Pancreas Transplantation 

Updated: Dec 06, 2018
Author: Dixon B Kaufman, MD, PhD; Chief Editor: Ron Shapiro, MD 

Overview

Practice Essentials

The main purpose of pancreas transplantation is to ameliorate type 1 diabetes mellitus and produce complete independence from injected insulin. In addition, however, pancreas transplantation in patients with type 2 diabetes has increased steadily in recent years.[1] The pancreas is usually procured from a deceased organ donor, although select cases of living-donor pancreas transplantations have been performed. 

The number of pancreas transplants in the United States decreased every year from 2004 (when approximately 1500 were performed) to 2015. In 2016, pancreas transplants increased by 7.0% over the previous year, largely because of an increase in simultaneous pancreas-kidney (SPK) transplants.[1]  Of the 976 pancreas transplants performed in 2016; the majority (81.5%) were SPK transplantations, which is the most common multi-organ transplant performed in the United States; nearly 23,000 SPK transplantations performed between 1988 and 2017.[1, 2]   See image below.

Simultaneous pancreas-kidney transplantation with Simultaneous pancreas-kidney transplantation with enteric drainage. Illustrated by Simon Kimm, MD. Image courtesy of Landes Bioscience.

Pancreas transplantations are also performed after a previously successful kidney transplantation. This is referred to as a pancreas-after-kidney (PAK) transplantation and represented 11% of pancreas transplants in 2016.[1] The remaining cases are performed as pancreas transplantation alone (PTA) in nonuremic patients with very labile and problematic diabetes.  

An alternative therapy that may also ameliorate diabetes is islet cell transplantation. Pancreas and islet cell transplantation can be considered complementary transplant options and undergoing one or the other is not mutually exclusive. In an anlysis 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.[3]   

Background

Experiments in pancreas transplantation began long before the discovery of insulin. In 1891, pieces of dog pancreas autotransplanted beneath the skin prevented diabetes after removal of the intra-abdominal pancreas. Subsequent experimentation with intrasplenic transplantation did not succeed because of graft necrosis. In 1916, sliced human pancreas was transplanted into 2 patients, but the grafts were completely absorbed. The first pancreatic xenotransplantation was performed in 1893 in London; a 15-year-old boy underwent subcutaneous implantation of a pancreas.

Despite extensive animal experimentation, pancreatic transplantation did not become a reality until 1966, when W.D. Kelly performed the first human, whole-organ pancreatic transplantation for treatment of type 1 diabetes mellitus. Because of poor outcomes, few procedures were performed until 1978. Much of the early work was performed by Sutherland and colleagues at the University of Minnesota. With improved immunosuppressive regimens and newer surgical techniques, the 1980s ushered in a new era in pancreas transplantation.[4]  According to the International Pancreas Transplant Registry, nearly 10,000 pancreatic transplantations were recorded by 1998.

Most of the pancreatic transplantations have been performed in patients with type 1 diabetes mellitus and a lack of insulin production.[5, 6] The most common indication is renal failure; therefore, the pancreas transplantation is typically performed simultaneously with a kidney transplantation.[7, 8, 9, 10]  In some patients with hypoglycemic unawareness or other diabetic complications, isolated pancreas transplantation has been performed. However, the results have been somewhat inferior to those of the combined procedure.

Various technical concerns must be considered in patients undergoing pancreas transplantation, including whether or not the venous drainage should be into the systemic circulation or into the portal vein.[4]  Another controversial topic is whether the exocrine secretions should be drained enterically or into the bladder as initially described. The complications of graft pancreatitis and bladder leakage that plagued early experiences with pancreas transplantation have largely been resolved as a result of both better technical expertise and fewer rejection- and immunosuppression-related complications.

Pathophysiology

Type I diabetes mellitus is an autoimmune disease wherein the insulin-producing pancreatic beta cells are destroyed selectively. Presently, no practical mechanical insulin-delivery method exists that, coupled with an effective glucose-sensory device, replaces pancreatic insulin secretion well enough to produce a near constant euglycemic state without risk of hypoglycemia. Therefore, individuals with type I diabetes must resign themselves to manual regulation of blood glucose levels by subcutaneous insulin injection and, as a consequence, typically exhibit wide deviations of plasma glucose levels from hour to hour and from day to day.

