Techniques of pancreas transplantation

Introduction

Diabetes mellitus is associated with extensive morbidity and mortality and represents a significant medical, financial, and emotional burden on society. Long-term diabetes mellitus is frequently associated with cardiovascular, cerebrovascular, peripheral vascular, neurologic, renal, and ophthalmologic complications. Diabetes remains the leading cause of renal failure (44% of new cases every year) and increases the risk of mortality in uremic patients. Despite marked improvements in the medical management, poor glycemic control, hypoglycemic unawareness, and secondary complications of diabetes remain common. Pancreas transplantation not only results in insulin independence but also potentially slows down progression of or reverses some of the secondary complications of diabetes. Pancreas transplantation is currently only offered to select diabetic patients who meet the strict qualifying criteria. In this chapter we present a brief history, indications and types of transplants, donor selection, recipient evaluation, surgical techniques and complications, immunosuppression, and outcomes.

History of pancreas transplantation (also see Chapter 112 )

In 1922 the team of Banting, Best, and Collip successfully used pancreatic extracts in the treatment of diabetes mellitus; the purified substance was called insulin. Four decades later, in 1966, William Kelly and Richard Lillehei performed the first human simultaneous pancreas and kidney transplantation at The University of Minnesota. The pancreas allograft included the distal segment with ligation of the pancreatic duct and was placed in the left lower quadrant with the kidney on the right. The entire celiac axis was included and the superior mesenteric vein and portal vein were used as a bypass from the external to common iliac veins in order to improve venous flow. The patient immediately became independent of insulin and dialysis but died after 2 months due to sepsis and rejection. By 1969 the same team reported on their subsequent series of 13 grafts. This series included the whole pancreas placed again in the left lower quadrant with celiac arterial inflow and portal venous outflow into the left iliac vein. In the first few transplants, the exocrine secretions were exteriorized via a duodenostomy. Subsequently, the graft duodenum was anastomosed to the recipient jejunum. In this early era, David Sutherland and the team from Minnesota also performed the first successful living donor partial pancreas transplantation, which was also the first successful extrarenal living donor organ transplant.

Pancreas transplantation in this period was plagued with graft losses due to technical complications such as vascular thrombosis, death with a functioning graft, and lethal complications related to exocrine pancreatic drainage. Immunosuppression and organ preservation were in their infancy, so rejection and ischemia reperfusion injury precipitating severe allograft pancreatitis and dysfunction were common. Progress in the field of transplantation was greatly influenced by the development of better organ preservation techniques such as Collins’ solution in 1969, the University of Wisconsin (UW) solution in 1989, and improved immunosuppressive medications such as the calcineurin inhibitors (CNIs) cyclosporine and tacrolimus (see Chapter 104 ). Due to the high graft failure rate, the concept of draining the exocrine secretions into the urinary system was proposed by Sollinger et al. at The University of Wisconsin (duodenal patch) and by Nghiem and Corry at The University of Iowa (duodenal bubble). This technique had the advantages of eliminating an enteric anastomosis and providing more information about allograft function because the amount of amylase secreted by the pancreas could be measured in the urine. Unfortunately, bladder drainage was also associated with complications such as cystitis, metabolic acidosis, dehydration, reflux pancreatitis, and urethritis. More recently, with continued improvement in surgical techniques for the retrieval, preparation, and transplantation of the allograft, enteric drainage has again become the surgical procedure of choice at most transplant centers for whole organ pancreas transplantation. Pancreas transplant outcomes have also improved over the decades with excellent graft survival and function. The 1-year patient survival and pancreas graft function rates are 97.4% and 91.3% for simultaneous pancreas and kidney transplants, 97.9% and 86% for pancreas after kidney transplants, and 97% and 85.7% for pancreas transplants alone, respectively. The international 5- and 10- year patient survival rates for simultaneous pancreas-kidney transplant (1984–2009) are 90% and 76%, respectively. Pancreatic allograft survival rate is 73% at 5 years and 56% at 10 years; kidney survival rate is 81% at 5 years and 62% at 10 years.

Indications and types of pancreas transplant (see Chapter 112 )

Pancreas transplantation is traditionally performed in diabetic patients who do not produce insulin. Although it is commonly indicated for type 1 diabetes mellitus, the distinction between type 1 and type 2 diabetes mellitus is becoming less clear. Type 1 diabetics may continue to produce a detectable C-peptide level but inadequate insulin in order to maintain euglycemia, and type 2 diabetics may lose enough β-cell mass that they develop undetectable C-peptide levels. Also, as C-peptide is primarily metabolized in the kidney, levels in end-stage renal disease (ESRD) patients can be disproportionately high and may not be representative of the actual functioning β-cell mass.

It is critical to balance the long-term risk of remaining diabetic versus the risks of a pancreas transplant that includes the risk of the operation itself as well as the risks of immunosuppression (see Chapter 104 )—including opportunistic infections and malignancy, some of which may be life threatening. Generally, the risk of remaining diabetic is less than the risks of immunosuppression, so most diabetics would not qualify for a pancreas transplant. However, candidates for a kidney transplant for end-stage diabetic nephropathy require immunosuppression anyway, so the trade-off between immunosuppression and diabetes is greatly lessened in those patients.

