Intestinal Intestinal TransplantationTransplantation

Jonathan Fryer MDJonathan Fryer MDAssociate Professor of SurgeryAssociate Professor of Surgery

Feinberg School of MedicineFeinberg School of MedicineNorthwestern UniversityNorthwestern University

ObjectivesObjectives

• To review the indications for intestinal To review the indications for intestinal transplant.transplant.

• To review the types of intestinal transplant.To review the types of intestinal transplant.

• To review management of intestinal To review management of intestinal transplant candidates and recipients.transplant candidates and recipients.

• To review the outcomes and potential To review the outcomes and potential complication of intestinal transplants.complication of intestinal transplants.

Intestinal FailureIntestinal Failure

• Inability to maintain adequate protein calorie Inability to maintain adequate protein calorie and/or micronutrient nutritional balance and/or micronutrient nutritional balance despite maximal delivery of enteral nutrients.despite maximal delivery of enteral nutrients.

• Intestinal Failure = PN dependence.Intestinal Failure = PN dependence.

Intestinal TransplantIntestinal TransplantCandidatesCandidates

• Intestinal Failure patients that are Intestinal Failure patients that are permanently dependent on Parenteral permanently dependent on Parenteral Nutrition (PN) or are Nutrition (PN) or are anticipatedanticipated to be. to be.

Short Bowel Short Bowel (70%) (70%) (i.e. < 100 cm of (i.e. < 100 cm of functionalfunctional SB) SB)

Dysmotility Dysmotility (15%)(15%) Malabsorption Malabsorption (15%)(15%)

Intestinal Failure Intestinal Failure (TPN dependency)(TPN dependency)

Intestinal RehabilitationIntestinal Rehabilitation -Dietary optimization-Dietary optimization

-Hormonal Enhancement Therapy-Hormonal Enhancement Therapy

-Gut lengthening Surgery-Gut lengthening Surgery

TPN freeTPN free

(30%)(30%)TPN reduced TPN reduced

(50%)(50%)

(lower-risk?)(lower-risk?)

--Monitor closely Monitor closely

TPN not reducible

(20%)

(high-risk)

-Transplant

Intestinal Transplantation Intestinal Transplantation IndicationsIndications

• PN failure PN failure (Medicare criteria)(Medicare criteria) Impending or overt liver failure: Impending or overt liver failure:

bili, bili, liver enzymes, liver enzymes, spleen, spleen, PT, PT, INR, INR, plts, varices, stomal bleeding, fibrosis, cirrhosis plts, varices, stomal bleeding, fibrosis, cirrhosis

Thrombosis of central veins:Thrombosis of central veins: 2 of subclavian, jugular, or fem veins 2 of subclavian, jugular, or fem veins

Frequent central line-related sepsis: Frequent central line-related sepsis: 2 line sepsis per year, 2 line sepsis per year, 1 if fungemia, septic shock, or ARDS1 if fungemia, septic shock, or ARDS

Frequent severe dehydration.Frequent severe dehydration.

•

Referral for SB transplantReferral for SB transplantUnresolved Issues re: timing of referralUnresolved Issues re: timing of referral

• Referral when liver complications develop.Referral when liver complications develop. PNALD is often benign / reversible. PNALD is often benign / reversible. Risk of transplanting too early.Risk of transplanting too early.

• Referral before liver complications develop.Referral before liver complications develop. High risk groups identifiable.High risk groups identifiable. Parameters of PNALD progression poorly defined. Parameters of PNALD progression poorly defined.

Transition to lethal / irreversible – unpredictable.Transition to lethal / irreversible – unpredictable. Candidates often unsalvageable when referred for transplant.Candidates often unsalvageable when referred for transplant. Outcomes worse when liver + intestine needed.Outcomes worse when liver + intestine needed. Optimal utility of donor livers? Optimal utility of donor livers?