Hyperglycemia is the most important factor in the development and progression of the secondary complications of diabetes. These observations, and the fact that conventional exogenous insulin therapy cannot prevent the development of secondary complications of type I diabetes, have led to a search for alternative methods of treatment.

One such treatment, pancreas transplantation, has the potential to achieve better glycemic control and alter the progression of long-term complications. A successful pancreas transplantation produces a normoglycemic and insulin-independent state. It reverses the diabetic changes in the native kidneys of patients with very early diabetic nephropathy, prevents recurrent diabetic nephropathy in patients undergoing an SPK transplantation, reverses peripheral sensory neuropathy, stabilizes advanced diabetic retinopathy, and significantly improves patients' quality and quantity of life.

The insulin released by the endocrine pancreas graft is secreted into the blood stream. Because the exocrine pancreas produces about 800-1000 mL per day of fluid, it must be diverted in either the bladder or bowel. If the pancreas graft is attached to the bladder, the losses of pancreatic fluid rich in bicarbonate may produce relative acidosis. This usually is treated by bicarbonate supplementation. Because the pancreas graft comes from another individual, the recipient's immune system can mount a rejection reaction and destroy the graft. To prevent that problem, immunosuppression medications must be taken daily and forever to prevent rejection. Chronic immunosuppression elevates the risk of viral and fungal infections and some types of malignancy.

Epidemiology

An estimated 30.3 million people in the United States have diabetes and over 50,000 individuals annually develop end-stage renal disease with diabetes as the primary cause.[11]   Although nearly 2500 candidates were on the waitlist for pancrease transplant (15% PTA, 70% SPK, 15% PAK) at the end of 2016, less than 1000 pancreas transplantations are performed each year.[1] The number of transplants is limited by the number of donor organs available for transplantation. See Tables 1 below for a breakdown of patient characteristics.

Table 1. Characteristics of adult recepients of pancreas transplantation, United States, 2016 [1] (Open Table in a new window)

Patient Characteristic

 

All Candidates

PAK PTA SPK
  Number  PCT Number  PCT Number  PCT Number  PCT

Age 18-34 y

232

23.8%

16 21.6% 28 26.2% 188 23.6%

Age 35-49 y

504

51.6%

39 52.7% 38 35.5% 427 53.7%

Age 50-60 y

221

22.6%

18 24.3% 37 34.6% 166 20.9%

Age > 60 y

19

1.9%

1 1.4% 4 3.7% 14 1.8%

Male

571

58.5%

44 59.5% 49 45.8% 478 60.1%

Female

405

41.5%

30 40.5% 58 54.2% 317 39.9%

White

599

61.4%

54 73.0% 96 89.7% 449 56.5%

Black

217

 

22.2%

7 9.5% 2 1.9% 208 26.2%

Hispanic

127

13.0%

11 14.9% 7 6.5% 109 13.7%

Asian

21

2.2%

2 2.7% 1 0.9% 18 2.3%
Other 12 1.2% 0 0% 1 0.9% 11 1.4%
All recipients 976 100% 74 7.5% 107 11.0% 795 81.5%

Prognosis

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 provided more precise definitions for pancreas graft failure and implementation should take place in  2018.[1]

Nevertheless, the number of recipients alive with a functioning pancreas allograft has contin­ued to rise over the past decade and exceeded 18,000 in 2016. Mortality has decreased consistently among all pancreas transplant groups as a result of safer and more effective immunosuppressive regimens. One-year mortality for PTA increased from 95.4% in 2012-2013 to 99.2% for transplants performed in 2014-2015. For SPK, the 5-year 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.[1]

In one published retrospective study, differences in mortality were examined in consecutive patients with diabetes who were older than 50 years compared with well-matched recipients younger than 50 years undergoing pancreas transplantation (the majority were simultaneous kidney-pancreas transplants) at a high-volume European center. Despite US data suggesting an increased risk of mortality in recipients older than 45 years compared with patients younger than 45 years, it is becoming clear that carefully selected patients with diabetes who are older than 50 years can undergo successful pancreas transplantation with similar patient and allograft survival outcomes.[12]  This trend toward considering pancreas transplantation in older recipients appears to have begun earlier in the United States and is now gaining momentum in Europe as well, as evidenced in this study. It must be emphasized that careful cardiac evaluation is essential to this process of patient selection.

