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Prolonged Warm Ischemia Affects Long-Term Prognosis of Kidney Transplant Allografts From Non–Heart-Beating Donors
Prolonged Warm Ischemia Affects Long-Term Prognosis of Kidney Transplant Allografts From Non–Heart-Beating Donors R. Shiroki, K. Hoshinaga, T. Higuchi, Y. Tsukiashi, Y. Kubota, T. Maruyama, M. Izumitani, M. Horiba, Y. Naide, and T. Kanno
T
HE alternative of using kidneys from non– heart-beating donors (NHBDs) has been increasing to maintain an active transplant program. One of the most critical problems determining the prognosis of kidney allograft from NHBD is warm ischemia prior to organ harvest. Kidneys from NHBDs are subjected to prolonged warm ischemic time (WIT) and reperfusion injury, leading to a high incidence of delayed graft function (DGF) and primary nonfunction (PNF). In addition, during and post recovery from DGF, acute transplant rejection was reported to occur more frequently.1 Thus, the kidney grafts suffer from both acute rejection and DGF resulting in deleterious transplant outcome.2 The kidney grafts from NHBDs were obliged to overcome the various obstacles to reach the long-term survival. Previously, our data showed no disadvantage in shortterm graft function on kidney transplant with grafts from NHBDs using in situ cooling method.3 Kidney grafts procured from NHBDs even with cardiac massage (CM) prior to harvest manipulation developed compatible transplant results with grafts from the standard harvest group in early-phase posttransplantation.4 In addition, the long-term survival of grafts from NHBDs brought compatible outcome with that of the living-related donor grafts. It is, however, still uncertain whether kidney grafts harvested after extremely prolonged WIT could provide adequate function after the recovery of acute tubular necrosis (ATN) or not. In this paper, the feasibility of cadaveric kidney allografts from NHBDs was evaluated by investigating whether prolonged warm ischemia might affect posttransplantation graft function in short-term as well as long-term graft survival.
PATIENTS AND METHODS Between January 1983 and December 1996, 289 kidneys were harvested from NHBDs under in situ cooling method using a double balloon catheter placed in the donor aorta.3 Out of the harvested organs, 263 kidneys were transplanted at our center or other hospitals. The posttransplant follow-up period of graft function and survival ranged from 4 to 172 months (median, 63 months). Transplanted grafts were retrospectively stratified into two groups: (1) WIT equal to or longer than 30 minutes (group 1; n 5 32); and (2) WIT shorter than 30 minutes (group 2; n 5 231). Donor and recipient backgrounds, graft procurement conditions, © 1998 by Elsevier Science Inc. 655 Avenue of the Americas, New York, NY 10010 Transplantation Proceedings, 30, 111–113 (1998)
time to graft function, short-term graft function, and long-term graft survival of recipients were investigated for each group. Delayed graft function (DGF) and immediate function (IF) were defined as the recipient needed for posttransplant dialysis or no need for dialysis with functioning grafts, respectively. Categorical variables were analyzed using a chi square test. Continuous variables were analyzed using the Mann–Whitney test or Student t test where appropriate. Graft and patient survivals were estimated using the Kaplan–Meier method and comparisons of the survival curves were based on generalized Wilcoxon test.
