Donation after Cardiac Death Pediatric En Bloc Renal Transplantation Marie Dion, Neal Rowe, Jeffrey Shum, Corinne Weernink, Sarah Felbel, Vivian C. McAlister, Alp Sener and Patrick P. Luke* From the Department of Surgery, Division of Urology (MD, NR, SF, AS, PPL) and Department of General Surgery (JS, VCMcA), Western University and Multi-Organ Transplant Program, London Health Sciences Center (NR, JS, CW, SF, VCMcA, AS, PPL), London, Ontario, Canada
Purpose: Use of small pediatric kidneys obtained from extremely young donors after cardiac death has been limited. This potential organ source remains under used by transplant teams. Materials and Methods: We reviewed all renal transplants at our institution from 2000 to 2013 to identify recipients of an en bloc pair of kidneys from deceased pediatric donors younger than 4 years. The outcomes of donation after cardiac death en bloc allografts were compared with neurological determination of death en bloc allografts. Results: A total of 21 recipients of en bloc renal allografts were identified, of which 4 organ pairs were obtained through donation after cardiac death. Mean SD donor age was 20.6 11.6 months and weight was 12.4 3.7 kg. Delayed allograft function occurred in 2 of 4 recipients of allografts obtained from donation after cardiac death en bloc and 3 of 17 recipients of allografts from neurological determination of death en bloc. One year after transplantation mean SD glomerular filtration rates were similar, at 80.7 15.3 and 85.7 33.4 ml/minute/1.73 m2 in the cardiac and neurological allograft groups, respectively (difference not significant). Surgical complications occurred in 3 patients, and no allograft was lost to thrombosis. Conclusions: We report successful transplantation of a small cohort of pediatric en bloc kidneys obtained through donation after cardiac death from donors younger than 4 years. Outcomes at 1 year are comparable to those in neurological determination of death en bloc allograft recipients.
Abbreviations and Acronyms DCD ¼ donation after cardiac death DGF ¼ delayed graft function GFR ¼ glomerular filtration rate NDD ¼ neurological determination of death Accepted for publication July 14, 2014. Study received institutional review board approval. * Correspondence: Division of Urology, University Hospital, 339 Windermere Rd., P. O. Box 5339, London, Ontario, Canada N6A 5A5 (telephone: 519-663-3180; FAX: 519-663-3858; e-mail: [email protected]).
Key Words: donor selection, kidney transplantation, tissue and organ procurement
RENAL allografts from young donors are under used by organ transplantation teams.1,2 This situation likely stems from concerns over early graft loss, since venous thrombosis of pediatric kidneys is reported to be approximately 10%.3e6 However, detailed analysis of the Scientific Registry of Transplant Recipients shows that the risk of graft loss is mitigated when renal allografts are
transplanted en bloc rather than as single units when procured from donors weighing less than 21 kg.2 En bloc renal allografts are kidney pairs with intact vasculature that are procured from donors and transplanted as a single unit. Initial studies of pediatric en bloc kidneys have revealed good long-term function compared to single deceased donor adult allografts.3e7 More recent
0022-5347/15/1931-0281/0 THE JOURNAL OF UROLOGY® © 2015 by AMERICAN UROLOGICAL ASSOCIATION EDUCATION AND RESEARCH, INC.
http://dx.doi.org/10.1016/j.juro.2014.07.089 Vol. 193, 281-285, January 2015 Printed in U.S.A.
www.jurology.com
j
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DONATION AFTER CARDIAC DEATH EN BLOC KIDNEY TRANSPLANTATION
studies have demonstrated that recipients of pediatric en bloc renal allografts have comparable graft survival to living donor recipients.8,9 During the last decade the use of DCD renal allografts in North America has increased. Several studies support that, despite a higher rate of DGF, long-term allograft survival outcomes are similar to those following NDD transplant.10,11 DCD now constitutes up to 33% of donations in the United Kingdom,11 as well as 12% of all deceased donations in the United States.12 Interest in DCD in the pediatric population has increased significantly, driven by the ongoing disparity between supply of and demand for transplantable organs, and increased interest and knowledge among caregivers and families of children who are potential donors.13 A study of 105 American pediatric hospitals showed that 72% have policies on DCD and 19% have policies in development.14 Although approximately 5.5% of children dying in a pediatric intensive care unit were deemed eligible for DCD donation in 1 series,15 few documented cases of pediatric DCD transplantation exist, and the functional outcomes of these grafts have not been studied. We review our experience with pediatric en bloc renal transplantation. We compare the baseline characteristics and functional outcomes of NDD and DCD en bloc allografts, and describe our surgical methods and complications.