Effect of pancreas transplantation on secondary complications of diabetes

Recipients of successful pancreas transplantation maintain normal plasma glucose levels without the need of exogenous insulin therapy. This results in normalization of glycosylated hemoglobin levels and a beneficial effect on many secondary complications of diabetes. The durability of the transplanted endocrine pancreas has been established with the demonstration that normalization of glycosylated hemoglobin is maintained as long as the allograft functions. The potential lifespan of the transplanted pancreas is not known precisely because, at present, survivors with functioning pancreas transplantations still are doing well more than 16 years after transplantation. The implications of prolonged normalization of glycemia and glycosylated hemoglobin levels are significant with respect to patients' quality of life, kidney structure, and motor-sensory and nerve function.

One long-term follow-up study of 15 years showed that pancreas transplantation in patients with type 1 diabetes mellitus and end-stage renal failure has long-term functional viability. However, some deterioration in pancreas function should be expected, as shown in oral glucose tolerance test results.[13]

The quality of life of pancreas transplantation recipients has been well studied. Patients with a functioning pancreas graft describe their quality of life and rate their health significantly more favorably than those with nonfunctioning pancreas grafts. Satisfaction encompasses not only the physical capacities but also relates to psychosocial and vocational aspects. The functioning pancreas graft leads to even better quality of life when compared to recipients of kidney transplantation alone.[14, 15]  Virtually all patients with a successful pancreas transplantation report that managing their life, including immunosuppression, is much easier since the transplantation. Successful pancreas transplantation will not elevate all patients with diabetes to the level of health and functioning of the general population, but transplant recipients consistently report a significantly better quality of life than do patients who remain diabetic.

The development of diabetic nephropathy in transplanted kidneys residing in patients with type I diabetes has been well established. Marked variability is observed in the rate of renal pathology, including mesangial expansion and a widening of the glomerular basement membrane, in patients with type I diabetes and kidney transplantation alone. The onset of pathological lesions can be detected within a few years of kidney transplantation. Clinical deterioration of renal allograft function can lead to loss 10-15 years after transplantation.

A successful pancreas transplantation prevents glomerular structure changes of kidney allografts in patients with type I diabetes. This has been observed in transplanted kidneys of patients undergoing SPK transplantation, as well as in kidneys of recipients undergoing pancreas after kidney transplantation. These studies provide evidence of the efficacy of normalizing blood glucose and glycosylated hemoglobin levels to prevent the progression of diabetic glomerulopathy in renal allografts.

Furthermore, successful pancreas transplantation will halt or reverse the pathology in the native kidneys of patients with type I diabetes and very early proteinuria. Pancreas transplantation recipients all had persistently normal glycosylated hemoglobin values after transplantation for 5-10 years. The thickness of the glomerular and tubular basement membranes and mesangial volume steadily decrease over a 10-year interval. These early studies have important implications for the role of pancreas transplantation alone in patients with type I diabetes and very early changes in native renal function.

Successful pancreas transplantation has been shown to halt, and in many cases, reverse motor-sensory and autonomic neuropathy 12-24 months after transplantation. This has been studied most extensively in recipients of SPK transplantations. This raises the possibility that improvement of diabetic neuropathy occurs, in part, because of improvement of uremic neuropathy. However, pancreas transplantation alone in preuremic patients also has been shown to result in improvement in diabetic neuropathy. Many patients express subjective improvements of peripheral sensation 6-12 months after pancreas transplantation. Very interestingly, the effect of reversal of autonomic neuropathy in patients with type I diabetes with pancreas transplantation has been associated with better patient survival rates than patients with failed or no transplantation.

Pancreas transplantation does not have an immediate dramatic beneficial effect on preestablished diabetic retinopathy. Retinopathy appears to progress for at least 2 years following transplantation of the pancreas, but it begins to stabilize in 3-4 years compared to diabetic recipients of kidney transplantation only. Longer-term studies of 5-10 years, similar to those described above, have not been reported.

