Editorial Eur. surg. Res. 9: 399-402 (1977)
Farewell to Pancreatic Organ Transplantation? F elix L argiadèr
For 15 years, pancreatic organ transplantation has been an object of high interest to a rather small, but active number of surgical investigators. Some more physiologically oriented experimental work goes back even to earlier times, but transplantation for transplantation’s sake did start only in the 1960s [3, 8]. In the 15 years that have passed since then, a wealth of experimental data has been accumulated [7]. Under certain experi mental conditions, especially if exocrine drainage had been preserved, pancreatic transplantation proved to be a quite successful procedure. In canine experiments, long-term survival has been achieved [13], even with orthotopic pancreaticoduodenal allotransplantation [10]. Clinical interest for this procedure arose very early, not with the aim to treat an uncompli cated diabetes mellitus, of course, but for the severe and unresolved prob lem of juvenile diabetes with diabetic nephropathy. In the light of the ex perimental results it was, therefore, justified to approach this problem by a combination of renal and pancreatic transplantation, hoping that a suc cessful pancreatic transplant would stop the progression of the otherwise detrimental diabetic angiopathy. The first clinical reports of L illehei et al. [11] and later of G liedman et al. [4] stimulated a wave of pancreatic transplants around the world. But in the long run, the results have been very disappointing. Up to now, 52 transplants have been reported by 15 transplant teams, but at this moment none of these organs is functioning anymore [1J. Our own experience with 4 cases (included in the above 52) is quite in line with these worldwide results.
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Case reports. Between December 1973 and June 1976, a total of 4 pancreatic organ transplants have been performed in our department. The patients were male, 32, 35, 26, and 39 years of age, and all were suffering from juvenile diabetes melli-
400
L argiadèr
tus with glomerulosclerosis, terminal renal failure needing hemodialysis, retinopa thy, peripheral angiopathy, and 2 of them from very pronounced diabetic gastroenteropathy. In all patients, a kidney was transplanted into the right iliac fossa, and the pancreatic organ transplant (pancreaticoduodenal in the first 2 patients) was put into the left iliac fossa. Exocrine drainage was accomplished by a Roux-Y jejunal loop. The usual immunosuppressive regimen with azathioprine, prednisone, and anti lymphocyte globulin was applied. The immediate postoperative course was very satisfying in every case. All the kidneys functioned immediately, and blood sugar fell to normal values within 8-10 h and stayed there without any insulin medication and despite normal enteral feeding. Rejection crises of both organs were diagnosed with ease, and the pancreas responded even faster to antirejection therapy than the kidney [9], But local problems arised by transcapsular secretion. Local infections occurred despite adequate drainage and contributed to the fatal outcomes. The first patient had a local wound healing problem; he died after 64 days from fungus septi cemia after surgery for a gallbladder empyema. The second patient died after 28 days from cachexia and possibly septicemia despite an only minor local problem. The third patient developed local abscesses and finally necroses and perforations of the sigmoid; he did not survive sigmoid resection and he died 111 days after trans plantation. The last patient, finally, developed an undetected intra-abdominal ab scess, and he died unexpectedly on day 15 from massive aspiration.
In the light of these very disappointing experiences, we have stopped pancreatic organ transplantation for the time being, as have other centers active in this field. Today, islet transplantation is as promising as pan creatic organ transplantation was 10 years ago. In fact, the main and un resolved problem we had with the whole organ will be eliminated when separated islets are used. Therefore, it is understandable that since the pi oneering work of B allinger and L acy [2] and Scharp et al. [14], islet transplantation has become a very popular research object in many cen ters. International conferences have been devoted to this matter [5], and the wave of publications has now reached this journal, too. The papers published in the last and in the present issue give a very accurate picture of todays experimental achievements. But at the same time, evidence is now present that in patients success is much harder to achieve than in ex perimental animals. None of the patients described in a recent publication has lost the need for insulin injections following islet transplantation [12]. Our own clinical results are, up to now, not better.