MATERIALS AND METHODS Study Methods Institutional review board approval was obtained for our study. We reviewed all renal transplants at our center and identified 21 recipients of en bloc kidney pairs from pediatric donors 4 years or younger between July 2001 and January 2013. We examined donor and recipient characteristics, perioperative characteristics, surgical complications, allograft outcomes and recipient graft function. The primary goal was to examine allograft outcomes and report recipient renal function in NDD and DCD subgroups. We also evaluated the frequency and nature of perioperative complications.
Transplant Methods A total of 18 allografts were maintained with static cold storage and 3 with hypothermic pulsatile machine perfusion. Organs were flushed and preserved with University of Wisconsin solution. Organ allocation was modified to avoid recipients known to have severe atherosclerosis in an attempt to limit technical challenges to the vascular anastomoses. Highly sensitized recipients were also excluded to minimize the risk of acute rejection, which could necessitate postoperative biopsy of these small en bloc allografts. Accordingly all patients received antithymocyte globulin as induction therapy to minimize the risk of acute rejection and to curb the adaptive
immune response to the warm ischemic damage sustained by DCD retrieval. Maintenance immunotherapy included tacrolimus, mycophenolate mofetil and prednisone. Allograft Doppler ultrasounds were performed on post-transplant day 1 and as needed thereafter.
Surgical Methods During organ retrieval both kidneys and their vasculature, including proximal and distal portions of the aorta and vena cava, were removed en bloc. During preparation of the specimen the proximal inferior vena cava and aorta were oversewn and the distal ends were left open for anastomosis to the recipient iliac vessels. Lumbar, adrenal and gonadal vessels were clipped as required. In some cases more extensive vascular reconstruction was required at the discretion of the supervising surgeon. The distal vena cava and aorta were anastomosed to recipient external iliac vessels. The 2 ureters were spatulated and anastomosed via the Wallace technique and then implanted into the recipient bladder using an extravesical approach. Both ureters were stented and the stents were removed 4 weeks after transplantation. Postoperatively recipients underwent heparin infusion for thrombosis prevention. No preoperative anticoagulation was administered. The protocol for heparin infusion varied based on surgeon preference.
Data Analysis Glomerular filtration rate in adult recipients was calculated using the 4-variable MDRD (Modification of Diet in Renal Disease Study) equation.16 In pediatric donors GFR was calculated using the Schwartz formula.17 DGF was defined as the requirement for dialysis in the first week after transplantation. Length of followup was determined by the interval between transplantation and the most recent available creatinine value. Where completed, 2-sided p values were calculated using Student t-tests for continuous variables and Fisher exact tests for categorical outcomes. Statistical significance was designated as a 2-sided p value of less than 0.05.
RESULTS A total of 21 recipients of en bloc allografts were identified, of whom 4 received DCD allografts. Donor, recipient and transplantation characteristics are outlined in the supplementary table (http:// jurology.com/). Demographics were similar between the groups. Average donor age was younger than 2 years (mean SD 20.6 11.6 months), with 7 donors being younger than 1 year. Correspondingly mean SD donor weight was 12.4 3.7 kg, with 5 donors weighing less than 10 kg. Delayed graft function was observed in 2 of 4 DCD and 3 of 17 NDD recipients. Recipient GFR as a function of time following transplantation is outlined in the figure. In the first week following transplantation GFR was less in the DCD cohort. This was an anticipated finding, given the higher rates of delayed graft function associated with DCD
DONATION AFTER CARDIAC DEATH EN BLOC KIDNEY TRANSPLANTATION
100 90
GFR (mL/minute/1.73m )
80 70 60 50
Total
40
DCD NDD
30 20 10 0 Pre-Tx 1 Day 3 Days 5 Days 1 Week
1 3 6 1 Year Month Months Months
283
kidneys from a donor younger than 1 year had progressively impaired renal function associated with reversal of flow on Doppler ultrasound on postoperative day 1. On immediate exploration of the allograft a 25 ml perinephric hematoma that had compressed venous outflow was evacuated. The remainder of the postoperative course was unremarkable. In the NDD subgroup 2 complications were observed. One patient had a ureteral injury associated with cystoscopic stent removal and required reoperation with ureteral reimplantation. The other patient had a urine leak and required reoperation and repair of the ureterovesical anastomosis on postoperative day 1.
