The Role of Pancreas The Role of Pancreas Transplantation in the Long Transplantation in the Long

Term Management of Term Management of DiabetesDiabetes

Christopher Johnson MDChristopher Johnson MDProfessor of SurgeryProfessor of Surgery

Division of Transplant SurgeryDivision of Transplant SurgeryMedical College of WisconsinMedical College of Wisconsin

Learning objectives:Learning objectives:

1. 1. This talk will increase your understanding about This talk will increase your understanding about the rationale (including risk/benefit assessment) the rationale (including risk/benefit assessment) for pancreas transplantation in the for pancreas transplantation in the management of diabetes.management of diabetes.

2. This talk will allow you to better appreciate 2. This talk will allow you to better appreciate some of technical and immunological some of technical and immunological challenges associated with pancreas challenges associated with pancreas transplantation transplantation

3. This talk will help you to better anticipate 3. This talk will help you to better anticipate therapy options for diabetic patients who have therapy options for diabetic patients who have chronic kidney disease.chronic kidney disease.

no disclosuresno disclosures

Tight control reduces end organ damage but Tight control reduces end organ damage but increases the risk (2-3 fold) of severe increases the risk (2-3 fold) of severe hypoglycemic episodes (1).hypoglycemic episodes (1).

1 DCCT. The Diabetes Control and Complications DCCT. The Diabetes Control and Complications Trial Research Group The Effect of Intensive Trial Research Group The Effect of Intensive Treatment of Diabetes on the Development Treatment of Diabetes on the Development and Progression of Long-Term Complications in and Progression of Long-Term Complications in Insulin-Dependent Diabetes Mellitus. Insulin-Dependent Diabetes Mellitus. N Engl J N Engl J MedMed 1993; 1993; 329329: 977–986. : 977–986.

DCCT trial (1441 patients randomized to DCCT trial (1441 patients randomized to intensive insulin vs. conventional insulin) intensive insulin vs. conventional insulin) designed to examine the effect of tight designed to examine the effect of tight

control on 2control on 2°° complications (followed > 6yrs) complications (followed > 6yrs)

RetinopathyRetinopathy NeuropathyNeuropathy

Incidence progression Prevalence of neuropathy

A successful pancreas transplant A successful pancreas transplant completely normalizes blood completely normalizes blood

sugar controlsugar control

However, it requires life long immunosuppression

Types of pancreas Types of pancreas transplants:transplants:

Kidney/Pancreas (pts undergoing kidney transplantation)

Pancreas after kidney (already on IS) Pancreas transplant alone (severe life-

threatening complications of DM) Islet after kidney (no surgical

procedure) Islet transplant (no surgical procedure

but requires IS)

Combined kidney/pancreas Combined kidney/pancreas transplant is the most common transplant is the most common

scenario for pancreas scenario for pancreas transplantation:transplantation:

Indications for Simultaneous Indications for Simultaneous Kidney and Pancreas Kidney and Pancreas

Transplant:Transplant: Presence of ESRD (or eGFR < 20 Presence of ESRD (or eGFR < 20

ml/min)ml/min) Presence of diabetes: type 1 or 2 Presence of diabetes: type 1 or 2

(meeting age (< 55) and BMI criteria (meeting age (< 55) and BMI criteria (<30)(<30)

Lack of major complications and/or Lack of major complications and/or severe cardiovascular disease which severe cardiovascular disease which limits life expectancylimits life expectancy

Figure 13: Unadjusted 1-year, 3-year, 5-year and 10-year pancreas graft survival by transplant type

Reversal of Lesions of Diabetic Nephropathy after Pancreas Transplantation

Fioretto, Paola; Steffes, Michael W.; Sutherland, David E.R.; Goetz, Frederick C.; Mauer, Michael.

NEJM 339:69-75 July 9, 1998 Number 2

Survival estimates for patients with kidney graft function at 1 year. Abbreviations: LD, living donor; CAD, cadaveric.

Long-term survival following simultaneous kidney-pancreas transplantation versus kidney transplantation alone in patients with type 1 diabetes mellitus and renal failure

Am J Kid Disease 41:464-470. 2003

Figure 2: Waiting list death rates by diagnosis, 1999–2008.

