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Pancreas and Islet Allotransplantation
In 1993 the Diabetes Control and Complications Trial Research Group reported that patients with insulin-dependent diabetes mellitus (IDDM) treated with intensive insulin therapy showed a reduced risk of developing retinopathy, albuminuria or microalbuminuria, and clinical neuropathy, when compared with patients who received conventional insulin therapy. In this trial the intensive therapy group was shown to have achieved sustained lowered blood glucose concentrations over time, as reflected by significantly lower hemoglobin (Hb)A 1c values compared with those of the conventional insulin therapy group. Although the intensive therapy group benefited from reduced long-term complications, the risk of severe hypoglycemia, which compromised life quality associated with tight glycemic control, was three times greater than in the conventional therapy group. Successful β-cell replacement therapy in the form of pancreas or islet transplantation offers the advantages of attaining normal or near-normal blood glucose control without the risks of severe hypoglycemia associated with intensive insulin therapy. Thus the goal of pancreas and islet transplantation is to restore normal glycemic control and thereby reduce the complications of IDDM by providing sufficient β-cell mass. Although pancreas transplantation remains the gold standard as β-cell replacement therapy, an alternative approach (i.e., pancreatic islet transplantation), is a developing procedure, and results from studies in 2012 indicate it may be as effective as solitary pancreas transplantation. Over the last decade, islet cell allotransplantation has become an approved funded procedure in Canada, Europe, and Australia in selected patients. In the United States it should achieve the same status in a few years because results of the National Institutes of Health (NIH)-sponsored multicenter trial have just been published. Individual islet centers can currently apply to the US Food and Drug Administration (FDA) for a biological product license for the clinical islet cell processing after they can demonstrate safety and effectiveness of islet cell manufacturing and clinical outcome. Such a license is necessary for the center to offer islet allotransplantation as a standard of care procedure and to approach insurance for a reimbursement. All together, as pancreatic islet allotransplantation has become a clinical reality and an alternative β-cell replacement therapy option, we have elected to present it together with pancreas transplantation.
History of Pancreas Transplantation
The first pancreas transplants were performed in combination with a kidney in uremic type 1 diabetic patients in 1966 at the University of Minnesota. It was proved that pancreas transplantation could obtain a euglycemic state without the need for exogenous insulin. However, early procedures were complicated by a high rate of morbidity, early graft failure, and poor patient survival, so few transplants were performed. Improvements in transplantation techniques, immunosuppressive therapies, and posttransplantation monitoring of graft function and rejection have resulted in a dramatic improvement in patient morbidity and graft survival. According to the International Pancreas Transplant Registry (IPTR), from 1966 to 2014 more than 48,000 pancreases were transplanted worldwide (over 29,000 in the United States and 19,000 in Europe). Up until 2004 the number of pancreas transplants was growing and peaked at level of 1400 performed annually in the United States in 2000–2004, but since then, there has been a steady decline in numbers of these procedures. Between 2004 and 2011 the number of simultaneous pancreas-kidney transplants (SPKs) dropped by 10%, for pancreas transplant alone (PTA) by 34%, but for pancreas after kidney transplantation (PAK) dropped the most—by 55%; the same trend continued over the next few years (data available until 2014). Paradoxically, this drop-off occurred in the setting of improvements in graft and patient survival and transplanting higher risk patients. The drop in number of pancreas transplants was attributed to lack of a primary referral source, lack of acceptance by the diabetes care community, improvements in diabetes care and management, changing donor and recipient considerations, inadequate training opportunities, and increasing risk aversion because of regulatory scrutiny. However, at the same time, outside the United States, the number of pancreas transplants has been trending up, reaching 1400 annually in the past few years ( Fig. 104.1 ). Between 2004 and 2014, SPK transplantation has accounted for 74% of pancreas transplants and has been offered to uremic diabetic patients. PAK transplantation accounts for 17% of pancreas transplant procedures and is offered most commonly to those uremic diabetics, who received a living donor kidney transplant previously (80%). PTA is offered to labile diabetics with good renal function and accounts for 9% in the United States. Pancreas retransplantation accounts for 7% of pancreas transplant procedures; among those PAK was the most common one (68%) and performed in patients with stable function of the kidney graft.
