Long-Term Outcomes of Kidney Transplantation From Expanded Criteria Deceased Donors at a Single Center: Comparison With Standard Criteria Deceased Donors J.K. Hwang, S.C. Park, K.H. Kwon, B.S. Choi, J.I. Kim, C.W. Yang, Y.S. Kim, and I.S. Moon ABSTRACT Our objective was to compare the clinical outcomes of adult kidney transplants from expanded criteria deceased donors (ECD) with those from concurrent standard criteria deceased donors (SCD). Between January 2000 and December 2011, we transplanted 195 deceased donor renal transplants into adult recipients, including 31 grafts (15.9%) from ECDs and 164 grafts (84.1%) from SCDs. ECDs were classified using the United Network for Organ Sharing (UNOS) definitions. Donor and recipient risk factors were analyzed separately and their correlation with recipient graft function and survival was evaluated (minimum 6-month follow-up). ECDs were older (56.8 6.3 years), showed an increased incidence of hypertension, diabetes, and cerebrovascular brain death, and had a higher preretrieval serum creatinine level than SCDs. ECD kidney recipients had a shorter waiting time (P ¼ .019) but other baseline characteristics (age, gender, body mass index [BMI], cause of end-stage renal disease, type of renal replacement therapy, incidence of diabetes and hypertension, number of HLA antigen mismatches, positivity for panel-reactive antigen, and cold ischemic time) were not significantly different from those of SCD kidney recipients. Mean glomerular filtration rate (GFR) at 1 month, 6 months, 1 year, and 3 years after transplantation was significantly lower in recipients of ECD transplants than recipients of SCD transplants, but the GFR level at 5 and 10 years was not significantly different between ECD and SCD recipient groups (P ¼ .134 and .702, respectively). Incidence of acute rejection episodes and surgical complications did not differ significantly between the 2 recipient groups, but the incidence of delayed graft function (DGF) and infectious complications was higher in ECD kidney recipients than SCD kidney recipients (P ¼ .007 and P ¼ .008, respectively). Actual patient and graft survival rates were similar between the 2 recipient groups with a mean follow-up of 43 months. There were no significant differences in graft survival (P ¼ .111) or patient survival (P ¼ .562) between the 2 groups. Although intermediate-term renal function followed longitudinally was better in SCD kidney recipients, graft and patient survival of ECD kidney recipients were comparable with those of SCD kidney recipients. In conclusion, use of renal grafts from ECDs is a feasible approach to address the critical organ shortage.
T
HE SCARCITY of available donor kidneys has resulted in use of kidney grafts from expanded criteria deceased donors (ECDs), which have substantially increased the deceased donor (DD) kidney pool in the last 10 years [1,2]. Use of ECD kidneys needs to be evaluated objectively from the perspectives of the critical organ shortage and graft function and survival. On the one hand, transplanting ECD kidneys is associated with a significantly higher risk of medical complications, surgical complications,
ª 2014 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710 Transplantation Proceedings, 46, 431e436 (2014)
From the Department of Surgery (J.K.H.), Daejeon St. Mary’s Hospital; Department of Surgery (S.C.P.), Uijeongbu St. Mary’s Hospital; and Division of Transplantation Surgery, Department of Surgery (K.H.K., J.I.K., I.S.M.), Department of Internal Medicine (B.S.C., C.W.Y., Y.S.K.), Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea. Address reprint requests to Ji Il Kim, MD, PhD, Department of Surgery, Seoul St. Mary’s Hospital, 505 Banpo-dong, Seochogu, 137-701, Seoul, Korea. E-mail:
[email protected] 0041-1345/14/$esee front matter http://dx.doi.org/10.1016/j.transproceed.2013.11.061 431
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and graft failure than transplanting standard criteria deceased donors (SCD) kidneys [3e5]. On the other hand, recent studies of ECD kidneys have reported that graft survival is comparable with that of SCD kidneys [6,7]. To provide further long-term follow-up data, we retrospectively reviewed outcomes of ECD versus SCD kidney transplantation (KT) at a single center.