Downloaded by: UCL 144.82.238.225 - 2/21/2018 9:50:51 PM
Case reports. In June 1977, two patients with diabetic nephropathy (a 28-yearold woman and a 35-year-old man) were treated by combined renal and pancreatic islet allotransplantation. Islets were separated from the kidney donor’s pancreas ac cording to a method described elsewhere [6], Warm ischemia time was only a few minutes in both instances. The cold ischemia was 3 h for the separated islets in the first and 1 h for the whole organ before separation in the second case. During renal
Farewell to Pancreatic Organ Transplantation
401
transplantation, a catheter was placed into the portal vein through a mesenteric vein, and the islet suspension was infused slowly. With the exception of a rather light and short rise of the portal pressure (up to 20 cm H20 for 5 min) at the end of the infusion and a very transient rise of serum amylase during the first few post operative hours, no side effects were seen. The postoperative course was uneventful, up to now, but the need for exogenous insulin has not diminished in either patient.
We do not yet know the reasons for the insufficient function of these human islet transplants, and quite a number of problems remain to be solved. Was the amount of injected islets too small, or did they not take at all? Are there better implantation sites in humans than the portal circula tion? What about the cold ischemia tolerance of these islets which are not completely free from exocrine tissue in our technique? But on the other hand, we have seen that islet transplantation is very well tolerated. In the past, pancreatic transplantation was a very efficient, but dangerous proce dure; today it is harmless, but ineffective. We still wait for the combina tion of safeness and efficiency. References
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1 ACS/NIH Organ Transplant Registry: Cases reported to the Registry, Chicago, July 1, 1977. 2 Ballinger , W. F. and L acy, P. E.: Transplantation of intact pancreatic islets in rats. Surgery 72: 175 (1972). 3 D e J ode , R. L. and H oward , J. M.: Studies in pancreaticoduodenal homotrans plantation. Surgery Gynec. Obstet. 114: 553 (1962). 4 G liedman , M. L.; G old , M.; W hittaker , J.; R ifkin , H.; Soberman, R.; F reed , S.; T ellis , V., and V eith , F. J.: Pancreatic duct to ureter anastomosis for exo crine drainage in pancreatic transplantation. Am. J. Surg. 125: 245 (1973). 5 G oetz , F. C.: Conference on beta cell function, transplantation, and implantable glucose sensors. A summary. Metabolism 23: 875 (1974). 6 K olb , E.; R uckert, R., and L argiadèr, F.: Intraportal and intrasplenic auto transplantation of pancreatic islets in the dog. Eur. surg. Res. 9: 419-426 (1977). 7 L argiadèr, F.: Pankreastransplantation; in Handbuch der inneren Medizin, Band 3, Tcil 6, p. 1143 (Springer, Berlin 1976). 8 L argiadèr, F .; L yons, G. W.; H idalgo, F.; D ietzman, R. H., and L illehei , R. C.: Orthotopic allotransplantation of the pancreas. Am. J. Surg. 113:70 (1967). 9 L argiadèr, F.; U hlschmid , G.; B inswanger , U., and Z aruba, K.: Pancreas rejection in combined pancreaticoduodenal and renal allotransplantation in man. Transplantation 19: 185 (1975). 10 L argiadèr, F. and W egmann, W.: Experimental orthotopic transplantation of the pancreas. Transplantn Proc. 3: 497 (1971). 11 L illehei, R. C.; S immons, R. L.; N ajarian, J. S.; W eil , R.; U chida , H.; R u iz ,
402
L argiadèr
J. O.; Kjellstrand , C. M., and G oetz , F. G: Pancreatico-duodenal allotrans plantation. Experimental and clinical experience. Ann. Surg. 172: 405 (1970). 12 Najar Ian , J. S.; Sutherland , D. E. R.; M atas, A. J.; Steffes , M. W.; Simmons, R. L., and G oetz , F. G : Human islet transplantation. A preliminary report. Transplantn Proc. 9: 233 (1977). 13 Rausis, G ; C houdhury , A., and O gata, Y.: Influence of pancreatic duct anasto mosis on function of autotransplanted canine pancreatic segments. J. surg. Res. 10: 551 (1970). 14 Scharp , D. W.; M urphy , J. J.; N ew ton , W. T.; Ballinger, W. F., and L acy, P. E.: Transplantation of islets of Langerhans in diabetic rhesus monkeys. Surgery 77: 100 (1975).
