Pancreas Transplantation
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The main purpose of pancreas transplantation is to ameliorate type 1 diabetes mellitus and produce complete independence from injected insulin. In addition, however, pancreas transplantation in patients with type 2 diabetes has increased steadily in recent years. [1] The pancreas is usually procured from a deceased organ donor, although select cases of living-donor pancreas transplantations have been performed.
The number of pancreas transplants in the United States decreased every year from 2004 (when approximately 1500 were performed) to 2015. In 2016, pancreas transplants increased by 7.0% over the previous year, largely because of an increase in simultaneous pancreas-kidney (SPK) transplants. [1] Of the 976 pancreas transplants performed in 2016; the majority (81.5%) were SPK transplantations, which is the most common multi-organ transplant performed in the United States; nearly 23,000 SPK transplantations performed between 1988 and 2017. [1, 2] See image below.
Pancreas transplantations are also performed after a previously successful kidney transplantation. This is referred to as a pancreas-after-kidney (PAK) transplantation and represented 11% of pancreas transplants in 2016. [1] The remaining cases are performed as pancreas transplantation alone (PTA) in nonuremic patients with very labile and problematic diabetes.
An alternative therapy that may also ameliorate diabetes is islet cell transplantation. Pancreas and islet cell transplantation can be considered complementary transplant options and undergoing one or the other is not mutually exclusive. In an anlysis of 40 pancreas transplantations (50% PTA, 27.5% SPK, 22.5% PAK) after islet cell transplantation graft failure, overall survival rates (97% at 1 year and 83% at 5 years) were not adversely affected. [3]
Experiments in pancreas transplantation began long before the discovery of insulin. In 1891, pieces of dog pancreas autotransplanted beneath the skin prevented diabetes after removal of the intra-abdominal pancreas. Subsequent experimentation with intrasplenic transplantation did not succeed because of graft necrosis. In 1916, sliced human pancreas was transplanted into 2 patients, but the grafts were completely absorbed. The first pancreatic xenotransplantation was performed in 1893 in London; a 15-year-old boy underwent subcutaneous implantation of a pancreas.
Despite extensive animal experimentation, pancreatic transplantation did not become a reality until 1966, when W.D. Kelly performed the first human, whole-organ pancreatic transplantation for treatment of type 1 diabetes mellitus. Because of poor outcomes, few procedures were performed until 1978. Much of the early work was performed by Sutherland and colleagues at the University of Minnesota. With improved immunosuppressive regimens and newer surgical techniques, the 1980s ushered in a new era in pancreas transplantation. [4] According to the International Pancreas Transplant Registry, nearly 10,000 pancreatic transplantations were recorded by 1998.
Most of the pancreatic transplantations have been performed in patients with type 1 diabetes mellitus and a lack of insulin production. [5, 6] The most common indication is renal failure; therefore, the pancreas transplantation is typically performed simultaneously with a kidney transplantation. [7, 8, 9, 10] In some patients with hypoglycemic unawareness or other diabetic complications, isolated pancreas transplantation has been performed. However, the results have been somewhat inferior to those of the combined procedure.
Various technical concerns must be considered in patients undergoing pancreas transplantation, including whether or not the venous drainage should be into the systemic circulation or into the portal vein. [4] Another controversial topic is whether the exocrine secretions should be drained enterically or into the bladder as initially described. The complications of graft pancreatitis and bladder leakage that plagued early experiences with pancreas transplantation have largely been resolved as a result of both better technical expertise and fewer rejection- and immunosuppression-related complications.
Type I diabetes mellitus is an autoimmune disease wherein the insulin-producing pancreatic beta cells are destroyed selectively. Presently, no practical mechanical insulin-delivery method exists that, coupled with an effective glucose-sensory device, replaces pancreatic insulin secretion well enough to produce a near constant euglycemic state without risk of hypoglycemia. Therefore, individuals with type I diabetes must resign themselves to manual regulation of blood glucose levels by subcutaneous insulin injection and, as a consequence, typically exhibit wide deviations of plasma glucose levels from hour to hour and from day to day.
Hyperglycemia is the most important factor in the development and progression of the secondary complications of diabetes. These observations, and the fact that conventional exogenous insulin therapy cannot prevent the development of secondary complications of type I diabetes, have led to a search for alternative methods of treatment.
