Hepatitis B Virus and Renal Transplantation

Liver disease is a frequent complication [1, 2, 3, 4, 5, 6, 7, 8]and an important cause of morbidity and mortality in renal transplant (RT) recipients. The most important agents of liver disease in RT recipients are hepatitis B virus (HBV) and hepatitis C virus (HCV); TTV and GBV-C/HGV infections are frequent in this population, but their role in the pathogenesis of liver damage is controversial. Numerous papers reported on the impact of HBV on the morbidity and mortality of RT recipients; the influence of HBV on patient and graft survival remains controversial. The aim of this report is to review the epidemiology and the clinical manifestations related to the presence of HBV in RT recipients. In addition, current recommendations about RT in HBV-infected patients will be mentioned.RT recipients may acquire HBV over the posttransplant period as a ‘community-acquired’ infection or as a result of latent virus reactivation in the recipient with the onset of immunosuppressive therapy. Alternatively, HBsAg may be acquired while on dialysis or from organ donors.Various rates of HBsAg infection have been found in RT recipients [4, 6, 7, 9, 10, 11](table 1). The prevalence of HBsAg positivity in RT recipients over time is decreasing; Mathurin et al. [9]found a significant decrease of HBsAg-positive RT recipients in their series: 24.2% before 1982 versus 9.1% after 1982 (p = 0.001).The frequency of HBsAg acquisition following RT varies considerably among centers. Huang et al. [12]found that only 6.1% of the patients acquired HBsAg during or after RT, while Parfrey et al. [13]noted that the majority (13/22 = 59%) of their patients acquired HBsAg within 6 months after RT. Bang et al. [11]in Seoul observed that 16.4% (13/79) of their HBV-infected RT recipients acquired HBsAg following renal transplantation.It appears that the most important factor influencing the HBsAg positivity in RT recipients is the HBsAg positivity before renal transplantation rather than a transmission via infected kidneys.The possibility of transmission of HBV from HBsAg-positive kidney donors to seronegative recipients is well documented. Wolf et al. [14]identified three seronegative recipients that developed serological evidence of HBV (HBsAg or anti-HBs positive) after receiving a kidney transplant from HBsAg-positive donors. No clinical hepatitis developed in any of the recipients. Subtype analysis was performed for only one donor-recipient pair and gave identical results.Lutwick et al. [15]reported a case of a HBV infection acquired directly from the cadaveric kidney of a previously unrecognized hepatitis B carrier. The recipient had no symptoms of acute hepatitis after HBsAg acquisition, but showed raised aminotransferase activity some months after transplantation. The other kidney from the same donor caused only antibody conversion (anti-HBs and anti-HBc positive) in the recipient; differences in the pretransplantation handling of the kidneys likely determined the type of HBV infection occurring in the 2 seronegative graft recipients. It was not clear whether the vehicle for transmission was the kidney itself or residual blood in the kidney.Chan and Chang [16]observed opposite results; they found that none of 5 HBsAg-negative patients became HBsAg positive or developed clinically significant hepatitis after receiving kidneys from HBsAg-positive donors. However, only 1 of the 5 patients was HBV seronegative prior to transplantation, the others had isolated anti-HBc or anti-HBs positivity.It has been recently observed [17]that HBsAg-negative individuals with hepatitis B virus surface antibody (HBsAb) who are years beyond clinical HBV disease may still have circulating virus DNA (plasma and peripheral mononuclear cells) and continually stimulated polyclonal T cell responses to HBV antigens.The effect of RT on HBV activity has been described by Dusheiko et al. [18]and Nagington et al. [19]. These authors observed in RT recipients after transplantation an increased replication with reappearance or increase in serum HBV DNA levels and HBeAg as well as reappearance of serum HBsAg following apparent clearance of previous HBV infection. The reactivation of HBV infection in a RT recipient who was HBsAg negative but HBsAb and HBcAb positive has been noted by Grotz et al. [20]in the late 1990s. The recipient became HBsAg and HBV DNA positive after transplantation, and a life-threatening liver failure occurred, with a rapid rise in alanine aminotransferase activity and a decrease of the prothrombin time to 25% of normal values. Marcellin et al. [21]reported a patient with chronic renal failure who had had acute HBV infection 10 months prior to RT and then developed anti-HBs activity. He had chronic hepatitis B with detectable HBV DNA in serum after RT; the presence of HBV DNA sequences detected in the serum by polymerase chain reaction during the pretransplantation