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Long-Term Follow-Up of the Edmonton Protocol of Islet Transplantation in the United States
Open accessAbstract
We report the long-term follow-up of the efficacy and safety of islet transplantation in seven type 1 diabetic subjects from the United States enrolled in the multicenter international Edmonton Protocol who had persistent islet function after completion of the Edmonton Protocol. Subjects were followed up to 12 years with serial testing for sustained islet allograft function as measured by C-peptide. All seven subjects demonstrated continued islet function longer than a decade from the time of first islet transplantation. One subject remained insulin independent without the need for diabetic medications or supplemental transplants. One subject who was insulin-independent for over 8 years experienced graft failure 10.9 years after the first islet transplant. The remaining six subjects demonstrated continued islet function upon trial completion, although three had received a supplemental islet transplant each. At trial completion, five subjects were receiving insulin and two remained insulin independent, although one was treated with liraglutide. The median hemoglobin A1c was 6.3% (45 mmol/mol). All subjects experienced progressive decline in the C-peptide/glucose ratio. No patients experienced severe hypoglycemia, opportunistic infection, or lymphoma. Thus, although the rate and duration of insulin independence was low, the Edmonton Protocol was safe in the long term. Alternative approaches to islet transplantation are under investigation.
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“Although all but one of these patients required supplemental insulin 10 years post-transplant, all recipients retained some level of graft function that provided substantial benefits to glucose control and elimination of severe hypoglycemic events.17”
From Developments in stem cell-derived islet replacement therapy for treating type 1 diabetes (2023) · cites this paper as [17]
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“In 2001, the multicenter NIS01/ITN005CT (NIS01) protocol explored the feasibility and reproducibility of the methods used in the previously conducted ‘‘Edmonton Protocol’’ to evaluate islet transplantation together with a steroid-free immunosuppression (IS) regimen (1,2).”
Self-citationLevey, A. S., Eckardt, K., Tsukamoto, Y., Levin, A., Coresh, J., Rossert, J., de Zeeuw, D., Hostetter, T. H., Lameire, N. H., & Eknoyan, G. (2005) · Kidney International · doi:10.1111/j.1523-1755.2005.00365.x · Cited by 4,031 · cited 2×
“pdf and stage three or higher renal insufficiency or as defined by the Kidney Disease Outcomes Quality Initiative (4).”
InfluentialInternational trial of the Edmonton protocol for islet transplantation
Shapiro, A. M. J., Ricordi, C., Hering, B. J., Auchincloss, H., Lindblad, R., Robertson, R. P., Secchi, A., Brendel, M. D., Berney, T., Brennan, D. C., et al. (2006) · New England Journal of Medicine · doi:10.1056/nejmoa061267 · Cited by 1,942 · cited 1×
“In 2001, the multicenter NIS01/ITN005CT (NIS01) protocol explored the feasibility and reproducibility of the methods used in the previously conducted ‘‘Edmonton Protocol’’ to evaluate islet transplantation together with a steroid-free immunosuppression (IS) regimen (1,2).”
Self-citationFive-Year Follow-Up After Clinical Islet Transplantation
Ryan, E. A., Paty, B. W., Senior, P. A., Bigam, D., Alfadhli, E., Kneteman, N. M., Lakey, J. R. T., & Shapiro, A. M. J. (2005) · Diabetes · doi:10.2337/diabetes.54.7.2060 · Cited by 1,641 · cited 1×
“Two prior studies had followed patients for 5 years (12,13).”
Self-citationImprovement in outcomes of clinical islet transplantation: 1999–2010
Barton, F. B., Rickels, M. R., Alejandro, R., Hering, B. J., Wease, S., Naziruddin, B., Oberholzer, J., Odorico, J. S., Garfinkel, M. R., Levy, M., et al. (2012) · Diabetes Care · doi:10.2337/dc12-0063 · Cited by 725 · cited 2×
“…outcomes including near-normal HBA 1c , decrease in severe hypoglycemic episodes, a return of hypoglycemia awareness, and long-term islet function is also more common with some centers reporting rates of insulin independence at 3 years of 44% among patients transplanted between 2007 and 2010 (13).”
