Objectives: Immunosuppressive therapy in kidney transplant recipients with hepatitis B virus infection may increase the risk of disease progression.
Here, we compared outcomes of depleting (antithymocyte globulin/alemtuzumab) versus nondepleting (basiliximab/daclizumab) antibody induction in kidney transplant recipients at different serologic phases of hepatitis B virus infection.
Materials and Methods: We used the Organ Procurement and Transplantation Network/United Network for Organ Sharing database to identify adult kidney transplant recipients at different serologic phases of hepatitis B virus infection (transplants received from 2001-2011 after patients received perioperative induction with discharge on calcineurin inhibitors/mycophenolate mofetil with/without steroids). We used a Cox model to compare outcomes among patient groups.
Results: Median follow-up was 50.7 months (range, 28.6 to 82.6 mo). Serologic phase for the 7681 study patients were as follows: 1098 at HBsAg+/anti-HBc- (depleting = 652, nondepleting = 446), 446 at HBsAg+/anti-HBc+ (depleting = 250, nondepleting = 216), and 6117 at HBsAg-/anti-HBc+ (depleting = 3562, nondepleting = 2555) (where anti-HBc denotes hepatitis B core antibody, HBsAg denotes hepatitis B surface antigen, and +/– denote positive/negative). When we compared those with depleting versus nondepleting agents, hazard ratios (95% confidence intervals) for adjusted overall graft, death-censored graft, and patient survival were 0.97 (0.78-1.26; P = .86), 1.20 (0.83-1.60; P = .44), and 0.92 (0.66-1.30; P = .51) in the HBsAg+/anti-HBc-; 0.81 (0.55-1.18; P = .27), 0.59 (0.32-1.12; P = .11), and 0.95 (0.60-1.49; P = .83) in the HBsAg+/anti-HBc+; and 0.96 (0.86-1.05; P = .37), 0.95 (0.60-1.49; P = .97), and 0.92 (0.80-1.05; P = 0.22) in the HBsAg-/anti-HBc+ groups.
Conclusions: Our study did not show adverse graft and patient outcomes associated with depleting versus nondepleting antibody induction in kidney transplant recipients at different phases of hepatitis B virus infection. This supports the selection and use of induction agents based on immunologic risk in such patients.
Key words : Hepatitis B virus serostatus, Immunosuppression, Renal transplantation
Host response to hepatitis B virus (HBV) infection is variable, with some patients progressing to chronic liver disease. Hepatitis B virus infection generally goes through 3 sequential serologic phases in most patients: early infection characterized by hepatitis B surface antigen-positive (HBsAg+)/hepatitis B core antibody-negative (anti-HBc-) status, inactive carrier/immune-tolerant phase manifested as HBsAg+/anti-HBc+ serostatus, and a phase of clearing infection associated with HBsAg-/anti-HBc+ serology. Previous studies have shown increased morbidity and mortality in kidney transplant recipients (KTRs) with HBV infection.1-3 Immunosuppressive therapy in KTRs with HBV infection, particularly in the initial phases, could potentially increase the risk of disease progression. Perioperative induction therapy is increasingly used for kidney transplant in the United States to reduce incidence of early rejection and potentially improve long-term outcomes.
Induction agents are generally classified as depleting or nondepleting, with greater levels of immunosuppression resulting from depleting agents. Commonly used depleting agents for induction therapy in KTRs includes rabbit antithymocyte globulin (rATG) and alemtuzumab. Nondepleting agents, which are generally used for perioperative induction in KTRs, include basiliximab and daclizumab. Rabbit ATG is a polyclonal agent containing antibodies to various T-cell surface antigens that causes cell lysis and apoptosis. Alemtuzumab is a monoclonal antibody directed against CD52 expressed on circulating mononuclear cells, which also causes lymphocyte lysis and apoptosis. Both basiliximab and daclizumab are interleukin 2 receptor blockers that can cause altered interleukin 2 signal transduction on activated T cells, preventing their replication. It is unclear whether depleting antibody induction with the associated enhanced immunosuppression when compared with nondepleting induction would accelerate HBV infection with resultant adverse graft and patient outcomes. We aimed to compare the long-term outcomes of depleting versus nondepleting antibody induction in KTRs who were at different serologic phases of HBV infection at the time of transplant.
Materials and Methods
The study protocol was approved by the institutional review board and conformed to the ethical guidelines of the 1975 Helsinki Declaration. With use of the Organ Procurement and Transplant Network/United Network of Organ Sharing database, we identified patients ≥ 18 years of age who underwent kidney transplant between January 2001 and December 2011 and who were in 1 of the 3 serologic phases of HBV infection at the time of transplant: HBsAg+/anti-HBc, HBsAg+/anti-HBc+, or HBsAg-/anti-HBc+. All patients received perioperative induction with either a depleting (rATG or alemtuzumab) or nondepleting (basiliximab or daclizumab) antibody followed by a calcineurin inhibitor/mycophenolate mofetil-based maintenance immunosuppression with or without steroids. Patients who received no induction, multiple induction agents, or different induction agents or maintenance therapy other than those mentioned above were excluded from the analysis. Patients were also excluded if they received multiorgan transplants.