METHODS In this retrospective study, we reviewed medical records and the electronic transplantation registry of recipients who underwent KT at Seoul St. Mary’s Hospital, Catholic University of Korea, from January 2000 to December 2011. During the observational period, 786 KTs were performed. Specific exclusion criteria included pediatric recipients (younger than 18 years of age), simultaneous kidneypancreas transplant recipients, and all living donor kidney transplantations. A consecutive series of 195 DD KTs was studied. Patients were categorized as either ECD or SCD kidney transplant recipients based on the United Network for Organ Sharing (UNOS) definitions.
Definitions All DDs older than 60 years and DDs 50 to 59 years of age who met 2 of the following criteria: (1) history of hypertension, (2) cerebrovascular accident as a cause of brain death, and (3) final preprocurement serum creatinine (SCr) level >1.5 mg/dL were classified as ECDs based on UNOS definitions [8]. In this study, any DD who did not meet the above ECD criteria was regarded as a SCD. Deceased donors were compared with respect to gender and age at transplantation, body mass index (BMI), cause of death, history of hypertension, preretrieval SCr level, and days of intensive care unit (ICU) stay. Recipient outcomes were stratified according to the above DD criteria. The following variables were compared between the 2 recipient groups: gender and age at transplantation; BMI; cause of end-stage renal disease (ESRD); type and duration of renal replacement therapy (RRT); number of HLA mismatches and other immunologic factors; nephron mass index (donor kidney weight to recipient body-weight ratio [Kw/ Rw]; g/kg); total ischemic time; mean SCr level; modification of diet in renal disease (MDRD) glomerular filtration rate (GFR) at 1 month, 6 months, 1 year, 3 years, 5 years, and 10 years posttransplantation; incidence of acute rejection (AR) episodes; incidence of delayed graft function (DGF) episodes; duration of graft function; patient survival; and complications. DGF was defined as (1) failure of SCr to decrease within 72 hours and/or (2) the need for dialysis in the first week post-transplantation. Renal allograft loss was defined as graft nephrectomy, resumption of ongoing dialysis, or return to the pretransplantation SCr level. Patient death with a functioning graft was censored. Cytomegalovirus (CMV) infection was diagnosed based on a positive real-time polymerase chain reaction (PCR) result.
Donor and Recipient Selection No specific DD upper age limit was set, and this series included 12 transplants from DD 60 years of age or older. At the time of transplantation, patients were selected on the basis of blood type compatibility, waiting time, HLA match, and negative cross-match in accordance with the Korean Network for Organ Sharing (KONOS) guidelines [9].
HWANG, PARK, KWON ET AL
Statistical Analysis Unpaired t tests were used to compare continuous variables between the 2 groups, whereas chi-square tests were used to compare categorical variables between the groups. All data are expressed as means standard deviations (SDs). Kaplan-Meier method was used to compare patient and graft survival rates between the 2 groups. Data were censored at time of death or at the last available follow-up. Graft survival was also evaluated using multivariate analyses according to Cox regression with stepwise entry of variables. Statistical significance was defined as P < .05. All statistical analyses were carried out with SPSS version 18.0 software (SPSS, Chicago, Ill, United States).
RESULTS
During the observation period, we transplanted 195 DD transplants into adult recipients, comprising 31 grafts (15.9%) from ECDs and 164 grafts (84.1%) from SCDs. ECDs were older (56.8 6.3 years), had a higher incidence of hypertension, diabetes, and cerebrovascular brain death, and a higher preretrieval SCr level than SCDs. Donor characteristic are listed in Table 1. Characteristics of Transplant Recipients
Of the 195 kidney transplant recipients, 51.8% were male recipients and 65.6% received a kidney from a male donor. The average recipient age was 45.1 9.6 years, and the mean follow-up duration was 43.7 34.3 months. Characteristics of the recipients are provided in Table 2. ECD kidney recipients had a shorter waiting time (P ¼ .019) than SCD recipients, but other baseline characteristics (age, gender, BMI, cause of ESRD, type of RRT, incidence of diabetes and hypertension, number of antigen mismatches, positivity for panel-reactive antigen, and cold ischemic time) were not significantly different between the 2 recipient groups. Graft Renal Function, AR Episodes, and DGF
Mean MDRD GFR levels and incidence of AR episodes were compared between the 2 recipient groups to assess Table 1. Characteristics of DDs Group
Donor age (y) Gender of donor, M/F Donor BMI (kg/m2) Cause of death CVA Trauma Suicide Other History of HTN History of DM Preretrieval SCr (mg/dL) ICU stay (d)
ECD (n ¼ 31)
SCD (n ¼ 164)
P
56.8 6.3 21/10 23.1 3.1
37.5 13.5 107/57 22.7 3.4
<.001 .788 .500 <.001
27 (87.1%) 4 (12.9%) 0 0 15 (48.4%) 5 (16.1%) 2.57 1.5 5.05 6.0
84 (51.5%) 56 (34.4%) 14 (8.6%) 9 (5.5%) 12 (7.3%) 3 (1.8%) 1.65 1.46 2.95 3.2
<.001 .003 .002 .026
Abbreviations: M, male; F, female; HTN, hypertension; DM, diabetes mellitus; CVA, cerebrovascular accident.
