Simultaneous Pancreas-Kidney and Pancreas Transplantation (2001)

The discovery of insulin in 1922 changed the treatment of type 1 diabetes mellitus (DM) forever. Insulin was the first effective therapy for type 1 DM; however, its success engendered a terrible paradox for patients with this disease. The use of insulin transformed type 1 DM from a rapidly fatal condition to a chronic incurable illness, revealing the long-term complications associated with DM, e.g., nephropathy, vasculopathy, retinopathy, and neuropathy, and the terrible toll that they take throughout a lifetime. DM now affects approximately 20 million individuals in the United States, with at least 2 million individuals having classic type 1 DM (1). Hyperglycemia, alone or in concert with hypertension, is the primary factor influencing the development of major diabetic complications (2,3). Therefore, correcting hyperglycemia is an obvious strategy for altering the course of DM and its complications. The Diabetes Control and Complications Trial (4) demonstrated that glycemic control could limit the rate of progression of complications in type 1 DM. However, the best available method for achieving a steady euglycemic state among individuals with type 1 DM is wholepancreas transplantation. The goals of pancreas transplantation have developed beyond simply restoring normoglycemia for a period of time and improving the quality of life (QOL) (5). Pancreas transplantation, as simultaneous pancreas-kidney (SPK) transplantation or pancreas transplantation alone (PTA), is now a functional and effective therapy that can reverse metabolic abnormalities (6) and prevent or minimize many of the secondary complications of DM (7). Perhaps even more significantly, pancreas transplantation now seems to be a therapy that can improve survival rates in the setting of type 1 DM (8). Candidates for Pancreas Transplants Pancreas transplantation was first performed in 1966 (9). Since then, nearly 14,000 pancreas transplants have been reported to the International Pancreas Transplant Registry (10). C-peptide-deficient, insulin-dependent patients with type 1 DM and significant nephropathy or end-stage renal disease (ESRD) are potential candidates for SPK transplantation if they are <55 yr of age. Ideal patients for PTA are individuals with type 1 DM, low cardiac risk, and relatively mild and potentially reversible end-organ disease (Table 1) (11). The majority of pancreas transplants performed in the United States are for C-peptide-deficient individuals with DM. However, some insulin-dependent patients with normal C-peptide levels can achieve good glycemic control after pancreas transplants (12). This finding may reflect a greater native pancreatic β-cell reserve than expected, a greater transplanted β-cell load, or the problematic nature of C-peptide measurements as markers of type 1 DM, especially among patients with renal disease (13).Table 1: Clinical eligibility criteria for potential SPK transplant and PTA recipientsaSignificant cardiovascular disease is a contraindication to pancreas transplantation. A history of coronary revascularization is a less significant contraindication than in the past. Nevertheless, coronary event rates remain greater among pancreas transplant recipients who have undergone coronary revascularization (11% at 1 yr and 29% at 3 yr after transplantation), compared with individuals without pretransplantation coronary artery disease (2% at 1 yr and 8% at 3 yr) (14). Therefore, individuals with significant coronary artery disease are often preferentially referred for kidney transplantation alone (KTA), although they can subsequently receive a PTA after the kidney transplant (PAK). Severe peripheral vascular disease is another relative contraindication to SPK transplantation and PTA. Although patients with DM-related ESRD can still benefit from SPK transplants, they are unlikely to derive improved peripheral vascular function, given our present understanding of post-SPK transplantation complications and disease (15). Moreover, iliac atherosclerosis can complicate the technical procedure. Other relative contraindications to pancreas transplantation include obesity, substance abuse, poorly controlled psychiatric illnesses, noncompliance, and any recent malignancy (11). Ultimately, the principal consideration in the selection of candidates for pancreas transplantation is the balance between cardiovascular risk and the benefits of glucose homeostasis with respect to QOL, end-organ disease, and mortality rates. Options Available for Potential Pancreas Transplant Recipients SPK transplantation should be considered the primary transplant option for patients with type 1 DM who are acceptable candidates but for whom a suitable, HLA-identical, living donor is not available (Figure 1). Young diabetic patients with suitable, HLA-identical, living donors should also consider HLA-identical kidney transplantation. This option offers superior long-term renal graft function results, with less immuno-suppression than required for SPK transplantation. Moreover, this procedure does not disqualify patients from PTA at a later time or concurrent with the kidney transplantation (16). An optimal HLA-identical donor should lack islet cell antibodies (a risk factor for type 1 DM) and should be provided with information about the risks of developing type 1 DM in the future. It should be noted also that the long-term renal graft function for SPK transplant recipients is comparable to that for haplotype-identical or living unrelated donor kidney transplant recipients (17).Figure 1.: Options for potential simultaneous pancreas-kidney (SPK) transplant recipients. DM, diabetes mellitus; BMI, body mass index; KTA, kidney transplantation alone; LRD, living related donor.Individuals who undergo HLA-identical kidney transplantation and then PAK transplantation are part of an increasing group of PTA recipients throughout the world (18). Such individuals now account for 9% (PAK transplantation) and 4% (PTA) of all pancreas transplants in the United States. The indications for PAK transplantation are relatively broad, because these patients are already undergoing life-long immuno-suppression. However, patients with stable kidney transplant function (creatinine clearance of ≥50 ml/min and the absence of significant proteinuria) should be considered for PAK transplantation. Patients with marginal kidney transplant function are not candidates, because the intensified calcineurin inhibitor therapy after surgery can precipitate renal failure. Such individuals should be monitored carefully and considered for preemptive kidney retransplantation or SPK transplantation as their renal function declines further. The presence of two or more diabetic complications that have not yet progressed to end-organ failure defines the eligibility criteria for PTA. These complications include early nephropathy, with microalbuminuria but preserved native renal function (normal serum creatinine concentrations and creatinine clearance values of ≥80 ml/min), and labile glycemic control, with recurrent hypoglycemia or hypoglycemic unawareness. Finally, issues of access and reimbursement are important in pancreas transplantation. Pancreas transplantation needs to be offered to all potential candidates. Isaacs et al. (19) documented striking racial disparities in access to SPK transplantation in the United States, with Caucasian individuals receiving 92% of all SPK transplants. Those authors attributed these differences to differences in employment status, the prevalence of private insurance among certain racial and ethnic groups in the United States, and general health care. Their data supported the recent change in the Medicare policy pertaining to SPK transplantation. Medicare coverage was approved, as of July 1999, for clinically indicated pancreas transplantation in the SPK and PAK transplantation settings. Surgery The critical aspects of the transplant operation are donor selection and preparation of the pancreaticoduodenal allograft. Optimal pancreas donors are young (age, 4 to 55 yr), nondiabetic, nonobese, and without significant aortoiliac atherosclerotic disease. Pancreata from obese and/or older donors are associated with an increased risk of postoperative intra-abdominal infections and poor posttransplantation glycemic control (20). Most transplant surgeons also consider “fibrotic or fatty” pancreata to represent higher risks. However, the effects of these characteristics on outcomes have not been formally evaluated. Preoperative isolated donor hyperglycemia or hyperamylasemia is actually not a contraindication to the use of the pancreas for transplantation. Ultimately, the most important determinant of suitability is the intraoperative assessment of organ quality by an experienced transplant surgeon. During cadaveric donor operations at our center, the donor pancreas, duodenum, and spleen are perfused in situ with cold University of Wisconsin solution and are collected en bloc with the liver. The pancreaticoduodenal graft is then separated from the liver graft at 4°C. The technical aspects of the recipient procedure are largely the same whether SPK transplantation, PTA, or PAK transplantation is being performed. The native pancreas is not removed, because it may still provide some digestive function. The pancreaticoduodenal allograft is transplanted to an ectopic location, usually the right iliac fossa. The kidney allograft is transplanted ectopically to the contralateral iliac fossa. Solitary pancreaticoduodenal allografts can be implanted into either iliac fossa, although the right side is used more frequently. In all other respects, the operative sequence for PTA duplicates the combined procedure. Intraperitoneal placement of the pancreatic allograft is important. This technique is associated with fewer peripancreatic fluid collections and wound complications. Previous peritoneal dialysis increases the risk of postoperative intra-abdominal fluid collections related to lymphatic or pancreatic secretions. Systemic venous drainage is obtained by anastomosing the donor graft portal vein to the recipient iliac vein or inferior vena cava. Portal venous drainage is an alternative approach in which the portal vein of the allograft is anastomosed to the superior mesenteric vein of the recipient. This technique results in drainage of released