period suggested that no definitive resolution of the acute infection occurred.Degos et al. [22]demonstrated reactivation of HBV replication in 11 of 12 (92%) HBsAg-positive patients and an increase of viral replication when positive in the initial sample in 6 of 11 (54%) patients. In addition, they described a subset of patients (20%, 7/35) without HBsAg or HBV DNA in serum before RT, but with HBV DNA detected by dot blot hybridization in serum following RT, a finding which suggests that immunosuppression can amplify even minimal residual HBV replication. Twenty-seven patients were tested for HBV DNA in the liver, 12 of them with a normal liver and 15 with chronic hepatitis. HBV DNA was detected in 10 (67%) patients with chronic hepatitis, including 2 patients without any HBV marker, whereas it was detected in only 2 (17%) patients with a normal liver.Therapeutic immunosuppression may increase HBV replication by various mechanisms [23]: the activity of cytotoxic T lymphocytes is decreased, and the HBV genome contains a glucocorticoid-responsive element that serves as a signal for augmenting glucocorticoid-dependent activity of the HBV enhancer I [24]. The glucorticoids can cause production of HBsAg and HBeAg and expression of viral DNA and RNA by stimulating transcription of HBV [25, 26]. Azathioprine (AZA) seems to stimulate intracellular HBV synthesis [27]. Finally, ciclosporin A (Cs-A) may have also direct effects on HBV replication [28].Reactivation of HBV infection has been recognized in various clinical settings; it has been observed in HBsAg-positive patients receiving cytotoxic cancer therapy and has led to death from acute liver failure in some patients [29, 30]. Analogous to RT, orthotopic liver transplantation in many HBV-infected patients is associated with reinfection of the liver graft followed by rapidly progressive liver disease with lowered survival of both patient and graft [31]. Absence in serum of hepatitis B e antigen and/or HBV DNA in RT recipients may decrease the likelihood of hepatic decompensation, but does not preclude a poor outcome due to worsening of liver disease [32]. The advent of polymerase chain reaction testing has demonstrated that even a minute viral level before transplantation can be associated with HBV reinfection of the liver graft [31].Organ transplantation has become the therapy of choice for many patients with end-stage renal disease. While the number of cadaveric organ donors remains rather stable, the number of patients awaiting transplantation continues to increase, creating a relative shortage of donor organs. To meet this shortage, more organs are currently transplanted from living donors, older donors, hemodynamically unstable donors and non-heart-beating donors. Whether HBcAb-positive donors should also be considered for RT is still an unsolved problem.Numerous observations have suggested that HBV DNA can be present in the serum and/or liver of healthy individuals long after complete clinical and serologic recovery from acute hepatitis B infection [33, 34]. Rehermann et al. [17]have noted HBV DNA in plasma and circulating lymphocytes of patients up to 23 years after resolution of HBV infection. Liang et al. [35]have detected by polymerase chain reaction HBV DNA in 30% of the healthy blood donors with IgG responses to HBcAb and negative HBsAb and IgM HBcAb assays; 8% of the donors with IgG HBcAb and high-titer HBsAb were HBV DNA positive. The Scientific Committee of the American Red Cross has concluded that HBcAb is an independent indicator of infectivity for HBV [36].Few prospective and retrospective studies investigated the consequences of using kidneys from HBsAg-negative but hepatitis B core antibody positive donors (IgG antibodies). Prospective and retrospective investigations have been recently made for this purpose; it appears that the risk of transmission depends upon the organ transplanted. Wachs et al. [37]from San Francisco found 25 (0.08%) of 1,190 donors who were HBcAb positive and HBsAg negative; 1/42 (2.4%) kidney, 3/6 (50%) liver, and 0/7 (0%) heart HBsAg-negative transplant recipients of organs from these donors became HBsAg positive after transplantation, the difference in infection rate (liver versus kidney and heart) being significant (p = 0.005). Kadian et al. [38]in their series of HBcAb-positive organ donors observed that 4 (33%) of 12 liver recipients became HBsAg positive and that 3 had poor outcomes directly related to HBV infection. In contrast, 19 kidney and 12 heart recipients have all remained HBV negative after 12–33 months of follow-up. The difference in rate and severity is probably related to a higher viral load in the transplanted liver as compared with the kidneys from the same donors. Despite recent evidence that HBV is not purely hepatotropic, the amount of HBV DNA isolated from infected livers is much greater than that seen in other organs [39]. The transplanted liver is