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Keywords:

  • Chronic kidney disease;
  • Diabetic;
  • Immunosuppression;
  • Rejection;
  • Transplantation;
  • Treatment

SUMMARY

  1. Top of page
  2. SUMMARY
  3. BACKGROUND
  4. THE BENEFITS OF PANCREAS TRANSPLANTATION
  5. SELECTION OF THE POTENTIAL RECIPIENT
  6. LISTING AND ALLOCATION
  7. DONOR SELECTION AND FACTORS
  8. RECIPIENT OPERATIVE TECHNIQUES
  9. INTRA-OPERATIVE MANAGEMENT
  10. POST-OPERATIVE MANAGEMENT AND COMPLICATIONS
  11. IMMUNOSUPPRESSION AND REJECTION
  12. LONG-TERM OUTCOMES
  13. SPECIAL SITUATIONS
  14. CONCLUSION
  15. CONFLICT OF INTEREST
  16. Appendix
  17. REFERENCES

Simultaneous Pancreas and Kidney (SPK) transplantation in the 21st century is a proven therapeutic intervention for diabetes with renal failure. Although it is a major invasive procedure, successful transplantation leads to an overall improvement in the quality of life of the recipient, freedom from insulin and dialysis, along with stabilisation and improvement in several of the multi-system complications associated with long-term diabetes. It is also associated with improved longevity when compared to diabetics who have had a kidney transplant alone. The combined transplant could be considered a curative procedure albeit at the expense of long-term immunosuppression. In essence, successful SPK transplantation may be considered the gold standard against which all other therapeutic interventions may be measured in diabetes with end-stage renal failure.


BACKGROUND

  1. Top of page
  2. SUMMARY
  3. BACKGROUND
  4. THE BENEFITS OF PANCREAS TRANSPLANTATION
  5. SELECTION OF THE POTENTIAL RECIPIENT
  6. LISTING AND ALLOCATION
  7. DONOR SELECTION AND FACTORS
  8. RECIPIENT OPERATIVE TECHNIQUES
  9. INTRA-OPERATIVE MANAGEMENT
  10. POST-OPERATIVE MANAGEMENT AND COMPLICATIONS
  11. IMMUNOSUPPRESSION AND REJECTION
  12. LONG-TERM OUTCOMES
  13. SPECIAL SITUATIONS
  14. CONCLUSION
  15. CONFLICT OF INTEREST
  16. Appendix
  17. REFERENCES

Diabetes Mellitus (DM) is a disease associated with affluent societies with an ever-increasing clinico-socioeconomic impact that consumes a significant proportion of the healthcare costs of different countries (http://www.idf.org/diabetesatlas/). While considered a disease primarily of the developed nations, the developing economies like China are seeing explosions in diabetes (Yang et al. 2010). More importantly, it causes a major disruptive impact on the health and well-being of the affected individual through its effect on quality of life and multi-system complications. The primary aetiology in Diabetes is the absolute deficiency of insulin, in Type 1 DM as a result mainly of autoimmunity and a resistance to insulin in Type 2 DM. Major advances have been made in the pharmacologic and multi-disciplinary management of diabetes and its multi-system complications. The underpinning principle however is adequate, accurate and safe exogenous insulin delivery or beta cell replacement. Exogenous insulin products and insulin delivery methods have become increasingly sophisticated since 1922 when Banting and Best first discovered human insulin to the current era of therapeutic insulin pumps linked to regular glucose sensing. The Diabetes Control and Complications Trial (DCCT) (1993) showed the benefits of tight sugar control but closely linked with the unavoidable unpleasant side effects of hypoglycaemic episodes. This is to an extent ameliorated in the modern era by insulin pumps. However, even with the most sophisticated insulin pump, there is still a significant discrepancy when compared to normal physiological secretion of insulin where there is an instantaneous feedback mechanism that leads to smooth euglycaemic levels. Pancreas transplantation is the only organ allograft done for replacing the endocrine function of an organ for an improvement in quality of life, stabilisation of disease complications and perhaps increasing longevity. The transplanted beta cells in the pancreas hence replicates the lost endocrine function of the native Islets of Langerhans by immune or other idiopathic mechanisms leading to a return to normoglycaemia with stabilisation of the progressive metabolic and multi-system derangements albeit at the expense of long-term immunosuppression.

The management of DM took a dramatic and promising turn with the first combined pancreas and kidney transplant done by William Kelly and Lillehei on 16 December 1966 in Minnesota (Kelly et al. 1967).

In the early pioneering years, although it was being adopted by different centres, and going through the ‘learning curve’ it was associated with significant morbidity and mortality. This perhaps restricted its overall uptake and acceptance on the scale of a kidney-alone transplant in diabetes with renal failure. It still is a procedure that could be associated with a significant degree of morbidity or mortality directly related to the surgical procedure. In the last two decades, simultaneous pancreas and kidney (SPK) transplantation has become technically more refined and standardised and to date over 32,000 procedures have been done worldwide with ever improving results (http://www.iptr.umn.edu/; Perosa et al. 2011).

