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Effects of Portal Versus Systemic Venous Drainage in Pancreas and Kidney-Pancreas Transplantation
Effects of Portal Versus Systemic Venous Drainage in Pancreas and Kidney-Pancreas Transplantation A. Alonso, C. Fernández, S. Cillero, M. Gómez, J. Aguirrezabalaga, and F. Valdés ABSTRACT We performed a retrospective analysis to compare pancreas transplantation with systemicenteric drainage (SE) or portal-enteric drainage (PE). Methods. We reviewed 38 consecutive pancreas transplants including 31 simultaneous kidney-pancreas (SKP) and 7 pancreas after kidney (PAK), using either systemic (n ⫽ 18) or portal (n ⫽ 20) venous drainage. Demographic, clinical, and immunologic variables were similar for both groups. Results. There were no significant differences in patient, kidney, or pancreas allograft survival rates after a mean follow-up of 23 months (range 1– 60). The mean length of hospital stay within 3 months was 34 days among the SE group versus 20 days in the PE group (P ⫽ ns). The incidences of intraabdominal infection, early relaparotomy, and acute rejection episodes were not different between groups. The blood pressure levels were similar among the SE and PE groups. There was no significant difference in creatinine, or fasting glucose, C-peptide, cholesterol, or triglyceride levels or homeostatic model assessment (HOMA) beta cell, HOMA-S, and HOMA-IR index. HbA1c was lower at 6 and 12 months in the PE group (P ⬍ .05). Mean prednisone and mycophenolate mofetil doses as well as tacrolimus levels were identical for both groups. Conclusion. The results suggested sustained long-term endocrine function in both groups, showing that in the short term, portal venous drainage did not offer major metabolic or immunologic advantages compared with systemic delivery of insulin.
S
YSTEMIC venous drainage of pancreas transplants has been associated with hyperinsulinemia and dyslipidemia and a risk of accelerated atherosclerosis.1,2 Portal drainage has resulted in significantly reduced plasma insulin and c-peptide levels, as well as improvements in lipoprotein compositions.3 However, the immunologic benefits observed among a small number of patients4 were not confirmed in other studies.5 We sought to analyze the outcomes in patients who received pancreas transplants, comparing portal with systemic venous drainage.
was administered to all patients; thymoglobulin (n ⫽ 27), basiliximab (n ⫽ 9), daclizumab (n ⫽ 1), or OKT3 (n ⫽ 1). The patient groups included 26 males and 12 females of overall mean age of 47⫹/⫺7 years (range 27–58) with a mean duration of pretransplant diabetes of 25.5 years (range, 15– 40) and a mean dialysis time of 22.2 months (range, 0 –72). Demographic and transplant characteristics were similar for both groups (Table 1). The subjects were studied at 3, 6, 12, 24, and 36 months after transplantation. The statistical analysis included Student’s t test, chi-square test, logistic, and Cox regression analysis. For survival analysis, we used Kaplan-Meier curves. Univariate analysis used the log-rank test.
PATIENTS AND METHODS From July 2000 through March 2006, we performed 38 pancreas transplantations: 31 simultaneous kidney-pancreas (SKP) and 7 pancreas after kidney (PAK) including 18 patients receiving systemic enteric (SE) drainage and 20, portal-enteric (PE) drainage. Maintenance immunosuppression consisted of tacrolimus (TAC), mycophenolate mofetil (MMF), and steroids. Induction therapy
From the Services of Nephrology (A.A., C.F., S.C., F.V.) and General Surgery (J.A., F.V.), Hospital Juan Canalejo, A Coruña, Spain. Address reprint request to Dr Angel Alonso. Servicio de Nefrologı´a, C.H.U.Juan Canalejo, Xubias de Arriba, n° 84. 15006, A Coruña, Spain. E-mail: [email protected]
© 2007 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
0041-1345/07/$–see front matter doi:10.1016/j.transproceed.2007.06.065
Transplantation Proceedings, 39, 2335–2337 (2007)
2335
2336
ALONSO, FERNÁNDEZ, CILLERO ET AL
Table 1. Demographic and Transplant Characteristics
Age (years) Gender (n) Male Female Weight (kg) BMI (kg/m2) PRA (%) HLA match ABDR Cold ischemia (hours) Kidney Pancreas SKP (n)
SE Drainage (n ⫽ 18)
PE Drainage (n ⫽ 20)
39.5 ⫾ 6.4
41.3 ⫾ 9.2
12 6 65 ⫾ 11 23 ⫾ 3.6 3.5 ⫾ 10 1.1 ⫾ 0.9
14 6 67 ⫾ 12 25 ⫾ 3.4 3.7 ⫾ 12 1⫾1
10 ⫾ 3.6 11 ⫾ 3 14
11.9 ⫾ 4.8 11.6 ⫾ 3 17
P ⫽ NS for all variables.
