Pediatr Transplantation 2014: 18: 357–362
© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Pediatric Transplantation DOI: 10.1111/petr.12252
Delayed graft function in pediatric deceased donor kidney transplantation: Donor-related risk factors and impact on two-yr graft function and survival: A single-center analysis Cesca E, Ghirardo G, Kiblawi R, Murer L, Gamba P, Zanon GF. Delayed graft function in pediatric deceased donor kidney transplantation: Donor-related risk factors and impact on two-yr graft function and survival: A single-center analysis. Abstract: There is mounting evidence that the quality of organs from cadaver donors may be influenced by events occurring around the time of brain death. Aim of this present study was to analyze the correlation of DGF with brain-dead donor variables in a singlecenter pediatric population and to evaluate DGF influence on patients- and grafts outcome. End-points of the study were DGF prevalence, DGF donor-related risk factors, graft function, patientand graft survival rate, respectively, at six, 12, and 24 months FU. The univariate analysis showed that donor age above 15 yr and vascular cause of donor brain death represented risk factors for DGF. The multivariate analysis confirmed as independent risk factors for DGF donor age >15 yr. At six months FU, DGF showed a negative impact on graft function. In conclusion, among all considered brain-dead donor resuscitation parameters, just nontraumatic cause of death turned out to be of impact for DGF. Donor age >15 yr represented the only independent risk factor for prolonged DGF in our series of children. At two-yr FU, DGF showed a transient negative impact on six-month graft function.
Despite a decade of progress in kidney transplantation, non-immune factors, such as DGF, have still shown to be negative for graft outcome (1, 2). Although experimental studies have shown the crucial role of ischemia–reperfusion injury in the physiopathology of DGF (3), the relative contribution of donor- or recipientrelated factors to the development of DGF is still debated. There is mounting evidence from experimental and clinical studies that the level Abbreviations: CI, confidence intervals; CIT, cold ischemia time; CrCl, creatinine clearance rate; DGF, delayed graft function; FU, follow-up; GRF, glomerular filtration rate; HES, hydroxyethyl starch; ICU, intensive care unit; NITp, Nord Italia Transplant program; OR, odds ratio; PAS, periodic acid-Schiff.
Eleonora Cesca1, Giulia Ghirardo2, Rim Kiblawi1, Luisa Murer2, Piergiorgio Gamba1 and Giovanni Franco Zanon1 1
Pediatric Surgery, University of Padova, Padova, Italy, 2Pediatric Nephrology, University of Padova, Padova, Italy
Key words: kidney transplantation – children – chronic renal failure – graft function – graft survival – delayed graft function Eleonora Cesca, Pediatric Surgery, University of Padova, via Giustiniani, 3 Padova 35121, Italy Tel.: 0498213690 Fax: 0498211781 E-mail: [email protected] Accepted for publication 21 February 2014
of injury to organs from cadaver donors may be influenced by events occurring in the ICU (2, 4–6) and around the time of brain death (7– 10). Some drugs used during donor resuscitation, such as adrenergic agents (1, 11), certain types of colloid plasma expanders (i.e., HES) (12) or desmopressin (13), seem to be associated with poor subsequent graft outcome. To our knowledge, most studies devoted to brain-dead donor parameters are found on adult populations with small donor cohorts (5, 10) or with a restricted number of parameters (4). Aim of the present study was to analyze a single-center group of pediatric renal transplant recipients with a 24-month FU to identify donor-related risk factors for DGF, as well as the impact of DGF on patient and graft outcome. 357
Cesca et al. Subjects and methods Population characteristics Between 2004 and 2011, 126 pediatric deceased donor renal transplants were performed at the Pediatric Surgery Division at the University of Padova. The Institutional Review Board at the University of Padova approved the study. Donors