CLINICAL OUTCOMES OF ECD KIDNEY TRANSPLANTS
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Table 2. Transplant Recipient Characteristics
Table 3. Outcomes of Study Groups
Group ECD (n ¼ 31)
SCD (n ¼ 164)
Recipient age (y) 46.4 10.6 44.8 9.3 Gender of recipient, M/F 20/11 81/83 Recipient BMI (kg/m2) 22.7 2.9 22.4 3.2 Pretransplantation evaluation Cause of ESRD Chronic GN 8 (26.7%) 78 (47.9%) DM 1 (3.3%) 18 (11%) HTN 19 (63.3%) 30 (18.4%) Chronic PN 0 1 (0.6%) PCKD 0 6 (3.7%) Lupus nephritis 0 4 (2.5%) Unknown 2 (6.7%) 26 (15.9%) Duration of RRT (waiting time) 69.4 43.3 91.8 49.1 History of pregnancy 7 (22.6%) 15 (37.2%) History of transfusion 2 (6.5%) 2 (1.2%) Immunology No. of KTs, % (>1) 1 (3.2%) 23 (14.0%) No. of HLA mismatches 3.8 1.2 3.6 1.3 0 antigen mismatches 1 (3.2%) 4 (2.4%) PRA (>20%) 5 (19.2%) 28 (20.6%) 0% PRA 21 (80.8%) 104 (77.6%) Operation evaluation Nephron mass index (g/kg) 3.21 0.5 3.17 0.7 Cold ischemic time (min) 251.6 101.3 242.0 135.9 Multiple renal arteries (>1) 6 (19.4%) 40 (24.4%)
Group P
.391 .122 .542 .798
.019 .230 .120 .073 .398 .583 .875 .722 .805 .708 .545
Abbreviations: GN, glomerrulonephritis; PN, pyelonephritis; PCKD, polycystic kidney disease; PRA, panel reactive antibody.