Time
Recipient GFR during first year after transplantation (Tx). By 6 months no significant differences were seen between DCD and NDD groups. GFR was calculated using 4-variable MDRD equation. Solid line with diamond data points indicates total population. Slotted line with triangle data points represents DCD group. Dashed line with square data points indicates NDD group.
transplantation in adults. At 1 year after transplantation GFRs in both groups were similar. Graft Survival At a median followup of 17 months all pediatric DCD en bloc allografts were functioning, with a mean SD GFR of 81.6 5.5 ml/minute/1.73 m2. At 73 months of followup NDD graft recipients had a mean SD GFR of 111.2 35.5 ml/minute/1.73 m2. Although the most recent GFRs available were greater in the NDD group, the difference was not statistically significant (p ¼ 0.119). Followup was shorter for recipients of DCD allografts because these procedures have only been undertaken in more recent years. In the NDD cohort 2 patients suffered allograft failure, 1 at 9 months after transplant secondary to severe chronic immune mediated and vascular rejection, and 1 at 35 months secondary to recurrent IgM nephropathy. In the NDD cohort 2 transplant recipients died with functioning grafts. One patient was an 81-year-old female who died of respiratory complications from pulmonary hypertension and congestive heart failure 34 months after transplantation. GFR at the time of death was 68.9 ml/minute/1.73 m2. The other patient was an 82-year-old male who died of unknown cause 94 months after transplantation. His graft was functioning at the most recent followup (within 1 month of death), and the most recent available GFR was 98.4 ml/minute/1.73 m2. Surgical Complications In this cohort of patients there were 3 notable surgical complications. One patient who received DCD
DISCUSSION There is a lack of published data regarding the function of pediatric DCD organs. Transplantation of these organs has the potential to increase the availability of organs for patients who remain on renal transplantation waiting lists. For the first time we demonstrate success with transplantation of pediatric DCD en bloc renal allografts. Overall we found excellent allograft function and survival in DCD en bloc renal allografts even from the extremely young (less than 1 year) and small (less than 10 kg) donor. Although initial GFR was inferior in pediatric en bloc DCD kidneys, by 1 year renal function was similar to that with NDD kidneys. As with single kidney DCD allografts,10 we anticipated a significantly higher rate of delayed graft function in our DCD subgroup. Accordingly of our 4 DCD recipients 2 had delayed graft function. We believe that delayed graft function rates would remain higher in the DCD group even with a larger cohort. Despite high rates of delayed graft function, DCD transplants were associated with excellent serum creatinine values (mean SD 70.3 10.7 mmol/l) and GFR (80.7 15.3 ml/minute/ 1.73 m2) at 1 year after transplantation. Of the patients who required dialysis after transplantation only 1 to 2 runs were required for hyperkalemia before dialysis independence. Although the difference was not statistically significant, glomerular filtration rate appeared to be greater in NDD recipients than in DCD recipients, particularly based on the most recent available data (111.2 vs 81.6 ml/minute/1.73 m2, p ¼ 0.119). Due to limitations in sample size, our study was not powered to assess this outcome, and it is possible that this difference would reach statistical significance in a larger cohort. However, this difference might more accurately represent the disparity in median followup between the 2 groups (73 vs 17 months) as GFR tended to improve through time in both groups. It is possible that with longer
284
DONATION AFTER CARDIAC DEATH EN BLOC KIDNEY TRANSPLANTATION