RESULTS
The mean follow-up for all pancreas transplants was 23⫹/ ⫺19 months (range, 1– 60). The mean follow-up for SEdrained pancreas transplants was 18⫹/⫺15 months and 33 ⫹/⫺19 months for PE-drained organs (P ⫽ .01). Patient survival was similar for both groups: PE: 80% vs SE: 86% (P ⫽ ns). Death-censored pancreas (SKP and PAK) graft survival was 73% for PE group and 81% for SE (P ⫽ ns). By category, SKP graft survival was similar for both PE and SE groups (P ⫽ ns). The mean length of hospital stay at 3 months was 34 days among the SE group and 20 days for the PE cohort (P ⫽ ns). Also, the incidences of intraabdominal infections and early relaparotomy were similar between groups. The incidence of acute rejection episodes at 1 year was similar in both groups: 6.3% for PE vs 8.3% for SE (P ⫽ ns). Blood pressure levels were not different between SE and PE groups. Over the follow period, there was no significant difference in serum creatinine, fasting glucose, C-peptide, cholesterol, triglycerides levels, and homeostatic model assessment (HOMA) beta-cell, HOMA-S, and HOMA-IR indices at several times of follow-up between the SE and PE groups. HbA1c was lower at 6 months at 1 year among the PE group (P ⬍ .05). Prednisone, MMF, and TAC doses as well as TAC levels were identical for SE and PE groups (Table 2). DISCUSSION
By bypassing the liver, systemic drainage causes peripheral hyperinsulinemia and portal hypoinsulinemia. Hyperinsulinemia has been associated with development of atherosclerosis, both directly through stimulation of vascular smooth muscle growth and indirectly through development and progression of dyslimia and hypertension. In addition, peripheral hyperlipidmia has been associated with insulin resistance, reduced postprandial peripheral glucose disposal, and reduced insulin-stimulated glucose storage. Also, this method downregulates insulin receptors and postreceptor pathways in muscle and adipose tissues, thus causing insulin resistance.1–3
Portal hypoinsulinemia may improve lipoprotein composition because of the role of the liver in lipid metabolism3 but no convincing evidence presently exists that systemic versus drainage places pancreas recipients at a disadvantage by increasing their risk of vascular disease.5,6 Our results showed comparable metabolic control with portal versus systemic vein drainage as determined by glucose, C-peptide, and HbA1c (after 1 year) levels and HOMA-B, HOMA-S, and HOMA-IR indices as has been previously reported.7 Also, the lipid levels and hypertension severity were similar for the PE and SE groups. Portal vein drainage may be more difficult to perform. In our series, the incidence of intraabdominal infection, early relaparotomy, and first-year hospitalization rates were similar in the PE and SE groups. One controversy is whether portal vein drainage has beneficial effects on pancreas graft acceptance.4,8 Philosophe et al showed a significantly lower incidence of graft rejection episodes among those with PE drainage.4 But two prospective studies of SE versus PE drainage in SKP recipients failed to observe a difference in the incidence of rejection, thereby disputing an immunologic advantage in favor of portal venous drainage.6,9 In our study the incidence of acute rejection episodes was similar among the PE and SE groups. Patient and graft survivals were no different in both groups, as in previous studies.5,10 In summary, portal vein drainage creates a more physiological state of insulin metabolism, but comparable metabolic control was achieved with portal and systemic vein drainage. They should not be considered competing but rather complementary techniques. Therefore, an individualized approach seems desirable. Our results suggested that pancreas and kidney-pancreas transplantation with SE or PE drainage may be performed with comparable intermediate-term outcomes. Long-term studies are required to evaluate whether PE and SE are equivalent in terms of patient and graft survivals as well as metabolic consequences.
