DIABETICMedicine DOI: 10.1111/dme.12373

Review Article Pancreas transplantation: a treatment option for people with diabetes S. Mittal1,2,3 and S. C. L. Gough2,3 1

Nuffield Department of Surgical Sciences, 2Oxford Centre of Diabetes, Endocrinology and Metabolism and 3NIHR Oxford Biomedical Research Centre, Oxford, UK Accepted 17 November 2013

Abstract Since the first pancreas transplants in the early 1960s, whole-organ pancreas transplantation, either alone or combined with kidney transplantation, has become commonplace in many countries around the world. Whole-organ pancreas transplantation is available in the UK, with ~200 transplants currently carried out per year. Patient survival and pancreas graft outcome rates are now similar to other solid organ transplant programmes, with high rates of long-term insulin independence. In the present review, we will discuss whole-pancreas transplantation as a treatment for diabetes, focusing on indications for transplantation, the nature of the procedure performed, graft survival rates and the consequences of pancreas transplantation on metabolic variables and the progression of diabetes-related complications. Diabet. Med. 31, 512–521 (2014)

Introduction Although scientists experimented with pancreas and islet cell transplantation before the discovery of insulin, it was not until the 1960s and the advancements in immunosuppression that clinical organ transplantation became a reality. In 1966, William Kelly and Richard Lillehei performed the first human pancreas transplant at the University of Minnesota, when they implanted a segmental pancreas graft simultaneously with a kidney transplant from a deceased donor into a 28-year-old woman [1]. Unfortunately, the operation was followed by a number of complications resulting in the recipient’s death 2 months later. The same team performed the next recorded transplant in 1969, hailed as a success with both graft and patient survival at 1 year. Nevertheless, the morbidity and mortality associated with these early transplants was high and in a publication in 1970 only two patients out of a series of 10 were alive [2]. Fortunately, the morbidity and mortality associated with pancreas transplantation has improved greatly and the rate of success has increased to a level which is now similar to that of kidney and liver transplantation [3]. As a result, simultaneous pancreas–kidney transplantation was recommended, by the American Diabetes Association in 2002, as an acceptable treatment for advanced insulin-dependent diabetes associated with imminent or established end-stage renal failure. For those not eligible for kidney Correspondence to: Shruti Mittal. E-mail: [email protected]

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transplantation, pancreas transplant alone may be considered for selected patients with difficult-to-manage diabetes associated with specific complications [4].

Current state of pancreas transplantation Pancreas transplantation, either with a kidney or alone, is now commonplace; ~1600 pancreas transplants are performed annually and >42 000 have been performed worldwide to date [5]. Pancreas transplantation has been performed in the UK since 2000, and it is currently undertaken in eight UK transplant centres: Oxford, Manchester, Guy’s Hospital (London), Cambridge, Cardiff, West London, Edinburgh and Newcastle, in order of programme size. Transplantation in the UK is nationally co-ordinated by NHS Blood and Transplant (NHSBT) via a central registry, whereby organ allocations are made through NHSBT according to predetermined protocols and allocation algorithms agreed through its own Pancreas Advisory Group. The most recent annual transplant data show that between April 2011 and April 2012, 173 simultaneous pancreas– kidney transplants and 36 isolated pancreas transplants were performed, (including 22 pancreas transplants alone and 14 pancreas after kidney) across all UK centres [6]. In Europe, Eurotransplant, initially founded in 1967 in the Netherlands, now co-ordinates the allocation of donor organs in Austria, Belgium, Croatia, Germany, Luxembourg, the Netherlands and Slovenia, including 37 pancreas and islet cell transplantation programmes reporting 219

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whole-organ pancreas transplants in 2012. Data from Eurotransplant and the American-based United Network for Organ Sharing are submitted to the International Pancreas Transplant Registry which reported a total of 1043 transplants for the same year [3].

