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Surgery JUNICO T.

VISAYA, MD March 10, 2017

INTRODUCTION TO TRANSPLANTATION

Transplantation
- transferring an organ, tissue or cell from one place to another

Types
1. Autograft same person (Skin graft)
2. Allograft same specie (Usual transplant)
3. Isograft identical twin (1st kidney transplat)
4. Xenograft other specie (Pig)

History: Several Key Events


1. Carrel technique of anastomosis
2. Yuyu Voronoy human-to-human KT
3. Peter Medawar skin grafting rejection immunology
Paul terasaki
4. Murray 1st successful in terms of long term function
5. 60s AZA Steroid ATG Concepts & nomenclature
Starzl liver transplant 1. Recognition of danger
6. 80s CYA 2. Histocompatibility
90s Induction immunosuppression improved long term Major histocompatibility complexes
outcomes MICA
Minor
3. T-cells

Immune system defense against pathogens, prevents tumor


growth, graft rejection

In order to understand the alloimmune response, it is necessary to


understand how the host recognises and responds to danger.
In the context of transplantation, this is the ability of the recipient
to distinguish between self and non-self

Recognition of danger
SELF v. NON-SELF
Antigen-presenting cells (APCs)

Danger to the host is sensed through pattern recognition receptors


on APCs (e.g. TISSUE MACROPHAGES, DENDRITIC CELLS)

APCs engulf, process and present peptide antigen on their cell


surface in the context of mhc antigens Migrate to lymphoid
tissue and present the antigen to T cells resulting to an adaptive
response (stimulatory v. Inhibitory)

Histocompatibility
MHC or HLA in humans
Immunology Class I (HLA-A, HLA-B, HLA-C)
- Follows the basic rule of ABO compatibility Class II (HLA-DP, HLA- DQ, HLA-DR)

Histocompatibility antigens were first defined on the basis of their


preventing transplantation between outbred members of the same
species (mice by Snell).

Genes responsible for rejection were found on chromosome 17 at


just one locus this complex was termed MHC

MHC in humans is termed as the HLA, these are a set of genes


located on the short arm of chromosome 6.

6 main loci grouped into class I and II.. Most important of these
are A B DR.

Donor-recipient mismatches at these loci have a much greater


effect on rejection than mismatches at other loci.

Just to emphasize the importance of HLA matching.


The more mismatches the poorer the outcome or graft survival.
Surgery JUNICO T. VISAYA, MD March 10, 2017

Now improved outcomes because of better immunosuppressive T CELLS


drugs
CD8+ T cells
cytotoxic
Types of MHC molecules R: antigenic peptides derived from intracellular protein
in MHC class I
Cell-surface glycoproteins expressed on all nucleated lyse cells that display peptide recognised as foreign
cells
Binds and presents peptides derived from intracellular T cells play a major role in cell-mediated immunity
proteins (endogenous peptides) Highly specific; defects lead to autoimmunity
Polymorphic alpha chain (heavy chain) non-covalently Recognize peptide antigen bound to MHC displayed on the surface
bound to a non-polymorphic beta chain (light chain) of APCs, and upon receiving the appropriate co-stimulatory signals
Alpha and beta chains covalently bonded to each other Are capable of either:
Only on antigen-presenting cells (apcs) 1. Cytotoxic activity, or
Binds extracellular proteins that have been brought 2. Coordinating the innate immune response
inside the cells through endocytosis (exogenous
peptides)
CD4+ T cells
MHC Class I helper
all nucleated cells R: extracellular in MHC class II
binds endogenous peptides coordinates the innate immune response
MHC Class II promotes activation & proliferation of CD8+ T cells
present only on APCs, B cells absence can abolish rejection
binds exogenous peptides

Common to both is the presence of a peptide binding groove.


Different peptides line the groove and determine which other Phases of immune response
peptides can bind in the groove.
Highly polymorphic! So it can express hundreds of variants of mhc 1. Allorecognition
proteins,
2. Activation of lymphocytes
Antigen associates with MHC molecule T cell recognizes T-cell activation
combination initiates T cell activation
MHC class I proteins present ag to CD8+ (cytotoxic) t-cells. Th cells activate Tc cells along different pathways,
Important roles in defense against viral infection and malignancy. depending on the cytokine milieu
lead to Rejection
MHC class II present ag to CD4+ (helper) t-cells. Cell-mediated
Defence against extracellular infections. Antibody-mediated
or Regulation limits immune response

