1 Department of Medicine, Clinical Islet Transplant Program, University of Alberta and Capital Health, Edmonton, Alberta, Canada
2 Department of Surgery, Clinical Islet Transplant Program, University of Alberta and Capital Health, Edmonton, Alberta, Canada
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ABSTRACT |
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Sustained C-peptide production and successful insulin independence after pancreatic islet transplantation in type 1 diabetic patients was reported over 4 years ago by the Edmonton group (1). This reality became possible with the use of newer, more potent immunosuppressive agents, the avoidance of corticosteroids, and high-quality islet preparations, although typically two islet infusions were necessary to attain insulin independence. Over this period, other centers have been able to replicate the initial success of the Edmonton Protocol with further refinements in technique (25), and islet transplantation is increasingly being used (68).
However, the need for ongoing immunosuppressive therapy and the scarcity of donor islets have precluded the widespread adoption of islet transplantation. The main indications for solitary islet transplantation have been frequent recurrent hypoglycemia or labile glucose values that have defied optimization of medical therapy. An additional hoped for, but unproven, benefit has been stabilization or improvement of diabetes complications with the achievement of stable good glycemic control.
Now, 5 years after the first islet transplant was performed with the Edmonton Protocol, we have had the opportunity to review the outcomes in terms of C-peptide secretion, insulin independence, correction of hypoglycemia and lability, acute complications encountered, chronic problems related to immunsuppressive therapy, and some assessment of the effect on diabetes complications.
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RESEARCH DESIGN AND METHODS |
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Sixty-five patients had at least one transplant, 52 patients had two transplants, and 11 patients had three transplants. At the first transplant, islets combined from two donors were used on eight occasions, and on both the second and third transplants, islets from two donors were combined on two occasions. Of the 128 total procedures, 124 were perfomed by the percutaneous route and the remainder via a mini-laparotomy with cannulation of a mesenteric venous portal tributary. The latter approach was used if a hepatic hemangioma was present precluding a percutaneous approach or more recently if aspirin could not be discontinued pretransplant.
Transplant procedures.
Islets were prepared as previously described (1,1113). Briefly, human cadaveric pancreases were removed from brain dead multi-organ donors following in situ vascular flushing with cold University of Wisconsin solution and transported to the clinical islet isolation laboratory using a two-layer (University of Wisconsin/perfluorochemical) cold-storage method where possible (14). Upon arrival at the laboratory, the pancreatic duct was cannulated and liberase enzyme (Roche Diagnostics, Indianapolis, IN) (11) perfused. The pancreas was enzymatically and mechanically dissociated before the islets were separated on a refrigerated Cobe 2991 centrifuge (Cobe BCT, Lakewood, CO). The majority of the islet preparations, 97 of 140, were placed in culture (median 13.0 h [IQ range 6.423.0]) before infusion to facilitate timing of islet infusion or as part of the immunosuppressive protocol. Islet numbers were quantified in duplicate with the use of an islet standard diameter of 150 µm (15). Once the islets were obtained, the patient was admitted and subjected to the following tests under the Edmonton Protocol: complete blood count (CBC), chest X-ray, liver function tests (LFTs), and coagulation screen. The patient was then brought to the Department of Radiology, and portal vein cannulation was performed. When the portal vein was cannulated, the islets in 250 ml of medium in an intravenous fluid bag were allowed to infuse under gravity pressure (16); before 2001 a syringe was used. Portal pressure was monitored during and after infusion of 5 ml of islet tissue, after each subsequent milliliter of tissue, and again when the transplant was completed. To minimize the risk of bleeding, the catheter tract was plugged with coils and Tisseel. The glucose was monitored hourly initially and insulin therapy withheld until the capillary glucose increased to >6.0 mmol/l premeal or >8.0 mmol/l 2-h postmeal.