Which patients should be considered for pancreas transplantation? For most people with Type 1 diabetes, glycaemic control is optimized with exogenous insulin, using basal bolus insulin injection regimens or, in some people, continuous subcutaneous insulin infusion via a pump. However, many people with diabetes do not achieve optimum blood glucose control; they struggle with disabling and life-threatening hypoglycaemia, and complications remain common [7–9]. Whole-organ pancreas transplantation, either alone or in combination with a kidney is therefore considered a viable and important treatment option for selected people with diabetes. In the UK, the Pancreas Advisory Group has agreed criteria to guide decisions on recipient selection (Table 1). In general, patients who develop chronic end-stage renal failure, secondary to either Type 1 or Type 2 diabetes, who

are on insulin and are not obese are considered for simultaneous pancreas–kidney transplantation or kidney transplantation followed at a later date by pancreas transplantation. There is increasing evidence to suggest that, for people with diabetes and end-stage renal disease, simultaneous pancreas–kidney transplantation offers the best outcome in terms of survival, graft survival and quality of life, such that in 2012 this procedure accounted for 84% of all pancreas transplants worldwide [10]. In the same year, pancreas transplantation alone, either after a kidney transplant or for people with difficult-to-control diabetes without renal failure, accounted for a much smaller number of transplants at 9% and 7%, respectively. Where a living donor option for kidney transplantation is available, this may be preferred in order to achieve earlier independence from dialysis; however, in light of the inferior pancreas graft survival outcomes of pancreas transplant after kidney transplants compared with those of simultaneous pancreas–kidney transplants [11], the former remains controversial and the decision on how best to proceed must be made with careful consideration of the individual patient’s circumstances and their likely waiting time on the combined pancreas–kidney list. This decision may also be influenced by

Table 1 Pancreas Advisory Group guidelines on b-cell transplantation indications, contraindications, risks and benefits

Procedure

Simultaneous pancreas–kidney transplantation

Pancreas transplant alone

Pancreas after kidney

Islet cell transplantation

Insulin-treated diabetes (Type 1 or Type 2 with BMI53 mmol/mol or 7% at time of listing

Insulin-treated diabetes (Type 1 or secondary to pancreatectomy/ pancreatitis) C-peptide negative in presence of glucose >4mmil/l Frequent and severe episodes of hypoglycaemia (>2 severe hypoglycaemic episodes within last 24 months); assessed by diabetologist to have disabling hypoglycaemia

Indication

Insulin-treated diabetes (Type 1 or Type 2 with BMI 1.5 units/kg/day Extensive aorta/ iliac and/or peripheral vascular disease Continued abuse of alcohol or drugs

Absolute: Excessive cardiovascular risk (significant non-correctable coronary artery disease; left ventricular ejection fraction 2 severe hypoglycaemic episodes within last 24 months); assessed by diabetologist to have disabling hypoglycaemia

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pre-assessment cardiac investigations, since patients must have sufficient cardiac reserve to tolerate the larger combined pancreas–kidney transplantation operation. Finally, in patients receiving pancreas transplants alone, careful consideration must be given to renal function which can be adversely affected by calcineurin-inhibitor immunotherapy [12].

Whole-organ pancreas vs islet cell transplantation For people with frequent severe hypoglycaemia despite best medical therapy, pancreas alone or islet cell transplantation may be considered in the absence of renal failure and other diabetes-related complications. One of the goals of solid whole-organ pancreas transplantation compared with islet cell transplantation is insulin independence and this is frequently achieved. It does, however, represent a major surgical procedure with higher morbidity, related to ischaemia-reperfusion injury, potential sepsis and increased cardiac risk. Although the results of islet cell transplantation continue to improve, the primary goal is not insulin independence but improvements in the frequency, severity and symptoms of hypoglycaemia alongside reduced insulin requirement, improved glycaemic control and improved quality of life [13]. Whilst it is not without surgical complications, the procedure is minimally invasive; islet cells are infused via a percutaneous transhepatic approach into the portal vein, with most recipients requiring more than one donor pancreas. Both procedures require lifelong immunosuppression with the associated increased risk of opportunistic infection and malignancy. Whilst these two treatment options are frequently compared, with many authors alluding to higher medium- and long-term insulin-independence rates with whole-organ pancreas transplantation, it is wise to consider them as complementary procedures informed by patient preference. Pancreas transplant may be favoured in those with an over-riding drive for freedom from diabetes and insulin, while islet cell transplantation is favoured where there is an over-riding drive for freedom from severe hypoglycaemia. The decision as to

whether someone should proceed to either a pancreas or islet cell transplantation is complex and should be reached after a detailed discussion with the patient, taking into consideration any medical comorbidities and the results of an extensive pre-operative assessment (Table 2).

