Therapeutics Iii Exam 3 - Transplant Rejection Questions

Front 1

Allograft rejection depends on what?

Back 1

-activation of alloreactive T cells
-APCs (dendritic cells, macrophages, B cells)

Front 2

What is meant by a hyperacute rejection?

Back 2

It is complement mediated and occurs immediately upon revascularization of the transplanted organ. Host antibodies immediately attach to donor tissue and kill it.

Front 3

What is meant by an acute rejection?

Back 3

It is caused by infiltration of the allograft by T cells, which causes inflammatory and cytotoxic effects on the graft. It is relatively easy to treat.

Front 4

What is meant by vascular rejection?

Back 4

Also known as humoral rejection. It is caused by antibodies directed against the vascular endothelium of the transplanted organ. It is more difficult to treat than cellular rejection, but is usually responsive.

Front 5

What is meant by chronic rejection?

Back 5

It is caused by complex interactions of cytokines, cellular interactions, CD4+ and CD8+ T cells, and B cells. It is difficult to treat and will ultimately lead to graft loss.

Front 6

When does hyperacute rejection take place?

Back 6

It occurs when preformed donor-specific antibodies are present in the recipient's blood at the time of transplant. Recipient IgG antibodies bind to donor vascular endothelium. Tissue damage occurs through antibody dependent cytotoxicity and complement cascade.

Front 7

How can we prevent hyperacute rejection?

Back 7

1. ABO blood testing (x2)
2. HLA matching (kidney only)
3. Final crossmatching (x2)
4. Panel Reactive Antibody (PRA) (kidney only)

Front 8

What blood type is the universal recipient?

Back 8

AB

Front 9

What blood type is the universal donor?

Back 9

O

Front 10

What is the perfect HLA match?

Back 10

6/6
(less than that is a mismatch, if 3 are different it is called a 3 antigen mismatch)

Front 11

What is Panel Reactive Antibody testing?

Back 11

It is a test routinely performed on patients awaiting kidney transplantation. It measures anti-human (HLA) antibodies in the recipients blood. PRA is expressed as a percentage (0-99%). The lower the number, the better (the fewer human antibodies the donor has). If a patient has a PRA of 40, then that person has antibodies to 40% of the tissue types expressed in a given population (donor pool).

Front 12

How do patients develop HLA antibodies in a PRA test?

Back 12

Exposure to other human HLA antigens through:
1. previous transplants
2. blood transfusions
3. pregnancy

Front 13

What can we do for patients with a high PRA needing transplant?

Back 13

Patients with high PRA are considered high immunological risk and are less likely to receive transplants. Some center do have high PRA protocols though:
1. rituximab (deletes B cells)
2. IVIG (removes some circulating antibodies)
3. immunoadsorption columns ("antibody dialysis")
4. bortezomib (deletes plasma cells)

Front 14

What PRA value is typically considered high risk?

Back 14

-Current PRA > 30% OR
-Historical PRA > 50%
High risk patients at UAMS are given ATG on days 0, 1 and 3 (6mg/kg total dose)

Front 15

How does acute cellular rejection happen?

Back 15

It is primarily a cell mediated process. T-lymhocytes infiltrate and attack the allograft.
Lab Finding Examples:
Kidney - increased SrCr
Liver - elevated enzymes, bilirubin

Front 16

First line treatment of acute rejection?

Back 16

Corticosteroids
-methylprednisolone 500 mg IV daily x 3 days followed by PO prednisone taper (works 95% of the time)

Front 17

Second line treatment of acute rejection?

Back 17

Polyclonal antibodies (ATG or ATGAM) for steroid resistant rejection. ATG is dosed at 1.5mg/kg IV x 7-14 days (premedicate with corticosteroids, Tylenol, and Benadryl to avoid adverse effects)

Front 18

Organ rejection and calcineurin inhibitor toxicity can look similar. What findings are consistent with rejection?

Back 18

-occurs <4 weeks postop
-fever
-weight gain
-graft swelling/tenderness
-decreased daily urine volume
-rapid risk in SrCr (0.3 mg/kl/day)
-normal CSA or TAC conc

Front 19

Organ rejection and calcineurin inhibitor toxicity can look similar. What findings are consisten with CNI toxicity?

