Expanding Pancreas Transplantation, Improving Islet Transplantation, and the Search for Alternative Sources of Beta Cells

Expanding Pancreas Transplantation

December 16-17, 2016 marked the 50th anniversary of the first successful human pancreas transplant which was performed at the University of Minnesota by Richard C. Lillehei and William D. Kelly. A symposium commemorating this historic milestone will be held on May 19, 2017 at the University of Minnesota, when Drs. Jean-Michel Dubernard, David E.R. Sutherland, Hans W. Sollinger and Frederick Merkel, who scrubbed on that first successful case, will present their perspectives at an evening dinner symposium. More information about the symposium can be found at z.umn.edu/50pancreas or on the IPITA website, www.ipita.org.

Since this groundbreaking pancreas transplant in 1966, more than 30,000 pancreas transplants have been performed worldwide. Yet, for the last 10 years, the number of pancreas transplants in the US has been declining, the reasons for which are multifactorial.^1,2 Several opportunities for programmatic expansion of pancreas transplant volume are worth noting and highlighted by recent publications and an IPITA Webinar.

The use of pediatric donors for pancreas transplantation is not new, but a recent publication by Spaggiari et al. retrospectively studied the UNOS database and stratified donors by age and weight.³ They showed that pediatric donors exhibited superior long term patient and graft survival compared to adult donors, and donors as small as <30 kg also had excellent short-term outcomes, though long-term outcomes were less optimal. Another potential area for expansion is to consider selected patients with insulin-dependent Type 2 diabetes (T2D) for pancreas transplantation. Traditionally, many transplant centers do not routinely offer pancreas transplantation to this population due to concerns for overwhelming peripheral insulin resistance and potential inability to achieve insulin independence. However, it is now well documented that insulin independence can be readily achieved in selected patients with T2D. In fact, 8-10% of all pancreas transplants in the US are now performed in patients categorized as T2D. Dr. Matthew Cooper recently reviewed this topic in an excellent IPITA Webinar which can be downloaded and viewed at:
https://www.tts.org/index.php?option=com_tts&view=presentation&id=183627&Itemid=2003.

Whether to offer a uremic T1D patient a living donor kidney (LDK) transplant alone or a simultaneous kidney pancreas (SPK) transplant is a decision frequently encountered in the clinic. To address this issue, Barlow et al. used the UK Registry to retrospectively compare SPK to LDK outcomes.⁴ Emphasizing the benefits of pancreas transplantation, they showed that SPK recipients with a functioning pancreas graft had significantly better kidney graft and patient survival than LDK recipients or those with a failed pancreas graft. Finally, other recent studies investigated the impact of donor HbA1c on pancreas graft survival and recipient age on overall outcomes.^5,6 These new interesting data may encourage pancreas transplant centers to expand their donor and recipient criteria, spurring an opportunity to offer more patients the benefits of pancreas transplantation. These publications also underscore the fact that the primary clinical outcome data in the field of pancreas transplantation derives from retrospective studies. As the field matures and evolves, increasing attention is being given to the need for prospective, randomized studies to evaluate outcomes in comparison to other therapeutic options.

Improving Islet Transplantation

With the recent passing of Dr. Thomas E. Starzl, liver transplant pioneer and founding member of the ASTS, it is worthwhile to reflect that he and his team performed the first successful human islet transplants at the University of Pittsburgh in 1990. Five patients underwent upper abdominal exenteration followed by liver transplantation and intraportal infusion of pancreatic islets isolated from the pancreas of the same cadaver liver donor and were rendered free of insulin for up to 5 years. Around that same time dozens of islet allotransplants were attempted in autoimmune T1DM patients and insulin independence was not achieved in any case.⁷

Since that time, many T1D patients have achieved insulin independence with islet transplantation at centers around the world. Reflecting in large measure the recent US experience, the Clinical Islet Transplant Consortium published the results of a multicenter Phase III trial of islet transplantation in T1D patients with hypoglycemic unawareness.⁸ In this landmark study, the primary endpoint of HbA1c <7% and freedom from severe hypoglycemic events was met in 87.5% of subjects at 1 year and 71% at 2 years. While the majority of patients reduced their insulin requirements and had evidence of graft function, insulin independence was observed in only approximately 52% of patients one year and 42% of patients two years after transplantation suggesting some islet graft attrition. Despite these limitations, another study from Australia demonstrated superior glycemic control and fewer hypoglycemic events in subjects after islet transplantation compared to subjects receiving intermittent or continuous subcutaneous insulin therapy.⁹