Self-citationBellin, M. D., Barton, F. B., Heitman, A., Harmon, J. V., Kandaswamy, R., Balamurugan, A. N., Sutherland, D. E. R., Alejandro, R., & Hering, B. J. (2012) · American Journal of Transplantation · doi:10.1111/j.1600-6143.2011.03977.x · Cited by 350 · cited 1×
“The more recent use of potent T cell–depleting agents and anti–tumor necrosis factor-a agents allows for better islet transplant outcomes with lower islet-mass infusions (10).”
Self-citationSmall‐Sample Adjustments for Wald‐Type Tests Using Sandwich Estimators
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“only seven subjects contributed to the analysis, p-values were computed using both a small sample adjustment to theWald chi-square statistic (7) and a score statistic.”
Update on Islet Transplantation
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“Similarly, the group from the University of Alberta recently reported sustained islet function as measured by the presence of C-peptide in 73% of their transplanted subjects, with 15% insulin independent at 9 years after transplantation (16).”
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“Participation in CITR is intended to provide long-term data to determine whether the usual progression of diabetes complications can be changed by islet transplantation.”
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“Three subjects received one additional islet transplant in a different clinical trial upon completion of the originally planned 3-year followup of NIS01 (3).”
Self-citation
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“(2,14,16-20) In fact, complete and stable long-term insulin independence is uncommon and, in current studies, is not even a primary endpoint following ITx.”
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“Studies have also consistently demonstrated a persistent decline in insulin production posttransplantation.(66,67) The lack of success in the”
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Pharmacological Targeting of GLUT1 to Control Autoreactive T Cell Responses
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“Despite improvements in immunosuppressive regimens, most CIT recipients do not achieve long-term insulin independence due to smoldering host-versus-graft immune responses (12).”
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Encapsulated islet transplantation
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BackgroundMethodInfluentialReprogramming human gallbladder cells into insulin-producing β-like cells
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Self-citationHo, B. X., Teo, A. K. K., & Ng, N. H. J. (2024) · Frontiers in Immunology · doi:10.3389/fimmu.2024.1375177 · Cited by 32
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“In the recently published 10-year f/u multicenter study, only 1 patient out of 7 (13%) was able to tolerate sirolimus in long term with good clinical outcome.(22) As noted, the pattern of achieving insulin independence varied between patients.”
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“The recently published long-term follow-up of the Edmonton Protocol demonstrated that the ITx was associated with longterm islet function, excellent glucose control, avoidance of severe hypoglycemia, and stable renal function without serious infection or malignancy over a period of 11 years.(2) Therefore, ITx is expec…”
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Nijhoff, M. F., & de Koning, E. J. P. (2018) · Current Diabetes Reports · doi:10.1007/s11892-018-1073-6 · Cited by 19
Rattananinsruang, P., Dechsukhum, C., & Leeanansaksiri, W. (2018) · Front. Cell Dev. Biol. · doi:10.3389/fcell.2018.00049 · Cited by 16
“Although the feasibility of this curative therapy is the prevention of the diabetes complications (Brennan et al., 2016), the insufficient islets supply remains a critical issue for the success of islet transplantation for diabetes treatment (Noguchi, 2009; McCall and Shapiro, 2012).”
BackgroundAn optimized protocol for purification of functional islets of Langerhans
Saliba, Y., Bakhos, J., Itani, T. M., & Farès, N. (2016) · Laboratory Investigation · doi:10.1038/labinvest.2016.123 · Cited by 18
Wong, J. M., & Pepper, A. R. (2024) · Frontiers in Transplantation · doi:10.3389/frtra.2024.1485444 · Cited by 19
“However, long-term follow-up of seven T1DM recipients enrolled in the multicenter international Edmonton Protocol failed to show sustained islet allograft function over a decade from their fi rst infusion, with only one subject remaining insulin independent (25).”
Whole-Organ Pancreas and Islets Transplantations in UK: An Overview and Future Directions
Martin, D. J., Alberti, P., Demartines, N., Phillips, M., Casey, J., & Sutherland, A. (2023) · Journal of Clinical Medicine · doi:10.3390/jcm12093245 · Cited by 16
“It has been shown that islet transplantation with the use of the Edmonton protocol could successfully restore long-term endogenous insulin production and prevent severe hypoglycaemia in subjects with type 1 DM, but insulin independence was usually not sustainable [63,64].”