 

Presentation

History

Evaluation of candidates for pancreas transplantation involves the following:

Renal disease

Preexisting advanced renal disease is observed in significant numbers of pancreas transplantation candidates. Therefore, coincident extrarenal disease should be assumed present.

Diabetic retinopathy

Diabetic retinopathy is a ubiquitous finding in patients with diabetes and end-stage renal disease (ESRD). Significant vision loss may be observed. Also, patients may be overtly blind. Blindness is not an absolute contraindication to transplantation because many blind patients lead very independent lives. Although rarely a problem, confirm that a patient with significant vision loss has an adequate support system to ensure help with travel and immunosuppressive medications.

Gastroparesis

Impaired gastric emptying (gastroparesis) is an important consideration because of its significant implications in the posttransplantation course. Patients with severe gastroparesis may have difficulty tolerating oral immunosuppressive medications that are essential to prevent rejection of the transplants. Episodes of volume depletion with associated azotemia frequently occur in patients with SPK transplants. Patients typically require careful treatment, including motility agents such as metoclopramide, cisapride, or erythromycin.

Coronary artery disease

The most important comorbidity to consider in patients with type I diabetes with diabetic nephropathy is coronary artery disease (CAD). Patients with diabetes and ESRD are estimated to carry a nearly 50-fold greater risk of cardiovascular events than the general population. This type of patient may have several risk factors in addition to diabetes for development of CAD, including hypertension, hyperlipidemia, and smoking. Because of neuropathy associated with diabetes, patients may have asymptomatic myocardial ischemia-induced angina. The prevalence of significant (>50% stenosis) CAD in patients with diabetes who are starting treatment for ESRD is estimated to be 45-55%.

Stroke

Patients with ESRD and diabetes also experience an increased rate of strokes and transient ischemic attacks. Deaths related to cerebral vascular disease are approximately twice as common in patients with diabetes compared to patients without diabetes once ESRD has occurred. Patients with diabetes experience strokes more frequently and at a younger age than do age- and gender-matched nondiabetic patients with stroke.

Peripheral vascular disease

Lower extremity peripheral vascular disease is significant in patients with diabetes. Patients with ESRD 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 commonly is underestimated.

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.

Sensory and motor neuropathies

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

Mental or emotional illnesses

Mental illnesses, including neuroses and depression, are common. Diagnosis and appropriate treatment of these illnesses is an important pretransplantation consideration, with important implications for ensuring a high degree of medical compliance.

 

Workup

Approach Considerations

The emphasis of the pretransplantation evaluation should be to identify and treat all coexisting medical problems that may increase the rate of morbidity and mortality of the surgical procedure and adversely impact the posttransplantation course. In addition to a thorough medical evaluation, the social issues of the patient should be evaluated to determine conditions that may jeopardize the outcome of transplantation, such as financial and travel restraints or a pattern of noncompliance.

A complete cardiac workup, including angiography, is not necessary in every patient. However, individuals with a significant cardiac history, positive review of systems, type I diabetes, or hypertensive renal disease should undergo a complete evaluation to rule out significant coronary artery disease. A 12-lead ECG may be needed prior to transplantation.

Determining donor human leukocyte antigen (HLA) typing, serologies, and crossmatch results with patients on the pancreas transplantation waiting list will permit the ideal situation of allocating the cadaveric pancreas (plus kidney, with SPK transplantation) prior to procurement of the organs. 

The timing of allocation of the pancreas to a specific patient relative to the procurement of the organ has important implications. Prior allocation allows the transplantation center performing the pancreas transplantation the choice to procure the pancreas as well. It allows patients to be admitted to the hospital and the reevaluation process to begin simultaneously with the procurement of organs, rather than sequentially. 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, prior allocation also allows identification of 0-antigen mismatched donor-recipient pairs before procurement, which minimizes cold-ischemia time if the organs need to be transported across country.