History of Pancreatic Islet Transplantation
In 1965 Moskalewski first isolated pancreatic islets from the guinea pig, but in 1967 Lacy's group described a novel collagenase-based method to isolate rat islets, thus paving the way for islet transplantation. Subsequent studies showed that transplanted islets could reverse diabetes not only in rodents but also in nonhuman primates. However, early efforts to treat type 1 diabetics with pancreatic islet transplantation were mostly unsuccessful. Although the first human pancreatic islet allografts were performed in 1977, it was not until 1990 that a pancreatic islet transplant recipient achieved sustained euglycemia off insulin (for 1 year). The same authors reported the first successful series of human islet allografts when transplanted together with the liver from the same donor. Although they did not address the added issue of autoimmunity in type 1 diabetes (none of their patients were type 1 diabetics), this study provided the first evidence of long-term reversal of diabetes after islet allotransplantation, with more than 50% of recipients having sustained insulin independence, lasting in one case up to 5 years.
Edmonton Protocol
Of the patients receiving islet transplants in the 1990s, only 7% of patients remained insulin free 1 year after islet transplantation. In 2000 the Edmonton group reported seven consecutive islet transplant recipients, all of whom achieved insulin independence at the end of 1 year without major complications. All recipients received islets from at least two donors and were maintained on a glucocorticoid-free immunosuppression protocol using rapamycin and low-dose tacrolimus. The success of the Edmonton program has led to a general acceptance that islet transplantation is a clinically feasible therapy, which may be considered for the treatment of patients with labile type 1 diabetes experiencing hypoglycemia unawareness with severe hypoglycemic episodes (SHEs). Since the report of success from Edmonton, interest has grown in islet transplantation, and more than 46 centers worldwide have performed this procedure. According to the Collaborative Islet Transplant Registry (CITR), from 1999 to 2012, a total of 1679 allogeneic islet transplantations in 828 recipients were reported.
Candidates for Pancreas or Islet Allotransplantation
Neither pancreas nor islet transplantation is a life-saving intervention. The aim for both procedures is to prevent secondary diabetic complications and improve quality of life. Therefore patient selection criteria are stricter than for other organ transplantation in order to protect patient safety and properly identify candidates who can benefit from the procedures.
Guidelines of the American Diabetes Association for indications for pancreas transplantation include patients with IDDM, with undetected C-peptide who suffer from end-stage renal disease or symptoms of hypoglycemic unawareness with progressive secondary diabetic complications, such as (1) history of frequent, acute, and severe metabolic complications (hypoglycemia, hyperglycemia, ketoacidosis) requiring medical attention; (2) clinical and emotional problems with exogenous insulin therapy that are so severe as to be incapacitating; or (3) consistent failure of insulin-based management to prevent acute complications.
Currently, general indications for islet allotransplantation in most of the clinical studies are the same as described earlier for pancreas transplantation. For example, the NIH-funded, FDA-regulated, multicenter Clinical Islet Transplantation trial targets patients who failed intensive insulin treatment defined as intensive insulin therapy with target HbA 1c levels of less than 6.5%, as suggested by the American Association of Clinical Endocrinologists/American College of Endocrinology (AACE/ACE) consensus panel statement on type 1 diabetes mellitus and glycemic control. Following a period of longer than 4 months on this therapy, only patients who evidence continued inadequate glucose control characterized by either HbA 1c level higher than 7.5% or HbA 1c level less than 7.5% but with SHEs are included.
Currently, one limitation of islet allotransplantation is the insufficient number of islets isolated from a single organ to restore normoglycemia in each type 1 diabetic patient. Even with two or three sequential infusions, success cannot be achieved in patients with high insulin demand. Most studies limit recipients to body mass index (BMI) less than 30 kg/m 2 , body weight less than 90 to 100 kg, and daily insulin requirements below 1 unit/kg.
As results of pancreas transplantation have been improving, the percentage of patients older than 50 years who received a pancreas transplant has been increasing, reaching 35% in 2009. Mortality of the uremic patient older than 50 years on the waiting list is extremely high and much higher than after SPK, so this group of patients has actually much more to gain than younger population. Immunologic risk of rejection is also lower in older than younger patients, so those patients should be considered for transplant as long as there is no contraindication for surgery.
It is worth emphasizing that 6% of pancreas transplants (mostly SPK) are performed in selected type 2 diabetic patients (age <55 with low surgical risk). United Network for Organ Sharing (UNOS) policy allows for accruing waiting time for SPK when serum C-peptide ≤2 ng/mL, or if higher, then BMI needs to be below maximum allowed (approximately 28). Overall, number of type 2 diabetic patients receiving SPK has increased in recent years and accounted for 9% of those procedures. In addition, 7% of pancreas allografts are implanted in nondiabetic patients after extended intraabdominal resection as part of multiorgan transplantation (including liver, intestine, and/or kidney transplants). Islet transplantation is also an option in such cases with good results, in cases in which the patient is not suitable for whole pancreas transplantation.
