- Email: [email protected]
Ninety-Five Percent Insulin Independence Rate 3 Years After Pancreas Transplantation Alone With Portal-Enteric Drainage
Outcomes Ninety-Five Percent Insulin Independence Rate 3 Years After Pancreas Transplantation Alone With Portal-Enteric Drainage U. Boggi, F. Mosca, F. Vistoli, S. Signori, M. Del Chiaro, T. Vanadia Bartolo, G. Amorese, A. Coppelli, P. Marchetti, R. Mariotti, L. Rondinini, S. Del Prato, and G. Rizzo ABSTRACT Aims. Portal-enteric drainage (PED) might be particularly suitable for pancreas transplantation alone (PTA), since it has been associated with an immunologic advantage and achieves excellent metabolic results. We describe our experience with a consecutive series of 40 PTAs with PED. Methods. Between April 2001 and March 2004, 40 consecutive PTAs were performed with PED. Recipients were selected according to the American Diabetic Association recommendations. Donors were selected according to standard criteria irrespective of HLA match, although matching for A and B loci was considered at the time of graft allocation. Immunosuppression consisted of induction treatment with basiliximab (n ⫽ 34) or thymoglobulin (n ⫽ 6), and maintenance therapy with steroids, mycophenolate mofetil, and tacrolimus. Results. After a mean cold ischemia time of 690 minutes (range, 517–965 min) all pancreases functioned immediately. Three grafts were lost due to hyperacute or accelerated rejection. No graft was lost to vascular thrombosis, although 5 (12.5%) nonocclusive thromboses were identified and the grafts were rescued with intravenous heparin infusion. A repeat laparotomy was required in 7 recipients (17.5%) No patient required multiple repeat laparotomies, and none died. After a mean follow-up of 16.4 months (range, 1–36 mo), 2 recipients were diagnosed with rejection episodes, which were reversed with steroid boluses. Actuarial 3-year patient, and graft survival rates were 100% and 94.9%, respectively. The following parameters showed significant improvement compared with pretransplantation evaluation: hemoglobin A1C concentration, total and high-density lipoprotein cholesterol levels, arterial blood pressure, cardiac performance, retinopathy, proteinuria, and neuropathy. Conclusions. Pancreas transplantation alone with PED provides high rates of long-term insulin-independence.
P
ANCREAS TRANSPLANTATION ALONE (PTA) is by far the most effective treatment that allows tight glucose control and corrects dysmetabolism in diabetic patients without end-stage nephropathy in whom other avenues of intensive insulin therapy fail.1 Restoring euglicemia should prevent, arrest, and, it is hoped, reverse the progression of chronic vascular complications that otherwise would occur in more than 50% of diabetic patients.2 Moreover, PTA improves the quality of life of diabetic
patients by eliminating the need for exogen insulin, frequent glucose monitoring, and many of the dietary and
From the Department of Surgery and Transplantation, University of Pisa, Pisa, Italy. Address reprint requests to Franco Mosca, MD, FACS, FRCS Ed, Department of Surgery and Transplantation, University of Pisa, Via Paradisa 2, Pisa 56124, Italy. E-mail: f.mosca@ med.unipi.it
0041-1345/05/$–see front matter doi:10.1016/j.transproceed.2005.01.024
© 2005 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
1274
Transplantation Proceedings, 37, 1274 –1277 (2005)
INSULIN INDEPENDENCE AFTER PANCREAS TRANSPLANTATION
1275
Table 1. Recipient Characteristics Age (y; mean ⫾ SD) Sex (% male) Duration of diabetes (y; mean ⫾ SD) Hemoglobin A1C (%; mean ⫾ SD) Chronic complications (%) Nephropathy Proliferant retinopathy Autonomic neuropathy Unknown hypoglycemia (%) A, B mismatch (n; mean ⫾ SD) DR mismatch (n; mean ⫾ SD) Pannel reactive antibodies (%; mean ⫾ SD)
37.7 ⫾ 8.5 52.5% 23.9 ⫾ 10.5 9.5 ⫾ 1.2 90.0 45.0 85.0 70.0 15.0 2.7 ⫾ 0.9 1.2 ⫾ 0.6 0.4 ⫾ 2.0
