antigens are present only on RBCs.
False
also on kidneys, GI, respiratory, and other organ systems.
What is the order of tissue barriers to transplantation?
ABO > MHC > non-MHC
Why do MHC matched sibling recipient still need to be on immunosuppresion?
Because of presence of non MHC molecules (“minor” HLA), to prevent graft rejection.
no need if identical twins.
What can happen if ABO incompatible kidney transplant occurs without prior desensitization?
Hyperacute rejection and graft loss .
What is A1 and A2 antigen? What’s the clinical significance?
A1 antigen is more potent antigen than A2
A2 kidneys (donor) can go to O recipients.
A2 and A2B kidneys can go to B recipients.
Where are MHC genes located?
Chromosome 6
They are the most polymorphic genes in human genome.
What are the most pre-dominant antigens in transplant?
HLA (major)
What are the chances of siblings being:
1) 0 haplotype
2) 1 haplotype
3) 2 haplotype
25 % each for 0 and 2
50% for 1 haplotype
What are the 3 classical HLA Class I antigens?
A, B, C
HLA Class I are expressed on ___1__ and present peptides to _2___ cells.
- all nucleated cells
2. Cytotoxic CD8+ T cells.
What are the 3 classical HLA Class II antigens?
DP, DQ, DR
HLA 2 is expressed on __1_ and may be upregulated on on __2_ cells after exposure to pro-inflammatory cytokines.
- Only on APCs (dendritic cells, macrophages, B cells)
2. epithelial and vascular endothelial cells
Donors and recipients are typed for these HLAs.
A, B, DRB, and DQB
What HLA typing is mandatory for all DDRTs?
HLA-Cw
What is more important to graft survival – having more matches or having less mismatches?
Less mismatches –> better graft outcome
1 year graft survival is more related to HLA Class __ mismatching than to Class __
more related to Class II MM than Class I.
what are minor HLA?
small endogenous peptides that occupy the antigen binding site of donor MHC molecules
minor HLA are usually recognized by __ cells
CD8+ cytotoxic T-cells.
The _____ pathway of allorecognition is more common in acute rejection.
Direct pathway – where recipient T cells recognize HLAs from DONOR cells.
The _____ and ___ pathway of allorecognition are primarily involved in chronic rejection.
Indirect pathway (recipient APC + MHC present Donor derived peptide to rec T cell).
Semidirect pathway also plays role (rAPC w/ donor MHC/allopeptide presenting to rT-cell).
Why is a crossmatch test done prior to transplant?
to determine whether pt has antibody directed against a potential donor.
What is the goal of CDC test?
CDC = Complement dependent cytotoxicity crossmatch test is used to determine high titer of HLA Abs in pt’s serum against donor lymphocytes.
Preformed IgG anti-donor HLA Abs is a CI to transplant.
T/F Flow cytometry is more sensitive as compared to CDC XM for HLA Ab detection
True
Flow can be useful if donor lymphocytes are non-viable.
Abs directed against HLA class I –> + XM with ___ cells
both B and T cells
Abs directed against HLA class II will cause a +XM with ___cells
only B cells
+ XM against T cells is indication of anti-class ___ Antibodies in the pt
anti Class I
+ XM against B cells is indication of anti-class ___ Antibodies in the pt
both anti Class I and II
B cells are nucleated (I) and are APCs (II)
what can cause sensitization to allogeneic HLA antigens?
Give 3 common situations
1) Pregnancy
2) prior transplant
3) blood transfusions
If a pt is sensitized, what does that mean in re: to recipients’ reactivity to donor pool?
Anti-HLA Abs in recipient’s serum may react with cells from panel of donors.
What does PRA stand for?
Panel reactive antibodies
ie, antibodies reactive to a panel of donor HLA antigens
Define PRA
expressed as %
PRA is % of potential donors’ cells tested that were killed by pt’s serum.
PRA estimates % of donors who would be XM incompatible w/ a recipient in given donor pool tested.
T/F
PRA 80% indicates that pt has 80% chance to receive negative XM
False –
higher PRA = lower chance for negative XM
in this case there’s only 20% chance for negative XM
T/F
CDC and Flow both use recipient serum mixed w/ donor lymphocytes
True
T/F
The use of donor lymphocytes can detect whether a pt has Abs against donor Ag’s but does not allow identification of SPECIFIC antigens to which the pt has Abs.
True
What is advantage of Luminex technology?
Luminex uses Ag-coated beads that can determine PRA and identify Abs to specific Ag’s
(but it’s not FDA approved)
What is MFI?
MFI = Mean Fluorescence Intensity
semi-quantitative measurement of Ab titer (i.e., “strength” of the anti-HLA Abs).
what is CPRA?
Calculated Panel Reactive Antibodies
– UNOS uses a cPRA based on “unacceptable antigens” as measured by MFI.
What is “DSA”?
DSA = Donor specific antibodies aka = anti-HLA Abs
What is clinical significance of presence of DSA in recipient?
poorer graft survival.
What is a virtual XM?
involves a determination of presence or absence of DSA in a pt by comparing the pt’s HLA Ab specificity profile to the HLA type of the proposed donor w/o performing an actual XM (such as CDC or Flow).
What are the requirements for a virtual XM?
