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TRANSPLANTATION

SURGERY
July 24, 2013
by munsTHREEfic

DEFINITION

Transplantation transferring an organ, tissue or cell from


one place to another
Autotransplant transferring of tissue from one part of an
individual to another part of the same individual
Allotransplant from one individual to a different one of
the same species
Xenotransplant across species barriers

TRANSPLANT IMMUNOBIOLOGY
Transplant Antigens
- Major Histocompatibility complex (MHC) main antigen
trigerring rejection
- Human Leukocyte Antigen (HLA) Human MHC in
chromosome 6; responsible for recognition and rejection
- Main function to present as fragments of foreign protein
recognizable by T lymphocytes
- Rejection via Humoral (antibodies) or cellular mechanism
(T-lymphoctes)

Accelerated Acute
Within few days
Both cellular and antibody-mediated injury
Immunologic memory response
Acute
Within days to months
Cell-mediated process
Bipsy of affected organ reveals cellular infiltrate
with membrane damage and apoptosis of graft
cells
Fever, chills, malaise and arthralgia
Abnormal labs of organ involved
May also be mediated by Humoral response
Chronic
Months to years
Most common type of rejection
Characterized by atrophy, fibrosis and
arteriosclerosis
Clinically graft function slowly deteriorates

HLA Class

Class I HLA-A, -B, -C


-Found in membrane of nucleated cells

Class II HLA-DR, -DP, -DQ


-Generally expressed by antigen-presenting cells (APCs)
such as B-lymphocytes, monocytes and dendritic cells
ALLORECOGNITION AND DESTRUCTION
1. Direct method T-cells interact directly with donor HLA
leading to activation of cytotoxic T-cells
2. Indirection method via APC, who present to T-cells
*All T cell mediated

CLINICAL REJECTION *difference in time of reaction

Hyperacute
Within minutes
Preformed antibodies against donor
Platelet activation and diffuse intravascular
coagulation
Generally irreversible
Prevented by pretransplant crossmatching

CLINICAL IMMUNOSUPPRESSION

Induction immunosupression immediate postransplant

Maintenance immunosuppression

Classified into
1. Biologic Agents usually used as induction
2. Nonbiologic agents maintenance
st
*if there os no evidence of rejection for the 1 few weeks, consider
chronic rejection
Classification
1. Immunophilin binders

Calcineurin inhibitors
Cyclosporine
Tacrolimus (FK506)

Noninhibitors of calcineurin
Sirolimus (Rapamycin)
-

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2.

Antimetabolites
Inhibitors of de novo purine synthesis
Azathioprine
Mycophenolatemofetil (MMF)

Inhibitors of de novo pyrimidine synthesis


Leflunomide
3. Biologic Immunosuppression

Polyclonal antibodies
ATGAM
Thymoglobulin

Monoclonal antibodies
OKT3
IL-2R (humanized)
4. Others

Deoxyspergualin

Corticosteroids

FTY720
CORTICOSTEROIDS
First line agents for acute rejection
Anti-inflammatory and immunosuppressive
Inhibit production of T-cell lymphokines
Lymphopenia redistribution of lymphocytes to
lymphoid tissues, inhibit migration of monocytes
First line of choice for acute cellular rejection
Induction and maintenance therapy
Cushingoid state, glucose intolerance, impaired wound
healing, risk of opportunistic infection, osteoporosis and
growth retardation in children
*used in bronchial asthma in pediatric patients
AZITHIOPRINE
AZA acts by interfering with DNA synthesis thus
suppressing proliferation of activated B and T-cell
Preventing onset of acute rejection
Bone marrow suppression of all hematopoietic cells
Hepatixic, GI disturbances, pancreatitis and alopecia
Suppression is dose-related
Allopurinol inhibits breakdown of AZA
CYCLOSPORINE
Renal and especially extrarenal transplant
Selective inhibition of immune response
Maintenance
Binds with cytoplasmic receptor protein, cyclophilin, which
inhibits calcineurin
Calcineurin activates T-cell expression leading to
IL-2
Metabolized via-cytochrome P450 system
Nephrotoxic vasoconstrictor effect
Hirsutism and gingival hyperplasia
TACROLIMUS
Soil fungal metabolite (Streptomyces tsukubaensi)
Acts by binding FK506-binding protein (FKBPs) resulting
Tacrolimus FK506 complex inhibits calcineurin
100 times more potent than cyclosporine
Nephrotoxic and neurotixic
Hyperglycemia
Risk for infection and malignancy
SIROLIMUS
Soil actinomycete
Similar to Tacrolimus
Does not affect calcineurin activity
Binds with target of rapamycin (TOR) resulting in inhibition
of P7056 kinase > halting cell division
Used in combination with calcineurin inhibitors

