01-27 Transplantation

Question 1

What impact does kidney tranplant have on lifespan?

Answer 1

increases it significantly

—?most true of all the organ transplants (qqch comme ça)

Question 2

What is the breakdown of etiologies of ESRD by %?

Answer 2

Diabetic nephropathy 43%
Hypertension 28%
GN 11%
cystic kidney disease 3%

Question 3

What are the three phases of rejection?

Answer 3

1. Host recognizes grafts as foreign
   —APC presents to
   —HLA I (A & B) and HLA II (DR) are most important
2. T-cell cells are activated
   —Activation, prolif, and differentiation 3 signals
   —i. calcineurin [Rx inhibs] → NFAT
   —ii. co-stim CDs
   —iii. IL-2 (CD25) [Rx] & CD3 receptors [OKT3 Ab]
3. T-cells kill
   —CD4: release inflamm/attractant cytokines
   —CD8: initiate apoptosis (upreg Fas ligand/ granzymes/ perforin) increase number of B cells

Question 4

What are the components of “triple therapy”?

Answer 4

1. calcineurin inhibitor
2. steroid
3. anti-metabolite

Question 5

Calcineurin Inhibitors
—Examples
—MoA
—ADRs

Answer 5

EXAMPLES
—Cyclosporine, tacrolimus

MoA
—blocks the enzyme cacnieurin which usually de-phosphorylates the nuclear factor of activation of T-cells (NFAT)

ADRs
—TIN b/c activates TNF-B
—Rx diltiazem to help prevent this complication
—competitively inhibits the CYP that tacrolimus uses, so you only have to use 1/5 the dose
—Tacrolimus also really diabetogenic
—Others: hirsutism, neurotoxic, gingival hyperplasia, HTN, hyperlipidemia

Question 6

Steroids as immunosuppressants
—MoA
—ADRs

Answer 6

MoA
—block cytokines (coming from T-cells and APCs) and their receptors

ADRs
—weight gain (>20% lean body mass) – hypertension (salt retention) – hyperlipidemia – osteopenia – cataracts – skin changes(acne, wound healing, striae) – impaired growth – chemical diabetes

Question 7

Azathioprine

Answer 7

NO LONGER USED
– purine analogue incorporated into DNA inhibiting purine synthesis and metabolism of RNA
– inhibits gene replication, causing myelosuppression
– can cause disruption of hepatobiliary fn, diarrhea/nausea, and gout (esp. in combination with CSA)

Question 8

Mycophenolate (CellSept)
—MoA
—ADRs

Answer 8

MoA
– reversible inhibitor of inosine monophosphate dehydrogenase which is a rate-limiting enzyme for guanosine nucleotides
– guanosine nucleotides are essential for lymphocyte DNA and thus inhibition causes selective antimetabolism for both T and B cells

ADRs
– major ADRs: myelosuppression and dramatic diarrhea

Question 9

Why do we think transplant pts are at such elevated risk of ASCVD?

Answer 9

b/c of systemic inflammation chronically

Question 10

rapamycin (Sirolimus)
—MoA
—ADRs

Answer 10

(not used at DHMC)
MoA
– binds to FKBP but engages mTOR (target of rapamycin protein) which reduces cytokine- proliferation by arresting the cell cycle at the G1 and S phases
– non- calcineurin inhibitor side effects makes it appealing, has anti-metabolite effects against proliferating cells

ADRs
major side effects are wound healing, acne, myelosuppression, and hyperlipidemia

Question 11

Anti-CD25
—MoA
—ADRs

Answer 11

(not used at DHMC)
Examples
basiliximab

MoA
– prevent acute rejection by interfering with specific component of the amplification cascade of activated T cells

ADRs
– side effects are negligible but efficaciousness is ? especially in the low risk population

Question 12

Atgam and thymoglobulin
—MoA
—ADRs

Answer 12

– Atgam is horse-derived; thymoglobulin is rabbit-derived
– mode of action is lymphocyte depletion with predominance of T cells
– side effects: constitutional sx, anaphylaxis, serum sickness, leukopenia, and thrombocytopenia, infectious risk

Question 13

Alemtuzumab

—MoA

Answer 13

monoclonal antibody against CD 52 on all T cells; rapid depletion of ALL T cells

Question 14

Rituximab

—MoA

Answer 14

monoclonal antibody against CD20 antigen on B cells used for highly sensitized recipient, B cell or Humoral rejections, and post Tx lymphoproliferative disorders

Question 15

Bortezomib

—MoA

Answer 15

proteasome inhibitor which acts against NF-kappa beta transcription factor in turn blocking VCAM-1 which is necessary for plasma cells to bind to inflamed tissues; used in refractory B cell/humoral antibody rejections

Question 16

Hyperacute Rejection
—Players involved in response
—Presentation
—Tx?
—Prevention?

Answer 16

preformed IgG, anti-Class I and II ab
– Immediate ischemia, necrosis, thrombosis
– no therapy, prevented by the cross-match
– cross-match = test donor lymphocytes with the recipients’ serum which contain preformed, cytotoxic ab

Question 17

Acute Rejection
—Players involved in response
—Presentation
—Tx?

Answer 17

cellular and humoral immune response
– tubulitis, vasculitis, lymphocytic infiltrate
– Rx:anti-lymphocyte ab or iv steroids

Question 18

Chronic Rejection
—Players involved in response
—Presentation
—Tx?

Answer 18

alloantigen dependent and independent mechanisms
– interstitial fibrosis, tubular atrophy, glomerular sclerosis
– no effective treatment but is linked to under immunosuppression, as much as other causes of ESRD such as hyperfiltration injury, drug- induced toxicity, hypertension, etc.

Question 19

Increased risk of malig s/p transplant.

—Two biggest risks?

Answer 19

CNS Lymphoma: RR = 1000
Skin: RR = 300
—Melanoma, Basal cell, Squamous cell
—33% overall chance skin CA
NHL: RR = 7.4

Question 20

Common infections that transplant recipients get

Answer 20

– CMV, EBV, and BK virus
– UTIs account for 30% of all post Tx infections; transplant pyelo leads to decline by 30% of graft longevity
– 40% of solid organ transplant patients can die from influenza
– Opportunistic pathogens: nocardia, aspergillosis – Zoonoses infections: e.g. “Kennel cough” bacterium

Question 21

How long does pancreatic trans last?

What does pancreas transplant help prevent?

Answer 21

—last approximately 8-10yrs
—Require dual immunosuppressants indefinitely •

No effects upon:
- Gastroparesis - ASCVD - Retinopathy
Positive effects: - Nephropathy, Neuropathy, PVD