Islet transplantation is generally performed using percutaneous transhepatic portal venous catheterization under fluoroscopic guidance. In circumstances when the risk of intraperitoneal hemorrhage is thought to be elevated, a mini-laparotomy approach with catheterization of a mesenteric vein is sometimes used (1; 32; 33). Islets are infused by gravity into the portal circulation and flow with the portal blood to lodge in the hepatic sinusoids. Islet survival after transplantation has been estimated at only 10-20% (34). This low rate of islet survival is likely due to a number of factors including hypoxia and the initiation of an inflammatory cascade including the so-called instant blood mediated inflammatory reaction (IBMIR), which may trigger the release of tissue factors detrimental to islet survival (35; 36).
At the University of Alberta the mean number of islets transplanted during a single infusion is 393,554 ± 10,582 IE (5,783 ± 142 IE/kg). The mean cumulative number of islets received by individuals receiving at least two islet infusions is 799,912 1617; 30,220 islet equivalents (IE) (11,910 ± 469 IE/kg ) (1). The median time between first and second transplants was 2.5 months and between second and third transplants was 1.8 months. The criteria for islet suitability for transplantation include an adequate islet mass (> 5000 IE/kg), ABO compatibility (HLA matching is not required), negative gram stain, endotoxin load < 5 EU/kg, total islet volume < 10cc (most < 5cc), islet purity > 30% (most > 50%). In vitro islet viability is assessed using membrane dye exclusion testing (fluoresceine diacetate/propidium bromide) and insulin secretory function is determined using a static incubation method.
Islets for transplantation are obtained from two sequential donors in most cases. After transplantation, all patients are monitored for 24-48 hours with frequent capillary glucose readings and periodic complete blood counts and liver enzyme measurements. An abdominal ultrasound is performed the day after transplantation to rule out portal venous thrombosis or intraperitoneal hemorrhage. The most common immediate post-transplant symptoms are transient abdominal pain (52%), nausea, and rarely vomiting in patients who develop post-transplant ileus. The mean hospital stay is 1 day (range: 1 - 2 days) (37).
After the first islet infusion, daily insulin requirements are reduced by a mean of 52% (range: 12 - 100%) and glycemic stability is usually greatly improved. Eight percent (5/65) of subjects transplanted by November 2004 became insulin independent after a single islet infusion (1). However, most recipients do not attain insulin independence before receiving a second islet infusion (37). The University of Minnesota has described a series of eight women who all became insulin independent after receiving islets isolated from a single donor (mean: 7271 ± 1035 SD IE/kg) (32). These excellent results may be partly due to careful selection of recipients, quality of donor islets, and possibly the use of anti-thymocyte globulin and etanercept for induction of immunosuppression.
The one-year rate of sustained insulin independence for all recipients transplanted under a tacrolimus/sirolimus-based protocol is approximately 75% by Kaplan-Meier survival analysis (Figure 2B). However, there is a gradual loss of islet function over time, with a 2-year insulin independence rate of less than 60% and a five year rate of around 10% (1). Despite these declines, most patients (~80%) have persistently positive C-peptide (Figure 2A). Mean glycated hemoglobin (A1C) is generally normalized in insulin independent recipients (Figure 3) and near normal in recipients who remain C-peptide positive. As expected, A1C tends to rise in those patients who lose all graft function. The reasons for the decline or complete loss of islet function after transplantation are not clear, but may involve direct immunosuppressive toxicity, allo or recurrent autoimmune rejection, or potentially islet cell apoptosis reflecting the natural life cycle of islets in the native pancreas (38).
Figure 2. Survival analysis for (A) C-peptide secretion and (B) insulin independence over time for all those who completed the islet transplant procedures. The curves are dated from the time of the final transplant. Copyright 2005 American Diabetes Association from Diabetes, Vol. 54, 2005; 2060-2069. Reprinted with permission from The American Diabetes Association.
Figure 3. HbA1c (mean ± SE), over time post-transplantation in those subjects who lost all graft function (—●), those subjects whose graft function remained but had to resume insulin (—○), and those subjects who remained insulin independent (—♦). The group off insulin was significantly different from the others. Copyright 2005 American Diabetes Association from Diabetes, Vol. 54, 2005; 2060-2069. Reprinted with permission from The American Diabetes Association.
Assessing in vivo graft function is challenging because there is no direct measure of functional islet mass after transplantation. Glucose-stimulated insulin secretion in islet recipients as measured by acute insulin response to glucose (AIRg) remains substantially lower than normal (21 1617; 5% of control), but is sustained up to two years after transplantation (Figure 4). Acute insulin response to arginine (AIRarg) is somewhat higher (56 ± 11% of control), although it is also substantially below normal (37).
Figure 4. AIRg over time in insulin independent subjects (n = 11) before and after islet transplantation. The number of subjects studied is shown across the top of the figure. Mean values ± SE are provided for each time point. All values of islet transplant recipients are significantly different from control subjects. Copyright 2002 American Diabetes Association from Diabetes, Vol. 51, 2002; 2148-2157. Reprinted with permission from The American Diabetes Association.
