© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Clin Transplant 2014: 28: 953–960 DOI: 10.1111/ctr.12388
Clinical Transplantation
Impact of donor kidney function and donor age on poor outcome of living-unrelated kidney transplantation (KT) in comparison with living-related KT Park KS, Shin J-h, Jang HR, Lee JE, Huh WS, Kim YG, Oh HY, Kim DJ. Impact of donor kidney function and donor age on poor outcome of living-unrelated kidney transplantation (KT) in comparison with living-related kidney transplantation. Abstract: Living-unrelated donors (LURD) have been widely used for kidney transplantation (KT). We retrospectively reviewed 779 patients who underwent living-donor KT from 2000 to 2012, to compare outcomes of 264 KT from LURD and 515 from living-related donors (LRD), and to identify risk factors for living KT. Median follow-up was 67 months. Mean donor age, total human leukocyte antigen (HLA) mismatches, and HLA–DR mismatches were higher, and mean estimated glomerular filtration rate (eGFR) was lower in LURD. Acute rejection (AR)-free survival (p = 0.018) and graft survival (p = 0.025) were lower for LURD than LRD, whereas patient survival rate was comparable. Cox regression analysis showed HLA–DR mismatches (OR 1.75 for one mismatch; OR 2.19 for two mismatches), recipient age ≤ 42 yr, and donor age > 50 yr were significant risk factors for acute rejection. For graft survival, AR and donor eGFR (OR 1.90, p = 0.035) were significant. We also identified significant impact of recipient age > 50 yr and diabetes for patient survival. However, KT from LURD was not a significant risk factor for AR (p = 0.368), graft survival (p = 0.205), and patient survival (p = 0.836). Our data suggest that donor eGFR and donor age are independent risk factors for clinical outcomes of living KT, which can be related with poor outcome of KT from LURD.
Kyung Sun Park, Jung-ho Shin, Hye Ryoun Jang, Jung Eun Lee, Woo Seong Huh, Yoon Goo Kim, Ha Young Oh and Dae Joong Kim Division of Nephrology, Department of Internal Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea Key words: donor estimated glomerular filtration rate – HLA–DR mismatches – Livingunrelated kidney transplantation Corresponding author: Dae Joong Kim, MD, PhD, Division of Nephrology, Department of Internal Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, 50 Irwon-dong, Gangnam-gu, Seoul 135-710, Korea. Tel.: +82 2 3410 3449; fax: +82 2 3410 0064; e-mail: [email protected] Conflict of interest: The authors declare no conflict of interest. Accepted for publication 21 May 2014
Kidney transplantation (KT) is the most preferred therapy for end-stage renal disease (ESRD). Living-donor KT is preferable to deceased-donor KT for better short- and long-term outcomes, shorter waiting time, and for the possibility of pre-emptive intervention. One of the major concerns in KT is the shortage of donor organs. To overcome this problem, KT from living-unrelated donors (LURT) has been widely performed, and favorable outcomes of LURT have been reported in comparison with KT from living-related donors (LRT) (1–12). Living-donor KT outcomes have been reported to be influenced by several risk factors, such as HLA matching, donor age, and relation between donor and recipient (13–16). However, there is a relative paucity of investigations regarding these
factors in large populations, and the results available are ambiguous. Defining such risk factors more clearly will be helpful in predicting clinical outcomes and proper donor selection, when more than one potential living donor is available. Furthermore, such information is a prerequisite for application of ideal matching algorithm to improve patient outcome in kidney paired donation, which is another established method of overcoming organ shortage. The aims of this study were to compare the clinical outcomes of LRT and LURT and to identify the risk factors associated with long-term outcome of living-donor KT, specifically biopsy-proven acute rejection (BPAR), graft survival, and patient survival.