With the use of a multivariate Cox model, we compared adjusted graft and patient survival outcomes in depleting versus nondepleting induction groups for the 3 HBV serologic status groups. Values are expressed as hazard ratio (HR) with 95% confidence intervals (CI). Confounding variables included in the analysis were donor related (age, sex, expanded criteria donor kidney, donations after cardiac death); recipient related (age, African American ethnicity, diabetes mellitus, dialysis duration, panel reactive antibody titer [with current including up to 2009 and “calculated” afterward], human leukocyte antigen mismatch, hepatitis C serostatus, lamivudine therapy); and transplant related (type of transplant, cold ischemia time, delayed graft function [defined as need for dialysis within first posttransplant week], previous transplant, acute rejection within first year, steroid maintenance, and transplant year). Values are expressed as either means ± standard deviation or as percentages. P < .05 was considered statistically significant. Statistical analysis was performed using SPSS software (SPSS: An IBM Company, version 18, IBM Corporation, Armonk, NY, USA).
Median follow-up of the whole study group was 50.7 months (range, 28.6-82.6 mo). Among the 7681 patients included in the study, 1098 were in the HBsAg+/anti-HBc- group (depleting = 652, nondepleting = 446), 446 were in the HBsAg+/anti-HBc+ group (depleting = 250, nondepleting = 216), and 6117 were in the HBsAg-/anti-HBc+ group (depleting = 3562, nondepleting = 2555). Demographic features of the different serologic status groups stratified by induction type are shown in Table 1. Compared with the nondepleting group, the depleting group had a higher number of African American and previous transplant recipients, longer pretransplant dialysis duration, higher panel reactive antibody, a higher number of kidney recipients with donations after cardiac death, and longer cold ischemia time. The nondepleting group had a higher number of living-donor kidney recipients and a higher proportion of patients discharged on steroid maintenance.
There were no significant differences in adjusted overall graft survival for depleting versus nondepleting induction for the 3 hepatitis B serologic status groups (Figure 1). Similarly, adjusted death-censored graft survival and patient survival results were not significantly different between depleting and nondepleting groups (Table 2).
Our analyses did not show adverse graft and patient survival outcomes associated with depleting compared with nondepleting antibody induction in KTRs at various serologic phases of HBV infection at the time of transplant and who were discharged on a calcineurin inhibitor/mycophenolate mofetil-based maintenance regimen with or without steroids. This supports the selection and use of induction agents based on the immunologic risk of HBV-infected patients.
Hepatitis B surface antigen seropositivity was found to be an independent risk factor for inferior survival in patients who underwent kidney transplant before the development of the HBV vaccine in 1982 and before the availability of the antiviral agent lamivudine in 1996.4,5 In the recent era of new anti-HBV agents, kidney transplant outcomes were found to be similar for patients with and without HBV infection.6 However, the risk for progressive liver disease was significantly higher in HBV-infected KTRs. A recent study from our group found inferior death-censored graft survival in patients who underwent kidney transplant and who were in the early stages of HBV infection (HBsAg+/anti-HBc-) compared with patients who had already developed an immune response following HBV infection (HBsAg+/anti-HBc+) at the time of kidney transplant.7 These findings support a practice of delaying kidney transplant procedures in HBV-infected patients until after they have developed an immune response. Despite the availability of effective therapies against HBV infection, only a small proportion of HBV-infected KTRs appeared to be on lamivudine posttransplant. However, it should be noted that data on lamivudine use were missing in 50% to 64% of patients, reflecting underreporting in the transplant database. Moreover, the database used for our study does not have information regarding other newer anti-HBV agents such as tenofovir, entecavir, and adefovir.
The retrospective design of our study is a limitation. Data on HBV DNA assays and liver histology were not available, which may impact outcomes. Doses of induction and maintenance immunosuppressive agents were also not available. Despite the use of an adjusted model, residual confounding may still exist. However, the relatively large number of patients from different centers nationally adds to the validity of our findings.
In summary, our study showed no higher adverse effects of depleting versus nondepleting antibody induction on outcomes in KTRs at different serologic phases of HBV infection at the time of transplant. This supports the selection and use of induction agents based on immunologic risk in such patients. However, it is preferable to delay kidney transplant procedures in HBV-infected patients until after they develop an immune response following the infection.
DOI : 10.6002/ect.2017.0286
From the Division of Nephrology and Hypertension, Department of Medicine,
Allegheny General Hospital, Allegheny Health Network, Pittsburgh, Pennsylvania,
Acknowledgements: The authors have no sources of funding for this study and have no conflicts of interest to declare. This work was presented in part as a poster at the American Society of Nephrology Kidney Week, November 2015 (San Diego, CA, USA).
Corresponding author: Kalathil K. Sureshkumar, Division of Nephrology and Hypertension, Allegheny General Hospital, 320 East North Avenue, Pittsburgh, PA 15212, USA
Phone: +1 412 359 3319
Table 1. Demographic Features of the Study Population
Table 2. Graft and Patient Outcomes for Depleting Versus Nondepleting Groups
Figure 1. Adjusted Overall Graft Survival