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Pancreas transplantation from marginal donors
Pancreas Transplantation From Marginal Donors U. Boggi, M. Del Chiaro, F. Vistoli, S. Signori, T. Vanadia Bartolo, F. Gremmo, P. Marchetti, A. Coppelli, G. Rizzo, and F. Mosca ABSTRACT Background. Marginal donor organs are a supplementary source of grafts that has not been fully exploited for pancreas transplantation (PTx). Methods. A total of 100 PTx were performed with grafts procured from either 48 nonmarginal donors (NMD) or 52 marginal donors (MD), namely age greater than 45 years and/or severe hemodynamic instability at the time of procurement. PTx outcome was evaluated as the incidence of delayed endocrine pancreas function (DEPF), the complication rate, and the patient and graft survivals. Results. The DEPF rate was 6.2% for NMD as compared to 0 for MD (P ⬎ .05). Relaparotomy rate was 12.5% for NMD and 9.6% for MD (P ⬎ .05). Actuarial 1-year graft survival was 91.7% and 94.2% for NMD and MD, respectively (P ⬎ .05). Equivalent figures for patients were 97.9% and 98.1%, respectively (P ⬎ .05). Conclusions. Pancreas from MD may be safely employed and significantly expand the donor pool for PTx.
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ESPITE THE BENEFICIAL effects of pancreas transplantation (PTx) on the quality of life of diabetic patients1,2 and the continuously growing evidence of its possible lifesaving effect in the long-term period,3–5 much fewer pancreata are procured than are actually needed.6 Unwillingness to share a donor kidney with the pancreas, even despite mandatory payback policies, as well as fear of compromising the safety of liver transplantation may explain the reduced rates of pancreas procurement compared with other abdominal organs. However, it is likely that the main factor limiting the donor pool for PTx is the highly restrictive donor selection criteria used by many transplant centers.6,7 We herein report our experience with expanded donor criteria for PTx.
Donor Selection and Graft Procurement All cadaveric donors aged less than 55 years without a history of diabetes, pancreas trauma, or chronic pancreatic disease were considered potentially eligible for pancreas donation. The final decision to accept a pancreas was based on the gross appearance of the graft and the vessels and on the quality of visceral perfusion. The pancreata were procured en bloc with the liver and kidneys, and separated on the back table, as described previously.8
Definition of Graft Function Primary endocrine pancreas nonfunction (PEPNF) was defined as the absence of any metabolic improvement with constant insulin requirements. Delayed endocrine pancreas function (DEPG) was defined as a total insulin requirement of ⬎30 U between post-Tx days 5 and 10, and/or ⬎15 U between days 11 and 15, irrespective of the insulin dose administered during the first 5 days after Tx.9
MATERIALS AND METHODS A retrospective analysis was performed to analyze the outcome of 100 consecutive PTX performed between January 2000 and May 2003. Donors were classified as nonmarginal (NMD) or marginal (MD) based on the criteria previously described by Kapur and colleagues.6 In detail, each donor aged over 45 years was considered an MD, as were donors who were hemodynamically unstable at the time of procurement. Hemodynamic instability was defined as the need for high-dose dopamine (⬎10 g/kg/min) or at least two vasopressors.6 By these criteria there were 48 NMD and 52 MD. 0041-1345/04/$–see front matter doi:10.1016/j.transproceed.2004.02.031 566
From the Divisione di Chirurgia Generale e Trapianti (U.B., M.D.C., F.V., S.S., T.V.B., F.G., F.M.) and Divisione di Diabetologia (P.M., A.C.), Universita` di Pisa, Pisa, Italy, and Unita´ Operativa Nefrologia e Trapianti (G.R.), Azienda Ospedaliera Universitaria Pisana, Pisa, Italy. This work was supported by a grant from ARPA Foundation (www.fondazionearpa.it). Address reprint requests to Franco Mosca, MD, FACS, Head, Divisione di Chirurgia Generale e Trapianti, Universita` di Pisa, Ospedale di Cisanello, via Paradisa 2, 56124, Pisa, Italy. © 2004 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710 Transplantation Proceedings, 36, 566 –568 (2004)
MARGINAL PANCREAS DONORS
Transplant Technique The pancreas was transplanted either alone (n ⫽ 27) or simultaneously with a kidney procured from the same cadaveric donor (n ⫽ 55) or from a living donor (n ⫽ 16). Two pancreata were transplanted after successful kidney transplantation. Most grafts (n ⫽ 74) were transplanted using portal-enteric drainage, while the remaining 26 pancreata had systemic venous effluent exocrine drainage, either bladder (n ⫽ 20) or enteric (n ⫽ 6).