RESULTS
The demographic characteristics of the 123 donors and 263 recipients are shown in Tables 1 and 2, respectively. Donor and recipient backgrounds, including age, gender, and cause of donor death showed no statistical differences between two groups. For the procurement status, in spite of far distinction of WIT, in situ cold ischemic time (ISCIT) and total ischemic time (TIT) showed no statistical difference between the two groups. For the time between engraftment and graft function, the incidence of PNF in Group 1 (21.8%) was significantly higher than that of Group 2 (3.9%, P , .001). The incidence of DGF and IF showed no statistical differences. For the graft function of early posttransplant phase, the lowest serum creatinine (SCr) level, 1.60 6 0.68 versus 1.57 6 0.77 mg/dL, and posttransplant dialysis period in DGF cases, 15.1 6 8.2 versus 13.5 6 11.9 days, showed no statistical differences between two groups. As shown in Fig 1, the graft survival rates of group 1 and group 2 were 45.1% versus 74.6% at 3 years, and 38.7% versus 69.2% at 5 years, respectively, showing significantly lower survival in group 1 (P , .001). Because of the higher incidence of PNF in group 1, it seemed to be unfair to compare the graft survival simply between the two groups. Thus, graft survivals of both groups were compared only for the cases without PNF. Even though the PNF cases were From the Departments of Urology (R.S., K.H., T.H., Y.T., Y.K., T.M., M.I., M.H., Y.N.) and Neurosurgery (K.T.), Fujita Health University School of Medicine, Toyoake, Aichi, Japan. Address reprint requests to R. Shiroki MD, Department of Urology, Fujita Health University School of Medicine, Toyoake, Aichi, 470-11 Japan. 0041-1345/98/$19.00 PII S0041-1345(97)01195-0 111
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SHIROKI, HOSHINGA, HIGUCHI, ET AL
Table 1. Demographic Characteristics of Cadaveric Kidney Transplant Donors and WIT WIT ^ 30 min (Group 1)
Donor N Age (range) M/F ratio Cause of Death CVD* Non-CVD Procurement Status WIT (min) In situ CIT (min) TIT (min)
16 37.4 (18 – 64) 10/6 20 (62.5%) 12 (37.5%)
WIT , 30 min (Group 2)
117 45.4 (0 –70) 62/55 139 (60.2%) 92 (39.8%)
P
NS NS NS*
43.3 (30 –71) 8.7 (1–26) ,.0001† 84.3 (64 –125) 76.9 (35–137) NS 880 (313–1889) 681 (244 –2603) NS
Abbreviations: CIT, cold ischemia time; CVD, cerebrovascular disease; NS, not significant; TIT, total ischemic time; WIT, warm ischemic time. *P by chi square. † P Mann–Whitney test.
excluded from both groups for graft survival curve calculations, group 1 (n 5 25) showed a significantly lower graft survival than group 2 (n 5 222; P 5 .045), 57.8% versus 77.4% at 3 years, and 49.5% versus 71.8% at 5 years, respectively (Fig 1B). DISCUSSION
In Japan, the vast majority of cadaveric kidney grafts were harvested from NHBDs, indicating that grafts were definitely exposed to longer warm ischemia times than those from heart-beating, brain-dead donors. With prolonged hypotension and cardiac arrest, the warm ischemia and reperfusion injury are likely to cause renal tubular cell dysfunction, leading to DGF and PNF in kidney transplant using NHBDs. In situ cooling was developed as a procureTable 2. Demographic Characteristics of Cadaveric Kidney Transplant Recipients and Graft Function WIT ^ 30 minutes (Group 1)
Recipient N Age (range) M/F ratio Graft Function Immediate DGF PNF Lowest SCr (mg/dL) Dialysis duration in DGF (days) Graft Survival 3 y (%) 5 y (%)
32 39 (15–57) 22/10
WIT , 30 minutes (Group 2)
231 38.5 (7– 61) 157/74
P
NS NS
3 (9.4) 22 (68.8) 7 (21.8) 1.6 (0.7–3.5) 15.1 (1–31)
41 (17.7) 181 (78.4) 9 (3.9) 1.57 (0.5–5.4) 13.5 (1–102)
NS NS ,.001* NS NS
45.1 38.7
74.6 69.2
,.001†
Abbreviations: DGF, delayed graft function; NS, not significant; PNF, primary non-function; SCr, serum creatinine. *P by chi square. † P by generalized Wilcoxon test.
Fig 1. Kaplan–Meier graft survival of renal allograft survival compared by the length of warm ischemic time. (a) 263 grafts— primary non-function (PNF) cases included. (b) 247 grafts—PNF cases excluded.
