Kidney-Pancreas Transplantation

Updated: Aug 03, 2015
  • Author: Edgar V Lerma, MD, FACP, FASN, FAHA, FASH, FNLA, FNKF; Chief Editor: Ron Shapiro, MD  more...
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Overview

Overview

Background

The purpose of pancreas transplantation is to ameliorate insulin-dependent type 1 diabetes and produce complete independence from injected insulin. [1] In 2012, approximately 1.25 million individuals in the United States had type 1 diabetes. [2] The first successful pancreas transplantation was performed in 1966, simultaneously with kidney graft. (See the image below.)

Kidney-pancreas allograft placement Kidney-pancreas allograft placement

Until about 1990, the procedure was considered experimental. Now it is widely accepted as standard of care, with virtually all insurance providers covering the procedure, including Medicare. The pancreas most commonly is procured from a deceased organ donor. However, select cases of living-donor pancreas transplantations have been performed.

About 100 transplant centers in the United States perform pancreas transplantations. The number of pancreas transplants has decreased every year since 2004, when approximately 1500 were performed; 1043 pancreas transplants were performed in 2012. However, the percentage of pancreas transplants performed as part of a multi-organ transplant has increased since 2004. The most common multi-organ transplant was kidney-pancreas transplant. [3]

About 75% of pancreas transplantations are performed simultaneously with a kidney transplantation from the same deceased donor. These are placed into insulin-dependent diabetics with end-stage renal disease (ESRD). [4] About 15% of pancreas transplantations are performed after a previously successful kidney transplantation from a living or deceased donor. This is referred to as a pancreas-after-kidney transplantation. The remaining 10% of cases are performed as pancreas transplantation alone in patients who have normal renal function, but with very labile and problematic diabetes, such as patients with life-threatening hypoglycemic unawareness. [5, 6, 7, 8]

An alternative therapy that may also ameliorate diabetes is islet cell transplantation, but this procedure is experimental and has not yet demonstrated equivalence to whole-graft 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, so many 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 pancreas transplantation alone (PTA) or simultaneous pancreas-kidney (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). Prospective trials are needed to compare the two groups, because most studies have lacked sufficient control groups. [9, 10]

Diabetic nephropathy

Studies comparing renal function in SPK transplantation recipients versus diabetic KTA recipients did not demonstrate significant differences during the early posttransplant period. 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. [11]

Diabetic neuropathy

Neuropathy improves after both kidney and pancreas transplantation, suggesting that renal failure and diabetes contribute to the sensory neuropathy commonly observed at the time of transplantation. Autonomic neuropathies take 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. [12, 13, 14, 15, 16]

Cardiovascular disease

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 ration was greater, and endothelium-dependent dilation of the brachial artery was improved in SPK recipients compared with type 1 diabetic patients who received KTA. [17, 18, 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. [20]  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. [21]

Indications and Contraindications

Simultaneous pancreas-kidney (SPK) transplantation is typically offered to patients who have insulin-dependent diabetes mellitus and in whom diabetic nephropathy has developed. Eligibility criteria for pancreas transplantation alone (PTA) or simultaneous pancreas-kidney (SPK) transplantation include the following [22] :

  • Age less than 55 years
  • Low C-peptide value
  • Minimal cardiovascular risk
  • Absence of significant diabetes-related peripheral vascular disease - Negative thallium stress test and/or absent or mild coronary artery disease
  • History of medical compliance
  • Ability to understand the procedure and comply with posttransplant management
  • Body mass index of less than 32 kg/m 2
  • Presence of more than two end-organ complications related to type 1 diabetes - In the absence of chronic renal failure or ESRD secondary to type 1 diabetes mellitus, this defines eligibility for PTA

Absolute contraindication to an SPK includes active infection and recent or current history of malignancy. Human immunodeficiency virus (HIV) infection is a relative contraindication. Clinical conditions that need to be considered before proceeding with transplantation are discussed in more detail below. [23]

Renal disease

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.

Diabetic retinopathy

Diabetic retinopathy is a pervasive finding in patients with diabetes and ESRD. Significant vision loss/blindness may be observed. Blindness is not an absolute contraindication to transplantation, because many blind patients lead very independent lives. [9]

Impaired gastric emptying

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 transplantations. Gastrointestinal morbidity is a common indication for readmission following pancreas transplantation.

Coronary artery disease

The most important comorbidity to consider in patients with type 1 diabetes with diabetic nephropathy is coronary artery disease (CAD). Patients with diabetes and ESRD 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 ESRD is estimated to be 45-55%. [18, 24]  Because of diabetic neuropathy, patients may not experience angina during episodes of myocardial ischemia.

Stroke and transient ischemic attack

Patients with ESRD and diabetes have an increased rate of strokes and transient ischemic attacks. Deaths related to cerebral vascular disease in patients with ESRD 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 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 is often 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 transplantations who are predisposed to volume depletion. Therefore, careful reassessment of the posttransplantation antihypertensive medication requirement is important. [17]

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 increased risk of injury to the feet and subsequent diabetic foot ulcers.

Mental or emotional illnesses

Mental illnesses, including neuroses 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, with some centers reporting  graft failure upon resump­tion of any diabetes medication and other centers reporting it only if diabetes medications need to be resumed at levels similar to or higher than pretransplant levels. [3] The Organ Procurement and Transplantation Network is preparing a standardized definition. [25]

Nevertheless, the number of recipients alive with a functioning pancreas allograft has contin­ued to rise over the past decade and exceeded 13,000 in 2012. Unadjusted graft survival at 5 years was 53% for pancreas transplantation alone (PTA) and 65% for pancreas after kidney (PAK) transplants. The relative risks for pancreas graft loss for PTA recipients are increasing donor age and HLA mismatches, and a positive effect has been observed with the use of anti–T-cell induction immunotherapy and the use of tacrolimus maintenance immunotherapy. [26]

For simultaneous pancreas-kidney (SPK) transplants performed in 2007, 5-year survival of the pancreas graft was 73%. The better long-term survival for SPK transplants may reflect the fact that elevation in the serum creatinine level is a readily available marker for early detection of rejection in those patients. [3]

Rejection markers

Markers for rejection include clinical signs and symptoms of pancreas graft pancreatitis and elevation of serum amylase or lipase levels, coupled with biopsy results. One advantage of a bladder-drained pancreas transplantation is the ability to monitor urinary amylase levels, which provides a method to monitor for rejection.

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.

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.

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 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 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.

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Technique

Approach Considerations

Various technical concerns must be considered in patients undergoing pancreas transplantation, including 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. 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 pancrease was a modification introduced in the mid-1980s. Although this technique minimizes the occurrence of intra-abdominal abscess that occurs with enteric-drained pancreas grafts, 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.

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Periprocedural Care

Preprocedure Planning

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. This sequence of events has several advantages

For example, prior allocation allows the transplantation center performing the procedure 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.

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, 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. (See the image below.)

Acceptable Warm and Cold Ischemia Times for Renal Acceptable Warm and Cold Ischemia Times for Renal Allografts
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