life-style restrictions enforced by the disease.3 The need for long-term immunosuppression and the surgical risk of the transplant procedure, however, remain the main penalties for insulin-independence and are the main arguments against which the benefits of PTA should be appraised. Portal-enteric drainage (PED) of pancreas grafts might be advantageous in PTA. Indeed, if on one hand enteric drainage eliminates the metabolic4 and infectious consequences of bladder drainage.5 On the other hand, insulin delivery into the portal stream should improve the recipient’s metabolic profile by reproducing the physiologic situation. Moreover, recent data support the hypothesis that portal venous drainage may have an immunologic advantage,6 –9 thus potentially reducing the need for immunosuppression and improving long-term results. We report our experience with a consecutive series of PTAs with PED. MATERIALS AND METHODS From April 2001 & March 2004, 40 consecutive PTAs were performed with PED in type 1 diabetic recipients. Recipients (Table 1) were selected according to current recommendations of the American Diabetes Association.10 Pancreas procurement and donor selection were carried out according to the methods described previously.11 Human leukocyte antigen match was not regarded as a mandatary donor acceptance criterion, although the lowest mismatching for either A or B loci was considered at the time of graft allocation. All pancreas grafts were drained into the superior mesenteric vein and into the gut, according to the method described previously.12 Immunosuppression consisted of a quadruple regimen, including induction with either basiliximab (n ⫽ 34; 85.0%), 20 mg before graft reperfusion and on posttransplantation day 4, or thymoglobulin (n ⫽ 6; 15.0%), 1 mg/kg for 5 to 7 days), and maintenance therapy with low-dose steroids, tacrolimus (trough levels, 12 to 15 ng/mL in the first month after transplantation), and mycophenolate mofetil (2 g/d). Pancreas rejection was suspected, and therefore treated empirically, in the presence of any of the following: hyperamylasemia, hyperlipasemia, otherwise unexplained hyperglycemia, fever, or graft tenderness. Transplant outcomes were recorded prospectively in a computer data base. Delayed endocrine pancreas function was defined according to the criteria reported by Troppmann et al.13 Recipient and graft survival rates were determined with the Kaplan-Meier method.
Fig 1.
Actuarial survival curves.
RESULTS
After a mean period of cold ischemia time of 690 minutes (range, 517 to 965 min) all grafts functioned promptly. At the longest follow-up of 36 months (mean, 16.4 mo) a total of 5 acute rejection episodes (12.5%) were diagnosed in 5 recipients, including 3 hyperacute or accelerated rejections (7.5%) leading to graft loss and requiring allograft pancreatectomy. The remaining 2 acute rejection episodes responded well to higher steroid doses. No graft was lost to portal vein thrombosis, although 5 nonocclusive thromboses (12.5%) were identified, and the grafts were rescued with intravenous heparin infusion only (n ⫽ 4) or heparin infusion followed by surgical thrombectomy (n ⫽ 1). A total of 7 recipients (17.5%) required a repeat laparotomy. Indications for repeat operation were bleeding (n ⫽ 2; 7.5%), allograft pancreatectomy following graft loss due to hyperacute or accelerated rejection (n ⫽ 3; 7.5%), leakage from a duodenojejunostomy (n ⫽ 1; 2.5%), and hematoma evacuation associated with portal vein thrombectomy (n ⫽ 1; 2.5%). No patient required multiple repeat laparotomies, and none died. Actuarial 3-year patient survival rates were 100% and 94.9%, respectively (Fig 1). As compared with pretransplantation evaluation, the following parameters showed significant improvement: hemoglobin A1C concentration, total and high-density lipoprotein cholesterol levels, arterial blood pressure, cardiac performance, diabetic retinopathy, proteinuria in the presence of stable renal function, and autonomic or peripheral neuropathy (Table 2). DISCUSSION
The standard surgical approach to PTA includes drainage of exocrine secretions into the bladder and diversion of venous outflow into the systemic circulation.14 This technique remains a milestone in pancreas transplantation, because it is safe and facilitates monitoring for rejection through urine amylase assay. However, this method is clearly nonphysiologic, and is associated with potential surgical,5 infectious,5 and metabolic4 complications that
1276
BOGGI, MOSCA, VISTOLI ET AL Table 2. Parameters Showing Improvement After PTA with PED Parameter
