Pancreas and Islet Transplantation

1
Pancreas and Islet Transplantation

• J. Keith Melancon M.D.
• Director Kidney and Pancreas Transplantation
• Georgetown University

2
Introduction - Diabetes

• Diabetes represents one of the most attractive
  targets for cellular or regenerative therapy.
• Chronic disease is characterized by a failure of
  glucose homeostasis, results in severe
  complications
• Type 1 DM autoimmune destruction of Beta cells
  in islets of Langerhans, and affects
  approximately 5 million patients worldwide.

3
Introduction - continued

• An ideal cure for type 1 diabetes requires a
  device ( tissue, cells, organ ) capable of
  performing the two essential functions of the
  missing Beta cells sensing blood glucose levels
  and secreting appropriate levels of insulin to
  the blood steam.

4
Whole organ pancreas transplantation

• First performed at the University of Minnesota in
  1966
• Results have steadily improved and currently 1 yr
  and 3 yr patient survival rates are 95 and 89
  respectively
• Graft survival rates are approximately 80 at 1
  yr and 65 at 3 yrs

5
Transplantation for Type 1 Diabetes

• It has been clearly shown that patients with Type
  1 diabetes benefit from improved blood glucose
  control.
• In 1993 the Diabetes Control and Complications
  trial Research group reported that diabetics
  receiving intensive insulin therapy decreased all
  associated diabetic morbidity.

6
Transplantation for Type 1 diabetes

• Successful pancreas or Islet transplantation
  offers the advantage of euglycemia without the
  risks of hypoglycemia associated with intensive
  insulin protocols.

7
Goals of pancreas and Islet Transplantation

• Low morbidity and/or mortality
• Eliminate need for insulin therapy
• Eliminate hypoglycemic events
• Create Euglycemic state
• Sustained glucose homeostasis over time

8
Introduction - continued

• The Edmonton protocol (2000) for pancreatic islet
  transplantation has established that allogeneic
  human islets can be safely grafted to diabetes
  patients.
• Islet grafts can survive and normalize glucose
  homeostasis for several years.
• Thus a cure for diabetes is within reach, given a
  sufficient supply of islets or beta cells.

9
Pancreatic Islet Transplantation

• One of the key elements in the success of the
  Edmonton program of Islet Transplantation was the
  need to transplant high-quality, purified islets
  in sufficient numbers ( Appox. 3000 islets / kg
  or total exceeding 200,000 IEQ)
• Refinement of islet isolation, standardization of
  pancreas digestion, and the use of cell
  processors have provided purified islets.

10
International Trial of Edmonton Protocol

• 2006 the Immune Tolerance Network ( Initiated by
  the NIH) enrolled 6 North American and 3 European
  centers to assess feasibility and reproducibility
  of Edmonton protocol.
• 36 patients received 77 islet transfusions and
  44 remained insulin independent at 1 year and
  14 remained insulin independent at 2 years

11
International Trial of Edmonton Protocol

• Although outcomes were sobering, C peptide
  levels were detectable in 70 of patients at 2
  years.
• All patients with residual islet function ( even
  if not insulin free) were protected from severe
  hypoglycemic episodes.

12
White Paper Financial Issues Constraining Islet
Transplantation

• Published April 2008 (AJT)
• Argues for continued clinical investigation of
  islet transplantation.
• The authors lament that clinical islet
  transplantation is severely limited and
  threatened by complex financial accounting issues
  that unduly burden OPOs and transplant centers
  venturing into islet transplantation.

13
Background

• In 2004 10 societies broadly representing the
  field of transplantation commented in a joint
  society letter to CMS with concerns regarding
  payment for pancreatic islet transplantation.
• In 2006 CMS ruled that a full standard
  acquisition fee was to be collected for recovered
  pancreata regarding intent to transplant
  (CMS-1543-R Dec 21 2006)

14
Islet Transplant Paradox

• More experience and investigation is needed to
  improve outcomes and increase recovery and
  utilization of available pancreata.
• Current financial entanglements stricture usage
  of available pancreata, and conflicts with
  missions of key stakeholders in islet
  transplantation ( CMS, NIH, HRSA, FDA, AOPO,
  UNOS, JDRF, transplant community)

15
Undue Financial Burden

• Organ acquisition costs to render a single
  diabetic patient insulin independent which
  generally requires 2-3 donor pancreata is 50
  90k
• This cost is dramatically increased up to 2-fold
  (or appox. 180k) if additional pancreata procured
  but yielding insufficient or poorly functional
  islets

16
Collaborative mission

• Currently gt60 of available pancreata are not
  recovered for transplantation
• HRSA has identified pancreas and islet
  transplantation as central to its mission of
  increasing organs transplanted per donor
• The cost of pancreata for islet transplantation
  is a potential negative stimulus for pancreas
  organ utilization in the United States.

17
The Problem

• There is not currently any method of determining
  in advance if a procured pancreas will yield
  islets appropriate for transplantation.
• The rate of procured pancreata to appropriate
  islet isolations stands at approximately 50
• This highlights the inherit differences between
  whole organ pancreas transplantation and cellular
  islet transplantation

18
Proposed Action

• Clarify the language in CMS final rule by taking
  into account the suitability for transplantation
  of the final islet product following the islet
  manufacturing process.
• Pancreata allocated for islet transplantation
  that do not yield a final islet preparation
  suitable for clinical transplant can be treated
  for cost accounting purposes as tissue, so as to
  allow for the lesser charge for the pancreas

19
Future directions

• Recent studies have documented improving outcomes
  after isolated islet transplantation with novel
  immunosuppressive strategies
• Islet transplantation seems uniquely suited for
  xenotransplantation preclinical pig to primate
  data is promising.

20
Conclusions

• More investigations into methods to decrease
  immune responsiveness to alloislets are needed,
  and may shed light on islet autoimmunity of Type
  1 diabetes.
• Decreasing financial disincentives of islet
  transplantation will allow for better utilization
  of deceased donor pancreata