Patients were usually discharged the following day when an ultrasound had confirmed the absence of any portal vein thrombosis or intraperitoneal bleed and that the CBC and LFTs were acceptable. Aspirin (81 mg/day for 14 days) and enoxaparin (30 mg b.i.d. s.c. for 10 days) was prescribed once major bleeding had been excluded. Immunosuppressive therapy consisted of daclizumab (2 mg/kg) at transplant and at 5 days posttransplant, sirolimus with a loading dose of 0.2 mg/kg followed by 0.1 mg/kg with target trough levels of 1215 ng/ml, and tacrolimus at a dose of 24 mg twice daily with a target trough level of 36 ng/ml. Before 2003, daclizumab was given at a dose of 1 mg/kg every 2 weeks for five doses, but the change in daclizumab therapy was made for patient convenience together with the evidence for efficacy of the simpler regimen in other solid organ transplantation (17). At 3 months posttransplant, the target dose of sirolimus was reduced to 810 ng/ml. Pneumocystis carinii prophylaxis with sulfamethoxazole/trimethoprim was used for 6 months. Ganciclovir 1,000 mg t.i.d. was given for cytomegalovirus (CMV) prophylaxis for 3 months in subjects who were CMV negative and receiving islets from CMV-positive donors. Complete blood count, drug levels, and basic laboratory parameters (LFTs, electrolytes, calcium, and magnesium) were measured three times a week for the 1st 2 weeks, twice a week for the next 2 weeks, weekly for the next month, and then every 2 weeks for a month, depending on the clinical need. Ten subjects were transplanted with a modification of the standard protocol using infliximab (10 mg/kg) given at the time of transplant, and a further nine subjects were transplanted using a lymphocyte depletion protocol (Campath-1H, ultra low-dose tacrolimus and higher-dose sirolimus) and will be the subject of a separate report.
For longer-term posttransplant follow-up, the transplant subjects were seen every 16 months depending on how near they lived to the transplant center. At these visits, glucose control and any adverse events were reviewed and weight and blood pressure were assessed. Lipids, LFTs, electrolytes, calcium, magnesium, and CBC were measured together with fasting glucose, insulin, and A1C. Islet cell and insulin antibodies were determined in collaboration with Dr. George Eisenbarth. Every 6 months, a full physical examination was performed, neuropathy was assessed with a neurothesiometer (Horwell, Nottingham, U.K.) applied at the big toe on each side, and the mean of six readings was taken (three on each side). Every 6 months a meal tolerance test was performed in the fasting state, with blood drawn for glucose and C-peptide at baseline and then at 90 min after drinking Ensure High Protein (6 ml/kg to a maximum of 360 ml, providing 391 kcal with 8.5 g fat, 44 g carbohydrate, and 17 g protein). Yearly determinations of the HYPO score and LI were made (9), as was a composite measure of graft function, the ß-score (18). Homeostasis model assessment (HOMA) was calculated for an estimation of insulin sensitivity (19,20).
Patients were deemed to have completed the islet transplant procedure once they gained insulin independence as defined by the use of no exogenous insulin for 4 weeks and no more than two values per week >10.0 mmol/l on their capillary glucose testing records. Patients who received >15,000 islet equivalents (IE)/kg were deemed complete even if they were not insulin independent. On longer-term follow-up, insulin therapy was recommenced if the fasting capillary glucose was >8.0 mmol/l, the 2-h postprandial glucose was >10.0 mmol/l, and/or the A1C was >7% consistently. Patients were judged to have completely lost islet graft function when two stimulation tests showed C-peptide levels below the level of detectability of the assay (0.1 nmol/l) or if the fasting glucose was >15.0 mmol/l with no measurable C-peptide present. As of 1 November 2004, 36 patients were complete using the Edmonton protocol, 7 using the infliximab protocol, and 4 using the Campath-1H protocol.
Assays.
Plasma glucose concentrations were determined by the glucose oxidase method. C-peptide was measured using a commercial assay (Diagnostic Systems Laboratories, Webster, TX). The lower limit of sensitivity for C-peptide was 0.1 nmol/l in our laboratory, the intra- and interassay coefficients of variations were <9.5%, and the normal range was 0.31.32 nmol/l. Panel reactive antibodies (PRAs) were measured with anti-human globulin and more recently by flow cytometry.
Statistics.
Results are expressed as means ± SE or the median (25th 75th IQ range) as appropriate. Comparisons were made with a two-tailed Students t test, paired or unpaired as appropriate. For group comparisons, one-way repeated-measures ANOVA was used and the Holm-Sidak or Dunn test used when normality tests failed. All statistical analyses including Kaplan-Meier survival curves were performed using Sigma Stat for Windows (v. 3.0; SPSS, Chicago, IL). Significance was taken at the P < 0.05.