Hemoglobin A1C Total cholesterol (mg/dL) LDL cholesterol (mg/dL) Systolic blood pressure (mm Hg) Diastolic blood pressure (mm Hg) Cardiac performance Left ventricular ejection fraction (%) Left ventricular mass index (g/m2) E-wave/A-wave ratio Isovolumetric relaxation time (msec) Retinopathy Microaneurisms (per field) Microhemorrhages (per field) Proteinuria* (g/24 h) Autonomic and peripheral neuropathy DP NCV (msec) PT NCV (msec) LS ratio PH (⌬ mm Hg)
No. of Recipients
38 38 38 38 38 13
Before PTA
After PTA
P
9.4 ⫾ 1.1 207 ⫾ 36 134 ⫾ 35 127 ⫾ 17 81 ⫾ 8
5.5 ⫾ 0.3 165 ⫾ 35 107 ⫾ 31 104 ⫾ 7 71 ⫾ 8
⬍.01 ⬍.05 ⬍.05 ⬍.05 ⬍.05
54.0 ⫾ 4 86.7 ⫾ 16.9 1.2 ⫾ 0.2 90.5 ⫾ 9.1
56.5 ⫾ 3.9 72.0 ⫾ 8.9 1.4 ⫾ 0.3 85.0 ⫾ 5.1
⬍.05 ⬍.05 ⬍.05 ⬍.05
17 ⫾ 4 12 ⫾ 3 1.4 ⫾ 2.5
9⫾3 5⫾2 0.7 ⫾ 1.9
⬍.05 ⬍.05 ⬍.05
41 ⫾ 4.5 42 ⫾ 4.0 130 ⫾ 9 14 ⫾ 0.8
45 ⫾ 2.5 49 ⫾ 3.5 260 ⫾ 13 9 ⫾ 0.5
⬍.05 ⬍.05 ⬍.05 ⬍.05
25
15 20
Data expressed as mean ⫾ SD. Abbreviations: LDL, low-density lipoprotein; DP-NCV, deep peroneal nerve conduction velocity; PT NVC, posterior tibial nerve conduction velocity; LS, lying to standing ratio; PH, postural hypotension. *In the presence of stable renal function.
may reduce significantly the degree of posttransplantation rehabilitation of the recipient. Moreover, systemic venous effluent causes hyperinsulinemia,15 which has been credited to contribute to the progression of atherosclerosis16,17 and possibly to the development of insulin resistance.18 Portal venous effluent coupled with enteric drainage of exocrine secretions, as popularized by Gaber et al19 in the early 1990s, is clearly the transplantation technique that most strictly mimics the physiologic situation. Potential advantages of this method in case of PTA are avoidance of metabolic and infectious complications related to bladder drainage, and possibly improved metabolic profile. Moreover, recent data support the hypothesis that venous drainage into the portal circulation may be associated with an immunologic advantage.6 –9 Since solitary pancreas grafts are particularly susceptible to acute rejection, and there are no reliable markers for early detection of such episodes, with the exception of protocol pancreas biopsy,20,21 an immunologic advantage, possibly leading to improved longterm results or permitting a reduction of immunosuppression therapy, would be useful for solitary pancreas grafts. In this series we recorded an acute rejection rate of 12.5% after PTA with portal venous effluent. Despite 3 grafts being lost in the early posttransplantation period, due to hyperacute or acelerated rejection, no further grafts were lost at the longest follow-up, giving an actuarial 3-year insulin independence rate of 94.9%. This result was not obtained as a consequence of improved HLA matching or enhanced immunosuppression. Indeed, donors deemed otherwise suitable for PTA were not discarded based solely on low or nil HLA matching with possible recipients, while
immunosuppression was not heightened to overcome poor HLA matching. The relatively low burden of the immunosuppression regimens that were used is mirrored by the lack of posttransplantation lymphoproliferative disorders in this series, a dreadful complication of immunosuppression therapy that frequently occurs in the first year after transplantation.22 Strict posttransplantation graft surveillance by means of protocol biopsy cannot be claimed as a determinant for the high rate of long-term insulin independence, since biopsy was not used frequently in this series. Indeed, although the reported rate of complications after percutaneous pancreas biopsy is currently very low,20,21 thanks to modern immunosuppression therapy and possibly to portal venous drainage, pancreas biopsy would have improved rarely the management of our recipients. Indeed, if the main value of pancreas biopsy is in preventing unnecessary antirejection treatment,20 in our series the management of only 2 patients, treated with steroid boluses, might have been changed by pancreas biopsy. Although in the absence of a control group the advantages of PED cannot be demonstrated comparatively, data from the current literature and from our series suggest that PED in PTA is at least as safe as the classic technique of systemic bladder drainage and that it may allow high rates of long-term insulin-independence.