Immunosuppression Immunosuppression consisted of a quadruple regimen including induction with either basiliximab (n ⫽ 94; 94.0%) delivered as 20 mg before graft reperfusion and on posttransplant day 4, or ATG (n ⫽ 6; 6.0%) delivered as 1 mg/kg for 7 to 10 days. Maintenance therapy included low-dose steroids, tacrolimus (n ⫽ 68; 68.0%) targeted to trough levels of 12 to 15 ng/mL during the first two posttransplant weeks or cyclosporine (n ⫽ 32; 32.0%) targeted to trough levels 200 to 250 ng/mL in the first two posttransplant weeks, and mycophenolate mofetil (2 g/daily).
Graft Survival and Statistical Analysis Graft loss was determined when the patient required exogenous insulin to remain euglycemic or upon death. Survival estimates were calculated using the Kaplan-Meier method.
RESULTS
The donor pool for PTx was more than doubled in this series with the use of expanded donor criteria. Early functional outcome was not worsened among MD as compared to NMD. Indeed, no PEPNF was diagnosed among MD, while the rate of DEPF was 6.2% for NMD (P ⬎ .05). Relaparotomy rate was 12.5% for NMD and 9.6% for MD (P ⬎ .05); no graft was lost to surgical complications. Three partial portal thromboses developed in two NMD pancreata and one MD pancreas (P ⬎ .05); all grafts were rescued by intravenous heparin. Infections occurred in 12.5% of NMD and in 9.6% of MD pancreas recipients (P ⬎ .05). Actuarial 1-year insulin-independence rate was 91.7% and 94.2% for NMD and MD, respectively (P ⬎ .05). MD pancreata from donors aged more than 45 years showed 90.2% actuarial 1-year graft survival compared with 93.4% for MD pancreata from hemodynamically unstable donors (P ⬎ .05). Patient survival rates at the same time point were, 97.9% for NMD compared with 98.1% for MD (P ⬎ .05). DISCUSSION
Donor selection criteria for PTx are among the most restrictive of all routinely performed solid organ transplants. The pancreas is indeed particularly susceptible to surgical complications,10 potentially leading to increased rates of both graft loss and recipient death10,11 as well as to ischemia-reperfusion injury, potentially initiating the cascade of events associated with graft pancreatitis.12 Donor age over 45 years,13,14 cerebro/cardiovascular cause of death,14 and hemodynamic instability6,7 have been tradi-
567
tionally considered negative prognostic factors affecting posttransplant graft survival. Accordingly, many transplant centers continue to restrict their donor acceptance criteria for PTx to young, hemodynamically stable donors. On one hand, this policy ensures optimal transplant outcomes; on the other hand, it significantly limits the number of patients that may actually receive a pancreas graft. Acceptance of expanded donor criteria for PTx, as defined by Kapur and coworkers,6 provided 52 additional organs during the time of this study. Thus, the donor pool was more than doubled with the use of MD pancreata. Our PTx outcome are similar to those reported by the University of Pittsburgh6,7 and shown to not be affected by either donor age or hemodynamic instability. Although a longer follow-up period is needed before any final conclusion may be drawn, the 1-year graft survival rate of over 90% seems to justify an optimistic atitude on the possibility of a satisfactory longterm outcome. Indeed, a theoretical analysis of the benefits of solitary pancreas transplantation by Kiberd and Larson estimated than a graft half-life expectancy of 10 years should be reached with a 1-year graft survival of 80%.15 Thus, according to this theoretical estimate, the half-life of an MD pancreas might be longer than that of cadaveric kidney transplantation.16 We conclude that direct donor and graft