Patient Selection

Candidates for islet transplantation are selected in a similar manner as for whole-organ pancreas

transplantation. Islet transplantation is currently limited to adult type 1 diabetics with progressive

diabetic complications who have failed intensive insulin therapy. Because islet transplantation remains

experimental therapy with limited availability, the procedure is generally offered only to ideal

candidates with minimal medical conditions other than diabetes. Most centers require evaluation and/or

a period of treatment by an experienced endocrinologist specializing in diabetes. Candidates with

coronary artery disease, chronic infections, including hepatitis B and C, or a prior solid-organ transplant

are excluded. Nonuremic candidates must be free of renal insufficiency, due to concerns about

aggravation of nephropathy by calcineurin inhibitors. Since efficacy of the islet transplant appears to be

related to the number of islets transplanted per kilogram of recipient body weight, only lean (<70 kg

or BMI <28) recipients are selected. Although most islet transplants are currently performed in

nonuremic diabetics, islet transplants either concurrent with or following kidney transplantation are

also performed.145,146

Donor Selection/Procurement/Preservation

Donor selection for islet isolation differs from that for whole-pancreas transplantation in several

respects. While the ideal donor for islet isolation is still young and healthy, the age and weight criteria

are less stringent than for whole-pancreas transplantation. Donors greater than age 50, donors on

vasopressors, and especially obese donors are all perfectly suitable for islet isolation. Since the ideal

pancreas is easily distensible and digestible, fatty pancreata are felt to be especially suitable, whereas

fibrotic pancreata are not. As previously mentioned, pancreata from older and obese donors (which are

infrequently used for whole pancreas) are preferentially allocated for islet transplantation rather than

for regional and national sharing for whole-pancreas transplantation.52

The pancreas is procured in a manner similar to whole-pancreas transplantation. However, less

attention to preservation of vascular structures is required. Attention is paid to surface cooling

following flushing of preservation solution, and avoidance of pancreatic injury. A number of reports

have highlighted the importance of a dedicated team trained in pancreas procurement in the success of

islet isolation.147,148 Expanded use of the two-layer technique of pancreas preservation, using both

standard preservation solution (UW solution or HTK) and oxygenated perfluorocarbon solution, has

resulted in increased islet yields.149–152 The two-layer technique also permits the successful use for islet

transplantation of pancreata subjected to prolonged cold ischemia as long as 18 hours. Success with

pancreata from DCD has been reported.153

Transplant Techniques

The portal circulation of the liver is currently the preferred site for islet transplantation (Fig. 40-8).154

This can be performed by a minilaparotomy, with infusion of the islets into a peripheral mesenteric

vein. However, most centers utilize interventional radiology techniques, avoiding both a surgical

incision and general anesthesia. Percutaneous transhepatic portal vein catheterization is done under

ultrasound and fluoroscopic guidance, with usually a small gauge (4-French) catheter. The islets are

infused into the portal vein through the catheter by either gravity from an infusion bag or by hand

injection, and the islets lodge in the hepatic parenchyma. Portal vein pressure is monitored

intermittently throughout the procedure. Following infusion of the islets, hemostasis is usually achieved

using a combination of coils and gelfoam. Recipients receive heparin in the islet preparation,

systemically during the procedure, and in the perioperative period as prophylaxis against portal vein

thrombosis, a now rare but serious complication.

Perioperative Care

Although islet transplantation is in theory an outpatient procedure, it is not uncommon for recipients to

receive a few days of inpatient care for monitoring purposes. Immediately following the islet transplant,

patients are maintained on bed rest for a short interval and monitored for bleeding. Liver function tests

are monitored, and a liver ultrasound is frequently done to assess portal venous flow and to check for

hematoma. It has been demonstrated that intensive glycemic control with insulin in the immediate

posttransplant period is beneficial for islet function.155 Hence, many centers will give insulin

postoperatively to keep the serum glucose tightly controlled, in order to “rest” the islets. Additional

adjuncts to prevent the instant blood-mediated inflammatory reaction (IBMIR), which results in early

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islet loss and reduced β-cell mass in the recipient, may include antioxidants such as Vitamin E,

etanercept (anti-TNFα antibody), anakinra (IL-1β antagonist), reparixin (CXCR1/2 inhibitor),

pentoxifylline, and others.156

Figure 40-8. Islet transplantation. The pancreas is procured as a whole organ from the donor. The islets are isolated from the

pancreas and are purified and infused into a cannula placed in a branch of the recipient’s portal vein.

Immunosuppression

Current thinking focuses on the importance of the elimination of steroids from the immunosuppressive

regimen, which typically uses basiliximab induction, and maintenance therapy with low-dose tacrolimus

and sirolimus. Regimens employing mycophenolate mofetil and cyclosporine are also used, and

thymoglobulin is an alternative induction agent. The best results for islet–kidney transplantation are

cases where steroids are avoided or eliminated at the time of islet transplantation. While long-term

effects of either the islet transplant or steroid elimination on kidney function are not known, steroid

avoidance in kidney transplant recipients is now routine.50 Regimens that avoid both steroid and

calcineurin inhibitors have been successfully used.157

Metabolic Control

Islet recipients show significant improvement in metabolic function and glycemic reserve, although

hormonal counter regulation to hypoglycemia is diminished, actual hypoglycemic events are rare.158

Data from the Collaborative Islet Transplant Registry show that at 1 year, approximately 59% of all

transplant recipients were free of severe hypoglycemic events and maintained hemoglobin A1C

