, Introduction
It has been reported that the prevalence rate of chronic kidney disease (CKD; estimated glomerular filtration rate [eGFR] of <60 mL/min/1.73 m2) is 2.7%, and 0.17% of the population is in the CKD stage 4 to 5 in China [1]. Considering the huge population base of 1.4 billion in China, more than 2 million patients are undergoing or heading for dialysis. As displayed in a previous study, in 2015, over 600 thousand end-stage renal disease (ESRD) patients were receiving dialysis [2]. In contrast, kidney transplantation is an effective treatment alternative to dialysis for ESRD patients, with excellent advantages in morbidity and mortality [3]. However, donor scarcity is still an outstanding problem; thus, expanded criteria donors (ECDs) are gradually being accepted to expand the donor pool. Previously discarded kidneys from hepatitis B virus (HBV) infected donors have been renewed in the current age of organ shortage.
HBV infection is also a severe public health burden in China, with nearly 1 million new infections per year during the last decade. The estimated HBV prevalence rate in 2019 was 7.8% [4]. It is obviously much higher in adults (especially the middle-aged population), who are the predominant source of donors, due to the low carrier rate in children and youth under the national active immune vaccination schema of HBV. The hepatitis B surface antigen (HBsAg) prevalence rate has even reached approximately 25% in the male population over 35 years old in a small community-based survey in China [5,6]. Therefore, HBV-positive donors are infinitely common in China compared to Western countries, and discarding such kidneys would be a great waste in an organ shortage situation.
Donors with resolved HBV infection (i.e., HBsAg-negative and hepatitis B core antibody [HBcAb]-positive donors) were deemed to increase the reactive risk of HBV infection, and HBV-positive (HBsAg-positive) donors were regarded to pose a high risk of HBV transmission to immunosuppression recipients. Furthermore, subsequent rapid exhausted liver injury, fibrosis, cirrhosis, liver failure, and HBV-related hepatocellular carcinoma were identified as fatal morbidities and catastrophes. Currently, with advances in anti-HBV therapy in the last few decades, these morbidities can be substantially reduced and even interrupted. Although HBV infection is not a contraindication in kidney donation, the match of such kidneys was restricted [7]. Due to the relatively low prevalence rate of HBV in Western countries, there is currently insufficient evidence regarding the safety and efficacy of HBV-positive kidneys. Most existing studies have been based on small-sample cohorts (Supplementary Table 1, available online). In this study, we aimed to retrospectively analyze the impact of donor HBV infection on transplant outcomes at a single transplant center.
Methods
Study design and patients
We retrospectively retrieved kidney transplantation cases from January 1, 2015 to December 31, 2021, in our transplant center. All transplant records were collected from The China Organ Transplant Response System (COTRS), which is the sole legitimate official registry site designated by the National Health Commission of China for solid organ donation, matching, and allocation. It includes a potential donor registry system maintained by the donation coordinators in each organ procurement organization (OPO), a waiting list system maintained by each transplant registry center and an allocation system maintained by the OPO. Inclusion criteria were set as single-kidney transplantation with a recipient age ≥18 years. Any case lost to follow-up was excluded from the analysis. The detailed screen diagram is shown in Fig. 1. All donor sources were from deceased citizen donors since it has been the unique legal procedure for non-related solid organ transplantation procurement in China mainland since January 1, 2015. All donor death-related evaluation and confirmation profiles of each single donor were submitted to the COTRS. All donors and procured organs were numbered, matched, and allocated at the COTRS (https://www.cot.org.cn/). All cases of HBV-positive donors to HBV-negative recipients were discussed by the transplant teams and the recipients before transplantation. Informed consent was obtained after discussing the balance of benefits and risks with the participants. The majority of recipients received prophylaxis with hepatitis B immune globulin with or without lifelong entecavir (except one recipient received lamivudine).
Ethics statement
This study was approved by the Research Ethics Committee at the Third Affiliated Hospital of Sun Yat-sen University (No. [2020]02-243-01). Donor profile access was permitted after ethical review. The requirement for informed consent was waived by the Ethics Committee, as all inpatients provided explicit authorization for the use of their medical data in scientific research related to transplantation at admission. This research is compliant with the Declaration of Helsinki. The clinical and research activities being reported are consistent with the Principles of the Declaration of Istanbul as outlined in the ‘Declaration of Istanbul on Organ Trafficking and Transplant Tourism.’
