Azathioprine is a purine antimetabolite, introduced as an immunosuppressive agent in solid organ transplantation in 1961 (40). In kidney transplant recipients, this drug can induce dose-dependent liver injury (6,11,41,42). The pathogenesis of azathioprine hepatotoxicity, although incompletely understood, seems to involve direct injury to hepatic endothelial cells, hepatocytes and intralobular ducts (6,24,39,41,43). In cases with present HBV infection, the concurrent use of azathioprine and corticosteroids may favor HBV replication thus creating an additional insult to the liver (44, 45, 46).

The clinical presentation of azathioprine hepatotoxicity varies widely from isolated moderate to severe jaundice, sometimes with marked pruritus (6,23) to fully manifested portal hypertension with ascites, variceal hemorrhage, and severe edema. Biochemical abnormalities are consistent with cholestatic pattern of liver injury (i.e., direct hyperbilirubinemia with increased serum levels of alkaline phosphatase and gamma-glutamyltranspeptidase). These abnormalities, commonly improve or resolve with a decrease in azathioprine dose or with its discontinuation (42), but recur in about 50% of the patients if the drug is reinstituted (47).

The spectrum of azathioprine-related histological lesions on liver biopsy includes peliosis hepatis (28), perisinusoidal (Disse space) fibrosis (48), venoocclusive disease (38), nodular regenerative hyperplasia, hepatic sinusoidal dilatation (49) and intrahepatic cholestasis (24,39,41). Azathioprine-induced direct injury to the endothelial cells has been implicated in the pathogenesis of the characteristic vascular lesions observed in peliosis hepatis, nodular regenerative hyperplasia, and veno-occlusive disease (39).

Although azathioprine hepatotoxicity has not been uniformly recognized, there is evidence to demonstrate its occurrence in kidney transplant recipients. As an example, in one study azathioprine-treated patients tended to have higher serum AST levels than those who received cyclosporine (CsA) treatment (50). In another study, in a cohort of kidney transplant recipients without preexisting liver disease, azathioprine-treated patients had a higher incidence of posttransplantation chronic liver disease than those who received CsA-treatment (51). Further evidence in support of the role of azathioprine in the etiology of posttransplantation liver disease was provided recently by a group of French investigators (43). In their report, 21 (2%) out of 1,035 patients, who received a kidney transplant between 1969 and 1992, were diagnosed with azathioprine-induced hepatitis based on the following criteria: (a) presence of jaundice, which disappeared after azathioprine dose reduction or withdrawal; (b) absence of any other overt explanation of the liver disease (mainly severe cirrhosis, chronic alcoholism, other hepatotoxic drug or biliovesicular disease); (c) histopathological findings consistent with intrahepatic cholestasis, sometimes associated with centrilobular hepatocellular necrosis and vascular lesions, which were reversible on repeat liver biopsies performed in two patients, 2 and 4 months after withdrawal of azathioprine. All patients with azathioprine-induced hepatitis were also positive for viral markers of hepatotropic infection (HBsAg, HBV RNA, or anti-HCV antibodies). Consequently, the authors speculated that active hepatotropic viral infection (HBV and/or HCV) could predispose to or even induce azathioprine toxicity by causing liver disease, which in turn could slow down the catabolism of azathioprine toxic metabolites. Therefore, dose reduction or withdrawal of azathioprine during diagnostic evaluation and treatment of viral liver disease in patients whose immunosuppressive regimens included this medication should be considered (43). Vice versa, it has been speculated that azathioprine itself may play a role in the enhancement of HBV replication posttransplantation as some authors have observed higher HBV DNA levels (although not significantly) in kidney transplant recipients whose immunosuppressive regimen included azathioprine as compared to those who were treated only with cyclosporine A and low dose steroids (52).

The importance of azathioprine hepatotoxicity in the etiology of posttransplantation liver disease in kidney transplant recipients will most likely diminish in the future due to the rarity of this condition, the fall in the prevalence of HBV and HCV infection among patients receiving kidney replacement therapy, and the replacement of azathioprine by the newer immunosuppressive agent mycophenolate mofetil.

CsA was introduced in clinical transplantation in 1978. This drug has dramatically improved the long-term survival of transplanted organs. However, CsA has demonstrated a number of side effects, among which nephrotoxicity has been a major concern. CsA-related hepatotoxicity, although well-documented, appears to be a less important issue (53, 54, 55). The pathogenesis of CsA hepatotoxicity has not been completely unveiled. Some investigators suspect that the increase in total intracellular calcium concentration resulting from hepatocyte exposure to CsA is highly toxic to the hepatocyte function and could be responsible for the liver injury (56).

