what about a pancreas transplant?

July 13, 2004

Hi all.

Does anyone know much or anything about having a pancreas transplant?

Has anyone had one? Is there a long waiting list? Does anyone know the

answers to these questions?

I am considering the TP/ICT and many people have asked me about a

transplant so I just thought I would ask my trusted group.

Let me know what you all know/think.

T.

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July 16, 2004

Hi Iam Lucy and would be interested in that question also about the tranplant?

does anyone know anything please let us know Lucy

July 17, 2004

http://www.med.umich.edu/lrc/presentation/endo/panctran.htm

TRANSPLANTATION OF PANCREAS AND PANCREATIC ISLETS IN THE TREATMENT OF DIABETES

MELLITUS

A. Introduction

In a patient with diabetes mellitus, who has no endogenous insulin-secretory

reserves, currently available methods of delivery of exogenous insulin are not

adequate to maintain normal metabolism consistently.

There is evidence that an " artificial endocrine pancreas " , comprised of a

glucose sensor, a microprocessor and an insulin pump can achieve euglycemia,

when tested for up to two months in patients with type-1 insulin-dependent

diabetes mellitus. However, technical difficulties in miniaturization,

particularly involving the implantable glucose sensor, have delayed the

development of such a device.

Transplantation of insulin-producing tissue is the only currently viable means

of achieving euglycemia over long periods of time in patients with type-1

diabetes.

B. Unique features of insulin-producing pancreatic islet beta-cells

In evaluating successes, failures and developmental challenges of transplanting

insulin-producing islet beta-cells, the following unique features of these cells

have to be taken into consideration: [1] Islet cells are embedded in the

pancreas, 99% of which is dedicated to producing digestive enzymes. These

enzymes render the organ fragile; they have the potential to damage the

recipient's tissues. [2] The islet cells do not regenerate well. [3] When islet

beta-cells are stimulated to regenerate or are placed in unnatural growth

environments, they often develop defects in their glucose-sensing mechanisms.

C. Technical approaches to transplant insulin-producing tissues

The following experimental transplantation approaches have been tested for their

feasibility: [1] Vascularized intact pancreas. [2] Vascularized pancreatic

segment. [3] Collagenase-digested pancreas fragments containing endocrine and

exocrine tissues. [4] Purified pancreatic islets.

Attempts to transplant crude pancreas fragments have been unsuccessful; this

approach is no longer investigated. Transplantation of vascularized intact or

segmental pancreas and of isolated islets is the subject of this review.

D. Transplantation of pancreas

Pancreas transplantation for the treatment of type-1 diabetes mellitus has been

introduced in 1966 ( and Lillehei at the University of Minnesota). Since

that time, marked improvements have been made in clinical pancreas

transplantation, as a result of following technical advances (given in the order

of their importance): [1] Improvement and standardization of surgical technique.

[2] Advances in organ procurement and preservation. [3] Development of new

immunosuppressive regimens. [4] Improvement in the diagnosis and treatment of

rejection.

Surgical technique

" Back-table " preparation of the donor pancreas for transplantation is an

important phase of the surgery. Meticulous preparation of the organ and its

vasculature, and the duodenal segment is critical in reducing the risk of

technical transplant failures.

The intraperitoneal approach for anastomosis of the vessels of the pancreas

graft to the common iliac vessels, and complete mobilization of these vessels

has resulted in decreases in the incidence of postoperative abscess, wound

infection and thrombosis. Three methods have been developed to manage the

exocrine secretion of the pancreas graft: [1] Bladder drainage, with a

side-to-side duodenocystostomy. [2] Enteric drainage, by way of a

duodenoileostomy. [3] Sclerosing of the pancreatic duct with a polymer. In

recent years, bladder drainage technique has emerged as the method of choice.

Graft survival has been shown to be superior to that of enteric drainage or duct

injection. Ability to monitor urinary amylase as a marker of pancreatic

rejection may be a factor.

Organ procurement and preservation

A rapid and efficient surgical technique has been developed for safe removal of

the donor pancreas. This method involves en-bloc removal of the liver and

pancreas, together with a portion of the duodenum (to keep the exocrine

pancreatic duct intact). Prior to procurement, the duodenal lumen is sterilized

using povidone-iodine and amphotericin-B. After appropriate preservation, the

pancreas is separated from the liver, maintaining the vasculature of both organs

intact.