graft function. The mean MDRD GFR level at 7 days, 1 month, 6 months, 1 year, 2 years, and 3 years after transplantation was significantly lower in patients who received a transplant from ECDs than those who received a transplant from SCDs, but the MDRD GFR level at 5 and 10 years was not significantly different between the 2 recipient groups (P ¼ .134 and .702, respectively). Renal allograft function for up to 10 years post-transplantation is shown for the 2 recipient groups in Figure 1. The incidence of AR episodes was 19.4% in the ECD group and 19.5% in the SCD group. This difference was not significant (P ¼ .984; Table 3). The rate of DGF was higher in ECD kidney recipients than SCD
AR episodes, % (1) Actual graft survival Actual patient survival Primary nonfunction DGF MDRD GFR (postoperative) 7d 1 mo 6 mo 1y 3y 5y 6y 7y 10 y
ECD (n ¼ 31)
SCD (n ¼ 164)
6 (19.4%) 25 (80.6%) 29 (93.5%) 0 (0%) 10 (32.3%)
32 (19.5%) 148 (90.2%) 156 (95.1%) 4 (2.4%) 21 (12.8%)
33.5 43.6 44.9 47.6 44.9 48.6 62.8 51.9 45.4
24.7 20.6 15.0 14.3 19.4 0.60 17.0 2.50 0.00
47.5 63.5 62.4 62.2 63.6 65.1 64.5 59.2 57.1
29.6 24.7 17.6 21.7 17.9 15.2 17.6 13.1 27.1
P
.984 .121 .492 .497 .007 .015 <.001 <.001 <.001 .001 .134 .891 .449 .702
kidney recipients (P ¼ .007). Although the incidence of DGF was significantly different between the 2 groups, the presence of DGF was not a significant risk factor for graft survival in this study (Table 4). Infections and Surgical Complications
The overall infectious complication rate was significantly higher in ECD kidney recipients than SCD kidney recipients (P ¼ .008). In detail, the incidence of CMV infection was significantly higher in ECD kidney recipients than SCD kidney recipients (79.3% in ECD vs 54.5% in SCD; P ¼ .018). CMV infection was one of the significant risk factors for graft survival in DD recipients (Table 4). In addition, the rate of BK virus (BKV) infection was 45.2% (n ¼ 14) in the ECD group versus 22.0% (n ¼ 36) in the SCD group. When analyzing surgical complication types, the majority of complications in both groups were early (within 30 days after KT) operative complications (vascular, urologic, and wound-related complications; Table 5). The overall surgical complication rates of the 2 groups were comparable (P ¼ .180). Table 4. Results of Cox Multivariate Analysis of Risk Factors for Graft Survival
Fig 1. Renal allograft function according to MDRD GFR in ECD and SCD transplant recipients.
Characteristic
P
HLA mismatches No. of KTs, % (>1) ECD PRA (> 20%) Nephron mass index (g/kg) Total ischemic time Surgical complications CMV infection Bacterial infection AR episode DGF episode
.279 .559 .500 .134 .018 .270 .046 .040 .708 .024 .131
Hazard Ratio 95% Confidence Intervals
1.393 0.579 0.551 0.352 2.457 0.996 0.272 0.117 0.793 0.144 4.685
0.764e2.540 0.093e3.619 0.907e3.118 0.090e1.378 1.165e5.179 0.989e1.003 0.075e0.979 0.015e0.097 0.236e2.670 0.027e0.772 0.632e34.713
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HWANG, PARK, KWON ET AL Table 5. Infectious and Surgical Complications Group
Infectious complications Viral infection CMV infection CMV infection* CMV disease BKV infection Herpes zoster infection Bacterial infection Fungal infection Surgical complications Vascular Urologic GI Hematoma Lymphocele Wound infection
ECD (n ¼ 31)
SCD (n ¼ 164)
P
29 (93.5%)
120 (73.2%)
.008
23 11 1 14 7 8 1 8 1 1
(79.3%) (37.9%) (3.2%) (45.2%) (22.3%) (25.8%) (3.2%) (25.8%) (3.2%) (3.2%) 0 1 (3.2%) 1 (3.2%) 4 (12.9%)
78 41 3 36 17 56 17 26 5 8 3 2 3 5
(55.7%) (29.7%) (1.9%) (22.0%) (10.4%) (34.1%) (10.4%) (15.9%) (3.0%) (4.9%) (1.8%) (1.2%) (1.8%) (3.0%)
.018 .385 .509 .013 .058 .364 .176 .180
Abbreviation: GI, gastrointestinal. *CMV real-time PCR >500 copies/mL.