Data sources and variables
The primary outcomes of this research comprised HBV infection, delayed graft function (DGF), death-censored graft survival (DCGS), patient survival (PS), and graft function (measured by eGFR) at distinct time points. All data sources were from the COTRS (including the waiting list system and allocation system), medical records, tests, and examinations from donation hospitals and transplant hospitals. These data were legally protected and inspected for their authenticity. The authors were authorized to retrieve related data from these platforms.
DGF was defined as the need for dialysis during the first week after transplantation [8]. HBV infection was defined as detectable HBV DNA or the appearance of HBsAg during follow-up in HBsAg-negative recipients. Hepatitis B surface antibody (HBsAb) was categorized as positive (above 10 mIU/mL) and negative (below 10 mIU/mL). Graft function included the recipients’ peak eGFR within 12 months during the follow-up surveillance. Creatinine and eGFR were routinely monitored during follow-up weekly within the first 3 months, semimonthly within 4 to 6 months, and monthly within 7 to 12 months. After 1 year of monitoring, the follow-up frequency was tapered to every 1 to 3 months. eGFR was calculated by the CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) equation [9]. Graft loss was defined as a return to dialysis due to irreversible deterioration of kidney function or progression to an eGFR below 15 mL/min/1.73 m2. Additionally, recipients who died with a functioning graft prior to readmission to the hospital were considered dead with graft function, regardless of their renal function (acute kidney injury) during terminal hospitalization.
Common variables from donors included donor age, sex, blood type, body mass index (BMI), HBsAg carrier status, terminal serum creatinine, cause of death, and donor death category (donation after brain death/donation after circulatory death). The ECD was defined by Rao’s definition [10]. Cold ischemia time was estimated as the interval from donor cardiac death to the unclamping of vessels during the transplantation operation, ignoring the short duration (minutes) between cardiac death and initial cold perfusion in donors. All donated kidneys were static cold stored and transported. Common variables from recipients included recipient age, sex, BMI, HBV infection status, transplant history, diabetes history, dialysis modality, dialysis vintage, preoperative creatinine level, induction therapy, and peak panel reactive antibody (PRA) level. There was no ABO- incompatibility transplantation and no positive crossmatch in this study.
Considering the different transmission risks of various donor and recipient HBV crossmatch statuses, all transplant cases were divided into three groups: donor HBsAg+/recipient HBsAg– (D+R–) group, donor HBsAg–/recipient HBsAg– (D–R–) group and donor HBsAg±/recipient HBsAg+ (D±R+) group. In this study, we only included the D–R– and D–R– cases for analysis. Recipients who carried HBsAg before transplantation were excluded. Regarding the HBV monitoring of both D+R– and D–R– recipients in the past period, a routine monitoring test for HBV (including HBsAg, HBsAb, hepatitis B e antigen, hepatitis B e antibody, total HBcAb and/or HBV DNA titer) was not performed. Instead, the recipients were tested irregularly during their follow-up or only when there were suspicions of HBV infection (e.g., unexplained abnormality of alanine transaminase/aspartate transaminase, jaundice, and other acute viral hepatitis symptoms). Therefore, an analysis of HBV infection was conducted based on the available HBV-tested data (n = 72) (Fig. 1), excluding recipients who did not undergo HBV testing during follow-up. Those who did not undergo HBV testing during follow-up were considered HBV negative in the full set (n = 94). A sensitive analysis was performed using this full set, and the results are presented in the Supplementary Table 2 and 3 (available online).
Statistical analysis
Categorical variables are presented as counts (percentage), with a comparison between groups conducted by using the Fisher exact test or the chi-square test. Continuous variables were expressed as the mean and standard deviation (for normalized distribution) or median and interquartile range (IQR; for skewed distribution), which were compared by the t test or Mann-Whitney U test. To explore the correlation between donor HBV status and recipient DGF, graft loss, PS, multilevel logistic or survival regression models were used considering the synchrony effect in the posttransplant recovery of the mate kidneys [11]. Mixed linear regression was performed to investigate the impact of donor HBV status on eGFR recovery. When performing survival analysis for graft survival, the graft survival time of zero was entered as 0.0001 for those primary nonfunction or transplant failure recipients. We were unable to drop these cases during analysis, which would otherwise result in significant bias. Additionally, the shared-frailty model was applied in survival analysis as a type of multilevel model. Any factors with a p-value of <0.1 in the univariable analysis were adjusted in the multivariable analysis. The donor identical number was set as the random variable (or frailty grouping variable). All statistical analyses were performed using Stata 16.1 IC (StataCorp LLC) and R version 4.2.1 (R Foundation for Statistical Computing). A two-sided p-value of <0.05 was considered statistically significant.