insulin into the portal venous blood flow. There is debate regarding whether this is the most physiologic drainage technique. Systemic venous drainage can result in peripheral hyperinsulinemia. However, mild peripheral hyperinsulinemia is present among the vast majority of all transplant recipients. Systemic insulin release does lead to greater peripheral hyperinsulinemia, compared with portal venous drainage (21); however, the long-term results of the two techniques are comparable. Ultimately, the method of venous drainage may be dictated by the anatomic considerations for each patient. PTA recipients, by definition, have good renal function and thus lack the platelet dysfunction so common in ESRD. This may explain the increased risk of graft thrombosis (venous or arterial) in this population (10%), compared with SPK transplant recipients (6.4%) (22). Intra-arterial or systemic heparin administration is often performed perioperatively, with subsequent antiplatelet therapy (e.g., aspirin or dipyridamole), to decrease the likelihood of graft thrombosis. Drainage of Pancreatic Exocrine Secretions: BladderversusEnteric Drainage A variety of techniques to manage pancreatic exocrine secretions, including duct occlusion, open drainage into the peritoneal cavity, anastomosis of the pancreatic duct to the ureter or bladder, and creation of a duodenal button for anastomosis to the urinary tract, have been proposed throughout the years (23). All of these techniques have been abandoned. Currently, bladder drainage (BD) of pancreatic exocrine secretions (Figure 2A) or drainage into the small intestine [enteric drainage (ED)] (Figure 2B) are the most commonly used techniques (22). The donor duodenum is anastomosed to the dome of the recipient bladder for BD, with exocrine secretions being diverted into the urinary tract. This technique, although safe and well tolerated, is associated with intravascular volume depletion, metabolic acidosis, reflux pancreatitis, and urinary tract complications, including hematuria, urethritis, and recurrent urinary tract infections in which the donor duodenal is anastomosed to the to be more is associated with fewer and metabolic complications, as well as fewer urinary tract infections and fewer of volume depletion, compared with (Table However, is associated with a greater of compared with Pancreas transplant with bladder Pancreas transplant with with from complications of pancreas transplantation. Transplant of complications related to drainage is in certain as PTA, because it of urinary levels as an of may be more important in this setting than in SPK transplantation. However, serum and combined with clinically indicated allograft are also effective for diabetic chronic or intraoperative to are all relative contraindications to e.g., bladder, or urinary tract are all relative contraindications to is In United for Pancreas Transplant Registry data that an increasing of are the long-term graft survival thrombosis and primary rates are for the two the of drainage procedure an and The obvious of any transplant procedure is long-term graft the success of PTA or SPK transplantation was in part by early pancreatic graft thrombosis to the first have also that SPK transplant recipients renal graft more than recipients and that renal graft may be more to the the vascular in SPK transplantation renal renal graft may be two to more than pancreatic graft among SPK transplant recipients. However, it be a to pancreatic graft because this the most significant of pancreatic graft The early of pancreatic graft is a graft usually or pancreatic graft after SPK transplantation. Pancreas is with as allograft and (e.g., hyperamylasemia or increased serum creatinine levels may decrease in with in urinary There may even be in blood to the pancreatic with graft and of the pancreatic Other that have been used to pancreas transplant include of in urinary insulin and/or C-peptide and in or levels However, all of these have significant as the for the of after pancreas transplantation. for the of pancreatic allograft can now be obtained by and an of pancreas transplant with pancreatic other disease and a of and criteria that pancreatic graft (Table Their demonstrated a significant with graft for and for for for and for with the of because of increasing with beyond of pancreas allograft is risk in receiving a cadaveric pancreas transplant with a kidney transplant the that higher rates of blood to the kidney from the pancreatic the likelihood of graft the presence of two allografts may the of that can a graft a the of any in the setting of SPK transplantation renal graft may lead to of the renal allograft normal pancreatic graft function. The risk for graft after SPK transplantation are increasing donor yr), recipient of and retransplantation cold time of of exocrine drainage and use of cell therapy not outcomes The increases in graft function rates for PTA are more than for SPK transplantation. The United for Pancreas Transplant Registry now pancreatic graft function rates of for PAK transplantation and for PTA These rates represent the 20 to graft survival rates for transplants in the University of Wisconsin solution and A have