ment method to reduce the organ injury by prolonged WIT.3 Under these conditions, we reported previously that kidney grafts from NHBDs provided relatively good graft function in the cyclosporine-treated recipients.3 Procurement status—WIT or TIT—showed no association with posttransplant graft function in the short term.3 Out of the donor factors, younger age and non-CVD as the cause of donor death provided significantly better recipient graft function in the short term. In addition, kidney grafts procured from NHBDs with cardiac massage prior to the harvest manipulation developed a compatible transplant outcome as compared with those from the standard harvest group under in situ cooling method.4 We analyzed the early and late posttransplant outcomes of 263 kidneys harvested from NHBDs at our hospital using in situ cooling methods in early and long-term results. Although the incidence of PNF was significantly higher in the longer WIT group, prolonged WIT induced no disadvantage on the early-phase transplant outcome, such as the lowest SCr level and the dialysis period. DGF is thought to be due to ischemic and/or immunologic causes which may act synergistically. It was reported in the animal experiments using mice that ischemic injury induced altered MHC gene expression to up-regulate the graft antigenecity.5 Several papers indicated that DGF was associated with a high incidence of acute rejection, playing a major role in the development of chronic rejection.6 The
PROLONGED WARM ISCHEMIA
long-term graft survival was reported to be affected by episodes of DGF and acute rejection, donor age, and other factors.6 Even though using in situ cooling with a double balloon catheter, the incidence of DGF in kidney transplants from NHBDs was almost three times higher than that of kidneys from the heart-beating, brain-dead donors, three quarters versus a quarter, respectively.4 Our results also suggested that the grafts from NHBDs with the longer WIT showed significantly lower graft survival than those with the shorter WIT group in the long run. Even though PNF cases were excluded for survival calculation, a significant difference in the long-term survival of the two groups was noted. Interestingly, the graft survival curve of the longer WIT group fell significantly faster than the other group after one year posttransplant, suggesting that prolonged warm ischemia might cause some kinds of chronic ongoing graft dysfunction resulting in graft loss. The results of this study emphasize the premium importance of donor factors, not only for early-phase graft function but also for long-term graft survival. WIT plays a major role even in the long-term graft survival of kidneys from NHBDs. Major organ damage, which could affect indeed the long-term graft survival, is thought to occur before the retrieval of grafts.
113
In conclusion, the prolonged warm ischemia was suggested to cause a chronic ongoing process, possibly leading to the late graft failure in the kidney transplant from NHBDs. The response to prolonged ischemic injury is complicated, and may increase graft immunogenecity and promote the chronic changes seen in chronic allograft rejection. Kidney grafts from NHBDs with the extremely prolonged WIT had significantly poor chance to survive for the long period.
REFERENCES 1. Howard RJ, Pfaff WW, Croker BP, et al: Clin Transplant 8:527, 1994 2. Troppmann C, Najarian JS, Matas AJ, et al: Transplantation 59:962, 1995 3. Hoshinaga K, Fujita T, Naide Y, et al: Transplant Proc 27:703, 1995 4. Shiroki R, Hoshinaga K, Naide Y, et al: Transplant Proc 29:1388, 1997 5. Shoskes DA, Parfrey NA, Halloran PF: Transplantation 49:201, 1990 6. Shoskes DA, Halloran PF: J Urol 155:1831, 1996
T
HE alternative of using kidneys from non– heart-beating donors (NHBDs) has been increasing to maintain an active transplant program. One of the most critical problems determining the prognosis of kidney allograft from NHBD is warm ischemia prior to organ harvest. Kidneys from NHBDs are subjected to prolonged warm ischemic time (WIT) and reperfusion injury, leading to a high incidence of delayed graft function (DGF) and primary nonfunction (PNF). In addition, during and post recovery from DGF, acute transplant rejection was reported to occur more frequently.1 Thus, the kidney grafts suffer from both acute rejection and DGF resulting in deleterious transplant outcome.2 The kidney grafts from NHBDs were obliged to overcome the various obstacles to reach the long-term survival. Previously, our data showed no disadvantage in shortterm graft function on kidney transplant with grafts from NHBDs using in situ cooling method.3 Kidney grafts procured from NHBDs even with cardiac massage (CM) prior to harvest manipulation developed compatible transplant results with grafts from the standard harvest group in early-phase posttransplantation.4 In addition, the long-term survival of grafts from NHBDs brought compatible outcome with that of the living-related donor grafts. It is, however, still uncertain whether kidney grafts harvested after extremely prolonged WIT could provide adequate function after the recovery of acute tubular necrosis (ATN) or not. In this paper, the feasibility of cadaveric kidney allografts from NHBDs was evaluated by investigating whether prolonged warm ischemia might affect posttransplantation graft function in short-term as well as long-term graft survival.
