Surg Med - Transplant Surgery

transplantation

the process of transferring cells, tissues, or organs from one site to another to restore function

autograft

graft coming from the same individual (e.g., skin or bone) - no need for immunosuppression

isograft

graft coming from genetically identical twins

allograft

- “other” graft

- coming from someone else

- this is the most common!

xenograft

transplant coming from another species (ex: pig kidneys going into humans)

orthotopic

occurring in its natural place; organ being put back where it was previously; ex: remove old liver and put in new liver into same spot

heterotopic

occurring somewhere else than its natural location; ex: kidney transplant (place new kidney anterior in the abdomen instead of retroperitoneally)

1) MHC on APC finds an antigen from the donor organ and binds it

2) APC takes antigen back to secondary lymphoid tissues (LNs, spleen) and presents it to a T cell

3) CD8(+) T cells bind to MHC class I APCs (Signal 1); additional costimulation with CD80 bound to CD28 (Signal 2) helps to allow a T cell response

4) T cell makes IL-2 and other cytokines that kicks off T-cell proliferation

5) T cells are now CD8(+) and cytotoxic to the foreign object and lyse the cells from the donor organ

Describe the process of allogenic recognition.

donor MHC molecules from donor APC is recognized by recipient T cells, and these T cells realize something is not compatible

Describe the direct pathway.

donor MHC molecules are fragmented and taken up by the recipient's cells to be presented to the recipient's T cells

Describe the indirect pathway.

via the indirect pathway

What is the standard way that T cells encounter antigens?

direct pathway

Which pathway is thought to be more associated w/ acute rejection and occurs early on after a transplant?

identical twins (receiving isograft)

Who DOESN'T need immunosuppression after organ transplantation?

induction immunosuppression

a short course of potent immunosuppressive therapy given during the period of transplantation to prevent early acute rejection

1) polyclonal ATG*** (anti-thymocyte globulin)

2) basiliximab

3) steroids

What drugs are used for induction immunosuppression (given intraoperatively)?

corticosteroids (methylprednisolone, prednisone)

What maintenance immunosuppression agent?:

Indications: maintenance therapy, acute rejection treatment

Functions: MOA: binds to steroid receptors to inhibit antigen presentation, cytokine production, and lymphocyte proliferation

(they kind of do everything)

SEs: post-transplant diabetes, decreased bone density, wt gain, infxns

azathioprine (antimetabolite)

*2nd line - really only used if trying to get pregnant

What maintenance immunosuppression agent?:

Indications: one of the earliest immunosuppression drugs; alternative to MMF for pregnancy, intolerance to MMF

Functions: MOA: prodrug that releases 6-mercaptopurine. Inhibits reproductive cell cycle of T cells

SEs: leukopenia (bone marrow suppression)

Mycophenolate mofetil / mycophenolic acid (MMF/MPA) (antimetabolite)

** MAIN ANTI-METABOLITE USED FOR immunosuppression

What maintenance immunosuppression agent?:

Indications: better at preventing rejection that azathioprine

Functions: MOA: inhibits synthesis of nucleic acids → preventing T and B cell proliferation bc there is no nucleic acid to reproduce the DNA

SEs: leukopenia (bone marrow suppression), increased risk of infxn and CA, teratogenic, diarrhea and n/v (n/v is more common w/ MMF)

*MPA is enteric coated MMF (which can help with the n/v/d)

cyclosporine (calcineurin inhibitor)

What maintenance immunosuppression agent?:

Indications: maintenance therapy

Functions: calcineurin inhibitor, blocks T cell activation

SEs: nephrotoxicity, HTN, HLD, hirsutism, gingival hyperplasia, tremor

**CYP3A4 — If you mix this w/ CCBs, antifungals, paxlovid, erythromycin/clarithromycin, grapefruit juice = will have HA/tremor/confusion @ high doses

Decreased levels w/ rifampin and anticonvulsants

tacrolimus (calcineurin inhibitor) - MAIN CNI USED FOR IS (esp the immediate release) - one of the most effective immunosuppressants

What maintenance immunosuppression agent?:

Indications: better potency than cyclosporine; maintenance therapy, especially in kidney/liver transplants

Functions: calcineurin inhibitor, blocks T cell activation

SEs: nephrotoxicity, neurotoxicity (HA, tremor, confusion at high doses), post-transplant diabetes, alopecia, thrombotic microangiopathy (TMA) (syndrome of hemolytic anemia with low PLTs where you get organ damage from microscopic clots → usually switch pts to cyclosporine if this happens)

CYP3A4 — If you mix w/ CCBs, antifungals, paxlovid, erythromycin/clarithromycin, grapefruit juice = will have HA/tremor/confusion @ high doses

Decreased levels w/ rifampin and anticonvulsants

sirolimus (mTOR inhibitor)

What maintenance immunosuppression agent?:

Indications: when CNIs are not an option (usually d/t CNI toxicity or TMA), cancer post-transplant

Functions:

MOA: binds to FK-binding protein and block mTOR → interrupts DNA and protein synthesis in T cells, B cells, and NK cells

SEs: leukopenia (bone marrow suppression), dyslipidemia, delayed wound healing, aphthous ulcers, peripheral edema

Also CYP3A4 → similar interactions w/ CNIs

optimize immunosuppression regimen (make sure pt is getting enough immunosuppression to prevent them from having another rejection)

What is the general mgmt of acute/active rejection?

1) T-cell mediated rejection (tx: pulse steroids followed by a taper (+/- ATG if it's severe))

2) Antibody mediated rejection (tx: steroids, IVIG, +/- plasmapheresis, +/- 1-2 doses of rituximab)

What are the 2 types of active rejection?

