Pancreas and Islet Transplantation

Canadian Diabetes Association Clinical Practice Guidelines Expert Committee

Breay W. Paty MD, FRCPC Angela Koh MD Peter Senior MBBS, PhD, MRCP

  • Key Messages
  • Recommendations
  • Figures
  • Full Text
  • References

Key Messages

  • Simultaneous pancreas kidney transplantation in persons with type 1 diabetes and end stage renal disease can improve kidney graft survival and result in prolonged insulin independence.
  • Successful pancreas or islet allotransplantation can stabilize glucose and possibly result in insulin independence in persons with type 1 diabetes and glycemic lability or recurrent hypoglycemia.
  • Islet autotransplantation can stabilize glucose and possibly result in insulin independence in people undergoing total pancreatectomy for benign pancreatic disease.

Introduction

Restoring endogenous insulin secretion by whole pancreas or islet transplantation has been established as an alternative to insulin injection therapy in select individuals with type 1 diabetes (1,2) . Nonrandomized studies demonstrate that both pancreas and islet transplantation can result in insulin independence and glucose stability, especially in the setting of glucose lability or frequent, severe hypoglycemia. Unfortunately, the absence of prospective randomized controlled trials makes it difficult to draw firm conclusions about the overall efficacy and safety of these therapies compared with exogenous insulin treatment. Also, the limited number of specialized islet and pancreas transplantation centres and the relatively small number of donor pancreases limit the availability of these treatments. Nevertheless, general recommendations regarding the role of pancreas and islet transplantation may be made in the context of current clinical experience.

Pancreas Transplantation

Pancreas transplantation can result in complete independence from exogenous insulin in the majority of cases (3) . As shown in Table 1, worldwide, noncontrolled 1- and 3-year mean pancreas graft and patient survival rates differ slightly among the 3 major types of transplantations (4) . Long-term pancreas graft survival declines with time, with a median graft survival of 9 years and <10% survival at 21 years (5) .

Glycemic control and glycated hemoglobin (A1C) are markedly improved after successful pancreas transplantation, with most recipients achieving normal glucose tolerance, albeit with hyperinsulinemia (6,7) . A reduction in albuminuria has been noted at 1 year (8), and improvements in the histological changes associated with diabetic nephropathy have been reported 5 to 10 years posttransplantation (9,10) . Whether successful simultaneous pancreas kidney (SPK) transplantation improves renal graft survival is unclear. In 1 study, recipients of SPK transplantations had better renal graft survival over 72 months than deceased-donor kidney transplantations but lower graft survival than living-donor kidney transplantations (11) . The impact of pancreas transplantation on overall patient survival also is uncertain. Studies suggest lower short-term survival in the perioperative period up to 18 to 24 months after SPK, but for patients with successful functioning pancreas grafts at 12 months post-transplantation, survival was similar or improved compared to living- or deceased-donor kidney transplantation (12–14) . A retrospective cohort study of individuals with diabetes and preserved kidney function who received a solitary pancreas transplantation suggested that overall survival was worse compared with wait-listed patients receiving conventional medical therapy (15) . Improvement and/or stabilization of diabetic retinopathy have been demonstrated (16) . Peripheral sensory and motor neuropathies also have been shown to improve after pancreas transplantation (17,18), but these findings are not consistent and may take years to achieve (19–21) . Pancreas transplantation appears to improve cardiovascular (CV) function, carotid intimal medial thickness, blood pressure and lipid parameters (22–24) . A single, small, nonrandomized study showed a reduction in CV events in SPK recipients compared to those undergoing kidney transplantation alone (25) ; however, this has not been examined in a randomized controlled fashion. Finally, diabetes-related quality of life (QOL) appears to improve after pancreas transplantation, although overall QOL appears to be unchanged (26,27) .