Results
Baseline demographics
A total of 985 kidney-related transplant records were collected from our center between 2015 and 2021. The donor HBsAg carrier rate was 14.5% (not listed). Finally, a total of 743 screened kidney transplantation cases were included for analysis. It comprised 649 D–R– cases and 94 D+R– cases. In total, 231 of 649 D–R– cases and 72 of 94 D+R– cases had HBV tests during follow-up, which constituted the HBV-tested set. The screening process is illustrated in Fig. 1. The median follow-up time was 34 months (IQR, 16–52 months). Table 1 presents the characteristics of the two groups. D+R– cases differed significantly from the D–R– cases in terms of donor sex ratio, donor diabetes history, donor age, recipient peak PRA, recipient age, and recipient HBcAb status. Specifically, the D+R– population had a higher proportion of male donors, higher donor and recipient age, a lower proportion of positive PRA and recipient HBcAb prevalence rate, and a higher proportion of donors with a history of diabetes.
Recipient hepatitis B virus infection
During follow-up, a total of nine new HBV infection episodes were observed. None of the recipients who received desensitization therapy with rituximab experienced HBV infection. As shown in Table 2 and 3, the D+R– group had a significantly higher risk of HBV infection compared to the D–R– group (6/72 vs. 3/231; relative risk [RR], 6.4; p = 0.007). In the D+R− group, four HBV transmissions occurred in HBV-naïve recipients, resulting in a transmission rate of 26.7% (4/15). In recipients with HBsAb titers of 10–100 mIU/mL, the transmission rate was 10.5% (2/19). However, no transmission occurred in recipients with HBsAb titers of 100–1,000 mIU/mL and over 1,000 mIU/mL (0/21 and 0/17). The Cochrane-Armitage test showed a significant trend in the transmission rate with increasing HBsAb titer (p for trend = 0.003). Fig. 2 presents a mosaic plot of the results. Among 94 D+R– cases, not all recipients were prescribed oral anti-HBV therapy, and there was no significant difference in HBV infection risk between recipients using and not using nucleotide analogs (NAs) (1/22 vs. 5/50, p = 0.66). Of the nine HBV-infected recipients, all three infections in the D–R– group developed chronicity. In the D+R– group, three of six HBV infections became chronic, while the remaining three were transient infections and returned to both HBV DNA and HBsAg negativity. Unfortunately, one of the three recipients with transient infection died of severe pneumonia (Table 4). A sensitive analysis using the full set data yielded similar results, which are presented in the Supplementary Tables 2 and 3.
Donor hepatitis B virus and transplant outcomes
The recovery of recipient graft function was assessed by examining recipient DGF and eGFR. As shown in Table 5, the D+R– group did not exhibit an increased risk of DGF compared to the D–R– group (odds ratio, 0.70; p = 0.51) in the multivariable mixed model. Furthermore, both groups demonstrated similar peak eGFR values within 12 months (β = 1.01, p = 0.71).
To investigate the potential impact of the D+R– group on transplant survival outcomes, recipient survival and DCGS were used as endpoints. The regression results are shown in Table 6. The D+R– group had no significant effect on PS (hazard ratio [HR], 0.36; p = 0.10) or DCGS (HR, 0.79; p = 0.59) after adjustment in the shared-frailty Cox model.