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RESULTS |
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Acute complications.
Fifteen subjects had evidence of a major bleed related to the procedure as defined by a drop in hemoglobin of >25 g/l or a drop in hemoglobin requiring intervention following percutaneous islet infusion, and a blood transfusion was given on seven occasions with two subjects requiring a laparotomy. The risk of bleeding has recently been resolved by effective sealing of the portal catheter tract using coils and Tisseel and by discontinuation of aspirin 2 weeks before transplantation (unpublished data). Five patients had evidence of a thrombus in segmental branches of the portal vein and were treated with anticoagulation, and none of these patients has developed clinical sequelae of portal hypertension. The gall bladder was punctured in two subjects, but both resolved with conservative management. Mean portal pressure at the start of the procedure was 11.0 mmHg (IQ range 813) and increased by the end of the transplant to 13 mmHg (10-17) (P < 0.001). Liver transaminases (aspartate aminotransferase) increased to >2.5 times the upper limit of normal in 55% of procedures and to >5 times the upper limit of the normal range in 23% of procedures. These abnormalities usually resolved over 4 weeks (median 23 days [IQ range 1735]). In the longer term, changes consistent with fatty liver were seen in 8 of 36 subjects who had magnetic resonance imaging post-transplantation.
Short-term outcomes.
Five subjects became insulin independent with a single infusion of islets, having received 502,211 ± 79,770 IE (6,713 ± 944 IE/kg provided); 33 came off insulin with two infusions, having received 792,396 ± 27,867 IE (11,951 ± 398 IE/kg provided); and 6 required three infusions of islets for insulin independence, having received 987,820 ± 47,463 IE (14,443 ± 1,052 IE/kg provided). Two subjects became insulin independent for a brief period after one transplant but then required a second transplant and thus are considered as having had two transplants to be complete. Insulin use in relationship to the transplant is shown in Fig. 1A. Those patients who became insulin independent with two transplants had a greater fall in insulin requirements after the first transplant compared with those who did not become insulin independent after two transplants (Fig. 1B), despite receiving a similar number of islet equivalents (11,791 ± 395 vs. 11,059 ± 479 IE/kg, respectively, P = 0.272).
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Three patients had pneumonia, one of which was thought to be fungal in etiology. One patient was found to have two small foci of papillary carcinoma of the thyroid. Of 43 subjects who were CMV negative but had transplants from donor-positive subjects, 2 had seroconversion (6%) but no overt CMV disease. The titer was indeterminate pretransplant in one of these subjects, and the remaining subject was felt to have a community-acquired CMV. Of the 43 patients who used sirolimus and tacrolimus as initial immunosuppression, 33 (77%) remained on these drugs as the main immunosuppressive regimen. Five patients were changed to tacrolimus and mycophenolate mofetil, three to sirolimus and mycophenolate mofetil, and two to low-dose sirolimus, tacrolimus, and mycophenolate mofetil.
Diabetes complications.
In the 47 completed subjects, 4 had a deterioration of eye disease and required photocoagulation or vitrectomy within 5 months of transplant. The median serum creatinine pretransplant was 80 µmol/l (IQ range 6990) and at 1 year posttransplant was 84 µmol/l (70106). The most recent serum creatinine determination was 92 µmol/l (77115) (P < 0.001 vs. pretransplant and P < 0.05 vs. 1 year posttransplant). The creatinine clearance pretransplant was 1.8 ml/s · 1.73 m2 (1.42.0) pretransplant, at 1 year posttransplant was 1.6 ml/s · 1.73 m2 (1.31.8), and most recently was 1.4 ml/s · 1.73 m2 (1.11.7) (P = NS). The albumin excretion rate was 11 µg/min (620), at 1 year posttransplant was 16 µg/min (839), and most recently was 19 µg/min (959) (P = NS). The 24-h urine protein excretion rate was 0.2 g/day (0.10.2) pretransplant, 0.1 g/day (0.10.2) at 1 year posttransplant, and 0.1 (0.10.2) most recently (P = NS). Five of 11 subjects had progression of microalbuminuria to macroproteinuria, and 3 of 30 subjects with no microalbuminuria pretransplant progressed to macroproteinuria. Mean systolic and diastolic blood pressure was unchanged pre- and posttransplant, but this was only achieved with the increased use of antihypertensive medications posttransplantation. Pretransplant, 36% of subjects were on no antihypertensives and 6% were on more than one medication for hypertension. Posttransplant, the current respective percentages are 15 and 42.