1) Complete tissue typing of donor (HLA- A, B, C, DP, DQ, DR)
2) …of recipient
3) Up-to-date solid phase anti-HLA Ab analysis of recipient (using Luminex)
Basically, the top part of the transplant sheet we look at.
How is virtual XM different from real XM?
We can now accurately predict XM results (CDC, Flow) without actually doing those tests using only the MFI values derived from DSA. MFI thresholds need to be standardized in each institution that correlate w/ +XM.
In which clinical scenario is virtual XM very useful?
in deceased donor transplants (particularly Lung and Heart tx, and IMPORT DDRTs) to reduce CIT.
Identify the absolute and relative contraindications to kidney transplant in this case:
90F with DM2, stage 4 lung cancer, NYHA Class IV CHF, decom liver cirrhosis, PAD, BMI 36, non -healing ulcers, lives alone.
Absolute: metastatic cancer, severe irreversible extra-renal dz (CHF class 4), liver cirrhosis, non-healing ulcers, lack of social support (could mean poor adherence), life expectancy < 2 yrs.
Relative: advanced age, morbid obesity (> 35), PAD.
Pt with CKD 4 undergoing transplant eval, gets cath for ACS, s/p PCI with (1) DES or (2) BMS.
What is the recommendation you and cardiology make for pt who is planned for transplant?
elective surgery (non-cardiac) should be delayed:
(1) DES –> 6 months
(2) BMS –> 30 days
b/c on DAPT.
What is the UNOS listing criteria for DDRT?
CKD w/ eGFR <20ml/min or ESRD
What heme condition require no waiting time to get kidney transplant?
Long standing MGUS
Heme should be called in pts with newly dx monoclonal gammopathy.
In which Onc conditions is no waiting time required if there is cure at time of transplant?
1) Incidental RCC
2) in situ carcinoma of bladder
3) in situ carcinoma of cervix
4) BCC, SCC of skin
What is the typical wait time if pt has cancer?
2-5 years of tumor free period
what is the problem with IFN based therapy in pt with Heaptitis C who gets a kidney tx?
increases risk of allograft rejection
not much of an issues now that there are newer therapies.
why should all patients with HBV be placed on anti-viral therapy after tx?
to avoid HBV reactivation and progression of liver dz a/w IS therapy.
Pt with HIV. What is expected of them so they can get a kidney?
1) Viral load < 50copies/mL (some centers require undetectable)
2) CD4 > 200
3) absence of opportunistic infxn in prior year.
____ is an HIV drug (integrase inhibitor) that has no known drug interaction with tacrolimus.
Raltegravir
Which IS drugs can potentially interact with HIV meds?
CNIs and mTOR inhibitors (eg, sirolimus) via P450 3A4
Is latent TB (ie, +PPD or +Quant Gold) a contraindication to getting renal tx? What do you do with latent TB pts?
Not a Contraindication.
They need a chest X-ray (already part of eval) and the should get ppx INH+ B6 x 9 months.
is active TB a contraindication to transplant?
yes (obviously) lol
Young woman has CKD 5 now s/p transplant. She asks you about pregnancy options. What do you tell her?
- she must be at least 1 yr post tx
- sCr < 2 (preferably < 1.5) – higher Cr –> higher chance for graft loss.
- no recent acute rejection episodes
- well controlled HTN on minimal anti-HTN therapy.
- minimal to no proteinuria
- normal tx - US
- switch Cellcept to Azathioprine.
significance of lower KDPI?
Low KDPI assoc. w/ longer-estimated graft fxn
T/F Candidates with high cPRA scores receive local/regional/national priority.
True
What is the 3-signal model of allo-immune responses?
T-cell activation need 3 signals:
Signal 1: Ag-TCR binding
Signal 2: Costim (B7 + CD28)
Signal 3: IL2 binds IL2R –> mTOR –> cell proliferation
Describe Signal 1 of the 3 signal model of allo-immune responses
Signal 1 (Ag-TCR binding): allo-Ag binds to surface of APC to the T-Cell receptor-CD3 complex
Describe Signal 2 of the 3 signal model of allo-immune responses.
What happens to the T cell if Signal 2 is not present?
Signal 2 (co-stim): non-Ag specific co-stimulatory signal (APC’s B7 w/ T-cells CD28/CTLA4). This costim –> + intra-cellular pathways –> activate IL2 and other growth-promoting cytokines.
If a TCR is triggered w/o the accompanying costim signal 2, Tcell is driven to anergy.
Describe Signal 3 of the 3 signal model of allo-immune responses
Signal 3 (IL2 + IL2R; mTOR): IL2 binding to IL2R activates mammalian target of Rapamycin (mTOR) pathway --> cell proliferation.
What are the targets of various immunosuppresants?
1) Anti-TCR (signal 1)
2) Anti-CTLA4 (signal 2)
3) Anti-IL2R (signal 3)
4) mTOR inhibitors (signal 3)
5) Anti-metabolites (signal 3)
6) Calcineurin inhibitors
7) Anti-CD52
What is calcineurin?
CN = Phosphatase that deP and facilitates translocation of NFAT to the nucleus –> promotes expression of IL2 and other cytokines –> promote T cell activation.
CNIs inhibit this.
What is thymoglobulin?
POLYclonal Ab made by immunization of rabbits with human lymphoid tissue. The purified product contains cytotoxic Abs directed against variety of T cell markers.