Data related to donors and the retrieval process were obtained from NITp. Donor-related resuscitation data were extracted from ICU observations from the time of the brain death diagnosis (first flat electroencephalography or cerebral tomodensitometry) to organ recovery procedure. For statistical analysis, resuscitation parameters included the following: type and volume of gelatin as a volume plasma expander (HES colloid vs. gelatins), number of blood transfusions, type of vasopressor employed (dobutamine, dopamine, epinephrine, norepinephrine), occurrence of hypotensive shock due to high variations in blood pressure during the intensive care stay (hypotensive shock criteria were retained as defined by at least one episode of systolic pressure below 80 mm Hg), number of cardiac arrest and cardiopulmonary reanimation episodes, duration in intensive care, creatinemia and uremia at retrieval procedure, and urine production. Other considered parameters were as follows: donor age and gender, cause of death (vascular or traumatic), and multiple-organ retrieval procedure (liver, heart, lung, pancreas, and kidney). The organ recovery technique and preservation fluid were unchanged during the study period. Recipients
Recipient data were extracted from our database (Pediatric Kidney Transplant Database, Access, Microsoft Corporation, Redmond, WA, USA), in which the biologic and clinical data of our transplant patients have been retrospectively recorded by our medical team since 2009. The inclusion criteria included the following: recipient age 15 (%) 72% (8) Relation between D and R, % ♀?♂ 44.44 (4) ♀?♀ 0 ♂?♂ 22.22 (2) ♂?♀ 27.27 (3) Cold ischemic time (hours) 13.5 (12–19) [n = 8] Weight (kg) D weight 63.11 R weight 45.79 R/D weight 0.76 (0.58–0.89) D cause of death, % Vascular 55.56 (5) Traumatic 33.33 (3) Other 11.11 (1) D hypotensive shock 55.56 (5) Inotropics, % Total 77.78 (7) Dopamine 33.33 (3) Epinephrine 11.11 (1) Norepinephrine 55.56 (5) Dodutamine 22.22 (2) D no. RCP 45.45 (5) D multi-organ removal 81.81 (9) D no. blood transfusions 80 (4) (n = 5) D BUN (mg/L) 25 (12.5–37) [n = 8]
Population characteristics Donors
In this cohort, the median donor age was 13 yr (interquartile range 6.75–18.25 yr). Sex distribution (male/female) in donors was 79/37. Data related to donors and the retrieval process were available for 116/126 cases. Recipients
The median recipient age was 14.64 yr (interquartile range 8.56–18.24 yr), and sex distribution (male/female) was 76/40. Two of 116 subjects who required graft removal for massive vascular thrombosis in the immediate post-operative period met the study exclusion criteria of graft failure in the first week and were excluded from the analysis of DGF. The 114 remaining recipients were classified into two groups: group 0 (No. 9; 7.9%), characterized by showing DGF after kidney transplant; and group 1 (No. 105; 92.1%), whose members did not experience DGF after surgery. Only one of two patients transplanted prior to needing dialysis presented DGF. End-points Primary end-points
Group 0 (n = 9)
Group 1 (n = 105)
p-value
13 (6.75–17) 35% (37)
0.032* 0.002*
21.90 (23) 7.6 (8) 42.8 (45) 27.62 (29) 13 (11–15.25) [n = 97]
0.133 0.507 0.199 0.488 0.36
47.35 35.09 0.75 (0.55–0.99)
0.065 0.12 0.89
17.14 (18) 61.90 (65) 20.95 (22) 53.08 (43)
0.016* 0.094 0.422 0.585
79.04 (83) 48.57 (51) 2.85 (3) 43.81 (46) 12.38 (13) 26.13 (23) (n = 88) 94.28 (99) 80.32 (49) (n = 61) 25 (15–39) [n = 87]
0.604 0.300 0.284 0.368 0.337 0.452 0.16 1 0.87
D, donor; R, recipient; RCP cardiopulmonary reanimation; BUN, blood urea nitrogen. *Significant value.
Delayed graft function.
1 DGF prevalence. Nine of 114 (7.89%) cases experienced DGF. 2 DGF risk factors – Univariate Analysis. The univariate analysis showed that donor age above 15 yr (p = 0.002, OR: 0.2, 95% CI for OR: 0.05–0.8) and vascular cause of donor brain death (p = 0.016, OR: 0.2, 95% CI for OR: 0.06–0.9), such as spontaneous intracerebral hemorrhage or subarachnoid hemorrhage, represented risk factors for DGF. Comparisons between the two groups are summarized in Table 1. Data about type and volume of plasma expanders, duration in intensive care, creatinemia uremia at retrieval procedure, and urine production were not available for enough cases to be considered for statistical analysis. DGF risk factors – Multivariate Analysis. The multivariate analysis confirmed through a multilogistic regression method as independent risk factors for DGF just donor age >15 yr (p = 0.0109, OR: 0.1338, 95% CI for OR: 0.0285–0.6290).
Secondary end-points Graft function.