953
Park et al. Materials and methods Population
Between January 2000 and December 2012, 1343 patients had undergone KT at Samsung Medical Center, Sungkyunkwan University School of Medicine. Among these cases, 894 allografts had come from living donors. Of the 894 patients, 115 recipients were excluded (22 for age < 18, 44 for positive HBsAg, 13 for positive anti-HCV, 24 for ABO incompatibility, and 12 for positive cross-match). The clinical outcomes were reviewed for the remaining 779 patients, consisting of 515 (66.1%) living related and 264 (33.9%) LURT. To preclude the impact of HLA-identical LRTs on outcomes of our population, separate subgroup analysis was performed, excluding the HLA-identical LRTs. Patients with positive complement-dependent cytotoxic cross-match and/or positive T cell flow cytometric cross-match (TFXM) were defined as positive cross-match. The cutoffs of positive TFXM are as follows: (i) mean fluorescence intensity (MFI) of patient ≥ MFI + 3SD of negative control (NC), (ii) MFI displacement (MFI of patient–MFI of NC) ≥ 40, (iii) percent displacement over cutoff gate of NC > 10–20%, and (iv) fluorescence ratio (median channel fluorescence [MCF] of patient/MCF of NC) > 2.0. TFXM is defined as positive if one or more of these parameters are significant. Data collection
Data were obtained from the electronic medical recording system of the Samsung Medical Center. Age and gender of recipients, cause of ESRD, history of hypertension and diabetes, donor–recipient HLA mismatches, panel reactive antigen (PRA), and induction and maintenance immunosuppression were recorded. Age, gender, height, weight, body mass index, level of serum creatinine, estimated glomerular filtration rate (eGFR), and relation (i.e., related vs. unrelated) of donors were also reviewed. Outcome data obtained included delayed graft function (DGF), BPAR, graft loss, and patient death. DGF was defined as the need for dialysis during the first week post-transplantation. Death with functioning graft was censored as functioning graft. Immunosuppression
During the KT operation, each patient received 500 mg intravenous methylprednisolone. Antibody induction has started being used for KT since 2007 at our center. Therefore, the patients who received
954
KT before 2007 did not receive any antibody induction. Antibody induction was used for 388 patients (49.8%) with basiliximab (220 in LRT and 101 in LURT) or antithymoglobulin (49 in LRT and 18 in LURT). Antithymoglobulin has been used for immunologically high-risk patients such as ABO incompatibility, positive cross-match, history of prior graft failure (retransplantation), high PRA (>50%), or positive donor-specific antibody. Maintenance immunosuppression comprised a calcineurin inhibitor, mycophenolate mofetil, and low-dose prednisolone. Tacrolimus-based immunosuppression was used for 300 patients (58.6%) with LRT and 145 (55.6%) with LURT (Table 1). Statistical analysis
All statistical analyses were performed with SPSS software (Statistical Package for the Social Science, version 21.0, Datasolution, Seoul, South Korea). Continuous variables were reported as mean and standard deviation and discrete variables as percentages (%). Numeric variables were compared using Student’s t test and Mann–Whitney’s U test. Nominal variables were analyzed using the chisquare test. BPAR-free survival, graft survival, and patient survival were analyzed by the Kaplan– Meier method and were compared by log-lank test. Cox regression analysis was applied to identify factors related to BPAR, graft loss, and patient death. To construct the multivariate model, variables identified as significant in univariate analysis and those considered as clinically relevant, including donor type, were introduced into the model. A p value < 0.05 was considered statistically significant.