assessment by an experienced surgeon allows safe use of a pancreas procured from a donor over age 45 years or with hemodynamic instability, thereby expanding the donor pool. REFERENCES 1. Nathan DM, Fogel H, Norman D, et al: Long-term metabolic and quality of life results with pancreatic/renal transplantation in insulin-dependent diabetes mellitus. Transplantation 52:85, 1991 2. Hathaway DK, Hartwig MS, Milstead J, et al: Improvements in quality of life reported by diabetic recipients of kidney-only and pancreas-kidney allografts. Transplant Proc 26:512, 1994 3. Smets YF, Westendorp RG, van der Pijl JW, et al: Effect of simultaneous pancreas-kidney transplantation on mortality of patients with type-1 diabetes mellitus and end-stage renal failure. Lancet 353:1915, 1999 4. Tyde´n G, Bolinder J, Solders G, et al: Improved survival in patients with insulin-dependent diabetes mellitus and end-stage diabetic nephropathy 10 years after combined pancreas and kidney transplantation. Transplantation 67:645, 1999 5. Becker BN, Brazy PC, Becker YT, et al: Simultaneous pancreas-kidney transplantation reduces excess mortality in type 1 diabetic patients with end-stage renal disease. Kidney Int 57:2129, 2000 6. Kapur S, Bonham CA, Dodson SF, et al: Strategies to expand the donor pool for pancreas transplantation. Transplantation 67: 284, 1999 7. Bonham CA, Kapur S, Dodson SF, et al: Potential use of marginal donors for pancreas transplantation. Transplant Proc 31:612, 1999 8. Boggi U, Vistoli F, Del Chiaro M, et al: Pancreas procurement from cadaveric donors of multiple grafts: In Farinon A (ed): Advances in Abdominal Surgery. The Netherlands: Kluwer Academic Publisher, 2002, p 359 9. 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
568 10. Troppmann C, Gruessner AC, Dunn DL, et al: Surgical complications requiring early relaparotomy after pancreas transplantation. A multivariate risk factor and economic analysis of the cyclosporine era. Ann Surg 227:255, 1998 11. Humar A, Kandaswamy R, Granger D, et al: Decreased surgical risk of pancreas transplantation in the modern era. Ann Surg 231:269, 2000 12. Benz S, Bergt S, Obermaier R, et al: Impairment of microcirculation in the early reperfusion period predicts the degree of graft pancreatitis in clinical pancreas transplantation. Transplantation 71:759, 2001
BOGGI, DEL CHIARO, VISTOLI ET AL 13. Odorico JS, Heisey DM, Voss BJ, et al: Donor factors affecting outcome after pancreas transplantation. Transplant Proc 30:276, 1998 14. International Pancreas Transplant Registry Newsletter. August 31, 2002; Volume 14, Number 1 15. Kiberd BA, Larson T: Estimating the benefits of solitary pancreas transplantation in nonuremic patients with type 1 diabetes mellitus: a theoretical analysis. Transplantation 70:1121, 2000 16. Cecka JM: Living donor transplants. In Cecka JM, Terasaki P (eds): Clinical Transplants 1995. Los Angeles, Calif: UCLA Tissue Typing Laboratory; 1996, p 363
D
ESPITE THE BENEFICIAL effects of pancreas transplantation (PTx) on the quality of life of diabetic patients1,2 and the continuously growing evidence of its possible lifesaving effect in the long-term period,3–5 much fewer pancreata are procured than are actually needed.6 Unwillingness to share a donor kidney with the pancreas, even despite mandatory payback policies, as well as fear of compromising the safety of liver transplantation may explain the reduced rates of pancreas procurement compared with other abdominal organs. However, it is likely that the main factor limiting the donor pool for PTx is the highly restrictive donor selection criteria used by many transplant centers.6,7 We herein report our experience with expanded donor criteria for PTx.
