Kidney-Pancreas Transplantation

The main goal of pancreas transplantation is to ameliorate insulin-dependent diabetes mellitus (type 1 or type 2) and produce complete independence from injected insulin. ^[1] Simultaneous pancreas-kidney (SPK) transplantation (see the image below) is the primary option if the patient also has diabetic nephropathy and qualifies for listing for a kidney transplant. The first successful human pancreas transplant along with a kidney transplant was performed in 1966 at the University of Minnesota by Dr. William Kelly and Dr. Richard Lillehei. In 2020, 872 pancreas-kidney transplants were performed in the United States. ^[2]  

An estimated 34.2 million people—10.5% of the total United States population—have diabetes mellitus. However, 21.4% of all US adults who met laboratory criteria for diabetes were not aware of or did not report having diabetes. Of the estimated 88 million US adults with prediabetes, only 15.3% are aware of their condition; however, awareness of prediabetes doubled between 2005–2008 and 2013-2016. Diabetic nephropathy is the leading cause of chronic kidney disease in the US, and each year, over 58,000 people develop end-stage kidney disease (ESKD) with diabetes as the primary cause. ^[3]

This article focuses on SPK transplantation. For complete discussion of kidney transplantation, see Pediatric Kidney Transplantation and Kidney Transplantation.

In 2021, the United Network for Organ Sharing (UNOS) implemented a new system for matching kidney and pancreas transplant candidates with organs from deceased donors. Instead of distribution based on donation service area and Organ Procurement and Transplantation Network (OPTN) region, the new system uses the distance between the donor and transplant hospitals for each candidate. Kidney-pancreas transplants will be offered first to candidates listed at transplant hospitals within 250 nautical miles of the donor hospital. Offers not accepted for any of these candidates will then be made for candidates beyond the 250 nautical-mile distance. ^[4]

Forms of pancreas transplantation

A donor pancreas may be used for endocrine replacement therapy in one of the following ways:

1. Pancreas transplant alone (PTA): Indicated for patients with type 1 diabetes who have frequent episodes of hypoglycemia with or without unawareness, impaired quality of life, or other issues with insulin therapy tolerance. These patients have adequate kidney function and kidney transplantation is not indicated.

2. SPK transplant: The organs are from the same donor. The primary use has been in patients with type 1 diabetes who have an estimated glomerular filtration rate (eGFR) of < 20 mL/min/1.73 m² or are on renal replacement therapy, but patients with type 2 diabetes make up an increasing percentage of SPK transplant recipients. 

3. Pancreas after kidney transplant (PAK): Deceased donor pancreas transplantation after a previous kidney transplant; indications are similar to those for PTA ^[5]

4. Pancreatic islet cell transplantation: Offers lower morbidity but inferior long-term results compared with solid organ (pancreas) transplantation.

About 86% of pancreas transplantations are performed as an SPK transplantation. ^[2]  Approximately 10% of pancreas transplantations are performed as a PAK transplant after a previously successful kidney transplantation from a living or deceased donor. The remaining cases are performed as PTA. ^{[6, 7, 8, 9]}

Pancreas and islet transplantation can be considered complementary transplant options and undergoing one or the other is not mutually exclusive. In an analysis of 40 pancreas transplantations (50% PTA, 27.5% SPK, 22.5% PAK) after islet cell transplantation graft failure, overall survival rates  (97% at 1 year and 83% at 5 years) were not adversely affected. ^[10]  

Transplantation assessment testing

In evaluating a patient for SPK transplantation eligibility, the quantification of daily insulin requirement is used to determine the type of diabetes present, the severity of insulin resistance, and the possible benefit of pancreas transplantation. A highly insulin-resistant patient will have a high insulin requirement (> 1-1.5 units/kg) and a high fasting C-peptide level (> 4 ng/mL).  These patients might remain insulin dependent despite a pancreas transplant.

However, these values must be considered within the overall clinical picture. For example, a patient on peritoneal dialysis with dextrose-containing dialysate will have greater insulin requirements that will decrease once kidney transplantation eliminates the need for dialysis. C-peptide is not an exact marker in patients with chronic kidney disase, as it has varying clearance in these patients. In addition, in a patient who is taking insulin, the C-peptide level will be falsely low if the sample is drawn when the patient is hypoglycemic; thus, the C-peptide result must be interpreted in light of a concomitant glucose measurement.