surveillance the recipients in the DCD group would achieve equivalent GFRs. Finally, given the excellent renal function in all patients with surviving grafts, a greater GFR might not translate into an improved clinical outcome. Two NDD allografts and 1 DCD allograft were maintained with hypothermic pulsatile machine perfusion rather than cold storage. This change in methodology reflects an institutional shift whereby renal allografts are placed on hypothermic machine perfusion, particularly when a long cold ischemia time is anticipated. This alteration applies to all transplants, not just pediatric en bloc allografts, and was undertaken to minimize the risk of graft loss and delayed graft function. Three of our patients (14.3%) suffered surgical complications, of which 2 were related to the ureterovesical anastomosis and 1 to a small perinephric hematoma. These complications highlight the difficulty of achieving a successful anastomosis with tiny ureters. Alternative implantation techniques (such as individual ureteroneocystotomy) have been used. However, no study has compared the outcomes of different methodologies in this population. Vascular thrombosis did not occur despite the relatively high thrombosis rate reported in the pediatric transplant literature. We believe that these complications highlight the need for vigilance in these procedures for meticulous hemostasis and precise vascular and ureteral anastomoses. Despite these efforts, the overall surgical complication rate remained approximately 10%, and patients must be aware of this increased risk compared to single adult allografts.4,6,8 It is noteworthy that to limit the likelihood of vascular complications (thrombosis) or the need for biopsy after transplantation, recipients were selected carefully to avoid those with atherosclerosis or sensitization. More studies are currently being published on the topic of pediatric DCD. One series highlights a lack of consensus among pediatricians regarding
what clinical situations allow for a confident declaration of death in the pediatric patient.18 In a study of eligibility for DCD 14 of 24 eligible donors died within 1 hour of withdrawal of life support (in the remaining 10 donation would have been aborted due to prolonged time to death).15 Ethical treatment of patients and their families at end of life is paramount in DCD. A report from the Children’s Hospital of Philadelphia reveals that the topic of donation was introduced by the family in 9 of 12 cases of pediatric DCD.19 When pediatric staff described why a policy for pediatric DCD should be initiated, they suggested that the most important reason was to benefit the families of extremely ill children who expressed an interest in organ donation.13 This study was a small, single center, retrospective case series. Without greater patient numbers conclusions regarding differences in survival, DGF rates and renal function cannot be made. In the future a multicenter review of outcomes encompassing larger numbers of en bloc DCD transplants will likely provide a more robust assessment of the DCD pediatric en bloc transplant pool. Finally, this study is limited by our intermediate followup length in the DCD vs NDD group.
CONCLUSIONS This is the first known study to address the excellent functional outcomes of DCD pediatric en bloc renal allografts. We also report the smallest DCD en bloc renal allograft in the literature (from a 4.7-month-old donor weighing 7.7 kg). In the current era of policy development regarding pediatric DCD our experience with these allograft pairs continues to support use of pediatric en bloc kidneys for adult transplantation. Previous studies suggesting increased use of pediatric en bloc allografts to better manage transplant waiting lists are supported by our experience.
REFERENCES 1. Kayler LK, Magliocca J, Fujita S et al: Recovery factors affecting utilization of small pediatric donor kidneys. Am J Transplant 2009; 9: 210. 2. Pelletier SJ, Guidinger MK, Merion RM et al: Recovery and utilization of deceased donor kidneys from small pediatric donors. Am J Transplant 2006; 6: 1646. 3. Thomusch O, Tittelbach-Helmrich D, Meyer S et al: Twenty-year graft survival and graft function analysis by a matched pair study between pediatric en bloc kidney and deceased adult donors grafts. Transplantation 2009; 88: 920.
4. Sanchez-Fructuoso AI, Prats D, Perez-Contin MJ et al: Increasing the donor pool using en bloc pediatric kidneys for transplant. Transplantation 2003; 76: 1180.
7. Smyth GP, Eng MP, Power RP et al: Long-term outcome of cadaveric pediatric en bloc transplantationda 15-year experience. Transplant Proc 2005; 37: 4228.
5. Bresnahan BA, McBride MA, Cherikh WS et al: Risk factors for renal allograft survival from pediatric cadaver donors: an analysis of United Network for Organ Sharing data. Transplantation 2001; 72: 256.
8. Sharma A, Fisher RA, Cotterell AH et al: En bloc kidney transplantation from pediatric donors: comparable outcomes with living donor kidney transplantation. Transplantation 2011; 92: 564.
6. Satterthwaite R, Aswad S, Sunga V et al: Outcome of en bloc and single kidney transplantation from very young cadaveric donors. Transplantation 1997; 63: 1405.