PATIENTS AND METHODS Between January 1983 and December 1996, 289 kidneys were harvested from NHBDs under in situ cooling method using a double balloon catheter placed in the donor aorta.3 Out of the harvested organs, 263 kidneys were transplanted at our center or other hospitals. The posttransplant follow-up period of graft function and survival ranged from 4 to 172 months (median, 63 months). Transplanted grafts were retrospectively stratified into two groups: (1) WIT equal to or longer than 30 minutes (group 1; n 5 32); and (2) WIT shorter than 30 minutes (group 2; n 5 231). Donor and recipient backgrounds, graft procurement conditions, © 1998 by Elsevier Science Inc. 655 Avenue of the Americas, New York, NY 10010 Transplantation Proceedings, 30, 111–113 (1998)
time to graft function, short-term graft function, and long-term graft survival of recipients were investigated for each group. Delayed graft function (DGF) and immediate function (IF) were defined as the recipient needed for posttransplant dialysis or no need for dialysis with functioning grafts, respectively. Categorical variables were analyzed using a chi square test. Continuous variables were analyzed using the Mann–Whitney test or Student t test where appropriate. Graft and patient survivals were estimated using the Kaplan–Meier method and comparisons of the survival curves were based on generalized Wilcoxon test.
RESULTS
The demographic characteristics of the 123 donors and 263 recipients are shown in Tables 1 and 2, respectively. Donor and recipient backgrounds, including age, gender, and cause of donor death showed no statistical differences between two groups. For the procurement status, in spite of far distinction of WIT, in situ cold ischemic time (ISCIT) and total ischemic time (TIT) showed no statistical difference between the two groups. For the time between engraftment and graft function, the incidence of PNF in Group 1 (21.8%) was significantly higher than that of Group 2 (3.9%, P , .001). The incidence of DGF and IF showed no statistical differences. For the graft function of early posttransplant phase, the lowest serum creatinine (SCr) level, 1.60 6 0.68 versus 1.57 6 0.77 mg/dL, and posttransplant dialysis period in DGF cases, 15.1 6 8.2 versus 13.5 6 11.9 days, showed no statistical differences between two groups. As shown in Fig 1, the graft survival rates of group 1 and group 2 were 45.1% versus 74.6% at 3 years, and 38.7% versus 69.2% at 5 years, respectively, showing significantly lower survival in group 1 (P , .001). Because of the higher incidence of PNF in group 1, it seemed to be unfair to compare the graft survival simply between the two groups. Thus, graft survivals of both groups were compared only for the cases without PNF. Even though the PNF cases were From the Departments of Urology (R.S., K.H., T.H., Y.T., Y.K., T.M., M.I., M.H., Y.N.) and Neurosurgery (K.T.), Fujita Health University School of Medicine, Toyoake, Aichi, Japan. Address reprint requests to R. Shiroki MD, Department of Urology, Fujita Health University School of Medicine, Toyoake, Aichi, 470-11 Japan. 0041-1345/98/$19.00 PII S0041-1345(97)01195-0 111
112
SHIROKI, HOSHINGA, HIGUCHI, ET AL
Table 1. Demographic Characteristics of Cadaveric Kidney Transplant Donors and WIT WIT ^ 30 min (Group 1)
Donor N Age (range) M/F ratio Cause of Death CVD* Non-CVD Procurement Status WIT (min) In situ CIT (min) TIT (min)
16 37.4 (18 – 64) 10/6 20 (62.5%) 12 (37.5%)
WIT , 30 min (Group 2)
117 45.4 (0 –70) 62/55 139 (60.2%) 92 (39.8%)
P
NS NS NS*
43.3 (30 –71) 8.7 (1–26) ,.0001† 84.3 (64 –125) 76.9 (35–137) NS 880 (313–1889) 681 (244 –2603) NS
Abbreviations: CIT, cold ischemia time; CVD, cerebrovascular disease; NS, not significant; TIT, total ischemic time; WIT, warm ischemic time. *P by chi square. † P Mann–Whitney test.
excluded from both groups for graft survival curve calculations, group 1 (n 5 25) showed a significantly lower graft survival than group 2 (n 5 222; P 5 .045), 57.8% versus 77.4% at 3 years, and 49.5% versus 71.8% at 5 years, respectively (Fig 1B). DISCUSSION
In Japan, the vast majority of cadaveric kidney grafts were harvested from NHBDs, indicating that grafts were definitely exposed to longer warm ischemia times than those from heart-beating, brain-dead donors. With prolonged hypotension and cardiac arrest, the warm ischemia and reperfusion injury are likely to cause renal tubular cell dysfunction, leading to DGF and PNF in kidney transplant using NHBDs. In situ cooling was developed as a procureTable 2. Demographic Characteristics of Cadaveric Kidney Transplant Recipients and Graft Function WIT ^ 30 minutes (Group 1)
Recipient N Age (range) M/F ratio Graft Function Immediate DGF PNF Lowest SCr (mg/dL) Dialysis duration in DGF (days) Graft Survival 3 y (%) 5 y (%)
32 39 (15–57) 22/10
WIT , 30 minutes (Group 2)
231 38.5 (7– 61) 157/74
P
NS NS
3 (9.4) 22 (68.8) 7 (21.8) 1.6 (0.7–3.5) 15.1 (1–31)
41 (17.7) 181 (78.4) 9 (3.9) 1.57 (0.5–5.4) 13.5 (1–102)
NS NS ,.001* NS NS
45.1 38.7
74.6 69.2
,.001†
Abbreviations: DGF, delayed graft function; NS, not significant; PNF, primary non-function; SCr, serum creatinine. *P by chi square. † P by generalized Wilcoxon test.