Not associated with long term nephrotoxicity


Neutropenia, thrombocytopenia hypertriglycerolemia, and
impaired wound healing
MYCOPHENOLATE MOFETIL
Mold Penicillium glaucum
De
Inhibits inosine monophosphate dehydrogenase, a catalyst
for the formation of guanosine nucleotides from tyrosine
Selective, reversible antiproliferative effect on T and B
Lymphocytes
effective because selective
Does not affect cytocrine production
Antimetabolite but more effective than AZA
Dose related, reversible Leukopenia
POLYCLONAL ANTIBODIES
Produced by immunizing animals with human lymphoid
tissue
Use to prevent rejection and to treat acute rejection
episodes
Antithymocyte globulin (from horses)
Thymoglobulin (from rabbits)
MONOCLONAL ANTIBODIES
more specific
Hybridization of murine antibody-secreting B lymphocytes
OKT3 most commonly used MAB
Directed against CD3 antigen complex found in all mature
human lymphocytes
Efficacy measured by monitoring CD3-postive cell levels
<5% : effective
>5% : ineffective
-

Treat severe acute rejection


Life-threatening adverse reaction 2* to cytokine released
in circulation
Severe pulmonary edema
Basiliximab and Dacluzimab-currently approves to target
IL-2 receptors
Alemzumab-directed against CD52 antigen found in B and
T cells

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Return to liver volume within 4-6 weeks after


donation

Hypothermia to slow down metabolic processes

University of Wisconsin (UW) solution most commonly


used fluid worldwide
1. Lactobionate impermeable and prevents
intracellular edema
-lowers intracellular calcinerin and free iron
2. Hydroxyethyl starch decreases hypothermiainduced intracellular swelling
3. Raffinose
KIDNEY TRANSPLANT

First organ to be transplanted and remains the most


common

Treatment fo choice for end stage renal disease (ESRD)

The recipient operation is done through a retroperitoneal


incision using the iliac vessels to revascularize the kidney
and a ureteronneocystostomy to establish urinary
continuity

ORGAN PROCUREMENT AND PRESERVATION


Deceased donor
Living donor
1. Deceased donor

Criteria for clinical diagnosis of brain death


1. Irreversibility of neurologic insult
2. Absence of clinical evidence of cerebral function
3. Absence of clinical evidence of brain stem function

Dissection for cadaver kidney donation. Cannulas are


placed in the aorta and vena cava for hypothermic
perfusion to protect the kidneys during the terminal
phases of the operation and for short-term storage.
Segments of the aorta and vena cava are left intact when
the kidneys are separated. The use of a Carrel patch of
aorta is especially helpful when there are multiple renal
arteries.
2. Living Donors

Advantages
Availability of life-saving organs
Shorter waiting time
Planned procedures
Superior long term results

Disadvantages
To the donor

The guiding principle of all living-donor transplants should


be the minimization of risk to the donor

Kidney most common organ


Normal renal function w/ 2 equally functioning kidney
and they do not have any significant factors for
developing renal disease
Left kidney preferred longer vein

Liver
Left lateral segment (*longer)

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Infection most common

PANCREATIC TRANSPLANT (PT)

Concomitant with kidney transplant

PTA (alone) in nonuremic diabetics if their daily quality of


life is poor

Three types of drainage


1. Enteric drainage
2. Urinary drainage
3. Duct injection

Options:
1. Deceased-donor, simultaneous pancreas-kidney
transplant (SPK) most common
2. Living-donor kidney followed weeks and months by
deceased-donor pancreas transplant
3. Simultaneous decreased-donor pancreas and livingdonor kidney transplant (SPLK)

Preoperative Preparation

Medical

Surgical

Immunologic

Psychosocial

Cardiac Evaluation

Untreated cancer and active infection is a contraindication


to a transplant

Concentrate on GI problems

Vascular or urological abnormalities (esp. chronic


infection)

