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Future of pancreatic transplantation
Future of Pancreatic Transplantation J.M. Dubernard, X. Martin, N. Lefrancois, M. Dawahra, and L.C. Feitosa
T
HE FUTURE of pancreatic transplantation depends upon progress in three directions: surgical technique, immunosuppression and selection of the best nonuremic type 1 diabetic subjects. The choice of the best surgical technique is yet an unsolved problem with two main questions relative to duct management and drainage of the graft. Duct obstruction has been the key issue in the development of pancreatic transplantation.1 It was abandoned by most pancreatic transplantation centers when bladder diversion developed in the mid-1980s. The concept of duct obstruction, which aims to transform a bifunctional organ into a monofunctional one, could regain interest if better methods of destroying exocrine parenchyma were developed. The main theoretical advantage is to transplant normally vascularized islets. Its main practical advantage is the simplicity of the technique that requires only two vascular anastomosis. At present, bladder diversion is the most popular technique.2 It allows urinary amylases in the indirectly diagnosis of graft rejection especially in recipients of a pancreas transplant alone. However, the relatively high rate of conversion to another technique secondary to surgical or metabolic complications3 is a serious disadvantage. At present, the tendency in most European centers and in many American centers is to move to enteric diversion. Enteric diversion was initially used in the pioneering experience of Kelly and Lillehei.4 It certainly is the more physiologic mode of diversion of the exocrine secretion with good results in simultaneous pancreaticorenal transplantation.5 The choice between portal and systemic venous drainage is another technical debate. Portal drainage has the advantage of simulating nature. Insulin secreted by the graft is first delivered in the liver reducing insulinemia and leading to more physiologic glucose metabolism with potential favorable effects on secondary complications. Only well-conducted, randomized studies will show the long-term benefits of this more complex surgical procedure.6 Progress in immunosuppression may result in improved protocols for pancreatic transplantation using less diabetogenic drugs and early withdrawal of steroids. Antithymocyte globulins, monoclonal antibodies, azathioprine, and mycophenolate mofetil are not diabetogenic. Steroids, tacrolimus, and, to a lesser degree, cyclosporine are diabetogenic. The diabetogenicity of these substances has to be balanced with their immunosuppressive efficacy. When cyclosporine and Tacrolimus were compared in pancreatic transplanta-
tion alone, no difference was observed for 1-year graft survival rates, although the number of immunologic failures was higher with cyclosporine than with tacrolimus.1 At present, in spite of its toxicity and because of its immunosuppressive efficacy, Tacrolimus is part of the protocol for pancreas transplantation alone in most centers. The decision of performing a pancreatic transplantation depends on the appreciation of the risks of transplantation, mainly surgical or related to immunosuppression as well as the risks of evolution of diabetes. Simultaneous pancreaticorenal transplantation is now recognized as the best treatment for insulin-dependent diabetics with chronic renal failure. The results are much better than those on dialysis. Ideally, pancreatic transplantation should be performed earlier in the course of the disease, before appearance of secondary complications including nephropathy. Indication of pancreatic transplantation alone has become the main debate as results have considerably improved during the past 5 years. Respective advantages and drawbacks of pancreatic transplantation and insulin therapy have to be honestly and carefully analysed for specific populations of diabetics as well as for each individual. Pancreatic transplantation has many advantages: secretion by the graft of C peptide and normalization of glucose metabolism. Immunosuppression is given orally and monitoring of the graft is simple. No dietary restriction is necessary. When done before secondary complications occur or when they are not severe, pancreatic transplantation might stop or improve neuropathy,7 vasculopathy,8 retinopathy,9 nephropathy,10 and macroangiopathy. Quality of life is excellent. Drawbacks of pancreatic transplantation are related to the surgical risks and to the side effects of immunosuppression. The main advantages of exogenous insulin are the relative simplicity of treatment and monitoring. It requires multiple daily injections and capillary glycemia which might influence the quality of life. Intensive therapy delays the onset and slows the progression of diabetic retinopathy, nephropathy and neuropathy. However intensive therapy does not reduce ketoacidosis incidence. It increases the
From the Service d’urologie et de chirurgie de la transplantation, Hospital Edouard Herriot, Lyon, France. Address reprint requests to J.M. Dubernard, Service d’urologie et de chirurgie de la transplantation, Hospital Edouard Herriot, 5 place d’Arsonval 69003, Lyon, France.
