Abstract
Islet transplantation is one of the most promising treatments for an unstable form of type 1 diabetes. However, islet transplantation still has some obstacles, such as low success rate of islet isolation, difficulty to obtain long-term insulin freedom, and adverse events related to transplant protocol. We describe the adverse events of current clinical islet transplantation at our institute in this report. Nine type 1 diabetic patients received 17 islet infusions from March 2005 to October 2008. The islet infusion procedure and immunosuppression regimen were based on a modified Edmonton protocol. Severe adverse events (SAEs) were defined as events that were more than grade 3 according to the Terminology Criteria for Adverse Events in Trials of Adult Pancreatic Islet Transplantation, version 4.1 (Collaborative Islet Transplant Registry, CITR). Sixteen events were reported as SAEs and among them 12 events were probably or definitely related to transplant protocols; all occurred within 1 year after infusion except for one. Five adverse events (31%) occurred within 10 days after transplantation and were related to infusion procedures. Seven events (44%) occurred after 50 days and were related to immunosuppressive therapy. SAEs related to the protocol included three events of elevated liver enzymes, two of hemorrhage into gall bladder or peritoneal cavity, two of neutropenia, two of infection, one of vomiting, one of diarrhea, and one of renal dysfunction. All events were grade 3, except for one case that was grade 4 of neutropenia. All SAEs resolved with no sequelae. Neoplasms and deaths were not observed in our study. The present study suggests need to improve both infusion procedure and immunosuppressive strategy from the view of preventing SAEs.
Introduction
Islet transplantation is the one of most promising therapies for unstable type 1 diabetes. Several clinical trials of islet transplantation have been performed since results of the Edmonton group were published in 2000 (17). In recent years, many reports revealed benefits of islet transplantation such as improvement of glycemic stabilization, quality of life, and long-term diabetic complications (2,3,16,18,20,21). However, results of islet transplantation need to further improve to justify its disadvantages. Fiorina et al. mentioned the main obstacles for current islet transplantations in their review: poor long-term graft survival, low rate of successful of islet isolation, and side effects of immunosuppressive therapy (4). Adverse events of islet transplantation include the risk of bleeding, portal vein thrombosis, and common problems with immunosuppression or other concomitant agents: mouth ulcers, diarrhea, and acne (1,5,14). Longer term risks also are malignant disease and serious infection, although these are rare (15). Therefore, analysis of adverse events is important step on the way to improvement in results of islet transplantation.
We started clinical trials of islet transplantation based on the Edmonton protocol in 2005, and a novel protocol that has graft-protective immunosuppression strategy has been performed since last year (6). We focused on adverse events of islet transplantation in our institute in this article.
Materials and Methods
Patients
Patients with type 1 diabetes who met the inclusion criteria of the Edmonton protocol (17) received islet transplantations. The protocol was approved by the institutional review board (IRB) of Baylor Research Institute and Food and Drug Administration (FDA) and each subject gave written informed consent.
Islet Transplantation
Islet isolations were performed as previously reported (6–9,12). The criteria for the approval of clinical transplantation are that islets yield more than 4,000 islet equivalents/kg, purity more than 30%, viability more than 70%, tissue volume less than 10 ml, endotoxin level less than 5 endotoxin units/kg, and a negative Gram stain.
The islet infusion was performed as a percutaneous transhepatic procedure performed in Interventional Radiology using the Seldinger technique and sonographic guidance. Once access was confirmed by portogram, a Kumpe catheter was inserted within main portal vein. Islets were infused by gravity and using the bag technique (10).
For the first seven patients, immunosuppression regimen was based on the Edmonton protocol (17) (first-generation protocol). The last two patients received administrations of thymoglobulin (Genzyme Corp., MA, USA) for induction of immunosuppression, tacrolimus and mycophenolate mofetile for maintenance, and ethanercept (Wyeth Pharmaceutical Corp., NJ, USA) and anakinra (Biovitrium Corp., Stockholm, Sweden) for anti-inflammation during islet transplantation (second-generation protocol).
When patients received less than the optimal dose of 10,000 islet equivalent/kg body weight or did not achieved insulin independence, islet infusions were repeated up to a total of three.
Adverse Events
All adverse events (AEs) were reported according to the Terminology Criteria for Adverse Events in Trials of Adult Pancreatic Islet Transplantation, version 4.1 (Collaborative Islet Transplant Registry, CITR) which was based on the Common Terminology Criteria for Adverse Events of the National Cancer Institute, version 3.0 and categorized as grade 1 (mild), 2 (moderate), 3 (severe), 4 (life-threatening), and 5 (death) (1). AEs more than grade 3 were defined as severe adverse events (SAEs). The relationship between each adverse events and transplant protocol was categorized as causality 1 (not related), 2 (unlikely), 3 (possibly), 4 (probably), and 5 (definitely) by islet investigators.
