Basic Immunology

Solid Organ Transplantation

Daniel Maluf, MD Assistant Professor of Surgery VCU School of Medicine

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Basic Immunology Basic Immunology

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History of organ transplantation History of organ transplantation 1981 First successful heart-lung transplant 1954 First successful kidney transplant* Dr. Bruce Reitz, Stanford University Hospital, Stanford, CA Dr. Joseph E. Murray, Brigham & Women's Hospital, Boston, MA 1983 First successful single lung transplant* Dr. Joel Cooper, Toronto Lung Transplant Group, Toronto General 1966 First successful pancreas/kidney transplant Hospital, Toronto Canada Drs. Richard Lillehei, William Kelly, University of Minnesota, Minneapolis, MN 1986 First successful double lung transplant* Dr. Joel Cooper, Toronto Lung Transplant Group, Toronto General 1967 First successful liver transplant* Hospital, Toronto Canada Dr. Thomas Starzl, University of Colorado Health Sciences Center, 1989 First successful living-related liver transplant Denver, CO Dr. Christoph Broelsch, University of Chicago Medical Center, 1968 First isolated pancreas transplant Chicago, IL Dr. Richard Lillehei, University of Minnesota, Minneapolis, MN 1990 First successful living-related lung transplant Dr. Vaughn A. Starnes, Stanford University Medical Center, 1968 First successful heart transplant Stanford, CA Dr. Norman Shumway, Stanford University Hospital, Stanford, CA *Transplant was the first of its kind in the world

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1 Cadaveric Donors, Cadaveric Transplants, Waiting List Additions 1994-2003: and Number on Waiting List U.S.

60,000 80,000

70,000 50,000

60,000 Waiting List at Year’s End 40,000 50,000 30,000 40,000 20,000 30,000

20,000 Transplants 10,000 Number of Registrations of Number 10,000 Donors 0 0 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 Year Kidney Liver Source: Donors from OPTN data as of 9/5/00; transplants from Scientific Registry data as of 9/5/00; snapshot of OPTN waiting list on the last day of each year. 7 8

Waiting List Additions 1994-2003: Patients waiting for transplantation U.S. 5000

4000 Type of Transplant Patients Waiting s

3000 kidney 52,216 istration g 2000 liver 17,546 pancreas 1,317 1000 pancreas islet 295 Number of Re 0 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 kidney-pancreas 2,540 Year

Heart Lung Pancreas Heart-Lung Kidney-Pancreas 9 10

Percent of Cadaveric Donors Contributing to Each Organ Type

6,000 92% 85% All Donors N = 5,849 5,000 Organ Donor and Recovery 4,000 3,000 40% 2,000 28% 1,000 13% 2% 0

Kidney Liver Pancreas Heart Lung Intestine N=5,396 N=4,954 N=1,627 N=2,316 N=781 N=97

Source: OPTN data as of 9/5/00.

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2 Recovered and Transplanted Organ Disposition (N=21,213) Cadaveric Organs Cadaveric Donors

Used Research 12,000 Not Used 10,710 3% Recovered Organs 10,000 9,233 9% Transplanted Organs 8,000 6,000 5,012 4,496 4,000 2,316 Transplanted 1,627 2,238 Transplanted 2,000 1,451 1,333 1,298 (Shared) (Local) 0 28% 60% Kidney Liver Pancreas Heart Lung

Note:Each liver and pancreas segment is counted as an individual organ in this figure. Source:OPTN data as of 9/5/00. Note: Disposition is shown for 21,213 organs which includes liver and pancreas segments. 13 Source: OPTN data as of 9/5/00. 14

Need more organs for transplant!!! Deceased and Living Donors Living Donor: 1993 - 2003

6802 7,000 6,000 6455 5,000 4,000 3,000

2,000 Deceased Donor Number of Donors of Number 1,000 Living Donor 0 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 Year

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Using Live-donor Organs: Kidney Transplantation Considerations

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3 Kidney Transplantation Kidney Transplantation: Etiology

Europe US Australia ƒ 1997 National Wait Time glomerulonephritis 25 17 37 – 1099 days diabetes 12 33 13 ƒ 2001 MCVH Wait Time cystic disease 8 4 7 – 845 days HTN 10 29 8 analgesic 2 1 11 ƒ 2001 Length of Stay interstitial nephritis 17 ? 11 –7 days UNK 261513

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Kidney Transplantation: Kidney Transplantation Severity of renal failure ƒ MCV Evaluation: The Listing process Severity GFR (ml/min) Signs – history and physical, financial and social mild 30-50 HTN support system evaluation moderate .10-29 HTN, anemia – blood typing, CXR, EKG, TB, Hep C, Hep B, HIV testing and dental clearance severe <10 pericarditis, osteodystrophy – Women must have a pap smear & end-stage <5 pruritis,edema, dyspnea mammogram – Diabetics:VCUG & gallbladder u/s & cardiac clearance – Colonoscopy mandatory for age>50