Currently, the liver, pancreas, and kidney can be successfully preserved for up

to two days by flushing the organs with the Belzer-University of Wisconsin (UW)

organ preservation solution and storing them at hypothermia (0-5deg.C). With

this method of preservation, the interval between procurement and

transplantation of a pancreas may be as long as 30 hours. The effectiveness of

the UW solution is based on the use of [1] several cell-impermeant agents

(lactobionic acid, raffinose, hydroxyethyl starch) that prevent the cells from

swelling during cold ischemic storage, and [2] glutathione and adenosine, which

are thought to stimulate recovery of normal metabolism upon reperfusion, by

augmenting the antioxidant capacity of the organs, and stimulating high-energy

phosphate generation, respectively.

Immunosuppressive regimens

Quadruple induction immunosuppressive therapy is initiated intraoperatively. It

involves [1] OKT3 monoclonal antibody, [2] glucocorticoids (prednisone), [3]

azathioprine, and [4] cyclosporine. Anti-lymphocyte immunoglobulin is used

rarely for induction. For maintenance, prednisone, azathioprine, and

cyclosporine are employed (azathioprine may be deleted in case of excellent

tissue match).

Toxicity of Immunosuppressive drugs currently in use is a major problem. In

particular, bone marrow suppression caused by azathioprine, and kidney damage

caused by cyclosporine are major concerns. Search continues for safer

immunosuppressants; among drugs in various stages of development are tacrolimus

(FK 506) and deoxypergualin.

Diagnosis and treatment of rejection

Detection of rejection of pancreas is quite difficult. An increase in serum

glucose is a late phenomenon in rejection. None of the imaging procedures is

helpful. Percutaneous biopsy under ultrasound guidance is very risky. Drainage

of the exocrine secretions into the urinary bladder has provided the advantage

of monitoring amylase levels in urine; a decrease in amylase usually indicates

dysfunction of the graft. A kidney graft transplanted simultaneously may serve

as an excellent index organ for rejection. In 90% of the rejection events, both

organs are affected; methods to detect kidney rejection are quite reliable. Once

rejection is detected, treatment with " steroid burst " , anti-lymphocyte globulin,

and occasionally OKT3 is implemented.

Demographic information on pancreas transplantation

An International Pancreas Transplant Registry (IPTR) has been established in

1966. Since 1987, all United States (US) cases are also being reported to the

United Network for Organ Sharing (UNOS) Registry.

1966 through June 30, 1993, 4799 pancreas transplants were reported to the IPTR.

Under-reporting is suspected for non-US cases, because reporting is mandatory in

the US, but voluntary elsewhere. Over the years, the outcomes of the pancreas

transplantation for the treatment of type-1 diabetes improved rapidly and

progressively, as summarized in the table below.

1-Year Survival

Time Period

Number of Cases

Patient

Graft

1966-1977

64

44%

5%

1978-1983

336

73%

26%

1984-1985

387

81%

40%

1986-1988

988

87%

54%

1987-1993

3001

91%

74%

In this review, only the data for the cases reported to the IPTR since October

1, 1987 are taken into consideration. October 1, 1987 through November 15, 1992,

2870, cases have been reported (2061 US; 809 non-US, 759 of which from Europe).

In the US, only 16 of the 2061 cases involved segmental pancreas transplant from

a living donor. In 85% of the US cases, pancreas was transplanted simultaneous

with a kidney (SPK), in most instances using organs from a single donor, in 8%

pancreas was transplanted after a kidney (PAK), and 6% were pancreas transplants

alone (PTA). Rare cases of simultaneous pancreas+liver, pancreas+liver+kidney,

pancreas+heart, and pancreas+heart+kidney were reported (<1%).

In the US, the method of exocrine duct management was bladder drainage (BD) in

95% of the cases, enteric drainage (ED) in 3%, ureter drainage in 0.3%; duct

injection (DI) was used in a single case. In other countries, 60% were BD, 31%

DI, and 8% ED, and 1% other techniques.

Pancreas graft and recipient survival rates

The rate of technical failure of the graft improved progressively. Most failures

occurred during the first three months, and were due to mainly to graft

thrombosis and local infection. The operative mortality rate is now less than

1%. For the interval 1987-1993, the overall technical failure rates were 12% for

the US, and 18% for non-US cases. For the US and non-US cases, respectively,

technical failure rates were 12% and 15% for BD, 24% and 11% for ED. The

technical failure cases have been included in the graft survival data given

below.

For the US, for the period October 1987 to September 1993, the rates of survival

of patients and functioning pancreas graft (defined as insulin-independence of

the patient) are shown below.