Over 70% of pancreas transplants are done simultaneously with an SPK in individuals who have developed diabetic nephropathy from long-term Insulin Dependent Diabetes Mellitus (IDDM). The benefits of combining a pancreas with a deceased donor kidney are convincingly shown in several studies (Reddy et al. 2003). It is demonstrated that the long-term survival in Type I Diabetics undergoing kidney transplantation are increased significantly if a pancreas is transplanted simultaneously and the pancreas functions maintaining normal blood sugar levels (Tyden et al. 2000; Ojo et al. 2001). The next group of recipients is the pancreas after kidney (PAK) group, where a kidney has been previously transplanted and individuals undergo a pancreas transplant subsequently for continuing complications associated with diabetes. A subgroup of this is pancreas after living donor kidney (PALK) transplantation where there is improved kidney graft and patient survival after transplantation but with increased pancreas graft loss (Poommipanit et al. 2010). The third group, pancreas transplant alone (PTA) are recipients who undergo pancreas transplantation alone for brittle diabetes with major diabetic complications including hypoglycaemia unawareness and other end-organ involvement without renal dysfunction requiring the need for a kidney transplant also.

Islet transplantation is to be considered as a different entity altogether compared to pancreas transplantation and its indications are mainly limited to individuals with severe hypogly-caemia unawareness in its current state.

THE BENEFITS OF PANCREAS TRANSPLANTATION

  1. Top of page
  2. SUMMARY
  3. BACKGROUND
  4. THE BENEFITS OF PANCREAS TRANSPLANTATION
  5. SELECTION OF THE POTENTIAL RECIPIENT
  6. LISTING AND ALLOCATION
  7. DONOR SELECTION AND FACTORS
  8. RECIPIENT OPERATIVE TECHNIQUES
  9. INTRA-OPERATIVE MANAGEMENT
  10. POST-OPERATIVE MANAGEMENT AND COMPLICATIONS
  11. IMMUNOSUPPRESSION AND REJECTION
  12. LONG-TERM OUTCOMES
  13. SPECIAL SITUATIONS
  14. CONCLUSION
  15. CONFLICT OF INTEREST
  16. Appendix
  17. REFERENCES

Successful kidney pancreas transplantation is perhaps the one therapeutic technique in the treatment of diabetes with renal failure that addresses the entire multi-system complications of diabetes and whose benefits extend far beyond that of normal glucose homeostasis and re-established allograft renal function. The most immediate benefit is freedom from insulin delivery by whatever method with normal blood sugar levels and an instantaneous improvement in quality of life, and relief of hypoglycaemic episodes both with unawareness or awareness which are potentially life threatening in a subgroup of diabetics on insulin therapy. Demartines reviewed 2,481 articles including 48 randomised controlled trials and 214 clinical trials and found kidney pancreas transplantation to significantly improve quality of life and to be superior to a combination of dialysis/transplantation and insulin (Demartines et al. 2005). Additionally, sustained euglycaemia leads to stabilisation in progression of diabetic multi-system complications. Jukema showed that the progressive narrowing of coronary arteries slowed with successful pancreas transplantation (Jukema et al. 2002). Cardiac contractility and ejection fraction has also been shown to be improved (Fiorina et al. 2000). A Minnesota study shows that diabetic lesions in kidneys of individuals receiving pancreas transplants alone show improvement (Fioretto et al. 1998). Improvements have been shown in nerve conduction (Navarro et al. 1997) and more recently corneal nerve regeneration has been demonstrated to occur within six months of successful pancreas transplantation by corneal confocal microscopy (Mehra et al. 2007; see Figure 1). It has also been shown by investigators that retinal changes of diabetes stabilise and there is some improvement in reported eye symptoms and sight with reduction in the need for ophthalmic intervention (Koznarova et al. 2000; Giannarelli et al. 2005). Gastric emptying has also been shown to be improved after pancreas transplantation (Gaber et al. 1991). There have also been isolated individual reports, like resolution of diabetic cheiroarthropathy (Hider et al. 2004).

image

Figure 1. Corneal confocal microscopy images showing corneal nerve regeneration after pancreas transplantation (Courtesy: Professor Rayaz Malik and Dr. Mitra Tavakoli, Cardiovascular Research Group, Manchester University).

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There have been no randomised controlled trials comparing pancreas transplantation with optimum insulin therapy, however significant benefits have been demonstrated in cohorts of recipients who have undergone the procedure not withstanding the benefits from reversal of uraemia by the associated kidney allograft. Although all these benefits are clearly described and documented, there is still a large discrepancy in the numbers of simultaneous pancreas kidney transplants done versus the diabetic population overall. SPK transplantation is considered to be one transplant procedure associated with significant perioperative morbidity and mortality and hence recipients need to be much more critically selected than kidney transplants alone.