One such treatment, pancreas transplantation, has the potential to achieve better glycemic control and alter the progression of long-term complications. A successful pancreas transplantation produces a normoglycemic and insulin-independent state. It reverses the diabetic changes in the native kidneys of patients with very early diabetic nephropathy, prevents recurrent diabetic nephropathy in patients undergoing an SPK transplantation, reverses peripheral sensory neuropathy, stabilizes advanced diabetic retinopathy, and significantly improves patients’ quality and quantity of life.
The insulin released by the endocrine pancreas graft is secreted into the blood stream. Because the exocrine pancreas produces about 800-1000 mL per day of fluid, it must be diverted in either the bladder or bowel. If the pancreas graft is attached to the bladder, the losses of pancreatic fluid rich in bicarbonate may produce relative acidosis. This usually is treated by bicarbonate supplementation. Because the pancreas graft comes from another individual, the recipient’s immune system can mount a rejection reaction and destroy the graft. To prevent that problem, immunosuppression medications must be taken daily and forever to prevent rejection. Chronic immunosuppression elevates the risk of viral and fungal infections and some types of malignancy.
An estimated 30.3 million people in the United States have diabetes and over 50,000 individuals annually develop end-stage renal disease with diabetes as the primary cause. [11] Although nearly 2500 candidates were on the waitlist for pancrease transplant (15% PTA, 70% SPK, 15% PAK) at the end of 2016, less than 1000 pancreas transplantations are performed each year. [1] The number of transplants is limited by the number of donor organs available for transplantation. See Tables 1 below for a breakdown of patient characteristics.
Table 1. Characteristics of adult recepients of pancreas transplantation, United States, 2016 [1] (Open Table in a new window)
Patient Characteristic
All Candidates
Age 18-34 y
232
23.8%
Age 35-49 y
504
51.6%
Age 50-60 y
221
22.6%
Age > 60 y
19
1.9%
Male
571
58.5%
Female
405
41.5%
White
599
61.4%
Black
22.2%
Hispanic
127
13.0%
Asian
2.2%
Assessment of pancreas graft outcome rates has been hampered by lack of uniformity in the criteria for graft failure. Some programs do not report a failed graft if C peptide production continues, whereas others report a graft failure if the recipient is no longer insulin independent. The OPTN/UNOS Pancreas Transplantation Committee has provided more precise definitions for pancreas graft failure and implementation should take place in 2018. [1]
Nevertheless, the number of recipients alive with a functioning pancreas allograft has continued to rise over the past decade and exceeded 18,000 in 2016. Mortality has decreased consistently among all pancreas transplant groups as a result of safer and more effective immunosuppressive regimens. One-year mortality for PTA increased from 95.4% in 2012-2013 to 99.2% for transplants performed in 2014-2015. For SPK, the 5-year survival rates were similiar in patients with type 1 and type 2 diabetes (90.5% and 91.5% respectively), despite the older age and comorbidity associated with type 2 diabetes. This is likely due to selection of candidates with type 2 diabetes whose cardiovascular status can tolerate the high operative risks. [1]
In one published retrospective study, differences in mortality were examined in consecutive patients with diabetes who were older than 50 years compared with well-matched recipients younger than 50 years undergoing pancreas transplantation (the majority were simultaneous kidney-pancreas transplants) at a high-volume European center. Despite US data suggesting an increased risk of mortality in recipients older than 45 years compared with patients younger than 45 years, it is becoming clear that carefully selected patients with diabetes who are older than 50 years can undergo successful pancreas transplantation with similar patient and allograft survival outcomes. [12] This trend toward considering pancreas transplantation in older recipients appears to have begun earlier in the United States and is now gaining momentum in Europe as well, as evidenced in this study. It must be emphasized that careful cardiac evaluation is essential to this process of patient selection.
Recipients of successful pancreas transplantation maintain normal plasma glucose levels without the need of exogenous insulin therapy. This results in normalization of glycosylated hemoglobin levels and a beneficial effect on many secondary complications of diabetes. The durability of the transplanted endocrine pancreas has been established with the demonstration that normalization of glycosylated hemoglobin is maintained as long as the allograft functions. The potential lifespan of the transplanted pancreas is not known precisely because, at present, survivors with functioning pancreas transplantations still are doing well more than 16 years after transplantation. The implications of prolonged normalization of glycemia and glycosylated hemoglobin levels are significant with respect to patients’ quality of life, kidney structure, and motor-sensory and nerve function.
