Organ Transplantation (Heart & Lung Transplant)

Dr R S Dhaliwal MBBS,M.S.,DNB(Surgery).M.Ch,DNB(CTVSurg)

FACS,FCCP,FNCCP,FICA,FICAS Former,Prof & HOD, CTV Surgery, PGIMER Chandigarh

Introduction• Organ transplantation is the moving of an

organ from one body to another or from a donor site to another location on the patient's own body, for the purpose of replacing the recipient's damaged or absent organ

• The emerging field of regenerative medicine is allowing scientists and engineers to create organs to be re-grown from the patient's own cells (stem cells) or cells extracted from the failing organs

Introduction• Earliest transplant- 300 AD Christian Arab Saints Cosmas

and Damian reported to have replaced diseased leg of a patient with normal leg from a dead person

• 1901-10 Jaboulay and Alex Carrel developed techniqu es of vascular suturing and anastomosis

• 1954-Joseph Murray, Boston USA , First kidney transplant in world between identical twins Got Nobel prize in 1990

• 1962- Roy Calne , U.K. –introduced Azathioprine for prevention of rejection of kidney allograft

• 1963 – Tom Starzl , USA- First Liver transplant

Alex Carrel Roy Calne

Joseph Murray Tom Starlz

Miles stones in organ transplantion• 1966-Tom Starlz et al ,USA- Used ALG –anti lymphocyte globulin for

immunosuppresion • 1966- Lillehei & Kelly,USA- First human pancreas transplant (with

kidney transplant• 1967-Christiaan Bernard,South Africa- First heart transplant • 1968-Friz Derom-Belgium- first lung transplant• 1969- Geof Collins- Developed solution for organ preservation • 1974- Sutheranland & Najarin USA- First human pancreatic islet

transplant • 1978-Roy Calne,UK- Introduced Cyclosporine • 1981-Reitz & Shumway USA-First heart lung transplant• 1981-Ben Cosini et al- Monoclonal antibody OKT3• 1987-Foker Belzer et al- Univ. of Wisconsin solution • 1989- Tom Starzl- introduced FK506 (tacrolimus) • 1995- Lloyd Ratner et al –Laproscopic living donor

nephercectomy

Transplant -Definitions• Allograft- An organ or tissue transplanted from one

person to another• Isograft (Syngeneric) graft- A transplant between two

identical twins • Orthotopic graft- A graft placed in its normal anatomical

site• Heterotopic graft- A graft placed in a site different from its

normal site• Xenograft- A graft between two species • Alloantigen- Transplant antigen • Alloantibody- Transplant antibody• HLA – Human leukocyte antigen , the main trigger of graft

rejection

Graft Rejection

• ABO blood group antigens- recipients should receive a graft that is ABO compatible. Permissible transplants are- -Group O donor to Grp O,A,B or ABO rcpt

-Group A donor to Grp A or AB rcpt -Grp B donor to Grp B or AB recipient -Grp AB donor to Grp AB recipient

• HLA antigens- are most common cause of graft rejection, act as antigen recognition unitsHLA –A,-B(Class I ) and –DR(class II) are most important In organ transplant Anti HLA antibodies may cause hyperacute rejection

Graft Rejection• Allografts act as powerful antigen resulting in rapid graft

rejection which can be controled by immunosuppressive therapy

• Studies done by Peter Medawar in 1940-50 proved that allograft rejection was due to an immune response,not an inflamatory esponse

• Later studies showed that T lymphocytes play an essential role in graft rejection mechanism

• Allografts produce graft rejection due to histo compatibility antigens which are of three types -

-ABO blood group antigens -HLA human leukocyte (major antigens) - Minor HLA antigens

Types of Graft rejection• Hyperacute rejection-

Immediate graft destruction due to ABO or preformed anti HLA antibodies, intravascular thrombosis occurs

• Acute rejection- Occurs during first 6months mediated by T cell dependent immune response.Reversible Characterise mononuclear cell infilteration

• Chronic rejection- Occurs in first 6months.Most common cause of graft failure.Myointimal proliferation in graft arteries causing ischemia and fibrosis.Non immune factors may also be responsible in pathogenesis