How are pancreas donors selected? Although some US centres perform segmental pancreas transplantation after distal pancreatectomy from living donors, donor pancreases are usually from deceased donors and mostly from donors after brainstem death [7]. Donors after circulatory death have been used with comparable success; however, this has only been achieved with a highly selective approach [14]. Donor selection criteria for pancreas transplantation remain more stringent than for other organs, and there remains a poor rate of conversion from organ donor to transplant. Frequently, donor organs are found to be abnormal at the time of retrieval with fibrosis or fat deposition within the gland. Although steatotic organs often provide good immediate function if transplanted, they are liable to severe reperfusion pancreatitis with substantial associated morbidity [15]; for this reason, fatty organs are usually discarded. For the same reason, in the UK, donors with a BMI > 30 kg/m2 are declined for solid organ donation, although the evidence base for this rationale is limited [16]. An objective approach to donor risk factors has been carried out by Axelrod et al. [17] with the construction of a pancreas donor risk index. Independent factors predicting outcome have been identified, with the highest hazard ratios found to be associated with increasing donor age and donors after circulatory death. As such, organ donors up to the age of 55 or 60 years are considered, with preference for donors < 45 years old in the case of a circulatory death.

How are organs allocated? For pancreas transplantation, organ allocation algorithms guide the selection of donors and matching to recipients. In the UK, a national allocation policy has been agreed and is based upon a points-based system including various criteria

Table 2 Summary of the multidisciplinary pretransplant assessment that should be completed within 18 weeks of referral unless medical issues requiring intervention are identified Clinical history and examination

Immunology

Cardiac investigations

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Confirmation of diabetic state and complications Assessment of renal function Identification of contraindications (e.g. malignancy, active infection) Dental examination for disease likely to require treatment within next 6 months Social history and psychological assessment (in relation to medication compliance and support) Tissue typing: blood grouping and HLA typing; clinical assessment of previous sensitizing events (transplantation, pregnancy, blood transfusion) Virology/parasite/bacterial assessment (hepatitis B, hepatitis C, human immunodeficiency virus, cytomegalovirus, Epstein–Barr virus, human T-cell lymphotropic virus, toxoplasmosis, treponemapallidum) Assessment of cardiovascular fitness: electrocardiography, myocardial perfusion study, cardiology review

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selected for optimized individual outcomes and equity of access [18]. The scoring system is based on a combination of seven donor, recipient and transplant factors. Patient scores and ranking positions will, therefore, differ over time and for each given donor (Table 3). Donor pancreases are centrally offered to named recipients, and recipient centre surgeons and physicians accept or decline the offer based on knowledge of the donor and recipient clinical history.

Pancreas transplant operation Surgical technique

Most transplant units around the world transplant the whole pancreas together with a segment of donor duodenum. The arterial inflow is usually from the recipient common iliac artery with venous drainage to the common iliac vein. Although techniques may vary slightly between centres, most will follow a relatively standard procedure [19]. A small proportion of units advocate venous drainage into the portal venous system which, although associated with more physiological systemic levels of insulin, is not supported by evidence of substantial benefit with respect to graft or patient survival [20]. Although there has been concern that the hyperinsulinaemia associated with systemic venous drainage may be associated with adverse events such as an increased risk of atherosclerosis, there is no convincing evidence that systemic venous drainage places pancreas recipients at a disadvantage [21].

Exocrine drainage

In the 1990s the anastomosis of the donor duodenum was usually to the bladder, with the advantage of enabling Table 3 Factors affecting the UK national pancreas transplant waiting list Recipient factors* Waiting time Sensitisation Dialysis

Patients accrue points with time on the waiting list Highly sensitized patients are prioritized for a given match Dialysis-dependent patients are prioritized

Donor-related factors Travel time Points awarded to transplant centres close to donor hospital (especially for donors after circulatory death) Total HLA A, B and Preference to better matched recipients DR mismatch Donor BMI Donors with high BMI preferred for islet cell transplantation; low BMI preferred for whole organ Donor to recipient Points awarded for better age match age matching *A central computer system awards points to every blood group suitable recipient on the national waiting list and the pancreas is allocated to the patient with the most points. The system is designed to optimize outcomes and provide equity of access.