The incidence of CsA hepatotoxicity among kidney transplant recipients ranges from 4% to 63% (53,54,57, 58, 59). This wide variation among studies is mainly due to differences in the definition of liver disease, the degree of severity of liver injury, CsA dose, follow-up period, selection of study population and the presence of confounding factors, such as infection, hemolysis, graft versus host disease, congestive heart failure, drug interactions, etc., which could potentially cause liver injury on their own thus making it difficult to recognize the real contribution of CsA in the liver damage (53,54,60). The incidence of CsA-related hepatotoxic events seems to have decreased over the last few years presumably due to the use of a lower dose of CsA as a part of the newer immunosuppressive regimens (54,55).

CsA-induced liver disease commonly presents clinically as acute hepatic injury, mainly of cholestatic type and occurs early in the posttransplantation period, usually within the first 3 months (61). There is a possible association of CsA with biliary tract disease (i.e., formation of gallstones and biliary sludge) (61). The most common biochemical abnormality is conjugated hyperbilirubinemia alone, or in association with minimal elevation in liver enzymes. The increase in serum bilirubin appears to be dose-dependent and reversible after dose reduction or discontinuation of the drug (53).

Other investigators have failed to associate CsA therapy in kidney transplant recipients with elevations in serum bilirubin and AST levels (50). In another study, among kidney transplant recipients without preexisting liver disease, CsA-treated
patients had a lower incidence of posttransplantation chronic liver disease than azathioprine-treated patients (51). Furthermore, it has been reported that kidney transplant recipients with preexisting chronic liver disease who were treated with CsA did not present any clinical evidence of progression to severe chronic liver disease, demonstrated complete normalization of the biochemical abnormalities with persistent clinical remission, showed a slightly higher probability of remaining stable as compared to azathioprine-treated patients (51), and had liver morphology, which remained unchanged over follow-up period of 1 year (62). These data provide evidence against true hepatotoxic properties of CsA and add confidence that the drug can be safely used in patients with chronic liver disease. Long-term CsA therapy seems unlikely to produce chronic hepatotoxicity. Furthermore, CsA might be considered the drug of choice in patients with chronic liver disease undergoing kidney transplantation (51).

Hepatitis B virus is a small, enveloped DNA virus, which is a member of the hepadnavirus family (hepatotropic DNA viruses). The viron consists of a surface that incorporates the envelope protein, referred to as hepatitis B surface antigen (HBsAg) and core, which contains a DNA polymerase, double-stranded DNA, core antigen (HBcAg) and a protein subunit of the core, known as “e” antigen (HBeAg). HBsAg may have one of several subtype-specific antigens, which can be used as epidemiological markers in tracing the routes of HBV transmission.

The serologic markers used to detect infections with HBV include HBsAg, anti-hepatitis B surface antigen antibody (HBsAb), antibody to HBcAg (anti-HBc), HBeAg and antibody to HBeAg (anti-HBe). Assays for HBV serologic testing are commercially available and largely used in practice.

The presence of HBsAg indicates current HBV infection and implies potential infectivity. The production of HBsAb is a manifestation of immunologic response to HBsAg and therefore is a marker of prior infection with HBV or immune response to hepatitis B vaccine. Anti-HBc of IgM class discloses current or recent infection with HBV, while anti-HBc of IgG class is a marker of past infection with HBV at undetermined time. HBeAg unveils HBV replication, and therefore, a high degree of infectivity. In contrast, anti-HBe in the serum of HBsAg carrier coupled with the absence of HBeAg and HBV DNA implies lower titer of HBV and lower degree of infectivity.

Hepatitis B is a ubiquitous blood borne infection that has worldwide distribution. The virus is mainly transmitted by parenterally exposure or sexual contact (63,64). Vertical transmission, i. e., transmission from chronically infected mothers to their infants occurs and usually plays a major role in geographic areas where HBV infection is endemic (65). Horizontal transmission among household contacts of HBV carriers is possible, but rare (66,67). Several studies have demonstrated that HBV can be transmitted by organ transplantation (68). Transmission by casual contact or food has never been documented.