Fig 1. Kaplan–Meier graft survival of renal allograft survival compared by the length of warm ischemic time. (a) 263 grafts— primary non-function (PNF) cases included. (b) 247 grafts—PNF cases excluded.
ment method to reduce the organ injury by prolonged WIT.3 Under these conditions, we reported previously that kidney grafts from NHBDs provided relatively good graft function in the cyclosporine-treated recipients.3 Procurement status—WIT or TIT—showed no association with posttransplant graft function in the short term.3 Out of the donor factors, younger age and non-CVD as the cause of donor death provided significantly better recipient graft function in the short term. In addition, kidney grafts procured from NHBDs with cardiac massage prior to the harvest manipulation developed a compatible transplant outcome as compared with those from the standard harvest group under in situ cooling method.4 We analyzed the early and late posttransplant outcomes of 263 kidneys harvested from NHBDs at our hospital using in situ cooling methods in early and long-term results. Although the incidence of PNF was significantly higher in the longer WIT group, prolonged WIT induced no disadvantage on the early-phase transplant outcome, such as the lowest SCr level and the dialysis period. DGF is thought to be due to ischemic and/or immunologic causes which may act synergistically. It was reported in the animal experiments using mice that ischemic injury induced altered MHC gene expression to up-regulate the graft antigenecity.5 Several papers indicated that DGF was associated with a high incidence of acute rejection, playing a major role in the development of chronic rejection.6 The
PROLONGED WARM ISCHEMIA
long-term graft survival was reported to be affected by episodes of DGF and acute rejection, donor age, and other factors.6 Even though using in situ cooling with a double balloon catheter, the incidence of DGF in kidney transplants from NHBDs was almost three times higher than that of kidneys from the heart-beating, brain-dead donors, three quarters versus a quarter, respectively.4 Our results also suggested that the grafts from NHBDs with the longer WIT showed significantly lower graft survival than those with the shorter WIT group in the long run. Even though PNF cases were excluded for survival calculation, a significant difference in the long-term survival of the two groups was noted. Interestingly, the graft survival curve of the longer WIT group fell significantly faster than the other group after one year posttransplant, suggesting that prolonged warm ischemia might cause some kinds of chronic ongoing graft dysfunction resulting in graft loss. The results of this study emphasize the premium importance of donor factors, not only for early-phase graft function but also for long-term graft survival. WIT plays a major role even in the long-term graft survival of kidneys from NHBDs. Major organ damage, which could affect indeed the long-term graft survival, is thought to occur before the retrieval of grafts.
113
In conclusion, the prolonged warm ischemia was suggested to cause a chronic ongoing process, possibly leading to the late graft failure in the kidney transplant from NHBDs. The response to prolonged ischemic injury is complicated, and may increase graft immunogenecity and promote the chronic changes seen in chronic allograft rejection. Kidney grafts from NHBDs with the extremely prolonged WIT had significantly poor chance to survive for the long period.
REFERENCES 1. Howard RJ, Pfaff WW, Croker BP, et al: Clin Transplant 8:527, 1994 2. Troppmann C, Najarian JS, Matas AJ, et al: Transplantation 59:962, 1995 3. Hoshinaga K, Fujita T, Naide Y, et al: Transplant Proc 27:703, 1995 4. Shiroki R, Hoshinaga K, Naide Y, et al: Transplant Proc 29:1388, 1997 5. Shoskes DA, Parfrey NA, Halloran PF: Transplantation 49:201, 1990 6. Shoskes DA, Halloran PF: J Urol 155:1831, 1996