Impact of acute kidney injury in expanded criteria deceased donors on post-transplant clinical outcomes: multicenter cohort study

Five-hundred and nine kidney transplant recipients (KTRs) receiving kidneys from 386 DDs were included. The KTRs were treated at three transplant centers (A, Seoul St. Mary’s Hospital, B, Uijeongbu St. Mary’s Hospital, and C, Keimyung University Hospital) between October 1996 and May 2016. ECD was defined according to the United Network for Organ Sharing (UNOS) criteria [21]. AKI was diagnosed according to the Kidney Disease: Improving Global Outcomes (KDIGO) criteria. This criteria defines that AKI is an increase in a serum creatinine (SCr) level by ≥0.3 mg/dL (26.5 μmol/L) within 48 h or an increase in a SCr level to ≥1.5 times baseline that had already been known or presumed to have developed within 7 days, or a reduction in urine output (< 0.5 mL/kg/hour for 6 h). The stages of AKI were defined according to the severity of an increase in a SCr level or a reduction in urine output [17, 22].

We retrospectively analyzed the donor and recipient data. The donor data included age, sex, body mass index (BMI) (kg/m²), history of diabetes mellitus (DM) and hypertension (HTN), cause of death, and estimated glomerular filtration rate (eGFR). The recipient data included age, sex, BMI, history and duration of dialysis before KT, number of previous KTs, cause of end-stage renal disease, history of DM and HTN, cold ischemic time, number of human leukocyte antigen (HLA) mismatches, immunosuppressant type and percentage of panel-reactive antibodies (PRAs). We also analyzed the findings of allograft biopsies obtained within 3 months from KT in KTRs, and analyzed the extent of chronic damage (interstitial fibrosis (IF, ci > 0), tubular atrophy (TA, ct > 0), glomerulosclerosis (GS)) in the allograft tissue. We calculated the average score of IF and TA in each group [23]. DGF was defined as dialysis requirement within the first week after KT [24].

The primary outcome was to investigate the impact of AKI on the death-censored allograft survival for DDKT using SCDs versus ECDs, and analyze the interaction between AKI in DDs and ECDs. The secondary outcomes were to investigate the incidence of DGF, the change of allograft function by eGFR calculated using the modification of diet in renal disease (MDRD) equation until 1 year after KT [25], the chronic change in allograft tissue by allograft kidney biopsies performed within 3 months after KT, and the patient survival between SCD-KT and ECD-KT and between the AKI-KT and non-AKI-KT subgroups, respectively.

This study was approved by the institutional review boards of Seoul St. Mary’s Hospital (XC15RIMI0061K), Uijeongbu St. Mary’s Hospital (XC15RIMI0061U), and Keimyung University School of Medicine, Dongsan Medical Center (2017–08-019).

Student’s t-test was used for the analysis of continuous variables with a normal distribution, and those were expressed as the mean ± standard deviation. On the contrary, the Mann-Whitney test was used for the analysis of those with a non-normal distribution. The Chi-square test or Fisher’s exact test was used to analyze categorical variables, and those were expressed as the number and percentage. Kaplan-Meier curves and log-rank tests were used for the description of the death-censored graft survival and patient survival. Logistic regression analysis was used to investigate whether AKI in DDs or ECD is an independent risk factor for the development of DGF and recipient age, transplant year (1996~2005 vs. 2006~2010 vs. 2011~2016), transplant center, prior KT, recipient diabetes, HLA mismatch number, high PRA, donor gender were included as confounding variables. Cox proportional hazards regression analysis was used to investigate whether AKI in ECD is an independent risk factor for death censored allograft failure. Interaction effects between donor type (ECD vs. SCD) and AKI in donors were explored by adding interaction terms to the model in which donor type was treated as an ordinal in overall population. P-values < 0.05 were considered statistically significant. All statistical analyses were performed using SPSS 19.0 software (SPSS Inc., Chicago, IL, USA) and the statistical package MedCalc version 15.5 (MedCalc, Mariakerke, Belgium).

The median follow-up period of this study was 48.1 (interquartile range 29.6–75.3) months. The mean age of the ECD group was higher than that of the SCD group (58.4 ± 5.2 vs. 38.9 ± 13.4 years, p < 0.001). The proportions of HTN, DM, and death due to cerebrovascular accident (CVA) were significantly higher in the ECD group than in the SCD group (47.6% vs. 13.4%, p < 0.001, 18.1% vs. 5.5%, p < 0.001 and 82.4% vs. 72.7%, p = 0.049, respectively). The baseline MDRD eGFR was significantly lower in the ECD group than in the SCD group (58.8 ± 23.6 ml/min/1.73 m² vs. 76.0 ± 44.9 ml/min/1.73 m², p < 0.001). The proportion of AKI was significantly higher in the ECD group than in the SCD group, but there was no significant difference according to the AKI stage between the two groups. All donors with AKI stage 3 took hemodialysis prior to organ procurement (Table 1).