SELECTION OF THE POTENTIAL RECIPIENT

  1. Top of page
  2. SUMMARY
  3. BACKGROUND
  4. THE BENEFITS OF PANCREAS TRANSPLANTATION
  5. SELECTION OF THE POTENTIAL RECIPIENT
  6. LISTING AND ALLOCATION
  7. DONOR SELECTION AND FACTORS
  8. RECIPIENT OPERATIVE TECHNIQUES
  9. INTRA-OPERATIVE MANAGEMENT
  10. POST-OPERATIVE MANAGEMENT AND COMPLICATIONS
  11. IMMUNOSUPPRESSION AND REJECTION
  12. LONG-TERM OUTCOMES
  13. SPECIAL SITUATIONS
  14. CONCLUSION
  15. CONFLICT OF INTEREST
  16. Appendix
  17. REFERENCES

The selection process for listing a potential recipient for each of the three categories of pancreas transplantation (SPK, PAK and PTA) is critical and should be rigorously done, as the combination of diabetes and renal failure with multi-system comorbidity potentially increases the morbidity and mortality of the procedure when compared to a kidney transplant alone. It is essential, hence that the risk benefit ratio of the addition of a pancreas with the kidney is fully evaluated and determined and also discussed with the patient before activation on the list (Table 1).

Table 1.  Selection criteria for simultaneous pancreas and kidney transplant.
Confirmed diabetic nephropathy on insulin
On dialysis or pre-dialysis
Creatinine clearance <30 ml/min
Presence of other secondary diabetic complications
Ability to withstand surgery and immunosuppression
Adequate cardiovascular reserve
Normal myocardial perfusion scan
If abnormal, adequate evaluation and intervention prior to listing
Proven history of compliance with treatment
Understanding of potential morbidity and mortality
BMI below 30
Age below 65

The first step in the evaluation process is determination of the type of diabetes. The American Diabetes Association (ADA) classifies DM into Type 1 and Type 2. Type 1 diabetics are patients with low or absent insulin production as confirmed by low or absent levels of C-peptide (ADA guidelines 2010). It is perhaps good practice to document C-peptide levels as part of the listing evaluation of potential recipients and levels are obtained in recipients by many transplanting centres. Most of the patients with Type 1 diabetes are young (below 25 years of age) at the time of initial diagnosis, Type 1 diabetes may develop at any age, even in older individuals. Type 2 diabetes may range from predominantly insulin resistance with relative insulin deficiency to a predominantly secretory defect with insulin resistance. There are reports in literature of pancreas transplantation in Type 2 Diabetes (Orlando et al. 2010). Pancreas transplantation is also rarely considered in Type 2 Diabetes associated with diseases of the exocrine pancreas, for example, pancreatectomy after chronic pancreatitis or other benign indications, cystic fibrosis (Fridell et al. 2008) and rarer conditions like insulin allergy.

In an SPK, the essential organ in almost all instances is the kidney and the addition of a pancreas, while improving quality of life primarily, contributes to increasing longevity after the initial increased mortality associated with the periopera-tive period. This comes into effect perhaps a year after transplantation (Dean et al. 2008). Stabilisation with consolidation of diabetic complications occur incrementally after the pancreas has been functioning for several years (Nakache et al. 1989). It should however be recognised that there is a significant incidence of death on the waiting list (Casingal et al. 2006). Listing older recipients for transplantation increases the potential morbidity and mortality. Most transplanting units are reluctant to offer simultaneous kidney pancreas transplantation to individuals over the age of 50 years, quoting high mortality, however there are now increasing reports of good outcomes in older recipients (Ablorsu et al. 2008; Gruessner & Sutherland 2011). Complications like amputations, significant peripheral neuropathy, Charcot's joints, autonomic neuropathy with postural hypotension, diabetic gastroparesis, etc. are considered relative contraindications and centres approach these patients according to individual degree of experience and expertise. These may be, however, individuals who stand to gain the most from successful kidney pancreas transplantation. An important determinant in assessing suitability is the recipient's cardiovascular status. Listed recipients have had diabetes for long periods of time, with underlying macro and microvascular disease, with overt or subclinical coronary artery insufficiency and myocardial dysfunction, and also peripheral vascular insufficiency. If unrecognised, these may substantially increase the perioper-ative risk of death or graft loss. Cardiac evaluation hence forms an important and crucial part of transplant workup. Until the last decade, clear coronary angiograms were considered mandatory before activation on the transplant waiting list; however, now nuclear myocardial perfusion scans give equivalent results and coronary angiograms are usually reserved for individuals with abnormal perfusion scans (Ruparelia et al. 2011). Significant flow limiting lesions detected are dealt with by angioplasty, stenting or coronary artery bypass grafting before activation on the list. The functional capacity of the heart is evaluated by echocardiography and an ejection fraction below 40% is considered a relative contraindication for pancreas transplantation.

