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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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Shapiro, A. M. J., Lakey, J. R. T., Ryan, E. A., Korbutt, G. S., Toth, E., Warnock, G. L., Kneteman, N. M., & Rajotte, R. V. (2000) · New England Journal of Medicine · doi:10.1056/nejm200007273430401 · Cited by 5,237 · 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-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
Fay, M. P., & Graubard, B. (2001) · Biometrics · doi:10.1111/j.0006-341x.2001.01198.x · Cited by 289 · cited 1×
“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
McCall, M., & James Shapiro, A. M. (2012) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a007823 · Cited by 226 · cited 1×
“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).”
Self-citationBalamurugan, A., Naziruddin, B., Lockridge, A. D., Tiwari, M., Loganathan, G., Takita, M., Matsumoto, S., Papas, K., Trieger, M., Rainis, H., et al. (2014) · American Journal of Transplantation · doi:10.1111/ajt.12872 · Cited by 150 · cited 2×
“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.”
Self-citationFaradji, R. N., Tharavanij, T., Messinger, S., Froud, T., Pileggi, A., Monroy, K., Mineo, D., Baidal, D. A., Cure, P., Ponte, G., et al. (2008) · Transplantation · doi:10.1097/tp.0b013e31818fe448 · Cited by 99 · cited 1×
“Three subjects received one additional islet transplant in a different clinical trial upon completion of the originally planned 3-year followup of NIS01 (3).”
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Items 101–150 of 150
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“1 3 colleagues in 2016 published a long-term follow-up of the seven participants who enrolled in the multicenter International Edmonton Treatment study, finding that, despite the low insulin independence, the protocol was safe in the long run (Brennan et al. 2016).”
BackgroundIn Vivo Differentiation of Stem Cell-derived Human Pancreatic Progenitors to Treat Type 1 Diabetes
Maloy, M. H., Ferrer, M. A., & Parashurama, N. (2020) · Stem Cell Reviews and Reports · doi:10.1007/s12015-020-10018-5 · Cited by 4
de Souza, B. D., Rodrigues, M., de Oliveira, F. S., da Silva, L. A., Bouças, A. P., Portinho, C. P., Santos, B. P. D., Camassola, M., Rocha, D., Lysakowski, S., et al. (2020) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2020.110729 · Cited by 3
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Guo, M., Han, S., Liu, Y., Guo, W.-Y., Zhao, Y.-Y., Liu, F., Shi, X.-M., Ding, G.-S., & Wang, Q.-X. (2019) · Biochemical and Biophysical Research Communications - BBRC · doi:10.1016/j.bbrc.2019.05.188 · Cited by 3
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La thérapie cellulaire du diabète
Lysy, P. A. (2016) · médecine/sciences · doi:10.1051/medsci/20163204019 · Cited by 4
“Ces nouveaux protocoles pourraient avoir un impact important sur la survie à long terme des greffons comme en témoigne l’étude de suivi des patients EXIIST (extended immunosuppression in islet transplantation - ITN040CT) [8] qui montre, chez sept patients traités au long cours (avec le tacrolimus associé au sirolimus…”
BackgroundGutermann, L., Decottignies, A., Sharif, K., Sinclair, A., Rieutord, A., & Terry, D. R. P. (2014) · European Journal of Hospital Pharmacy · doi:10.1136/ejhpharm-2013-000439 · Cited by 3
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“Confocal fluorescence video microscopy (Zeiss, LMS 750) was used to follow the expression of the fluorescent reporters (mCherry for OKMS expression) in addition to EGFP for the islets derived from the four-transgenic mouse [see Additional files 1, 2, 3].”
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El-Badri, N. (2020) · doi:10.1007/978-3-030-55359-3 · Cited by 2
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Alekberzade, A., Krylov, N., Adzhun, Z., Laftavi, M., Shakhbazov, R., & Zuykova, K. S. (2018) · Khirurgiia · doi:10.17116/hirurgia201811180 · Cited by 2
Pancreatic tissue engineering: towards a vascularized bioengineered cure for diabetes
Park, J., Olawuyi, K., Jikaria, N. R., Dawes, J. S., Dabsha, I. E., Dick, A. A., & Ravnic, D. J. (2026) · Frontiers in Transplantation · doi:10.3389/frtra.2026.1768497 · Cited by 1
“Progressive graft attrition occurs due to a combination of instant blood-mediated inflammatory reaction, alloimmune rejection, recurrent autoimmunity, and islet exhaustion in the relatively hypoxic hepatic microenvironment (20, 23, 24).”
Seyyedi, M. S., Monfared, M., Mirzaei, E., & Azarpira, N. (2022) · Scientific Reports · doi:10.1038/s41598-022-25736-8 · Cited by 3
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Pancreatic Islet Transplantation: A Surgical Approach to Type 1 Diabetes Treatment
Rodriguez, S., Alexander, M., & Lakey, J. R. T. (2020) · Springer eBooks · doi:10.1007/978-3-030-53370-0_48 · Cited by 3
Progress toward islet transplantation tolerance
Markmann, J. F., & Rickert, C. G. (2019) · Elsevier eBooks · doi:10.1016/b978-0-12-814833-4.00058-7 · Cited by 2
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“Blood Glucose Levels According to five cohort studies, the average number of random blood glucose levels of subjects underwent islet transplantation ranges from 140 to 203 mg/dL [18,19,21,23,24].”
BackgroundInfluentialHassanein, A., Cyprian, F., & Akhtar, S. (2026) · Expert Opinion on Biological Therapy · doi:10.1080/14712598.2026.2721412
“Clinical experience shows gradual graft dysfunction linked to reactivation of CD4 + T cells memory populations upon re-exposure to β-cell antigens via indirect presentation by host APCs [50,51,55,56].”
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“Furthermore, islet isolations from donors with an HbA1c ≥6.5% did not correct blood glucose levels when transplanted into diabetic mice, whereas 75% of the islets from nondiabetic donors restored blood glucose levels to within normal ranges.”
InfluentialCarr, A. L. J., Shah, R., Marfil‐Garza, B. A., Lam, A. P., Dajani, K. Z., Anderson, B. L., Owen, R. J., O’Gorman, D., Kin, T., Bigam, D. L., et al. (2025) · PLoS ONE · doi:10.1371/journal.pone.0329074
“Although long term outcomes of allogenic ITx demonstrate a favourable profile for patient safety and sustained metabolic control [4,11–13], both acutely elevated portal pressures and elevated packed cell volume (PCV) of the transplantation preparation have been suggested as potential risk factors…”
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Self-citationPancreas and Islet Allotransplantation
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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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