The LDL cholesterol level was 2.6 ± 0.1 mmol/l pretransplant, 2.6 ± 0.1 at 1 year posttransplant, and 2.2 ± 0.1 mmol/l most recently (P = NS). However, pretransplant, 23% of subjects were on lipid-lowering medications, and most recently 83% were requiring therapy. The triglyceride level pretransplant was 0.87 ± 0.07 mmol/l, increased posttransplant to 1.32 ± 0.11 at 1 year, and was 1.23 ± 0.10 mmol/l most recently (P < 0.002). The neurothesiometer score did not change significantly pretransplant (6.2 V [IQ range 4.512.1]), at 1 year posttransplant was 7.6 V (5.312.4), and most recently was 8.9 V (6.014.2) (P = NS). One patient with functioning islets died suddenly 22.5 months posttransplant of an accidental cause.
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DISCUSSION |
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The divergence of persisting insulin secretion and the need for exogenous insulin is indicative of inadequate insulin reserve. The defects in insulin secretion may be due to inadequate islet mass or impaired function. Although nearly 800,000 IE were transplanted per patient, it is likely that many islets were lost at the time of engraftment, perhaps due to the instant blood-mediated inflammatory reaction (21). Islet transplantation is associated with activation of the coagulation cascade and an increase in serum cross-linked fibrin degradation products (21,22). Certainly the acute insulin response to secretagogues is well below normal when studied shortly after transplantation (23,24), suggesting that the surviving islet mass is marginal. In addition, even with excellent function it is rare to have a normal fasting glucose after islet transplantation, likely reflecting some problem with islet mass or function from the outset (18). However, there was a deterioration of glycemic control over time that may reflect a further loss of islets or problems with function. Either auto- or alloimmune destruction may be occurring. The fact that the survival curve for insulin use is different from the curve representing persisting C-peptide secretion in most subjects may suggest that the problem is not simply due to loss of cells from immune destruction. If the ß-cells were being destroyed on an immune basis, one might expect that the survival curves would be similar, with the C-peptide survival curve falling steeply and simply shifted to the right. Finally, an increase in insulin resistance could also explain these changes, but the comparable HOMA values in those on and off insulin and the lack of success of thiazolidinediones argue against a prominent role for insulin resistance.
The finding of a lower increment in C-peptide just before recommencing insulin therapy compared with that a year earlier supports the conclusion that islet function declined and indicates that the lower increment in C-peptide postmeal challenge seen in Fig. 4B was not primarily due to taking exogenous insulin. The reason for this decline is not readily apparent. Perhaps the normal cycle of neogenesis and apoptosis is lost, but the reports of long-term survival of both allo- and autoislet transplants belie this (25,26). Allotransplanted islets are also exposed to the first pass of immunosuppressive drugs, agents that are toxic to ß-cells at higher concentrations (2729). Whether over time these toxic effects lead to dysfunction and the need for exogenous insulin is unknown. The finding of more sustained long-term insulin independence with autoislet transplants (26) may point to the deleterious effects of the immunosuppressive drugs on function, although clearly allo- or autoimmune roles cannot be discounted. In some subjects, alloimmunity appeared to be involved as evidenced by an increase in the percentage of PRA and the relationship of the ß-score to this activation at 1 year posttransplant. However, the percentage of PRA reflects the reactivity to a panel of antibodies and examination of donor-specific antibody positivity on a case-by-case basis will be important. Other measures of graft rejection, especially granzyme B, may become useful as measures of graft loss (30). The blood supply that the transplanted islets develop in the liver over the first 4 weeks of engraftment does not follow the pattern of the native islet. Normally an islet arteriole delivers blood centrally that then flows to the periphery. The vessels are also fenestrated (31,32). The vasculature that develops posttransplant appears to grow in from the periphery (33). This may contribute to impaired function over time. A further consideration is that the final mass of islet tissue engrafted may be only 20% of normal, and such a limited mass may not be able to cope in the long term with the metabolic demands. Lastly, the liver may not be an optimal site for islets in terms of function in that the insulin release may be into the hepatic vein, and the islets are exposed to high concentrations of nutrients entering from the portal vein (34).