Causes of allograft dysfunction• Early- Primary non function(irreversible ischemic

damage) • Delayed function(reversible ischemic injury • Hyperacute and acute rejection• Arterial or venous thrombosis of graft vessels• Drug toxicity(cyclosporine and tacrolimus)• Infection (CMV disease in the graft)• Mechanical obstruction (ureter/CBD)Late- -Chronic rejection -Arterial stenosis

-Recurrance of original disease in the graft -Mechanical obsruction(ureter,CBD)

Immunosuppressive agents• Azathioprine- Prevents lymphocyte proliferation • Mycophenolate mofetil- Prevents lymphocyte

proliferation • Cyclosporin- Blocks IL-2gene transcription• Tacrolimus –Blocks IL-2 gene transcription • Rapamycin-Blocks IL-2 receptor signal transduction• OKT3 mAb – Depletion and blockade of T cells• ALG/ALS- Depletion and blockade of lymphocytes • Anti CD25 mAB- Targets activated T cells• Corticosteroids – potent anti inflamatory effect

Side effects of immunosuppressive drugs

• Steroids- Hypertension,Diabetes,osteoporosis dyslipidemia, Cushingoid appearance

• Azathioprine- leucopenia,thrombocytopenia, hepatotoxicity,GIT symptoms

• Cyclosporin- Nephrotoxicity,hypertension,dyslipidemia hirsutism,ginigival hyperplasia

• Tacrolimus-Neurotoxicity,diabetes,hypertensio nephrotoxicity,dyslipidemia

• ALG – Leucopenia, thrombocytopenia• OKT3 – Pulm Oedema,leucopenia,cytokine release syn. • Sirolimus- Thrombocytopenia, dyslipidemia • Mycophenolate mofetil-GIT symptoms,leucopenia,

Thrombocy topenia

Complications of immunosuppression • Infection- High risk of viral infetions

-Bacterial and fungal infections common -Highest risk in first 6 months after transplant –Chemoprophylaxis important in high risk pts -Virus infection due to reactivation of latent virus or primary infetion -Cytomegalovirus infection is major problem -Early diagnosis and prompt treatment is must –Pre-transplant vaccination for community acquired infections should be considered

• Malignancy- -PTLD-Post transplant lymphoproli ferative disease and Kaposi ‘s sarcoma -

High risk of squamous carcinoma of skin

Organ donation and procurement• Most organs for transplant are obtained from brainstem dead, heart

beating cadaveric donors , multiple organs are procured• In kidney transplant live donors and arrested heart cadaveric donors are

common• Acceptable donor age- Kidney -2 yrs to no upper age limit

Liver – No age limit - Heart -0 to 65 yrs Lung – 0 to 60 yrs -Pancreas-10-50yrs

• Donor organ should be free from primary disease and infection • Organs are procured through midsternotomy (heart & lungs ) and

midline laparotomy (liver,pancreas & kidneys). Organs are perfused in situ and after removal with –heart with cold cardioplegia solution, lungs with University of Wisconsin UW sol. Liver with UW sol, kidneys and pancreas with Euro- Collins sol.

• Various organs can be stored for different period after cold perfusion Kidney - 24-48hrs Liver 12-24hrs Pancreas -10-24hrsSmall intestine 4-8hrs Heart 3-6hrs Lung 3-8hrs

Evaluation of potential recipients• Evaluation by multidisciplinary team including a

surgeon and physician• Presence of comorbid factors (DM,CAD,Renal or

Liver dysfunction, uncontroled HTN)• Exclude systemic sepsis and malignancy • Psychologically normal for transplan and

immunotherapy• Any pre-operative surgery required • Evaluate for organ specific criteria for transplant • Optimise recipient condition prior to transplant

Organ function after transplantation

• Donor factors- -Extreme of age -Presence of pre-existing disease -Hemodynamic and metabolic instability

• Procurement related factors- -Warm ischemic time - Type of preservation solution - Cold ischemic time

