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Islet Cell Transplantation in Australia: Screening, Remote Transplantation, and Incretin Hormone Secretion in Insulin Independent Patients DOI 10.1055/s-0034-1389941 Horm Metab Res 2015; 47: 16–23 For personal use only. No commercial use, no depositing in repositories.
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16 Review
Islet Cell Transplantation in Australia: Screening, Remote Transplantation, and Incretin Hormone Secretion in Insulin Independent Patients
Authors
C. S. Marathe1, C. J. Drogemuller2, J. A. Marathe3, T. Loudavaris4, W. J. Hawthorne5, P. J. O’Connell5, T. Radford2, T. W. H. Kay4, M. Horowitz1, P. T. Coates2, D. J. Torpy1
Affiliations
Affiliation addresses are listed at the end of the article
Key words ▶ pancreas ● ▶ islets ● ▶ transplantation ● ▶ remote centers ● ▶ type 1 Diabetes ● ▶ incretin hormones ●
Abstract
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Islet cell transplantation has emerged as a treatment modality for type 1 diabetes in the last 15 years due to the Edmonton protocol leading to consistent and sustained exogenous insulin independence post-transplantation. In recent years, consortia that involve both local and remote islet cell centers have been established, with local centers responsible for processing and shipping of islet cells, and remote centers only transplant-
Introduction
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received 08.07.2014 accepted 20.08.2014 Bibliography DOI http://dx.doi.org/ 10.1055/s-0034-1389941 Published online: October 28, 2014 Horm Metab Res 2015; 47: 16–23 © Georg Thieme Verlag KG Stuttgart · New York ISSN 0018-5043 Correspondence Prof. D. J. Torpy Endocrine & Metabolic Unit Level 7, Emergency Block Royal Adelaide Hospital Adelaide 5000 Australia Tel.: + 61/43/1266 075 Fax: + 61/8/8222 853
[email protected]
Type 1 diabetes, caused by autoimmune destruction of the pancreatic beta cells, accounts for 10 % of all cases of diabetes. Management is dependent on the administration of exogenous insulin, with the main limiting factor of therapy being hypoglycemia. Hypoglycemia can become disabling when awareness of sympathetic nervous system activation is impaired, to the point that impaired consciousness is the first symptom of hypoglycemia [1]. The “Edmonton protocol” which combined effective islet cell isolation and steroid-free immunosuppression [2], led the way to clinical islet cell transplantation internationally, with recipients drawn from a subset of type 1 diabetes patients with severe uncontrollable hypoglycemia/hypoglycemia unawareness and often chaotic blood glucose patterns. The expense and expertise needed for successful clinical islet transplantation (CIT) has led to the formation of islet transplant networks that involve both local and remote centers. CIT may be performed in a local center, that is, the same center in which the donor pancreas is processed and the islets are isolated as well as transplanted – also known as a center co-located with transplant (CLTC). Alternatively, islet transplantation may occur at a site remote from the islet isolation
Marathe CS et al. Remote Islet Transplant & Incretins … Horm Metab Res 2015; 47: 16–23
ing them. There are, however, few data on patient outcomes at remote centers. A tendency for high fasting glucose despite insulin independence was noted by us and others with an unknown mechanism. This review provides a brief history of islet cell transplantation, and focuses on the South Australian remote center experience: the challenges, screening criteria, and the impact on incretin hormone secretion of insulin independent transplant patients.
center – remote center transplantation (RTC). The data that are available on the outcomes in remote centers with patients with type 1 diabetes are not robust and involve very small numbers and short follow-up periods. One of the earliest reports was published in 2002 by Goss et al.: pancreata obtained in Houston were transported by air to a Miami center for isolation, before being transported back to Houston to be implanted into 3 patients via the right portal vein. The follow-up period in these patients varied between 2 to 8 weeks, and during this time there were no significant hyper- or hypoglycemic episodes, or complications related to the procedure [3]. The same center reported the transplant outcomes of 11 patients in 2004: 6 achieved insulin independence at the remote center, although the specific details taken to achieve independence were not included (time frame and number of transplants required, although it may be assumed that 3 were required in all cases) [4]. More recently, established consortiums have been recruiting remote sites, with the UK and GRAGIL being notable examples [5, 6], but standalone remote outcomes have been rarely reported as primary outcomes. We report the results from a center remote from islet isolation, where transport and delay in infusions may conceivably compromise outcomes. This review includes a brief
Review 17 background of islet transplantation, the Australian set-up, particularly the remote center based at Royal Adelaide Hospital (RAH), and novel data on incretin secretion in insulin independent patients at RAH.
