Pancreas Transplantation

Despite significant advances in medical treatment, whole pancreas transplantation is the only treatment for T1DM that consistently achieves the ultimate goal of normoglycaemia without a significantly increased risk of hypoglycaemia. Whole pancreas transplantation allows also freedom from the continuous attention to blood glucose control that medical therapies require. Enthusiasm for the outcomes offered by transplantation is tempered by fear of the risks of the transplant procedure, in particular the risks associated with the need for immunosuppressive therapy. Furthermore, evidence of benefit with regard to microvascular and macrovascular complications of diabetes has been lacking. Data are now available to allow objective discussion of risks and benefits for individual patients. It is essential that the benefits offered by pancreas transplantation are embraced and that this treatment is offered to patients for whom it is likely to result in significant improvement in quality of life. Whole pancreas transplantation may be carried out as simultaneous pancreas kidney (SPK) transplantation for the patient who also requires renal replacement therapy, pancreas after kidney (PAK) transplantation for the patient with a successful kidney transplant, or solitary pancreas transplantation (PTA) for the patient with normal kidney function.

Development of Pancreas Transplantation

Following the first clinical pancreatic transplantation, performed on 16th December 1966, 25,030 procedures have been reported to the international pancreas transplant registry (IPTR) up to 31st Dec 2010 [1].

The development and current standing of pancreas transplantation have been reviewed recently by two of the pioneers in the field [2] and by White et al [3]. Techniques for pancreas transplantation have evolved over this time, in particular with regard to ‘management’ of the endocrine and exocrine secretions of the transplanted pancreas. Most centres now use drainage of exocrine secretions into the gastrointestinal tract (enteric drainage - ED), with drainage of endocrine secretions into the recipient’s systemic circulation (systemic venous drainage - SVD) [3].

Outcomes

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Patient and graft survival for transplants reported to the IPTR up to 31st December have been reviewed by Gruessner [1]. At 10 years post-transplant, the overall patient survival rate is >70% with the highest patient survival rate in PTA recipients, with a 10-year survival rate of 82%.
One-year pancreas graft function was 85.5%, 79.9% and 77.8% for SPK, PAK and PTA grafts respectively in 2006-2010 with an overall technical failure rate of 8-9% for all three categories. This translates to half-lives for both primary SPK pancreas and kidney grafts of more than 10 years. In comparison the graft half-lives for primary solitary pancreas transplantation for transplantations performed between 1998 and 2001 are 76 months for PAK and 71 months for PTA.

Microvascular complications

Data on the impact of whole pancreas transplantation on microvascular complications are poor as reviewed by Smith and Friend [4]. The impact of pancreas transplantation on diabetic nephropathy is complicated by the deleterious effects of immunosuppressive agents on kidney function, although data using calcineurin inhibitor free immunosuppressive regimens, which may avoid these effects, are currently lacking. Giaranelli et al [5] have demonstrated a convincing benefit on retinopathy. Study of the impact on neuropathy is confined to case reports and small series, but improvement in neurophysiological parameters has been demonstrated. Overall, insufficient data are available to allow transplantation for prevention of progression of microvascular complications as a primary indication. However, in some patients, the possibility of protection against progression of these complications may form part of the overall risk benefit analysis.

Macrovascular complications

Rigorous demonstration of improvement in macrovascular complications is lacking such that this cannot be used as an indication for whole pancreas transplantation.

Quality of Life

Perhaps the most important outcome measure following beta cell replacement is quality of life, in many respects this integrating and prioritising all of the above measures, appropriately for the individual patient. Successful whole pancreas transplantation is a very effective treatment for hypoglycaemia and it frees the patient from the daily rigors of blood glucose management. Thus, improvements in quality of life might be expected. However, the burden of transplantation should not be underestimated and the impact of decades of managing diabetes often grumbles on. Thus, objective assessment of the impact of pancreas transplantation on quality of life is largely lacking and urgently needed [6]. Anecdotally, appropriately selected patients find this a life changing procedure, but this is not universally the case.

Complications

Current US data show a 12 month patient mortality of 4.5% after pancreas transplantation, which compares with a waiting list mortality (SPK) of 3.9% [7]. In all 3 categories, cardio/cerebrovascular (CCV) complications and infections are the leading causes of death. In all 3 categories the initial rate of malignancies is low, but malignancy accounts for 7% of all deaths occurring more than 1 year post-transplant.

Indications for beta cell replacement

The ADA position statement [8] considers pancreas transplantation, as SPK or PAK, an ‘acceptable therapeutic alternative to continued insulin therapy’ as survival is not ‘jeopardized’ and kidney transplant survival may be improved.
The ADA statement further considers: (i) a history of frequent, acute, and severe metabolic complications requiring medical attention (ii) clinical and emotional problems with exogenous insulin therapy that are so severe as to be incapacitating (iii) consistent failure of insulin-based management to prevent acute complications as indications for pancreas transplantation alone.

The UK criteria are in accordance with the ADA position statement for SPK. PTA is considered appropriate for patients with two episodes of severe hypoglycaemia within 24 momths. It is suggested that SPK as opposed to PTA is appropriate if eGFR is <20ml/min.

Summary

Outcomes of whole pancreas transplantation are now good, making this an important treatment option for many patients with type 1 diabetes. Selection of the patient whose specific problems are amenable to treatment by transplantation and who is able to survive the physical and psychological demands of the procedure, is central to the success of whole pancreas transplantation. When deciding whether to refer for whole pancreas transplantation, the patient must be at least an equal partner in the decision making process, the clinician ensuring that their own risk aversion is not a significant factor.

References

  1. ^ Gruessner AC 2011 Update on Pancreas Transplantation: Comprehensive Trend Analysis of 25,000 Cases Followed Up Over the Course of Twenty-Four Years at the International Pancreas Transplant Registry (IPTR) Rev Diabet Stud. 8: 6-16.

  2. ^ Sutherland DER and Groth CG 2010 History of pancreas transplantation in Pancreas, Islet and Stem Cell Transplantation for diabetes eds Hakim NS, Stratta RJ, Gray DWR, Friend P and Colman A p1-18 Oxford University Press

  3. ^ White SA, Shaw JA, Sutherland DE 2009 Pancreas transplantation. Lancet 379:1808-1817

  4. ^ Smith RM and Friend P 2010 Indications, patient evaluation and selection in Pancreas, Islet and Stem Cell Transplantation for diabetes eds Hakim NS, Stratta RJ, Gray DWR, Friend P and Colman A p51-62 Oxford University Press

  5. ^ Giannarelli R, Coppelli A, Sartini MS, del Chiaro M, Vistoli F, Rizzo G, Barsotti M, Del Prato S, Mosca F, Boggi U, Marchetti P 2006 Pancreas transplant alone has beneficial effects on retinopathy in type 1 diabetic patients Diabetologia 49:2977–2982

  6. ^ Speight J, Reaney MD, Woodcock AJ, Smith RM and Shaw JAM 2010 Patient-reported outcomes following islet cell or pancreas transplantation (alone or after kidney) in type 1 diabetes: a systematic review Diabet. Med. 27: 812-22

  7. ^ 2008 SRTR Report on the State of Transplantation 2009 Am J Transplant 9 Suppl 1: 867-868 or www.ustransplant.org

  8. ^ Pancreas and islet transplantation in type 1 diabetes 2006 Diab Care 29: 935

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