0041-1345/99/$–see front matter PII S0041-1345(99)00780-0
© 1999 by Elsevier Science Inc. 655 Avenue of the Americas, New York, NY 10010
3190
Transplantation Proceedings, 31, 3190–3191 (1999)
FUTURE OF PANCREATIC TRANSPLANTATION
incidence of severe hypoglycemic coma and weight gain (threefold). There is no change in quality of life.11 Exogenous insulin has its drawbacks: absence of C peptide secretion that may protect against secondary complications, daily injection and monitoring, and diet, which may represent a psychological burden. In the absence of feedback mechanism, insulin concentrations are unphysiologic. Balance between hypoinsulinemia and hyperinsulinemiahyperglycemia and hypoglycemia is difficult to adjust. Lipodystrophy at injection sites and allergy may be a problem in some patients. In diabetic patients without renal failure, the choice of pancreatic transplantation has to be dictated by the balance between risks of surgery and immunosuppression on one hand, and risks of secondary complications of diabetes and insulinotherapy on the other hand. The three key questions are: Will pancreas transplantation have a positive or negative effect on patient survival? Will the benefits of insulin independence offset the side effects of antirejection drugs? Will management of immunosuppression be less or more difficult than the management of diabetes? Cooperation of diabetologists and transplant surgeons is mandatory to select the patients in whom pancreatic transplantation will reduce the risk of severe complications of diabetes while offering a better quality of life. The population of diabetics is not homogenous. At present candidates for pancreatic transplantation could be selected among various categories of diabetics. In some patients with labile diabetes, immunosuppression could be an acceptable alternative. Some patients with frequent hypoglycemia episodes needing constant family attention also could benefit from pancreatic transplantation especially when HbA1C is high. Some patients with poor compliance to insulin injections and monitoring could prefer immunosuppressive drugs. Trials comparing insulinotherapy and transplantation of the pancreas alone could be performed at the onset of diabetes or after a delay, for example of 10 years of microalbuminuria. Candidates could also be chosen among patients with advanced autonomic and peripheral neuropathy, patients with oscillating ketoacidosis and hypoglycemia or patients with rapidly evolutive retinopathy and loss of visual acuity. In the future, pancreatic transplantation could also be
3191
used prophylactically to prevent secondary complications. This will be based on the study of genetic susceptibility to complications. At present, genetic markers are lacking, although microalbuminuria has been demonstrated as an early marker of nephropathy in some patients. Elevated Na/Li counter transport might be an interesting marker if its capacity to predict development of nephropathy was confirmed. Candidates for pancreatic transplantation alone also could be selected from the prepubertal diabetic population. The younger the age of onset of diabetes, the greater is the risk of complications. We know that a well-controlled insulin treatment regimen during childhood and adolescence is not without psychological consequences. Transplantation could be considered when the patients reach their maturity, and when they are able to choose a mode of treatment themselves. However, before considering these types of studies, results of pancreatic transplantation alone have to improve and immunosuppression has to progress. Only well conducted prospective randomized studies could compare the potential advantages of transplantation weighing the use of immunosuppression over the conventional treatment of diabetes. REFERENCES 1. Dubernard JM, Traeger J, Neyra P: Surgery 84:633, 1978 2. International Pancreas Transplant Registry Minneapolis 9:1, 1997 3. Martin X, Lefrancois N, Dawahra M: Transplant Proc 25: 1182, 1993 4. Kelly WD, Lillehei RC, Idezuki Y: Surgery 61:827, 1967 5. Groth CG, Lundgren G, Arner P: Surg Gynecol Obstet 143:933, 1976 6. Martin X, Faure JL, Dubernard JM: Transplant Proc 12:400, 1980 7. Laftavi MRA, Chapuis F, Vial C, et al: Transplant Proc 27:1406, 1995 8. Martin X: Transplant Proc 27:2441, 1995 9. Ramsay RC, Goetz FC, Sutherland DER: N Engl J Med 318:208, 1988 10. Fioretto P, Steffes MW, Sutherland DER: N Engl J Med 339:69, 1998 11. The Diabetes Control and Complications Trial Research Group. N Engl J Med 329:977, 1993
T