• Recipient factors- Technical surgical factors - Hemodynamic and metabolic stability -Immunological factors –sensitisation status - Drug therapy impairing function of organ

Outcome after transplantation• Transplant improves the quality and duration of life in most

of recipients• Transplant outcome has improved progressivel due to better

immunotherapy,organ preservat ion, chemoprophylaxis and technical advances

• Graft survival after kidney,heart and liver trans plant is around 90% at 1 yr and 70-80% at 5yrs

• Results of lung and small intestine transplant are less impressive

• Chronic rejection is most common cause of graft failure after all types of solid organ transplant

• Recurrance of original disease may lead to graft failure • Death from CV disease with functioning transplanted organ

is common

Heart Transplant• 1967-1st human heart transplant by Dr Christiaan

Barnard in Cape Town South Africa (based on labortory work of Shumway & Lower)

• Indications - End stage cardiac disease where all conventional therapy has failed -

a. Idiopathic cardiomyopathy b. Ischemic heart disease ( diffuse smal vessels) c uncorrectabe congenial heart disease d.Myocarditis

• Pre requisite- Age – Below age of 65 yrs ,PVR should be in normal range , Other organ systems ( kidney,liver) are not permanently damaged

Dr Christian Barnard 1st heart transplant patient

Dr Barnard with ICU nurses Dr Barnard briefing media

Dr Norman Shumway Transplanted Heart

Contraindications to transplantation• Absolute- Active

infection ( or HIV positve ) -Irreversible PAH-Malignancy - Presence of

another serious disease • Relative contraindications-

Age > 60yrs -Active D U - Significant raised PVR -Drug or Alcohol abuse - Psychiateric illness - Low creatinine clearance

Surgical technique• Median sternotomy- Systemic heparinisation

and pt is placed on CP Bypass,cooled to 26 C -Aorta cross clamped and recipient heart excised at mid atrial level - Donor heart is removed from ice, left atrium opened by incisions in post. wall between orifices of pulm. Veins to make atrial cuff

- Left and then right atrial anastomoses done and Pulm artery and Aorta anastomosed to donor vessels. Pt rewarmed and weaned off from CPB.

Heart transplant technique

Prognosis

Graft survival of transplanted Heart• 1 year : 88.0% (males), 86.2% (females)• 3 years: 79.3% (males), 77.2% (females)• 5 years: 73.2% (males), 69.0% (females) Graft survival of Heart lung and Lung transplant

1 yr survival 75%5 yrs survival 40%

Heart –lung transplant

• 1981 –1st successful combined heart lung transplan by Bruce Ritz

• It is done in pts with Pulm.Vascular disease due to Eisenmenger Synderome or due to acquired heart disease

• Through midsternotomy diseased lungs and heart are excised preserving phrenic, vagus and recurrent laryngeal nerves.Donor heart lungs block placed and end to end tracheal anastomo sis is done and RA and aortic anastomoses are done as for cardiac ransplantation

Bruce Ritz Ist heart lung transplant

Lung transplant • James Hardy USA did 1st lung transplant in 1964, Joel Cooper USA

popularised it• Single and double lung transplant are effetive treatment of chronic

lung disease with declin ing PFT limiting life expectancy • Indications- Single lung transplant Pulmonary fibrosis

Double lung transplantt b-Cystic fibrosis c-B/L bronchiectasis

• Single lung transplant is done through PLT and B/L lung transplant is done through midsternoto myor B/L ant. thoracotomy.

• Incidence of post op airway anastomosis dehiscence used to be common is now less than 5%due to better organ pre servation and better surgical techniques.Late airway stenosis at bronchial anasto mosis due to ischemia ois ccurs in about 10% and is treated by dilatation

• Prognosis - 1 and 5 yrs survival of heart transplant is 85% and 70% Results of heart lung and lung transplant is 75% and 40% at 1 and 5yrs

James Hardy Joel D Cooper

Future developments

• Better immunosuppressive drugs• Xenotransplantation• Stem cell engineering• Non invasive biomarkers for monitoring

rejection• Methods to induce donor specific immunolo-

gical tolerance

Thank You