Laboratory Studies

Laboratory studies should include blood chemistries, liver function tests, CBC count, coagulation profile, urinalysis, urine culture, and cytospin (when indicated).  C-peptide level confirms that transplantation candidate has type I diabetes. In addition, test for the following infections: 

  • Hepatitis B and Hepatitis C serologies

  • Cytomegalovirus (CMV) serologies (immunoglobulin M/immunoglobulin G [IgM/IgG])

  • Epstein-Barr virus serologies (IgM/IgG)

  • Varicella-zoster serologies (IgM/IgG)

  • Rapid plasma reagin (syphilis)

  • HIV serology

  • Purified protein derivative (tuberculosis skin test with anergy panel, when indicated)

Imaging Studies

Imaging studies performed in the pretransplantation evaluation are chest radiography (posteroanterior and lateral) and exercise/dipyridamole thallium scintigraphy. If indicated, coronary arteriography and/or stress cardiac ultrasonography may also be performed.

Other Tests

 

 

 

Treatment

Surgical Care

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. The native pancreas is not removed. Pancreas graft arterial revascularization typically is accomplished using the recipient right common or external iliac artery. The Y-graft of the pancreas is anastomosed end-to-side. 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. The kidney is based on the recipient left iliac vessels. Both organs may be transplanted through a midline incision and placed intraperitoneal.

Occasionally, considering placement of pancreas transplantation based on the left iliac vessels is necessary because of previously placed kidney transplantation on the right side. In this sequential pancreas-after-kidney transplantation procedure, the intra-abdominal approach is used. Mobilization of the left iliac vessels medial to the sigmoid colon is somewhat more challenging.

Most programs have had good experience with enteric drainage of the pancreas transplantation alone. Markers for rejection include clinical signs and symptoms of pancreas graft pancreatitis and measurement of serum amylase or lipase levels coupled with biopsy. The pancreas is sometimes drained into the bladder if a pancreas transplantation alone or pancreas-after-kidney transplantation is performed in order to measure urinary amylase levels as a method of detecting rejection.

Two choices are available for venous revascularization—systemic and portal. No clinically relevant difference in glycemic control has been documented. Currently, approximately 15% of pancreas transplantations are performed with portal venous drainage and the remainder with systemic venous drainage.

Systemic venous revascularization commonly involves the right common iliac vein or the right external iliac vein following suture-ligation and division of the hypogastric veins.

If portal venous drainage is used, dissecting out the superior mesenteric vein (SMV) at the root of the mesentery is necessary. The pancreas portal vein is anastomosed end-to-side to a branch of the SMV. This may influence the methodology of arterial revascularization using a long Y-graft placed through a window in the mesentery to reach the right common iliac artery. Portal venous drainage of the pancreas is more physiologic with respect to immediate delivery of insulin to the recipient liver. This results in diminished circulating insulin levels relative to that in systemic venous-drained pancreas grafts.

Handling the exocrine drainage of the pancreas is the most challenging aspect of the transplantation procedure. Several methods exist. Very few programs use duct injection. Pancreatic exocrine drainage is handled by means of anastomosis of the duodenal segment to the bladder or anastomosis to the small intestine. Currently, approximately 80% of pancreas transplantations are performed with enteric drainage; the remaining 20% are performed with bladder drainage.

See the images below.

Solitary pancreas transplantation with enteric dra Solitary pancreas transplantation with enteric drainage. Illustrated by Simon Kimm, MD. Image courtesy of Landes Bioscience.
Solitary pancreas transplantation with bladder dra Solitary pancreas transplantation with bladder drainage. Illustrated by Simon Kimm, MD. Image courtesy of Landes Bioscience.

The bladder-drained pancreas transplantation was a very important modification introduced in about 1985. This technique significantly improved the safety of the procedure by minimizing occurrence of intra-abdominal abscess from leakage of enteric-drained pancreas grafts.

With the successful application of the new immunosuppressant agents and the reduction of the incidences of rejection, enteric drainage of the pancreas transplantations has enjoyed a successful rebirth. Enteric drainage of pancreas grafts is physiologic with respect to the delivery of pancreatic enzymes and bicarbonate into the intestines for reabsorption. Enterically drained pancreases can be constructed with or without a Roux-en-Y. The enteric anastomosis can be made side-to-side or end-to-side with the duodenal segment of the pancreas. The risk of intra-abdominal abscesses is extremely low, and avoidance of the bladder-drained pancreas has significant implications with respect to the potential complications that include the following: bladder infection, cystitis, urethritis, urethral injury, balanitis, hematuria, metabolic acidosis, and the frequent requirement for enteric conversion.