Hemoglobin A1C should be measured, to assess the severity of the patient's diabetes. 

If the patient has a type 1 diabetes, consider baseline assessment of autoimmune markers, including antibodies against glutamic acid decarboxylase. A rise in the antibody level after pancreas transplantation would suggest possible pancreas graft dysfunction and hyperglycemia due to an autoimmune reaction as opposed to rejection. ^[11]

Indications and contraindications

The number of pancreas transplants has decreased every year since 2004, when approximately 1500 were performed; 135 pancreas transplants were performed in 2020. The most common multi-organ transplantation is kidney-pancreas, with nearly 23,000 performed between 1988 and 2017. ^[12]  In 2020, 827 SPK transplantations were performed. ^[13] Patients with type 2 diabetes make up an increasing proportion of SPK transplantations, accounting for 17% of cases in 2019. ^[2]

in July 2019, the Organ Procurement and Transplantation Network (OPTN) and the United Network of Organ Sharing (UNOS) made a proposal to change the allocation system and waiting time criteria for kidney-pancreas transplant candidates. The OPTN/UNOS proposal suggested removing body mass index (BMI) and C-peptide level from the waiting time criteria. ^[14]  The rationale behind these changes was that BMI is confusing and undermines transparency and that it was too restrictive for certain candidates with a high BMI. It was also concluded that the existing criteria were limiting access to transplantation for suitable candidates, particularly those from minority populations. 

As per the OPTN/UNOS guidelines, ^[14]  if a kidney-pancreas candidate is 18 years or older on the date the candidate is registered for a kidney-pancreas, then the candidate begins to accrue waiting time once the candidate has met all of the following conditions:

1. The candidate is registered for a kidney-pancreas
2. The candidate qualifies for kidney waiting time
3. The candidate is on insulin 

The following are the criteria for the specific type of pancreas transplant:

• PTA - Frequent, acute metabolic complications, including hypoglycemia or ketoacidosis; inability to tolerate exogenous insulin therapy; and persistence of acute complications despite insulin-based management
• SPK - ESKD and eligibility for pancreas transplant
• PAK - Pancreas transplant eligibility and a previous successful kidney transplant

The eligible patient will also have to undergo appropriate medical evaluation, in particular for cardiovascular risk stratification and peripheral vascular disease. They will also have to show a history of medical adherence. ^[15] The historical age limit for pancreas transplantation, which some centers have continued to employ, is 55 years. However, the number of pancreas transplant recipients older than 55 years has steadily increased. In 2019, 24.9% of all pancreas transplant recipients were older than 50 years (PTA: 33.3%, SPK: 24.5%, PAK: 22.8%). ^[2]  Patient survival is comparable for younger and older pancreas transplant recipients but older recipients have had more frequent cardiovascular events. ^[16] ​ 

Absolute contraindications, as follows, are similar to those for other solid organ transplantation:

• Excessive cardiovascular risk
• Active malignancy or infection that would have to be treated and cleared prior to transplant
• High social risk factors such as medication non-adherence, lack of insurance, and illicit drug use

Relative contraindications include the following:

• BMI > 30-35 kg/m ²
• Insulin requirement of >1.5 U/kg per day
• Cerebrovascular, aortic/iliac, cardiovascular, or peripheral vascular disease

Benefits of pancreas transplantation

The microvascular complications of diabetes are directly related to glucose concentration. Thus, normalizing glucose through successful pancreas transplantation might be expected to stabilize or reverse microvascular complications. The resulting benefits of pancreas and kidney transplantation are discussed below.

Diabetic retinopathy

Most pancreas transplantation candidates have had diabetes for 20-25 years on average prior to consideration for transplantation and consequently, many of them have had laser surgery for retinopathy. This was a common peritransplantation finding in most studies. The severity of these ophthalmologic changes may obviate a clear salutary effect of PTA or SPK transplantation on retinopathy.

Studies suggest, however, that retinopathy may improve 3 years after SPK and that the need for further laser surgery is less after SPK than kidney transplantation alone (KTA). It is thought that pancreas transplantation and maintaining a euglycemic state at minimum stabilizes diabetic retinopathy. Prospective trials are needed to compare the two groups, because most studies have lacked sufficient control groups. ^{[17, 18, 19]}

Diabetic nephropathy

Significant numbers of pancreas transplantation candidates have advanced renal disease. The most common scenario for pancreas transplantation is in combination with a kidney transplant to treat patients with diabetic uremia. SPK would help to prevent the deleterious effects of diabetes on the new kidney transplant. 