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urinary amylase to be used as a biochemical marker of pancreatic function and fewer complications with regard to contamination from enterotomy or duodenal leaks [22]; however, bladder drainage has the disadvantage of being associated with metabolic and urological complications including dehydration, metabolic acidosis and irritation from cystitis. For this reason, bladder drainage has been largely supplanted by enteric drainage in which the donor duodenum is anastomosed to the proximal jejunum. This is a more physiological technique but one which renders the pancreas less easily monitored. Despite this, as a result of improvements in surgical technique, radiological imaging and antimicrobial prophylaxis, outcomes after pancreas transplantation with enteric drainage are equivalent to those after bladder drainage, although some centres still use bladder drainage for closer pancreas monitoring [23].

Immunosuppression

Immunosuppression in pancreas transplantation follows a similar pattern to other solid organ transplants. The majority of units use biological antibody induction (thymoglobulin, alemtuzumab or basiliximab) to achieve profound immune cell depletion lasting for the first 3 months when the risk of rejection is greatest. This is followed by a maintenance combination of tacrolimus (a calcineurin inhibitor) and mycophenolatemofetil (an antiproliferative agent) to block T-cell activation and expansion, respectively. There is an increasing trend towards the use of steroid-free regimes in all areas of transplantation and steroids are not routinely used in either pancreas or islet cell transplantation [24]. There have been several single-centre randomized controlled trials and descriptive studies examining induction immunosuppression in pancreas transplantation, but there is no conclusive evidence favouring one regimen over another. Maintenance immunosuppression has followed developments in other solid organ transplantation procedures [25].

Metabolic and functional outcomes after pancreas transplantation Whole-organ pancreas transplantation achieves a high degree of insulin independence, usually with normalization of many of the frequently measured variables of metabolic function including HbA1c and appropriate insulin, C-peptide and glucagon responses to circulating blood glucose levels; however, the physiology of glucose homeostasis after pancreas transplantation is not fully understood. The effect of systemically drained insulin on blood glucose and the regulation of native and transplanted a cells is unclear [26], as is the incidence, relevance and physiology of hypoglycaemia after pancreas transplantation [27]. A number of studies in insulin-independent pancreas transplant recipients have noted that many recipients (although insulin-independent with normal HbA1c) display impaired, or even diabetic,

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glucose tolerance based on standard WHO criteria [28]. Pfeffer et al. [29] examined 13 simultaneous pancreas– kidney transplant recipients with impaired glucose tolerance and compared them with 28 recipients with normal glucose profiles and found raised glucose values to be associated with reduced early phase insulin secretory response, and that this may be related to injury caused during the transplantation process as a result of ischaemia-reperfusion. Christiansen et al. [30] studied four simultaneous pancreas–kidney transplant recipients with impaired glucose values, five similar subjects with normal glucose tolerance, six kidney transplant recipients without diabetes and eight healthy control subjects. Basal insulin secretion rates and glucose-stimulated early insulin secretion rates were markedly reduced in simultaneous pancreas–kidney transplant recipients with impaired glucose tolerance, as were glucose disappearance rates with less non-oxidative glucose metabolism and less glucagon suppression contributing to hyperglycaemia. It has also been suggested that patients with post-transplant impaired glucose tolerance have poorer pancreas graft survival compared with those with normal glucose tolerance [31]. Battezzati et al. [32] showed that the early metabolic profile is predictive of long-term graft survival, with high mean glucose on 24-h profiling at 1 year postoperatively being associated with shorter graft survival. The importance of donor factors in predicting graft survival [17,33] may indicate the necessity for transplantation of a critical mass of functioning b cells and that the lifespan of a graft may, in part, be determined at the time of transplantation. A proportion of patients have been shown to require exogenous insulin supplementation only in the early post-transplant period, implying delayed graft function in some subjects. Troppman et al. [34] suggested that this may also be a manifestation of reduced functional reserve of the donor organ and could be an indicator of poorer long-term graft survival.