BackgroundHypoparathyroidism: State of the Art on Cell and Tissue Therapies
Miglietta, F., Palmini, G., Giusti, F., Donati, S., Aurilia, C., Iantomasi, T., & Brandi, M. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms221910272 · Cited by 15
“In endocrinology, transplantation can be performed using a whole endocrine gland (such as for the pancreas [15,16]), endocrine tissues (such as parathyroid tissue [17,18]), or endocrine cells (such as for pancreatic islet cell transplants [19,20]).”
BackgroundBeta Cell Imaging—From Pre-Clinical Validation to First in Man Testing
Demine, S., Schulte, M. I., Territo, P. R., & Eizirik, D. L. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21197274 · Cited by 15
“A long-term endogenous insulin production and glycemic stability can be achieved in many patients, although insulin independence is progressively lost in spite of continuous immunosuppression [10,11,75,76].”
BackgroundIdentification and Characterization of microRNAs Associated With Human β‐Cell Loss in a Mouse Model
Roat, R., Hossain, M. M., Christopherson, J., Free, C., Jain, S., Guay, C., Regazzi, R., & Guo, Z. (2017) · American Journal of Transplantation · doi:10.1111/ajt.14073 · Cited by 15
Early Barriers to Neonatal Porcine Islet Engraftment in a Dual Transplant Model
Samy, K., Davis, R., Gao, Q., Martin, B., Song, M., Cano, J., Farris, A., McDonald, A., Gall, E., Dove, C., et al. (2017) · American Journal of Transplantation · doi:10.1111/ajt.14601 · Cited by 14
Beta-cell function and human islet transplantation: can we improve?
Chen, J. H., & Gunton, J. E. (2021) · Journal of Endocrinology · doi:10.1530/joe-20-0590 · Cited by 16
“The longevity of graft function has clearly progressed since the initial successes with the Edmonton protocol immunosuppression regimen (Brennan et al. 2016).”
BackgroundPomposelli, T., Wang, P., Takeuchi, K., Miyake, K., Ariyoshi, Y., Watanabe, H., Chen, X., Shimizu, A., Robertson, N., Yamada, K., et al. (2020) · Diabetes · doi:10.2337/db20-0517 · Cited by 17
“All recipients of allogeneic islets (n 5 6) received a consistent number of islets (6,650–8,750 IEQ/kg), which is considered to be marginal (4).”
BackgroundKuncorojakti, S., Rodprasert, W., Yodmuang, S., Osathanon, T., Pavasant, P., Srisuwatanasagul, S., & Sawangmake, C. (2020) · Journal of Biological Engineering · doi:10.1186/s13036-020-00246-1 · Cited by 17
Economics of Beta-Cell Replacement Therapy
Bandeiras, C., Hwa, A. J., Cabral, J. M. S., Ferreira, F. C., Finkelstein, S. N., & Gabbay, R. A. (2019) · Current Diabetes Reports · doi:10.1007/s11892-019-1203-9 · Cited by 19
Yang, K., Yanai, G., Yang, S., Canning, P., Satou, Y., Kawagoe, M., & Sumi, S. (2018) · Biotechnology and Bioengineering · doi:10.1002/bit.26730 · Cited by 14
“Since the Edmonton protocol first showed promising midterm and even long‐term follow‐up results, islet transplantation has become an accepted technique to manage hyperglycemia (Brennan et al., 2016).”
Backgroundβ‐Cell and renal transplantation options for diabetes
Flatt, A. J., Bennett, D., Counter, C., Brown, A. L., White, S. A., & Shaw, J. (2019) · Diabetic Medicine · doi:10.1111/dme.14177 · Cited by 14
Advancements in transplantation therapy for diabetes: Pancreas, islet and stem cell
Nakamura, T., Fujikura, J., & Inagaki, N. (2020) · Journal of Diabetes Investigation · doi:10.1111/jdi.13358 · Cited by 11
Fouad, A. M., Gabr, M. M., Abdel‐Hady, E. K., Zakaria, M. M., Khater, S. M., Ismail, A. M., & Refaie, A. F. (2018) · Journal of Genetic Engineering and Biotechnology · doi:10.1016/j.jgeb.2018.09.003 · Cited by 12
“The shortage of cadaveric donors, poor of oxygenation, vascularization of the graft and the immune rejection activity are considered as disadvantages of pancreas and islet transplantation [8].”