Most of the other components of the transplant workup are similar to other solid organ transplants and include a thorough history and clinical examination, taking into account all previous medical conditions, especially related to diabetic comorbidity. Laboratory studies, include haematology, coagulation profile, liver and renal function tests, lipid profile, viral serology, tissue typing including ABO blood group typing, HLA typing including DR typing, antibody titres and panel reactive antigen activity. All recipients have a cancer screen with mam-mograms in women over 35 years, and also gynaecological examination and a PAP smear. All men over 40 years should have a PSA and a flexible sigmoidoscopy in individuals with lower GI symptoms (Table 2).

Table 2.  Evaluation Protocol for a Pancreas Recipient.
Preliminary evaluationMultidisciplinary initial evaluation for suitability (Nephrology, Diabetology, Dialysis Team, Transplant Coordinator). If found suitable, general workup commences
HaematologyHb, WCC, differential, platelets
Blood group and typeABO
Renal function testsCreatinine with clearance, urea, Po4, Hco3
Liver function testsALT, AST, albumin, total proteins
Coagulation profileAPTT, PT
Lipid profile 
C peptide levels 
Hb A1c 
CRP 
Transplant virologyCMV, Hepatitis B, Hepatitis C, HIV, EBV, Herpes simplex, Herpes zoster, Varicella
Immunologic testsHLA typing including DR typing, Antibody levels, PRA levels
RadiologyCXR. US scans if indicated. Vascular Dopplers and CT angiograms or MR angiograms if clinically indicated
Cancer screeningMammograms in women >35, PSA levels >40 yrs,
SigmoidoscopyIf indicated
Cardiac evaluationECG, Echo, myocardial perfusion scan, cardiopulmonary exercise test
Final surgical assessmentDiscussion of results and informed consent
Transplant listing 

The selection of recipients for kidney pancreas transplantation continues to evolve with more complex and higher risk patients being listed as overall results improve. To an extent, these are dictated by the preferences, numbers and experience of transplant centres. Coupled with more complex recipients more and more marginal donors are being considered as pancreas donors (UK National Health Service Blood and Transplant [NHSBT] donor offering data) making the ultimate decision to transplant a pancreas into an individual recipient quite critical.

LISTING AND ALLOCATION

  1. Top of page
  2. SUMMARY
  3. BACKGROUND
  4. THE BENEFITS OF PANCREAS TRANSPLANTATION
  5. SELECTION OF THE POTENTIAL RECIPIENT
  6. LISTING AND ALLOCATION
  7. DONOR SELECTION AND FACTORS
  8. RECIPIENT OPERATIVE TECHNIQUES
  9. INTRA-OPERATIVE MANAGEMENT
  10. POST-OPERATIVE MANAGEMENT AND COMPLICATIONS
  11. IMMUNOSUPPRESSION AND REJECTION
  12. LONG-TERM OUTCOMES
  13. SPECIAL SITUATIONS
  14. CONCLUSION
  15. CONFLICT OF INTEREST
  16. Appendix
  17. REFERENCES

Once listed, waiting times and allocation are dictated by national and local guidelines and allocation schemes. This leads to an impact on individual waiting times. In the United Kingdom, there are very clear allocation guidelines that are overseen by NHSBT. The role of Human Leukocyte Antigen (HLA) matching and pancreas transplant outcomes is complex and has several other interlinked issues other than transplant outcomes alone (Lo et al. 2005). If poorly matched organs are transplanted, the sensitisation caused may impact on subsequent transplants especially of the kidney. The underpinning principle however is to offer as well-matched grafts as possible with the shortest possible cold ischemic time.

DONOR SELECTION AND FACTORS

  1. Top of page
  2. SUMMARY
  3. BACKGROUND
  4. THE BENEFITS OF PANCREAS TRANSPLANTATION
  5. SELECTION OF THE POTENTIAL RECIPIENT
  6. LISTING AND ALLOCATION
  7. DONOR SELECTION AND FACTORS
  8. RECIPIENT OPERATIVE TECHNIQUES
  9. INTRA-OPERATIVE MANAGEMENT
  10. POST-OPERATIVE MANAGEMENT AND COMPLICATIONS
  11. IMMUNOSUPPRESSION AND REJECTION
  12. LONG-TERM OUTCOMES
  13. SPECIAL SITUATIONS
  14. CONCLUSION
  15. CONFLICT OF INTEREST
  16. Appendix
  17. REFERENCES

Donor selection is a critical factor which affects transplant and graft outcomes. The best outcomes are achieved with organs from young donors below 45 years of age, with Body Mass Index (BMI) below 28 and with short cold ischemic times below 12 hours. Outcomes are best if the donor has not succumbed to cerebrovascular disease (Douzdjian et al. 1995). The donor procedure has to be meticulously carried out by an experienced retrieval surgeon, keeping in mind the importance of thorough evaluation of the pancreas, confirming lack of fibrosis, steatosis and other pathology with minimal handling of the organ, using the spleen as a handle, ensuring that the vascular supply, especially the inferior pancreaticoduodenal artery is intact. The University of Wisconsin (UW) solution is used for perfusion of the pancreas and care taken to avoid portal perfusion if possible to prevent pancreatic congestion with potential graft pancreatitis. Graft outcomes are closely related to cold ischemic times with best results below 12 hours and increasing perioperative morbidity the longer the cold ischaemic time. Nevertheless, good outcomes are being obtained with non-heart beating pancreas transplants (D’Alessandro et al. 2000)