Studies comparing kidney function in SPK transplantation recipients versus diabetic KTA recipients did not demonstrate significant differences during the early posttransplant period. However, recurrent diabetic nephropathy is observed as early as 2 years after KTA in a diabetic recipient or upon failure of the pancreas graft after SPK but has never been reported with a functioning SPK transplant. ^[20]   Patients with a pancreas transplant have been shown to have delayed progresssion or reversal of diabetic nephropathy. ^[21]

Diabetic neuropathy

Neuropathy improves after both kidney and pancreas transplantation, suggesting that kidney failure and diabetes contribute to the sensory neuropathy commonly observed at the time of transplantation. Autonomic neuropathies such as gastroparesis takes years to develop and can be difficult to quantitate. However, objective improvement in autonomic neuropathic findings has been reported 4 years following SPK and is noted to be greater after SPK than after KTA. ^{[22, 23, 24, 25, 26]}

Cardiovascular disease

Cardiovascular disease is the most common cause of death in patients with diabetes with renal failure.  Few prospective studies have examined the relationship between the establishment of normoglycemia in patients with long-term diabetes and a reduction in cardiovascular morbidity and mortality. In one cross-sectional study, left ventricular ejection fraction was higher, peak filling rate to peak ejection rate ratio was greater, and endothelium-dependent dilatation of the brachial artery was improved in SPK recipients compared with type 1 diabetes patients who received KTA. ^{[27, 28, 29]}  Other evidence shows that SPK transplantation reduces cardiovascular death rates with concomitant reduction in blood pressure. ^[19]  

Another study observed a greater decrease in left ventricular mass and greater normalization of diastolic dysfunction in SPK recipients than in those who underwent KTA. In this report, 2-dimensional (2-D) and M-mode echocardiography was performed before and 1 year after transplantation in SPK and KTA recipients. ^[30]  A large, retrospective study suggested an association with reductions in the incidence of myocardial infarction, acute pulmonary edema, and hypertension in SPK versus KTA recipients. ^[31]

Coronary artery disease (CAD) is the most important comorbidity to consider in patients with type 1 diabetes and diabetic nephropathy. Patients with diabetes and ESKD are estimated to carry an estimated 50-fold greater risk for cardiovascular events than the general population. The prevalence of significant CAD (>50% stenosis) in patients with diabetes who are starting treatment for ESKD is estimated to be 45-55%. ^{[28, 32]}  Because of diabetic neuropathy, patients may not experience angina during episodes of myocardial ischemia.

Stroke and transient ischemic attack

Patients with ESKD and diabetes have an increased rate of strokes and transient ischemic attacks. Deaths related to cerebral vascular disease in patients with ESKD are approximately twice as common in those with diabetes as in those without diabetes. Strokes occur more frequently and at a younger age in patients with diabetes than in age- and gender-matched nondiabetic patients.

Peripheral vascular disease

Lower-extremity peripheral vascular disease is significant in patients with diabetes. Patients with ESKD are at risk for amputation of a lower extremity. These problems typically begin with a foot ulcer associated with advanced somatosensory neuropathy.

Autonomic neuropathy

Autonomic neuropathy is prevalent and may manifest as gastropathy, cystopathy, and orthostatic hypotension. The extent of diabetic autonomic neuropathy is often underestimated.

Impaired gastric emptying (gastroparesis) is an important consideration because of its significant implications for the posttransplant course. Patients with severe gastroparesis may have difficulty tolerating oral immunosuppressive medications that are essential to prevent rejection of the transplanted organs. Episodes of volume depletion with associated azotemia frequently occur in patients with SPK transplants. Gastrointestinal morbidity is a common indication for readmission following pancreas transplantation.

Neurogenic bladder dysfunction is an important consideration in patients undergoing bladder-drained pancreas-alone transplantation or SPK transplantation. Inability to sense bladder fullness and empty the bladder predisposes to high postvoid residuals and the possibility of vesicoureteral reflux. This may affect renal allograft function adversely, increase the incidence of bladder infections and pyelonephritis, and predispose to graft pancreatitis.