REFERENCES 1. Stratta RJ, Taylor RJ, Bynon JS, et al: Surgical treatment of diabetes mellitus with pancreas transplantation. Ann Surg 220:809, 1994
INSULIN INDEPENDENCE AFTER PANCREAS TRANSPLANTATION 2. Brayman KL, Weber M, Sutheland DER: Pancreatic and islet cell transplantation. In Trede M, Carter DC (eds): Surgery of the pancreas. New York: Churchill Livingstone, 1997, p 637 3. Giannarelli R, Coppelli A, Sartini MS, et al: Early improvement of unstable diabetic retinopathy after solitary pancreas transplantation. Diabetes Care 25:2358, 2002 4. Ngheim DD, Gonwa TA, Corry RJ: Metabolic effects of urinary diversion of exocrine secretions in pancreatic transplantation. Transplantation 43:70, 1987 5. Sollinger HW, Messing EM, Eckhoff DE, et al: Urological complications in 210 consecutive simultaneous pancreas-kidney transplants with bladder darinage. Ann Surg 218:561, 1993 6. Stratta RJ, Gaber AO, Shokouh-Amiri H, et al: Evolution in pancreas transplantation techniques: simultaneous pancreas-kidney transplantation using portal enteric drainage without antilymphocytic induction. Ann Surg 229:701, 1999 7. Lo A, Buell JF, Thistlehwaite JR, et al: Clinical experience with 114 portal-enteric drained simultaneous pancreas-kidney transplants. Acta Chir Austr 33:4, 2001 8. Troppmann C, Cecka M, McVicar J, et al: Does portal venous drainage of the pancreas graft in simultaneous pancreas-kidney transplant confer an immunologic advantage? Acta Chir Aust 33:3, 2001 9. Philosophe B, Farney AC, Schweitzer EJ, et al: Superiority of portal venous drainage over systemic venous drainage in pancreas transplantation: a retrospective study. Ann Surg 234:689, 2001 10. Robertson P, Davis C, Larsen J, et al: American Diabetes Association: pancreas transplantation in type 1 diabetes. Diabetes Care 27(suppl 1):S105, 2004 11. Boggi U, Vistoli F, Del Chiaro M, et al: A simplified technique for the en bloc procurement of abdominal organs that is suitable for pancreas and small-bowel transplantation. Surgery 135:629, 2004 12. Boggi U, Vistoli F, Del Chiaro M, et al: Retroperitoneal pancreas transplantation with portal-enteric drainage. Transplant Proc 36:571, 2004
1277 13. Troppmann C, Gruessner AC, Papalios BE, et al: Delayed endocrine pancreas graft function after simultaneous pancreaskidney transplantation: incidence, risk factors and impact on long term outcome. Transplantation 61:1323, 1996 14. Sutherland DER, Gruessner RWG, Dunn DL, et al. Lessons learned from more than 1,000 pancreas transplants at a single institution. Ann Surg 233:463, 2001 15. Diem P, et al: Systemic venous drainage of pancreas allografts as independent cause of hyperinsulinemia in type I diabetic recipients. Diabetes 39:534, 1990 16. Stout RW, Bierman EI, Ross R: Effects of insulin on the proliferation of cultured primate arterial smooth muscle cells. Circ Res 36:319, 1975 17. De Fronzo RA, Ferranini E. Insulin resistance: a multifaced syndrome responsible for NIDDM, obesity, hypertension, dyslipidemia, and atherosclerotic cardiovascular disease. Diabetes Care 14:173, 1991 18. Madsbad S, Christiansen E, Tibell A, et al: -Cell dysfunction following successful segmental pancreas transplantation. Danish-Swedish Study Group of Metabolic Effect of Pancreas Transplantation. Transplant Proc 26:469, 1994 19. Gaber AO, Shokouh-Amiri H, Grewal HP, et al: A technique for portal pancreas transplantation with enteric drainage. Surg Gynecol Obstet 177:417, 1993 20. Bartlett ST, Schweitzer EJ, Johnson LB, et al: Equivalent success of simultaneous pancreas kidney and solitary pancreas transplantation: a prospective trial of tacrolimus immunosuppression with percutaneous biopsy. Ann Surg 224:440, 1996 21. Kuo P, Johnson LB, Schweitzer EJ, et al: Solitary pancreas allografts: the role of percutaneous biopsy and standardized histologic grading of rejection. Arch Surg 132:52, 1997 22. Opelz G, Henderson R, for the Collaborative Transplant Study: Incidence of non-Hodgkin lymphoma in kidney and heart transplant recipients. Lancet 342:1514, 1993
