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Pancreas and islet cell transplantation: beta-cell replacement therapy


Introduction

The discovery of insulin by Banting and Best in the early part of the 20th century saw type I diabetes become a treatable chronic illness rather than a rapidly fatal diagnosis. Since then, patients with diabetes have been able to lead relatively normal lives, thanks to ongoing refinements in insulin therapy. Despite this, many patients suffer from the secondary complications of diabetes, including retinopathy, neuropathy, nephropathy and premature cardiovascular disease. The prognosis for a patient who has diabetic nephropathy is poor and the 10-year survival for a 45-year-old patient on dialysis is < 10%. These patients can benefit from simultaneous pancreas and kidney (SPK) transplantation. This not only removes the need for dialysis but also results in normoglycaemia without the need for insulin in > 85% of patients. Pancreas transplant alone (PTA) is reserved for patients in the absence of renal disease with life-threatening complications of diabetes, principally intractable impaired awareness of hypoglycaemia (IAH). For this set of patients, the risk of the surgery and life-long immunosuppression outweighs the risk associated with IAH and coma.

Unfortunately the morbidity and mortality associated with pancreas transplantation means that only a limited number of patients are deemed fit enough for surgery. An alternative treatment for these patients is islet transplantation. Many of the complications of whole pancreas transplantation are associated with the exocrine portion of the pancreas (pancreatitis, pancreatic fistula). The islets of Langerhans account for only 1% of pancreatic mass but contain the beta and alpha cells responsible for insulin and glucagon production necessary for glycaemic control. Islet cell isolation and transplantation has emerged over the last decade as an excellent treatment option for intractable hypoglycaemic awareness and offers a much lower risk alternative to PTA. Together pancreas transplant and islet transplant come under the banner of ‘beta-cell replacement therapy’.

Beta-cell replacement therapy

History of beta-cell replacement therapy

The concept of extracting and transplanting islets is not new and was initially attempted in 1893 in Bristol when a fragmented sheep’s pancreas was transplanted subcutaneously into a 15-year-old boy dying of ketoacidosis. This early xenograft was, not surprisingly, unsuccessful but predated the discovery of insulin by nearly 30 years. The era of experimental islet research began in 1911, when Bensley stained islets within the guinea pig pancreas using a number of dyes, and was able to pick free the occasional islet for morphological study. The average adult human pancreas weighs 70 g, contains an average of 1–2 million islets of average diameter 157 μm, constituting between 0.8% and 3.8% of the total mass of the gland. Mass isolation of large numbers of viable islets from the human pancreas has proven to be a challenge ever since and it was almost 100 years later that Scharp et al. reported insulin independence after islet transplantation in 1990. The first pancreas transplant was performed over 50 years ago in the University of Minnesota in 1966. Early experience with pancreatic transplantation was disappointing and remained so for many years. Difficulties were related to the management of the exocrine secretions and septic complications, a high incidence of thrombosis, acute rejection and pancreatitis. For the first half of its 50-year history, less than 1200 pancreas transplants were performed worldwide. Even after the introduction of ciclosporin in 1983, 1-year patient and graft survival rates were only 75% and 37%, respectively. Understandably, in the 1970s and 1980s enthusiasm for pancreas transplantation was scarce; the predominant sentiment was scepticism. Throughout the 1990s significant changes occurred. These came about as a consequence of improvements in organ retrieval and preservation methods, refinements in surgical techniques, advances in immunosuppression, progress in the prophylaxis and treatment of infection, and the experience gained in donor and recipient selection. Success rates following pancreas transplantation are now comparable with other forms of organ transplantation. There have now been over 42 000 pancreas transplants performed worldwide.

Interestingly, neither pancreas nor islet cell transplantation has ever been compared with insulin therapy in a prospective controlled trial and it is very unlikely that such a trial will ever be performed. However, considerable experience and a substantial body of evidence has accumulated, which now favours the viewpoint of the enthusiasts rather than of the sceptics.

Indications for beta-cell replacement

Both pancreas and islet cell transplantation aim to replace beta-cell function, reduce short- and long-term complications of diabetes and increase long-term survival. There are two main scenarios when transplantation is considered in diabetic patients:

  • 1.