The long-term function of the islets could not be predicted by any of the simple donor characteristics, including age, sex, or weight, other than a higher insulin requirement pretransplant being associated with poorer outcome as evidenced by the lower ß-score. Likewise, islet numbers transplanted (based on the accuracy of counting islets, which is problematic) did not predict insulin independence. In fact, the patients who required three islet transplants and had more islets than those with two transplants appeared to fare less well (Fig. 2C), but limited numbers prevent definitive conclusions. Some patients did well with just one transplant, having obtained a number of islet equivalents far less than the mean for those who had two transplants. In addition, if someone showed more than a 50% decline in insulin requirements following the first transplant, then they were more likely to become insulin independent with a further transplant, but if there was only a modest decline after the first transplant, then it was likely they would need more than two transplants to become insulin independent (Fig. 1B). A favorable response to the first transplant appeared more predictive of future insulin independence than the total numbers of cells provided. In our previous report (23), 10,000 IE/kg was usually enough for insulin independence, but this is less clear cut as more patients are transplanted (Fig. 1A). More than 20% of patients required in excess of 15,000 IE/kg to become insulin independent, and one subject did not become insulin independent despite having >20,000 IE/kg. Clearly islet quality, viability, engraftment, and/or function is as important as the numbers transplanted. If there is minimal response to the first and especially a subsequent transplant, then further transplantation without a new immunosuppressive regimen may not make sense.
The recent report from the Minnesota group (5) of insulin independence with a single donor is of note. Many differences are evident, including their selection of recipients who were lighter (maximum weight 67.2 kg) and had a pretransplant insulin requirement of <41 units/day. We have been less selective in our program, as evidenced by a median weight in our recipients of 68.5 kg and insulin requirement of 45 units/day. The donor age of <50 years, BMI >27 kg/m2, peritransplant use of intravenous insulin and heparin, potent induction therapy, and after 1 month posttransplant changing tacrolimus to mycophenolate mofetil were also factors that differed between our two programs. Additionally, the Minnesota Group used etanercept as antitumor necrosis factor therapy in place of infliximab. Which one or combination of these factors contributed to their success is not clear, but at 1 year the insulin independence rate was 62.5%.
One benefit that was clearly gained from islet transplantation was the amelioration of the problems with glycemic lability and hypoglycemia. Both the LI and the HYPO score improved posttransplant, and correction of the problems with lability and hypoglycemia, the primary indication for transplant, was achieved (Fig. 5A and B). It is notable that the glucagon response to hypoglycemia is not normalized by the intrahepatic islet transplantation (35). Thus, when insulin is recommenced, the risk of hypoglycemia increases, as demonstrated in Fig. 5A, and this was in part related to the effort of the subjects to maintain excellent glycemic control. The LI also increased as insulin was resumed.
The major acute complications of the percutaneous transhepatic approach are serious bleeding or portal vein thrombosis, as seen in this summary and reported by others (36,37,38). The risk of acute bleeding has been markedly reduced with the avoidance of aspirin and the use of coils and Tisseel at the time of the transplant (unpublished data). The risk of a portal thrombus remains but appears to be best abrogated by minimizing the packed cell volume and thrombogenicity of the preparation. For islet autotransplants, much higher packed cell volumes are used with unpurified preparations, but these are administered under direct vision at the time of surgery and with the protection of therapeutic heparinization (39,40). The continued risk of portal vein thrombosis together with the blunted glucagon response to hypoglycemia and the loss of function over time prompts consideration of using alternative sites for the islets. Animal studies demonstrate that the glucagon response to hypoglycemia is normal when islets are placed intraperitoneally (41), but it remains to be determined how initial islet engraftment in the intraperitoneal site compares with intraportal delivery.