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Kidney transplant Operation Kidney Transplantation

ƒ Contraindications – Active Infection – Cancer w/in 5 years – Morbid Obesity – Active Substance Abuse – Severe Coronary Artery or Peripheral Vascular Disease – Medical Non-Compliance

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4 Kidney transplant Operation Kidney transplant Operation

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National Data. UNOS.ORG Kidney Graft Survival 95% Confidence Blood Type Years Post Transplant # Alive Survival Rate Interval One- and Five-Year by Level of O 1 Year 17451 95.7 (95.4, 96.0) A 1 Year 14786 95.4 (95.1, 95.8) HLA Mismatch B 1 Year 4765 95.7 (95.1, 96.3) 100 AB 1 Year 1795 95.4 (94.4, 96.4) 91% 92% 90% 85% O 3 Year 17232 90.9 (90.5, 91.3) 80 68% A 3 Year 15095 90.7 (90.3, 91.1) 64% 61% 60 55% B 3 Year 4831 90.7 (90.0, 91.5) One-Year

AB 3 Year 1783 89.7 (88.4, 91.0) 40 Five-Year

O 5 Year 13117 85.4 (84.9, 85.9) Percentage

A 5 Year 11393 84.9 (84.3, 85.4) 20

B 5 Year 3536 85.2 (84.2, 86.2) 0 AB 5 Year 1317 84.9 (83.2, 86.5) 0 MM 1 MM 3 MM 6 MM

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Renal Transplant Patient Using Live-donor Organs: Survival VCUHS vs National Considerations Average 1

0.8

Patient 0.6 Survival 0.4

0.2

0 0 365 730 1095 Days United States VCUHS

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5 Living-Donor Liver Kidney Transplantation At Transplantation in the U.S. VCUHS Living Donor Transplants

30

25

20

15

10

5

0 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002

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Kidney Transplantation: Kidney Transplantation: Complication - rejection Complication - infection

T cell

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Post-Transplantation Cancer Post-Transplantation Cancer (by age)

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6 Incidence of Skin Cancer in Kidney-Pancreas Transplantation Organ Transplant Recipients

ƒ Squamous cell ƒ Melanoma carcinoma –3.4-fold –65-fold ƒ Kaposi’s sarcoma ƒ Squamous cell –8.4-fold carcinoma of the lip ƒ Other: –20-fold – lung, ƒ Basal cell – prostate, carcinoma – colon, –10-fold –PTLD, etc.

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1-Year Graft and Patient Survival Rates Multiple Organ Transplants 5-Year Graft and Patient Survival Rates 1997-1998 Transplant Cohort 1990-1998 Transplant Cohort

100 100 Graft Patient 80 80 60 60 40 Percent

20 Percent 40

0 20 Kidney- Kidney-Liver Kidney-Heart Intestine-Liver Pancreas 0 Cadaveric Living Donor Liver Pancreas Heart Lung Heart-Lung 1st Organ Graft 2nd Organ Graft Patient Kidney Kidney

Source: Scientific Registry data as of 9/5/00. Source: Scientific Registry data as of 9/5/00.

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Pancreas Transplantation Pancreas Transplantation ƒ Indications – Pancreas alone ƒ Arterial inflow • Retransplant/Graft Failure provided by ‘y graft’ ƒ Splenic attachment • Diabetes Mellitus – Type I preserved to decrease • Diabetes Mellitus – Type II Diabetes graft hyperperfusion – Chronic Pancreatitis ƒ Spleen is removed and exocrine – Cystic Fibrosis secretions drained via – Pancreas after kidney duodeno-ileostomy or •DM duodeno-cystostomy

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7 Kidney-Pancreas Kidney-Pancreas Transplantation Transplantation

ƒ Success rates – Patient Survival (1995-1999) MCV National • 30 day 100% 98.4% • 1 year 95.6% 94.5% • 5 years 83.8% 90%

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Kidney-Pancreas Kidney-Pancreas Transplantation: success rates Transplantation Graft Survival (1995 – 1999)

MCV National

Pancreas Kidney Pancreas Kidney ƒ 1997 National Wait Time - 335 days ƒ 2000 MCVH Wait Time - 238 30 day 90% 97.9% 95.8% 96.2% days 1 year 82.6% 95.7% 91.4% 91.4% ƒ 2000 MCV Length of Stay- 9 days

5 years 75.7% 90.2% 82.5% 82.5%

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Kidney-Pancreas Kidney-Pancreas Transplantation Transplantation ƒ Etiology of early renal graft ƒ Etiology of early renal graft dysfunction dysfunction – Immunologic issues – Donor issues • ABO incompatibility • Hypotension/pressor agent usage •high PRA • age • african-american descent • oliguria • hyperacute rejection (preformed antibodies) – Preservation issues • accelerated rejection (second set exposure) • Acute and chronic rejection • prolonged warm ischemia –Drug toxicity • prolonged cold ischemia 47 48