Determine blood & tissue type (HLA-A,-B, or DR antigens)


and presence of antibodies against HLA
3 things to check before operation:
tissue typing, blood type matching, serum matching

Early Postoperative Care

Stabilization of major organ systems

Evaluating of graft function

Achieving adequate immunosuppression

Monitoring and treating complications directly and


indirectly related to the transplant
Complications

Hemorrhagic hilum and retroperitoneum

Vascular complications
1. Renal artery thrombosis urgent thrombectomy
2. Stenosis interventional radiology and surgery
3. Renal vein thrombosis nephrectomy

Urologic complications leakage & obstruction

Lymphocele fluid collection of lymph that results from


cut lymphatic vessels
Mass effects and compression

The goal of late posttransplant care is 1) optimized


immunosuppression, 2) monitoring of graft function and 3)
to monitor complication

Drainage Procedures
1. Bladder drainage
-measure pancreatic graft activity via urinary amylase
-10-20% converted to enteric bypass
2. Enteric drainage (*jejunum)
-more physiologic and fewer long term complications
-Rejection in SPK almost always affects both kidney
and pancreas, therefore, serum creatinine is a marker
for rejection
Complication

Thrombosis graft removal

Hemorrhage

Pancreatitis self limited secondary to ischemic


preservation injury

Urologic complication calculi, UTI, leaks

Infection significant problem


ISLET TRANSPLANTATION

OPD procedure

Deceased-donor isolating islets w/ complex process

Purified cells injected into the portal vein

Disadvantage long term immunosuppression, rejection


difficult to monitor

Microencapsulation to prevent immunosuppression

Dismal results 5%

Multiple Organ donation, non-steroid immunosuppression

May replace whole organ transplantation


LIVER TRANSPLANT

Indicated for liver failure acute or chronic

Disease amenable to liver transplant

Chronic diseases account for the majority of liver


transplant w/ chronic hepatitis (Hep C)

Chornic hepatitis Cirrhosis 10-20 yrs

Hepatocellular carcinoma single lesions <5cm in size or


with no more than 3 lesions
-fibrolamellar hepatoma

Fulminant hepatic failure acute disease characterized by


hepatic encephalopathy and profound coagulopathy with
onset of symptoms
Diseases amenable to treatment with transplant

Cholestatic liver disease


Primary Biliary Cirrhosis
Primary sclerosing cholangitis

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Biliary atresia
Alagile syndrome
Chronic Hepatitis
Hepatitis B
Hepatitis C
Autoimmune hepatitis
Alcoholic Liver Disease
Metabolic diseases
Hemochromatosis
Wilsons disease
Alpha1-antitrypsin deficiency
Tyrosinemia
Cystic fibrosis
Hepatic Malignancy
Hepatocellular carcinoma
Neuroendocrine tumor liver mets
Fulminant heptic failure
Other
Crytogenic cirrhosis
Polycystic liver disease
Budd-Chiari Syndrome
Amyloidosis

DECOMPENSATED CIRRHOSIS

Hepatic encephalopathy

Ascites

Spontaneous bacterial peritonitis

Portal Hypertension bleeding

Hepatorenal syndrome

Others
Sever weakness and fatigue
Fulminant Hepatic Failure (FHF)

Coagulopathy impaired hepatic synthesis of clotting


factors

Bacterial infection respiratory and urinary system

Multiple organ dysfunction syndrome

Cerebral edema 80% who died of FHF

Contraindication to Transplant

Severe hypoxemia

Right atrial pressure >60 mmHg

Uncontrolled systemic infection and malignancy

Ongoing Substance abuse-most common

Hepatopulmonary syndrome impaired gas exchange


secondary to intrapulmonary shunting especially when
patient is upright (orthodeoxia)

Pulmonary Hypertension
Surgical Procedure
Usually in orthotopic position (same place).