Table 2. Results at the End of Follow-Up Variable
SE Drainage (n ⫽ 18)
PE Drainage (n ⫽ 20)
P
Creatinine (mg/dL) Glucose (mg/dL) C-peptide (ng/mL) Hb A1c (%) Cholesterol (mg/dL) Triglicerydes (mg/dL) HOMA-B (%) HOMA-S (%) HOMA-IR index PRED dose (mg/day) TAC levels (ng/mL)
1.7 ⫾ 0.4 89 ⫾ 15 3.3 ⫾ 0.5 5.9 ⫾ 1.1 183 ⫾ 38 139 ⫾ 96 226 ⫾ 46 42 ⫾ 79 2.27 ⫾ 0.3 8⫾2 10.5 ⫾ 0.5
1.3 ⫾ 0.5 77 ⫾ 6 3.6 ⫾ 1.2 5 ⫾ 0.7 157 ⫾ 34 133 ⫾ 74 190 ⫾ 35 49 ⫾ 14 2.18 ⫾ 0.6 7.9 ⫾ 2 9.1 ⫾ 2.2
.23 .61 .68 .92 .08 .85 .47 .36 .80 .76 .32
PORTAL VERSUS VENOUS DRAINAGE EFFECTS
REFERENCES 1. Diem P, Abid M, Redmon JB, et al: Systemic venous drainage of pancreas allografts as independent causes of hyperinsulinemia in type 1 diabetic recipients. Diabetes 39:534, 1990 2. Bagdade JD, Ritter MC, Kitabchi AE, et al: Differing effects of pancreas-kidney transplantation with systemic versus portal venous drainage on cholesterol ester transfer in IDDM subjets. Diabetes Care 19:1108, 1996 3. Hughes TA, Gaber AO, Amiri H, et al: Kidney-pancreas transplantation. The effect of portal venous versus systemic venous drainage of the pancreas on the lipoprotein composition. Transplantation 60:1406, 1995 4. Philosophe B, Farney AC, Schweitzer EJ, et al: Superiority of portal venous drainage over systemic venous drainage in pancreas transplantation. Ann Surg 234:689, 2001 5. Stratta RJ, Shokouh-Amiri H, Egidi F, et al: A prospective comparison of simultaneous kidney-pancreas transplantation with
2337 systemic-enteric versus portal-enteric drainage. Ann Surg 233:770, 2001 6. Bak M, Grochowieckit T, Galazka Z, et al: Proinsulinemia in simultaneous pancreas and kidney transplant recipients. Transplant Proc 38:280, 2006 7. Aguilera E, Recasens L, Flores L, et al: HOMA test in diabetic patients with simultaneous pancreas and kidney transplantation. Transplant Proc 34:206, 2002 8. Nyman T, Hathaway D, Shokouh-Amiri H, et al: Patterns of acute rejections in portal-enteric versus systemic-bladder pancreaskidney transplantation. Clin Transplant 12:175, 1998 9. Petruzzo P, Da Silva M, Feitosa L, et al: Simultaneous pancreas-kidney transplantation: portal versus systemic venous drainage of the pancreas allograft. Clin Transplant 14:287, 2000 10. Sutherland DER, Gruessner A: Internacional Pancreas Transplant Registry. IPTR Newsletter 12:1, 2000
S
YSTEMIC venous drainage of pancreas transplants has been associated with hyperinsulinemia and dyslipidemia and a risk of accelerated atherosclerosis.1,2 Portal drainage has resulted in significantly reduced plasma insulin and c-peptide levels, as well as improvements in lipoprotein compositions.3 However, the immunologic benefits observed among a small number of patients4 were not confirmed in other studies.5 We sought to analyze the outcomes in patients who received pancreas transplants, comparing portal with systemic venous drainage.
was administered to all patients; thymoglobulin (n ⫽ 27), basiliximab (n ⫽ 9), daclizumab (n ⫽ 1), or OKT3 (n ⫽ 1). The patient groups included 26 males and 12 females of overall mean age of 47⫹/⫺7 years (range 27–58) with a mean duration of pretransplant diabetes of 25.5 years (range, 15– 40) and a mean dialysis time of 22.2 months (range, 0 –72). Demographic and transplant characteristics were similar for both groups (Table 1). The subjects were studied at 3, 6, 12, 24, and 36 months after transplantation. The statistical analysis included Student’s t test, chi-square test, logistic, and Cox regression analysis. For survival analysis, we used Kaplan-Meier curves. Univariate analysis used the log-rank test.