P
ANCREAS TRANSPLANTATION ALONE (PTA) is by far the most effective treatment that allows tight glucose control and corrects dysmetabolism in diabetic patients without end-stage nephropathy in whom other avenues of intensive insulin therapy fail.1 Restoring euglicemia should prevent, arrest, and, it is hoped, reverse the progression of chronic vascular complications that otherwise would occur in more than 50% of diabetic patients.2 Moreover, PTA improves the quality of life of diabetic
patients by eliminating the need for exogen insulin, frequent glucose monitoring, and many of the dietary and
From the Department of Surgery and Transplantation, University of Pisa, Pisa, Italy. Address reprint requests to Franco Mosca, MD, FACS, FRCS Ed, Department of Surgery and Transplantation, University of Pisa, Via Paradisa 2, Pisa 56124, Italy. E-mail: f.mosca@ med.unipi.it
0041-1345/05/$–see front matter doi:10.1016/j.transproceed.2005.01.024
© 2005 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
1274
Transplantation Proceedings, 37, 1274 –1277 (2005)
INSULIN INDEPENDENCE AFTER PANCREAS TRANSPLANTATION
1275
Table 1. Recipient Characteristics Age (y; mean ⫾ SD) Sex (% male) Duration of diabetes (y; mean ⫾ SD) Hemoglobin A1C (%; mean ⫾ SD) Chronic complications (%) Nephropathy Proliferant retinopathy Autonomic neuropathy Unknown hypoglycemia (%) A, B mismatch (n; mean ⫾ SD) DR mismatch (n; mean ⫾ SD) Pannel reactive antibodies (%; mean ⫾ SD)
37.7 ⫾ 8.5 52.5% 23.9 ⫾ 10.5 9.5 ⫾ 1.2 90.0 45.0 85.0 70.0 15.0 2.7 ⫾ 0.9 1.2 ⫾ 0.6 0.4 ⫾ 2.0
life-style restrictions enforced by the disease.3 The need for long-term immunosuppression and the surgical risk of the transplant procedure, however, remain the main penalties for insulin-independence and are the main arguments against which the benefits of PTA should be appraised. Portal-enteric drainage (PED) of pancreas grafts might be advantageous in PTA. Indeed, if on one hand enteric drainage eliminates the metabolic4 and infectious consequences of bladder drainage.5 On the other hand, insulin delivery into the portal stream should improve the recipient’s metabolic profile by reproducing the physiologic situation. Moreover, recent data support the hypothesis that portal venous drainage may have an immunologic advantage,6 –9 thus potentially reducing the need for immunosuppression and improving long-term results. We report our experience with a consecutive series of PTAs with PED. MATERIALS AND METHODS From April 2001 & March 2004, 40 consecutive PTAs were performed with PED in type 1 diabetic recipients. Recipients (Table 1) were selected according to current recommendations of the American Diabetes Association.10 Pancreas procurement and donor selection were carried out according to the methods described previously.11 Human leukocyte antigen match was not regarded as a mandatary donor acceptance criterion, although the lowest mismatching for either A or B loci was considered at the time of graft allocation. All pancreas grafts were drained into the superior mesenteric vein and into the gut, according to the method described previously.12 Immunosuppression consisted of a quadruple regimen, including induction with either basiliximab (n ⫽ 34; 85.0%), 20 mg before graft reperfusion and on posttransplantation day 4, or thymoglobulin (n ⫽ 6; 15.0%), 1 mg/kg for 5 to 7 days), and maintenance therapy with low-dose steroids, tacrolimus (trough levels, 12 to 15 ng/mL in the first month after transplantation), and mycophenolate mofetil (2 g/d). Pancreas rejection was suspected, and therefore treated empirically, in the presence of any of the following: hyperamylasemia, hyperlipasemia, otherwise unexplained hyperglycemia, fever, or graft tenderness. Transplant outcomes were recorded prospectively in a computer data base. Delayed endocrine pancreas function was defined according to the criteria reported by Troppmann et al.13 Recipient and graft survival rates were determined with the Kaplan-Meier method.