(a)

Patient and graft survival

Data from the International Pancreas Transplant Registry and the United Network for Organ Sharing have shown that patient survival is equivalent after simultaneous pancreas– kidney, pancreas transplant alone and pancreas after kidney transplantation. Patient survival rates have continued to improve, reaching 96% at 1 year and 80% at 5 years post-transplantation [10]. Pancreas graft survival has also improved but remains higher with simultaneous pancreas– kidney transplantation. One-year graft survival reached 89% in simultaneous pancreas–kidney transplantation compared with 82% in pancreas transplant alone, with 5-year graft survival rates of 71% and 58%, respectively [10]. The most recent UK data, from the NHSBT 2012 report, are similar with 1-year patient survival of 97% in the period 2007–2010 and 5-year survival of 88% in 2004– 2006 for patients receiving simultaneous pancreas–kidney transplants. Pancreas graft survival for the same patients stands at 87% for 1 year and 76% at 5 years, as shown in Fig. 1. Graft failure, for the purposes of registry reporting, is typically defined as the need for exogenous insulin. The need for exogenous insulin may not necessarily represent total b-cell destruction as the pancreas graft may still be functioning but against greater insulin insensitivity [35]. Classification of the causes of pancreas graft failure lacks definition and clarity. Life expectancy

People with diabetes and end-stage renal failure have a high mortality risk, and death rates among patients on the

(b)

100

100

90

90

80

80

70 60 50 40 N Survival (%) SPK (K) 311 86 SPK (P) 311 76 PTA 11 46 PAK 47 46

30 20 10

95% CI (81 – 89) (71 – 80) (17 – 71) (31 – 59)

0

% patient survival

% graft survival

Clinical outcomes of pancreas transplantation

70 60 50 40 30

N 311 11 47

SPK PTA PAK

20 10

Survival (%) 95% CI 88 (84 – 92) 100 (–) 87 (69 – 95)

0

0

1

2

3

4

Years post-transplant

5

0

1

2

3

4

5

Years post-transplant

FIGURE 1 Five-year survival rates in the UK in recipients of pancreas transplantation using donors after brainstem death, stratified for transplant type: (a) Pancreas graft survival and (b) Patient survival. Adapted from Mumford [86]. SPK(K), simultaneous pancreas and kidney transplant — kidney survival); SPK(P), simultaneous pancreas and kidney transplant — pancreas survival; PTA, pancreas transplant alone; PAK, pancreas-after-kidney transplant.

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waiting list are high [36]. Kidney transplant confers a survival benefit compared with dialysis [37,38], but there has been debate over the added benefit of a pancreas transplant. It has been shown that survival after simultaneous pancreas–kidney transplantation is superior to survival after cadaveric kidney transplant [37,39,40], despite added surgical risk [41]; however the two groups of patients may not be matched in terms of medical comorbidities, with those unfit for simultaneous pancreas–kidney transplantation undergoing kidney transplant alone. Survival after living kidney transplantation was thought to be equivalent to that after simultaneous pancreas–kidney transplantation [42], but there is now considerable evidence that successful pancreas transplantation increases life expectancy. Reddy et al. [43] showed that, although patients undergoing simultaneous pancreas–kidney transplantation had a higher mortality risk compared with those undergoing living kidney transplantation in the first 18 months, this risk was actually lower thereafter because of the effects of good metabolic control. The long-term benefit of simultaneous pancreas–kidney transplantation over living kidney transplantation was also seen by Morath et al. [44], who showed the early survival benefit of living kidney transplantation to be lost after 10 years. Although stabilization of renal function contributes significantly to improved life expectancy after simultaneous pancreas– kidney transplantation, studies comparing simultaneous pancreas–kidney transplantation recipients with functioning grafts, those with either kidney or pancreas graft failure and recipients of living and cadaveric kidney transplantation, have shown the pancreas graft to confer significant additional benefit beyond that offered by the kidney transplant alone [45–47].