The pancreas is retrieved en bloc with the duodenum, peripancreatic tissue and the spleen. Variations in anatomy, especially the right hepatic artery arising from the superior mesenteric artery are noted and retrieval techniques adapted to incorporate them. The distal superior mesenteric artery is divided with care distally in order not to damage the inferior pancreaticoduodenal artery. Once retrieved the graft is prepared on the bench, after further careful evaluation of the organ and quality of perfusion excising surface fatty tissue, ensuring that the parenchyma is not breached. Meticulous haemostasis is maintained during preparation, ligating or suturing all potential bleeding points. Once defatted, vascular inflow is reconstructed with a donor iliac artery Y graft consisting of the external iliac artery, which is usually anastomosed to the superior mesenteric artery and the internal iliac artery anastomosed to the splenic artery. Some centres use additional arterial inflow by anastomosing the gastroduodenal artery to a point of variable inflow. The venous outflow is through the portal vein, which may in certain situations need a venous extension graft (Fridell et al. 2011).

RECIPIENT OPERATIVE TECHNIQUES

  1. Top of page
  2. SUMMARY
  3. BACKGROUND
  4. THE BENEFITS OF PANCREAS TRANSPLANTATION
  5. SELECTION OF THE POTENTIAL RECIPIENT
  6. LISTING AND ALLOCATION
  7. DONOR SELECTION AND FACTORS
  8. RECIPIENT OPERATIVE TECHNIQUES
  9. INTRA-OPERATIVE MANAGEMENT
  10. POST-OPERATIVE MANAGEMENT AND COMPLICATIONS
  11. IMMUNOSUPPRESSION AND REJECTION
  12. LONG-TERM OUTCOMES
  13. SPECIAL SITUATIONS
  14. CONCLUSION
  15. CONFLICT OF INTEREST
  16. Appendix
  17. REFERENCES

Most transplant centres now use the intra-peritoneal approach for graft placement with the pancreas positioned on one side and the kidney placed on the opposite side. Extraperitonel and ipsilateral placement of both grafts have also however been described with varying approaches from a long mid-line incision, lower curved transverse and bilateral incisions.

Generally, the usual vascular management is to anastomose the arterial conduit to the common iliac artery and the portal vein to the common iliac vein or the lower inferior vena cava. A more metabolically superior physiological variation of venous drainage was described by (Shokouh-Amiri et al. 1992) and (Gaber et al. 1993) where the portal vein of the graft is anastomosed to a portal venous radicle, a tributary of the superior mesenteric vein. Portal venous drainage is thought to prevent hyperinsulinism with insulin resistance, dyslipidaemia, accelerated atherosclerosis and microangiopathy.

An inherent drawback of solid organ pancreas transplantation is the production of exocrine secretion by the pancreas and the requirement to deal with it in a suitable manner. Historically, the pancreatic duct was dealt with by varying techniques, including ligation, injection with polymers, followed by duodenal drainage to the bladder and then to ileum, jejunum and to the duodenum by a variety of techniques. The most popular current technique is an enteric drainage to a loop of jejunum. However, variations of the technique use duodenal drainage to the ileum or a Roux-en-Y method. Retroperitoneal placement with duodeno-duodenal anastomosis is also done. Over 50% of recipients with grafts drained into the bladder will require an enteric conversion some time in the future due to various complications.

INTRA-OPERATIVE MANAGEMENT

  1. Top of page
  2. SUMMARY
  3. BACKGROUND
  4. THE BENEFITS OF PANCREAS TRANSPLANTATION
  5. SELECTION OF THE POTENTIAL RECIPIENT
  6. LISTING AND ALLOCATION
  7. DONOR SELECTION AND FACTORS
  8. RECIPIENT OPERATIVE TECHNIQUES
  9. INTRA-OPERATIVE MANAGEMENT
  10. POST-OPERATIVE MANAGEMENT AND COMPLICATIONS
  11. IMMUNOSUPPRESSION AND REJECTION
  12. LONG-TERM OUTCOMES
  13. SPECIAL SITUATIONS
  14. CONCLUSION
  15. CONFLICT OF INTEREST
  16. Appendix
  17. REFERENCES

Although successful pancreas transplantation is highly effective, the main criticism of the procedure is that it is a major surgical procedure for the treatment of diabetes compared to optimum medical management that is non-invasive. The potent mix of a long-term diabetes with significant cardiovascular and other systemic morbidity undergoing a major operative procedure leads to significant intra-operative physiologic shifts requiring invasive monitoring along with large volume transfusion of crystalloids, colloids and blood. A crucial time is revascularisation where there may be haemorrhage and cardiovascular instability due to cytokine release from the revas-cularised pancreas, requiring prompt response from the anaesthetic team. This may lend to coronary insufficiency in recipients with underlying disease, hence the importance of thorough cardiovascular screening during the workup period.