HE FUTURE of pancreatic transplantation depends upon progress in three directions: surgical technique, immunosuppression and selection of the best nonuremic type 1 diabetic subjects. The choice of the best surgical technique is yet an unsolved problem with two main questions relative to duct management and drainage of the graft. Duct obstruction has been the key issue in the development of pancreatic transplantation.1 It was abandoned by most pancreatic transplantation centers when bladder diversion developed in the mid-1980s. The concept of duct obstruction, which aims to transform a bifunctional organ into a monofunctional one, could regain interest if better methods of destroying exocrine parenchyma were developed. The main theoretical advantage is to transplant normally vascularized islets. Its main practical advantage is the simplicity of the technique that requires only two vascular anastomosis. At present, bladder diversion is the most popular technique.2 It allows urinary amylases in the indirectly diagnosis of graft rejection especially in recipients of a pancreas transplant alone. However, the relatively high rate of conversion to another technique secondary to surgical or metabolic complications3 is a serious disadvantage. At present, the tendency in most European centers and in many American centers is to move to enteric diversion. Enteric diversion was initially used in the pioneering experience of Kelly and Lillehei.4 It certainly is the more physiologic mode of diversion of the exocrine secretion with good results in simultaneous pancreaticorenal transplantation.5 The choice between portal and systemic venous drainage is another technical debate. Portal drainage has the advantage of simulating nature. Insulin secreted by the graft is first delivered in the liver reducing insulinemia and leading to more physiologic glucose metabolism with potential favorable effects on secondary complications. Only well-conducted, randomized studies will show the long-term benefits of this more complex surgical procedure.6 Progress in immunosuppression may result in improved protocols for pancreatic transplantation using less diabetogenic drugs and early withdrawal of steroids. Antithymocyte globulins, monoclonal antibodies, azathioprine, and mycophenolate mofetil are not diabetogenic. Steroids, tacrolimus, and, to a lesser degree, cyclosporine are diabetogenic. The diabetogenicity of these substances has to be balanced with their immunosuppressive efficacy. When cyclosporine and Tacrolimus were compared in pancreatic transplanta-
tion alone, no difference was observed for 1-year graft survival rates, although the number of immunologic failures was higher with cyclosporine than with tacrolimus.1 At present, in spite of its toxicity and because of its immunosuppressive efficacy, Tacrolimus is part of the protocol for pancreas transplantation alone in most centers. The decision of performing a pancreatic transplantation depends on the appreciation of the risks of transplantation, mainly surgical or related to immunosuppression as well as the risks of evolution of diabetes. Simultaneous pancreaticorenal transplantation is now recognized as the best treatment for insulin-dependent diabetics with chronic renal failure. The results are much better than those on dialysis. Ideally, pancreatic transplantation should be performed earlier in the course of the disease, before appearance of secondary complications including nephropathy. Indication of pancreatic transplantation alone has become the main debate as results have considerably improved during the past 5 years. Respective advantages and drawbacks of pancreatic transplantation and insulin therapy have to be honestly and carefully analysed for specific populations of diabetics as well as for each individual. Pancreatic transplantation has many advantages: secretion by the graft of C peptide and normalization of glucose metabolism. Immunosuppression is given orally and monitoring of the graft is simple. No dietary restriction is necessary. When done before secondary complications occur or when they are not severe, pancreatic transplantation might stop or improve neuropathy,7 vasculopathy,8 retinopathy,9 nephropathy,10 and macroangiopathy. Quality of life is excellent. Drawbacks of pancreatic transplantation are related to the surgical risks and to the side effects of immunosuppression. The main advantages of exogenous insulin are the relative simplicity of treatment and monitoring. It requires multiple daily injections and capillary glycemia which might influence the quality of life. Intensive therapy delays the onset and slows the progression of diabetic retinopathy, nephropathy and neuropathy. However intensive therapy does not reduce ketoacidosis incidence. It increases the
From the Service d’urologie et de chirurgie de la transplantation, Hospital Edouard Herriot, Lyon, France. Address reprint requests to J.M. Dubernard, Service d’urologie et de chirurgie de la transplantation, Hospital Edouard Herriot, 5 place d’Arsonval 69003, Lyon, France.