One long-term follow-up study of 15 years showed that pancreas transplantation in patients with type 1 diabetes mellitus and end-stage renal failure has long-term functional viability. However, some deterioration in pancreas function should be expected, as shown in oral glucose tolerance test results. [13]
The quality of life of pancreas transplantation recipients has been well studied. Patients with a functioning pancreas graft describe their quality of life and rate their health significantly more favorably than those with nonfunctioning pancreas grafts. Satisfaction encompasses not only the physical capacities but also relates to psychosocial and vocational aspects. The functioning pancreas graft leads to even better quality of life when compared to recipients of kidney transplantation alone. [14, 15] Virtually all patients with a successful pancreas transplantation report that managing their life, including immunosuppression, is much easier since the transplantation. Successful pancreas transplantation will not elevate all patients with diabetes to the level of health and functioning of the general population, but transplant recipients consistently report a significantly better quality of life than do patients who remain diabetic.
The development of diabetic nephropathy in transplanted kidneys residing in patients with type I diabetes has been well established. Marked variability is observed in the rate of renal pathology, including mesangial expansion and a widening of the glomerular basement membrane, in patients with type I diabetes and kidney transplantation alone. The onset of pathological lesions can be detected within a few years of kidney transplantation. Clinical deterioration of renal allograft function can lead to loss 10-15 years after transplantation.
A successful pancreas transplantation prevents glomerular structure changes of kidney allografts in patients with type I diabetes. This has been observed in transplanted kidneys of patients undergoing SPK transplantation, as well as in kidneys of recipients undergoing pancreas after kidney transplantation. These studies provide evidence of the efficacy of normalizing blood glucose and glycosylated hemoglobin levels to prevent the progression of diabetic glomerulopathy in renal allografts.
Furthermore, successful pancreas transplantation will halt or reverse the pathology in the native kidneys of patients with type I diabetes and very early proteinuria. Pancreas transplantation recipients all had persistently normal glycosylated hemoglobin values after transplantation for 5-10 years. The thickness of the glomerular and tubular basement membranes and mesangial volume steadily decrease over a 10-year interval. These early studies have important implications for the role of pancreas transplantation alone in patients with type I diabetes and very early changes in native renal function.
Successful pancreas transplantation has been shown to halt, and in many cases, reverse motor-sensory and autonomic neuropathy 12-24 months after transplantation. This has been studied most extensively in recipients of SPK transplantations. This raises the possibility that improvement of diabetic neuropathy occurs, in part, because of improvement of uremic neuropathy. However, pancreas transplantation alone in preuremic patients also has been shown to result in improvement in diabetic neuropathy. Many patients express subjective improvements of peripheral sensation 6-12 months after pancreas transplantation. Very interestingly, the effect of reversal of autonomic neuropathy in patients with type I diabetes with pancreas transplantation has been associated with better patient survival rates than patients with failed or no transplantation.
Pancreas transplantation does not have an immediate dramatic beneficial effect on preestablished diabetic retinopathy. Retinopathy appears to progress for at least 2 years following transplantation of the pancreas, but it begins to stabilize in 3-4 years compared to diabetic recipients of kidney transplantation only. Longer-term studies of 5-10 years, similar to those described above, have not been reported.
Kandaswamy R, Stock PG, Gustafson SK, Skeans MA, Curry MA, Prentice MA, et al. OPTN/SRTR 2016 Annual Data Report: Pancreas. Am J Transplant. 2018 Jan. 18 Suppl 1:114-171. [Medline]. [Full Text].
United Network for Organ Sharing (UNOS). Data. UNOS. Available at https://unos.org/data/. January 31, 2018; Accessed: March 6, 2018.
Gruessner RW, Gruessner AC. Pancreas After Islet Transplantation: A First Report of the International Pancreas Transplant Registry. Am J Transplant. 2016 Feb. 16 (2):688-93. [Medline]. [Full Text].
Demartines N, Schiesser M, Clavien PA. An evidence-based analysis of simultaneous pancreas-kidney and pancreas transplantation alone. Am J Transplant. 2005 Nov. 5(11):2688-97. [Medline].
Burke GW 3rd, Vendrame F, Virdi SK, Ciancio G, Chen L, Ruiz P, et al. Lessons From Pancreas Transplantation in Type 1 Diabetes: Recurrence of Islet Autoimmunity. Curr Diab Rep. 2015 Dec. 15 (12):121. [Medline].
Kerr HR, Hatipoglu B, Krishnamurthi V. Pancreas transplant for diabetes mellitus. Cleve Clin J Med. 2015 Nov. 82 (11):738-44. [Medline].
Ziaja J, Bozek-Pajak D, Kowalik A, Krol R, Cierpka L. Impact of pancreas transplantation on the quality of life of diabetic renal transplant recipients. Transplant Proc. 2009 Oct. 41(8):3156-8. [Medline].