Islet Transplantation: Background
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The history of islet transplantation attests to the value of perseverance – reflecting outcomes of collaboration, sacrifice and setback, followed by re-emergence at the turn of the millennium. The first recorded case of pancreatic transplant was in 1893 when a sheep’s pancreas was implanted subcutaneously in a 13 year-old boy as a desperate (and unsuccessful) measure to prevent death from ketoacidosis [7]. This was followed by a century of hurdles in successful beta-cell transplantation – chief amongst those were 1) translating success of murine models to human pancreas, 2) islet isolation, and 3) achieving insulin independence consistently. Two major advances in the past 25 years are noteworthy. The first was the breakthrough in islet isolation: Ricordi et al. developed the “automated digestion method” – a technique by which pancreas is chopped and then placed in a closed system (‘Ricordi Chamber’) for digestion by collagenase to yield morphologically intact islets [8, 9]. This technique has been central to most of the isolation techniques being conducted today. The second was the development of the so-called “Edmonton protocol” [2], which in 2000 reported to result in insulin independence in seven consecutive islet transplantations. The model owes its success to advances in immunosuppression, including a corticosteroid-free immunosuppressive regimen, transplantation of adequate islet mass ( > 10 000 islet equivalents per kilogram recipient body weight), and immediate infusion of islets [7]. The Edmonton protocol has now adopted across the world and with replication of the higher rate of early insulin independence. A fundamental challenge remains the capacity to achieve independence from exogenous insulin in the longer term (i. e., > 5 years).
Australian Islet Transplant Consortium and the Remote Transplant Center at Royal Adelaide Hospital
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Australia’s geographical location and size pose distinct logistic issues for the delivery of islets for transplantation. Most of the Australian population is concentrated on the eastern seaboard, with large distances between centers, mandating that the delivery of islet transplantation either requires the patient to travel to an islet transplant center, or for islet preparations to be shipped to remote centers for transplantation. Clinical islet transplantation in Australia began in 2002 at Westmead Hospital in Sydney with the transplantation of 6 patients with long standing type 1 diabetes using the Edmonton protocol [10]. In 2006, a consortium of Australian centers was established for the development of CIT and to provide human islets for research [10, 11]. These centers are federally funded, enabling equal access for all Australians. Three hospitals are currently involved in the Australian Islet Transplant Consortium – Westmead Hospital (WH) in Sydney, St Vincent’s Institute (SVI) in Melbourne, and The Queen Elizabeth Hospital/Royal Adelaide Hospital (RAH) in Adelaide. The clinical program comprises 2 clinical islet isolation centers co-located with transplant centers (CLTC) (WH/SVI) and one remote transplantation center (RTC)
(RAH). In a large country such as Australia, with a small number of deceased organ donors suitable for clinical islet transplantation, it is not feasible for each state to possess complex and expensive islet isolation facilities. Therefore, isolation of human pancreatic islets at centralized locations and shipping of the isolated islets to outside centers for transplantation is a model for delivery of clinical islet transplantation that is more feasible. The outcome of islet transplants in the Australian Islet Consortium was recently reported [11], and is comparable to the results described in the UK [12] and GRAGIL [13] networks. In the following section, we describe the successful establishment of remote center clinical islet transplantation, with high rate of insulin independence, achieved with islet overnight culture and commercial airline shipping in Australia for treatment of selected patients. The challenges in identifying suitable patients and the clinical outcomes achieved at a RTC compared with Australian CLTC are discussed.
Screening Criteria
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Donors
Whilst it is not often considered, donor factors can influence the success of the transplant, beyond the methods of islet cell isolation. The characteristics of the donor may influence graft survival, in particular the donor’s age, BMI, glycemia, presence of hypotension, and use of vasopressors prior to death, and eventual cause of death [14–17], with cerebrovascular stroke and intracranial hemorrhage being associated with a higher likelihood of failure [18]. Several biochemical markers have also been identified as predictors: elevations of transaminases and creatinine amongst them [19]. Shorter preservation time is also associated with a better outcome [19], which is likely a reflection of newer isolation techniques. In Australia, donor characteristics include age > 40 years, higher BMI, and nondiabetic background: with the initial Australian donors having an age of 46 ± 12.8 years and BMI of 32.7 ± 6.3 kg/m2 [11]. Additional criteria considered are patients in whom there was not a prolonged intensive care admission and/or prolonged period of hypotension. All pancreata are allocated according to the TSANZ Guidelines [20]: the pancreata are first offered for whole pancreas transplantation; if declined, they are potentially used for islet cell transplantation.