8 Kidney-Pancreas Kidney-Pancreas Transplantation Transplantation ƒ Contraindications ƒ Early complications – Active Infection – Vascular thrombosis – Cancer w/in 5 years • venous/ arterial – Morbid Obesity/Type II diabetes – Ureteral issues – Active Substance Abuse • leakage/stenosis – Severe Coronary Artery or Peripheral – Lymphocele Vascular Disease – Incisional issues – Medical Non-Compliance – age >50 years

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Liver Transplantation Liver Transplantation ƒ Severity, Signs and Symptoms • quality of life issues – recurrent cholangitis, intractable ascites or pruritis, severe lethargy or bone disease • severe hepatic dysfunction & complications – hyperbilirubinemia / jaundice – severe coagulopathy – marked hypoalbuminemia / ascites – variceal hemorrhage – spontaneous bacterial peritonitis

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Liver Transplantation Liver Transplantation

ƒ Etiology ƒ Contraindications – Hepatitis C 23% –HIV – Alcohol 20% – Extrahepatic malignancy – Cryptogenic 12% – Uncontrolled sepsis – PSC 10% – On going substance abuse – PBC 11% – Advanced cardiopulmonary disease – Autoimmune 5% – Severe pulmonary hypertension – Fulminant failure 5% – Noncompliance

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9 Liver Transplantation Liver Transplantation

ƒ MCV evaluation – multidisciplinary team assessment ƒ Cadaveric liver • surgical (alternative or adjunct procedures) – National 1997 Wait Time - 439 days • hepatologist (intensive medical management) – MCVH 2000 Wait Time - 178 days • cardiologist (catheterization/stenting/ P-Thal) • pulmonologist (PFT, bubble echo, ABGs) – Average 2000 Length of Stay- 9 days • psychologist (organic brain syndromes/dependency) • social work (support system analysis) • financial (can it be done)

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Liver Transplantation Liver Transplantation

ƒ Success rates ƒ Success rates – Cadaveric liver patient survivals – Cadaveric liver graft survivals MCV National MCV National • 30 day 93.2% 94% • 30 day 89.8% 90% • 1 year 83.8% 85.6% • 1 year 79.5% 79.8% • 5 years 78.5% 75.9% (3yr) • 5 years 73.7% 68.8% (3yr)

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Liver Transplantation Liver Transplantation

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10 Liver Transplantation Liver Transplantation

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Liver Transplantation Liver Transplantation

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Living Donor Relationship To Liver Transplants by Donor Type Recipient 1997-1999 1990, 1995, 1999 4500 4000 60 53 3500 1990 50 3000 45 1995 2500 37 2000 40 1999 29 1500 30 1000 23 20 Percent 18 500 20 15 18 0 11 12 1997 1998 1999 10 6 7 5 2 Cadaveric 3929 4270 4367 0 Living 76 86 219 Parent Sibling Offspring Other Unrelated Related

Source: Scientific Registry data as of 9/5/00. 65 Source: OPTN data as of 9/5/00. 66

11 Liver Transplantation Liver Transplantation

ƒ Live donor liver ƒ Live donor liver- – 2000 Wait Time- 108 days Survival 1999-2000 – Recipient Length of Stay- 10.5 days Patient Graft – Donor Length of Stay- 6.5 days 30 day 95% 92% 1 year 83% 81%

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Liver Transplantation Liver Transplantation

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Liver Transplant Liver Transplant

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12 Liver Transplantation Liver Transplantation

ƒ Early complications ƒ Graft loss etiology – primary graft dysfunction – Sepsis – hepatic artery thrombosis –MI – bile duct leakage –CVA – rejection – Recurrent disease • acute cellular • chronic – infection

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Liver Transplant Graft Survival Liver Transplant Patient Survival VCUHS vs National Average VCUHS vs National Average

1 1 0.8 0.8 0.6 Graft Patient 0.6 Survival 0.4 Survival 0.4 0.2 0.2 0 0 0 365 730 1095 0 365 730 1095 Days Days United States VCUHS United States VCUHS

Source: www.ustransplant.org 75 Source: www.ustransplant.org 76

Living Donor Liver Transplant At Living Donor Liver Transplant At VCUHS Graft Survivals VCUHS Patient Survivals

1 1 0.8 0.8 Patient 0.6 Graft 0.6 Survival Survival 0.4 0.4 0.2 0.2

0 0 0 365 730 1095 0 365 730 1095 Days Days

Living Cadaveric Living Cadaveric

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13 Solid Organ Transplantation

Daniel Maluf, MD Assistant Professor of Surgery VCU School of Medicine

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