BackgroundJawahar, A. P., Narayanan, S., Loganathan, G., Pradeep, J., Vitale, G. C., Jones, C. M., Hughes, M. G., Williams, S. K., & Balamurugan, A. N. (2018) · Current Stem Cell Research & Therapy · doi:10.2174/1574888x13666180918092729 · Cited by 13
Oppler, S. H., Stone, L. H., Leishman, D. J., Janecek, J. L., Moore, M. E. G., Rangarajan, P., Willenberg, B. J., O’Brien, T. D., Modiano, J. F., Pheil, N., et al. (2024) · Science Advances · doi:10.1126/sciadv.adi4919 · Cited by 11
“Even in conventional intraportal transplant, portal blood pO 2 is typically ~ 40 mmHg exposing islets to hypoxia at transplant ( 69 , 70 ).”
BackgroundSawangmake, C., Rodprasert, W., Osathanon, T., & Pavasant, P. (2020) · Biochemical and Biophysical Research Communications - BBRC · doi:10.1016/j.bbrc.2020.06.145 · Cited by 9
Insulin-Producing Cell Transplantation Platform for Veterinary Practice
Kuncorojakti, S., Srisuwatanasagul, S., Kradangnga, K., & Sawangmake, C. (2020) · Frontiers in Veterinary Science · doi:10.3389/fvets.2020.00004 · Cited by 13
“Many investigators have raised concerns about the side effects of long-term use of steroids or immunosuppressants (5, 6).”
BackgroundSionov, R. V., & Ahdut-HaCohen, R. (2023) · Biomedicines · doi:10.3390/biomedicines11092558 · Cited by 13
He, S., & Lim, G. E. (2022) · Advanced Biology · doi:10.1002/adbi.202200151 · Cited by 7
Fluorogenic Peptide Substrate for Quantification of Bacterial Enzyme Activities
Al-Abdullah, I., Bagramyan, K., Bilbao, S., Qi, M., & Kalkum, M. (2017) · Scientific Reports · doi:10.1038/srep44321 · Cited by 8
“Furthermore, we examined how the enzymes cleave the peptide substrate under different conditions that exist in actual process of pancreatic tissue digestion: (1) effect of reaction components on enzyme activity; (2) effect of pH; and (3) effect of endogenous pancreatic proteases on the peptide substrate.”
BackgroundRecent Developments in Islet Biology: A Review With Patient Perspectives
Basu, L., Bhagat, V., Ching, M. E. A., Giandomenico, A. D., Dostie, S., Greenberg, D. T., Greenberg, M., Hahm, J., Hilton, N. Z., Lamb, K., et al. (2022) · Canadian Journal of Diabetes · doi:10.1016/j.jcjd.2022.11.003 · Cited by 7
“Although clinical islet transplantation was successful in some patients, recent studies (78,81e84) confirm previous conclusions that islet transplantation is not yet a viable solution for all individuals living with T1D (82,83).”
BackgroundResultSabbah, S., Liew, A., Brooks, A. M., Kundu, R., Reading, J., Flatt, A., Counter, C., Choudhary, P., Forbes, S., Rosenthal, M., et al. (2020) · American Journal of Transplantation · doi:10.1111/ajt.16285 · Cited by 7
Chen, Y.-J., Yamazoe, T., Leavens, K. F., Cardenas-Diaz, F. L., Georgescu, A., Huh, D., Gadue, P., & Stanger, B. (2019) · JCI Insight · doi:10.1172/jci.insight.124644 · Cited by 7
Pharmacologic targeting of the diabetic stem cell mobilopathy
Albiero, M., & Fadini, G. P. (2018) · Pharmacological Research · doi:10.1016/j.phrs.2018.07.017 · Cited by 7
β Cell replacement: improving on the design.
Castro-Gutiérrez, R., Michels, A. W., & Russ, H. A. (2018) · PubMed · doi:10.1097/med.0000000000000418 · Cited by 6
Advances in stem cell–derived beta-cell therapy: A new frontier in type 1 diabetes treatment
Upadhye, K. S., & Tayade, P. (2026) · Cell Transplantation · doi:10.1177/09636897261417623 · Cited by 8
“Strategies for directing pluripotent stem cells toward a β -cell fate have evolved from two-dimensional monolayer cultures to advanced three-dimensional systems, including suspension bioreactors and pancreatic organoid models, which better recapitulate developmental and metabolic cues 41,42 .”