subject to the cumulative burden of allograft insults as well as HBV replication and injury.Satterthwaite et al. [40]studied 38 cadaveric kidney transplants from HBsAg-negative/HBcAb-positive donors. Twenty-seven of them were transplanted into HBcAb-negative and 11 into HBcAb-positive recipients. None of the first group became HBsAg positive, 3 became HBsAb positive, and 2 became HBcAb positive. Of the second group, none became newly HBsAg positive or HBsAb positive. No patient receiving a kidney from a HBsAg-negative/HBcAb-positive donor developed signs or symptoms of clinical hepatitis B.Madayag et al. [41]in Baltimore found that transplantation of renal allografts from HBcAb-positive/HBsAg-negative donors was not associated with clinically detectable HBV disease or antigenemia. However, among the HBcAb-positive kidney recipients, 27% (12/45) developed new HBcAb and/or HBsAb after transplant; in contrast, only 4% (2/45) of the control patients developed new antibody responses (relative risk: 4.94; confidence interval: 1.07–22.83).Van Thiel et al. [42]have measured the putative risk for HBV infection associated with the use of organs obtained from a hepatitis B core antibody positive donor in liver transplant recipients. A total of 8.2% of individuals undergoing liver biopsy for clinical reasons had detectable HBV DNA in liver tissue; the risk of transmission of HBV infection with the use of such organs should be a figure around this number. No data exist about this issue concerning RT recipients.Very few data exist on HDV epidemiology in RT recipients with HBV. In Taiwan, Huang et al. [12]found a prevalence of HDV superinfection of 9.1% in their HBsAg-positive renal allograft recipients as compared with a prevalence of HDV superinfection of 1% in patients with chronic type B hepatitis, but without renal transplant. In France Pol et al. [6]found that none of 77 HBsAg-positive patients who underwent a kidney transplantation over a 10-year period had any marker of HDV infection. Harnett et al. [43]observed absence of anti-D antibody in 36 serum samples from HBsAg-positive renal allograft recipients. Grekas et al. [44]from Greece observed a frequency of HDAg and anti-D (IgG) of 7% (1/13) in their HBV-negative RT recipients; none of 8 HBsAg-positive RT recipients was positive for HDV.It is generally estimated that the greater the elevation in liver enzymes, the higher is the probability of histological evidence of the liver disease. Nonetheless, the relationship between serum aminotransferase activity and severity of liver disease is not very strong. The frequency of chronic liver disease, as defined by a raised serum aminotransferase activity, in large series of RT recipients is shown in table 2. A large number of RT recipients with HBV infection does not show biochemical signs of liver Huang et al. that of the patients with HBsAg positivity had chronic hepatitis, an increase of normal et al. that up to of their patients had minimal and HBsAg during the first 12 months following kidney transplantation, and all a retrospective Parfrey et al. of chronic increased aminotransferase activity than normal of and in their RT recipients and dialysis for the of biochemical in RT recipients very levels of HBV of the HBV viral or healthy with chronic renal failure on therapy or undergoing show aminotransferase activity in with the studies are in to whether this in RT recipients. In addition, is in the biochemical for the presence of liver et al. no relationship between serum aminotransferase activity, and serum and various histological in 77 RT recipients who showed clinical or biochemical evidence of liver of them being HBsAg positive. has been found also in the series of et al. Parfrey et al. HBV DNA in serum has been observed in liver and/or serum of RT recipients after the clearance of HBsAg from The possibility of alanine aminotransferase in this subset of patients has not been and that the of and in RT recipients with chronic liver disease may in the absence of or can the increase of aminotransferase activity seen in RT recipients with HBV. The of activity has also been described in other HBV-infected including orthotopic liver transplant recipients patients with acquired et al. found a of histological of liver disease in a large = of RT recipients who underwent liver they observed = chronic hepatitis = = 9, chronic hepatitis = and chronic hepatitis = of them were HBsAg B in RT recipients has an with liver only minimal to authors have demonstrated by analysis that the of hepatitis B after RT is authors liver in HBsAg-positive patients. a of in of the the of chronic hepatitis increased from 25 to and was a in the of chronic hepatitis 25 to and normal liver to et al. by that the to liver was more in HBsAg-positive than in HBsAg-negative patients who underwent RT; the difference not or or the after to was observed in HBsAg-positive RT recipients with liver in the of Parfrey