reported even results, to graft function rates after pancreas transplantation cell therapy in with a SPK transplant recipients with and experienced rates of for kidney and to for pancreatic compared with to and to for kidney and pancreas, among patients with and Patients with and experienced rates greater than for patients for kidney and to for pancreatic The graft function rates for pancreas and kidney reflect these in the rate of of Pancreas that the and mortality rates associated with SPK transplantation any potential survival In the was of the of SPK transplantation, with et al. the improved survival rates for SPK transplant recipients, compared with diabetic recipients. the group at the University of Wisconsin demonstrated a significant after SPK transplantation with a of the survival These have been for the lack of a control population and selection that could SPK and recipients. the well controlled reported by et al. which noted a in mortality rates after SPK transplantation, is to this Therefore, the data reported by et al. are of group patients with type 1 DM for whom renal therapy was in the between and In SPK transplantation was offered to In another was the transplant SPK transplantation was associated with a for of to all individuals with ESRD evaluated. This to to transplant recipients evaluated. Therefore, SPK transplantation seems to be a therapy that can mortality rates among individuals with type 1 DM and ESRD. of Pancreas transplantation many of the aspects of type 1 DM, including hypoglycemic metabolic glycemic control, insulin glucose and Therefore, it could be that pancreas transplantation improve the for individuals with type 1 DM. The majority of that pancreas transplantation SPK transplant recipients. a in which for SPK transplant recipients for diabetic recipients Pancreas transplantation, however, improved of health and et al. whether the among SPK transplant recipients changed with The on for diabetic transplant recipients transplantation and higher than the reported normal values for patients with chronic disease, or and to for patients with The of may be important in of the effects of SPK transplantation. In SPK transplant recipients their pretransplantation after transplantation, compared with the procedure In is a benefit from the transplant procedure and the to the pancreas transplant on the obvious from the diabetic state to a a transplant with a pancreas and a kidney is of nephropathy in type 1 DM. However, most renal function among SPK transplant recipients diabetic recipients not significant differences the early posttransplantation time period although diabetic recipients may microalbuminuria after transplantation The lack of long-term renal graft data to a greater on SPK transplant and diabetic recipients. is the of diabetic Therefore, its presence recurrent diabetic nephropathy in SPK transplant recipients are less to the of diabetic nephropathy early after transplantation, compared with diabetic recipients Moreover, PAK transplantation to prevent the development of diabetic nephropathy in from individuals who PAK transplantation 1 to yr after This that even of normoglycemia may have significant effects on of DM The Diabetes Control and Complications Trial (4) that of glycemic control to effects on There was an of early after the of glycemic This was by a of and even mild It could be that SPK transplantation have the same In 20 to of PTA and SPK transplant recipients early of after the transplant Severe diabetic retinopathy, with was a common finding in most The of these may a of PTA or SPK transplantation on the of alone with SPK transplantation or among diabetic individuals may improve retinopathy, thus the Nevertheless, a of controlled or of after SPK transplantation, especially was in its early without to treatment The also a SPK and pancreas transplant recipients experienced less of their than diabetic recipients is after PTA and SPK transplantation, It stable in the majority of patients but can or in to of PTA and SPK transplant recipients diabetic and and type of all after transplantation. all of increased after transplantation in that this among PTA and SPK transplant recipients with time Therefore, in the absence of retinopathy, PTA or SPK transplantation can or improve DM-related However, may as a result of other associated after pancreas transplantation. major peripheral vascular disease after PTA and SPK transplantation. The of DM transplantation increases the risk for posttransplantation disease. In hyperinsulinemia, with its could disease. have been controlled the effects of PTA and SPK transplantation on type 1 DM complications after transplantation. In peripheral vascular disease stable after kidney transplantation and that after SPK transplantation not improve peripheral vascular disease. A for significant vascular disease is the rate among Pancreas transplantation not rates in the this to These the in among pancreas transplant recipients other risk may in disease and that complications may be by pancreas transplantation, in to many of the complications of DM. is a major risk factor for coronary artery disease and commonly affects individuals with DM. small have whether