0041-1345/99/$–see front matter PII S0041-1345(99)00780-0
© 1999 by Elsevier Science Inc. 655 Avenue of the Americas, New York, NY 10010
3190
Transplantation Proceedings, 31, 3190–3191 (1999)
FUTURE OF PANCREATIC TRANSPLANTATION
incidence of severe hypoglycemic coma and weight gain (threefold). There is no change in quality of life.11 Exogenous insulin has its drawbacks: absence of C peptide secretion that may protect against secondary complications, daily injection and monitoring, and diet, which may represent a psychological burden. In the absence of feedback mechanism, insulin concentrations are unphysiologic. Balance between hypoinsulinemia and hyperinsulinemiahyperglycemia and hypoglycemia is difficult to adjust. Lipodystrophy at injection sites and allergy may be a problem in some patients. In diabetic patients without renal failure, the choice of pancreatic transplantation has to be dictated by the balance between risks of surgery and immunosuppression on one hand, and risks of secondary complications of diabetes and insulinotherapy on the other hand. The three key questions are: Will pancreas transplantation have a positive or negative effect on patient survival? Will the benefits of insulin independence offset the side effects of antirejection drugs? Will management of immunosuppression be less or more difficult than the management of diabetes? Cooperation of diabetologists and transplant surgeons is mandatory to select the patients in whom pancreatic transplantation will reduce the risk of severe complications of diabetes while offering a better quality of life. The population of diabetics is not homogenous. At present candidates for pancreatic transplantation could be selected among various categories of diabetics. In some patients with labile diabetes, immunosuppression could be an acceptable alternative. Some patients with frequent hypoglycemia episodes needing constant family attention also could benefit from pancreatic transplantation especially when HbA1C is high. Some patients with poor compliance to insulin injections and monitoring could prefer immunosuppressive drugs. Trials comparing insulinotherapy and transplantation of the pancreas alone could be performed at the onset of diabetes or after a delay, for example of 10 years of microalbuminuria. Candidates could also be chosen among patients with advanced autonomic and peripheral neuropathy, patients with oscillating ketoacidosis and hypoglycemia or patients with rapidly evolutive retinopathy and loss of visual acuity. In the future, pancreatic transplantation could also be
3191
used prophylactically to prevent secondary complications. This will be based on the study of genetic susceptibility to complications. At present, genetic markers are lacking, although microalbuminuria has been demonstrated as an early marker of nephropathy in some patients. Elevated Na/Li counter transport might be an interesting marker if its capacity to predict development of nephropathy was confirmed. Candidates for pancreatic transplantation alone also could be selected from the prepubertal diabetic population. The younger the age of onset of diabetes, the greater is the risk of complications. We know that a well-controlled insulin treatment regimen during childhood and adolescence is not without psychological consequences. Transplantation could be considered when the patients reach their maturity, and when they are able to choose a mode of treatment themselves. However, before considering these types of studies, results of pancreatic transplantation alone have to improve and immunosuppression has to progress. Only well conducted prospective randomized studies could compare the potential advantages of transplantation weighing the use of immunosuppression over the conventional treatment of diabetes. REFERENCES 1. Dubernard JM, Traeger J, Neyra P: Surgery 84:633, 1978 2. International Pancreas Transplant Registry Minneapolis 9:1, 1997 3. Martin X, Lefrancois N, Dawahra M: Transplant Proc 25: 1182, 1993 4. Kelly WD, Lillehei RC, Idezuki Y: Surgery 61:827, 1967 5. Groth CG, Lundgren G, Arner P: Surg Gynecol Obstet 143:933, 1976 6. Martin X, Faure JL, Dubernard JM: Transplant Proc 12:400, 1980 7. Laftavi MRA, Chapuis F, Vial C, et al: Transplant Proc 27:1406, 1995 8. Martin X: Transplant Proc 27:2441, 1995 9. Ramsay RC, Goetz FC, Sutherland DER: N Engl J Med 318:208, 1988 10. Fioretto P, Steffes MW, Sutherland DER: N Engl J Med 339:69, 1998 11. The Diabetes Control and Complications Trial Research Group. N Engl J Med 329:977, 1993