Diabetics who receive k/p gain more Diabetics who receive k/p gain more life-years than k-alone or non-life-years than k-alone or non-

diabeticsdiabetics::

k/p transplants are equally successful for type 1 and type 2 diabetes:

data from SRTR 2010

What is the role of pancreas What is the role of pancreas transplant in type 2 transplant in type 2

diabetes?diabetes? Diabetes affects 10% of the Diabetes affects 10% of the

populationpopulation 90-95% is type 290-95% is type 2 Distinction between type 1 and 2 not Distinction between type 1 and 2 not

always clear cutalways clear cut

cC –peptide is not accurate in renal failure

suggested criteria:suggested criteria:

Organ Procurement: Simultaneous Liver and Pancreas Removal

Back table dissection:Back table dissection:

More back table dissection…More back table dissection…

Back table Reconstruction of Pancreatic Allograft

Arterial “Y” Graft of Donor Iliac Artery

Portal Vein Mobilization

Bladder Drainage with Systemic VenousAnastomosis

Enteric Drainage with Portal VenousAnastomosis

Trends in maintenance immunosuppression therapy prior to discharge for simultaneous kidney-pancreas transplantation 1994-2003American Journal of Transplantation 2005;5(Part 2):874-886

Incidence of rejection during first year among simultaneous kidney-pancreas recipients

American Journal of Transplantation 2005;5(Part 2):874-886

ADVANCES IN PANCREAS TRANSPLANTATION.Transplantation. 77(9) Supplement:S62-S67, May 15, 2004.

Burke G, Ciancio G, Sollinger H

Post-Transplant Complications•Early post-operative complications (Bleeding, infection)•Venous Thrombosis

•Reperfusion pancreatitis•Pancreas is a relatively low-flow organ•Unrecognized inherited hypercoagulable state

in the recipient•Transplant Pancreatitis

•Mild - transient amylase elevation for 48-96h•Severe – fat necrosis, infected peripancreatic fluid

•Kidney (urine leak, ureteral stricture)

Surgical Aspects of Pancreas Transplantation:

Radiologic tools for transplant evaluation:

Splenic vein thrombosis:

Fluid collection on CT:

Drachenberg CB, Papadimitriou JC, Klassen DK, et.al: Evaluation of pancreas transplant needle biopsy. Reproducibility and revision of histologic grading system. Transplantation 1997;63(11):1579-1586.

Drachenberg C, Klassen D, Bartlett S, Hoehn-Saric E, Schweitzer E, Johnson L, Weir J and Papadimitriou J:Histologic grading of pancreas acute allograft rejection in percutaneous needle biopsies.

Transplant Proc 1996;28(1):512-513

Diagnosis of Pancreatic Allograft Rejection (is difficult)

PAK and PTA have higher rate of PAK and PTA have higher rate of immunologic graft loss after 1 immunologic graft loss after 1

yearyear

Indications for isolated pancreas transplant (PAK or

PTA): Frequent and/or severe

hypoglycemic events consistent failure of insulin-based

management to prevent acute and chronic complications (poor control).

clinical and/or emotional problems associated with the use of exogenous insulin therapy that are so severe as to be incapacitating

Isolated Pancreas Transplant: Recipient Selection Criteria

IDDM, age > 18 years with an upper age limit of ?Ability to withstand surgery and immunosuppressionPsychosocial stability/ social support/ compliance/ commitment to long-term follow-upDiabetic secondary complicationsHyper-lability/ Hypoglycemic UnawarenessFinancial resources (USA)Absence of any exclusionary criteria: - renal function - coronary disease

Mortality risk/benefit of PAK and PTA:

American Journal of Transplantation 2004; 4: 2018–2026

Mortality on waiting list: Mortality after transplant:

spkSPK

Islet IsolationIslet Isolation1. Organ Procurement

2. Distension with Collagenase

3. Digestion & Mechanical Separation

4. Purification of Islets

5. Quantification

The “Edmonton Protocol”The “Edmonton Protocol”

Efficient Isolation ProcedureEfficient Isolation Procedure Reliable CollagenaseReliable Collagenase Steroid Free Immunosuppressive Steroid Free Immunosuppressive

ProtocolProtocol IL-2R BlockadeIL-2R Blockade TacrolimusTacrolimus SirolimusSirolimus

Only 31% remained insulin independent at 2 years

N Engl J Med 2006;355:1318-30.

Failed islet transplants are associated with sensitization to

HLA antigens:

Whole Pancreas Transplantation

+ +

Pancreatic Islet Cell Transplantation

Successful islet transplants decrease Successful islet transplants decrease progression of nephropathy and progression of nephropathy and

retinopathyretinopathy

Preservation of renal function

Decreased progression of retinopathy

Conclusions:

Pancreas transplants when successful, normalize glucose metabolism and increase quality (and quantity) of life.

“Good risk” diabetics (type 1 or 2) with renal failure should receive either a living donor kidney transplant or a combined kidney/pancreas transplant

Conclusions:

“Good risk” diabetics with a functioning kidney transplant (and problematic BS control) should be considered for pancreas after kidney

“Better risk” diabetics without kidney disease, but with life threatening manifestations should be considered for pancreas transplant alone

“Good” = age < 55, BMI < 30, insulin use < 1U/kg/day, no or minimal CAD, PVD