    Diabetic patients with renal failure: SPK transplant is the treatment of choice in patients with type I diabetes and an estimated glomerular filtration rate of < 20 mL/min/1.73 m 2 . Transplantation can also be considered in type II diabetics with renal failure who have a body mass index (BMI) of < 27. In patients who have already received a living or deceased kidney transplant, pancreas after kidney (PAK) transplant can be considered. In patients who are not deemed fit enough for SPK transplant, simultaneous islet kidney (SIK) transplant can be considered.

  • 2.

    Diabetic patients in the absence of renal failure: Patients with diabetes complicated by frequent, severe metabolic complications despite optimum insulin therapy may be suitable for PTA. These patients are often at risk of IAH and coma, or severe hyperglycaemia that requires hospital admission. For patients with severe IAH, an alternative and lower risk option to PTA is islet transplantation. The risks and benefits of SPK transplant and contraindication and risks for transplant are summarised in Boxes 10.1 and 10.2 . A treatment algorithm for beta-cell replacement is presented in Fig. 10.1 .

    Box 10.1
    Potential risks and benefits of simultaneous pancreas–kidney (SPK) transplantation

    Risks

    • Perioperative morbidity and mortality

    • Potential for pancreas transplant to adversely affect kidney transplant outcome

    • Consequences of higher immunosuppression

    Benefits

    • Improved quality of life, insulin independence

    • Potential benefits on diabetic complications

    • Improved life expectancy

    Box 10.2
    Contraindications and risk factors for pancreas transplantation

    • Inability to give informed consent

    • Active drug abuse

    • Major psychiatric illness or non-compliant behaviour

    • Recent history of malignancy

    • Active infection

    • Recent myocardial infarction

    • Evidence of significant uncorrectable ischaemic heart disease

    • Insufficient cardiac reserve with poor ejection fraction

    • Any other illness that significantly restricts life expectancy

    • Age > 60 years

    • Significant obesity (BMI > 30)

    • Severe aortoiliac atherosclerosis

    Figure 10.1, Beta-cell replacement treatment algorithm.

Pancreas retrieval operation

The pancreas is a close neighbour of the liver and shares important vascular structures. However, specific arterial anomalies of the blood supply to the liver that preclude successful liver or pancreas procurement for transplantation are very rare. Although a detailed description of the surgical procedure for pancreas retrieval is not given, several pertinent points are highlighted below.

University of Wisconsin (UW) solution was first developed as a pancreatic preservation solution and remains the benchmark for pancreas preservation. The cold ischaemia tolerance of the pancreas is somewhere between that of the liver and the kidney. In pancreas allografts perfused with UW solution, 20 hours was thought to be the limit for successful preservation, beyond which a time-dependent deterioration in outcome occurred. Although earlier data failed to demonstrate a clear benefit from a preservation time of < 20 hours, most surgeons intuitively aimed for shorter preservation times. More recent data now suggest that ischaemia time is of greater importance in recipients of suboptimal grafts. In such cases, ischaemia times > 12 hours are likely to be associated with poorer outcomes, and in the US median cold ischaemia time (CIT) for all pancreas transplants has been < 12 hours since 2006. ,

The pressure gradient between mean arterial pressure and portal venous (PV) pressure that maintains blood flow through the pancreas can be significantly diminished during the perfusion of the abdominal organs in retrieval operations. Particular attention is required to maintain an adequate gradient if a cannula for perfusion is placed in the PV system as well as the aorta. Many transplant units perfuse abdominal organs with an aortic cannula only, and there is some evidence that supports the view that additional portal perfusion is unnecessary. For the interests of the pancreatic allograft, aortic perfusion alone is the most ‘physiological’ state that allows satisfactory perfusion and adequate drainage of the effluent.

Some units flush the donor duodenum using a nasogastric tube with an antiseptic or antibiotic solution during the retrieval operation. No evidence exists to demonstrate the superiority of any solution used for duodenal decontamination, and povidone–iodine during cold storage may be toxic to duodenal mucosa. Donor duodenal contents should be submitted for bacterial and fungal culture. The results may be important in guiding the management of infection in pancreas transplant recipients.

Careful and minimal handling of the pancreas during retrieval is important. Removal of the spleen and the pancreatico-duodenal graft en bloc with the liver is the quickest and safest method for both organs. The organs are then easily and quickly separated on the back table at the retrieval centre.