A, Kantonsspital
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Prof. Dr. F elix L argiadLr , Chirurgische Universitätsklinik Zürich, 8091 Zurich (Switzerland)
Farewell to Pancreatic Organ Transplantation? F elix L argiadèr
For 15 years, pancreatic organ transplantation has been an object of high interest to a rather small, but active number of surgical investigators. Some more physiologically oriented experimental work goes back even to earlier times, but transplantation for transplantation’s sake did start only in the 1960s [3, 8]. In the 15 years that have passed since then, a wealth of experimental data has been accumulated [7]. Under certain experi mental conditions, especially if exocrine drainage had been preserved, pancreatic transplantation proved to be a quite successful procedure. In canine experiments, long-term survival has been achieved [13], even with orthotopic pancreaticoduodenal allotransplantation [10]. Clinical interest for this procedure arose very early, not with the aim to treat an uncompli cated diabetes mellitus, of course, but for the severe and unresolved prob lem of juvenile diabetes with diabetic nephropathy. In the light of the ex perimental results it was, therefore, justified to approach this problem by a combination of renal and pancreatic transplantation, hoping that a suc cessful pancreatic transplant would stop the progression of the otherwise detrimental diabetic angiopathy. The first clinical reports of L illehei et al. [11] and later of G liedman et al. [4] stimulated a wave of pancreatic transplants around the world. But in the long run, the results have been very disappointing. Up to now, 52 transplants have been reported by 15 transplant teams, but at this moment none of these organs is functioning anymore [1J. Our own experience with 4 cases (included in the above 52) is quite in line with these worldwide results.
Downloaded by: UCL 144.82.238.225 - 2/21/2018 9:50:51 PM
Case reports. Between December 1973 and June 1976, a total of 4 pancreatic organ transplants have been performed in our department. The patients were male, 32, 35, 26, and 39 years of age, and all were suffering from juvenile diabetes melli-
400
L argiadèr
tus with glomerulosclerosis, terminal renal failure needing hemodialysis, retinopa thy, peripheral angiopathy, and 2 of them from very pronounced diabetic gastroenteropathy. In all patients, a kidney was transplanted into the right iliac fossa, and the pancreatic organ transplant (pancreaticoduodenal in the first 2 patients) was put into the left iliac fossa. Exocrine drainage was accomplished by a Roux-Y jejunal loop. The usual immunosuppressive regimen with azathioprine, prednisone, and anti lymphocyte globulin was applied. The immediate postoperative course was very satisfying in every case. All the kidneys functioned immediately, and blood sugar fell to normal values within 8-10 h and stayed there without any insulin medication and despite normal enteral feeding. Rejection crises of both organs were diagnosed with ease, and the pancreas responded even faster to antirejection therapy than the kidney [9], But local problems arised by transcapsular secretion. Local infections occurred despite adequate drainage and contributed to the fatal outcomes. The first patient had a local wound healing problem; he died after 64 days from fungus septi cemia after surgery for a gallbladder empyema. The second patient died after 28 days from cachexia and possibly septicemia despite an only minor local problem. The third patient developed local abscesses and finally necroses and perforations of the sigmoid; he did not survive sigmoid resection and he died 111 days after trans plantation. The last patient, finally, developed an undetected intra-abdominal ab scess, and he died unexpectedly on day 15 from massive aspiration.
In the light of these very disappointing experiences, we have stopped pancreatic organ transplantation for the time being, as have other centers active in this field. Today, islet transplantation is as promising as pan creatic organ transplantation was 10 years ago. In fact, the main and un resolved problem we had with the whole organ will be eliminated when separated islets are used. Therefore, it is understandable that since the pi oneering work of B allinger and L acy [2] and Scharp et al. [14], islet transplantation has become a very popular research object in many cen ters. International conferences have been devoted to this matter [5], and the wave of publications has now reached this journal, too. The papers published in the last and in the present issue give a very accurate picture of todays experimental achievements. But at the same time, evidence is now present that in patients success is much harder to achieve than in ex perimental animals. None of the patients described in a recent publication has lost the need for insulin injections following islet transplantation [12]. Our own clinical results are, up to now, not better.