SPK transplantation the prevalence of posttransplantation hypertension, with from the early that of SPK transplant recipients posttransplantation hypertension, with to rates of after SPK transplantation was as a in the of or in that control greater among SPK transplant recipients data that the prevalence of post-SPK transplantation may be with the increasing use of and after SPK transplantation authors have that the type of pancreatic exocrine drainage could the prevalence of transplantation to urinary of and with a state of mild volume and metabolic seems to be more common with primary compared with However, from to is not associated with an in This that other than noted have greater effects on or SPK transplantation than that was in cardiac risk among SPK transplant recipients a history of dysfunction or failure increased the mortality risk after pancreas transplantation greater patients with cardiac risks for PTA and SPK transplantation. It is not that cardiac rates for SPK transplant recipients are now to or than cardiac rates for other transplant recipients with type 1 DM individuals with of coronary artery disease and revascularization are potential candidates for pancreas transplantation. However, their cardiac rates remain greater than for individuals without pretransplantation coronary artery disease risk, (14). Such information is important for as well as the of optimal or SPK transplantation cardiac The transplant may cardiac function. from small that pancreas transplantation improved and function, as well as These to in concert with in cardiac function among individuals at low risk, PTA or SPK transplantation seems to provide some benefits with respect to cardiac function. collected data be to whether pancreas transplantation effects on coronary artery disease after transplantation. The effects of PTA and SPK transplantation may be most in of the of diabetic after transplantation. SPK transplantation to and at least of peripheral diabetic potential of the and as well as demonstrated by after transplantation potential (a of of demonstrated of after SPK transplantation, with for at least yr and potentially for as as yr after transplantation function also demonstrated long-term with the being yr after transplantation These greater than for diabetic recipients, and they the in in the Diabetes Control and Complications Trial and dysfunction is a common that affects approximately to of all individuals with DM and renal failure. dysfunction is a primary among diabetic to of all especially with renal disease. dysfunction is as common in DM and is in a with in to failure of normal and of potential There are data whether PTA or SPK transplantation dysfunction after transplantation. is actually a risk that the for the procedure could precipitate However, at least in SPK transplantation was associated with in function, although a of SPK transplant recipients still required at least therapy to improve function are data available to whether pancreas transplantation However, are data that pancreas transplantation is associated with in The Registry reported on a group of SPK transplant recipients in 20 and low in of the The however, developing well at the time of the the as urinary tract infections of the also and two recipients kidney transplant and SPK 2 yr after the risk after SPK transplantation the potential effects of certain and are all safe for use its in transplantation, is information regarding the use of It was associated with effects in Therefore, although of therapy have been documented at this time it is not that treatment or they Clinical the of for in these Finally, SPK transplant recipients have 20 to without major complications Therefore, it is for SPK transplant and PTA recipients to after the transplant although these are transplantation effects on The of PTA and SPK transplantation are now more obvious as in techniques and have an increasing of PTA and SPK transplants and functional in the The obvious benefits of normoglycemia be even more if it to PTA for patients without significant renal dysfunction or for patients early in the progression of DM-related renal disease. Nevertheless, SPK transplantation can be as a for type 1 DM. It can improve survival rates and limit many DM-related complications, improving The effects of SPK transplantation and PTA on other aspects of DM, e.g., and are also be performed to whether early in these metabolic and good outcomes after SPK transplantation and PTA. Finally, the recent by et al. the of the pancreas should be Their that islet cell transplantation may be a of transplantation in the future. It is that islet cell transplantation the same with respect to survival rates and diabetic complications, as PTA and SPK transplantation This transplantation approach to the treatment of type 1 DM is the first alternative to insulin It does the risks of and it is to the of disease. However, PTA and SPK transplantation, and islet cell transplantation in the with the for normoglycemia and of a of to life for individuals with type 1 DM. all of the most our patients at the University of Wisconsin for their and as they regarding good and associated with and pancreas transplantation.