Graft and Patient Survival
Graft survival rates at 1 year, 2 years, 5 years, and 10 years post-transplantation were 93.5%, 86.0%, 76.3%, and 76.3%, respectively, in the ECD group compared with 93.8%, 90.7%, 89.2%, and 81.7%, respectively, in the SCD group. Patient survival rates at 1 year, 5 years, and 10 years posttransplantation were 96.8%, 89.3%, and 89.3%, respectively, in the ECD group and 98.1%, 95.4%, and 89.0%, respectively, in the SCD group (Table 6). There were no significant differences in graft survival (P ¼ .111) or patient survival (P ¼ .562) between the 2 groups. Overall cumulative graft and patients survival rates in these groups are shown as Kaplan-Meier curves in Figure 2. Risk Factors for Graft Survival
Multivariate logistic regression analysis revealed that graft survival was clearly associated with nephron mass index (Kw/Rw) at the time of transplantation, surgical Table 6. Kidney Graft Survival and Patient Survival Group ECD (n ¼ 31)
Graft survival 1y 2y 3y 5y 10 y Patient survival 1y 2y 3y 5y 10 y
SCD (n ¼ 164)
P
.111 93.5% 86.0% 76.3% 76.3% 76.3%
93.8% 90.7% 90.7% 89.2% 81.7%
96.8% 96.8% 96.8% 89.3% 89.3%
98.1% 96.5% 95.4% 95.4% 89.0%
.562
Fig 2. Graft (A, P ¼ .111) and patient survival (B, P ¼ .562) in both groups.
complications, CMV infection, and number of AR episodes (Table 4). DISCUSSION
KT is one of the most attractive RRT for improving a patient’s quality of life. Because of the donor organ shortage in relation to the large number of patients with ESRD, kidney allografts previously considered to be unsuitable for transplantation are now engrafted without hesitation. Thus, kidneys from ECDs are routinely transplanted. An ECD kidney refers to a kidney whose relative risk of graft failure exceeds 1.7 when compared with a reference group of ideal DD kidneys [8]. The ideal organ donor is generally a younger person who dies from a traumatic head injury that is isolated to the brain and who has intact solid abdominal organ function [10]. The organs of an ideal DD generally have excellent graft function and survival rates. Use of ECD kidneys started increasing after it was proven that risk factors did not negatively affect graft and patient survival when adequate management approaches were
CLINICAL OUTCOMES OF ECD KIDNEY TRANSPLANTS
adopted [2,11,12]. Approximately 17% of deceased donor transplantations in the United States in the past few years were performed using ECD kidneys [13,14]. In our series, 15.9% of DD kidney transplants were from ECDs. In this study, ECDs were older, had significantly more comorbid conditions, such as cerebrovascular brain death, hypertension, and diabetes, a longer ICU stay, and a higher preretrieval SCr level than SCDs. However, there were no significant differences between ECD kidney recipients and SCD kidney recipients with the exception of a shorter waiting time for the former. In our center, we offer information about donor-related risk factors to patients on the waiting list for KT; ECD kidneys are only allocated to those patients who provide informed consent. The shorter waiting time of ECD kidney recipients suggests that patients on the waiting list for a KT have negative perceptions of ECD KT. We evaluated the effect of using ECD versus SCD kidneys on clinical outcomes, long-term graft function, and survival. Some earlier studies have questioned the value of using ECD kidneys because ECD kidneys have a higher rate of primary nonfunction (PNF), DGF, and AR episodes than SCD kidneys [3,15]. In our study, the rate of DGF was indeed higher in ECD kidney recipients than SCD kidney recipients. However, there were no significant differences in the rates of AR and PNF between the 2 recipient groups. Although the incidence of DGF differed significantly between the 2 groups, the presence of DGF was not a significant risk factor for graft survival after DD transplantation in this study. Stratta et al [6] reported that renal function stabilized initially at approximately 60% of the estimated donor GFR in both groups, so that renal function followed longitudinally was consistently better in SCD recipients than ECD recipients. These data are similar to ours; we found that the mean MDRD GFR at 7 days, 1 month, 6 months, 1 year, 2 years, and 3 years after transplantation was significantly lower in patients with ECDs than SCDs, but that the MDRD GFR level at 5 and 10 years did not differ significantly between these 2 groups. This effect was due not only to the adaptive ability of SCD recipients, but also removal from the data set of those recipients with