Medical Care

Immunosuppression must be taken for as long as the patient's transplanted organs are functioning. Immunosuppression cannot be stopped, or rejection of the organs will ensue. 

Transplantation outpatient follow-up care

During hospitalization, transplant recipients are prepared for discharge with respect to expectations of medical compliance, education about the pharmacology of their new immunosuppression medications, and lifestyle issues. Patients usually are provided a booklet that delves into the above-mentioned topics.

Following successful pancreas transplantation, no dietary restrictions are required. In fact, the diet can be liberalized to include virtually anything because blood sugar control is restored to normal.  Extreme contact sports probably should be avoided to prevent accidental trauma to the newly placed intra-abdominal organs.

Typical visit schedule following discharge from the hospital is as follows:

  • Two or 3 visits in week 1

  • Two visits in week 2

  • One visit in week 3

  • Monthly thereafter, until 6 months posttransplantation

  • Every 3 months through the first year

  • Every 6 months through the second year

  • Annually thereafter

Laboratory follow-up studies occur in the transplantation clinic and at a local laboratory near the patient's home. A typical schedule is as follows:

  • Every Monday, Wednesday, and Friday in month 1

  • Every Monday and Thursday in month 2

  • Every Monday in months 3-6

  • Every other week in months 7-24

  • Every month after 24 months

Typical laboratory evaluation includes complete blood count, electrolytes, BUN, creatine, glucose, serum amylase, and immunosuppression blood levels (if transplantation recipient is receiving cyclosporine, tacrolimus, or sirolimus).

Complications

Rejection

The first criteria for the diagnosis of acute cell-mediated allograft rejection (ACMR) were established in 2008. At the time, only tentative criteria for the diagnosis of antibody-mediated rejection (ABMR) were characterized. Since then, the criteria have been reviewed and updated approximately every two years to account ongoing advances in the understanding of ABMR.[16]

Surgical and nonimmunological complications of pancreas transplantation

Surgical complications are more common after pancreas transplantation as compared to kidney transplantation. Nonimmunological 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 SPK transplantation as acute rejection is.

Thrombosis

Vascular thrombosis is a very early complication, typically occurring within 48 hours and usually within 24 hours of the transplantation.[8]  This generally is due to venous thrombosis of the pancreas portal vein. The etiology is not defined entirely but is believed to be associated with 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.

Transplantation pancreatitis

Pancreatitis of the allograft occurs to some degree in all patients postoperatively. Temporary 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 simultaneous kidney-pancreas transplantation commonly have a greater degree of fluid retention for several days after transplantation, as compared to a recipient of a kidney transplant alone. Though not proven, this may be related to the graft pancreatitis that ensues in the perioperative period. The retained fluid is mobilized early postoperatively. It is important to minimize the risk of delayed kidney graft function by shortening cold-ischemia time so that the retained third-spaced fluid may be eliminated rapidly to avoid an episode of heart failure or pulmonary edema.

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 less morbid complications. The pancreas transplantation eliminates approximately 500 mL of richly bicarbonate fluid with pancreatic enzymes into the bladder each day. Change in pH level of the bladder accounts, in part, for a greater 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 of the bladder-drained pancreas 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 to minimize vascular thrombosis. These cases are self-limited but may require change in bladder irrigations and, if severe, cystoscopy to evacuate the clots. Occasionally, performing 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 treatments.

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 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 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, the urine is found to be infected with bacteria. This frequently occurs in a patient with neurogenic bladder dysfunction. This complication is managed by 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.