The combination of orthostatic hypotension and recumbent hypertension results from dysregulation of vascular tone. This has implications for blood pressure control following transplantation, especially in patients with bladder-drained pancreas transplants who are predisposed to volume depletion. Therefore, careful reassessment of the posttransplantation antihypertensive medication requirement is important. ^[27]

Sensory and motor neuropathies

These conditions are common in patients with longstanding diabetes. This may have implications for rehabilitation after transplantation. Peripheral neuropathy is also an indicator for increased risk of injury to the feet and subsequent diabetic foot ulcers.

Mental or emotional illnesses

Mental illnesses, including neurosis and depression, are common in the insulin-dependent diabetic population. Diagnosis and appropriate treatment of these illnesses prior to obtaining a pancreas transplantation can significantly enhance medical compliance.

Outcomes

Assessment of pancreas graft outcome rates has been hampered by lack of uniformity in the criteria for graft failure. Some programs do not report a failed graft if C-peptide production continues, whereas others report a graft failure if the recipient is no longer insulin independent. The OPTN/UNOS Pancreas Transplantation Committee has proposed the following more precise definitions for pancreas graft failure, which are currently pending implementation ^{[13, 33]} :

• Removal of the transplanted pancreas
• Re-registration for a pancreas transplant
• Registration for an islet transplant after receiving a pancreas transplant
• Insulin use of ≥0.5 units/kg/day for a consecutive 90 days
• Death of the recipient 

The number of recipients alive with a functioning pancreas allograft has contin­ued to rise over the past decade and exceeded 19,000 in 2019. Mortality has decreased consistently among all pancreas transplant groups as a result of safer and more effective immunosuppressive regimens. One-year mortality for PTA declined from 4.6% in 2012-2013 to 0.8% for transplants performed in 2014-2015. For SPK, the 5-year patient survival rates were similiar in patients with type 1 and type 2 diabetes (90.5% and 91.5% respectively), despite the older age and comorbidity associated with type 2 diabetes. This is likely due to selection of candidates with type 2 diabetes whose cardiovascular status can tolerate the high operative risks. ^[2]  

The greatest risk of graft loss is within the first year post-transplant and in particular the first 3 months, regardless of type of pancreas transplant.  The International Pancreas Transplant Registry data analyses have used independence from insulin as the main criteria for graft survival. The best SPK transplant pancreas graft survival rates have been 86% at one year and 73% at 5 years. SPK outcomes are superior to those with PAK and PTA transplantation.  An advantage of SPK transplantation is that acute rejection can be detected more easily, because serum creatinine can be used as a marker.

In PAK transplantation, 1-year and 5-year pancreas graft survival rates are 80% and 58%, respectively. For PTA, the comparable rates are 77% and 56%.

Acute rejection rates are similar for SPK and PAK at about 4% for each. The estimated half-life of grafts has improved over the years, with SPK lasting about 14 years, PAK 7 years, and PTA 7 years. ^{[5, 19]}

Pre-procedure planning

Criteria for pancreas donor selection include age and body mass index.  Donors are typically younger than 55 years of age and the body mass index should be less than 30 kg/m². 

The timing of allocation of the pancreas graft to a specific patient relative to the procurement of the organ has important implications. Determining donor human leukocyte antigen (HLA) typing, serologic testing, and immune compatibility testing prior to procurement of the organs is preferred.

In addition, the cold ischemia time of the pancreas prior to implantation is minimized. Pancreas allografts do not tolerate cold ischemia as well as kidney allografts. Ideally, the pancreas should be revascularized within 24 hours from the time of cross-clamping at procurement.

Finally, the transplant surgical team tries to minimize the warm and cold ischemic times. (See the image below.)

Surgical approach considerations

Technical concerns that must be considered in patients undergoing pancreas transplantation include whether the venous drainage should be placed into the systemic circulation or into the portal venous circulation. Another controversial topic is whether the exocrine secretions should be drained into the small bowel (enteric drainage) or into the bladder.

The surgical techniques for pancreas transplantation are diverse, and no standard methodology is used by all programs. The principles are consistent, however, and include providing adequate arterial blood flow to the pancreas and duodenal segment, adequate venous outflow of the pancreas via the portal vein, and management of the pancreatic exocrine secretions.

Pancreas graft arterial revascularization typically is accomplished using the recipient's right common or external iliac artery. A Y-graft (procured from a deceased donor's iliac arteries) of the pancreas is anastomosed end-to-side to the pancreas graft's superior mesenteric vein and splenic vein. Positioning of the head of the pancreas graft cephalad or caudad is not relevant with respect to successful arterial revascularization.