a high creatinine level whose grafts failed over 5 years. Theoretically, transplanting a kidney from an ECD has several drawbacks, such as older donor age and a higher prerecovery SCr level than an SCD, which can decrease graft function. Morgan et al [16] reported that kidneys from DDs with increased levels of terminal creatinine could be used safely with reasonable early outcomes. An earlier study reported that unadjusted death-censored graft survival at 1 year and 5 years post-transplantation was 93.7% and 79.4%, respectively, for SCD transplants and 87.4% and 66.4%, respectively, for ECD transplants. In this study, death with a functioning graft (DWFG) occurred in 1 (3.2%) ECD and 6 (3.7%) SCD kidney recipients. When DWFG was defined as renal allograft loss, graft survival rates at 1 year, 2 years, and 5 years post-
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transplantation were 93.5%, 86.0%, and 76.3%, respectively, in the ECD group, and 91.3%, 89.0%, and 86.5%, respectively, in the SCD group. This difference in graft survival between the 2 groups was not significant (P ¼ .298). We therefore found no significant differences in graft survival or patient survival between the 2 groups, indicating that ECD kidneys had no negative effect on graft survival. Furthermore, we found that the graft survival rate of ECD kidneys in our study was slightly more favorable than that reported by a study performed in the United States. There are 2 possible reasons for this: the short cold ischemic time in our study (mean, 4.05 2.18 hours) and the comparative ethnic homogeneity of Koreans. In conclusion, although intermediate-term renal function followed longitudinally was better in SCD kidney recipients than ECD kidney recipients, graft and patient survival of ECD kidney recipients were comparable with those of SCD kidney recipients. We therefore conclude that use of renal grafts from ECDs is a feasible approach that can help address the critical organ shortage. REFERENCES [1] Stratta RJ, Rohr MS, Sundberg AK, et al. Increased kidney transplantation utilizing expanded criteria deceased organ donors with results comparable to standard criteria donor transplant. Ann Surg 2004;239:688e95 [discussion: 95-7]. [2] Karatzas T, Gompou A, Bokos J, et al. Optimal utilization of expanded criteria deceased donors for kidney transplantation. Int Urol Nephrol 2011;43:1211e9. [3] Port FK, Bragg-Gresham JL, Metzger RA, et al. Donor characteristics associated with reduced graft survival: an approach to expanding the pool of kidney donors. Transplantation 2002;74: 1281e6. [4] Ojo AO, Hanson JA, Meier-Kriesche H, et al. Survival in recipients of marginal cadaveric donor kidneys compared with other recipients and wait-listed transplant candidates. J Am Soc Nephrol 2001;12:589e97. [5] Barba J, Zudaire JJ, Robles JE, Rosell D, Berian JM, Pascual I. Complications of kidney transplantation with grafts from expanded criteria donors. World J Urol 2013;31:893e900. [6] Stratta RJ, Rohr MS, Sundberg AK, et al. Intermediate-term outcomes with expanded criteria deceased donors in kidney transplantation: a spectrum or specter of quality? Ann Surg 2006;243: 594e601 [discussion: 603]. [7] Kim JM, Kim SJ, Joh JW, et al. Is it safe to use a kidney from an expanded criteria donor? Transplant Proc 2011;43:2359e62. [8] Metzger RA, Delmonico FL, Feng S, Port FK, Wynn JJ, Merion RM. Expanded criteria donors for kidney transplantation. Am J Transplant 2003;3(Suppl. 4):114e25. [9] Kim MS, Il Kim S, Kim YS. Current status of deceased donor organ recovery and sharing in Korea. J Korean Med Assoc 2008;51: 685e91. [10] Alexander JW, Zola JC. Expanding the donor pool: use of marginal donors for solid organ transplantation. Clin Transplant 1996;10:1e19. [11] Carter JT, Lee CM, Weinstein RJ, Lu AD, Dafoe DC, Alfrey EJ. Evaluation of the older cadaveric kidney donor: the impact of donor hypertension and creatinine clearance on graft performance and survival. Transplantation 2000;70:765e71. [12] Lopez-Navidad A, Caballero F. Extended criteria for organ acceptance. Strategies for achieving organ safety and for increasing organ pool. Clin Transplant 2003;17:308e24.
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HWANG, PARK, KWON ET AL [15] Pascual J, Zamora J, Pirsch JD. A systematic review of kidney transplantation from expanded criteria donors. Am J Kidney Dis 2008;52:553e86. [16] Morgan C, Martin A, Shapiro R, Randhawa PS, Kayler LK. Outcomes after transplantation of deceased-donor kidneys with rising serum creatinine. Am J Transplant 2007;7:1288e92.