Decker E, Coimbra C, Weekers L, et al. A retrospective monocenter review of simultaneous pancreas-kidney transplantation. Transplant Proc. 2009 Oct. 41(8):3389-92. [Medline].
Becker LE, Hallscheidt P, Schaefer SM, Klein K, Grenacher L, Waldherr R, et al. A Single-center Experience on the Value of Pancreas Graft Biopsies and HLA Antibody Monitoring After Simultaneous Pancreas-Kidney Transplantation. Transplant Proc. 2015 Oct. 47 (8):2504-12. [Medline].
Redfield RR, Scalea JR, Odorico JS. Simultaneous pancreas and kidney transplantation: current trends and future directions. Curr Opin Organ Transplant. 2015 Feb. 20 (1):94-102. [Medline].
Centers for Disease Control and Prevention. National Diabetes Statistics Report, 2017. Atlanta, GA: U.S. Department of Health and Human Services; 2017. [Full Text].
Schenker P, Vonend O, Krüger B, Klein T, Michalski S, Wunsch A, et al. Long-term results of pancreas transplantation in patients older than 50 years. Transpl Int. 2011 Feb. 24(2):136-42. [Medline].
Mora M, Ricart MJ, Casamitjana R, Astudillo E, López I, Jiménez A, et al. Pancreas and kidney transplantation: long-term endocrine function. Clin Transplant. 2010 Nov. 24(6):E236-40. [Medline].
McCullough KP, Keith DS, Meyer KH, Stock PG, Brayman KL, Leichtman AB. Kidney and pancreas transplantation in the United States, 1998-2007: access for patients with diabetes and end-stage renal disease. Am J Transplant. 2009 Apr. 9(4 Pt 2):894-906. [Medline].
Ojo AO, Meier-Kriesche HU, Hanson JA, et al. The impact of simultaneous pancreas-kidney transplantation on long-term patient survival. Transplantation. 2001 Jan 15. 71(1):82-90. [Medline].
[Guideline] Loupy A, Haas M, Solez K, et al. The Banff 2015 Kidney Meeting Report: Current Challenges in Rejection Classification and Prospects for Adopting Molecular Pathology. Am J Transplant. 2017 Jan. 17 (1):28-41. [Medline]. [Full Text].
Patient Characteristic
All Candidates
Age 18-34 y
232
23.8%
Age 35-49 y
504
51.6%
Age 50-60 y
221
22.6%
Age > 60 y
19
1.9%
Male
571
58.5%
Female
405
41.5%
White
599
61.4%
Black
22.2%
Hispanic
127
13.0%
Asian
2.2%
Dixon B Kaufman, MD, PhD Ray D Owen Professor and Chief, Division of Transplantation, Department of Surgery, University of Wisconsin School of Medicine and Public Health
Dixon B Kaufman, MD, PhD is a member of the following medical societies: American Surgical Association, American College of Surgeons, American Society of Transplant Surgeons, Association for Academic Surgery, Central Surgical Association, Society of University Surgeons
Disclosure: Nothing to disclose.
Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference
Disclosure: Received salary from Medscape for employment. for: Medscape.
Douglas M Heuman, MD, FACP, FACG, AGAF Chief of Hepatology, Hunter Holmes McGuire Department of Veterans Affairs Medical Center; Professor, Department of Internal Medicine, Division of Gastroenterology, Virginia Commonwealth University School of Medicine
Douglas M Heuman, MD, FACP, FACG, AGAF is a member of the following medical societies: American Association for the Study of Liver Diseases, American College of Physicians, American Gastroenterological Association
Disclosure: Received grant/research funds from Novartis for other; Received grant/research funds from Bayer for other; Received grant/research funds from Otsuka for none; Received grant/research funds from Bristol Myers Squibb for other; Received none from Scynexis for none; Received grant/research funds from Salix for other; Received grant/research funds from MannKind for other.
Ron Shapiro, MD Professor of Surgery, Robert J Corry Chair in Transplantation Surgery, Associate Clinical Director, Thomas E Starzl Transplantation Institute, University of Pittsburgh Medical Center
Ron Shapiro, MD is a member of the following medical societies: American Society of Transplantation, American Surgical Association, American College of Surgeons, Transplantation Society, International Pediatric Transplant Association, American Society of Transplant Surgeons, Association for Academic Surgery, Central Surgical Association, Society of University Surgeons
Disclosure: Nothing to disclose.
Pancreas Transplantation
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