9. Sureshkumar K, Reddy CS, Nghiem DD et al: Superiority of pediatric en bloc renal allografts over living donor kidneys: a long-term functional study. Transplantation 2006; 82: 348.
DONATION AFTER CARDIAC DEATH EN BLOC KIDNEY TRANSPLANTATION
10. Weber M, Dindo D, Demarines N et al: Kidney transplantation from donors without a heartbeat. N Engl J Med 2002; 347: 248. 11. Summers D, Johnson R and Allen J: Analysis of factors that affect outcome after transplantation of kidneys donated after cardiac death in the UK: a cohort study. Lancet 2010; 376: 1303. 12. United States Renal Data System: 2010 Annual Data Report: Atlas of Chronic Kidney Disease and End-Stage Renal Disease in the United States. Bethesda, Maryland: National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases 2010.
13. Curley MA, Harrison CH, Craig N et al: Pediatric staff perspectives on organ donation after cardiac death in children. Pediatr Crit Care Med 2007; 8: 212. 14. Antommaria AH, Trotochaud K, Kinlaw K et al: Policies on donation after cardiac death at children’s hospitals: a mixed-methods analysis of variation. JAMA 2009; 301: 1902. 15. Durall AL, Laussen PC and Randolph AG: Potential for donation after cardiac death in a children’s hospital. Pediatrics 2007; 119: 219. 16. Levey AS, Coresh J, Greene T et al: Expressing the Modification of Diet in Renal Disease Study equation for estimating glomerular filtration rate
285
with standardized serum creatinine values. Clin Chem 2007; 53: 766. 17. Schwartz GJ, Munoz A, Schneider MF et al: New equations to estimate GFR in children with CKD. J Am Soc Nephrol 2009; 20: 629. 18. Joffe AR, Anton NR and deCaen AR: Survey of pediatricians’ opinions on donation after cardiac death: are the donors dead? Pediatrics 2008; 122: e967. 19. Naim MY, Hoehn KS, Hasz RD et al: The Children’s Hospital of Philadelphia’s experience with donation after cardiac death. Crit Care Med 2008; 36: 1729.
Purpose: Use of small pediatric kidneys obtained from extremely young donors after cardiac death has been limited. This potential organ source remains under used by transplant teams. Materials and Methods: We reviewed all renal transplants at our institution from 2000 to 2013 to identify recipients of an en bloc pair of kidneys from deceased pediatric donors younger than 4 years. The outcomes of donation after cardiac death en bloc allografts were compared with neurological determination of death en bloc allografts. Results: A total of 21 recipients of en bloc renal allografts were identified, of which 4 organ pairs were obtained through donation after cardiac death. Mean SD donor age was 20.6 11.6 months and weight was 12.4 3.7 kg. Delayed allograft function occurred in 2 of 4 recipients of allografts obtained from donation after cardiac death en bloc and 3 of 17 recipients of allografts from neurological determination of death en bloc. One year after transplantation mean SD glomerular filtration rates were similar, at 80.7 15.3 and 85.7 33.4 ml/minute/1.73 m2 in the cardiac and neurological allograft groups, respectively (difference not significant). Surgical complications occurred in 3 patients, and no allograft was lost to thrombosis. Conclusions: We report successful transplantation of a small cohort of pediatric en bloc kidneys obtained through donation after cardiac death from donors younger than 4 years. Outcomes at 1 year are comparable to those in neurological determination of death en bloc allograft recipients.
Abbreviations and Acronyms DCD ¼ donation after cardiac death DGF ¼ delayed graft function GFR ¼ glomerular filtration rate NDD ¼ neurological determination of death Accepted for publication July 14, 2014. Study received institutional review board approval. * Correspondence: Division of Urology, University Hospital, 339 Windermere Rd., P. O. Box 5339, London, Ontario, Canada N6A 5A5 (telephone: 519-663-3180; FAX: 519-663-3858; e-mail: [email protected]).