PATIENTS AND METHODS From July 2000 through March 2006, we performed 38 pancreas transplantations: 31 simultaneous kidney-pancreas (SKP) and 7 pancreas after kidney (PAK) including 18 patients receiving systemic enteric (SE) drainage and 20, portal-enteric (PE) drainage. Maintenance immunosuppression consisted of tacrolimus (TAC), mycophenolate mofetil (MMF), and steroids. Induction therapy
From the Services of Nephrology (A.A., C.F., S.C., F.V.) and General Surgery (J.A., F.V.), Hospital Juan Canalejo, A Coruña, Spain. Address reprint request to Dr Angel Alonso. Servicio de Nefrologı´a, C.H.U.Juan Canalejo, Xubias de Arriba, n° 84. 15006, A Coruña, Spain. E-mail: [email protected]
© 2007 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
0041-1345/07/$–see front matter doi:10.1016/j.transproceed.2007.06.065
Transplantation Proceedings, 39, 2335–2337 (2007)
2335
2336
ALONSO, FERNÁNDEZ, CILLERO ET AL
Table 1. Demographic and Transplant Characteristics
Age (years) Gender (n) Male Female Weight (kg) BMI (kg/m2) PRA (%) HLA match ABDR Cold ischemia (hours) Kidney Pancreas SKP (n)
SE Drainage (n ⫽ 18)
PE Drainage (n ⫽ 20)
39.5 ⫾ 6.4
41.3 ⫾ 9.2
12 6 65 ⫾ 11 23 ⫾ 3.6 3.5 ⫾ 10 1.1 ⫾ 0.9
14 6 67 ⫾ 12 25 ⫾ 3.4 3.7 ⫾ 12 1⫾1
10 ⫾ 3.6 11 ⫾ 3 14
11.9 ⫾ 4.8 11.6 ⫾ 3 17
P ⫽ NS for all variables.
RESULTS
The mean follow-up for all pancreas transplants was 23⫹/ ⫺19 months (range, 1– 60). The mean follow-up for SEdrained pancreas transplants was 18⫹/⫺15 months and 33 ⫹/⫺19 months for PE-drained organs (P ⫽ .01). Patient survival was similar for both groups: PE: 80% vs SE: 86% (P ⫽ ns). Death-censored pancreas (SKP and PAK) graft survival was 73% for PE group and 81% for SE (P ⫽ ns). By category, SKP graft survival was similar for both PE and SE groups (P ⫽ ns). The mean length of hospital stay at 3 months was 34 days among the SE group and 20 days for the PE cohort (P ⫽ ns). Also, the incidences of intraabdominal infections and early relaparotomy were similar between groups. The incidence of acute rejection episodes at 1 year was similar in both groups: 6.3% for PE vs 8.3% for SE (P ⫽ ns). Blood pressure levels were not different between SE and PE groups. Over the follow period, there was no significant difference in serum creatinine, fasting glucose, C-peptide, cholesterol, triglycerides levels, and homeostatic model assessment (HOMA) beta-cell, HOMA-S, and HOMA-IR indices at several times of follow-up between the SE and PE groups. HbA1c was lower at 6 months at 1 year among the PE group (P ⬍ .05). Prednisone, MMF, and TAC doses as well as TAC levels were identical for SE and PE groups (Table 2). DISCUSSION
By bypassing the liver, systemic drainage causes peripheral hyperinsulinemia and portal hypoinsulinemia. Hyperinsulinemia has been associated with development of atherosclerosis, both directly through stimulation of vascular smooth muscle growth and indirectly through development and progression of dyslimia and hypertension. In addition, peripheral hyperlipidmia has been associated with insulin resistance, reduced postprandial peripheral glucose disposal, and reduced insulin-stimulated glucose storage. Also, this method downregulates insulin receptors and postreceptor pathways in muscle and adipose tissues, thus causing insulin resistance.1–3
Portal hypoinsulinemia may improve lipoprotein composition because of the role of the liver in lipid metabolism3 but no convincing evidence presently exists that systemic versus drainage places pancreas recipients at a disadvantage by increasing their risk of vascular disease.5,6 Our results showed comparable metabolic control with portal versus systemic vein drainage as determined by glucose, C-peptide, and HbA1c (after 1 year) levels and HOMA-B, HOMA-S, and HOMA-IR indices as has been previously reported.7 Also, the lipid levels and hypertension severity were similar for the PE and SE groups. Portal vein drainage may be more difficult to perform. In our series, the incidence of intraabdominal infection, early relaparotomy, and first-year hospitalization rates were similar in the PE and SE groups. One controversy is whether portal vein drainage has beneficial effects on pancreas graft acceptance.4,8 Philosophe et al showed a significantly lower incidence of graft rejection episodes among those with PE drainage.4 But two prospective studies of SE versus PE drainage in SKP recipients failed to observe a difference in the incidence of rejection, thereby disputing an immunologic advantage in favor of portal venous drainage.6,9 In our study the incidence of acute rejection episodes was similar among the PE and SE groups. Patient and graft survivals were no different in both groups, as in previous studies.5,10 In summary, portal vein drainage creates a more physiological state of insulin metabolism, but comparable metabolic control was achieved with portal and systemic vein drainage. They should not be considered competing but rather complementary techniques. Therefore, an individualized approach seems desirable. Our results suggested that pancreas and kidney-pancreas transplantation with SE or PE drainage may be performed with comparable intermediate-term outcomes. Long-term studies are required to evaluate whether PE and SE are equivalent in terms of patient and graft survivals as well as metabolic consequences.