Pre-anhepatic phase mobilizing the recipients disease


liver in preparation for removal
Anhepatic phase liver removed
Decrease venous return
Venovenous bypass (VVP) system
New liver placed orthotopic position
Post-anhepatic phase reperfusion
Hypotension, cardiac arrhythmias, coagulopathies
Biliary anastomosis

Variations

Piggy-back technique improved hemodynamic stability,


improved kidney perfusion, avoidance of VVB

Use of living-donor
Pediatric left lateral segment or left lobe
Adult right lobe

Split-liver transplant

The Donor procedure, UW, University of Wisconsin solution


LIVING - DONOR TRANSPLANT

Avoids lengthy waiting

Pediatrics lateral segment (25%)

Adults right lobe (60%)

Complications
-bile leak
-intrabdominal infection
-DVT and PE (*pulmonary embolism)
SPLIT LIVER TRANSPLANTS

Donor is split to be transplanted to 2 recipients = left later


and extended right lobe

One of pediatric and one for adult recipient


Postoperative Care
1. Stabilization of major organ systems
2. Evaluating organ function and achieving adequate
immunosuppression
3. Monitoring and treating complication directly or indirectly
related to transplant
*Complications

Bleeding

Hepatic artery thrombosis Doppler ultrasound


-urgent re-exploration

Thrombosis of the portal vein

Biliary complications 10-30% of all recipients

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Primary nonfunction of the hepatic allograft


Mortality rate > 80%
Results from poor or no hepatic function from the
time of the transplant procedure
Urgent retransplant

Medical Complications

Neurologic Complication
Deceased sensorium 2* to sedation, proof function of
the graft, central pontine myelinolysis
Seizures

Pulmonary System most common site, infectious


75%

Kidney dysfunction HRS(*hepatorenal syndrome) or ATN


(*acute tubular necrosis)

Infectious complications
PEDIATRIC LIVER TRANSPLANT

Biliary Atresia most common indication

Metabolic disorfer
Alpha 1-antrypsin deficiency most common
Tyrosinemia
Wilsons disease copper accumulation

Chronic hepatitis

Hepatoblastoma

Recipients size

Graft implantation may be more demanding

VVB not possible

HAT more common

Survival rates 80-90% in 1 year


INTESTINAL TRANSPLANT

1996 first transplant in humans

Lest performed transplant

High rejection rates

For irreversible intestinal failure not successfully managed


by TPN or has life threatening complications

Most patients can tolerate resection of 50% of intestine


with subsequent adaptation

>75% require TPN

Living-donor 200cm of ileum

Deceased-donor SMA based

Endoscopy to a stoma is only reliable method to monitor


rejection

Associated with high complication rate


HEART TRANSPLANT
End stage Failure

Ischemic or dilated cardiomyopathy

Intractable angina

Valvular disease

Congenital heart disease

Life threatening recurrent ventricular arrhythmias

Isolated intracardiac tumors

Cardiac output maintained by establishing 90-110 heart


rate
Swan-Ganz catheter monitoring
Monitoring of lung graft failure
Transcbronchial biopsy for rejection
Bronchoalveolar lavage for early infection
Cardiac tamponade (*presence of fluid at pericardium)

Complications

Airway complications poor blood supply

Bronchial anatomosis complications bronchoscopy


*Signs of dehiscence
- abnormal looking mucosa
- loosened suture or knots
- herniation of tissues into the airway

Infection Candida and Aspergillus (more serious)

Rejection acute or chronic


Infection

Risk Factors
1. Surgery itself
2. Long-standing end-stage organ failure
3. Impaired tissue healing
4. Poor vascular flow due to coexisting illness
MALIGNANCY

Skin Cancers
o Squamous or Basal Cell Carcinoma
Human papillomavirus DNA

Posttransplant Lymphoproliferative Disorder


o Lymphomas
o B-cell proliferative disorder associated with EBV
o Central nervous system involvement
o Treatment-reduction of immunosuppresin,
Ganciclovir, surgery, chemotherapy, monoclonal
antibodies against B-cells (anti-CD20 MAB)
FUTURE OF TRANSPLANTATION

Xenotransplantation pig (they stay away from primates)

Cellular transplant injection of cells that have the


potential to replace cells in an organ that has been
damage by disease thereby augmenting the function of
that organ (stem cells)

Organogenesis growing organs de novo

Artificial or bioartificial devises primarily temporary


devices

LUNG TRANSPLANT

COPD

Idiopathy pulmonary fibrosis (idiopathic?)

Cystic fibrosis

Pulmonary hypertension

Combined transplant pulmonary hypertension with


right-sided heart failure and Eisenmengers syndrome
Postoperative care and Complications (Heart and Lung Transplant)

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