1-Year Survival

3-Year Survival

Patient

Pancreas Graft

SPK

91% (n= 2037)

76%

67%

PAK

92% (n= 197)

47%

30%

PTA

92% (n= 143)

49%

32%

For SPK-BD, the most commonly employed simultaneous pancreas and kidney

transplant with bladder drainage, for the US, for the period October 1987 to

July 1993, the rates of survival of patients and grafts are as follows (n=

1947).

1-Year Survival

4-Year Survival

Patient

91%

80%

Pancreas Graft

76%

61%

Kidney Graft

84%

70%

The results of a study from the University of Minnesota involving patients

receiving simultaneous pancreas and kidney transplants, revealed that the age of

the recipient is an important determinant of patient survival. At that

institution, in diabetic patients, one-year patient survival is 94% for kidney

transplant alone, and 85% for simultaneous pancreas and kidney transplants. When

the data are stratified according to age, one-year survival rates for recipients

under age 45 years are approximately the same for kidney transplant alone and

for simultaneous pancreas and kidney transplants. On the other hand, for the age

group over 45 years, patient survival is 94% for kidney alone and 33% for

simultaneous pancreas and kidney transplants.

The rates of survival of the kidney graft are the same for diabetic patients

receiving a kidney transplant alone or simultaneous pancreas and kidney

transplant. On the other hand, the morbidity and duration and frequency of

hospitalizations are significantly greater for SPK transplant than for kidney

transplant alone.

Prevention of long-term complications of diabetes with successful pancreas

transplantation

The data are inconclusive in regards to prevention of progression or reversal of

long-term complications of diabetes in the recipients of successful pancreas

transplants.

Retinopathy: In one study, as compared to 16 patients with failed pancreas

transplants, in 22 patients with functional pancreas grafts, progression of

retinopathy was not any different at three years, but may have stabilized by 5

years.

Nephropathy: Assessment of any beneficial effect on nephropathy is difficult,

because most patients have had end-stage renal failure at the time of pancreas

transplant. In one study, as compared to diabetic patients receiving kidney

transplant alone, in patients receiving pancreas plus kidney transplants, 2

years after pancreas transplantation, a lesser degree of expansion occurred in

glomerular and mesangial volumes.

Neuropathy: In patients with functional pancreas grafts, after three years of

euglycemia, the progression of neuropathy may be prevented. In a study involving

11 patients with functioning pancreas grafts, motor and sensory nerve function

improved; nerve functions deteriorated in 12 patients with graft failure.

Improvement in quality of life with successful pancreas transplantation

In two studies involving patients with type-1 diabetes and end-stage renal

failure, as compared to successful kidney transplantation alone, simultaneous

successful transplantation of pancreas and kidney improved the quality of life

significantly, in terms of perception of health status, physical activity,

full-time employment, and sick days.

Cost of pancreas transplantation

In the United States, in 1990 if a diabetic patient with end-stage renal failure

receives a pancreas transplant at the time of kidney transplantation, the

transplantation costs increase by about $35,000. The cost of pancreas transplant

alone to a patient who does not have kidney failure is about $60,000; the cost

of subsequent immunosuppressive therapy is several thousand dollars annually.

Selection of patients for pancreas transplantation

The proven benefit of pancreas transplant is the improvement in quality of life

resulting from independence from insulin injections, blood glucose monitoring

and strict adherence to diet and exercise regimens. Prevention of development or

progression of long-term complications of diabetes is not a proven benefit at

this time, although such an outcome would be expected.

The risks of pancreas transplant are those of major surgery, and

immunosuppressive therapy. In the case of simultaneous pancreas and kidney

transplant (SPK), the assessment of risks against benefits becomes favorable, in

that the risks of immunosuppressive therapy would be justified by the

life-saving kidney transplant, and the pancreas would be grafted at the time of

the laparatomy for kidney transplant. For pancreas transplant alone, the

benefits could outweigh the risks, only if frequent and severe episodes of

ketosis, hyperglycemia and hypoglycemia have caused the quality of life to

deteriorate to an extent that makes life of the patient is no longer productive

or meaningful. The deterioration must have occurred despite all efforts of

diabetes management.

Type-1 diabetic patients in the age range 20-50 years may be considered for

pancreas transplant. There should be sufficient evidence that reasonable

metabolic control of diabetes cannot be achieved despite all efforts. The

following are criteria for exclusion: Presence of established, advanced

long-term complications of diabetes; significant coexisting cardiovascular

disease (all patients should be screened with a thallium stress test); presence

of advanced autonomic neuropathy (because of increased risk of sudden death);

ongoing drug or alcohol abuse; major ongoing psychiatric disease; active

infection or malignant disease; significant history of noncompliance.