Number of UNOS Listings for Intestinal Transplants (1987-2004)

IBL 185

0

200

400

600

800

1000

1200

Intestine + Liver Intestine only(74.3%) (25.7%)

(400)

(1,159)

Annual Waiting List Death Rates Annual Waiting List Death Rates All organsAll organs

((per 1,000 Patient-Years at Risk Waitingper 1,000 Patient-Years at Risk Waiting))

0

100

200

300

400

500

600

Kidney

KP

Liver

Intestine

Heart

Lung

Heart-Lung

Waiting List Mortality Waiting List Mortality (1999-2004)(1999-2004) ALIALI – – AAll patients ever listed for bothll patients ever listed for both LLiver andiver and IIntestinentestine -vs--vs-

INLINL – – listed forlisted for IIntestine,ntestine, NNever forever for LLiveriver

0

5

10

15

20

25

30

Pre Meld/ Post Meld/

ALI

INL

0

5

10

15

20

25

30

Pre Meld/ Post Meld/

0-17 Years 18 + yearsDeath rate %

Death rate %

(4/99-2/02) (2/02-12/04) (4/99-2/02) (2/02-12/04)PELD PELD PELD PELD

Intestinal Transplant Waiting List Outcomes Based On Their Liver Transplant Listing Status

51.9

29.8

6.3

12

65.5

8.8

15.5

10.3

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

ALI INL

Delisted/Lost to Follow-Up

Still Waiting

Died Waiting

Transplanted

Figure 3A

Types of Intestinal TransplantsTypes of Intestinal Transplants

Intestine only

Intestine + Liver

Multivisceral

Intestine only

Intestine + liver

Multivisceral

Adult Pediatric

39.2% 50.3%

10.5%

28.9%36.2%

34.9%

Preop ConsiderationsPreop Considerations

• Organs to be included.Organs to be included. SB, Liver, Pancreas, Stomach, Colon, Kidney.SB, Liver, Pancreas, Stomach, Colon, Kidney. Multivisceral transplant – definition? when? why?Multivisceral transplant – definition? when? why?

• Donor : Recipient size matchDonor : Recipient size match Usually 0.5-0.75 D:R size ratio preferred.Usually 0.5-0.75 D:R size ratio preferred. If D>R size ratio- abdominal wall reconstruction strategy?If D>R size ratio- abdominal wall reconstruction strategy?

• Recipient pre-sensitization (PRA)Recipient pre-sensitization (PRA) Higher risk of rejection? Higher risk of rejection? Desensitization or other strategy required?Desensitization or other strategy required?

• Donor and recipient CMV and EBV status.Donor and recipient CMV and EBV status. +ve +ve -ve at highest risk -ve at highest risk Antiviral / immunosuppression strategy modified?Antiviral / immunosuppression strategy modified?

Post-operative considerations Post-operative considerations ImmunosuppressionImmunosuppression

• Induction Induction Anti-lymphocyte productsAnti-lymphocyte products

Polyclonals: Thymoglobulin, AtgamPolyclonals: Thymoglobulin, Atgam Monoclonals: Campath (anti –CD52), Zenepax/Simulect (anti-CD25)Monoclonals: Campath (anti –CD52), Zenepax/Simulect (anti-CD25)

• MaintenanceMaintenance PrografPrograf RapamycinRapamycin

• Anti-rejection therapyAnti-rejection therapy SolumedrolSolumedrol Antilymphocyte productsAntilymphocyte products

Polyclonals: Thymoglobulin, AtgamPolyclonals: Thymoglobulin, Atgam Monoclonals: OKT3 (anti-CD3)Monoclonals: OKT3 (anti-CD3)

Post-operative considerations Post-operative considerations MonitoringMonitoring

• Rejection surveillance Rejection surveillance (No reliable serum marker)(No reliable serum marker): : Protocol biopsies (Protocol biopsies (Initially weeklyInitially weekly) ) If rejection: mildIf rejection: mildSteroids; Severe Steroids; Severe anti-lymphocyte products anti-lymphocyte products

• Viral surveillance Viral surveillance (CMV, EBV, adeno)(CMV, EBV, adeno):: PCR PCR (Initially weekly)(Initially weekly) If progressive If progressive replication replication immunosuppression and/or immunosuppression and/or

antiviral therapy antiviral therapy Immunusuppression monitoring:Immunusuppression monitoring:

Drug level: Drug level: (Prograf, Rapammune)(Prograf, Rapammune) Immune monitoring Immune monitoring (Lymphocyte count, Cylex)(Lymphocyte count, Cylex)

Post-op managementPost-op managementOther issuesOther issues

• Parenteral Parenteral enteral nutrition transition enteral nutrition transition Generally well tolerated early Generally well tolerated early