Key Words: donor selection, kidney transplantation, tissue and organ procurement
RENAL allografts from young donors are under used by organ transplantation teams.1,2 This situation likely stems from concerns over early graft loss, since venous thrombosis of pediatric kidneys is reported to be approximately 10%.3e6 However, detailed analysis of the Scientific Registry of Transplant Recipients shows that the risk of graft loss is mitigated when renal allografts are
transplanted en bloc rather than as single units when procured from donors weighing less than 21 kg.2 En bloc renal allografts are kidney pairs with intact vasculature that are procured from donors and transplanted as a single unit. Initial studies of pediatric en bloc kidneys have revealed good long-term function compared to single deceased donor adult allografts.3e7 More recent
0022-5347/15/1931-0281/0 THE JOURNAL OF UROLOGY® © 2015 by AMERICAN UROLOGICAL ASSOCIATION EDUCATION AND RESEARCH, INC.
http://dx.doi.org/10.1016/j.juro.2014.07.089 Vol. 193, 281-285, January 2015 Printed in U.S.A.
www.jurology.com
j
281
282
DONATION AFTER CARDIAC DEATH EN BLOC KIDNEY TRANSPLANTATION
studies have demonstrated that recipients of pediatric en bloc renal allografts have comparable graft survival to living donor recipients.8,9 During the last decade the use of DCD renal allografts in North America has increased. Several studies support that, despite a higher rate of DGF, long-term allograft survival outcomes are similar to those following NDD transplant.10,11 DCD now constitutes up to 33% of donations in the United Kingdom,11 as well as 12% of all deceased donations in the United States.12 Interest in DCD in the pediatric population has increased significantly, driven by the ongoing disparity between supply of and demand for transplantable organs, and increased interest and knowledge among caregivers and families of children who are potential donors.13 A study of 105 American pediatric hospitals showed that 72% have policies on DCD and 19% have policies in development.14 Although approximately 5.5% of children dying in a pediatric intensive care unit were deemed eligible for DCD donation in 1 series,15 few documented cases of pediatric DCD transplantation exist, and the functional outcomes of these grafts have not been studied. We review our experience with pediatric en bloc renal transplantation. We compare the baseline characteristics and functional outcomes of NDD and DCD en bloc allografts, and describe our surgical methods and complications.
MATERIALS AND METHODS Study Methods Institutional review board approval was obtained for our study. We reviewed all renal transplants at our center and identified 21 recipients of en bloc kidney pairs from pediatric donors 4 years or younger between July 2001 and January 2013. We examined donor and recipient characteristics, perioperative characteristics, surgical complications, allograft outcomes and recipient graft function. The primary goal was to examine allograft outcomes and report recipient renal function in NDD and DCD subgroups. We also evaluated the frequency and nature of perioperative complications.
Transplant Methods A total of 18 allografts were maintained with static cold storage and 3 with hypothermic pulsatile machine perfusion. Organs were flushed and preserved with University of Wisconsin solution. Organ allocation was modified to avoid recipients known to have severe atherosclerosis in an attempt to limit technical challenges to the vascular anastomoses. Highly sensitized recipients were also excluded to minimize the risk of acute rejection, which could necessitate postoperative biopsy of these small en bloc allografts. Accordingly all patients received antithymocyte globulin as induction therapy to minimize the risk of acute rejection and to curb the adaptive
immune response to the warm ischemic damage sustained by DCD retrieval. Maintenance immunotherapy included tacrolimus, mycophenolate mofetil and prednisone. Allograft Doppler ultrasounds were performed on post-transplant day 1 and as needed thereafter.
Surgical Methods During organ retrieval both kidneys and their vasculature, including proximal and distal portions of the aorta and vena cava, were removed en bloc. During preparation of the specimen the proximal inferior vena cava and aorta were oversewn and the distal ends were left open for anastomosis to the recipient iliac vessels. Lumbar, adrenal and gonadal vessels were clipped as required. In some cases more extensive vascular reconstruction was required at the discretion of the supervising surgeon. The distal vena cava and aorta were anastomosed to recipient external iliac vessels. The 2 ureters were spatulated and anastomosed via the Wallace technique and then implanted into the recipient bladder using an extravesical approach. Both ureters were stented and the stents were removed 4 weeks after transplantation. Postoperatively recipients underwent heparin infusion for thrombosis prevention. No preoperative anticoagulation was administered. The protocol for heparin infusion varied based on surgeon preference.