HLA-B Matching Prolongs Allograft Survival in Islet Cell Transplantation
Lemos, J., Baidal, D., Poggioli, R., Fuenmayor, V., Chávez, C., Alvarez, A., Ricordi, C., & Alejandro, R. (2023) · Cell Transplantation · doi:10.1177/09636897231166529 · Cited by 6
Self-citationNanno, Y., Sterner, E., Gildersleeve, J., Hering, B., & Burlak, C. (2021) · PLoS ONE · doi:10.1371/journal.pone.0253029 · Cited by 6
Mcgowan, N., Bailey, L., & Casey, J. (2020) · Definitions · doi:10.1056/nejmc062939 · Cited by 6
“Long-term results from the Edmonton Protocol were published by Brennan (2016), who reported that all seven of the original subjects continued to have some islet function more than ten years after the transplantation.[25] One of the patients achieved insulin independence for eight years, but had graft failure 10.”
Comparison of Clostripain and Neutral Protease as Supplementary Enzymes for Human Islet Isolation
Brandhorst, H., Johnson, P. R. V., Mönch, J., Kurfurst, M., Korsgren, O., & Brandhorst, D. (2018) · Cell Transplantation · doi:10.1177/0963689718811614 · Cited by 6
Dadheech, N., Cuesta‐Gomez, N., Jasra, I. T., Verhoeff, K. K., Marfil‐Garza, B. A., Mouhammed, O., & Shapiro, A. M. J. (2022) · Journal of Immunology and Regenerative Medicine · doi:10.1016/j.regen.2022.100064 · Cited by 6
Self-citationWilson, L., Kwok, T., Ma, Y., Wong, J. C., Ho, M., Ionova, Y., MCGRATH, M. T., Mueller, M. M., Gitelman, S. E., & Irony, T. (2022) · Transplantation · doi:10.1097/tp.0000000000004189 · Cited by 7
Isolated Pancreatic Islet Transplantation: A Coming of Age
Markmann, J. (2016) · American Journal of Transplantation · doi:10.1111/ajt.13538 · Cited by 5
“In the first report, Brennan et al (3) provide an update on a subset of the 36-patient international Immune Tolerance Network (ITN) trial cohort designed to replicate the Edmonton success with expansion to additional sites (4).”
Background
Metadata
- Authors
- Brennan, D. C., Kopetskie, H. A., Sayre, P. H., Alejandro, R., Cagliero, E., Shapiro, A. M. J., Goldstein, J. S., DesMarais, M. R., Booher, S., & Bianchine, P. J.
- Affiliations
- Washington University in St. Louis (US)
- Rho (United States) (US)
- Immune Tolerance Network (US)
- University of Miami (US)
- Harvard University (US)
- University of Alberta (CA)
- National Institute of Allergy and Infectious Diseases (US)
- Corresponding author
- Brennan, D.C.
- Venue
- American Journal of Transplantation
- Publisher
- Elsevier BV
- Published
- 2016-02
- Volume
- 16
- Issue
- 2
- Pages
- 509-517
- ISSN
- 1600-6135 (ISSN-L)
- OpenAlex
- W2128934917
- Cited by
- 176
- References
- 22
- Citations by year
- 2026: 9 · 2025: 12 · 2024: 9 · 2023: 12 · 2022: 14 · 2021: 19 · 2020: 19 · 2019: 23 · 2018: 19 · 2017: 17 · 2016: 20
- FWCI
- 19.49
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- American Journal of Transplantation (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Funders
- National Institute of Allergy and Infectious Diseases (NO1-AI-15416)
- National Institutes of Health (HSN272200800029C)
- Juvenile Diabetes Research Foundation Australia
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Pancreatic function and diabetes
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Diabetes and associated disorders
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Management and Research
- Keywords
- islet transplantation, Edmonton protocol, type 1 diabetes, C-peptide, insulin independence, graft failure, long-term follow-up, liraglutide, hypoglycemia, HbA1c
- MeSH terms
- Adult, Blood Glucose, C-Peptide, Diabetes Mellitus, Type 1, Female, Follow-Up Studies, Graft Survival, Glycated Hemoglobin, Humans, Hypoglycemia, Hypoglycemic Agents, Insulin, Male, Middle Aged, Prognosis, Risk Factors, Islets of Langerhans Transplantation
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