Fat-free diet until lymphatics reform (chylous ascites)Fat-free diet until lymphatics reform (chylous ascites)

PN catheter removalPN catheter removal When PN and IV hydration no longer requiredWhen PN and IV hydration no longer required

• G-tube / J-tube G-tube / J-tube Initial enteral nutrition administrationInitial enteral nutrition administration Safety line for admin of meds / nutritionSafety line for admin of meds / nutrition

• Loop ileostomy Loop ileostomy (all patients)(all patients)

Easy access for protocol biopsiesEasy access for protocol biopsies Usually closed at 6 mos- 12 mos postopUsually closed at 6 mos- 12 mos postop

1 YEAR PATIENT SURVIVAL 1 YEAR PATIENT SURVIVAL 1994 T0 20041994 T0 2004

40%

50%

60%

70%

80%

90%

100%

1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004

Kidney Liver All Intestine

SOURCE: OPTN/SRTR 2005 ANNUAL REPORT

2005-07 Graft Survival – Transplant Type2005-07 Graft Survival – Transplant Type

2 yr Analysis Intestinal Transplant Registry March 31, 2005

p = 0.255

Tx TypeTx TypeTotal Total

NN

IntestineIntestine 165165

Intestine + Intestine + LiverLiver 9494

MultivisceralMultivisceral 130130

OverallOverall 389389

2005-07 Patient Survival - Transplant Type2005-07 Patient Survival - Transplant Type

2 yr Analysis Intestinal Transplant Registry March 31, 2005

p = 0.001Tx TypeTx Type Total NTotal N

IntestineIntestine 165165

Intestine + Intestine + LiverLiver 9494

MultivisceralMultivisceral 130130

OverallOverall 389389

Causes of All Deaths Causes of All Deaths % Distribution% Distribution

0%

10%

20%

30%

40%

50%

60%

70%

% o

f Pat

ient

s <=1yr

>1 yr

Causes of Death - % DistributionCauses of Death - % Distribution

0

10

20

30

40

50

60

70

% o

f P

ati

en

ts

< 2000

2000 - 2004

>= 2005

Alive Patient Status > 6 Months Post TxAlive Patient Status > 6 Months Post Tx2005 - 20072005 - 2007

Graft Function (N=178)

Modified Karnofsky

Performance Score

(N=163)

0

10

20

30

40

50

60

70

% P

atie

nts

Full function Partialfunction

Graftremoved

0

10

20

30

40

50

60

70

% P

atie

nts

90 - 100% 61 - 89% 31 - 60% 1 - 30%

Score

SummarySummary

• Intestinal transplantation is indicated for intestinal Intestinal transplantation is indicated for intestinal failure patients that are at high risk for life- failure patients that are at high risk for life- threatening PN associated complications:threatening PN associated complications:

Consensus on “high risk” patients controversialConsensus on “high risk” patients controversial Timing of referral remains controversialTiming of referral remains controversial

• Additional organs are included with Intestinal Additional organs are included with Intestinal transplants based on:transplants based on:

Failure /dysfunction of native organs (liver, stomach, colon)Failure /dysfunction of native organs (liver, stomach, colon) Potential for reducing rejection (liver, spleen)Potential for reducing rejection (liver, spleen) Technical considerations (pancreas)Technical considerations (pancreas)

Summary (cont’d)Summary (cont’d)

• Due to high infection and rejection risk post-Due to high infection and rejection risk post-transplant surveillance is critical to optimize level of transplant surveillance is critical to optimize level of immunosuppression.immunosuppression.

Viral activity Viral activity (PCR)(PCR) Histologic evaluation for rejection Histologic evaluation for rejection (Endoscopic Biopsy)(Endoscopic Biopsy) Level of immunosuppression Level of immunosuppression (Prograf, etc.)(Prograf, etc.)

• Overall outcomes with intestinal transplant are Overall outcomes with intestinal transplant are improving:improving:

Outcomes with intestine only candidates are superior to intestine Outcomes with intestine only candidates are superior to intestine + liver candidates+ liver candidates

11stst year patient and graft loss is higher with intestine + liver year patient and graft loss is higher with intestine + liver Liver has survival benefit for SB graft in >1 yr survivorsLiver has survival benefit for SB graft in >1 yr survivors