Quality of life

Pancreas transplantation has been shown to lead to improved quality of life for people with diabetes [36,48,49]. Freedom from insulin is exchanged for the complications of immunosuppression, and the short-term difficulties of postoperative recovery are balanced against the long-term benefits. Reviews of the literature have clearly demonstrated a beneficial effect of transplantation on quality of life, even in the face of pancreas graft failure [49,50]; however, it is important to note that experiences of pancreatic transplantation may vary between recipients, with a considerable number requiring psychosocial support [51] to cope with the unique challenges, including the trauma of surgery, loss of control over their diabetes and the fear of potential graft failure. No specific quality-of-life questionnaire addressing these issues for use in transplantation currently exists, and so most studies have been limited not only by size but also by the use of generic and heterogeneous quality-of-life measures [49,52–54].

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Monitoring of pancreas graft function after pancreas transplantation The mechanisms underlying longer-term pancreas transplant failure remain unknown, although they may include b-cell exhaustion and/or injury by auto- and alloimmunity. Reduced recipient insulin sensitivity as a consequence of hyperinsulinaemia (secondary to systemic insulin drainage), historical use of steroids as maintenance immunosuppression and postoperative weight gain may each constitute contributory factors. In recent years, surgical technical complications have been the most common reason for graft loss in the first 3 months. Graft loss between 3 and 12 months is largely the result of acute rejection, with chronic rejection gradually increasing from the time of surgery. Consideration of the multiple factors involved in deteriorating graft function is important for the assessment and optimization of the failing pancreas graft. Postoperative monitoring of pancreas transplant recipients in most centres adopts a protocol of laboratory and radiological testing. Serum amylase, lipase, C-peptide, insulin and glucose are checked to monitor pancreas graft function, alongside periodic HbA1c and glucose tolerance testing [55]. Radiological imaging can check for adequate graft perfusion, thrombosis and intra-abdominal collections [56]. If bladder drainage has been carried out, urinary amylase can be monitored in 12- or 24-h urine collections, as rejection of the exocrine pancreas precedes rejection of the endocrine pancreas by 5–7 days. A value decrease > 50% would prompt further imaging or transcystoscopic biopsy of the donor duodenum [57]. Percutaneous biopsy of pancreas tissue may also be used in enterically drained pancreases where there is suspicion of graft rejection, but this must be weighed against the risks of bleeding and fistulation [58]. In general, however, the monitoring of whole-organ pancreas transplants remains a challenge and it is not clear how best to recognize the early manifestations of rejection to trigger a biopsy or how to identify grafts at greater risk of failure [55]. In most cases, clinical signs or symptoms of pancreas rejection are subtle or non-existent and, by the time abnormal glucose is apparent, damage is often irreversible. Although rises in serum amylase and lipase are commonly associated with pancreatitis, their relevance in the context of graft pancreatitis or graft rejection is less clear. In simultaneous pancreas–kidney transplantation, kidney graft function or rejection may be used as a surrogate for changes presumed to be also occurring within the pancreas; however, discordant rejection can occur [59] and, when the pancreas is transplanted alone, monitoring of pancreas function can be difficult.

Complications of diabetes It has been suggested that pancreas transplantation is beneficial with respect to the development and further progression of diabetes-related complications [10,60]. It

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has, however, also been acknowledged that there is a paucity of long-term, prospective randomized studies, of sufficient size to draw meaningful conclusions and that at the present time much of the benefit is circumstantial.

Diabetic nephropathy

Good glycaemic control has been shown to reduce the decline in renal function [12,61]. The effect of pancreas transplantation on renal function is particularly important since most transplant patients are treated with nephrotoxic calcineurin inhibitors, which may exacerbate any diabetes-associated glomerular disease. This is of particular relevance in pancreas-only recipients, where nephrotoxic immunosuppression may advance the patients’ need for dialysis. Fioretto et al. [62] studied eight non-uraemic patients who underwent pancreas transplantation alone. Although there was a decline in renal function at 5 years, this remained stable at 10 years. Diabetic glomerular lesions were not significantly changed at 5 years but were dramatically improved after 10 years, with most patients’ glomerular structure returning to normal at the 10-year follow-up. These studies also showed that tubulointerstitial remodelling was possible [63]. Indeed, Boggi et al. [64] noted a reduction in proteinuria in 71 pancreas-only recipients post-transplant. Pancreas transplantation has also been shown to prevent the development of diabetic nephropathy within kidney allografts [65]. Kleinclauss et al. [66] compared 175 recipients of pancreas after kidney to a matched group of 75 recipients of kidney transplant alone, and found superior glomerular filtration rates in the pancreas after kidney group after 4 years. Browne et al. showed that functional improvement translated into graft survival benefit in a comparison of 2776 pancreas after kidney and 13 635 kidney transplant alone recipients [67]. This would suggest that, in groups with equivalent immunosuppression loads, there is indeed an additional benefit from the pancreas graft in terms of preserving renal function, although it may take some years for this benefit to become evident.