Further back-table preparation of the pancreas, which takes place in the recipient centre, is a crucial part of the procedure and takes a minimum of 2 hours. The short stumps of the gastroduodenal artery (GDA) and the splenic artery should be marked with fine polypropylene sutures at the time of retrieval. Demonstration of good collateral circulation within the pancreatico-duodenal arcade (between the superior mesenteric artery [SMA] and the GDA) by flushing the arteries individually at the back table is reassuring. An iliac artery ‘Y’ graft of donor origin anastomosed to the SMA and the splenic artery is the most common method of reconstruction for the graft arterial inflow ( Fig. 10.2 ). Meticulous dissection and ligation of the lymphatic tissue and small vessels around the pancreas is important to prevent haemorrhage upon reperfusion of the graft in the recipient. Particular attention should be paid to secure the duodenal segment staple lines by inversion with further sutures.

Figure 10.2, Reverse view of the pancreas showing that the pancreatic graft reconstruction can be performed either using an aortic patch typically or in its absence using a donor iliac ‘Y’ graft.

The pancreas transplant operation

General considerations

In SPK transplantation, pancreatic implantation is usually performed first because of the lower ischaemia tolerance of the pancreas. It is easier to implant the pancreatic graft on the right side. The renal allograft can also be placed intra-abdominally with anastomoses to the left iliac vessels. Alternatively, an extraperitoneal renal transplant on the left side can be performed using the same incision or through a separate left iliac fossa incision. A further alternative is to implant the renal graft ipsilaterally, using more caudal segments of the recipient right iliac vessels.

Severely atherosclerotic and calcified vessels in some diabetic recipients can be a challenge during pancreatic implantation. Iliac ‘Y’ grafts used for reconstruction offer greater flexibility in choosing a suitable arterial anastomotic site in the recipient vessels. The most common technique used for pancreas transplantation has been intra-abdominal implantation of the whole pancreas together with a donor duodenal segment. Currently the choices available to the surgeon are related to the management of the exocrine secretions and venous drainage, as discussed below.

Management of exocrine secretions

Drainage of the exocrine secretions of pancreatic grafts into the recipient’s bladder was the most common technique, accounting for 90% of US pancreas transplants during the 1980s and early 1990s. The popularity of this technique was due to its perceived safety, primarily less serious consequences of anastomotic leak (compared with enteric drainage) in the days of higher doses of corticosteroids and unrefined immunosuppression. The ability to monitor amylase levels in the urine has been considered an additional advantage of bladder drainage. However, the unphysiological diversion of pancreatic exocrine secretions into the urinary bladder causes frequent complications, often leading to chronic and disabling symptoms. As a consequence, conversion of the urinary diversion to enteric drainage is required in many patients. It is for this reason that enteric drainage has largely replaced bladder drainage as the method of choice for the management of exocrine secretions in the US and in most European centres.

Any part of the recipient’s small bowel can be used for anastomosis with the allograft duodenum. No data exist to demonstrate the superiority of one particular site over another. Roux-en-Y loops, which were commonly used, are becoming rare and a simple side-to-side entero-enterostomy is preferred.

Delayed endocrine function from the transplanted graft is uncommon and insulin infusion should be discontinued at the time of reperfusion. Recipients achieving insulin independence for the first time in many years is a gratifying consequence for the surgeon; however, patients can become hypoglycaemic at this stage. Blood sugar levels should be checked frequently and a low rate of dextrose infusion is often required.

Management of venous drainage

Drainage of the venous outflow from pancreas grafts into the portal circulation was first described by Calne in 1984. This complex surgical technique using a segmental graft and gastric exocrine diversion in a paratopic position has never gained popularity. Drainage of the venous outflow into the systemic circulation at the level of the lower inferior vena cava has now become the norm in pancreatic transplantation. However, some units still use PV drainage via the superior mesenteric vein (SMV). Several studies, including prospective randomised comparisons, have shown that this offers at least equivalent outcome to that of systemic venous (SV) drainage, with no compromise in safety. The impetus for PV drainage was to achieve a more physiological delivery of insulin. A theoretical benefit was considered to be avoidance of hyperinsulinaemia, which has been linked with atherogenesis. However, none of the studies of metabolic function after PV drainage have shown a clear benefit in terms of glucose metabolism, lipid profiles or atherogenesis, but some studies have observed a reduction in acute rejection rates.