The reasons for islet graft loss after intraportal islet transplantation are multifaceted. Several recent articles highlight factors that contribute to this process, and begin to shed light on possible solutions. An important study by Smith et al. confirm that human islets placed in high density culture exhibit reduced viability and function which is associated with upregulation of inflammatory and hypoxia-response pathway genes.¹⁰ Many labs are investigating ways to improve oxygen delivery to transplanted islets exposed to hypoxic environments, such as certain transplant sites and encapsulation devices. In a recent study, scientists have engineered an innovative oxygen generating biomaterial, termed OxySite, to provide supportive in situ oxygenation and prevent hypoxia-induced damage.¹¹ They observed significantly improved graft function in a syngeneic diabetic rat model with islets embedded in this material. Another article studied pancreata from brain dead donors with laser capture microdissection and studied gene expression profiles compared with normal pancreatic tissue from surgical resections. Significant changes were found in pathways associated with ER stress apoptosis and inflammation.¹² These data suggest that apoptosis inhibitors as a part of a perioperative treatment protocol could have some benefits to reduce islet cell loss. The group from Edmonton recently demonstrated that the pan-capsase inhibitor F573 reduced islet apoptosis and improved engraftment in mouse and human islet transplant models.¹³ These and other investigators are moving the needle to improve islet engraftment and function in experimental animal models with the hope these exciting innovations will translate to large animal models and humans.

Search for Alternative Sources of Beta Cells

The prospect of successful xenotransplantation of porcine islets into humans is seeing a resurgence in interest with the recent report of eliminating 62 copies of PERV from the pig genome by CRISPR/Cas9 genome editing technology.¹⁴ This technology has enormous potential to impact the xenotransplantation field as scientists are now able to perform multiple genomic modifications, such as those that could dampen xenogeneic immune responses, much more rapidly than was previously possible.

The potential use of pluripotent stem cells for producing transplantable tissues is also in the news. Reporting in Nature, Yamaguchi et al.¹⁵ described the generation of autologous pancreata from pluripotent stem cells (PSCs) which brings science one step closer to growing new organs and solving the organ shortage crisis. Building on prior work, they demonstrated the viable production of mouse-rat chimeric pancreata using the technique of blastocyst complementation by injecting mouse PSCs into PDX1 mutant rat blastocysts and showed that isolated islets from these mouse-rat chimeric pancreata were capable of reversing streptozotocin-induced diabetes in mice syngeneic to the original mouse PSC line, remarkably without long-term immunosuppression. This study has profound implications as the transplantation field seeks to generate replacement organs and tissues from a patient’s own cells.

Towards a Definition of Success in Beta Cell Replacement Therapy

The improving results of both islet and pancreas transplantation underscore the need for a quantifiable and auditable definition of graft function that is applicable to these and other future forms of beta cell replacement therapy. With this goal in mind, a panel of experts was convened in Igls, Austria on January 28-29, 2017 at a Joint IPITA/EPITA Opinion Leaders Workshop on “Defining Outcomes for Beta Cell Replacement Therapy”. Workshop that was held in conjunction with the 7th EPITA Symposium. There was lively debate and a well-structured discussion and at the conclusion, an “Igls Workshop Definition of Beta Cell Graft Functional Outcomes” proposal was presented. Later this year, a meeting report will be published which will include a consensus statement on the definition of different tiers of function and failure, and will provide guidelines on collecting various metabolic and immunologic outcome measures. It is hoped that these guidelines for reporting outcomes of islet and pancreas transplantation will become a new standard.

(see references at the bottom)

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Related publications in Transplantation Journal

Submitted by: Dr Joel Thomas Adler, Editorial Fellow, Transplantation.

The volume–outcome relationship in surgical procedures is well studied and has significant policy implications, as many have suggested that complex procedures be performed only at high-volume centers. Kopp et al examine the volume–outcome relationship within Eurotransplant, and Almahad et al address this issue in the United States. Both studies found that short- and long-term outcomes were better at high-volume transplant centers. In particular, both groups noted the improved outcomes with pancreata of higher donor risk in high-volume centers.

Alhamad T, Malone AF, Brennan DC, et al. Transplant Center Volume and the Risk of Pancreas Allograft Failure. [published online January 17, 2017]. Transplantation. doi: 10.1097/TP.0000000000001628.
Read More

Kopp W, van Meel M, Putter H, et al. Center Volume Is Associated With Outcome After Pancreas Transplantation Within the Eurotransplant Region. [published online July 1, 2016]. Transplantation. doi: 10.1097/TP.0000000000001308.
Read More

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TTS 2018 - CALL FOR TOPICS AND IDEAS

Your opinion is important to us! The Scientific Program Committee of TTS 2018 invites YOU to submit your ideas and recommendations for the program by April 24, 2017.

CLICK HERE TO TAKE THE SURVEY

The SPC is looking for feedback in the following areas:

Keynote presentation topics should be applicable to a great majority of the audience and not focus on a niche topic. This year's program theme is OUTCOME DRIVEN. This theme would ideally be reflected in the presentation.

General presentation topic suggestions will be provided to the State-of-the-Art leads for the planning of SOTA sessions and Early-Morning Symposia.