Results
Seven females and two male patients received 17 islet infusions from March 2005 to October 2008. The average age at first islet infusion was 43.9 years (SE: 3.9, range: 26–57), and the mean of body mass index was 25.4 (SE: 1.0, range: 20.7–29.9). Seven out of nine patients (77.8%) reached insulin independence. The average follow-up period was 17.3 months (range: 2–37 months).
Number of Adverse Events
All patients had adverse events. SAEs related to either the infusion procedure or immunosuppressive therapy occurred in four patients (45%) in year 1 post-first infusion (Table 1). Twelve events (4.4%) among all 270 AEs were SAEs related to transplant protocol. There were no SAEs in patients who were transplanted using the second generation protocol although observation periods (0.42 person-years) were limited.
Number of Adverse Events in Follow-up Year 1
Relationships of the adverse event to the immunosuppression therapy and to the infusion procedure are based on classification of “probable” or “Definite.” AEs, adverse events; SAEs, severe adverse events.
Clinical Course of Adverse Events
Most of AEs and all SAEs occurred within first year after transplantation (Table 2). We analyzed SAEs related to either infusion procedure or immunosuppression therapy more precisely. All SAEs related to infusion procedure occurred and resolved within 4 months after each infusion, and durations of SAEs related to immunosuppression therapy lasted 2 weeks or less (Fig. 1). Among 12 SAEs related to the protocol, all events resolved without residual effects. There were no events resulting in death or chronic disability.
Time course of severe adverse events (SAE) related to the protocol. Hatched and shaded areas represent cumulative number of SAEs related to infusion procedure and immunosuppressive regimen, respectively.
Incidence of Posttransplant Adverse Events
AEs, adverse events; SAEs, severe adverse events.
SAEs related to the protocol included three events of elevated liver enzymes, two of hemorrhage into gall bladder or peritoneal cavity, two of neutropenia, two of infection, one of vomiting, one of diarrhea, and one of renal failure. Other SAEs were ischemic heart disease, diarrhea, and elevated liver enzymes for temporally used concomitants; antibiotics. All events were grade 3, except for one case that was grade 4 of neutropenia. There was no malignant disease.
Discussion
Although islet transplantation is a relatively safe procedure, adverse events and serious adverse events are frequent. More than half of patients experienced SAEs in the present study, and CITR reported similar statistics; 34% of patients who received islet transplantation alone had SAEs (1). However, the higher than usual incidence of adverse events is in part related to the fact that there is close follow-up of the patients and centers abide to the strict rules of reporting imposed by the FDA. The rate of SAEs in our institution was higher than those of CITR, which might be explained by higher frequency of SAEs related to infusion procedure. Although access to the portal vein is carefully performed by dedicated and experienced interventional radiologists, it is potentially difficult to completely avoid bleeding and vascular complications (13). In order to avoid bleeding from the liver site we are considering the following methods: local hemostatic agents such as microfibrillary collagen (19) and surgical portal venous access using a mesenteric vein branch. The site where islets are implanted also should also be reconsidered (11,22).
Immunosuppressive treatments also had SAEs such as infection and neutropenia, although most of them were self-limiting. The initial results show that the second-generation protocol had no SAEs. There is a possibility that improvement of graft protection and the immunosuppressive strategy might contribute to the reduction of the risk of SAEs. Longer follow-up is needed to confirm the initial results.
The time course of SAEs had features by the relationship to the protocol. All SAEs related to infusion procedure occurred within 10 days after each infusion while those related to immunosuppression therapy occurred later than 50 days after islet infusion. These findings could help clinicians to prevent or detect developing SAEs.
The present study had a limited number of subjects and needs further validation with more patients. Another limitation of our study is the determination of causality of AEs. The decision as to whether AEs are related or not to the treatment protocol are made by the principal investigator, and practice can vary across institution, especially with assessment of mild or moderate events. Therefore, the comparison with other databases needs careful interpretation. Preexisting disorders related to diabetes, such as silent cardiovascular disease, can result in serious AEs.
To conclude, adverse and serious adverse events are frequent after islet transplantation, but they resolve with no sequelae in our experience. Improvements in both the infusion procedure and the immunosuppressive therapy can prevent some of the adverse events associated with islet transplant protocols.
Footnotes
Acknowledgments
This work was supported in part by All Saint Health Foundation. The authors declare no conflict of interest.