Urine leak from breakdown of the duodenal segment can occur and is usually encountered within the first 2-3 months following transplantation but can occur years following transplantation. This is the most serious postoperative complication of the bladder-drained pancreas. The onset of abdominal pain with elevated serum amylase, which can mimic reflux pancreatitis or acute rejection, is a typical presentation. A high index of suspicion for urinary leak is necessary to make the diagnosis accurately and swiftly. Supporting imaging studies using a cystogram or CT scan are necessary to confirm the diagnosis. Operative repair is usually required with exploration. 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 even graft pancreatectomy is indicated.

Complications of enteric-drained pancreas transplantation

The most serious complication of the enteric-drained pancreas transplantation is leak and intra-abdominal abscess. This serious 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. Imaging studies involving CT scan are very helpful.

Percutaneous access of intra-abdominal fluid collection for Gram stain and culture is essential. The flora typically is mixed with bacteria and often fungus, particularly Candida. Broad-spectrum antibiosis is essential. Surgical exploration and repair of the enteric leak is necessary. A decision must be made on whether the infection can be eradicated 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 development of a mycotic aneurysm at the arterial anastomosis that could cause arterial rupture. Transplantation pancreatectomy is indicated if mycotic aneurysm is diagnosed.

Occurrence of intra-abdominal abscess has been reduced greatly with greater 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. No convincing evidence exists that a Roux-en-Y intestinal reconstruction decreases its incidence. Perhaps the most significant contribution to reducing the incidence of intra-abdominal abscess is the efficacy of the immunosuppressive agents in reducing the incidence of acute rejection and thereby minimizing the need for intensive antirejection immunotherapy.

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 diminished hemoglobin level associated with heme-positive or melanotic stool. Conservative management will suffice; the necessity for reoperative exploration is extremely unusual.

 

Guidelines

Guidelines Summary

Banff pancreas allograft rejection grading schema

In 2017, an update to the Banff pancreas allograft rejection grading schema was published. [16]  The current criteria are outlined below.

Normal criteria are as follows:

  • Absent inflammation  or inactive septal, mononuclear inflammation not involving ducts, veins, arteries, or acini
  • No graft sclerosis
  • The fibrous component is limited to normal septa, and its amount is proportional to the size of the enclosed structures (ducts and vessels). The acinar parenchyma shows no signs of atrophy or injury

When septal inflammation appears active, but the overall features do not fulfill the criteria for mild acute rejection, rejection is deemed indeterminate.

Acute T cell–mediated rejection (TCMR) has three grades. Criteria are as follows:

Grade I - Mild acute TCMR: Active septal inflammation (activated blastic lymphocytes and/or eosinophils) involving septal structures: venulitis (subendothelial accumulation of inflammatory cells and endothelial damage in septal veins), ductitis (epithelial inflammation and damage of ducts) and/or f ocal acinar inflammation (two or fewer foci per lobule) with absent or minimal acinar cell injury.

Grade II - Moderate acute TCMR: Multifocal (but not confluent or diffuse) acinar inflammation (three or more foci per lobule) with spotty (individual) acinar cell injury and dropout and/or mild intimal arteritis 

Grade III - Severe acute TCMR: Diffuse (widespread, extensive) acinar inflammation with focal or diffuse multicellular/confluent acinar cell necrosis and/or moderate or severe intimal arteritis and/or transmural inflammation-necrotizing arteritis

The diagnostic criteria for acute/active antibody‐mediated rejection (ABMR) are as follows:

  • Histologic evidence of acute tissue injury
  • C4d positivity in interacinar capillaries (≥1% of acinar lobular surface for immunohistochemistry)
  • Serologic evidence of DSA (HLA or other antigens)

Histologic evidence is categorized into three grades as follows:

  • Mild acute ABMR: Well‐preserved architecture, mild interacinar monocytic‐macrophagic or mixed (monocytic‐macrophagic/neutrophilic) infiltrates with rare acinar cell damage (swelling, necrosis)
  • Moderate acute ABMR: Overall preservation of the architecture with interacinar monocytic‐macrophagic or mixed (monocytic‐macrophagic/neutrophilic) infiltrates, capillary dilatation, interacinar capillaritis, intimal arteritis, a congestion, multicellular acinar cell dropout, and extravasation of red blood cells
  • Severe acute ABMR: Architectural disarray, scattered inflammatory infiltrates in a background of interstitial hemorrhage, multifocal and confluent parenchymal necrosis, arterial and venous wall necrosis, transmural/necrotizing arteritis, a and thrombosis (in the absence of any other apparent cause)

ABMR is diagnosed when all three diagnostic criteria are met.  If only 2 criteria are present, the diagnosis may be considered. ABMR is excluded if only one criteria is met.

