PHRM 542 Solid Organ Transplant Introduction and Induction Therapeutics

How long does it take for GFR to return to normal after a kidney transplantation?

Normal/near normal almost immediately

How long does it take for SCr/BUN to decrease after a kidney transplantation?

SCr/BUN decrease over days

Define delayed graft function (DGF)

Need for dialysis first 7 days post-op

Failure of SCr to fail by at least 30% of the pre-transplant value

What are causes of DGF?

Acute tubular necrosis (ATN)

Donors with cardiac arrest, hypotension, on vasopressors/shock, older than age 55

Define donor ischemic time

The amount of time blood was not flowing through the organ prior to donation

What are the types of rejection?

Hyperacute

Acute

Chronic

What are the two types of acute rejection?

T-cell mediated (cellular)

Antibody mediated (vascular or humoral)

Describe the pathophysiology of rejection

Primarily mediated by activation of alloreactive T cells and antigen-presenting B lymphocytes, macrophages and dendritic cells

What primarily causes acute rejection?

Infiltration of T cells into the allograft triggering inflammatory and cytotoxic graft effects

What is involved in chronic rejection?

Cellular cytokines, cell-cell interactions, CD4+ and CD8+ T cells and B cells

Describe acute cellular rejection (ACR)

Alloreactive T lymphocytes infiltrate allograft through vascular endothelium followed by cytotoxic cells targeting and killing functioning cells and allograft

Local release of lymphokines attract and stimulate macrophages to produce tissue damaged through delayed hypersensitivity-like mechanism

What is a sign of ACR in a kidney transplant?

Abrupt rise in SCr by ≥ 30%

Biopsy specimen with a diffuse lymphocytic infiltrate

What are causes of ACR?

Suboptimal immunosuppression therapy

Non-adherence to immunosuppression therapy

Reduction in immunosuppression medications

Infection

Cancer

What is antibody mediated rejection (AMR)?

Presence of antibodies directed against HLA antigens present on the donor vascular endothelium

Antibodies activate complement, which creates a membrane attach complex that directly damages the organ and further attracts inflammatory cells to the allograft

What three criteria are needed for a definitive diagnosis of AMR?

Presence of donor-specific antibodies against HLA antigens

Immunofluorescence staining of complement fraction C4d deposits in the peritubular capillaries

Histologic evidence of capillaritis

Evidence of allograft dysfunction

Define capillaritis

Accumulation of inflammatory cells in graft capillaries

When does AMR generally occur?

In the first 3 months after transplantation

What is AMR associated with?

Increased fatality rate

What is C4d?

A product of activation of the complement cascade formed after cleavage of C4 is covalently bound to endothelial tissue at the site of complement activation

What is a major cause graft loss?

Chronic rejection

What is the presentation of chronic kidney allograft dysfunction?

HTN

Proteinuria

Progressive decline in GFR

What are contributing factors to chronic kidney allograft dysfunction?

CNI nephropathy, polyomavirus infection, HTN

What are risk factors associated with chronic kidney allograft dysfunction?

Ischemic donor time, recurrence of primary kidney disease

Define cardiac allograft vasculopathy (CAV)

Intimal thickening and diffuse atherosclerosis in graft coronary arteries (leads to a narrowing of coronary arteries)

How can CAV be prevented?

Statins

Low-dose aspirin (not studied)

Glycemic control

Prevent CMV infection

Prevent ACR

What is the treatment for CAV?

Add sirolimus

What are the three stages of medical immunosuppression?

Induction therapy to prevent rejection

Maintenance immunosuppression therapy to prevent rejection

Treatment of acute rejection

What are examples of induction therapy in kidney transplantation?

Thymoglobulin (rATG)

Alemtuzumab or Basiliximab

What is an example of maintenance therapy in kidney transplantation?

Prednisone

CNIs (or belatacept)

Mycophenolate mofetil or enteric coated MPA/EC-MSP

What is the goal of induction therapy for transplant patients?

Provide high level of immunosuppression during time period when risk of acute rejection is the highest

What patients are at higher risk of acute transplant rejection?

History of previous transplants

Panel reactive antibody (PRA) > 0%

One or more HLA mismatches

Transplant organ with ischemic time > 24 hrs

Blood group incompatibility

Younger recipient and older donor

African/Caribbean descent (in US)

Delayed onset graft function

What is a common induction agent for transplant patients?

Methylprednisolone IV at induction

Prednisone oral

Rabbit antithymocyte globulin (rATG)

Thymoglobulin

What is the MOA of rATG?

Lymphocyte depleting agent

How long after transplantation is rATG administered?

For up to 3-7 days after transplantation

What are ADEs of rATG?

Cytokine release syndrome (CRS)

Fever, chills, HA, diarrhea, malaise, dizziness, leukopenia, thrombocytopenia, generalized pain, infection (particularly CMV)

Serum sickness delayed 14-30 days, fever, rash, arthritis, glomerulonephritis

What should be done before administration of rATG?

PREMEDICATION with diphenhydramine 50 mg and acetaminophen 500-1000 mg (and methylprednisolone)

When is rATG contraindicated?

In allergy/anaphylaxis to rabbit protein

Alemtuzumab

Campath

What is the MOA of alemtuzumab?

Monoclonal Ab CD52

What are ADEs of alemtuzumab?

ISMP high alert medication with a REMS

Infusion reactions = gradually escalate dosing

HA, fatigue, rash, nausea, diarrhea, pain, infection

What are other boxed warnings of alemtuzumab?

Thrombocytopenia, malignancies, stroke (within 3 days)

What should be done before administering alemtuzumab?

PREMEDICATION with diphenhydramine 50 mg, acetaminophen 500-1000 mg (and methylprednisolone)

What is the MOA of basiliximab?

IL2-RA (non-depleting)

Monoclonal Ab CD52

Does basiliximab require premedication?

No

Which induction therapy is no longer routinely used?

Alemtuzumab

What are drug options for induction in high risk transplant patients?

"High-dose" thymoglobulin

Alemtuzumab as an alternative but rarely used

What are drug options for induction in low risk transplant patients?

"Low-dose" thymoglobulin with basiliximab as an alternative