Data Analysis Glomerular filtration rate in adult recipients was calculated using the 4-variable MDRD (Modification of Diet in Renal Disease Study) equation.16 In pediatric donors GFR was calculated using the Schwartz formula.17 DGF was defined as the requirement for dialysis in the first week after transplantation. Length of followup was determined by the interval between transplantation and the most recent available creatinine value. Where completed, 2-sided p values were calculated using Student t-tests for continuous variables and Fisher exact tests for categorical outcomes. Statistical significance was designated as a 2-sided p value of less than 0.05.
RESULTS A total of 21 recipients of en bloc allografts were identified, of whom 4 received DCD allografts. Donor, recipient and transplantation characteristics are outlined in the supplementary table (http:// jurology.com/). Demographics were similar between the groups. Average donor age was younger than 2 years (mean SD 20.6 11.6 months), with 7 donors being younger than 1 year. Correspondingly mean SD donor weight was 12.4 3.7 kg, with 5 donors weighing less than 10 kg. Delayed graft function was observed in 2 of 4 DCD and 3 of 17 NDD recipients. Recipient GFR as a function of time following transplantation is outlined in the figure. In the first week following transplantation GFR was less in the DCD cohort. This was an anticipated finding, given the higher rates of delayed graft function associated with DCD
DONATION AFTER CARDIAC DEATH EN BLOC KIDNEY TRANSPLANTATION
100 90
GFR (mL/minute/1.73m )
80 70 60 50
Total
40
DCD NDD
30 20 10 0 Pre-Tx 1 Day 3 Days 5 Days 1 Week
1 3 6 1 Year Month Months Months
283
kidneys from a donor younger than 1 year had progressively impaired renal function associated with reversal of flow on Doppler ultrasound on postoperative day 1. On immediate exploration of the allograft a 25 ml perinephric hematoma that had compressed venous outflow was evacuated. The remainder of the postoperative course was unremarkable. In the NDD subgroup 2 complications were observed. One patient had a ureteral injury associated with cystoscopic stent removal and required reoperation with ureteral reimplantation. The other patient had a urine leak and required reoperation and repair of the ureterovesical anastomosis on postoperative day 1.
Time
Recipient GFR during first year after transplantation (Tx). By 6 months no significant differences were seen between DCD and NDD groups. GFR was calculated using 4-variable MDRD equation. Solid line with diamond data points indicates total population. Slotted line with triangle data points represents DCD group. Dashed line with square data points indicates NDD group.
transplantation in adults. At 1 year after transplantation GFRs in both groups were similar. Graft Survival At a median followup of 17 months all pediatric DCD en bloc allografts were functioning, with a mean SD GFR of 81.6 5.5 ml/minute/1.73 m2. At 73 months of followup NDD graft recipients had a mean SD GFR of 111.2 35.5 ml/minute/1.73 m2. Although the most recent GFRs available were greater in the NDD group, the difference was not statistically significant (p ¼ 0.119). Followup was shorter for recipients of DCD allografts because these procedures have only been undertaken in more recent years. In the NDD cohort 2 patients suffered allograft failure, 1 at 9 months after transplant secondary to severe chronic immune mediated and vascular rejection, and 1 at 35 months secondary to recurrent IgM nephropathy. In the NDD cohort 2 transplant recipients died with functioning grafts. One patient was an 81-year-old female who died of respiratory complications from pulmonary hypertension and congestive heart failure 34 months after transplantation. GFR at the time of death was 68.9 ml/minute/1.73 m2. The other patient was an 82-year-old male who died of unknown cause 94 months after transplantation. His graft was functioning at the most recent followup (within 1 month of death), and the most recent available GFR was 98.4 ml/minute/1.73 m2. Surgical Complications In this cohort of patients there were 3 notable surgical complications. One patient who received DCD
DISCUSSION There is a lack of published data regarding the function of pediatric DCD organs. Transplantation of these organs has the potential to increase the availability of organs for patients who remain on renal transplantation waiting lists. For the first time we demonstrate success with transplantation of pediatric DCD en bloc renal allografts. Overall we found excellent allograft function and survival in DCD en bloc renal allografts even from the extremely young (less than 1 year) and small (less than 10 kg) donor. Although initial GFR was inferior in pediatric en bloc DCD kidneys, by 1 year renal function was similar to that with NDD kidneys. As with single kidney DCD allografts,10 we anticipated a significantly higher rate of delayed graft function in our DCD subgroup. Accordingly of our 4 DCD recipients 2 had delayed graft function. We believe that delayed graft function rates would