Innovation. TTS 2018 is eager to highlight innovative presentations. You have the opportunity to propose a session / presentation that is novel. This implies that the topic is not currently listed as one of the SOTA topics and has never been part of a TTS meeting. It is assumed that you, as the submitter, would be the session organizer.

Feedback. Please share your general ideas and recommendations regarding the program and the congress at large (poster sessions, mobile app, catering, competitions, exhibits etc.).

Upcoming Meeting Deadlines

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ISODP 2017 - APRIL 21
ABSTRACT SUBMISSION DEADLINE

INTERNATIONAL SOCIETY FOR ORGAN DONATION AND PROCUREMENT (WWW.ISODP2017.ORG) - September 6-9 - Geneva, Switzerland

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ISVCA 2017 - APRIL 30
ABSTRACT SUBMISSION DEADLINE

13TH CONGRESS OF THE INTERNATIONAL SOCIETY OF VASCULARIZED COMPOSITE ALLOTRANSPLANTATION (WWW.ISVCA2017.ORG)
SALZBURG | AUSTRIA, OCTOBER 26 - 27, 2017

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CST/CTRMS 2017 - May 8
ABSTRACT SUBMISSION DEADLINE

Joint Scientific Meeting - Canadian Society for Transplantation and Cell Transplant and regenerative medicine society (HTTP://WWW.CST-TRANSPLANT.CA/2017_CST-CTRMS.HTML) - Halifax | Canada, Sept 26-29, 2017

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IPTA 2017 - May 14
STANDARD REGISTRATION DEADLINE

International Pediatric Transplant Association (http://ipta2017.org) - Barcelona | Spain | May 27-30, 2017

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TSS 2017 - May 15
STANDARD REGISTRATION DEADLINE

TTS Transplantation Science Symposium (www.tss2017.org) - Victoria, BC| Canada ,May 24-26, 2017

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ESTABLISHMENT OF BASKENT UNIVERSITY DIVISION OF TRANSPLANTATION

Announcement of the establishment of the Division of Transplantation, under the aegis of the Baskent University Faculty of Medicine Department of General Surgery. This is the first Transplantation Division of its kind at a University Hospital in Turkey, and was approved by the Higher Education Commission of Turkey on March 21, 2017READ MORE

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IN THE NEWS

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Scientists announce breakthrough in stem cell research
April 6 - UPI - Scientists have already successfully developed pluripotent stem cells in the lab, cells which can form any type of tissue. Totipotent stem cells are the pinnacle for stem cell scientists, however. And for the first time, researchers have found a way to engineer them.
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Heart disease breakthrough: Pump REVERSES heart damage without the need for a transplant
April 11 – Express (UK) - British doctors last night hailed a medical procedure which sees patients with severe heart disease recover full fitness – without the need for a transplant.
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Hong Kong urged to clarify legal issues before launching opt-out organ donation scheme
April 9 – South China Morning Post- City should first legislate on the definition of brain death, HKU professor says.
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Kidney transplant vouchers could address timing issues
April 7 - Reuters- Creating kidney transplant vouchers for future transplants could reduce the long waiting list for organs in the United States, a new study suggests.
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Care of patients pre, peri and post pregnancy addressed during 37th annual ISHLT meeting & scientific sessions
April 8 – Yahoo Finance - On the final day of the 37th Annual International Society for Heart and Lung Transplantation (ISHLT) Meeting & Scientific Sessions, members discussed women of reproductive age, who account for over a third of all solid organ transplants.
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Schoolgirl, 13, becomes first child in Britain to be given an artificial heart after being transferred between hospitals with her chest OPEN
April 11 – Mail Online- Surgeons have implanted an artificial heart in a British child for the first time after doctors decided it was the only way to save her life.
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Not enough donors, surgeons or teams for organ transplants in Malaysia
April 9 – The Straits Times- Malaysia is in critical need of more organ transplant surgeons but even if there were, there is a lack of medical teams to retrieve the organs from deceased donors.
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KIMS Hospitals sets new precedent in organ donation with ‘swap registry’
April 11 – United News of India- The Krishna Institute of Medical Sciences (KIMS) Hospitals has set new standards in organ donation and transplant by creating a ‘swap registry’. A team of experts at KIMS Hospitals led by Senior Transplantation Surgeon Padmashri Dr Sarbeswar Sahariah, have transplanted a compatible kidney of a donor from one family to a recipient of a different family, and vice versa. This form of kidney exchange or swap is a simple barter practice, which helps protect lives of two individuals.
Read More

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Potential number of organ donors after euthanasia in Belgium
April 11 – Medical Press- An estimated 10 percent of all patients undergoing euthanasia in Belgium could potentially donate at least one organ, according to a study published by JAMA.
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Call for nominations

The Thomas E. Starzl Transplantation Institute is accepting nominations for the 2018 Thomas E. Starzl Prize in Surgery and Immunology, awarded annually to a national or international leader in the field of organ transplantation and immunology.
CLICK HERE FOR DETAILS