(HbA1C) level of <6.5%. Of these 1-year responders, 69%, 54%, and 44% maintained this composite

endpoint at 2, 3, and 4 years, respectively. Ninety-one percent of all recipients were free of severe

hypoglycemic episodes at 1 year, and 80% at 4 years.141 Islet recipients also demonstrate a reduction in

behaviors adopted in avoiding hypoglycemia and attenuation in concerns about hypoglycemic

episodes.159 Islet transplantation also results in improved insulin sensitivity mediated by effects at both

the liver and skeletal muscle.160 However, islet recipients have significantly diminished β-cell reserve

than do recipients of whole-pancreas transplants, which may account for their reduced long-term

survival.161 Acute insulin response to intravenous glucose is commonly used to determine islet

engraftment, and is a robust early metabolic marker to predict return to insulin therapy.162 Analyses of

the impact on diabetic complications and mortality await further experience.

Complications

Morbidity from islet transplantation is substantial but much less than for whole-pancreas

transplantation. The most common serious complication is bleeding (1% to 5%). Most cases of bleeding

can be managed nonoperatively with adjustments in anticoagulation, though occasionally laparotomy is

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required. The side effects of immunosuppression, such as hyperlipidemia and mouth ulcers in sirolimuscontaining regimens, are much more common and can significantly affect quality of life.163 Renal

insufficiency is an uncommon but serious consequence.138 Transient elevations of portal venous pressure

during islet infusion and elevations of liver function tests following infusion are common and usually

well tolerated.164,165 However, reduction in liver perfusion during the islet infusion has been linked to

premature graft failure.166 The demonstration of late steatosis has raised concerns about chronic liver

disease; to date this has not been reported.167 CMV infection is rare. Mortality is virtually nil.

Sensitization and the development of posttransplant DSA, which was originally thought not to occur

following allogenic islet transplantation, are now recognized as a significant challenge. Recent

experience has shown that most recipients showed DSA or autoantibody increases (de novo expression

or titer increase) after islet transplantation. Recipients who have a posttransplant antibody increase

have similar initial performance but significantly lower graft survival than patients without an

increase.168 Patients with complete graft loss who discontinue immunosuppression had significantly

higher levels of anti-HLA antibodies than those with functioning grafts still on immunosuppression.169

Ways to minimize sensitization in these recipients includes minimizing the number of islet donors used

per recipient, and in the absence of donor-specific anti-HLA antibodies, repeating HLA mismatches with

subsequent islet infusions.

Results

10 The short-term results of islet transplantation at high-volume centers are approaching that of wholepancreas transplantation. The most successful centers achieve insulin independence rates of 80% to 90%

at 1 year.136,170–171 In the Immune Tolerance Network multicenter trial of the Edmonton Protocol,

success rates at the most successful centers (Edmonton, Minnesota, and Miami) were significantly

higher than at the other centers.137 However, long-term rates of insulin independence are worse than

whole-pancreas transplants, but continue to improve. Overall, insulin independence at 3 years after

transplant improved from 37% in the years 2003–2006 to 44% in the years 2007–2010, and the islet

reinfusion rate was lower: 48% by 1 year in 2007–2010 versus 60% to 65% in 1999–2006. While in

most centers less than 50% of recipients are insulin-free at 3 years, in experienced centers the 5-year

insulin independence rate approaches 50% which approaches the graft survival of PTA.138,141,142

One of the shortcomings of islet transplantation compared with whole-pancreas transplantation is the

inability to reverse diabetes with the islets from one pancreas. Most of the recipients in the modern era

have required two or more islet infusions to achieve insulin independence. However, some centers have

successfully employed single-donor islet transplantation by utilizing careful donor and recipient

selection, usually by transplanting islets from pancreata from large donors into small

recipients.170,172–173 As long-term outcome appears to be related to β-cell mass, which is likely to be

lower for single-donor infusions, these recipients may return to insulin or require retransplants

earlier.174 At the recipient level, administration of anti-inflammatory agents, whether nonspecific or

directed at specific molecular targets, has become the mainstay of perioperative treatment. The ability

to maximize the use of islets and minimize islet requirements and pancreas utilization for an individual

recipient is critical if islet transplantation is to compare favorably with whole-pancreas transplantation.

Graft Failure

Graft failure appears to occur earlier than for whole-pancreas transplants. This may be related to a

lower initial islet mass or the inability to histologically diagnose and treat islet rejection, since the islets

are scattered about the liver parenchyma. As with pancreas graft failure, there is no true agreement on

what constitutes graft failure, since recipients may require insulin yet make C-peptide and have superior

metabolic control compared with pretransplant. Most outcome measures focus on insulin independence

as the most stringent, and C-peptide production as the least stringent. Recent findings indicate that

immunologic markers of rejection or recurrent autoimmunity, and metabolic indicators may identify

recipients at risk for inferior outcomes and impending graft failure, although treatment algorithms

based on these predictors are not standardized.162,168,175–176 A number of investigators have

demonstrated the ability to label and identify islets in vivo in recipients in order to monitor functional

islet mass—an example of this is ferucarbotran-labelling of islets, which enables their long-term

noninvasive visualization by MRI and correlates with sustained C-peptide production.177

Recipients with prior graft function who have returned to insulin are candidates for retransplantation.

In fact, some centers have used transplanted islets from isolations where yields are insufficient for a

primary transplant as retransplants, where the islet requirement may be less if there is still sufficient

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