The incidence and prevalence of HBV infection (HBs-antigenemia) among dialysis patients in the United States in the year 2000 were 0.05% and 0.9%, respectively, and had shown a constant decrease over the years as a result of the implementation of dialysis unit precautions and hepatitis B vaccination of susceptible dialysis patients (69). The prevalence of HBs antigenemia among kidney transplant recipients reported in different studies varies widely from 1.8% to 21.3%, mostly due to differences in geographic areas, study populations, and transplant policies (70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83). The overwhelming majority of these infections are acquired prior to transplantation; only a very small portion develops due to HBV transmission by an infected graft or de novo infection in the posttransplantation period. Consequently, the prevalence of chronic HBV infection among kidney transplant recipients closely reflects the prevalence of HBV infection in the dialysis population and over the years has demonstrated similar decline associated with the routine HBV vaccination of dialysis patients. As an example, in one study the prevalence of HBsAg among kidney transplant recipients decreased significantly from 24.2% before 1982 to 9.1% after 1982, when routine HBV vaccination of dialysis patients was implemented (81).

The clinical course of hepatitis B in kidney transplant recipients is usually insidious or even asymptomatic due to the state of iatrogenic immunosuppression. If present, clinical symptoms most commonly consist of vague complaints of general fatigue, malaise or anorexia. Jaundice is rarely present, recognizable acute hepatitis is almost never observed and the disease tends to be discovered in its chronic phase (84).

Laboratory tests are usually consistent with only mild elevations in the serum aminotransferase levels, sometimes in association with hyperbilirubinemia. Occasionally, serum aminotransferases may remain abnormal and demonstrate persistent fluctuations (21). The presence of abnormal LFTs for more than 6 months defines the liver disease as chronic. While liver laboratory test abnormalities usually present within the first 12 months of transplantation, clinically overt liver disease is not manifested until advance stages are established, late in the posttransplantation period (85).

Serologic testing of HBV-infected kidney transplant recipients commonly reveals persistent HBs-antigenemia indicating continuous viral replication, likely secondary to iatrogenic immunosuppression (20,86). Enhanced HBV replication has been associated both with increased prevalence
and accelerated progression of liver disease (71,87). Consequently, persistent HBs-antigenemia seems to carry poor prognosis (15,87,88). Because HBV DNA concentration directly reflects the degree of viral replication, serial determinations of HBV DNA levels might be useful as a noninvasive means of monitoring liver disease activity. Peaks in HBV DNA concentrations may correctly identify transition from a relatively quiescent liver disease to an active course and alert the clinician to the need of liver biopsy or adjustment of the immunosuppressive regimen (87). However, a marked decline in the serum HBV DNA concentration in those with previously diagnosed CAH may signify progression to cirrhosis probably reflecting loss of hepatic mass that harbors the virus (87).

The time of acquisition of HBV infection, as ascertained by the appearance of HBsAg, is associated with differences in the virus-host interactions and therefore can have prognostic importance (4,86,88). Kidney transplant recipients who become HBsAg-positive in the posttransplantation period when large doses of immunosuppressive drugs are commonly used have a higher mortality rate than those who acquire HBs-antigenemia prior to transplantation (4,88).

The clinical presentation and the biochemical data among HBsAg-positive kidney transplant recipients have shown poor correlation with liver morphology. Liver biopsy can demonstrate histology consistent with advanced disease in the absence of any LFT abnormalities and vise versa, it may lack any pathologic changes in patients with biochemical evidence of liver dysfunction (20,85). Consequently, LFTs appear to be a poor predictor of liver disease activity, and liver biopsy remains the only means for precise diagnosis and monitoring the degree of liver injury among HBsAg-positive kidney transplant recipients (21,85,87).

Occasionally, hepatitis B may take a fulminant course with massive hepatic necrosis on liver histology and fatal outcome (6,15,16,80,89,90). The pathogenesis of the fulminant liver failure in HBsAg-positive kidney transplant recipient, although not completely clarified, has been related to coinfection or superinfection with hepatitis D virus (HDV) (16) or rapid cessation of immunosuppressive therapy with subsequent restoration of cell-mediated immunity and massive destruction of HBV-infected hepatocytes (89).

HBsAg-positive kidney transplant recipients also have an increased incidence of hepatocellular carcinoma. This is probably related to the unique combination of rapid histological progression to liver cirrhosis, which is the most important risk factor for hepatocellular carcinoma (91) and increased hepatocarcinogenesis from persistent or enhanced HBV replication (79,92). Furthermore, transplantation itself carries an increased risk of malignancy (93). Although data are rather inconsistent, hepatocellular carcinoma in HBsAg-positive kidney transplant recipients has been reported with variable, but mostly, relatively high frequency (1% to 23%) with mean time period between transplantation and manifestation of the tumor ranging from 1 to 320 months (20,21,79,93,94).

