1. Intestinal Transplantation Jonathan Fryer MD Associate Professor of Surgery Feinberg School of Medicine Northwestern University

2. Objectives • To review the indications for intestinal transplant. • To review the types of intestinal transplant. • To review management of intestinal transplant candidates and recipients. • To review the outcomes and potential complication of intestinal transplants.

3. Intestinal Failure • Inability to maintain adequate protein calorie and/or micronutrient nutritional balance despite maximal delivery of enteral nutrients. • Intestinal Failure = PN dependence.

4. Intestinal TransplantCandidates • Intestinal Failure patients that are permanently dependent on Parenteral Nutrition (PN) or are anticipated to be. • Short Bowel (70%) (i.e. < 100 cm of functional SB) • Dysmotility (15%) • Malabsorption (15%)

6. Intestinal Failure (TPN dependency) Intestinal Rehabilitation -Dietary optimization -Hormonal Enhancement Therapy -Gut lengthening Surgery TPN reduced (50%) (lower-risk?) -Monitor closely TPN not reducible (20%) (high-risk) -Transplant TPN free (30%)

7. Intestinal Transplantation Indications • PN failure (Medicare criteria) • Impending or overt liver failure: •  bili,  liver enzymes,  spleen,  PT,  INR,  plts, varices, stomal bleeding, fibrosis, cirrhosis • Thrombosis of central veins: •  2 of subclavian, jugular, or fem veins • Frequent central line-related sepsis: • 2 line sepsis per year, 1 if fungemia, septic shock, or ARDS • Frequent severe dehydration.

10. Referral for SB transplantUnresolved Issues re: timing of referral • Referral when liver complications develop. • PNALD is often benign / reversible. • Risk of transplanting too early. • Referral before liver complications develop. • High risk groups identifiable. • Parameters of PNALD progression poorly defined. • Transition to lethal / irreversible – unpredictable. • Candidates often unsalvageable when referred for transplant. • Outcomes worse when liver + intestine needed. • Optimal utility of donor livers?

11. Number of UNOS Listings for Intestinal Transplants (1987-2004) (1,159) IBL 185 (400) (74.3%) (25.7%)

12. Annual Waiting List Death Rates All organs(per 1,000 Patient-Years at Risk Waiting)

13. Waiting List Mortality (1999-2004)ALI – All patients ever listed for bothLiver andIntestine-vs-INL – listed forIntestine,Never forLiver Death rate % 0-17 Years 18 + years Death rate % PELD PELD PELD PELD (4/99-2/02) (2/02-12/04) (4/99-2/02) (2/02-12/04)

14. Figure 3A Intestinal Transplant Waiting List Outcomes Based On Their Liver Transplant Listing Status

16. Types of Intestinal Transplants Adult Pediatric 28.9% 36.2% 39.2% 50.3% 34.9% 10.5%

24. Preop Considerations • Organs to be included. • SB, Liver, Pancreas, Stomach, Colon, Kidney. • Multivisceral transplant – definition? when? why? • Donor : Recipient size match • Usually 0.5-0.75 D:R size ratio preferred. • If D>R size ratio- abdominal wall reconstruction strategy? • Recipient pre-sensitization (PRA) • Higher risk of rejection? • Desensitization or other strategy required? • Donor and recipient CMV and EBV status. • +ve  -ve at highest risk • Antiviral / immunosuppression strategy modified?

25. Post-operative considerations Immunosuppression • Induction • Anti-lymphocyte products • Polyclonals: Thymoglobulin, Atgam • Monoclonals: Campath (anti –CD52), Zenepax/Simulect (anti-CD25) • Maintenance • Prograf • Rapamycin • Anti-rejection therapy • Solumedrol • Antilymphocyte products • Polyclonals: Thymoglobulin, Atgam • Monoclonals: OKT3 (anti-CD3)

26. Post-operative considerations Monitoring • Rejection surveillance (No reliable serum marker): • Protocol biopsies (Initially weekly) • If rejection: mildSteroids; Severe  anti-lymphocyte products • Viral surveillance (CMV, EBV, adeno): • PCR (Initially weekly) • If progressive  replication  immunosuppression and/or antiviral therapy • Immunusuppression monitoring: • Drug level: (Prograf, Rapammune) • Immune monitoring (Lymphocyte count, Cylex)

27. Post-op managementOther issues • Parenteral  enteral nutrition transition • Generally well tolerated early • Fat-free diet until lymphatics reform (chylous ascites) • PN catheter removal • When PN and IV hydration no longer required • G-tube / J-tube • Initial enteral nutrition administration • Safety line for admin of meds / nutrition • Loop ileostomy (all patients) • Easy access for protocol biopsies • Usually closed at 6 mos- 12 mos postop

28. 1 YEAR PATIENT SURVIVAL 1994 T0 2004 SOURCE: OPTN/SRTR 2005 ANNUAL REPORT

29. 2005-07 Graft Survival – Transplant Type p = 0.255 2 yr Analysis Intestinal Transplant Registry March 31, 2005

30. 2005-07 Patient Survival - Transplant Type p = 0.001 2 yr Analysis Intestinal Transplant Registry March 31, 2005

31. Causes of All Deaths % Distribution

32. Causes of Death - % Distribution

33. Alive Patient Status > 6 Months Post Tx2005 - 2007 Modified Karnofsky Performance Score(N=163) Graft Function (N=178)

34. Summary • Intestinal transplantation is indicated for intestinal failure patients that are at high risk for life- threatening PN associated complications: • Consensus on “high risk” patients controversial • Timing of referral remains controversial • Additional organs are included with Intestinal transplants based on: • Failure /dysfunction of native organs (liver, stomach, colon) • Potential for reducing rejection (liver, spleen) • Technical considerations (pancreas)

35. Summary (cont’d) • Due to high infection and rejection risk post-transplant surveillance is critical to optimize level of immunosuppression. • Viral activity (PCR) • Histologic evaluation for rejection (Endoscopic Biopsy) • Level of immunosuppression (Prograf, etc.) • Overall outcomes with intestinal transplant are improving: • Outcomes with intestine only candidates are superior to intestine + liver candidates • 1st year patient and graft loss is higher with intestine + liver • Liver has survival benefit for SB graft in >1 yr survivors