Neuropathy

Evidence for improvement in diabetic neuropathy after pancreas transplantation is limited. Improvements in neurological function after 24 months of stable pancreatic function are reported with improvements in motor, sensory and autonomic neuropathy, which persisted up to 10 years post-transplant [68,69]. These and other studies suggest some degree of reversibility of diabetic neuropathy [70,71]; however, larger more robust studies have been hampered by the lack of a ‘gold standard’ outcome measure and by the invasive nature of current investigations. The recent establishment of confocal corneal microscopy as a reliable, non-invasive, readily repeatable investigation for detecting new nerve growth may address this difficulty, and early

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evidence after pancreas transplantation has been promising [72,73].

Retinopathy

Giannarelli et al. [74] studied 33 patients with Type 1 diabetes who underwent pancreas-only transplantation, and who were matched with 35 control subjects. Beneficial effects on retinopathy were reported, with a significant improvement in the incidence of proliferative retinopathy, the need for laser treatment, and also in non-proliferative retinopathy. Although the results of this and other small studies have been encouraging, a high proportion of patients already have advanced retinopathy at the time of transplantation. Koznarova et al. [75] suggest that improvement may be observed even in advanced retinopathy, but stabilization rather than improvement is a more realistic goal. Indeed stabilization of disease progression has been observed in a number of studies, although the absence of a large comparator group means it remains unclear whether this is a true deviation from the natural progression of advanced retinopathy [76,77]. It has been suggested that rejection episodes may have a deleterious effect on retinopathy progression and the potential for sudden deterioration in vision either early after transplantation or after graft failure [78,79].

Cardiac function

Data suggest that pancreas–kidney transplantation reduces cardiovascular death [80] and functional studies have shown improvement in blood pressure and dyslipidaemia compared with kidney transplant alone [81], improvements in systolic and diastolic ventricular function [81,82] and beneficial effects on endothelial dysfunction [83,84] as well as a reduction in the progression of atherosclerosis compared with recipients of kidney alone, or those with pancreas failure [85]; however, low cardiac event rates after pancreas transplantation may also reflect stringent cardiac screening and preoperative optimization in the pancreas transplant group, with kidney transplant recipients representing a less fit cohort. Additionally, long-term studies linking postoperative functional investigations and clinical endpoints are lacking.

Conclusion and future research Pancreas transplantation is a recognized treatment for selected people with diabetes, offering insulin independence and improved quality of life, with graft and patient survival rates comparable to other solid organ transplantation. Simultaneous pancreas–kidney transplantation offers benefits in terms of graft and patient survival compared with kidney transplant alone for people with diabetes and end-stage renal disease. At the present time, whole-organ pancreas trans-

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plantation alone should always be considered as an alternative for people being referred for islet cell transplantation as, although it is a more invasive procedure, it is more likely to lead to insulin independence with established long-term outcome benefits. Pancreas transplantation has traditionally been restricted to young and fit patients, but as the morbidity of pancreas transplantation diminishes and the longer-term outcomes improve, the potential indications for this procedure are increasing. There remains a need for improved graft monitoring by means of immunological or biochemical biomarkers to improve outcomes, and to help target appropriate intervention therapies for pancreas grafts showing suboptimal function. Nevertheless whole-organ pancreas transplantation offers great benefits to a challenging group of people with diabetes.

Funding sources

Funding was received from the NIHR Biomedical Research Centre, Oxford, UK.

Competing interests

None declared.

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Pancreas transplantation: a treatment option for people with diabetes.

Since the first pancreas transplants in the early 1960s, whole-organ pancreas transplantation, either alone or combined with kidney transplantation, h...
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