et al. Of from hepatitis, virus or chronic hepatitis on initial biopsy to chronic hepatitis or on In many the of liver disease normal or serum aminotransferase et al. to evidence of progressive liver disease in 11 patients who were HBsAg positive the time of their first kidney had no clinical or evidence of in liver over a period of 8 no histological was role by viral replication in the outcome of liver disease in RT recipients has been with et al. that 5 (50%) of 10 patients with detectable HBV DNA and/or hepatitis B e antigen in serum prior to transplantation of chronic liver only 1 of 15 recipients who were HBV DNA and/or HBeAg negative prior to transplantation of liver disease (p = Harnett et al. that during the when the liver from or chronic hepatitis to chronic hepatitis, the HBV DNA increased by greater than in 4 of 5 RT recipients who had whereas this not in 4 patients with disease. et al. HBsAg the time of RT for a period of months after of the 12 patients the only 2 developed chronic 1 was HBeAg positive and the other was HBeAg negative; 11 (92%) of the 12 RT recipients were HBeAg positive the time of transplantation. These authors suggested that the presence of HBeAg the time of RT does not a poor following RT; but the absence of liver and the period in their definitive et al. that the frequency of hepatitis B was in patients and in chronic hepatitis had a in RT recipients as demonstrated by the histological in the the period was Huang et al. that the to chronic liver disease was in HBsAg-positive RT recipients by or The of chronic hepatitis was in the group and in the group The mortality due to liver disease was and in the and role by the of HBsAg acquisition in the of liver disease in RT recipients has been by et al. patients who were HBsAg positive before RT had a mortality of 7% as compared with in 5 patients who became HBsAg positive within 6 months after RT. et al. that 4 of patients who were HBeAg negative the time of transplantation acquired HBV hepatitis during the after RT. Of 2 of acute of the a patient had chronic These authors suggested that the poor patient observed by some be related to HBsAg acquisition after transplantation or liver has been reported that the of large of during the posttransplant period to a more of liver disease. A mortality in HBsAg-positive RT recipients was observed by Huang et al. the that of them developed chronic hepatitis after RT; this is in to the obtained by Harnett et al. Parfrey et al. reported a mortality from liver disease after years and a mortality related to liver disease after Huang et al. that of the patients acquired HBsAg before RT; only 6 and 4 were HBsAg positive prior to RT in the series reported by Parfrey et al. Harnett et al. the series of et al. transplantation, and of chronic hepatitis were associated with following RT. These authors observed histological to hepatic in patients with and chronic no was seen in patients with or chronic hepatitis. Parfrey et al. a to also in patients with virus only or chronic superinfection in HBsAg-positive RT recipients can in chronic liver disease. to hepatitis was observed in 3 of HBsAg-positive RT recipients in the series of Huang et al. all 3 patients developed chronic hepatitis, and 2 of them developed liver In a series of RT recipients, et al. 3 of hepatitis in HBsAg-positive in the liver biopsy of of the antigen was has been recently observed liver failure in 7% of the RT patients with infection and in of recipients with with and HBV over a 10-year et al. suggested that seems to be a factor for histological as of their patients were by and HBV as compared with of the patients (p No data exist concerning the between RT recipients with by and HBV versus RT recipients with HBV infection of liver disease in RT recipients in with patients undergoing has been by Harnett et al. compared the outcome of HBsAg-positive dialysis patients with an group of RT HBV-infected recipients; of the dialysis patients became HBsAg negative as compared with none of the RT recipients hepatitis defined was more frequent in RT recipients than in versus = The mortality in the RT group was versus in the dialysis patients (p = differences in mortality between the from death due to liver versus = The for liver disease in RT recipients was to an of HBV viral in some the HBV DNA increased during the in which the disease from or chronic hepatitis to disease hepatitis or However, was a number of serum samples for RT recipients and dialysis patients were not during the same impact of HBsAg on patient survival in RT recipients has been have been to any increase in the mortality of HBsAg-positive RT recipients In et al. on HBsAg-positive and HBsAg-negative RT recipients with an period of 4 The survival rate was in HBsAg-positive versus (p 10 of the HBsAg-positive patients of liver 3 the mortality rates due to liver failure among RT recipients all over the et al. in one of the studies on