Overall, it has been estimated that a patient who is HBsAg-positive on the day of kidney transplantation has a 30-fold higher relative risk of developing posttransplantation chronic hepatitis than a HBsAg-negative patient (19). However, because liver disease in HBsAg-positive kidney transplant recipients progresses slowly and becomes clinically overt late in the posttransplantation period, sufficiently long follow-up period is needed to allow for disease manifestation. Indeed, only studies with follow-up extending beyond 3 years have been able to demonstrate an increased incidence of liver disease, in general, and of more severe forms of liver disease, in particular (85).

The course of the liver disease in HBsAg-positive kidney transplant recipients can be affected by the type of the immunosuppressive regimen and the type of HBV infection—reactivation or de novo infection. The association between the type of the immunosuppressive regimen and the incidence and progression of liver disease has been the focus of a number of studies. The combination of azathioprine and prednisone has been associated with a high incidence of chronic liver disease among HBsAg-positive patients. This is due, at least in part, to the hepatotoxic effect of azathioprine and the enhanced viral replication induced by high-dose prednisone (20,95,96). The use of immunosuppressive regimen that includes antilymphocyte preparations in addition to azathioprine and prednisone in HBsAg-positive kidney transplant recipients has been associated with high frequency of progression to liver cirrhosis and high mortality from liver disease (21,97). In contrast, CsA-based tripletherapy regimen (CsA, azathioprine and prednisone) has been associated with a lower incidence of posttransplantation liver disease among HBsAg-positive kidney transplant recipients (97). This regimen appears to be less hepatotoxic and to have less enhancing effect on viral replication because the use of CsA allows the employment of lower doses of both azathioprine and prednisone. Furthermore, a regimen that includes only CsA and prednisone has been associated with the lowest (27%) incidence of chronic liver dysfunction among HBsAg-positive kidney transplant recipients (97) and might be the optimal immunosuppressive regimen for HBsAg-positive patients undergoing kidney transplantation. Likewise, mycophenolate mofetil might be another safe choice for immunosuppression in this population. Evidence from a recent pilot study suggests that this drug does not affect HBV replication in stable HBV-infected kidney transplant recipients with high-level viremia, who are on maintenance immunosuppressive therapy consisting of corticosteroids and/or cyclosporine in addition to mycophenolate mofetil (98).

In contrast, other investigators have failed to detect any correlation between the type of the immunosuppressive regimen and the occurrence of hepatitis among HBsAg-positive kidney transplant recipients (84,86). In these studies, there was no statistically significant difference in the risk of developing chronic hepatitis and cirrhosis among patients treated with azathioprine as compared to those who received CsA therapy.

Reactivation of HBV (manifested serologically with reappearance of HBeAg and/or HBV DNA in the serum) occurs
frequently in chronic HBsAg carriers in the posttransplantation period (15,71,78,79,84,87). Reactivation of HBV was also reported in a kidney transplant recipient who was positive for both HBsAb and anti-HBc prior to transplantation; a serology indicative of previous HBV infection. Eight years after transplantation, he became HBsAg- and HBeAg-positive and developed a diffuse, large B-cell lymphoma (99). This phenomenon is commonly attributed to the immunosuppressive drugs (azathioprine, CsA and prednisone), which by suppressing the immune system compromise the natural immunity to HBV thus enabling sustained and enhanced viral replication (86,100). Consequently, among kidney transplant recipients, the overwhelming majority of cases of chronic hepatitis B results from persistence and/or reactivation of viral replication in the posttransplantation period (15,71,78,79,84,89,101). Because HBsAb appears to confer protection against hepatitis B despite the state of iatrogenic immunosuppression, de novo HBV infection is relatively rare (15,84). However, de novo HBV infection in the posttransplantation period has a more aggressive clinical course and a worse prognosis (4,88).