Table 2. Results at the End of Follow-Up Variable
SE Drainage (n ⫽ 18)
PE Drainage (n ⫽ 20)
P
Creatinine (mg/dL) Glucose (mg/dL) C-peptide (ng/mL) Hb A1c (%) Cholesterol (mg/dL) Triglicerydes (mg/dL) HOMA-B (%) HOMA-S (%) HOMA-IR index PRED dose (mg/day) TAC levels (ng/mL)
1.7 ⫾ 0.4 89 ⫾ 15 3.3 ⫾ 0.5 5.9 ⫾ 1.1 183 ⫾ 38 139 ⫾ 96 226 ⫾ 46 42 ⫾ 79 2.27 ⫾ 0.3 8⫾2 10.5 ⫾ 0.5
1.3 ⫾ 0.5 77 ⫾ 6 3.6 ⫾ 1.2 5 ⫾ 0.7 157 ⫾ 34 133 ⫾ 74 190 ⫾ 35 49 ⫾ 14 2.18 ⫾ 0.6 7.9 ⫾ 2 9.1 ⫾ 2.2
.23 .61 .68 .92 .08 .85 .47 .36 .80 .76 .32
PORTAL VERSUS VENOUS DRAINAGE EFFECTS
REFERENCES 1. Diem P, Abid M, Redmon JB, et al: Systemic venous drainage of pancreas allografts as independent causes of hyperinsulinemia in type 1 diabetic recipients. Diabetes 39:534, 1990 2. Bagdade JD, Ritter MC, Kitabchi AE, et al: Differing effects of pancreas-kidney transplantation with systemic versus portal venous drainage on cholesterol ester transfer in IDDM subjets. Diabetes Care 19:1108, 1996 3. Hughes TA, Gaber AO, Amiri H, et al: Kidney-pancreas transplantation. The effect of portal venous versus systemic venous drainage of the pancreas on the lipoprotein composition. Transplantation 60:1406, 1995 4. Philosophe B, Farney AC, Schweitzer EJ, et al: Superiority of portal venous drainage over systemic venous drainage in pancreas transplantation. Ann Surg 234:689, 2001 5. Stratta RJ, Shokouh-Amiri H, Egidi F, et al: A prospective comparison of simultaneous kidney-pancreas transplantation with
2337 systemic-enteric versus portal-enteric drainage. Ann Surg 233:770, 2001 6. Bak M, Grochowieckit T, Galazka Z, et al: Proinsulinemia in simultaneous pancreas and kidney transplant recipients. Transplant Proc 38:280, 2006 7. Aguilera E, Recasens L, Flores L, et al: HOMA test in diabetic patients with simultaneous pancreas and kidney transplantation. Transplant Proc 34:206, 2002 8. Nyman T, Hathaway D, Shokouh-Amiri H, et al: Patterns of acute rejections in portal-enteric versus systemic-bladder pancreaskidney transplantation. Clin Transplant 12:175, 1998 9. Petruzzo P, Da Silva M, Feitosa L, et al: Simultaneous pancreas-kidney transplantation: portal versus systemic venous drainage of the pancreas allograft. Clin Transplant 14:287, 2000 10. Sutherland DER, Gruessner A: Internacional Pancreas Transplant Registry. IPTR Newsletter 12:1, 2000