Incidence of Post-transplant Hepatitis B Virus Reactivation With the use of Kidneys From Donors With Resolved Hepatitis B Virus Infection

Ren Yamada; Kenichi Morikawa; Kiyohiko Hotta; Daiki Iwami; Tatsu Tanabe; Sachiyo Murai; Nobuo Shinohara; Sonoe Yoshida; Shunichi Hosoda; Akinori Kubo; Yoshimasa Tokuchi; Takashi Kitagataya; Megumi Kimura; Koji Yamamoto; Masato Nakai; Takuya Sho; Goki Suda; Mitsuteru Natsuizaka; Koji Ogawa; Naoya Sakamoto

Disclosures

J Viral Hepat. 2022;29(11):976-985. 

In This Article

Abstract and Introduction

Abstract

Donors with resolved hepatitis B virus (HBV) infection may be a solution for the organ shortage for kidney transplantation (KT). The purpose of this study was to clarify the current state of HBV markers after KT from donors with resolved HBV infection to HBV naïve recipients and the rate of HBV reactivation in recipients with resolved HBV infection. Furthermore, we investigated HBV covalently closed circular DNA (cccDNA) in transplanted organs from donors with resolved HBV infection and the capability of HBV replication in kidney cell lines. We retrospectively analysed the HBV status of 340 consecutive donors and recipients who underwent KT in a single centre. We prospectively measured cccDNA by real-time polymerase chain reaction in kidney biopsy specimens of 32 donors with resolved HBV infection. HBV reactivation was found in three recipients with resolved HBV infection (4.8%, 3/63) after KT. We analysed 45 cases of transplantation from donors with resolved HBV infection to HBV-naive recipients. One case (2.2%, 1/45) became seropositive for hepatitis B core antibody (anti-HBc) and in another case (2.2%, 1/45), HBV-DNA was detected qualitatively in an HBV naive recipient with a donor with resolved HBV infection. In the latter case, cccDNA was measured in the donor kidney during KT. HBV replication was observed in kidney cell lines with HBV plasmid transfection. In conclusion, the risk of reactivation in anti-HBc-positive donors is relatively low. However, post-transplant HBV monitoring should be conducted in all at-risk cases.

Introduction

Hepatitis B virus (HBV) is an incomplete double-stranded DNA virus. The HBV first enters the hepatocyte from the surface and then becomes internalized into the cytoplasm via an HBV-specific receptor. Following entry into the hepatocytes, the HBV nucleocapsid, containing the relaxed circular DNA, is released from the core particle and becomes converted into covalently closed circular (cccDNA) within the nucleus by using host DNA repair enzymes. This cccDNA is known as the key molecule of persistent HBV infection.[1]

Hepatitis B virus infection is a global health issue even with the existence of an HBV vaccine. The number of HBV carriers is estimated to be over 240 million people worldwide.[2] HBV establishes a persistent infection by evading the host immune system and is a major cause of chronic hepatitis, liver cirrhosis and hepatocellular carcinoma.[3] In Japan, HBV carriers account for about 1% of the population. The number of patients with resolved HBV infection [hepatitis B surface antigen (HBsAg) negative, hepatitis B core antibody (anti-HBc)-positive, and/or hepatitis B surface antibody (anti-HBs)-positive] is estimated to be about 20%–30% of the population.[4,5] Universal HBV vaccination programs initiated worldwide in the 1990s have reduced the incidence of HBV infection and the prevalence of chronic carriers.[6–12] In recent years, it has become clear that the number of infected patients other than those infected from mother to child is higher than expected, and that even transiently infected patients or those with resolved HBV infection can develop severe hepatitis due to reactivation of latently infected HBV under immunosuppressive conditions. The accumulation of these findings led to the start of universal HBV vaccination for infants under 1 year of age in Japan from October 2016.[13] Although most patients with resolved HBV infection are positive for both anti-HBc and anti-HBs, some are positive for either anti-HBc or anti-HBs alone.[14–17]

Kidney transplantation (KT) is the definitive treatment option for end-stage renal disease with the number of patients listed for KT increasing every year.[18] However, the issue of organ shortage persists and is relatively grim. As the number of transplants performed increases, the safety of donor organs needs to be ensured. Donors for KT with resolved HBV infection may be a solution. The 2017 Kidney Disease: Improving Global Outcome (KDIGO) Clinical Practice Guideline on the Evaluation and Care of Living Kidney Donors states that: (1) transplantation from HBsAg-positive donors to HBV naive recipients is contraindicated because of the risk of HBV transmission via blood; (2) kidney transplant recipients from anti-HBc-positive/HBsAg negative/HBV-DNA negative donors appear to have little risk of acquiring active HBV infection; (3) the recipient should be informed of the small potential risk of disease transmission and post-transplant monitoring should be performed.[19] KT recipients generally receive a combination of multiple immunosuppressive drugs, such as steroids, antimetabolites and calcineurin inhibitors, during their maintenance phase after KT. Case reports have been published describing hepatitis caused by HBV reactivation in patients with resolved HBV infection who received chemotherapy or immunosuppressive therapy.[4,15,20–23] Prevention of HBV reactivation secondary to chemotherapy or immunosuppressants is an important issue as it can lead to fulminant hepatitis. Rates of HBV reactivation in recipients with resolved HBV infection after KT are approximately 2.9%–6.5%.[24–26]

Mahboobi et al. performed a meta-analysis of the HBV seroconversion rate after KT from anti-HBc-positive donors. Among the 9 studies between 1995 and 2006 comprising 1385 eligible kidney recipients, the total rate of seroconversion based on HBV markers after KT was 3.24% (45 total: HBsAg (n = 4), anti-HBc (n = 32), anti-HBs (n = 5), and either anti-HBc or anti-HBs (n = 4)/1385).[27] However, these reports do not sufficiently test both the donor and recipient at the HBV-DNA level, which is considered to be the most sensitive level for HBV detection. He et al. investigated the impact and significance of HBV-DNA in the pathogenesis of HBV-associated nephropathy.[28] Renal tissue from 43 children with HBV-associated glomerulonephritis was examined for HBV-DNA via in situ hybridization assay. HBV-DNA was identified in 41 of the 43 cases (95.3%) and was distributed generally within the nucleus and cytoplasm of the epithelial and mesangial cells of the glomeruli and within the epithelial cells of the renal tubules. Chen et al. reported that two of five active HBV-infected patients with HBV-related nephropathy were positive for HBV cccDNA in kidney tissue by nested PCR.[29] In patients with resolved HBV infection, cccDNA remains within liver tissues for a long period of time without complete clearance;[30] however, whether latent or persistent HBV exists within the kidney is not well known. Therefore, donor organs with resolved HBV infection may or may not maintain the possibility for HBV transmission.

Assuming that HBV latently or persistently exists as cccDNA within the kidneys of patients with resolved HBV infection, HBV could potentially be transmitted via KT if the donor was previously infected with HBV. The purpose of this study was to clarify the current state of the HBV markers after KT from donors with resolved HBV infection to HBV naive recipients and the rate of HBV reactivation in recipients with resolved HBV infection. Moreover, we investigated the possibility of HBV transmission via transplanted kidneys of donors with resolved HBV infection by measuring cccDNA in kidney biopsy specimens and the capability of HBV replication in kidney cell lines in vitro.

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