Recipients
There are no clear criteria for patient selection, which vary between research facilities. Early donor eligibility criteria included age (18–65 years), duration and diagnosis of type 1 diabetes (usually greater than 5 years and confirmed by the measurement of low/undetectable C-peptide levels), and the severity of hypoglycemic events and/or impaired hypoglycemic awareness [2, 21]. Hypoglycemia is quantified in recent studies using the HYPO score, Clark score, and/or lability index score [7, 22, 23], with the HYPO score the most often reported. In more recent times, these traditional criteria have been expanded to often include BMI ( 0.7 unit/kg/day) Improved control via dietary methods Islets unsuitable for transplant from transplanted kidney donor Age > 65 years Detectable C-peptide Psychological unsuitability
Number 13 7 5 3 3 2 2 2 Transplant procedure
2 1 1
Site
Fig. 1 The Australian Islet Consortium: Collaboration between local and remote transplant sites during various stages of the transplant process.
Total number of patients screened and unsuccessful = 42. CGM: Continuous glucose monitoring
Remote centers have their own challenges in selecting patients, as they will often have limited transplant opportunities available. Since our service began screening eligible patients in 2006, 58 patients have been considered as potential candidates for CIT. Eight of these have progressed successfully through the entire workup, with 5 going onto the transplant list, and 4 patients having undergone transplantation (as described in this paper), and one still waiting. Another 4 patients were referred to another center, as they did not live in the catchment area (South Australia, Western Australia, or Northern Territory). ● ▶ Table 1 provides the primary reasons for failure to progress to transplantation in our service, although it should be noted that in many patients more than one reason may have contributed. The majority of patients chose not to proceed with the transplant themselves, after considering the risk benefit ratio, including immunosuppressive risks particularly in the context of hypoglycemia that remained manageable in the patients’ view. Our center also tolerates a higher BMI than previously reported. Two patients who were referred were able to improve their blood glucose control with dietary advice, with the recognition that a very low carbohydrate intake contributed to hypoglycemia and in another 3 patients’ insulin regimes were optimied, predominantly to achieve bolus doing in close relation to carbohydrate intake as opposed to glucose level driven insulin dosing. Additional criteria of note include glomerular filtration rate (GFR) quantified using radioisotope studies, high insulin requirements, and body mass index (BMI), psychological preparedness, and detectable C-peptide levels.
Islet Isolation, Transplantation, Follow-up and Outcomes: the South Australian Experience
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For all islet cell transplantations in Australia to date, islets were separated at 2 islet isolation facilities using a variation of the closed loop method described by Ricordi et al. [8, 9], with approximately 50 % of the pancreata being transported from the remote site. Pancreata were removed from heart-beating deceased donors and disaggregated by infusing the ducts with cold collagenase NB1 GMP grade (SERVA, Heidelberg, Germany) or, for one infusion, Liberase HIGMP grade (Roche Indianapolis, IN, USA). Dissociated islet and acinar tissue were separated on a continuous Biocoll (Biochrom AG, Berlin) density gradient (polysucrose 400 and amidotrizoic acid) on a refrigerated apheresis
system (Model 2991, COBE Laboratories, Lakewood, CO, USA). Purified islets were counted and islet number and mass expressed in terms of islet equivalents (IEQ) [14]. Islet preparations underwent a pre-transplant quality assurance process, including a Gram stain, purity and viability assessment, packed cell volume measurement and evaluation of islet morphology to exclude excessive fragmentation. Islets were cultured in Miami media in 95 % room air and 5 % CO2 at 37.8 °C for up to 24 h. Four patients transplanted at the RTC islets were isolated as above, and were then transported by air in 120 ml of medium 199 and 20 % human albumin at ambient temperature and transplanted ▶ Fig. 1). into the patient immediately upon arrival ( ● In Australia, there is a national waiting list with priority given to patients requiring a second transplant. To date, a total of 20 patients have received between one and 3 islet infusions and of these, 4 have received nine islet infusions at the RTC. All patients were transplanted and immunosuppressed using antithymocyte globulin, tacrolimus, mycophenylate mofetil followed by switching to sirolimus and mycophenylate with initial 12 month results previously reported [11], but we now have longer follow-up data available. ▶ Table 2 summarizes the recipient demographics and islet ● transplant details for the 3 centers, and a comparison of outcomes, duration of graft function and insulin requirement of the patients in the Australian Islet Consortium. There were several parameters that appeared to differ between the 3 centers including pre-transplant HbA1c, islet ischemia time, infusions per patient and IEQ/kg recipient weight. Islet ischemic time was longer in the RTC (326 ± 20 min) compared to CLTCs (207 ± 17 and
