Islet-after-Kidney Transplants Reduce Death and Return to Dialysis in T1D

Kidney transplant recipients with type 1 diabetes who also receive an islet transplant profit from a significant reduction in the risk of death and the likelihood of returning to dialysis, a recent study shows. According to the authors, these findings strongly support a broader reimbursement policy for islet transplantation.

In addition to kidney transplantation, people with type 1 diabetes (T1D) and end-stage renal disease (ESRD) benefit from beta-cell replacement to restore endogenous secretion of insulin and other pancreatic hormones. The aim is to reduce diabetes-related complications such as kidney graft damage. Currently, simultaneous whole pancreas transplantation remains the first choice for most people. However, transplantation of isolated islets into the portal vein has advanced significantly. It offers an alternative not only for transplant patients, but also for people with T1D and severe and frequent hypoglycaemia combined with hypoglycaemia unawareness or brittle diabetes.

“In recent years, islet transplantation progressively moved from a research approach to clinical prime time,” says François Pattou, EASD member and principal investigator of a retrospective cohort study (KAIAK) published in The Lancet Diabetes & Endocrinology. His team found that T1D patients who received an islet-after-kidney (IAK) transplant lived 19.6 months longer than those who received a kidney transplant alone. The number needed to treat to prevent a single death or return to dialysis was four. “The present study‘s results advocate in favour of beta cell replacement therapies for all diabetes patients with a kidney transplant,” says Pattou.

Nearly 20 years of IAK transplant data

The study included 2,391 individuals with T1D from the French CRISTAL registry who received a kidney transplant between 2000 and 2017, in 47 patients followed by islet-after-kidney (IAK) transplantation. Pattou and his colleagues matched these patients by ensuring comparability at the time of islet transplantation, resulting in 40 IAK patients and 80 kidney-only transplant patients. For their subsequent analysis, the primary outcome was patient-graft survival, defined as a composite of death, re-transplantation or return to dialysis.

During the study period, 33 % of the IAK patients returned to dialysis or died, compared with 45 % in the kidney-only group. Patient-graft survival was significantly higher in the IAK group, with survival rates of 98 % (vs. 88.6 %) at five years, and 82.9 % (vs. 72.7 %) at ten years. Overall, the authors calculated a hazard ratio of 0.44, mainly due to a protective effect of IAK transplants on the risk of death. (Figure 1)

Impact on glycaemic control

Prospective clinical studies have shown that IAK transplants are effective in restoring glycaemic control. In this study, insulin requirement was reduced from 100 % of patients to 46.8 % at three years, 53.7 % at five years and 61.2 % at ten years, respectively. IAK transplant patients also achieved significantly lower HbA1c levels, reaching 6.4 % (vs. 8.2 %) at six months, and 6.5 % (vs. 7.9 %) at five years. However, some patients experienced islet graft exhaustion (12.8 % at three and five years, 21.9 % at ten years). Eight patients died with a functioning islet graft, three of whom were insulin independent at that time.

Ensuring statistical rigour

Because IAK transplant patients are already following immunosuppressive protocols, they offer a unique opportunity to study the effects of islet transplantation on clinical outcomes. “One specificity of IAK transplantation lies in the variable timing between kidney and islet transplants,” explains Mehdi Maanaoui, first-author of the study. “To address this, we applied a method pioneered by two of the co-authors. It allowed us to accurately address time-dependent factors and competing risks, to balance confounders, and effectively emulate a randomised trial between patients receiving pancreatic islets and those maintained on insulin alone.” The use of the comprehensive national CRISTAL database to obtain data on transplant patients also proved to be a key asset of the study, Maanaoui and Pattou add.

What about the big picture?

“Given the demonstrated benefit on metabolic control and life expectancy, all patients with T1D and ESRD should be proposed IAK transplantation if pancreas transplantation is contraindicated,” Pattou urges. However, the main obstacle remains access to the technique, both authors agree. While reimbursement is available in some countries, such as France, it is not available in some of the pioneering countries in transplantation, such as the US or Spain. Another challenge is the limited availability of donors, which they believe could be addressed by expanded donor criteria or alternative sources such as xenotransplantation or stem cell-derived islets. “Reducing the need for lifelong immunosuppression will then remain the last challenge to overcome, but certainly not the least,” Pattou concludes.

To read this paper visit: Maanaoui M, Lenain R, Foucher Y, Buron F, Blancho G, Antoine C, Caillard S, Kessler L, Le Quintrec M, Villard O, Anglicheau D, Büchler M, Brodin-Sartorius A, Frimat L, Malvezzi P, Lablanche S, Badet L, Esposito L, Chetboun M, Hamroun A, Kerr-Conte J, Berney T, Vantyghem MC, Hazzan M, Pattou F; TREPID-ABM study group. Islet-after-kidney transplantation versus kidney alone in kidney transplant recipients with type 1 diabetes (KAIAK): a population-based target trial emulation in France. Lancet Diabetes Endocrinol. 2024 Oct;12(10):716-724. doi: 10.1016/S2213-8587(24)00241-9.

Author: Hanna Gabriel, BA MSc. Any opinions expressed in this article are the responsibility of EASD e-Learning.