However, in the majority of cases there is immediate graft function with normalisation of blood sugar and euglycaemia and on occasions the need for dextrose infusion due to persistent hypoglycaemia. It is imperative that blood sugars are regularly checked after revascularisation.

POST-OPERATIVE MANAGEMENT AND COMPLICATIONS

  1. Top of page
  2. SUMMARY
  3. BACKGROUND
  4. THE BENEFITS OF PANCREAS TRANSPLANTATION
  5. SELECTION OF THE POTENTIAL RECIPIENT
  6. LISTING AND ALLOCATION
  7. DONOR SELECTION AND FACTORS
  8. RECIPIENT OPERATIVE TECHNIQUES
  9. INTRA-OPERATIVE MANAGEMENT
  10. POST-OPERATIVE MANAGEMENT AND COMPLICATIONS
  11. IMMUNOSUPPRESSION AND REJECTION
  12. LONG-TERM OUTCOMES
  13. SPECIAL SITUATIONS
  14. CONCLUSION
  15. CONFLICT OF INTEREST
  16. Appendix
  17. REFERENCES

Post-operatively, patients should be monitored in a high dependency setting with regular evaluation of vital parameters and blood sugars. Different centres use different anti-coagulation protocols as it is fairly well recognised that thrombosis is a major complication because of the low flow state of the pancreas.

Pancreas transplantation is perhaps associated with more periop-erative morbidity than other solid organ transplants due to a combination of factors, including the long-term effects of diabetes in the recipient, and the difficult nature of the pancreas itself.

The commonest post-operative complications are vascular chiefly graft thrombosis, reported to range between 6% and 12% (Troppmann et al. 1996) manifested by a sudden rise in blood sugars. Confirmation is by duplex scanning, computed tomography (CT) or magnetic resonance (MR) angiography (Hagspiel et al. 2007). Unfortunately, in over 90%, the treatment is by explanting the graft although there have been case reports of thrombolysis or surgical thrombectomy (Nghiem 1995) resolving the thrombus. Haemorrhage is also common as diabetics with renal failure may be coaguopathic along with different anticoagulation regimes (Vaidya et al. 2007). It may require correction of Vitamin K deficiency, clotting factors, transfusions and repeat surgery to control bleeding. Other important but rarer complications are mycotic aneurysms associated with the arterial anastomoses (Verni et al. 2001), or pancreas, aortoenteric fistulae and a steal syndrome and also distal emboli.

In addition to vascular complications, other intra-abdominal complications may range from mild to life threatening. They include ileus, small bowel obstruction, wound infection, gas-troparesis, haematomas, seromas and wound infections. Intra-abdominal infections could be caused by infection of peripan-creatic collections, duodenal or duodenal enteric leaks. These infective complications have been found to be related to recipient and donor factors including BMI, donor age, pancreatic steatosis, cold ischaemic time, surgical technique, and peritoneal dialysis (Humar et al. 2000a).

The incidence of bladder-related complications have reduced with the overall move towards enteric drainage of pancreas allografts, however there is reported to be a high incidence of metabolic acidosis, dysuria, urethritis and reflux pancreatitis in the group (Baktavatsalam et al. 1998) leading to an over 50% need for cysto-enteric conversion with excellent outcomes (Sollinger et al. 2009).

In numerous analyses worldwide, there is increasing evidence that the incidence of surgical complications have decreased in the modern era (Humar et al. 2000b). These may be related to improved techniques, more stringent donor selection and earlier diagnosis and intervention.

IMMUNOSUPPRESSION AND REJECTION

  1. Top of page
  2. SUMMARY
  3. BACKGROUND
  4. THE BENEFITS OF PANCREAS TRANSPLANTATION
  5. SELECTION OF THE POTENTIAL RECIPIENT
  6. LISTING AND ALLOCATION
  7. DONOR SELECTION AND FACTORS
  8. RECIPIENT OPERATIVE TECHNIQUES
  9. INTRA-OPERATIVE MANAGEMENT
  10. POST-OPERATIVE MANAGEMENT AND COMPLICATIONS
  11. IMMUNOSUPPRESSION AND REJECTION
  12. LONG-TERM OUTCOMES
  13. SPECIAL SITUATIONS
  14. CONCLUSION
  15. CONFLICT OF INTEREST
  16. Appendix
  17. REFERENCES

With improving technical results, immunological graft loss is perhaps the largest reason for graft loss. The pancreas allo-graft is considered to elicit a more immunologic response than a liver and kidney allograft (Sollinger et al. 1998) and acute rejection can impact on long-term pancreas survival and has been demonstrated to be an important risk factor for development of chronic rejection (Humar et al. 2003). The incidence of pancreas rejection varies by recipient category: it is highest in non-uraemic PTA patients, next highest in post-uraemic PAK recipients and lowest in uraemic SPK recipients (Reddy et al. 2000).