In general, the waiting time for pancreas transplantation varies widely, depending on the country and region of the United States. For the United States the shortest waiting time is for PTA, at 4.9 months, and the longest is 10.5 months for PAK.
Donor Characteristics
Most pancreas allografts (95%) come from deceased heart-beating donors. The remainder are from highly selected non–heart-beating donors or from living donors. To improve results, optimal parameters of donors are as follows: age 14 to 45 years; BMI less than 28 kg/m 2 ; head trauma as the preferred cause of death; and organ procured by a local organ procurement organization to minimize cold ischemic time, preferably less than 12 hours. Pancreas donors are excluded based on presence of diabetes, pancreatitis, sepsis, malignancy, and positive markers for viral infection, such as hepatitis B or C, human immunodeficiency virus (HIV), or human T-lymphocyte virus. Undesired conditions include BMI greater than 30 kg/m 2 , Centers for Disease Control and Prevention (CDC) high risk, downtime, disseminated intravascular coagulopathy (DIC), need for pressors, and pancreas injury, fibrosis, or steatosis. Hyperglycemia or need for insulin therapy in the donor at the time of organ procurement is not a contraindication, but it is a minor risk factor for long-term graft loss. Hyperamylasemia can be of salivary origin, and it is not itself a contraindication for donation. Some centers have exclusion criteria for the pancreas based on age (younger than 8 years), body weight (<30 kg), or diameter of the splenic artery (<2 mm). Donors with a BMI greater than 35 kg/m 2 or who are older than 55 years are used very rarely; only 6% of donors are younger than 14 years of age, and 6% are older than 45 years of age.
Exclusion donor criteria for the purpose of islet transplantation are the same as for pancreas transplantation to prevent transmission of disease to the recipient. However, donor and organ quality criteria are much less restrictive. Desired age is older than 18 years without an upper limit, and BMI is unrestricted as long as the patient is not diabetic (HbA 1c ≤6%). The main limiting factor regarding the effectiveness of the islet isolation is cold ischemia time (≤12 hours) but preferably less than 8 hours. In the United States and United Kingdom, preferential pancreas allocation to islet transplant recipients was established for donors older than 50 years or with a BMI greater than 30 kg/m 2 . The goal is to limit cold ischemia time and enhance availability of the organ and improve isolation results. Otherwise, the current organ allocation system promotes pancreas transplantation over islet transplantation. Therefore, other than in the United Kingdom, each pancreas is offered first to potential whole-organ recipients, and then if rejected, is considered for islet transplant patients. In this way, mostly lower-quality organs are used for islet isolation. This allocation schema may be changed in the future, after islet transplantation achieves the same effectiveness and status as whole-organ pancreas transplantation, such as currently in the United Kingdom, where there is only one waiting list for islet/pancreas transplant. The next available organ is allocated for pancreas or islet transplantation, depending on the patient on the top of the common list.
Due to more extensive reperfusion injury and increased risk for thrombosis, donation after cardiac death (DCD) of the pancreas for whole-organ transplant is not very popular in the United States, whereas it is well developed in the United Kingdom and Japan. For the same reason of tissue ischemic injury and poor islet isolation yield, DCD donors have not been used broadly. However, the Edmonton group has reported comparable outcomes of islet isolation and transplantation, when pancreas was retrieved from DCD and brain-dead donors.
Pancreas Procurement Techniques
Pancreas Procurement for Whole-Organ Transplantation
Cadaveric-donor pancreatectomy is performed as part of a multiorgan procurement through a midline incision. The gastrocolic ligament is divided to enter the lesser sac and expose the anterior aspect of the pancreas. At this point the pancreas is evaluated for signs of fat infiltration, edema, injury, hematoma, calcification, and tumor. If the organ is still suitable, a Kocher maneuver is performed to expose the inferior vena cava and aorta. The gastroduodenal artery is ligated and divided. If a replaced (accessory) right hepatic artery is present, it may be divided at its origin. If liver is procured at the same time, usually the liver surgeon decides whether to include the superior mesenteric artery (SMA) with the right replaced hepatic artery, allowing for easier arterial reconstruction of pancreas vasculature and transplantation. Next, the spleen and tail of the pancreas are mobilized to allow for placement of the ice-slush posterior to the gland during perfusion. After the thoracic aorta is cross-clamped, cold preservation solution (most commonly University of Wisconsin or histidine-tryptophan-ketoglutarate) is introduced through cannulas in the inferior mesenteric vein and distal aorta. On completion of organ perfusion, the splenic artery is divided from the celiac trunk; the aorta is divided above and below the origin of the celiac trunk, and the portal vein is divided usually 2.5 cm above the superior border of the pancreas. The SMA is harvested with an aortic Carrel patch and distal to the origin of interior pancreaticoduodenal artery. The duodenum is divided by gastrointestinal anastomosis (GIA) stapler at the level of pylorus and ligament of Treitz after flushing the lumen with an antiseptic solution. The spleen remains attached to the pancreas to protect the tail during the procurement. Iliac venous and arterial grafts are obtained from the donor for the reconstruction of the pancreas vasculature. When the small bowel is procured for transplantation at the same time, it is essential to ensure that the inferior pancreaticoduodenal artery is not divided during dissection of the root of the small bowel. Next the pancreas with spleen and duodenum in continuity are placed in a container with preservation solution and placed on ice during transportation.