Result Baseline characteristics
Of the 779 living-donor kidney transplant recipients, 515 had undergone LRT and 264 had undergone LURT. Donor and recipient characteristics are summarized in Table 1. Every donor and recipient was ethnic Korean. The mean age of LRT recipients (40.4 yr) was significantly lower than that for LURT recipients (44.4 yr, p < 0.001). The median follow-up duration for LRT and LURT patients was 65 months (range, 1–156) and 74 months (range, 1–158), respectively (p = 0.193). There were no differences in gender, cause of ESRD, history of diabetes, and of hypertension between the two groups. The mean number of total HLA mismatches (4.1 vs. 2.5, p < 0.001) and of DR mismatches (1.2 vs. 0.8, p < 0.001) was
Donor GFR for living kidney transplantation Table 1. Continued Table 1. Baseline characteristics of the study population
Living related (n = 515) Age; yr, 40.4 (11.7) mean (SD) Sex; female, n (%) 232 (45.0) Transplant era, 2000/01–2012/ YYYY/MM 12 Duration of 65 (1–156) transplant; months, median (range) Causes of ESRD; n (%) Diabetes 68 (13.3) Hypertension 68 (13.3) Chronic 184 (39.5) glomerulonephritis Others 40 (7.8) Unknown 153 (29.8) Diabetes; n (%) 140 (27.2) Hypertension; n (%) 436 (84.7) Donors Age; yr, 38.4 (11.9) mean (SD) Sex; female, n (%) 231 (44.9) Height; cm, 165.2 (8.9) mean (SD) Weight; cm, 66.0 (11.7) mean (SD) BMI; kg/m2, 24.1 (3.4) mean (SD) Serum creatinine; 0.87 (0.31) mg/dL, mean (SD) eGFR; mL/min, 90.9 (16.3) mean (SD) CMV IgG; n (%) Donor+/recipient+ 490 (95.1) Donor+/recipient 8 (1.6) Donor /recipient+ 16 (3.1) Donor /recipient 1 (0.2) HLA mismatches; mean (SD) Total mismatches 0/1/2/3/4/5/6 81/26/103/223/ 50/21/11 Mean (SD) 0.5 (1.4) DR mismatches 0/1/2 135/343/37 Mean (SD) 0.8 (0.5) PRA, class I; n (%) 0–10% 470 (92.7) 10–80% 29 (5.7) 80–100% 8 (1.6) PRA, class II; n (%) 0–10% 491 (96.8) 10–80% 9 (1.8) 80–100% 7 (1.4) Induction immunosuppression; n (%) None 246 (47.8) Basiliximab 220 (42.7) Antithymoglobulin 49 (9.5)
Living unrelated (n = 264) 44.4 (9.1) 102 (38.6) 2000/01–2012/ 12 74 (1–158)
Living related (n = 515)
p
Clin Transplant 2014: 28: 953–960 DOI: 10.1111/ctr.12388
Clinical Transplantation
Impact of donor kidney function and donor age on poor outcome of living-unrelated kidney transplantation (KT) in comparison with living-related KT Park KS, Shin J-h, Jang HR, Lee JE, Huh WS, Kim YG, Oh HY, Kim DJ. Impact of donor kidney function and donor age on poor outcome of living-unrelated kidney transplantation (KT) in comparison with living-related kidney transplantation. Abstract: Living-unrelated donors (LURD) have been widely used for kidney transplantation (KT). We retrospectively reviewed 779 patients who underwent living-donor KT from 2000 to 2012, to compare outcomes of 264 KT from LURD and 515 from living-related donors (LRD), and to identify risk factors for living KT. Median follow-up was 67 months. Mean donor age, total human leukocyte antigen (HLA) mismatches, and HLA–DR mismatches were higher, and mean estimated glomerular filtration rate (eGFR) was lower in LURD. Acute rejection (AR)-free survival (p = 0.018) and graft survival (p = 0.025) were lower for LURD than LRD, whereas patient survival rate was comparable. Cox regression analysis showed HLA–DR mismatches (OR 1.75 for one mismatch; OR 2.19 for two mismatches), recipient age ≤ 42 yr, and donor age > 50 yr were significant risk factors for acute rejection. For graft survival, AR and donor eGFR (OR 1.90, p = 0.035) were significant. We also identified significant impact of recipient age > 50 yr and diabetes for patient survival. However, KT from LURD was not a significant risk factor for AR (p = 0.368), graft survival (p = 0.205), and patient survival (p = 0.836). Our data suggest that donor eGFR and donor age are independent risk factors for clinical outcomes of living KT, which can be related with poor outcome of KT from LURD.