The chronic complications of the immunosuppressive therapy must also be considered in the light of freedom from hypoglycemia and glycemic lability. The mouth ulcers were managed most effectively with the use of lower doses of sirolimus and triamcinolone ointment. They only became severe if the sirolimus was not reduced quickly enough. Acne was surprisingly common, as were ovarian cysts in premenopausal women, with the latter recently reported by the Miami group (42). Edema was resistant to all standard measures in 12% and was severe enough to warrant changes in immunosuppressive therapy, as has been reported (43). Also reported has been the occurrence of benign perinephric edema in a small percentage of patients (44). The finding of posttransplant fatty liver is of unknown significance at this time (45,46). The gastrointestinal upset associated with the immunosuppressive regimen was usually diarrhea and again typically settled as the immunosuppressive dose was reduced after 3 months. The only case of neoplasm found so far involved two tiny foci of papillary cancer of the thyroid that have been resected. One case of presumed fungal pneumonia required discontinuation of the sirolimus. Finally, the finding that 13% of patients with a pretransplant percentage of PRA <15% by flow cytometry had an increase in the percentage posttransplant is a potential concern, as it may render future transplantation more problematic in terms of matching appropriate donors. The fact that 23% of subjects transplanted with the standard protocol are currently on alternative combinations points to the need for further improvements in immunosuppressive regimens.
An evident drawback is that there is no control group of subjects with type 1 diabetes followed over time for comparison, although we have started such a prospective study. For the present, however, no clear advantages for the chronic complications of diabetes are yet evident. Peripheral neuropathy remained unchanged. Subjects with autonomic gastroparesis generally found that glucose levels were much more easily controlled, especially if vomiting occurred, but maintenance of immunosuppressive drug levels was sometimes more difficult because of erratic absorption. The cholesterol levels were no different from pretransplant, but many more subjects were placed on statin therapy posttransplant. Some of this was related to the increased awareness for the need for LDL cholesterol lowering in diabetic subjects, but as reported previously, the immunosuppressive regimen we used is associated with an increase in cholesterol (47). A slight rise in triglycerides was noted, but this was not unexpected (48). Any rise in blood pressure was contained by the increased use of antihypertensive medications. More concerning was the rise in serum creatinine and the trend for a decline in the creatinine clearance. In a few patients there was a marked increase in urine protein that improved with discontinuation of the sirolimus. There was one sudden death, which was not related to the islet transplant.
In conclusion, successful islet transplantation is still a relatively new procedure. It provides clear benefits for a subset of type 1 diabetic patients in terms of improving variations in blood glucose and alleviating problematic hypoglycemia, while achieving a better A1C. The problems encountered after islet transplant are becoming more delineated. Balancing the risk-to-benefit ratio remains central to selecting appropriate candidates for transplantation, and informed consent is crucial. If a subject has severe hypoglycemic unawareness or glycemic lability that is causing a major disruption of their life, then islet transplantation can be of value. However, such a person will likely not remain insulin independent in the long-term and must accept the risks of immunosuppression so that he/she may have the endogenous insulin production to facilitate more stable glucose control. Once stable glucose control is attained, serious consideration needs to be given as to whether a further transplant will achieve any more than transient insulin independence. These results make clear that safer immunosuppression associated with fewer side effects is needed. Further sources of islets and better engraftment remain obvious needs in order to build on the continuing islet function and to translate it into higher rates of insulin independence.
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ACKNOWLEDGMENTS |
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We are grateful to Sharleen Imes, Kathleen LaBranche, Vijayan Menon, and the coordinators and staff of the Clinical Islet Transplant Program for ongoing help with data analysis and clinical care; to Dr. C.G. McDonald, St. Josephs Health Care, London, ON, for assistance with assessment and follow-up of some patients from eastern Canada; to Dr. Tatsuya Kin and the staff of the Clinical Islet Isolation Laboratory for technical help in islet preparation; to the staff of the Clinical Investigation Unit of the University of Alberta Hospitals for assistance with metabolic testing; to our colleagues in the Division of Vascular and Interventional Radiology for their assistance with the portal vein cannulation; to our colleagues in the organ procurement programs in Alberta and across Canada for identifying cadaveric donors; to the Human Organ Procurement and Exchange program for assistance in organ procurement; and to Louise Bohachyk for secretarial assistance.
Address correspondence and reprint requests to Edmond A. Ryan, Clinical Islet Transplant Program, 2000 College Plaza, 8215 112th St., Edmonton, Alberta, Canada T6G 2C8. E-mail: edmond.ryan{at}ualberta.ca
Received for publication February 18, 2005 and accepted in revised form April 13, 2005
CBC, complete blood count; CMV, cytomegalovirus; HOMA, homeostasis model assessment; HYPO score, Hypoglycemic score; LI, lability index; LFT, liver function test; PRA, panel reactive antibody
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REFERENCES |
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