1 GFR. In all patients, pretransplant CrCl wasere 15 yr. No differences in use of vasoactive drugs or volume plasma expanders were observed between the groups. However, vascular, more than traumatic, cause of death could be related to a massive use of inotropic agents to control the hemodynamic imbalances and to older donors with possible worse arteries with vascular atheromatosis facilitating DGF. About age, older reports suggested inferior graft function for small kidneys transplanted in children due to infections and technical problems, such as vascular thrombosis and ureteral leak (21–23). Nevertheless, recent authors started to show that pediatric grafts develop compensatory hypertrophy, continue somatic growth, and have better long-term results when transplanted into pediatric recipients (24–27). Moreover, young donor age seems to reduce the risk of arterial hypertension and end-organ damage in pediatric recipients (28). Actually, although the study volume is small, we obtained better results when young (
© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Pediatric Transplantation DOI: 10.1111/petr.12252
Delayed graft function in pediatric deceased donor kidney transplantation: Donor-related risk factors and impact on two-yr graft function and survival: A single-center analysis Cesca E, Ghirardo G, Kiblawi R, Murer L, Gamba P, Zanon GF. Delayed graft function in pediatric deceased donor kidney transplantation: Donor-related risk factors and impact on two-yr graft function and survival: A single-center analysis. Abstract: There is mounting evidence that the quality of organs from cadaver donors may be influenced by events occurring around the time of brain death. Aim of this present study was to analyze the correlation of DGF with brain-dead donor variables in a singlecenter pediatric population and to evaluate DGF influence on patients- and grafts outcome. End-points of the study were DGF prevalence, DGF donor-related risk factors, graft function, patientand graft survival rate, respectively, at six, 12, and 24 months FU. The univariate analysis showed that donor age above 15 yr and vascular cause of donor brain death represented risk factors for DGF. The multivariate analysis confirmed as independent risk factors for DGF donor age >15 yr. At six months FU, DGF showed a negative impact on graft function. In conclusion, among all considered brain-dead donor resuscitation parameters, just nontraumatic cause of death turned out to be of impact for DGF. Donor age >15 yr represented the only independent risk factor for prolonged DGF in our series of children. At two-yr FU, DGF showed a transient negative impact on six-month graft function.
Despite a decade of progress in kidney transplantation, non-immune factors, such as DGF, have still shown to be negative for graft outcome (1, 2). Although experimental studies have shown the crucial role of ischemia–reperfusion injury in the physiopathology of DGF (3), the relative contribution of donor- or recipientrelated factors to the development of DGF is still debated. There is mounting evidence from experimental and clinical studies that the level Abbreviations: CI, confidence intervals; CIT, cold ischemia time; CrCl, creatinine clearance rate; DGF, delayed graft function; FU, follow-up; GRF, glomerular filtration rate; HES, hydroxyethyl starch; ICU, intensive care unit; NITp, Nord Italia Transplant program; OR, odds ratio; PAS, periodic acid-Schiff.
Eleonora Cesca1, Giulia Ghirardo2, Rim Kiblawi1, Luisa Murer2, Piergiorgio Gamba1 and Giovanni Franco Zanon1 1
Pediatric Surgery, University of Padova, Padova, Italy, 2Pediatric Nephrology, University of Padova, Padova, Italy
Key words: kidney transplantation – children – chronic renal failure – graft function – graft survival – delayed graft function Eleonora Cesca, Pediatric Surgery, University of Padova, via Giustiniani, 3 Padova 35121, Italy Tel.: 0498213690 Fax: 0498211781 E-mail: [email protected] Accepted for publication 21 February 2014
of injury to organs from cadaver donors may be influenced by events occurring in the ICU (2, 4–6) and around the time of brain death (7– 10). Some drugs used during donor resuscitation, such as adrenergic agents (1, 11), certain types of colloid plasma expanders (i.e., HES) (12) or desmopressin (13), seem to be associated with poor subsequent graft outcome. To our knowledge, most studies devoted to brain-dead donor parameters are found on adult populations with small donor cohorts (5, 10) or with a restricted number of parameters (4). Aim of the present study was to analyze a single-center group of pediatric renal transplant recipients with a 24-month FU to identify donor-related risk factors for DGF, as well as the impact of DGF on patient and graft outcome. 357
Cesca et al. Subjects and methods Population characteristics Between 2004 and 2011, 126 pediatric deceased donor renal transplants were performed at the Pediatric Surgery Division at the University of Padova. The Institutional Review Board at the University of Padova approved the study. Donors