Fig 1.
Actuarial survival curves.
RESULTS
After a mean period of cold ischemia time of 690 minutes (range, 517 to 965 min) all grafts functioned promptly. At the longest follow-up of 36 months (mean, 16.4 mo) a total of 5 acute rejection episodes (12.5%) were diagnosed in 5 recipients, including 3 hyperacute or accelerated rejections (7.5%) leading to graft loss and requiring allograft pancreatectomy. The remaining 2 acute rejection episodes responded well to higher steroid doses. No graft was lost to portal vein thrombosis, although 5 nonocclusive thromboses (12.5%) were identified, and the grafts were rescued with intravenous heparin infusion only (n ⫽ 4) or heparin infusion followed by surgical thrombectomy (n ⫽ 1). A total of 7 recipients (17.5%) required a repeat laparotomy. Indications for repeat operation were bleeding (n ⫽ 2; 7.5%), allograft pancreatectomy following graft loss due to hyperacute or accelerated rejection (n ⫽ 3; 7.5%), leakage from a duodenojejunostomy (n ⫽ 1; 2.5%), and hematoma evacuation associated with portal vein thrombectomy (n ⫽ 1; 2.5%). No patient required multiple repeat laparotomies, and none died. Actuarial 3-year patient survival rates were 100% and 94.9%, respectively (Fig 1). As compared with pretransplantation evaluation, the following parameters showed significant improvement: hemoglobin A1C concentration, total and high-density lipoprotein cholesterol levels, arterial blood pressure, cardiac performance, diabetic retinopathy, proteinuria in the presence of stable renal function, and autonomic or peripheral neuropathy (Table 2). DISCUSSION
The standard surgical approach to PTA includes drainage of exocrine secretions into the bladder and diversion of venous outflow into the systemic circulation.14 This technique remains a milestone in pancreas transplantation, because it is safe and facilitates monitoring for rejection through urine amylase assay. However, this method is clearly nonphysiologic, and is associated with potential surgical,5 infectious,5 and metabolic4 complications that
1276
BOGGI, MOSCA, VISTOLI ET AL Table 2. Parameters Showing Improvement After PTA with PED Parameter
Hemoglobin A1C Total cholesterol (mg/dL) LDL cholesterol (mg/dL) Systolic blood pressure (mm Hg) Diastolic blood pressure (mm Hg) Cardiac performance Left ventricular ejection fraction (%) Left ventricular mass index (g/m2) E-wave/A-wave ratio Isovolumetric relaxation time (msec) Retinopathy Microaneurisms (per field) Microhemorrhages (per field) Proteinuria* (g/24 h) Autonomic and peripheral neuropathy DP NCV (msec) PT NCV (msec) LS ratio PH (⌬ mm Hg)
No. of Recipients
38 38 38 38 38 13
Before PTA
After PTA
P
9.4 ⫾ 1.1 207 ⫾ 36 134 ⫾ 35 127 ⫾ 17 81 ⫾ 8
5.5 ⫾ 0.3 165 ⫾ 35 107 ⫾ 31 104 ⫾ 7 71 ⫾ 8
⬍.01 ⬍.05 ⬍.05 ⬍.05 ⬍.05
54.0 ⫾ 4 86.7 ⫾ 16.9 1.2 ⫾ 0.2 90.5 ⫾ 9.1
56.5 ⫾ 3.9 72.0 ⫾ 8.9 1.4 ⫾ 0.3 85.0 ⫾ 5.1
⬍.05 ⬍.05 ⬍.05 ⬍.05
17 ⫾ 4 12 ⫾ 3 1.4 ⫾ 2.5
9⫾3 5⫾2 0.7 ⫾ 1.9
⬍.05 ⬍.05 ⬍.05
41 ⫾ 4.5 42 ⫾ 4.0 130 ⫾ 9 14 ⫾ 0.8
45 ⫾ 2.5 49 ⫾ 3.5 260 ⫾ 13 9 ⫾ 0.5
⬍.05 ⬍.05 ⬍.05 ⬍.05
25
15 20
Data expressed as mean ⫾ SD. Abbreviations: LDL, low-density lipoprotein; DP-NCV, deep peroneal nerve conduction velocity; PT NVC, posterior tibial nerve conduction velocity; LS, lying to standing ratio; PH, postural hypotension. *In the presence of stable renal function.