Immunosuppression in pancreas transplantation

Historically, there is ample evidence that the incidence of acute rejection is higher after pancreas transplantation than after kidney transplantation. , The reasons for this difference are not clear. Nevertheless, there has been general acknowledgement of the higher immunological risk of pancreas transplantation. This has resulted in the evolution of strategies that use more intense immunosuppressive protocols for pancreas transplantation than for kidney transplantation.

In Europe, immunosuppressive protocols in solid organ transplantation in general have been less aggressive compared with US protocols. In the evolution of immunosuppression for pancreas transplantation, tacrolimus has largely replaced ciclosporin and mycophenolate mofetil (MMF) has replaced azathioprine based on sound evidence from prospective randomised trials showing improved outcomes.

Steroid withdrawal or avoidance has been a focus of study in the last decade. As yet, there is no evidence demonstrating a significant benefit from steroid avoidance or withdrawal, but experience reveals that it is feasible without adversely affecting outcome in pancreas transplant patients. ,

Induction therapy with biological agents is part of the immunosuppressive protocol in nearly all pancreas transplants. This is based on prospective multicentre trials that demonstrated a reduced incidence and severity of rejection episodes with biological induction therapy. A comparison of different induction therapies (OKT3, ATG, basiliximab or daclizumab) compared with no induction showed a reduction in acute rejection with induction therapy, but no consistent pattern has emerged to demonstrate the superiority of any one specific biological agent when used in conjunction with tacrolimus-based immunosuppression. More recent evidence from a single-centre randomised comparison suggests that alemtuzumab induction is associated with similar graft and patient survival rates compared with ATG induction, but results in a lower incidence of acute rejection and better safety profile, with a significantly lower incidence of cytomegalovirus (CMV) infection.

Diagnosis and management of acute rejection following pancreas transplantation

One of the notable features about pancreas transplantation over the last 15 years has been the considerable reduction in the incidence of acute rejection. In 1992, 74% of SPK transplant recipients and 50% of PTA recipients (this probably underestimates the true incidence) were reported to have received antirejection therapy. , This had reduced to 19% and 17%, respectively, by 2000.

An important feature of pancreatic graft rejection, for the purposes of patient management, is the lack of a reliable early marker. In SPK transplants, diagnosis of acute rejection almost completely relies on monitoring of renal allograft function by measuring serum creatinine levels and undertaking renal biopsy when indicated. Discordant rejection of allografts only occurs rarely following SPK transplantation, with isolated pancreas rejection in 5–10% of acute rejection episodes. Monitoring for acute rejection and patient management in the early postoperative period is a particular challenge in patients following solitary pancreas transplantation.

Acute rejection of the pancreas affects the exocrine pancreas first. The inflammation may cause pain and a low-grade fever associated with a rise in serum amylase. These symptoms and signs are non-specific, can be subtle and do not distinguish between acute rejection and other causes of graft inflammation (such as ischaemia–reperfusion injury or allograft pancreatitis). Islets of Langerhans are scattered sparsely throughout the exocrine pancreas and beta cells have considerable functional reserve. Therefore, dysfunction of the majority of islets resulting in hyperglycaemia as a consequence of rejection occurs only very late in the course of pancreatic rejection. Imaging modalities such as computed tomography (CT) or magnetic resonance imaging (MRI) visualise the pancreas and are helpful to exclude other pathology (such as lack of perfusion which may be segmental, or intra-abdominal collections). There are no specific radiological signs of acute rejection. Detection of urinary amylase in bladder-drained grafts is a sensitive indicator of exocrine function. However, detection of hypoamylasuria lacks specificity. A > 25% reduction in urinary amylase correlates with acute rejection in no more than half of the cases when assessed by biopsy. A stable urinary amylase may therefore be helpful in excluding acute rejection, but detection of hypoamylasuria is non-specific and unhelpful.

Pancreas allograft biopsy has recently become established as a reliable and safe technique, and is the gold standard in the diagnosis of acute rejection in solitary pancreas transplants. Percutaneous biopsy under ultrasound or CT guidance is the most common method. Histological criteria for the diagnosis and grading of rejection have been standardised.