Back 19

-often >6 weeks postop
-graft nontender
-good urine output
-gradual rise in SrCr (0.15 mg/dl/day)
-elevated CSA orTAC concentration

Front 20

How does humoral or vascular rejection happen?

Back 20

It is an antibody mediated process directed against HLA antigens on donor vascular endothelium (MHC II). It is less common than cellular rejection. It usually occurs in the first 3 months.

Front 21

Treatment of humoral or vascular rejection?

Back 21

-plasmapheresis with IVIG (antibody dialysis with antibody push)
-high-dose IVPB methylprednisolone
-cyclophosphamide
-rituximab (removes B cells)
-bortezomib (removes plasma cells)

Front 22

What is seen with chronic rejection?

Back 22

Hepatic allografts: vanishing bile duct syndrome
Cardiac: accelerated cardiac vasculopathy
Lung: bronchiole obliterations
Kidney: glomerulopathy

Front 23

Background on induction therapy.

Back 23

All patients except indentical twins need induction therapy to prevent rejection. You must deplete or modulate T cell function.

Front 24

What is the rationale for using IL-2 receptor antagonists (basiliximab) for induction therapy?

Back 24

They have a low cancer and infection risk vs. ATG. Higher cost but better graft survival vs. placebo. Higher rate of rejection than ATG but no difference in graft survival.

Front 25

What is the rationale for using lymphocyte depleting agents (ATG, ALG, OKT3) for induction therapy?

Back 25

They reduce acute rejection and graft failure in high-immunological risk patients. They also have higher risk of infections, cancer (PTLD), and other serious adverse events. Benefits outweigh the harm for high risk patients.

Front 26

What puts a person at high risk for acute rejection?

Back 26

1. Number of HLA mismatches
2. Younger recipient
3. Older donor age
4. African-American
5. PRA>0%
6. Presence of DSA (donor specific antibody)
7. Delayed onset of graft function

Front 27

KDIGO Induction Therapy Recommendations

Back 27

1. Combination induction therapy in the perioperative period (steroid, MMF, IL-2RA)
2. Biologic agent should be included in induction regimen (IL-2RA is first line, ATG for high immunological risk)

Front 28

What is steroid avoidance?

Back 28

Steroids for induction and then withdrawal within 1 week after transplant

Front 29

What is steroid withdrawal?

Back 29

Discontinuation after the first week

Front 30

Some maintenance therapy rationale.

Back 30

-earlier therapeutic levels of CNIs lowers risk of acute rejection
-delayed initiation of CNIs does not prevent delayed graft function (when kidney doesn't initially work)
-TAC improves graft survival and reduces risk of acute rejection vs CSA
-Low dose TAC reduces risk of NODAT
-MMF reduces risk of acute rejection compared to AZA
-avoiding maintenance steroids beyond 1st week reduces adverse effects without affecting graft survival
-mTOR inhibitors do not improve outcomes and have significant long-term adverse effects

Front 31

Tacrolimus vs. Cyclosporine, which is better?

Back 31

TAC has reduced acute rejection and better graft survival. There is moderate quality evidence that states TAC>CSA.

Front 32

MMF vs AZA, which is better?

Back 32

High quality evidence shows acute rejection is less likely with MMF and there is improved patient level outcomes. But, MMF is much more expensive.

Front 33

Benefits and Risk with Steroid avoidance or withdrawal

Back 33

Benefits: lower rate of long-term adverse effects
Risks: higher incidence of acute rejection
Evaluate on patient by patient basis

Front 34

What are the major adverse effects of mTOR inhibitors?

Back 34

-bone marrow suppression, dyslipidemias
-avoid combos with CNI as this can potentiate nephrotoxicity (leads to net harm)

Front 35

KDIGO Maintenance Therapy Recommendations

Back 35

-Use combination therapy: CNI, antiproliferative, with or without steroids
-TAC is 1st line CNI
-MMF is 1st line antiproliferative
-Low immunological risk patients could d/c steroids 1st week after transplant
-if mTOR inhibitor is used, wait until graft function is stable and wound have healed
-steroid withdrawal >3 months post transplant increases risk of rejection (if stopped, do so before 3 months)

Front 36

Low-Dose Tacrolimus

Back 36

-trough of 4-7 ng/ml
-preserves GFR
-decreased risk of NODAT