Pancreas Procurement for the Islet Allotransplantation
Basically the pancreas for the islet isolation is procured in the same way. However, different elements of the procurements are more crucial. First, the pancreas for islet procurement is more sensitive to warm injury; therefore, the organ should be well flushed with the preservation solution to eliminate blood. Then the organ should be kept constantly surrounded by ice, even during dissection. Next, because no blood vessels are necessary for the isolation, the presence of a right hepatic artery does not preclude pancreas procurement. Instead, it is extremely important during the dissection not to cut or open the pancreas capsule because it compromises enzyme distention, organ digestion, and eventually the yield of the isolation. Because results of the islet isolation depend strongly on proper pancreas preservation, it is hard to overemphasize the importance of the pancreas procurement technique for the success of the islet isolation and then transplantation. In multivariable analyses the procuring team from the islet isolation center is the strongest independent factor (odds ratio [OR] = 10.9) regarding the success of the isolation.
Back-Table Preparation for Whole Pancreas Transplantation
Before implantation, the pancreas needs to be prepared for transplantation while still on ice at the back table. During this important procedure, the pancreas vasculature is restored; excess surrounding fat, connective tissue, and the spleen are removed, followed by meticulous ligation of the surrounding blood vessels. This is all done to minimize unnecessary ischemic or bleeding injury, improving the results of pancreas transplantation. Because the celiac trunk and hepatic artery are allotted to the liver, the splenic artery and SMA are maintained with the pancreas. To make a single arterial pedicle, the donor iliac artery is used as a “Y” graft to suture onto the donor SMA and splenic artery. The portal vein is available for anastomosis and usually does not require elongation. The standard pancreas graft includes the entire pancreas and the second portion of the duodenum. Some authors recommend reconstruction of the gastroduodenal artery as well with an arterial conduit, to improve blood supply to the head and duodenum and decrease risk for complications; however, the advantage of such a maneuver has not been confirmed in comparative studies.
Living-Donor Pancreas Transplantation
Since 1978, when for the first time a living-donor pancreas transplantation was performed at the University of Minnesota, there have been 160 of those procedures reported to the IPTR, and only three American centers were involved. Improved graft survival was the main goal of the procedure when azathioprine and cyclosporine were the main immunosuppressive agents, despite the magnitude and potential complications of the donor operation. However, with the introduction of tacrolimus, mycophenolate mofetil (MMF), and clinical antibodies used for induction therapy, and better donor selection excluding donor-specific antibodies, graft survival improved dramatically for cadaveric-donor pancreas transplants. As a result, the immunologic advantage of pancreas transplantation with living-donor transplants in the recent era is no longer as critical as it was before. Moreover, cadaver donors for pancreas transplantation are more available than for other organ transplants, and there is a substantial risk for donors developing diabetes after donation (26%). Thus living donors for solitary pancreas transplants are only considered in order to limit long waiting times in highly sensitized recipients or if the donor is a nondiabetic identical twin or a six-antigen matched sibling. Of note, living-donor pancreas transplantation has been offered with good results not only as solitary organ but also in setting of SPK with kidney from the same donor or deceased donor.
In the living-donor pancreas recovery procedure, the short gastric artery arcade should be preserved so that the spleen can be safely left in place. The splenic artery is divided just distal to its origin, and the splenic vein is divided proximal to its confluence with the superior mesenteric vein. The splenic arterial anastomosis is to the recipient common iliac artery, whereas venous drainage is to the common iliac vein. The pancreatic drainage is accomplished by pancreaticojejunostomy or pancreaticocystostomy.