Islet Transplantation

Islet allotransplantation

Islet allotransplantation involves the infusion of islets isolated from cadaveric pancreata via the portal vein into the liver (28), either alone or in association with a renal transplantation (29,30) . Successful islet transplantation can result in stable, near-normal glycemic control (A1C, glycemic variability) with a reduction or elimination of hypoglycemia (31) over and above what can be achieved with insulin injections or even insulin pump therapy (32) . The ability of transplant recipients to achieve and maintain insulin independence varies between transplantation centres and is influenced by both donor and recipient factors (33,34) . Insulin independence can be achieved in most recipients but often requires 2 or more transplantation procedures. Insulin independence rates decline with time from approximately 70% at 1 year posttransplantation to approximately 10% after 5 years (31) . However, patients who are not able to maintain insulin independence may still benefit from more stable blood glucose control (35) that results from ongoing graft function, as evidenced by the sustained secretion of C peptide and the reduced requirement for exogenous insulin (33) . Small, short-term studies also suggest stabilization of retinopathy (36) and neuropathy (37) with islet allotransplantation. Renal outcomes vary, but recent reports suggest that the glomerular filtration rate achieved with the procedure does not differ significantly from that observed in the nondiabetic population (38,39) . Successful islet transplantation can improve QOL by reducing the fear of hypoglycemia (40) but can be negatively impacted by adverse effects from immunosuppressive agents (27) .

Table 1
Reported graft survival rates according to type of pancreas transplantation (4)
SPK, simultaneous pancreas kidney; PAK, pancreas after kidney; PTA, pancreas transplant alone.
Transplantation type     1 year 5 years 10 years 15 years
SPK 83% 69% 51% 33%
PAK 74% 45% 24% 13%
PTA 78% 54% 28% 9%

Islet autotransplantation

In islet autotransplantation, islets are isolated from an individual's own resected pancreas following pancreatectomy for benign pancreatic disease (e.g. chronic, painful pancreatitis) (41,42) . Islet yields from a resected, diseased pancreas may be lower than those from cadaveric donors, but immunosuppression is not required. Even if insulin independence is not achieved, islet autotransplantation may result in reduced exogenous insulin requirements and a lower risk of hypoglycemia (43) . As a result, the ratio of benefit to risk of this procedure may exceed that noted with islet allotransplantation (44) .

Table 2
Comparison of beta cell replacement modalities
A1C, glycated hemoglobin; ESRD, end stage renal disease; IAK, islet after kidney; PAK, pancreas after kidney; SPK, simultaneous pancreas kidney.
More than 1 islet infusion may be required.
Retinopathy and neuropathy may be stabilized.
Steroids are avoided in islet transplantation but may be used in whole pancreas transplantation.
§ No additional risk from immunosuppression.
  Islet Pancreas
Outcomes
Reduce or eliminate hypoglycemia Yes Yes
Improve A1C Yes Yes
Insulin independence Yes Yes
Effect on diabetes-related complications
Microvascular May be stabilized Improved
Macrovascular Not known May be improved
Risks
Procedural risks Minor procedural risk Major surgical risk
Immunosuppression Similar agents, life-long immunosuppression
Other considerations
ESRD Avoid Consider SPK
Functioning renal transplant     Consider IAK if glycemic lability or hypoglycemia § Consider PAK if glycemic lability or hypoglycemia §

Risks Associated with Pancreas and Islet Transplantation

Pancreas transplantation is associated with significant perioperative risks, including graft thrombosis, hemorrhage, pancreatitis, wound infection, peripancreatic abscesses and duodenal stump leakage (45) . Islet transplantation is associated with fewer procedural risks, which may include intraperitoneal hemorrhage, partial portal vein thrombosis or gallbladder puncture. These complications occur in <10% of procedures and usually are self-limited (31,34) . Both pancreas and islet transplantations require long-term immunosuppression, which is associated with a number of risks and side effects (46) . Drug side effects are generally mild and often respond to dose or agent adjustment. Although rare, life-threatening opportunistic infections and malignancies have been reported (34,46) . These risks must be carefully weighed against the potential benefits of transplantation for each individual. See Table 2 for a detailed comparison of pancreas vs. islet transplantation.

Recommendations

  1. 1.Individuals with type 1 diabetes and ESRD who are being considered for kidney transplantation should also be considered for simultaneous pancreas transplantation [Grade D, Level 4 (12,14)].
  2. 2.Individuals with type 1 diabetes with preserved renal function, or who have undergone successful kidney transplantation but have persistent metabolic instability characterized by severe glycemic lability and/or severe hypoglycemia despite best efforts to optimize glycemic control, may be considered for pancreas or islet allotransplantation [Grade D, Consensus].
  3. 3.Individuals undergoing total pancreatectomy for benign pancreatic disease may be considered for islet autotransplantation but only in the context of an experienced islet transplantation centre [Grade D, Consensus].

Abbreviation:
ESRD, end stage renal disease.

References

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