For SPK transplant, the patient should be placed on the transplant registry as

soon as progressive deterioration of kidney function is documented; the results

of SPK are much better, if the transplant occurs prior to institution of any

dialysis program for management of end-stage renal failure.

For PTA, among the inclusion criteria are evidence for presence of two or more

long-term complications of diabetes; severe disruption of quality of life; and

no more than early nephropathy, in consideration of anticipated cyclosporine

nephrotoxicity (creatinine clearance >70 ml/min, and proteinuria >150 mg/24 h,

but <3 g/24 h ). Intractable hypoglycemia unawareness is a secondary inclusion

criterion.

E. Transplantation of pancreatic islets

Transplantation of islet tissue is still in the experimental stage; progress has

been slow. Extensive work has taken place to develop and refine methods to

transplant pancreatic islets in animals.

Initially, methods to isolate viable and functional islets in sufficient numbers

have been developed in rodents, where the pancreas contains limited fibrous

tissue. In higher animals, harsher methods must be used to isolate the islets;

the islet yield has been less desirable. Recent advances in methodology now

allow isolation of 25% to 40% of the islets from an adult mammalian pancreas (up

to 250,000 islets from a human pancreas).

To prevent rejection of transplanted islet tissue, several methods have been

investigated: [1] Reduce immunogenicity of islets to be transplanted. [2] Alter

immune response of the recipient to induce tolerance of the transplanted islet

tissue. [3] Transplant the islet tissue into " immunologically privileged "

tissues of the recipient. [4] Isolate the islets from the immune of the

recipient, by encapsulating islet tissue to be transplanted.

To render islet tissue less immunogenic, the following approaches have been

tried: [1] The concept that immune cells ( " passenger leukocytes " ) embedded in

islet tissue are the principal activators of the immune response of the

recipient has led to the development of measures to induce the attrition of

these immune cells in short-term culture of islets at low temperature (1 week at

24deg.C) prior to transplantation. [2] Immunomodulation of islet cells, by

pretreating isolated islets with antibodies directed against major

histocompatibility antigens. [3] Prior culture in oxygen-enriched atmosphere.

[4] Ultraviolet irradiation. [5] Cryopreservation.

Altering immune response of the recipient to induce tolerance of the

transplanted islet tissue, by targeted neutralization of antigenic sites on the

immune cells is a subject of current investigation. Pretreatment of the

recipient with antibodies to CD4 antigen of the T-lymphocytes seem to give

promising results.

Transplanting islet tissue into the following " immunologically privileged "

recipient tissues has been tried, with equivocal outcomes: [1] Thymus. [2]

Brain. [3] Testicles.

Immune isolation of the islets to be transplanted, thus creating " hybrid

bioartificial pancreas " is an approach that is being investigated intensely at

academic institutions and at biotechnology companies. The transplanted islets

are sheltered within a selectively permeable membrane. The immune cells and the

immunoglubulins of the recipient cannot traverse the membrane. On the other

hand, the membrane is permeable to the nutrients and growth factors present in

the recipient's biological fluids, and to insulin produced by the islet graft.

Transplantation of immunoisolated islets promise two distinct advantages: [1]

Xenogeneic islets as well as allogeneic islets may be transplanted, thus

providing considerable freedom in terms of the source of the islets. [2] The

need for immunosuppressive therapy in the recipient is practically eliminated.

The following approaches are being tested in large animals: [1]

Microencapsulation of a single islet or several islets in alginate-poly-L-lysine

layers. Microencapsulated islets are deposited in the peritoneal cavity. [2]

Placing islets into tubular diffusion chambers made from selectively permeable

membrane. The material of these membranes include polyvinylchloride, polyamides

(nylon), polypropylene, polycarbonate, cellular nitrate, cellulose triacetate

and polysaccharide-polyamino acids. The membranes have a nominal molecular

cut-off of 50-80 kDa. Islets placed in multiple diffusion chambers of 5x20-mm

size are deposited in the peritoneal cavity. [3] The " vascularized artificial

pancreas " is designed to continuously perfuse the transplanted islets with the

recipient's blood. The islets are placed into an acrylic chamber, with a volume

of about 5 ml. The chamber has two seeding ports to add or remove islets. Within

the chamber is a tubular coil of selectively permeable membrane, with a wall

thickness of 120-140 um, an internal diameter of 6 mm, and a length of about 30

cm; The ends of the membrane coil are connected to polytetrafluoroethylene

vascular grafts; one end is anastomosed to a large artery, and the other to a

large vein (common iliac vessels in the dog). The blood of the recipient flows

within the tubule; risk of thrombus formation is reduced by treating the

recipient with aspirin or other anticoagulant.