Regarding the recipients, the mean age and BMI were significantly higher in the ECD-KT group than in the SCD-KT group (51.1 ± 9.4 vs. 46.6 ± 10.1 years, p < 0.001, 23.4 ± 3.4 vs. 22.5 ± 3.1, p = 0.003, respectively). The proportion of KTRs with DM was significantly higher in the ECD-KT group than in the SCD-KT group (27.0% vs. 15.7%, p = 0.004) (Table 1). In the comparison of baseline characteristics between the AKI and non-AKI subgroups within the SCD-KT or ECD-KT group, donors were significantly younger in the AKI-ECD-KT subgroup than in the non-AKI-ECD-KT subgroup (p < 0.001) (Table 2).

The incidence of DGF was not significantly different between the SCD-KT and ECD-KT groups (Fig. 2a). In a subgroup analysis, the incidence of DGF was significantly higher in the AKI-KT subgroup than in the non-AKI-KT subgroup in both SCD-KT and ECD-KT groups (p = 0.005, p = 0.002, respectively) (Fig. 2b). In multivariate analysis, AKI was a significant risk factor for the development of DGF, but ECD was not. AKI and ECD did not show significant interaction effect (p = 0.998) (Table 3).

Allograft function through the first 12 months post-KT was significantly lower in the ECD-KT group compared with the SCD-KT group (p < 0.05) (Fig. 2c). In the subgroup analysis of the SCD-KT group, allograft function was significantly lower in the AKI-SCD-KT subgroup compared with the non-AKI-SCD-KT subgroup (p < 0.05) (Fig. 2d). In the ECD-KT group, allograft function was significantly lower in the AKI-ECD-KT subgroup until 3 months post-KT (p < 0.05); however, no difference was observed after this time (Fig. 2e).

We analyzed the findings of allograft biopsies obtained within 3 months from KT in 243 KTRs (Additional file 1: Figure S1). Regarding the allograft biopsies performed within 3 months, proportions of allograft tissue with IF (a) and TA (b) were significantly higher in the ECD-KT group than in the SCD-KT group (38.8% vs. 18.6%, p = 0.010 and 38.8% vs. 18.6%, p = 0.010, respectively). The mean GS percentage was significantly higher in the ECD-KT group than in the SCD-KT group (17.5 ± 23.3% vs. 5.0 ± 9.2%, p = 0.001) (c). In the SCD-KT group, there was no significant difference in the proportion of allograft tissue with IF, TA, or the mean GS percentage between the non-AKI-SCD-KT and AKI-SCD-KT subgroups. In contrast, in the ECD-KT group, the proportion of allograft tissue with IF, TA, and the mean GS percentage all tended to be higher in the AKI-ECD-KT subgroup than in the non-AKI-ECD-KT subgroup (d, e, f).

A total of 73 cases (14.3%) of graft failure developed, including 52 (14.9%) cases in the SCD-KT group (33 patients in the non-AKI-SCD-KT subgroup and 19 patients in the AKI-SCD-KT subgroup) and 21 in the ECD-KT group (2 patients in the non-AKI-ECD-KT subgroup and 19 patients in the AKI-ECD-KT subgroup). No significant difference was detected in the causes of allograft failure between the SCD-KT and ECD-KT groups or between the AKI-KT and non-AKI-KT subgroups within the SCD-KT and ECD-KT groups (Table 4). Death-censored allograft survival tended to be higher in the SCD-KT group than in the ECD-KT group, but this difference was not significant (Fig. 3a). Meanwhile, it was significantly lower in the AKI-ECD subgroup in comparison with other 3 groups. However, AKI-SCD-KT or non-AKI-ECD-KT subgroup did not show a significant difference to non-AKI-SCD-KT group (Fig. 3b). Table 5 shows the incidence of allograft failure and the hazard ratios. The highest incidence of allograft failure was observed in AKI-ECD-KT subgroup. The predictors for allograft failure were evaluated using non-AKI-SCD-KT subgroup as the reference group. In multivariate analysis, KTRs from DDs with both AKI and ECD had the highest risks of the allograft failure after adjustment for recipient age, recipient diabetes, high PRA, transplant year, transplant center. There was a significant interaction between AKI in DDs and ECD for the allograft failure (p for interaction = 0.007). However, a significant hazard ratio for allograft failure was not observed in KTRs from DD with either AKI or ECD only.

A total of 27 patients (5.3%) died, 20 of whom were in the SCD-KT group (13 patients in the non-AKI-SCD-KT subgroup and 7 patients in the AKI-SCD-KT subgroup) and 7 of whom were in the ECD-KT group (all 7 in the AKI-ECD-KT subgroup). The causes of death of the KTRs in the SCD-KT group were as follows: cardiovascular disease, 6 (30.0%); infection, 7 (35.0%); malignancy, 4 (20.0%); gastrointestinal bleeding 1, (5.0%); and unknown cause 2 (10.0%). In the ECD-KT group, the causes of death were as follows: cardiovascular disease, 3 (42.9%); infection, 3 (42.9%); and CVA, 1 (14.3%). There was no significant difference in the cause of patient death (Table 4) or in the patient survival rate between the SCD-KT and ECD-KT groups (p = 0.61) (Fig. 4a). When we compared patient survival among 4 groups (non-AKI-SCD-KT, AKI-SCD-KT, non-AKI-ECD-KT and AKI-ECD-KT), there was no significant difference (p = 0.11) (Fig. 4b).