Histological examination of pancreas graft biopsies correlates with clinical and serological findings and has revealed two distinct pathways of rejection (similar to the more widely recognised pattern in kidney transplantation): T-cell-mediated rejection and antibody-mediated rejection.

A recent article by Papadimitriou and Drachenberg provides an authoritative and up-to-date review of the histological criteria for these two subtypes of acute pancreas allograft rejection, as well as mechanisms leading to graft injury and differential diagnosis.

The recognition of antibody-mediated rejection as a distinct entity in pancreas transplantation explains conflicting results in published data from earlier years, as some cases of treatment-resistant acute pancreas allograft rejection were thought to be cell-mediated rejection. It also partially explains the improved success rates in solitary pancreas transplantation as a consequence of liberal surveillance biopsies. Finally, the increasing utilisation of pancreas allograft biopsies has cast doubt on the validity of the assumption that isolated rejection of the kidney or the pancreas graft in SPK recipients is uncommon. Monitoring of donor-specific antibodies (DSA) has become routine. In a multivariate analysis of 433 pancreas transplants at the Oxford Transplant Centre, development of de novo DSA emerged as a strong independent predictor of pancreas graft failure (hazard ratio 4.66, P < 0.001).

Early or mild cell-mediated acute rejection of the pancreas allograft concurrent with kidney rejection can be successfully treated with high-dose corticosteroids. Recurrent acute rejection or moderate to severe rejection episodes require treatment with anti-T-cell agents. International Pancreas Transplant Registry (IPTR) data show that steroids were used in 85% of SPK and 80% of solitary pancreas transplant recipients diagnosed with acute rejection. However, 48% of SPK transplant recipients and 80% of solitary pancreas transplant recipients with acute rejection were also given anti-T-cell agents, suggesting that many patients were treated with both. There are not enough data to make evidence-based recommendations on the optimum treatment for acute antibody-mediated rejection. Experience with the management of antibody-mediated rejection in kidney transplantation would suggest a potential role for plasma exchange with or without intravenous immunoglobulin and/or rituximab.

Acute rejection in pancreas allografts is not life-threatening and caution is advised against overimmunosuppression. If diagnosed before the onset of hyperglycaemia, most rejection episodes are reversible. The United Network for Organ Sharing (UNOS) data for 4251 patients who received SPK transplants between 1988 and 1997 were analysed by Reddy et al. in order to determine the influence of acute rejection on long-term outcome. Acute rejection of either graft increased the relative risk (RR) of pancreas and kidney graft failure at 5 years. The RRs, adjusted for other risk factors, were 1.32 and 1.53 for pancreas and kidney, respectively, if acute rejection occurred. The worst outcome was in patients who had both kidney and pancreas rejection.

Complications of pancreas transplantation

Pancreas transplantation is associated with a higher incidence and a greater range of complications than kidney transplantation. Furthermore, postoperative patient management constitutes a greater challenge ( Box 10.3 ). Between a quarter and a third of patients require re-laparotomy following pancreas transplantation to deal with complications. Part of the reason for the increased incidence of complications is the higher level of immunosuppression in a high-risk diabetic population who already exhibit impaired infection resistance, poor healing and a high prevalence of comorbidity. Other factors relate to the allograft, which unlike kidney or liver allografts is not sterile and uniquely possesses rich proteolytic enzymes, making it susceptible to specific complications such as secondary haemorrhage, pancreatitis, leaks and fistula formation. The blood flow to the pancreas is much lower than that to the kidney and this is a further risk factor, specifically for thrombotic complications. Finally, bladder drainage of the exocrine secretions is associated with a high incidence of complications unique to this unphysiological diversion. Increasing donor age, prolonged preservation time, recipient obesity and donor obesity are risk factors for complications and early graft loss.

Box 10.3
Complications of pancreas transplantation

Vascular complications

  • Thrombosis: allograft venous or arterial thrombosis

  • Haemorrhage: early haemorrhage from allograft vessels and late haemorrhage (rupture of pseudoaneurysms)

Infective complications

  • Systemic infection: opportunistic infections associated with immunosuppression

  • Local infections: peritonitis, localised collections, enteric or pancreatic fistulas

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