For this reason, the most frequent form of pancreas transplant is simultaneous pancreas and kidney transplantation (SPK) for ESRD secondary to diabetic nephropathy in a type 1 diabetic patient. Pancreas after kidney transplantation (PAK) is offered if the candidate has already received a functioning kidney graft or if there is a potential living donor for the kidney. In diabetic patients with preserved renal function, a pancreas transplant alone (PTA) without a kidney transplant would be considered only for immediately life-threatening complications of diabetes such as hypoglycemic unawareness, frequent severe hypoglycemia, hyperglycemia or ketoacidosis, incapacitating clinical and emotional problems with exogenous insulin therapy, failure of medical management in preventing acute complications, or insulin allergy. PTA may also be indicated following total pancreatectomy for nonmalignant disease where the candidates typically manifest a particularly brittle form of diabetes (type 3c diabetes) as theirs is a deficiency of all pancreatic hormones, not just insulin. ^, These patients also exhibit pancreatic exocrine insufficiency, which typically resolves following pancreas transplantation with a proximal enteric drained pancreas allograft. PTA has been reported for treatment of generalized allergy to human insulin. Pancreas transplantation can achieve complete reversal of glycogen hepatopathy in certain cases. Simultaneous liver-pancreas transplantation and simultaneous lung-pancreas transplantation have also been successfully accomplished in recipients with cystic fibrosis, and provide both endocrine and exocrine function.

Per current US Organ Procurement and Transplantation Network (OPTN) policy, to qualify for registration for a pancreas transplant, each candidate must meet one of the following requirements:

• Be diagnosed with diabetes

• Have pancreatic exocrine insufficiency

• Require the procurement or transplantation of a pancreas as part of a multiple-organ transplant for technical reasons (e.g., a multivisceral transplant)

To qualify for a combined kidney-pancreas registration, each candidate registered on the kidney-pancreas waiting list must be eligible for the pancreas waitlist and for the kidney waitlist (measured or calculated creatinine clearance or glomerular filtration rate [GFR] less than or equal to 20 mL/min). These patients would also be eligible for a pancreas after kidney were they to have a living donor for the kidney. Waiting time for pancreas begins on the date the candidate is first registered as a candidate on the waiting list. For a combined kidney-pancreas, the candidate begins to accrue waiting time once the candidate has met all of the following conditions: registered for a kidney-pancreas; qualifies for kidney (GFR <20 mL/min or started regular dialysis); and is on insulin. If the patient is on dialysis before listing, the start date for waiting time is back-dated to the date of initiation of dialysis.

Type 2 diabetes was once considered an absolute contraindication to pancreas transplantation, but this is no longer the case. Chakkera et al., Light et al., ^, and others have shown that insulin secretion and sensitivity improve over the long term in type 2 diabetics who undergo SPK. The percentage of type 2 diabetic (per center reporting) recipients in the United States has increased from 2% in 1995 to 7% in 2010 and then 11.7% in 2015. ^, Although poorly understood, it is thought that the transplanted pancreas can overcome insulin resistance. Criteria for selection of type 2 diabetics for pancreas transplantation are essentially the same as for type 1 diabetics, but daily total insulin requirement should not be excessive (perhaps <1 unit/kg/day), and patients should make efforts to lose weight if they are obese. ^,

Pancreas after kidney (PAK) transplantation

PAK transplantation involves kidney transplantation, most frequently from a living donor, followed by subsequent deceased donor pancreas transplantation from a separate donor. PAK transplantation requires two separate operations; there is therefore the inherent risk of undergoing a second course of anesthesia, and the risk of a separate incision. Moreover, the kidney and pancreas allografts will be from separate donors; as a result, the organs may behave independently from an immunologic perspective. Despite this, patient survival is nearly identical to that of an SPK recipient. There are several likely explanations. The PAK transplantation is a shorter operation, and the patient is not uremic at the time of surgery. Also, the patient is already on baseline immunosuppression, which may provide an immunologic advantage. PAK allows one to preempt or shorten the duration of dialysis as well as prevent complications that can occur while waiting for a deceased donor kidney transplant. It is possible to entirely eliminate the second surgery by doing both the living donor kidney transplant and the deceased donor pancreas transplant simultaneously ; this eliminates the need for a second course of induction immunosuppression and potentially may provide the best results. The disadvantage of this approach is the necessity to set up a living donor retrieval operation on short notice and the extra resources required to run an extra operating room, potentially at inopportune times.

Even today, pancreas transplantation is frequently considered only a life-enhancing rather than a life-saving procedure. However, abundant evidence indicates that, similar to kidney transplantation, successful pancreas transplantation, in the long term, is clearly life-extending in all three recipient categories. The University of Wisconsin published their experience with 1000 kidney-pancreas transplantations with 22-year follow-up. In this report, patient survival following transplantation of both a kidney and a pancreas was dramatically superior to all other options for type 1 diabetic uremic patients, particularly cadaveric renal transplantation and dialysis ( Fig. 126.1 ). Although not evident for the first 4 to 5 years, with the extended follow-up in this particular study, patient survival following SPK was remarkably superior to that of type 1 diabetic uremic recipients undergoing living donor renal transplant alone, supporting the fact that freedom from diabetes has a clear survival advantage. If the patient ultimately comes off dialysis and insulin, there is a greater patient survival advantage compared with remaining diabetic but free from renal failure. This situation would best be accomplished through immediate living donor kidney transplantation if available followed by PAK transplantation. Additionally, if a kidney pancreas recipient receives a living donor kidney, there would be one more standard criteria kidney available for the deceased donor kidney transplant list. A recent study from the OPTN Pancreas Transplant Committee also indicated that the best long-term renal allograft survival was achieved with the combination of a living donor kidney transplant followed by a pancreas.