Donor Selection and Graft Procurement All cadaveric donors aged less than 55 years without a history of diabetes, pancreas trauma, or chronic pancreatic disease were considered potentially eligible for pancreas donation. The final decision to accept a pancreas was based on the gross appearance of the graft and the vessels and on the quality of visceral perfusion. The pancreata were procured en bloc with the liver and kidneys, and separated on the back table, as described previously.8
Definition of Graft Function Primary endocrine pancreas nonfunction (PEPNF) was defined as the absence of any metabolic improvement with constant insulin requirements. Delayed endocrine pancreas function (DEPG) was defined as a total insulin requirement of ⬎30 U between post-Tx days 5 and 10, and/or ⬎15 U between days 11 and 15, irrespective of the insulin dose administered during the first 5 days after Tx.9
MATERIALS AND METHODS A retrospective analysis was performed to analyze the outcome of 100 consecutive PTX performed between January 2000 and May 2003. Donors were classified as nonmarginal (NMD) or marginal (MD) based on the criteria previously described by Kapur and colleagues.6 In detail, each donor aged over 45 years was considered an MD, as were donors who were hemodynamically unstable at the time of procurement. Hemodynamic instability was defined as the need for high-dose dopamine (⬎10 g/kg/min) or at least two vasopressors.6 By these criteria there were 48 NMD and 52 MD. 0041-1345/04/$–see front matter doi:10.1016/j.transproceed.2004.02.031 566
From the Divisione di Chirurgia Generale e Trapianti (U.B., M.D.C., F.V., S.S., T.V.B., F.G., F.M.) and Divisione di Diabetologia (P.M., A.C.), Universita` di Pisa, Pisa, Italy, and Unita´ Operativa Nefrologia e Trapianti (G.R.), Azienda Ospedaliera Universitaria Pisana, Pisa, Italy. This work was supported by a grant from ARPA Foundation (www.fondazionearpa.it). Address reprint requests to Franco Mosca, MD, FACS, Head, Divisione di Chirurgia Generale e Trapianti, Universita` di Pisa, Ospedale di Cisanello, via Paradisa 2, 56124, Pisa, Italy. © 2004 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710 Transplantation Proceedings, 36, 566 –568 (2004)
MARGINAL PANCREAS DONORS
Transplant Technique The pancreas was transplanted either alone (n ⫽ 27) or simultaneously with a kidney procured from the same cadaveric donor (n ⫽ 55) or from a living donor (n ⫽ 16). Two pancreata were transplanted after successful kidney transplantation. Most grafts (n ⫽ 74) were transplanted using portal-enteric drainage, while the remaining 26 pancreata had systemic venous effluent exocrine drainage, either bladder (n ⫽ 20) or enteric (n ⫽ 6).
Immunosuppression Immunosuppression consisted of a quadruple regimen including induction with either basiliximab (n ⫽ 94; 94.0%) delivered as 20 mg before graft reperfusion and on posttransplant day 4, or ATG (n ⫽ 6; 6.0%) delivered as 1 mg/kg for 7 to 10 days. Maintenance therapy included low-dose steroids, tacrolimus (n ⫽ 68; 68.0%) targeted to trough levels of 12 to 15 ng/mL during the first two posttransplant weeks or cyclosporine (n ⫽ 32; 32.0%) targeted to trough levels 200 to 250 ng/mL in the first two posttransplant weeks, and mycophenolate mofetil (2 g/daily).
Graft Survival and Statistical Analysis Graft loss was determined when the patient required exogenous insulin to remain euglycemic or upon death. Survival estimates were calculated using the Kaplan-Meier method.
RESULTS
The donor pool for PTx was more than doubled in this series with the use of expanded donor criteria. Early functional outcome was not worsened among MD as compared to NMD. Indeed, no PEPNF was diagnosed among MD, while the rate of DEPF was 6.2% for NMD (P ⬎ .05). Relaparotomy rate was 12.5% for NMD and 9.6% for MD (P ⬎ .05); no graft was lost to surgical complications. Three partial portal thromboses developed in two NMD pancreata and one MD pancreas (P ⬎ .05); all grafts were rescued by intravenous heparin. Infections occurred in 12.5% of NMD and in 9.6% of MD pancreas recipients (P ⬎ .05). Actuarial 1-year insulin-independence rate was 91.7% and 94.2% for NMD and MD, respectively (P ⬎ .05). MD pancreata from donors aged more than 45 years showed 90.2% actuarial 1-year graft survival compared with 93.4% for MD pancreata from hemodynamically unstable donors (P ⬎ .05). Patient survival rates at the same time point were, 97.9% for NMD compared with 98.1% for MD (P ⬎ .05). DISCUSSION