Discussion
In this study, we have demonstrated the efficacy and safety of using HBsAg-positive donor kidneys for HBsAg-negative recipients. The presence of HBsAg in the donor did not have any impact on the recovery of graft function (DGF and peak eGFR). Furthermore, it did not affect the recipient’s overall survival and DCGS. Although the risk of HBV transmission to HBsAg-negative recipients is significantly higher in cases where the donor is HBsAg-positive, it is important to note that the overall transmission rate remains low. Most of the transmissions occur in HBV-naïve recipients. The pretransplant HBsAb titer of the recipients plays a crucial role in mitigating the risk of transmission. This study was designed to address several clinical concerns regarding the safety of using HBV-positive donated kidneys. The first concern is whether using such kidneys would affect graft recovery, graft survival, and recipient survival. Due to the low prevalence rate of HBV in Western countries and the limited number of transplantation cases, related studies are rare and typically have small sample sizes [12–19]. A previous study conducted by Yuan et al. [18] showed that donor or recipient HBsAg status did not influence long-term PS and graft survival in kidney transplantation. In this study, Yuan et al. [18] extracted 182,106 kidney transplantation cases from Organ Procurement and Transplantation Network (OPTN) data between 2000 and 2019. The cohort was divided into three groups, including D–R– (n = 178,374), D–R+ (n = 3,577), and D+R– (n = 144), by dropping D+R+ (n = 11). They found no significant difference among these three groups in terms of PS and all-cause graft survival via univariate analysis and propensity score matching analysis, which is consistent with our findings. In addition, we supplemented the effect of HBsAg status on short-term graft recovery DGF and peak eGFR within 12 months. The results showed that the D+R– group did not influence the risk of DGF or the level of peak eGFR compared to the D–R– group. Wang et al. [17] recently published their results comparing donor (HBsAg+)/recipient (HBsAg−) with donor (HBcAb+)/recipient (HBcAb−) living kidney transplantation. In this study, there were no significant differences in the rates of DGF, rejection, infection, liver injury, and graft loss. Although the recipient survival rate at 5 years was significantly lower in the donor (HBsAg+)/recipient (HBsAg−) group, simply comparing the survival counting rate was not appropriate for conclusion in a time-to-event study. In addition to this study, all above retrieved studies showed similar survival outcomes for recipient survival and graft survival. Wang et al.’s study [17] also displayed overall 5/83 deaths in the donor (HBsAg+)/recipient (HBsAg−) group, and three of the five deaths occurred in the HBsAb-negative recipients (3/20). This may indicate a potential risk of HBV-positive donor kidneys for HBV-naïve recipients. Currently, there is not enough data to clarify the survival detriment in such a subgroup. Furthermore, Yilmaz et al.’s study [16] showed no significant difference in the DGF, serum creatinine, and eGFR levels between donor HBV-positive and -negative groups. Tuncer et al.’s study [13] also revealed no difference in 1-year and 2-year eGFR levels between the two groups receiving living kidney transplantation. Wang et al.’s study [17] and their extended study [20] based on the same cohort displayed no differences in DGF rate, serum creatinine level, and eGFR level between the two groups receiving living kidney transplantation. In total, based on these studies and our results, we can conclude that donor HBV positivity did not influence graft recovery or graft and recipient survival at a short-to-middle–term follow-up.
The second concern is the transmission risk of HBV from donors to recipients. In kidney transplantation practice, this concern has hampered the utilization of HBV-positive kidneys and has constrained allocation rules for recipients who can accept such kidneys. Apart from incorporating covalently closed circular DNA into the hepatic cell genome, HBV can also infect peripheral blood mononuclear cells (PBMCs), mainly monocytes and B cells [21]. These residual PBMCs are still retained in the kidney after perfusion and could be a potential source of transmission. Of the eight studies mentioned above, five studies [12,14–17] reported the HBV infection rate in donor HBV-positive and -negative groups. Due to the small sample size effect, each study indicated no significantly different risk of HBV infection. Indeed, after we pooled these results by meta-analysis, a significantly higher HBV infection risk was shown in the donor HBsAg+ group (RR, 7.13; 95% CI, 2.75–18.50; p < 0.001, data was not shown). Obviously, this result is in accordance with our intuitive perception that HBV exposure, especially in immunosuppressive patients, would increase the HBV infection risk compared to that in nonexposed patients. However, the pooled infection proportion in the donor HBsAg+ group was relatively low (2.63%). Most of these studies presented transplantations from positive donors to negative recipients with positive HBsAb. In Wang et al.’s study [17], two HBV infections in 83 D+R− cases occurred only in HBsAb-negative recipients (2/20) and only in HBsAb−/HBcAb− recipients (2/11), and none of the remaining 63 HBV-immunized recipients developed HBV infection. Our results also confirmed these findings. Four of six HBV infections were found in HBsAb-negative recipients (4/15), and two infections (2/6) were found in recipients with HBsAb titers of 10−100 mIU/mL (with positive HBcAb). Both results strongly recommended against transplanting HBsAg+ kidneys to HBsAb− recipients in terms of HBV infection risk. Only emergency transplantation is under consideration. Overall, HBsAb plays a crucial role in protecting HBV transmission from HBsAg+ donors. Maintaining the HBsAb titer over 100 mIU/mL would substantially impede transmission. Additionally, a previous study indicated that the loss of protective immunity during the years following kidney transplantation was notable, particularly when the initial HBsAb titer was <100 mIU/mL [22]. This emphasized the importance of maintaining pre- and posttransplant HBsAb titers against HBV infection. However, the immune response to HBV vaccination in dialysis patients is very weak, with a response rate of only 49%, as shown in a previous study [23]. Boosting vaccination with a double dose (40 μg rather than 20 μg) or the newly enhanced HBV vaccine HEPLISAV-B (Dynavax Technologies Corp.) approved by the U.S. Food and Drug Administration may increase the HBsAb titer [24]. This gives the patients on the waiting list discretion to balance the risks and benefits of accepting such kidneys.