Kyung Sun Park, Jung-ho Shin, Hye Ryoun Jang, Jung Eun Lee, Woo Seong Huh, Yoon Goo Kim, Ha Young Oh and Dae Joong Kim Division of Nephrology, Department of Internal Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea Key words: donor estimated glomerular filtration rate – HLA–DR mismatches – Livingunrelated kidney transplantation Corresponding author: Dae Joong Kim, MD, PhD, Division of Nephrology, Department of Internal Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, 50 Irwon-dong, Gangnam-gu, Seoul 135-710, Korea. Tel.: +82 2 3410 3449; fax: +82 2 3410 0064; e-mail: [email protected] Conflict of interest: The authors declare no conflict of interest. Accepted for publication 21 May 2014
Kidney transplantation (KT) is the most preferred therapy for end-stage renal disease (ESRD). Living-donor KT is preferable to deceased-donor KT for better short- and long-term outcomes, shorter waiting time, and for the possibility of pre-emptive intervention. One of the major concerns in KT is the shortage of donor organs. To overcome this problem, KT from living-unrelated donors (LURT) has been widely performed, and favorable outcomes of LURT have been reported in comparison with KT from living-related donors (LRT) (1–12). Living-donor KT outcomes have been reported to be influenced by several risk factors, such as HLA matching, donor age, and relation between donor and recipient (13–16). However, there is a relative paucity of investigations regarding these
factors in large populations, and the results available are ambiguous. Defining such risk factors more clearly will be helpful in predicting clinical outcomes and proper donor selection, when more than one potential living donor is available. Furthermore, such information is a prerequisite for application of ideal matching algorithm to improve patient outcome in kidney paired donation, which is another established method of overcoming organ shortage. The aims of this study were to compare the clinical outcomes of LRT and LURT and to identify the risk factors associated with long-term outcome of living-donor KT, specifically biopsy-proven acute rejection (BPAR), graft survival, and patient survival.
953
Park et al. Materials and methods Population
Between January 2000 and December 2012, 1343 patients had undergone KT at Samsung Medical Center, Sungkyunkwan University School of Medicine. Among these cases, 894 allografts had come from living donors. Of the 894 patients, 115 recipients were excluded (22 for age < 18, 44 for positive HBsAg, 13 for positive anti-HCV, 24 for ABO incompatibility, and 12 for positive cross-match). The clinical outcomes were reviewed for the remaining 779 patients, consisting of 515 (66.1%) living related and 264 (33.9%) LURT. To preclude the impact of HLA-identical LRTs on outcomes of our population, separate subgroup analysis was performed, excluding the HLA-identical LRTs. Patients with positive complement-dependent cytotoxic cross-match and/or positive T cell flow cytometric cross-match (TFXM) were defined as positive cross-match. The cutoffs of positive TFXM are as follows: (i) mean fluorescence intensity (MFI) of patient ≥ MFI + 3SD of negative control (NC), (ii) MFI displacement (MFI of patient–MFI of NC) ≥ 40, (iii) percent displacement over cutoff gate of NC > 10–20%, and (iv) fluorescence ratio (median channel fluorescence [MCF] of patient/MCF of NC) > 2.0. TFXM is defined as positive if one or more of these parameters are significant. Data collection
Data were obtained from the electronic medical recording system of the Samsung Medical Center. Age and gender of recipients, cause of ESRD, history of hypertension and diabetes, donor–recipient HLA mismatches, panel reactive antigen (PRA), and induction and maintenance immunosuppression were recorded. Age, gender, height, weight, body mass index, level of serum creatinine, estimated glomerular filtration rate (eGFR), and relation (i.e., related vs. unrelated) of donors were also reviewed. Outcome data obtained included delayed graft function (DGF), BPAR, graft loss, and patient death. DGF was defined as the need for dialysis during the first week post-transplantation. Death with functioning graft was censored as functioning graft. Immunosuppression
During the KT operation, each patient received 500 mg intravenous methylprednisolone. Antibody induction has started being used for KT since 2007 at our center. Therefore, the patients who received
954
KT before 2007 did not receive any antibody induction. Antibody induction was used for 388 patients (49.8%) with basiliximab (220 in LRT and 101 in LURT) or antithymoglobulin (49 in LRT and 18 in LURT). Antithymoglobulin has been used for immunologically high-risk patients such as ABO incompatibility, positive cross-match, history of prior graft failure (retransplantation), high PRA (>50%), or positive donor-specific antibody. Maintenance immunosuppression comprised a calcineurin inhibitor, mycophenolate mofetil, and low-dose prednisolone. Tacrolimus-based immunosuppression was used for 300 patients (58.6%) with LRT and 145 (55.6%) with LURT (Table 1). Statistical analysis
All statistical analyses were performed with SPSS software (Statistical Package for the Social Science, version 21.0, Datasolution, Seoul, South Korea). Continuous variables were reported as mean and standard deviation and discrete variables as percentages (%). Numeric variables were compared using Student’s t test and Mann–Whitney’s U test. Nominal variables were analyzed using the chisquare test. BPAR-free survival, graft survival, and patient survival were analyzed by the Kaplan– Meier method and were compared by log-lank test. Cox regression analysis was applied to identify factors related to BPAR, graft loss, and patient death. To construct the multivariate model, variables identified as significant in univariate analysis and those considered as clinically relevant, including donor type, were introduced into the model. A p value < 0.05 was considered statistically significant.
