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Pancreas and Islet Transplantation


Diabetes represents one of the most attractive targets for cellular or regenerative therapy. ... Argues for continued clinical investigation of islet transplantation. ... – PowerPoint PPT presentation

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Title: Pancreas and Islet Transplantation

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

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
  • Type 1 DM autoimmune destruction of Beta cells
    in islets of Langerhans, and affects
    approximately 5 million patients worldwide.

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.

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

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

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.

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

Introduction - continued
  • The Edmonton protocol (2000) for pancreatic islet
    transplantation has established that allogeneic
    human islets can be safely grafted to diabetes
  • 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.

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.

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

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

White Paper Financial Issues Constraining Islet
  • 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.

  • 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)

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)

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

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.

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

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

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.

  • 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