Compared to previous studies, the current study has confirmed that there is no decrease in graft and recipient survival in D+R− cases. Additionally, there is no difference in graft recovery between the D+R− and D−R− groups. Furthermore, we have provided additional information on the protective role of pretransplant HBsAb titer and the efficacy of NAs prophylaxis in D+R− recipients for HBV infection. The results showed no difference in infection rates between the use and non-use of NAs in D+R− recipients (1/22 vs. 5/50, p = 0.66). However, it is important to interpret these results with caution due to the small sample size. Additionally, we have provided a detailed prognosis for each HBV-infected recipient. To confirm the relationship between donor HBV infection status and recipient transplant-related outcomes, we need more corresponding cases and events for robust statistical analysis. Understanding the number of transplant cases in each country, the low prevalence of HBV, and the low incidence rate of related outcome events, it is not easy to provide such resources for analysis. Currently, the largest cohort with positive HBV donors was reported by Yuan et al. [18]. The data were based on the U.S. OPTN from 2000 to 2019. In a wide database with twenty years of accumulation, only 155 HBV-positive donations (144 D+R− and 11 D+R+) were included in this study. This indicates the tremendous difficulty of conducting a statistically powerful study. The Chinese Scientific Registry of Kidney Transplantation (CSRKT) is a follow-up and monitoring system containing whole kidney transplantation records from all transplant centers in China mainland. Based on this system, it should provide a sufficient sample size to answer donor HBV-related concerns. However, currently, the data quality control caused by its greatly complicated contents in the registry system hampers its confidentiality.
There are several limitations to consider in this study. First, we did not include the donor’s HBV DNA viral load level in serum as an impact factor for analysis. This could be an important predictor of transmission. Second, we did not have a strict and regular schedule for HBV monitoring during the follow-up period. This may have led to an underestimation of transient episodes of HBV viremia before subsequent testing. Third, we did not differentiate between HBV transmission and HBV reactivation in HBcAb-positive recipients, although the rate of reactivation is extremely low. Finally, we did not subdivide the D+R− recipients into susceptible, immune, and resolved infection groups to further compare their transplant outcomes. These limitations should be taken into account when interpreting the results of this study.
In conclusion, this study demonstrates that the use of HBsAg-positive donor kidneys is relatively safe for HBV-immunized recipients during a short follow-up period. The graft function recovery of HBV-infected donor kidneys is not compromised, as evidenced by comparable rates of posttransplant DGF, eGFR levels, and graft and recipient survival. While the HBV transmission rate is low, the infection risk is high in recipients with negative HBsAb. Therefore, we strongly recommend against transplanting HBsAg+ kidneys to HBsAb− recipients due to the elevated risk of HBV infection. To mitigate this risk of HBV transmission from HBsAg-positive donors, our findings support the maintenance of an HBsAb titer above 100 mIU/mL (with or without a boosting vaccination) in all non-HBV chronic infection candidates. Given the limited number of cases in our study, further validation is necessary through a large sample size cohort from CSRKT or multiple centers.
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