may reduce significantly the degree of posttransplantation rehabilitation of the recipient. Moreover, systemic venous effluent causes hyperinsulinemia,15 which has been credited to contribute to the progression of atherosclerosis16,17 and possibly to the development of insulin resistance.18 Portal venous effluent coupled with enteric drainage of exocrine secretions, as popularized by Gaber et al19 in the early 1990s, is clearly the transplantation technique that most strictly mimics the physiologic situation. Potential advantages of this method in case of PTA are avoidance of metabolic and infectious complications related to bladder drainage, and possibly improved metabolic profile. Moreover, recent data support the hypothesis that venous drainage into the portal circulation may be associated with an immunologic advantage.6 –9 Since solitary pancreas grafts are particularly susceptible to acute rejection, and there are no reliable markers for early detection of such episodes, with the exception of protocol pancreas biopsy,20,21 an immunologic advantage, possibly leading to improved longterm results or permitting a reduction of immunosuppression therapy, would be useful for solitary pancreas grafts. In this series we recorded an acute rejection rate of 12.5% after PTA with portal venous effluent. Despite 3 grafts being lost in the early posttransplantation period, due to hyperacute or acelerated rejection, no further grafts were lost at the longest follow-up, giving an actuarial 3-year insulin independence rate of 94.9%. This result was not obtained as a consequence of improved HLA matching or enhanced immunosuppression. Indeed, donors deemed otherwise suitable for PTA were not discarded based solely on low or nil HLA matching with possible recipients, while
immunosuppression was not heightened to overcome poor HLA matching. The relatively low burden of the immunosuppression regimens that were used is mirrored by the lack of posttransplantation lymphoproliferative disorders in this series, a dreadful complication of immunosuppression therapy that frequently occurs in the first year after transplantation.22 Strict posttransplantation graft surveillance by means of protocol biopsy cannot be claimed as a determinant for the high rate of long-term insulin independence, since biopsy was not used frequently in this series. Indeed, although the reported rate of complications after percutaneous pancreas biopsy is currently very low,20,21 thanks to modern immunosuppression therapy and possibly to portal venous drainage, pancreas biopsy would have improved rarely the management of our recipients. Indeed, if the main value of pancreas biopsy is in preventing unnecessary antirejection treatment,20 in our series the management of only 2 patients, treated with steroid boluses, might have been changed by pancreas biopsy. Although in the absence of a control group the advantages of PED cannot be demonstrated comparatively, data from the current literature and from our series suggest that PED in PTA is at least as safe as the classic technique of systemic bladder drainage and that it may allow high rates of long-term insulin-independence.