When the pancreas transplantation is performed simultaneously with kidney transplantation, it is not uncommon for the kidney transplantation to be performed first. However, a vast majority of short-term graft failures are secondary to technical complications. Implanting the pancreas first decreases the risk of early graft loss, especially when cold ischemia time is prolonged or time lag between kidney and pancreas revascularization is expected to be extended. If the surgeon chooses to implant the kidney first, time lag between graft revascularization should not exceed 2 hours. ^[34]

The kidney is conventionally placed on the recipient's left iliac vessels. Both organs may be transplanted through a midline incision and are placed intraperitoneally.

Two choices are available for venous revascularization in pancreas transplantations: systemic and portal. Approximately 15% of pancreas transplantations are performed with portal venous drainage, and the remainder are performed with systemic venous drainage. No clinically relevant differences in glycemic control have been shown with the two approaches.

Exocrine Drainage

Handling the exocrine drainage of the pancreas is the most challenging aspect of the transplantation procedure. Currently, enteric drainage is used in more than 80% of pancreas transplantations.

Enteric drainage of pancreas grafts is physiologic with respect to the delivery of pancreatic exocrine enzymes and bicarbonate into the intestines for reabsorption. Enterically drained pancreas grafts can be constructed with or without a Roux-en-Y enterostomy. The enteric anastomosis can be made side-to-side or end-to-side with the duodenal segment of the pancreas. Intra-abdominal abscess from leakage was an important complication of enteric-drained pancreas grafts, but with current management techniques the risk of intra-abdominal abscesses is extremely low.

Bladder drainage of the transplanted pancreas was a modification introduced in the mid-1980s. Although this technique minimizes the occurrence of intra-abdominal abscess, its potential complications include cystitis, urethritis, urethral injury, balanitis, hematuria, metabolic acidosis, and the frequent requirement for enteric conversion. Consequently, enteric drainage has effectively replaced bladder drainage in most centers.

Immunosuppression following SPK transplantation is similar to that used for other solid-organ transplantation. Immunosuppression is conduced in two phases, as follows:

1. Induction: Thymoglobulin or alemtuzumab for T-cell depletion to reduce the number and severity of biopsy-proven rejection episodes
2. Maintenance: Tacrolimus plus mycophenolate and, in some centers, steroids 

Other medications are rarely used in current practice. Cyclosporine and azathioprine have been replaced by tacrolimus and mycophenolate, respectively. Limited data exist on the use of mechanistic target of rapamycin (mTOR) inhibitors (eg, sirolimus, everolimus). 

For further discussion, see the Medication section of Kidney Transplantation. 

Surveillance for dysfunction in the transplanted organ is the critical purpose of graft monitoring. Rejection is always a possible diagnosis but in pancreas transplantation other possible etiologies of dysfunction must be considered, including graft thrombosis and pancreatitis (these are further discussed in Complications of Transplantation, below).

Adherence to the immunosuppressive regimen should be confirmed. Obviously, if the patient is failing to take the medications as prescribed, that should raise concern for rejection, depending on the clinical picture. 

Pancreas transplant dysfunction

If the serum amylase and lipase rise, the usual next step is imaging of the pancreas, including visualization of pancreatic blood flow (with CT scan or Doppler ultrasound) to evaluate for bleeding, mass effect, or loss of blood flow. If no significant findings are noted, check donor-specific antibodies and consider ultrasound-guided biopsy of the pancreas transplant. Of note, abdominal distension (as in constipation) can cause elevations of amylase and lipase as well; another important differential diagnosis is native pancreatitis.

Additional indications of pancreas transplant dysfunction include the following ^{[21, 19]} :

• In bladder-drained pancreas transplants, decreasing urinary amylase levels
• Rising serum amylase and lipase levels (may be elevated immediately post-transplant but will trend down afterwards)
• Hyperglycemia (usually a late finding)
• Donor-specific antibody elevation (an indication of rejection)
• In patients with type 1 diabetes, rising autoantibody levels—specifically, anti-glutamic acid decarboxylase—in the setting of hyperglycemia suggest pancreas transplant dysfunction due to an autoimmune process.

Perform a pancreas transplant biopsy if there is high suspicion of rejection. If this procedure is technically difficult, consider a kidney transplant biopsy even if transplant kidney function is unchanged.