Types of allorecognition 3. Effector phase

- Recipient T-cells respond to intact MHC-peptide complexes Cytolytic CD8 t cells + NK cells cell death by
on donor APCs from the graft. 1. Release of soluble cytolytic factors (granzymes,
- APCs from the graft directly present the foreign MHC perforins)
molecules for recognition by the alloreactive t cells in the
context of cd4 and CD8. 2. Apoptosis
- Recipient t-cells respond to donor mhcs presented on CD4 helper t cells + B cells/plasma cells antibodies
recipient APCs cause cell damage by
-Donor MHCs are shed from the cell surfaces 1. Fixing complement
-Shed donor MHCs are taken up by recipient APCs, 2. 2. Mediating ab-dependent cell
then processed, then presented as foreign peptides in cytotoxicity (ADCC)
the context of CD4
Cell-mediated rejection
most acute allograft rejections are cell-mediated
Other Histocompatibility Genes In Rejection initiated when donor antigens are presented to the
MICA recipient T cells by APCs
MHC class I chain-related A antigens CD8+ and CD4+ T cells
functions related to innate immunity
contribution to rejection is controversial Antibody-mediated rejection
hyperacute/accelerated - results from preformed
miH antibodies
minor histocompatibility antigens deposition of antibodies against HLA antigens
less polymorphic expressed on the endothelium of the microvasculature
weaker response damage by complement fixation or ADCC
role in bone marrow transplantation Prior sensitizatioon
Fetal maternal reactivity
Previous transplant
Multiple bt
Surgery JUNICO T. VISAYA, MD March 10, 2017

- minimizing side effects of immunosuppressive


medications

4. Decline (Homeostasis) Dr. Merril (credited as the father of nephrology) explaining the
5. Memory artificial kidney machine (prototype of the dialysis machine) to
Richard and Ronald herrick.
KEY POINTS
Fundamental principle of transplant immunology Dr Joseph Murray performing the the 1st succesful KT at Peter
ability to recognise non-self as foreign. Bent Brigham hospital
MHC antigens present foreign peptide to T cells exist
in 2 classes
class I (HLA-A, -B, -C)
class II (HLA-DP, -DQ, -DR) Transplantation in the Philippines
Antigen is presented in the context of MHC class I to
CD8+ T cells, class II to CD4+, through direct and
indirect pathways of allorecognition.
Following T cell activation, nave T cells are induced to
various cell lineages.
Cell-mediated rejection characterised by infiltration
of CD4+ and CD8+ T cells into the allograft, giving
rise to inflammatory cytokine production and apoptosis.
Antibody-mediated rejection involves production of
antibodies resulting in endothelial damage, activation of
complement and microthrombi formation.

Accredited Transplant Hospitals


Lorma
AUF
R1MC
NKTI
SLMC
PGH
MDH
CAPITOL MC
QMMC
UST FEU UE PERPETUAL
CARDINAL SANTOS MC
MEDICAL CITY
Iloilo
Bacolod
Chong hui
Vicente Sotto
Cebu Doctors
Davao MC
Davao Doctors
Davao RH

Philippine statistics
ESRD is the 7th leading cause of death among the
Goals of Post-transplant Management
Filipinos.
1. Prevention of graft loss due to rejection One Filipino develops chronic renal failure every hour
(prolong graft survival)
2. Prevention of death with a functioning graft 120 Filipinos per million popn
(prolong patient survival) per year
- early detection & appropriate management of 10,000 12,500 new ESRD
complications cases annually
Philippine Renal Disease Control Program
Surgery JUNICO T. VISAYA, MD March 10, 2017

Philippine Renal Disease Registry Post-operative mgt


ICU setting
Neurovital signs q15mins - qhourly,
thermoregulation
Oxygenation
UO, drains qhourly
Fluid replacement/ hydration
watch out for congestion, dehydration
Pain management (no NSAIDs)

Vascular access complications

Peritoneal dialysis complications


Daily CBC, creatinine
other labs as necessary
Early mobilization/ambulation, deep breathing exercises
Who is Eligible for a KT?
DVT
Pneumonia
All patients with irreversible kidney disease Daily weight monitoring
requiring/eventually requiring dialysis to survive water retention
Most common causes of kidney failure:
Diabetes mellitus (DM)
Hypertension (HTN)
Glomerulonephritis (GN) Complications
Polycystic kidney disease (PKD) IMMUNOLOGIC
Rejection
healthy enough to undergo surgery NON-IMMUNOLOGIC
no severe/non-treatable issues with heart or lungs, CNI toxicity
recent cancer, or significant non- adherence to Infectious
medications or dialysis (good track record in dialysis, Hematologic, etc.
compliance with meds) SURGICAL (early)
Sufficient funds ( follow up costs, maintenance Bleeding, hematuria, thrombosis
medications) Urine leak
Seroma, infection

Kidney Transplant Work up for low urine output


Renal or kidney transplantation is the established
standard treatment for ESRD patients. HISTORY
It involves the transfer of a healthy and functioning Sudden decline vs. primary anuria
kidney from either a living or deceased donor. Donor source, ischemia time
Procurement of donor organ, either from a living or Volume status
clinical, CVP
deceased donor
Patency of FC, tubings, collecting bag
Ultrasound/renal scan
Kidney biopsy
Allograft function Low threshold to explore if suspecting thrombosis