REFERENCES 1. Stratta RJ, Taylor RJ, Bynon JS, et al: Surgical treatment of diabetes mellitus with pancreas transplantation. Ann Surg 220:809, 1994
INSULIN INDEPENDENCE AFTER PANCREAS TRANSPLANTATION 2. Brayman KL, Weber M, Sutheland DER: Pancreatic and islet cell transplantation. In Trede M, Carter DC (eds): Surgery of the pancreas. New York: Churchill Livingstone, 1997, p 637 3. Giannarelli R, Coppelli A, Sartini MS, et al: Early improvement of unstable diabetic retinopathy after solitary pancreas transplantation. Diabetes Care 25:2358, 2002 4. Ngheim DD, Gonwa TA, Corry RJ: Metabolic effects of urinary diversion of exocrine secretions in pancreatic transplantation. Transplantation 43:70, 1987 5. Sollinger HW, Messing EM, Eckhoff DE, et al: Urological complications in 210 consecutive simultaneous pancreas-kidney transplants with bladder darinage. Ann Surg 218:561, 1993 6. Stratta RJ, Gaber AO, Shokouh-Amiri H, et al: Evolution in pancreas transplantation techniques: simultaneous pancreas-kidney transplantation using portal enteric drainage without antilymphocytic induction. Ann Surg 229:701, 1999 7. Lo A, Buell JF, Thistlehwaite JR, et al: Clinical experience with 114 portal-enteric drained simultaneous pancreas-kidney transplants. Acta Chir Austr 33:4, 2001 8. Troppmann C, Cecka M, McVicar J, et al: Does portal venous drainage of the pancreas graft in simultaneous pancreas-kidney transplant confer an immunologic advantage? Acta Chir Aust 33:3, 2001 9. Philosophe B, Farney AC, Schweitzer EJ, et al: Superiority of portal venous drainage over systemic venous drainage in pancreas transplantation: a retrospective study. Ann Surg 234:689, 2001 10. Robertson P, Davis C, Larsen J, et al: American Diabetes Association: pancreas transplantation in type 1 diabetes. Diabetes Care 27(suppl 1):S105, 2004 11. Boggi U, Vistoli F, Del Chiaro M, et al: A simplified technique for the en bloc procurement of abdominal organs that is suitable for pancreas and small-bowel transplantation. Surgery 135:629, 2004 12. Boggi U, Vistoli F, Del Chiaro M, et al: Retroperitoneal pancreas transplantation with portal-enteric drainage. Transplant Proc 36:571, 2004
1277 13. Troppmann C, Gruessner AC, Papalios BE, et al: Delayed endocrine pancreas graft function after simultaneous pancreaskidney transplantation: incidence, risk factors and impact on long term outcome. Transplantation 61:1323, 1996 14. Sutherland DER, Gruessner RWG, Dunn DL, et al. Lessons learned from more than 1,000 pancreas transplants at a single institution. Ann Surg 233:463, 2001 15. Diem P, et al: Systemic venous drainage of pancreas allografts as independent cause of hyperinsulinemia in type I diabetic recipients. Diabetes 39:534, 1990 16. Stout RW, Bierman EI, Ross R: Effects of insulin on the proliferation of cultured primate arterial smooth muscle cells. Circ Res 36:319, 1975 17. De Fronzo RA, Ferranini E. Insulin resistance: a multifaced syndrome responsible for NIDDM, obesity, hypertension, dyslipidemia, and atherosclerotic cardiovascular disease. Diabetes Care 14:173, 1991 18. Madsbad S, Christiansen E, Tibell A, et al: -Cell dysfunction following successful segmental pancreas transplantation. Danish-Swedish Study Group of Metabolic Effect of Pancreas Transplantation. Transplant Proc 26:469, 1994 19. Gaber AO, Shokouh-Amiri H, Grewal HP, et al: A technique for portal pancreas transplantation with enteric drainage. Surg Gynecol Obstet 177:417, 1993 20. Bartlett ST, Schweitzer EJ, Johnson LB, et al: Equivalent success of simultaneous pancreas kidney and solitary pancreas transplantation: a prospective trial of tacrolimus immunosuppression with percutaneous biopsy. Ann Surg 224:440, 1996 21. Kuo P, Johnson LB, Schweitzer EJ, et al: Solitary pancreas allografts: the role of percutaneous biopsy and standardized histologic grading of rejection. Arch Surg 132:52, 1997 22. Opelz G, Henderson R, for the Collaborative Transplant Study: Incidence of non-Hodgkin lymphoma in kidney and heart transplant recipients. Lancet 342:1514, 1993