Data related to donors and the retrieval process were obtained from NITp. Donor-related resuscitation data were extracted from ICU observations from the time of the brain death diagnosis (first flat electroencephalography or cerebral tomodensitometry) to organ recovery procedure. For statistical analysis, resuscitation parameters included the following: type and volume of gelatin as a volume plasma expander (HES colloid vs. gelatins), number of blood transfusions, type of vasopressor employed (dobutamine, dopamine, epinephrine, norepinephrine), occurrence of hypotensive shock due to high variations in blood pressure during the intensive care stay (hypotensive shock criteria were retained as defined by at least one episode of systolic pressure below 80 mm Hg), number of cardiac arrest and cardiopulmonary reanimation episodes, duration in intensive care, creatinemia and uremia at retrieval procedure, and urine production. Other considered parameters were as follows: donor age and gender, cause of death (vascular or traumatic), and multiple-organ retrieval procedure (liver, heart, lung, pancreas, and kidney). The organ recovery technique and preservation fluid were unchanged during the study period. Recipients
Recipient data were extracted from our database (Pediatric Kidney Transplant Database, Access, Microsoft Corporation, Redmond, WA, USA), in which the biologic and clinical data of our transplant patients have been retrospectively recorded by our medical team since 2009. The inclusion criteria included the following: recipient age 15 (%) 72% (8) Relation between D and R, % ♀?♂ 44.44 (4) ♀?♀ 0 ♂?♂ 22.22 (2) ♂?♀ 27.27 (3) Cold ischemic time (hours) 13.5 (12–19) [n = 8] Weight (kg) D weight 63.11 R weight 45.79 R/D weight 0.76 (0.58–0.89) D cause of death, % Vascular 55.56 (5) Traumatic 33.33 (3) Other 11.11 (1) D hypotensive shock 55.56 (5) Inotropics, % Total 77.78 (7) Dopamine 33.33 (3) Epinephrine 11.11 (1) Norepinephrine 55.56 (5) Dodutamine 22.22 (2) D no. RCP 45.45 (5) D multi-organ removal 81.81 (9) D no. blood transfusions 80 (4) (n = 5) D BUN (mg/L) 25 (12.5–37) [n = 8]
Population characteristics Donors
In this cohort, the median donor age was 13 yr (interquartile range 6.75–18.25 yr). Sex distribution (male/female) in donors was 79/37. Data related to donors and the retrieval process were available for 116/126 cases. Recipients
The median recipient age was 14.64 yr (interquartile range 8.56–18.24 yr), and sex distribution (male/female) was 76/40. Two of 116 subjects who required graft removal for massive vascular thrombosis in the immediate post-operative period met the study exclusion criteria of graft failure in the first week and were excluded from the analysis of DGF. The 114 remaining recipients were classified into two groups: group 0 (No. 9; 7.9%), characterized by showing DGF after kidney transplant; and group 1 (No. 105; 92.1%), whose members did not experience DGF after surgery. Only one of two patients transplanted prior to needing dialysis presented DGF. End-points Primary end-points
Group 0 (n = 9)
Group 1 (n = 105)
p-value
13 (6.75–17) 35% (37)
0.032* 0.002*
21.90 (23) 7.6 (8) 42.8 (45) 27.62 (29) 13 (11–15.25) [n = 97]
0.133 0.507 0.199 0.488 0.36
47.35 35.09 0.75 (0.55–0.99)
0.065 0.12 0.89
17.14 (18) 61.90 (65) 20.95 (22) 53.08 (43)
0.016* 0.094 0.422 0.585
79.04 (83) 48.57 (51) 2.85 (3) 43.81 (46) 12.38 (13) 26.13 (23) (n = 88) 94.28 (99) 80.32 (49) (n = 61) 25 (15–39) [n = 87]
0.604 0.300 0.284 0.368 0.337 0.452 0.16 1 0.87
D, donor; R, recipient; RCP cardiopulmonary reanimation; BUN, blood urea nitrogen. *Significant value.
Delayed graft function.
1 DGF prevalence. Nine of 114 (7.89%) cases experienced DGF. 2 DGF risk factors – Univariate Analysis. The univariate analysis showed that donor age above 15 yr (p = 0.002, OR: 0.2, 95% CI for OR: 0.05–0.8) and vascular cause of donor brain death (p = 0.016, OR: 0.2, 95% CI for OR: 0.06–0.9), such as spontaneous intracerebral hemorrhage or subarachnoid hemorrhage, represented risk factors for DGF. Comparisons between the two groups are summarized in Table 1. Data about type and volume of plasma expanders, duration in intensive care, creatinemia uremia at retrieval procedure, and urine production were not available for enough cases to be considered for statistical analysis. DGF risk factors – Multivariate Analysis. The multivariate analysis confirmed through a multilogistic regression method as independent risk factors for DGF just donor age >15 yr (p = 0.0109, OR: 0.1338, 95% CI for OR: 0.0285–0.6290).
Secondary end-points Graft function.
1 GFR. In all patients, pretransplant CrCl wasere 15 yr. No differences in use of vasoactive drugs or volume plasma expanders were observed between the groups. However, vascular, more than traumatic, cause of death could be related to a massive use of inotropic agents to control the hemodynamic imbalances and to older donors with possible worse arteries with vascular atheromatosis facilitating DGF. About age, older reports suggested inferior graft function for small kidneys transplanted in children due to infections and technical problems, such as vascular thrombosis and ureteral leak (21–23). Nevertheless, recent authors started to show that pediatric grafts develop compensatory hypertrophy, continue somatic growth, and have better long-term results when transplanted into pediatric recipients (24–27). Moreover, young donor age seems to reduce the risk of arterial hypertension and end-organ damage in pediatric recipients (28). Actually, although the study volume is small, we obtained better results when young (