 

Medication

Medication Summary

All pancreas transplant recipients require life-long immunosuppression to prevent a T-cell alloimmune rejection response. The Food and Drug Administration (FDA) has approved several new immunosuppressive agents, and several others currently are in clinical trials.

Two broad classifications of immunosuppressive agents exist—intravenous induction/antirejection agents and maintenance immunotherapy agents. No consensus exists as to the single best immunosuppressive protocol, and each transplant program utilizes various combinations of agents slightly differently.

The goals are to prevent acute or chronic rejection, minimize drug toxicity, minimize rates of infection and malignancy, and achieve the highest possible rates of patient and graft survival.

Immunosuppressant agents for induction immunotherapy

Class Summary

Induction immunotherapy consists of a short course of intensive treatment with intravenous agents. Antilymphocyte antibody induction therapeutic agents are varied and include polyclonal antisera, mouse monoclonals, and so-called humanized monoclonals. Polyclonal antisera, such as antilymphocyte globulin (ALG), antilymphocyte serum (ALS), and antithymocyte globulin (ATG) are equine, goat, or rabbit antisera directed against human lymphoid cells. The effects significantly lower and almost abolish circulating lymphoid cells critical to rejection response.

The agents are very effective at prophylaxis against early acute rejection, which is especially beneficial in managing the recipient with delayed graft function. The agents provide an effective immunologic cover during a period where the calcineurin inhibitors either are delayed or administered in subtherapeutic doses until graft function improves. Induction agents are used less often if immediate graft function occurs, such as recipients of living kidney donors, especially HLA-ID grafts.

Basiliximab (Simulect)

Chimeric monoclonal antibody that specifically binds to and blocks the IL-2 receptor on the surface of activated T cells.

Antithymocyte globulin, rabbit (Thymoglobulin)

A purified immunoglobulin solution produced by the immunization of rabbits with human thymocytes is used to treat acute rejection.

Alemtuzumab (Campath)

A humanized monoclonal antibody against the CD52 antigen. The anti-CD52 antibody induces lympholysis from complement-mediated lysis or other effector mechanisms.

Maintenance immunosuppression agents

Class Summary

Several immunosuppressive agents currently are in use for maintenance immunotherapy in kidney transplant recipients. Optimal maintenance immunosuppressive protocol has not been developed. Maintenance immunosuppressive agents are required for life.

Prednisone (Sterapred)

Immunosuppressant for treatment of autoimmune disorders. May decrease inflammation by reversing increased capillary permeability and suppressing PMN activity.

Azathioprine (Imuran)

Active component of azathioprine is 6-mercaptopurine. Acts as purine analog that interacts with DNA and inhibits lymphocyte cell division.

Mycophenolate (CellCept, Myfortic)

Inhibitor of enzyme inosine monophosphate dehydrogenase (IMPDH). Results in inhibition of lymphocyte proliferation. Used for prophylaxis of organ rejection in patients receiving allogeneic renal allografts.

Cyclosporine (Sandimmune, Neoral)

Calcineurin inhibitors that diminish IL-2production in activated T cells. These agents bind to the intracellular immunophilin cyclophilin, interfering with the action of calcineurin, which inhibits nuclear translocation of the nuclear factor of activated T cells (NFAT).

Tacrolimus (Prograf)

Calcineurin inhibitor that diminishes IL-2 production in activated T cells. Binds to intracellular immunophilin, FKBP, interfering with the action of calcineurin, which inhibits nuclear translocation of the NFAT. FDA approved for prophylaxis of organ rejection in patients receiving allogeneic renal allografts.

Sirolimus (Rapamune)

Inhibits lymphocyte proliferation by interfering with signal transduction pathways. Binds to immunophilin FKBP to block action of mTOR. FDA approved for prophylaxis of organ rejection in patients receiving allogeneic renal allografts.