Kidney transplant dysfunction

In patients with SPK transplants, more than 85% of rejection cases involve rejection of the kidney graft as well as the pancreas transplant. Indications of kidney transplant dysfunction are a rise in serum creatinine, proteinuria, or decreased urine output. To evaluate for kidney transplant dysfunction, perform the following:

• A routine  acute kidney injury workup, including for pre-renal, post-renal, and intra-renal causes
• Kidney transplant Doppler ultrasound to evaluate for obstruction and blood flow loss
• Infectious work-up as needed, including for BK virus nephropathy and adenovirus infection
• Immunosuppressive drug levels
• Consider ordering a donor-specific antibody panel, if concern for rejection is high
• Kidney transplant biopsy, for unexplained acute kidney injury or proteinuria or high suspicion of rejection

When rejection or significant dysfunction is found it is prudent to contact the transplant center responsible for the patient.

Transplantation-related complications

Surgical complications are more common after pancreas transplantation than kidney transplantation. Nonimmunologic complications of pancreas transplantation account for graft losses in 5-10% of cases. These occur commonly within 6 months of transplantation and are as important an etiology of pancreas graft loss in simultaneous pancreas-kidney (SPK) transplantation as is acute rejection.

Infectious complications are common after SPK transplantation. It is important to note that transplanted patients are usually screened for infections (in particular for BK virus, with kidney transplants) and are placed on prophylaxis for the first 3- 6 months or longer for cytomegalovirus, urinary tract infection, Pneumocystis jiroveci pneumonia, and oral thrush. 

Kidney transplant complications:

Kidney transplant complications include the following (surgical complications usually occur earlier on):

• Delayed or slow graft function after transplant  (may require dialysis)
• Renal artery or vein thrombosis
• Rejection (cell-mediated and/or acute antibody mediated)
• Obstruction
• Recurrence of disease (eg, focal segmental glomerulosclerosis)
• Lymphocele
• Urinoma
• Infection
• BK virus nephropathy
• Drug toxicity (in particular, calcineurin inhibitor toxicity)
• Transplant renal artery stenosis
• Transplant glomerular nephropathy
• Malignancy (most commonly, skin cancer)

Pancreas transplant complications

The following complications should be evaluated for when the patient presents with pain at the graft site and abnormal biochemistries including persistent hyperglycemia and/or elevated amylase or lipase levels.

Vascular thrombosis

Vascular thrombosis is a very early complication, typically occurring within 48 hours and usually within 24 hours of the transplantation. Most cases involve the pancreas portal vein. The etiology has not been entirely defined but is believed to involve reperfusion pancreatitis and the relatively low-flow state of the pancreas graft. Prudent selection of donor pancreas grafts, short cold-ischemia times, and meticulous surgical technique are all necessary to minimize graft thrombosis.  Pancreatectomy is usually indicated for the thrombosed pancreas allograft. ^[5]

Transplantation pancreatitis

Pancreatitis of the allograft occurs to some degree in all patients postoperatively. Elevation in serum amylase levels for 48-96 hours after transplantation is common. These episodes are transient and mild, without significant clinical consequence.

Interestingly, patients undergoing SPK transplantation commonly have a greater degree of fluid retention for several days after transplantation than do recipients of kidney transplantation alone (KTA). Although not proven, this may be related to postoperative graft pancreatitis. The retained fluid is mobilized early postoperatively. It is important to minimize the risk of delayed kidney-graft function by shortening cold-ischemia time, promoting prompt elimination of the retained third-spaced fluid, and avoiding an episode of heart failure or pulmonary edema.

Complications of enteric-drained pancreas transplantation

The most serious complication of the enteric-drained pancreas transplantation is leak and intra-abdominal abscess. This problem usually occurs 1-6 months after transplantation. Patients present with fever, abdominal discomfort, and leukocytosis. A high index of suspicion is required to make a swift and accurate diagnosis. Computed tomography (CT) scans are very helpful.

A critical decision in these cases is whether to attempt to eradicate the infection without removing the pancreas allograft. Incomplete eradication of the infection will result in progression to sepsis and multiple organ system failure. Peripancreatic infections can result in the development of a mycotic aneurysm at the arterial anastomosis that could cause arterial rupture. Transplantation pancreatectomy is indicated if mycotic aneurysm is diagnosed.