1) ________________: T cells invade the tubules, interstitium, and possibly arterial intima

2) ________________: possibly d/t binding of antibodies to donor antigen on graft endothelium, leading to dysfunction

How is each treated?

hyperactive (hyperacute) rejection

What type of rejection?:

- Occurs in the first few minutes to hours post-transplant

- Prevented by induction immunosuppression given intraoperatively (ex: ATG)

acute/active rejection

What type of rejection?:

- Happens in weeks afterward, or anytime with nonadherence to IS meds

- Thought to be d/t direct pathway

- Inflammation often present

chronic rejection

What type of rejection?:

- Happens in months-yrs afterward

- Thought to be d/t indirect pathway

- Less likely to have inflammation present (more likely to have scarring instead tho which is irreversible)

* (-) crossmatch and blood typing

* psychosocial eval

* good health

What is the live donor criteria/process for organ transplantation?

* no malignancies

* no major infxns that are untreatable

* relatively healthy

What is the cadaveric donor criteria/process for organ transplantation?

DBD - donation after brain death

DBD or DCD?:

- ex: someone on life support in ICU

DCD - donation after circulatory/cardiac death

DBD or DCD?:

- ex: someone who comes in dead as you would expect them to be, then procure organs from there

ESRD stage 5 d/t HTN and DM

What are the main 2 indications for a kidney transplant?

~40hrs with a pump

What is the maximum time b/w harvest and transplant (i.e., cold ischemia time (CIT)) for patients receiving a kidney transplant?

10-15 yrs

What is the graft survival rate for a kidney transplant?

- attach ureter to bladder first

- attach vein

- attach artery

- unclamp

- see if it works

How do you do kidney transplantation?

heterotopic

Are kidney transplantations heterotopic or orthotopic?

kidney transplantation

The following are complications of...?:

- Delayed graft function (DGF) (Contributors: donor creatinine before procurement, CIT)

- Renal artery thrombosis

- Bleeding @ anastomosis

- Urine leak from anastomosis

- General surgical complications

- Acute liver failure, usually from viral and drug-induced hepatitis

- Decompensated cirrhosis with MELD > 15

- Hepatocellular carcinoma (HCC) (usually from alcoholism)

- 1 year survival prognosis (w/o transplant) of <90%

When would you want to consider a liver transplant?

- Cardiopulmonary dz that can't be corrected (bc this backs up into the liver and causes other complications)

- Metastasis or infxn (IS makes these things flare and get worse)

- Active alcohol use

- Too high of a MELD score (too ill to survive post-surgery)

When is a liver transplant contraindicated?

<12 hrs

What is the maximum time b/w harvest and transplant (i.e., cold ischemia time (CIT)) for patients receiving a liver transplant?

>10 yrs

What is the graft survival rate for a liver transplant?

- donor liver with common hepatic artery on an aortic patch, with IVC intact

- "Piggyback" technique happens when recipient native IVC is kept along w/ the donor IVC

What is the surgical technique for a liver transplant?

orthotopic

Is a liver transplant heterotopic or orthotopic?

bile duct complications

What is the main complication from liver transplantation?

T1 DM usually

Why would you want to do a pancreatic transplantation?

<12 hrs

What is the maximum time b/w harvest and transplant (i.e., cold ischemia time (CIT)) for patients receiving a pancreas transplant?

True

True or false:

- The pancreatic graft survival rate is less than that of livers/kidneys.

- typically placed along the right iliac vessels (usually done alongside a kidney transplant)

- can have exocrine drainage to duodenum or to bladder (higher complications (ex: metabolic acidosis))

What is the surgical technique for a pancreatic transplantation?

heterotopic

Are pancreas transplants usually heterotopic or orthotopic?

pancreas transplants

The following are potential complications of...?:

- graft thrombosis

- graft failure

- metabolic acidosis in bladder drainage

heart failure from nonischemic cardiomyopathy & CAD

What are the indications for heart transplants?

- acute pulmonary embolism

- current tobacco use

- uncontrolled DM

- kidney dz

Aside from standard contraindications, what other contraindications exist for heart transplantation?

4-6 hrs

What is the maximum time b/w harvest and transplant (i.e., cold ischemia time (CIT)) for patients receiving a heart transplant?

>12 yrs

What is the graft survival rate for a heart transplant?

sternotomy (on CPB)

What is the surgical technique for heart transplantation?

orthotopic

Is heart transplantation heterotopic or orthotopic?

heart transplantation

The following are complications of...?:

- primary graft dysfunction

- rejection

- infxn

- narrowing of coronary arteries

- COPD

- pulmonary fibrosis

- cystic fibrosis

- pulmonary HTN

- high likelihood for death w/o transplant

What are indications for lung transplantation?

high perioperative morbidity and mortality risk

When would lung transplantation be contraindicated?

6-8 hrs

What is the maximum time b/w harvest and transplant (i.e., cold ischemia time (CIT)) for patients receiving a lung transplant?

~6yrs

What is the graft survival rate for a lung transplant?

Anterolateral thoracotomy or sternotomy incision, then ligate the pulmonary artery/vein.

Anastomoses: bronchus, pulmonary artery, then pulmonary vein cuff to left atrium

What is the surgical technique for a lung transplant?

orthotopic

Are lung transplantations heterotopic or orthotopic?

higher rates of rejection than other organs → higher doses of immunosuppression → higher rates of infxns and CAs

What complications exist for lung transplantation?