Result Baseline characteristics
Of the 779 living-donor kidney transplant recipients, 515 had undergone LRT and 264 had undergone LURT. Donor and recipient characteristics are summarized in Table 1. Every donor and recipient was ethnic Korean. The mean age of LRT recipients (40.4 yr) was significantly lower than that for LURT recipients (44.4 yr, p < 0.001). The median follow-up duration for LRT and LURT patients was 65 months (range, 1–156) and 74 months (range, 1–158), respectively (p = 0.193). There were no differences in gender, cause of ESRD, history of diabetes, and of hypertension between the two groups. The mean number of total HLA mismatches (4.1 vs. 2.5, p < 0.001) and of DR mismatches (1.2 vs. 0.8, p < 0.001) was
Donor GFR for living kidney transplantation Table 1. Continued Table 1. Baseline characteristics of the study population
Living related (n = 515) Age; yr, 40.4 (11.7) mean (SD) Sex; female, n (%) 232 (45.0) Transplant era, 2000/01–2012/ YYYY/MM 12 Duration of 65 (1–156) transplant; months, median (range) Causes of ESRD; n (%) Diabetes 68 (13.3) Hypertension 68 (13.3) Chronic 184 (39.5) glomerulonephritis Others 40 (7.8) Unknown 153 (29.8) Diabetes; n (%) 140 (27.2) Hypertension; n (%) 436 (84.7) Donors Age; yr, 38.4 (11.9) mean (SD) Sex; female, n (%) 231 (44.9) Height; cm, 165.2 (8.9) mean (SD) Weight; cm, 66.0 (11.7) mean (SD) BMI; kg/m2, 24.1 (3.4) mean (SD) Serum creatinine; 0.87 (0.31) mg/dL, mean (SD) eGFR; mL/min, 90.9 (16.3) mean (SD) CMV IgG; n (%) Donor+/recipient+ 490 (95.1) Donor+/recipient 8 (1.6) Donor /recipient+ 16 (3.1) Donor /recipient 1 (0.2) HLA mismatches; mean (SD) Total mismatches 0/1/2/3/4/5/6 81/26/103/223/ 50/21/11 Mean (SD) 0.5 (1.4) DR mismatches 0/1/2 135/343/37 Mean (SD) 0.8 (0.5) PRA, class I; n (%) 0–10% 470 (92.7) 10–80% 29 (5.7) 80–100% 8 (1.6) PRA, class II; n (%) 0–10% 491 (96.8) 10–80% 9 (1.8) 80–100% 7 (1.4) Induction immunosuppression; n (%) None 246 (47.8) Basiliximab 220 (42.7) Antithymoglobulin 49 (9.5)
Living unrelated (n = 264) 44.4 (9.1) 102 (38.6) 2000/01–2012/ 12 74 (1–158)
Living related (n = 515)
p