The incidence rate of intra-abdominal abscess has been reduced greatly with better recognition of the criteria for suitable cadaveric pancreas grafts for transplantation. Improved perioperative antibiosis, including antifungal agents, has contributed to the decreased incidence of intra-abdominal infection, as well. Perhaps the most significant contribution to reducing the incidence of intra-abdominal abscess has been the efficacy of immunosuppressive agents in reducing the incidence of acute rejection, thereby minimizing the need for intensive antirejection immunotherapy.

Gastrointestinal (GI) bleeding occurs in the enteric-drained pancreas from a combination of perioperative anticoagulation and bleeding from the suture line of the duodenoenteric anastomosis. This is self-limited and will manifest as a diminished hemoglobin level along with heme-positive or melanotic stool. Conservative management will often suffice; reoperative exploration is rarely needed.

Complications of bladder-drained pancreas transplantation

Bladder-drained pancreas transplantation is a safer procedure than enteric-drained pancreas transplantation with respect to the possibility of intra-abdominal abscess. However, it is hampered by numerous, albeit less morbid, complications.

Urine and pancreatic exocrine leakage

Urine and pancreatic exocrine leakage from breakdown of the duodenal segment can occur and is usually encountered within the first 2-3 months following transplantation (although it can occur years following transplantation). This is the most serious postoperative complication of the bladder-drained pancreas. Operative exploration and repair is usually required. The degree of leakage can be determined best intraoperatively, and proper judgment can be made whether direct repair is possible or more aggressive surgery, involving enteric diversion or graft pancreatectomy, is indicated.

Urinary tract infections and stone formation

Pancreas transplantation results in the excretion of approximately 500 mL of bicarbonate-rich fluid with pancreatic enzymes into the bladder each day. The resulting change in the bladder urine pH accounts, in part, for an increase in urinary tract infections.

In some cases, a foreign body, such as an exposed suture from the duodenocystostomy, acts as a nidus for urinary tract infections or stone formation.

Acute postoperative hematuria

Acute postoperative hematuria in patients with a bladder-drained pancreas transplant usually is due to ischemia/reperfusion injury to the duodenal mucosa or to a bleeding vessel on the suture line that is aggravated by the antiplatelet or anticoagulation protocols often initiated to minimize vascular thrombosis. These cases are self-limited but may require a change in bladder irrigations and, if severe, cystoscopy, to evacuate the clots. Occasionally, a formal open cystotomy and suture ligation of the bleeding vessel is necessary intraoperatively. If relatively late chronic hematuria occurs, transcystoscopic or formal operative techniques may be necessary.

Cystitis, urethritis, and balanitis

Sterile cystitis, urethritis, and balanitis may occur after bladder-drained pancreas transplantation. This is due to the effect of the pancreatic enzymes on the urinary tract mucosa and is experienced more commonly in male recipients. Urethritis can progress to urethral perforation and perineal pain. Conservative treatment with Foley catheterization and operative enteric conversion represent the extremes of the continuum of treatment.

Metabolic acidosis

Metabolic acidosis routinely develops as a consequence of bladder excretion of large quantities of alkaline pancreatic secretions. Patients must receive oral bicarbonate supplements to minimize the degree of acidosis. Because of the relatively large volume losses, patients also are at risk of episodes of dehydration exacerbated by significant orthostatic hypotension.

Reflux pancreatitis

Reflux pancreatitis can result in acute inflammation of the pancreas graft, mimicking acute rejection. It is associated with pain and hyperamylasemia and is believed to be secondary to reflux of urine through the ampulla and into the pancreatic ducts. Often, bacteria are found in the urine. This frequently occurs in a patient with neurogenic bladder dysfunction.

This complication is managed with Foley catheterization. Reflux pancreatitis will resolve quickly. The patient may require a complete workup of the cause of bladder dysfunction, including a pressure-flow study and voiding cystourethrogram. Interestingly, in older male patients, even mild hypertrophy of the prostate has been described as a cause of reflux pancreatitis. If recurrent graft pancreatitis occurs, enteric conversion may be indicated.

Rejection

An evaluation and treatment algorithm for pancreas transplant rejection is discussed elsewhere. ^[11]  The treatment of kidney transplant rejection is detailed in multiple reviews. ^{[35, 36]}  

If rejection is detected either in one or both the pancreas and kidney the patient is usually hospitalized and treated with intensive immunosuppressive therapy. ^[21]  Over 90% of pancreas rejection episodes are reversible in the absence of hyperglycemia. ^[5]