Clinical trials on the efficacy of islet transplantation in reversing type-1

diabetes are progress since 1983. An international Islet Transplant Registry is

located in Giessen, Germany. Only human islets from one donor or multiple donors

have been used without encapsulation; recipients received immunosuppressive

therapy. Between December 12, 1983 and June 30, 1992, 167 adult islet

transplants were performed worldwide, (104 in the United States). The results

improved over time: After transplant, the percentage of patients that showed

positive basal C-peptide levels (i.e., >=1 ng/ml at >=1 mo) and that became

insulin independent (>1 wk), were 20% and 6%, respectively (n = 35) in

1985-1989, and 64% and 20%, respectively (n = 69) in 1990-1992. Through June 30,

1992, 19 patients were reported to be insulin independent for periods of 1 or

more weeks. At the present time islet transplantation for treatment of type-1

human diabetes is considered to be purely experimental.

F. References

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diabetes mellitus. Diabetes Care 1992;15:1668-72

Brayman KL, Sutherland DE. Factors leading to improved outcome following

pancreas transplantation--the influence of immunosuppression and HLA matching.

Transplant Proc 1992;24(Suppl 2):91-5

Clayton HA, RF, London NJ. Islet microencapsulation: a review. Acta

Diabetol 1993;30:181-9

Falagas ME, Snydman DR. Recurrent cytomegalovirus disease in solid-organ

transplant recipients. Transplant Proc 1995;27(Suppl 1):34-7

Faustman DL. Altered MHC class I expression: a role for transplantation and IDDM

autoimmunity. Diabetes Metab Rev 1995;11:1-19

Federlin KF. Islet transplantation. The connection of experiment and clinic

exemplified by the transplantation of islets of Langerhans. Exp Clin Endocrinol

1993;101:334-45

Fine A. Transplantation of fetal cells and tissue: an overview. Can Med Assoc J

1994;151:1261-8

Hering BJ, Browatzki CC, Schultz A, Bretzel RG, Federlin KF. Clinical islet

transplantation--registry report, accomplishments in the past and future

research needs. Cell Transplant 1993;2:269-82 (Discussion 283-305)

Holohan TV. Simultaneous pancreas-kidney and sequential pancreas-after-kidney

transplantation. Health Technol Assess 1995;4:1-53

Korsgren O, Jansson L, Moller E, Groth CG. Pancreatic islet transplantation in

the human. Adv Nephrol Necker Hosp 1993;22:371-86

Lacy PE. Treating diabetes with transplanted cells. Sci Am 1995;273:50-1, 54-8

Lafferty KJ, Hao L. Approaches to the prevention of immune destruction of

transplanted pancreatic islets. Transplant Proc 1994;26:399-400

Lafferty KJ, Hao L. Fetal pancreas transplantation for treatment of IDDM

patients. Diabetes Care 1993;16:383-6

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with immunoisolation. Diabetes 1992;41:1503-10

Larsen JL, Duckworth WC, Stratta RJ. Pancreas transplantation for type I

diabetes mellitus. Do the benefits offset the risks and cost? Postgrad Med

1994;96:105-11

Lefebvre PJ. Pancreatic transplantation: why, when and who? [see comments]

Diabetologia 1992;35:494-7

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cells to treat insulin-dependent diabetes mellitus. Clin Pharmacokinet

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1992;76:1225-33

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1993;25(Pt 1):52-4 (Matching article: Sutherland DER. Is there a need for

pancreas transplantation? Pro. Transplant Proc 1993;25(Pt 1):47-51)

Pirsch JD, s C, Hricik DE, phson MA, Leichtman AB, Lu CY, Melton LB,

Rao VK, Riggio RR, Stratta RJ, Weir MR. Pancreas transplantation for diabetes

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Pozniak MA, Propeck PA , Kelcz F, Sollinger H. Imaging of pancreas transplants.

Radiol Clin North Am 1995;33:581-94

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J Endocrinol Invest 1995;18:311-9

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(Oxf) 1993;39:399-400

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experimental medicine or real improvement? [see comments] Lancet 1994;343:27-31

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Transplant Proc 1994; 26:375-8

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Stratta RJ, Larsen JL, Cushing K. Pancreas transplantation for diabetes

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1995;17:323-37

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diabetes: review of observations at a single institution. Transplant Proc

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I hope this finds you and yours well

Mark E. Armstrong