Pancreas Transplantation
The pancreas may be transplanted as the only organ in PTA or as PAK transplantation. However, most commonly, it is transplanted from the same donor with the kidney as SPK transplantation. In this situation, during the same procedure, the pancreas may be transplanted first because it has a shorter “shelf life” (optimal cold storage time is <12 hours vs. 24 to 48 hours for kidney), so as to reduce preservation injury and the risk of complication. Alternatively, the kidney may be grafted first to reduce the incidence of acute tubular necrosis and to avoid pancreas manipulation during kidney transplantation. The pancreas is usually placed in the right pelvis, as in kidney transplantation, with the arterial anastomosis performed on the recipient common iliac artery. Venous drainage can be connected to the lower vena cava or the common iliac vein (systemic drainage) or superior mesenteric vein (portal drainage). The standard pancreas graft includes the entire pancreas and a portion of the duodenum. The donor duodenum is anastomosed to the recipient's small bowel or urinary bladder allowing drainage of the exocrine pancreas secretions. Each alternative procedure has its own pros and cons.
Portal Versus Systemic Venous Drainage
Portal venous drainage directs the insulin released by the pancreas transplant initially to the liver, in a fashion similar to normal physiologic conditions, allowing for 50% first-pass metabolism. It also lowers the concentration of low-density lipoprotein and apolipoprotein B, and free cholesterol, as well as very-low-density lipoprotein. It was postulated based on experimental models that portal venous drainage decreases immunologic response to the graft; however, this was not confirmed clinically. On the other hand, systemic drainage omitting first passage through the liver leads to hyperinsulinemia and increased level of low-density lipoprotein. However, clinically the advantages of the portal over systemic drainage in maintaining normal glucose homeostasis or lipid metabolism have never been shown. Similarly, carbohydrate metabolism does not differ in recipients having SPK transplantation compared with nondiabetic recipients after kidney transplantation only, when similar immunosuppression is used. Therefore portal drainage is currently used in only 20% of patients because it is more challenging, requires more experience, and has a somewhat higher risk of graft thrombosis.
Enteric Drainage Versus Bladder Drainage
Historically, restoration of pancreatic exocrine secretion drainage was challenging. After the failure of attempts at pancreatic duct ligation and obliteration, the urinary bladder with pancreas-duodenum anastomosis was developed. The advantage of this approach is that amylase concentration in urine allows for monitoring of graft function, enabling early detection of rejection. It is especially useful in PTA and PAK transplantation. However, the major disadvantage is metabolic acidosis because of loss of bicarbonate with the relatively large amount of pancreas juice, frequent reflux pancreatitis (50%), cystitis, urinary tract infection, and perineal irritation. Therefore, after more potent immunosuppression was introduced, including induction therapy, and the need for pancreas monitoring was diminished, enteric drainage was more widely adopted, improving postoperative course and patient satisfaction. In addition, pancreas rejection is usually associated with kidney graft dysfunction in SPK transplantation, which allows additional monitoring of the pancreas graft state. Therefore 90% of patients currently undergo enteric drainage for all three categories of pancreas transplantation. There are many different methods for enteric drainage in use: The duodenum may be connected with a loop of jejunum, ileum, or even recipient duodenum. It is usually a side-to-side configuration with the loop (most common) or Roux-en-Y limb of the bowel (15% to 20%), either a handsewn double layer or a stapled anastomosis. However, in the latter approach, there is a higher risk of postoperative mucosal bleeding. It seems that enteric drainage has a slightly higher incidence of graft thrombosis than bladder anastomosis: 5.5% to 11.6% versus 5% to 7.2%, respectively. Postoperative enteric leak usually requires reoperation for repair with Roux-en-Y conversion of the bowel loop. In cases of a leak from a bladder anastomosis, drainage with a Foley urinary catheter is usually sufficient. Based on considerable data from both registries and various retrospective and prospective trials, neither of those two drainage techniques has a clear advantage with regard to overall patient or pancreas graft survival.
Complications
The hypoxic injury inherent in cadaveric organ procurement accounts for some of the complications related to the pancreatic allograft. During the 1980s 25% of all pancreata were lost because of surgical technical failure. According to the IPTR, from 2004 through 2008, the incidence was reduced to an 8% average in all three categories (SPK, PTA, and PAK recipients). Nonetheless, surgical complications, such as pancreas graft thrombosis, leakage, graft pancreatitis, and bleeding, remain high concerns because the rate of the relaparotomy is as high as 35%.
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