Most immunosuppressive regimens currently use a quadruple regime with an induction agent; either polyclonal (Horse or Rabbit anti-thymocyte globulin, ATGAM or Thymoglobulin) or monoclonal (Basiliximab or Alentuzumab) followed by maintenance with a calcineurin inhibitor drug Tacrolimus which acts by inhibiting the phosphatase enzyme calcineurin leading to a reduced function of effector T-cells which encourages rejection and an anti-metabolite agent Mycophenolate Mofetil and steroids. An analysis of the United Network of Organ Sharing (UNOS) database, shows that since 1997, Tacrolimus use has increased substantially and is now being used in over 80% of SPK recipients (Heilman et al. 2010). Steroid withdrawal is feasible in pancreas transplantation (Humar et al. 2000c) and more recently with Alentuzumab induction there is a more definitive trend towards steroid-free regimes or steroid minimisation. Many of these strategies try to evaluate T-cell depletion followed by Tacrolimus monotherapy. However, it is extremely important to be aware of the fact that chronic rejection of pancreas transplantation is not well understood and that more studies will be required to come to the optimum long-term maintenance regimen (Cantarovich & Vistoli 2009).

In SPK transplantation, in over 90% of cases rejection occurs in both the pancreas and kidney allograft, although it is first manifest by a rise in serum creatinine and only later by a rise in blood glucose; however discordant rejection where one organ rejects (Sutherland et al. 1995) is described. Rejection is diagnosed by a combination of clinical suspicion along with biochemical confirmation. Biochemical parameters of pancreas rejection, include a raised amylase and lipase and blood sugars, which is however a late manifestation of pancreas rejection. Discordant pancreas rejection in which the pancreas rejects in isolation from the kidney is rare and along with rejection in PAK and PTA can only be made with certainty with a pancreas graft biopsy and histology (Figure 2). There is a grading system for pancreas transplant biopsies akin to the Banff system for kidneys (Drachenberg et al. 2008). The treatment of acute rejection episodes, are with steroid boluses initially with more powerful agents like Anti-thymocyte globulin (ATG) if there is no response. It is also extremely important that rejection has to be differentiated from graft pancreatitis by a combination of clinical features, biochemistry and graft biopsy.

image

Figure 2. Image of pancreas rejection.

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No universally accepted definition of chronic rejection exists for pancreas allografts. The clinical course is manifest by a gradual deterioration in graft function with the exocrine component affected first, followed by episode of hyperglycaemia and the need for insulin therapy. A biopsy generally shows arteriopathy with concentric narrowing of small vessels and parenchymal fibrosis with atrophy of acini. The vascular changes seen are similar to those observed in kidney and heart transplants with specific changes showing presence of recent and organised thrombosis in the arteries and veins (Drachenberg et al. 2001).

LONG-TERM OUTCOMES

  1. Top of page
  2. SUMMARY
  3. BACKGROUND
  4. THE BENEFITS OF PANCREAS TRANSPLANTATION
  5. SELECTION OF THE POTENTIAL RECIPIENT
  6. LISTING AND ALLOCATION
  7. DONOR SELECTION AND FACTORS
  8. RECIPIENT OPERATIVE TECHNIQUES
  9. INTRA-OPERATIVE MANAGEMENT
  10. POST-OPERATIVE MANAGEMENT AND COMPLICATIONS
  11. IMMUNOSUPPRESSION AND REJECTION
  12. LONG-TERM OUTCOMES
  13. SPECIAL SITUATIONS
  14. CONCLUSION
  15. CONFLICT OF INTEREST
  16. Appendix
  17. REFERENCES

Data from the International Pancreas Transplant Registry (IPTR) and the UNOS database shows a pancreas survival rate of around 50% at 10 years and a kidney survival rate of about 60% for all first time SPK grafts done in the USA between January 1987 and December 2010. In the United Kingdom, the 5-year survival of the pancreas in an SPK is 72% and a kidney survival of 88%. The majority of graft losses are due to early post-operative losses from thrombosis or other surgical complications, followed by loss due to chronic rejection. Loss of grafts from recurrent autoimmu-nity with recurrence of diabetes has been described (Burke et al. 2011). There are also a significant number of individuals who die with functioning grafts. In individuals whose grafts have failed due to various reasons, re-transplantation is a viable option (Wang et al. 2008) and increasingly being offered in many centres.

SPECIAL SITUATIONS

  1. Top of page
  2. SUMMARY
  3. BACKGROUND
  4. THE BENEFITS OF PANCREAS TRANSPLANTATION
  5. SELECTION OF THE POTENTIAL RECIPIENT
  6. LISTING AND ALLOCATION
  7. DONOR SELECTION AND FACTORS
  8. RECIPIENT OPERATIVE TECHNIQUES
  9. INTRA-OPERATIVE MANAGEMENT
  10. POST-OPERATIVE MANAGEMENT AND COMPLICATIONS
  11. IMMUNOSUPPRESSION AND REJECTION
  12. LONG-TERM OUTCOMES
  13. SPECIAL SITUATIONS
  14. CONCLUSION
  15. CONFLICT OF INTEREST
  16. Appendix
  17. REFERENCES

Successful living donor pancreas transplantation, and also combined simultaneous living donor pancreas and kidney transplantation has been described in literature in a small group of donors and recipients (Sutherland 2011). However, donor pancreatec-tomy is a major surgical adventure with the potential for severe comorbidity and the potential for donor diabetes, therefore there has to be strong ethical justification to embark on it even though recent literature suggests good outcomes in experienced centres (Boggi et al. 2011). There are also several reports of combined deceased donor pancreas along with living donor kidney transplants (Farney et al. 2000) which enable the deceased donor kidney to be used for someone else on the waiting list.