IMMEDIATE URINE LEAK


brisk diuresis Verified by renal scan/scintigraphy, fluid creatinine
rapidly decreasing serum creatinine Manifests as abdominal pain, wound leak/discharge, decreased
urine output, increasing serum crea
SLOW 3rd -5th pod, due to anastomotic technique or devascularization of
not anuric ureter
does not require dialysis
may be due to prolonged ischemia
LYMPHOCELE
DELAYED Perigraft fluid collection confirmed by ultrasound
minimal/ no urine output Fluid crea determination
requires dialysis support
variable causes STRICTURE
RGP
Surgery JUNICO T. VISAYA, MD March 10, 2017

5-year graft survival (living donor)


Goals of Post-transplant Management Based on US data in 2009, the 5-year survival of living donor renal
Prevention of graft loss due to rejection transplant and liver transplant has been reported at 91% and 79%,
Prevention of death with a functioning graft respectively.1
- Early detection & appropriate management In the Philippines, our graft survival rate approximates that of the
of complications US.
- Minimizing side effects of General surgeons now have a greater likelihood of encountering a
immunosuppressive medications posttransplant patient because of these improved survival.
With my training limited only to the field of renal transplantation,
Newer goal: prevention of all acute rejection episodes and with this surgery being the most commonly performed
- Acute rejection has a negative impact on transplantation in the country,
long-term graft survival from now on and for the remainder of the lecture, transplantation
- Treatment of acute rejection is expensive will refer only to renal or kidney tranplantation.
and is associated with morbidity

Maintenance Immunosuppression

Usually comprises a combination of:


Corticosteroid
Lymphocyte proliferation inhibitor
- Azathioprine
- Mycophenolate mofetil
- Sirolimus
Calcineurin inhibitors Cyclosporine, Tacrolimus

Risks of Immunosuppression
Immunodeficiency state
- Infections
- Post-transplantation lymphoproliferative
disease (PTLD)
Non-immune drug toxicity Causes of Death in Renal Transplant Recipients with
- Hypertension Functioning Grafts
- Diabetes mellitus
- Hyperlipidemia
- Bone marrow depression
- Nephrotoxicity

Clinic Visit Schedule

Organ transplantation has been around for more than a half century
now.
Most of the deaths occuring after renal transplantation are due to
CARDIOVASCULAR DISEASES ACCOUNTING FOR
ALMOST HALF OF DEATHS IN PXS WITH FUNCTIONING
GRAFTS!
But the most recent advances, particularly in the management and
the surgical techniques of solid-organ transplantation have led to a
growing number of patients living long term with transplanted
organs.
Measures to Improve Graft Survival
Living related donors ABSOLUTE CONTRAINDICATIONS
Preemptive transplantation
Younger previously healthy cadaver donors
Short life expectancy (<1 year)
Zero HLA mismatching
Untreatable malignancy
Better donor preparation
Untreated acute or chronic infection
ACE I, ARBs
Uncontrolled psychiatric disorder
High quality general medical care
Active substance abuse
Demonstrated non-compliance with medications, check
ups
Benefits Of Successful Renal Transplantation ABO blood group mismatch
Optimal treatment for most patients with End Stage Positive cross-match
Renal Disease
Improved quality of life Who can donate a kidney
Reduced medical expenses
Survival advantage LIVING DONATION
Anyone 18 years and older
Physically fit
Has undergone a complete work-up
Surgery JUNICO T. VISAYA, MD March 10, 2017

DECEASED DONOR ORGAN DONATION


5-65 years of age
Irreversible brain injury
accident victim
intracranial hemorrhage
anoxic brain death
primary brain tumor

No chronic renal disease


No severe hypertension
No active infection
No systemic malignancy
No high risk behavior/current IV drug abuse
No prolonged hemodynamic instability (cardiac arrest*)
Creatinine: < 1.5mg/dl

Philippine laws on organ donation

1949 RA 349 Medical, surgical , scientific purposes


1954 RA 1056 Amendments to RA 349
1975 PD 856 Transplant, medical, research
purposes
1991 RA 7170 Organ Donation Act; Brain Death
defined - An Act Authorizing the Legacy or
Donation of all or Part of a human
body after death for specified purposes.
1995 RA 7885 An Act to advance corneal transplant
in the Philippines.

What are the criteria for brain death?

1. Known cause of condition (ie, trauma)


2. No spontaneous or induced movement (except
DTRs)
3. Total unresponsivity/deep coma
4. No spontaneous respiration
5. Persistence of condition over time
6. Irreversibility (no hypothermia, depressant drugs,
metabolic disturbance)
*examined on two separate occasions, by two different doctors

COLD STORAGE
Bathe in preservation fluid
Containers surrounded by ice
T = 4 degrees centigrade
Cooling increases ischemia
tolerance
Stored while waiting for
recipient

One of the more recent organ donation wherein the liver, aside
from the usual kidney, was also donated.

DIFFERENT PRESERVATION SOLUTIONS AND THEIR


COMPONENTS
THEY TRY TO APPROXIMATE THE IC OR EX MILIEU
UW IS MOST WIDELY USED
HEPARIN, LIDOCAINE, VERAPAMIL, PAPAVERINE