HBsAg-positive and HBsAg-negative patients. These authors showed that patients who were HBsAg negative before RT had a survival versus in HBsAg-positive patients 10 years after RT (p Liver failure was the cause of death in HBsAg-positive RT recipients after the of the RT 30% versus in HBsAg-negative patients (p = Mathurin et al. that the 10-year patient survival was higher in patients than in and patients analysis showed in patients before 1982 of HBsAg was an independent factor associated with patient survival 10 years (p To the influence of Mathurin et al. a the patient survival was 10 years in infected by HBV than in 6 versus 4% (p = HBsAg became associated with patient survival 6 et al. demonstrated in a of patients with for 1 a patient survival rate higher in HBsAg-negative = than in HBsAg-positive = RT recipients = The mortality due to liver failure and/or was for HBsAg-positive versus for HBsAg-negative patients. In a group of patients followed for 1 no difference was found in the survival rate 10 years between HBsAg-positive and HBsAg-negative versus The mortality rate from liver failure and/or was 4 versus for HBsAg-positive and HBsAg-negative can the the number of the of the the for patient of immunosuppressive of patients between or in severity of liver disease can with suggested that HBsAg-positive RT recipients may have a graft et al. that the allograft of cadaveric kidney recipients, was increased among patients with liver disease cadaveric allograft survival as compared with for the recipients; = et al. a effect of HBsAg positivity on graft gave as no difference in graft survival between HBsAg-positive and individuals was found Pol et al. allograft survival in HBsAg-positive and HBsAg-negative RT versus In a very large and recent Mathurin et al. that the 10-year graft survival was higher in the group than in HBsAg-positive recipients showed that the 10-year graft survival was also in patients infected with HBsAg than in 36 5 versus (p therapy may be in patients without kidney disease chronic hepatitis of immunosuppressive therapy has been considered an important in the of liver disease in RT recipients. However, this may not to liver it has been reported of in RT recipients with chronic hepatitis can graft of even graft but others observed The activity of in these patients has been few data on with in RT recipients with chronic HBV are some HBsAg-positive RT recipients been with However, use in RT recipients is by of graft which is and therapy may also cause of graft by other mechanisms such as direct acute and of The role of in HBV in RT recipients is to of about to graft a of is a with activity HBV. Pol et al. a reported that a of HBV replication in of the infected RT recipients. The serum aminotransferase to normal levels in of who had become HBV DNA and were to in the renal was in some in However, of the a role of this in the of liver disease has not been is a in the and of infection. investigations in the of chronic hepatitis B among kidney transplant recipients, and a of HBV DNA levels after therapy was A therapy with a has been to HBsAg and HBV DNA in a RT patient with liver disease the most for use in RT recipients is the of a with activity HBV replication. It HBV by of the viral DNA during it is in chronic hepatitis B in normal patients in the of HBV after orthotopic liver transplantation It has also been in transplant recipients with acute HBV infection have been made in RT recipients was in HBV with clearance of HBV DNA from serum and in liver HBsAg effects were 1 patient acute and to therapy with of the of the In to has no effect and is However, the few data that when therapy is the HBV is In addition, is the possibility of to therapy in RT recipients as also shown in liver transplant recipients patients with the virus frequency of HBV is among RT recipients; it is not mechanisms of HBV acquisition are the most important factor influencing HBsAg positivity in RT recipients is probably the HBsAg positivity before RT. HBV is associated with liver in RT recipients, and in RT may the of liver disease, as immunosuppression can HBV replication. The influence of HBV on clinical graft outcome survival is a amount of data have shown a effect of HBV on patient and graft therapy appears the most HBV in RT recipients, but studies are to biopsy should be in the of the RT with HBsAg 1). should be on severity of liver as well as of HBV replication in serum HBeAg and/or HBV the absence in serum of HBV DNA or HBeAg before RT does not preclude reactivation of HBV infection after RT. with chronic hepatitis and or on liver biopsy are risk for hepatic after RT, and transplantation should be In patients with liver disease, RT should not be However, all patients infected with HBV be that even disease has the to the influence of The advent of the to of HBV. replication is should be before RT to of liver disease. patients with HBV should be on therapy after RT.