CONCLUSION

  1. Top of page
  2. SUMMARY
  3. BACKGROUND
  4. THE BENEFITS OF PANCREAS TRANSPLANTATION
  5. SELECTION OF THE POTENTIAL RECIPIENT
  6. LISTING AND ALLOCATION
  7. DONOR SELECTION AND FACTORS
  8. RECIPIENT OPERATIVE TECHNIQUES
  9. INTRA-OPERATIVE MANAGEMENT
  10. POST-OPERATIVE MANAGEMENT AND COMPLICATIONS
  11. IMMUNOSUPPRESSION AND REJECTION
  12. LONG-TERM OUTCOMES
  13. SPECIAL SITUATIONS
  14. CONCLUSION
  15. CONFLICT OF INTEREST
  16. Appendix
  17. REFERENCES

Combined kidney and pancreas transplantation in diabetes with renal failure is perhaps the single therapeutic measure that could be considered the gold standard of treatment. Kidney transplantation along with beta cell replacement addresses renal failure and also the underlying aetiology which is insulin deficiency leading to euglycaemia and stabilisation of diabetic complications. Although it involves major surgery, and the outcomes are governed by multiple variables, current techniques and immunosuppression, in suitably selected eligible recipients, combined kidney and pancreas transplantation lead to excellent results in experienced large volume centres. It should be considered in the management of any suitable person with diabetes and with renal failure in whom current insulin regimes and dialysis do not improve quality of life or who have progressive complications of diabetes.

Appendix

  1. Top of page
  2. SUMMARY
  3. BACKGROUND
  4. THE BENEFITS OF PANCREAS TRANSPLANTATION
  5. SELECTION OF THE POTENTIAL RECIPIENT
  6. LISTING AND ALLOCATION
  7. DONOR SELECTION AND FACTORS
  8. RECIPIENT OPERATIVE TECHNIQUES
  9. INTRA-OPERATIVE MANAGEMENT
  10. POST-OPERATIVE MANAGEMENT AND COMPLICATIONS
  11. IMMUNOSUPPRESSION AND REJECTION
  12. LONG-TERM OUTCOMES
  13. SPECIAL SITUATIONS
  14. CONCLUSION
  15. CONFLICT OF INTEREST
  16. Appendix
  17. REFERENCES

BIODATA

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Titus Augustine is a Consultant Transplant and Endocrine Surgeon and Cl inical Director of Transplantation at Central Manchester University Hospitals Manchester UK. He studied undergraduate medicine followed by a postgraduate residency in Surgery at St. John's National Institute of Health Sciences, Bangalore, India where he worked in the surgical faculty for a further three years before more training in the United Kingdom. In the United Kingdom, he completed the Edinburgh Fellowship and undertook further training in the Northwest. In 1996, he commenced training in kidney transplantation at Manchester Royal Infirmary followed by a Fellowship in Multi–organ transplantation at St. James's University Hospital Leeds in 1999 before being appointed consultant in Manchester in 2000 on completion of the Intercollegiate Examinations in Surgery and Transplantation. He led the revival of Pancreas transplantation in Manchester with several innovations including the first non-heart beating pancreas transplant in the United Kingdom. He is a member of the UK Pancreas advisory board. His other major interest is the Surgical Management of Encapsulating Peritoneal Sclerosis and he leads one of two UK referral centres for this condition with national and international referrals. He also leads laparoscopic donor nephrectomy and adrenalectomy and is keenly involved in the surgical training of juniors and mentoring. He enjoys travelling and has driven from Manchester to Gambia across the Western Sahara.

REFERENCES

  1. Top of page
  2. SUMMARY
  3. BACKGROUND
  4. THE BENEFITS OF PANCREAS TRANSPLANTATION
  5. SELECTION OF THE POTENTIAL RECIPIENT
  6. LISTING AND ALLOCATION
  7. DONOR SELECTION AND FACTORS
  8. RECIPIENT OPERATIVE TECHNIQUES
  9. INTRA-OPERATIVE MANAGEMENT
  10. POST-OPERATIVE MANAGEMENT AND COMPLICATIONS
  11. IMMUNOSUPPRESSION AND REJECTION
  12. LONG-TERM OUTCOMES
  13. SPECIAL SITUATIONS
  14. CONCLUSION
  15. CONFLICT OF INTEREST
  16. Appendix
  17. REFERENCES