Downloaded by: UCL 144.82.238.225 - 2/21/2018 9:50:51 PM
Case reports. In June 1977, two patients with diabetic nephropathy (a 28-yearold woman and a 35-year-old man) were treated by combined renal and pancreatic islet allotransplantation. Islets were separated from the kidney donor’s pancreas ac cording to a method described elsewhere [6], Warm ischemia time was only a few minutes in both instances. The cold ischemia was 3 h for the separated islets in the first and 1 h for the whole organ before separation in the second case. During renal
Farewell to Pancreatic Organ Transplantation
401
transplantation, a catheter was placed into the portal vein through a mesenteric vein, and the islet suspension was infused slowly. With the exception of a rather light and short rise of the portal pressure (up to 20 cm H20 for 5 min) at the end of the infusion and a very transient rise of serum amylase during the first few post operative hours, no side effects were seen. The postoperative course was uneventful, up to now, but the need for exogenous insulin has not diminished in either patient.
We do not yet know the reasons for the insufficient function of these human islet transplants, and quite a number of problems remain to be solved. Was the amount of injected islets too small, or did they not take at all? Are there better implantation sites in humans than the portal circula tion? What about the cold ischemia tolerance of these islets which are not completely free from exocrine tissue in our technique? But on the other hand, we have seen that islet transplantation is very well tolerated. In the past, pancreatic transplantation was a very efficient, but dangerous proce dure; today it is harmless, but ineffective. We still wait for the combina tion of safeness and efficiency. References
Downloaded by: UCL 144.82.238.225 - 2/21/2018 9:50:51 PM
1 ACS/NIH Organ Transplant Registry: Cases reported to the Registry, Chicago, July 1, 1977. 2 Ballinger , W. F. and L acy, P. E.: Transplantation of intact pancreatic islets in rats. Surgery 72: 175 (1972). 3 D e J ode , R. L. and H oward , J. M.: Studies in pancreaticoduodenal homotrans plantation. Surgery Gynec. Obstet. 114: 553 (1962). 4 G liedman , M. L.; G old , M.; W hittaker , J.; R ifkin , H.; Soberman, R.; F reed , S.; T ellis , V., and V eith , F. J.: Pancreatic duct to ureter anastomosis for exo crine drainage in pancreatic transplantation. Am. J. Surg. 125: 245 (1973). 5 G oetz , F. C.: Conference on beta cell function, transplantation, and implantable glucose sensors. A summary. Metabolism 23: 875 (1974). 6 K olb , E.; R uckert, R., and L argiadèr, F.: Intraportal and intrasplenic auto transplantation of pancreatic islets in the dog. Eur. surg. Res. 9: 419-426 (1977). 7 L argiadèr, F.: Pankreastransplantation; in Handbuch der inneren Medizin, Band 3, Tcil 6, p. 1143 (Springer, Berlin 1976). 8 L argiadèr, F .; L yons, G. W.; H idalgo, F.; D ietzman, R. H., and L illehei , R. C.: Orthotopic allotransplantation of the pancreas. Am. J. Surg. 113:70 (1967). 9 L argiadèr, F.; U hlschmid , G.; B inswanger , U., and Z aruba, K.: Pancreas rejection in combined pancreaticoduodenal and renal allotransplantation in man. Transplantation 19: 185 (1975). 10 L argiadèr, F. and W egmann, W.: Experimental orthotopic transplantation of the pancreas. Transplantn Proc. 3: 497 (1971). 11 L illehei, R. C.; S immons, R. L.; N ajarian, J. S.; W eil , R.; U chida , H.; R u iz ,
402
L argiadèr
J. O.; Kjellstrand , C. M., and G oetz , F. G: Pancreatico-duodenal allotrans plantation. Experimental and clinical experience. Ann. Surg. 172: 405 (1970). 12 Najar Ian , J. S.; Sutherland , D. E. R.; M atas, A. J.; Steffes , M. W.; Simmons, R. L., and G oetz , F. G : Human islet transplantation. A preliminary report. Transplantn Proc. 9: 233 (1977). 13 Rausis, G ; C houdhury , A., and O gata, Y.: Influence of pancreatic duct anasto mosis on function of autotransplanted canine pancreatic segments. J. surg. Res. 10: 551 (1970). 14 Scharp , D. W.; M urphy , J. J.; N ew ton , W. T.; Ballinger, W. F., and L acy, P. E.: Transplantation of islets of Langerhans in diabetic rhesus monkeys. Surgery 77: 100 (1975).
A, Kantonsspital
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Prof. Dr. F elix L argiadLr , Chirurgische Universitätsklinik Zürich, 8091 Zurich (Switzerland)