Donor selection criteria for PTx are among the most restrictive of all routinely performed solid organ transplants. The pancreas is indeed particularly susceptible to surgical complications,10 potentially leading to increased rates of both graft loss and recipient death10,11 as well as to ischemia-reperfusion injury, potentially initiating the cascade of events associated with graft pancreatitis.12 Donor age over 45 years,13,14 cerebro/cardiovascular cause of death,14 and hemodynamic instability6,7 have been tradi-
567
tionally considered negative prognostic factors affecting posttransplant graft survival. Accordingly, many transplant centers continue to restrict their donor acceptance criteria for PTx to young, hemodynamically stable donors. On one hand, this policy ensures optimal transplant outcomes; on the other hand, it significantly limits the number of patients that may actually receive a pancreas graft. Acceptance of expanded donor criteria for PTx, as defined by Kapur and coworkers,6 provided 52 additional organs during the time of this study. Thus, the donor pool was more than doubled with the use of MD pancreata. Our PTx outcome are similar to those reported by the University of Pittsburgh6,7 and shown to not be affected by either donor age or hemodynamic instability. Although a longer follow-up period is needed before any final conclusion may be drawn, the 1-year graft survival rate of over 90% seems to justify an optimistic atitude on the possibility of a satisfactory longterm outcome. Indeed, a theoretical analysis of the benefits of solitary pancreas transplantation by Kiberd and Larson estimated than a graft half-life expectancy of 10 years should be reached with a 1-year graft survival of 80%.15 Thus, according to this theoretical estimate, the half-life of an MD pancreas might be longer than that of cadaveric kidney transplantation.16 We conclude that direct donor and graft assessment by an experienced surgeon allows safe use of a pancreas procured from a donor over age 45 years or with hemodynamic instability, thereby expanding the donor pool. REFERENCES 1. Nathan DM, Fogel H, Norman D, et al: Long-term metabolic and quality of life results with pancreatic/renal transplantation in insulin-dependent diabetes mellitus. Transplantation 52:85, 1991 2. Hathaway DK, Hartwig MS, Milstead J, et al: Improvements in quality of life reported by diabetic recipients of kidney-only and pancreas-kidney allografts. Transplant Proc 26:512, 1994 3. Smets YF, Westendorp RG, van der Pijl JW, et al: Effect of simultaneous pancreas-kidney transplantation on mortality of patients with type-1 diabetes mellitus and end-stage renal failure. Lancet 353:1915, 1999 4. Tyde´n G, Bolinder J, Solders G, et al: Improved survival in patients with insulin-dependent diabetes mellitus and end-stage diabetic nephropathy 10 years after combined pancreas and kidney transplantation. Transplantation 67:645, 1999 5. Becker BN, Brazy PC, Becker YT, et al: Simultaneous pancreas-kidney transplantation reduces excess mortality in type 1 diabetic patients with end-stage renal disease. Kidney Int 57:2129, 2000 6. Kapur S, Bonham CA, Dodson SF, et al: Strategies to expand the donor pool for pancreas transplantation. Transplantation 67: 284, 1999 7. Bonham CA, Kapur S, Dodson SF, et al: Potential use of marginal donors for pancreas transplantation. Transplant Proc 31:612, 1999 8. Boggi U, Vistoli F, Del Chiaro M, et al: Pancreas procurement from cadaveric donors of multiple grafts: In Farinon A (ed): Advances in Abdominal Surgery. The Netherlands: Kluwer Academic Publisher, 2002, p 359 9. 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
568 10. Troppmann C, Gruessner AC, Dunn DL, et al: Surgical complications requiring early relaparotomy after pancreas transplantation. A multivariate risk factor and economic analysis of the cyclosporine era. Ann Surg 227:255, 1998 11. Humar A, Kandaswamy R, Granger D, et al: Decreased surgical risk of pancreas transplantation in the modern era. Ann Surg 231:269, 2000 12. Benz S, Bergt S, Obermaier R, et al: Impairment of microcirculation in the early reperfusion period predicts the degree of graft pancreatitis in clinical pancreas transplantation. Transplantation 71:759, 2001
BOGGI, DEL CHIARO, VISTOLI ET AL 13. Odorico JS, Heisey DM, Voss BJ, et al: Donor factors affecting outcome after pancreas transplantation. Transplant Proc 30:276, 1998 14. International Pancreas Transplant Registry Newsletter. August 31, 2002; Volume 14, Number 1 15. Kiberd BA, Larson T: Estimating the benefits of solitary pancreas transplantation in nonuremic patients with type 1 diabetes mellitus: a theoretical analysis. Transplantation 70:1121, 2000 16. Cecka JM: Living donor transplants. In Cecka JM, Terasaki P (eds): Clinical Transplants 1995. Los Angeles, Calif: UCLA Tissue Typing Laboratory; 1996, p 363