remain higher in the DCD group even with a larger cohort. Despite high rates of delayed graft function, DCD transplants were associated with excellent serum creatinine values (mean SD 70.3 10.7 mmol/l) and GFR (80.7 15.3 ml/minute/ 1.73 m2) at 1 year after transplantation. Of the patients who required dialysis after transplantation only 1 to 2 runs were required for hyperkalemia before dialysis independence. Although the difference was not statistically significant, glomerular filtration rate appeared to be greater in NDD recipients than in DCD recipients, particularly based on the most recent available data (111.2 vs 81.6 ml/minute/1.73 m2, p ¼ 0.119). Due to limitations in sample size, our study was not powered to assess this outcome, and it is possible that this difference would reach statistical significance in a larger cohort. However, this difference might more accurately represent the disparity in median followup between the 2 groups (73 vs 17 months) as GFR tended to improve through time in both groups. It is possible that with longer
284
DONATION AFTER CARDIAC DEATH EN BLOC KIDNEY TRANSPLANTATION
surveillance the recipients in the DCD group would achieve equivalent GFRs. Finally, given the excellent renal function in all patients with surviving grafts, a greater GFR might not translate into an improved clinical outcome. Two NDD allografts and 1 DCD allograft were maintained with hypothermic pulsatile machine perfusion rather than cold storage. This change in methodology reflects an institutional shift whereby renal allografts are placed on hypothermic machine perfusion, particularly when a long cold ischemia time is anticipated. This alteration applies to all transplants, not just pediatric en bloc allografts, and was undertaken to minimize the risk of graft loss and delayed graft function. Three of our patients (14.3%) suffered surgical complications, of which 2 were related to the ureterovesical anastomosis and 1 to a small perinephric hematoma. These complications highlight the difficulty of achieving a successful anastomosis with tiny ureters. Alternative implantation techniques (such as individual ureteroneocystotomy) have been used. However, no study has compared the outcomes of different methodologies in this population. Vascular thrombosis did not occur despite the relatively high thrombosis rate reported in the pediatric transplant literature. We believe that these complications highlight the need for vigilance in these procedures for meticulous hemostasis and precise vascular and ureteral anastomoses. Despite these efforts, the overall surgical complication rate remained approximately 10%, and patients must be aware of this increased risk compared to single adult allografts.4,6,8 It is noteworthy that to limit the likelihood of vascular complications (thrombosis) or the need for biopsy after transplantation, recipients were selected carefully to avoid those with atherosclerosis or sensitization. More studies are currently being published on the topic of pediatric DCD. One series highlights a lack of consensus among pediatricians regarding
what clinical situations allow for a confident declaration of death in the pediatric patient.18 In a study of eligibility for DCD 14 of 24 eligible donors died within 1 hour of withdrawal of life support (in the remaining 10 donation would have been aborted due to prolonged time to death).15 Ethical treatment of patients and their families at end of life is paramount in DCD. A report from the Children’s Hospital of Philadelphia reveals that the topic of donation was introduced by the family in 9 of 12 cases of pediatric DCD.19 When pediatric staff described why a policy for pediatric DCD should be initiated, they suggested that the most important reason was to benefit the families of extremely ill children who expressed an interest in organ donation.13 This study was a small, single center, retrospective case series. Without greater patient numbers conclusions regarding differences in survival, DGF rates and renal function cannot be made. In the future a multicenter review of outcomes encompassing larger numbers of en bloc DCD transplants will likely provide a more robust assessment of the DCD pediatric en bloc transplant pool. Finally, this study is limited by our intermediate followup length in the DCD vs NDD group.
CONCLUSIONS This is the first known study to address the excellent functional outcomes of DCD pediatric en bloc renal allografts. We also report the smallest DCD en bloc renal allograft in the literature (from a 4.7-month-old donor weighing 7.7 kg). In the current era of policy development regarding pediatric DCD our experience with these allograft pairs continues to support use of pediatric en bloc kidneys for adult transplantation. Previous studies suggesting increased use of pediatric en bloc allografts to better manage transplant waiting lists are supported by our experience.
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DONATION AFTER CARDIAC DEATH EN BLOC KIDNEY TRANSPLANTATION
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