A number of studies have associated HBs-antigenemia in kidney transplant recipients with more advanced histological forms of liver disease on initial liver biopsy, marked tendency to morphologic progression and increased risk of developing advanced stages of liver disease, in particular liver cirrhosis (20,21,79). For example, liver biopsies performed in kidney transplant recipients with clinical evidence of posttransplantation chronic liver disease have demonstrated that HBsAg-negative patients have predominantly benign histological lesions (fat metamorphosis and chronic portal triaditis), while HBsAg-positive patients commonly present with more severe histological forms of liver disease (CPH, CAH and cirrhosis). Furthermore, it has been reported that the incidence of liver cirrhosis on initial liver biopsy was 42% in HBsAg-positive recipients versus 19% in HBsAg-negative recipients, and the rate of histological deterioration was between 82% and 85% (20,21,79). This high rate of histological deterioration in HBsAg-positive kidney transplant recipients was attributed mainly to enhanced HBV replication, concomitant chronic HCV infection, and chronic alcohol consumption (79). In addition, there is evidence to suggests that development of liver cirrhosis and end-stage liver disease could be associated with persistence of HBV mutant populations characterized by deletions/insertions in core promoter plus deletions in the C gene and/or deletions in the pre-S region (102). Another severe form of liver damage, vanishing bile duct syndrome, has been reported in kidney transplant recipients coinfected with HBV and HCV. This syndrome, as reported earlier in this chapter, results from severe injury, and ultimately complete loss, of the small-size interlobular bile ducts. Its clinical course is notable for rapidly worsening cholestasis and fatal outcome.

The relentless progression of the posttransplantation liver disease in HBV-infected kidney transplant recipients has not been unanimously supported by currently published data. Indeed, some investigators have failed to detect any significant tendency to histolopathological deterioration on serial liver biopsies of HBsAg-positive kidney transplant recipients (103).

Lastly, an attempt has been made to correlate liver histological lesions in HBsAg-positive kidney transplant recipients to the type of immunosuppressive regimen. Data from one small study have suggested that HBsAg-positive kidney transplant recipients who are treated with CsA might have a lower risk of liver damage than those whose immunosuppressive regimen has included azathioprine and prednisone alone (104).

Role of donor/recipient serologic status. The risk of HBV transmission by organ transplantation can be predicted from the serologic status of both donor and recipient. Kidneys from HBsAg-positive donors are at a high risk of transmitting HBV infection to their recipients if these recipients are susceptible to HBV (i.e., HBsAg-negative/HBsAb-negative). Transmission of HBV is even more likely to occur with the use of organs from HBsAg-positive donors, who are concurrently positive for HBeAg, which is a marker of a highly infectious state (96,105). As an example, in a small study that included five HBV susceptible recipients of kidneys from three HBsAg-positive cadaver donors, two of whom were also HBeAg-positive, only HBsAg-negative/HBsAb-negative/anti-HBc-negative recipients of HBsAg-positive/HBeAg-positive donor kidneys became HBsAg-positive after transplantation acquiring an HBV subtype identical to that in the donor (106).

Technique for handling and preservation of harvested organs. The technique for handling and preservation of harvested kidneys may modify the risk of HBV transmission by kidney transplantation. Because the vector of transmission seems to be the residual donor blood retained in the harvested kidney, rather than the kidney tissue itself, the technique of continuous pulsatile perfusion in contrast to preservation on ice could potentially prevent HBV transmission by clearing some of the virus and thus reducing the infectious load below a certain level, which is probably needed to ensure viral transmission (107).

Because of the potential harmful effect of HBV infection on graft and patient survival following kidney transplantation, organ donors who are at risk of transmitting HBV to their recipients should be promptly identified. Such donors are generally excluded from the kidney donor pool, but their use may come into consideration in some particular circumstances, which will be reviewed below.

Kidney donors at low or no risk of transmitting HBV infection to their recipients. A donor with a serologic profile negative for HBsAg and anti-HBc should be considered at low to negligible or no risk of transmitting HBV to the recipients of his/her organs. Routine testing for HBsAb is consider unnecessary as the donor HBsAb-status alone would not modify the risk of HBV transmission from donor to recipient.

Use of kidneys from HBsAg-positive donors. The majority of organ procurement organizations ban the use of kidneys from HBsAg-positive donors. However, this moratorium has been challenged under certain circumstances.

In geographic areas endemic for HBV infection, such as South East Asia and some countries in the Middle East, HBsAg carrier rates are so high (for example, 10% in Hong Kong (108), 12% to 20% in Taiwan (109), 8.8% in Saudi Arabia (110)) that exclusion of HBsAg-positive donors from the donor pool would reduce significantly the supply of kidney allografts. Furthermore, it would be particularly difficult to reject HBsAg-positive donors if they are HLA-matched living relatives (84,109,111,112). At the same time, in these areas, there is a correspondingly high prevalence of naturally acquired immunity to HBV among the adult population (including kidney transplant candidates), for example, 40% to 50% in Saudi Arabia (110), which makes it relatively easy to find patients immune to HBV. Few small studies have demonstrated that HBsAg-negative patients with preexisting naturally acquired or vaccination-induced immunity to HBV can receive kidney allografts from HBsAg-positive donors with no or only minimal risk of acquiring HBV infection from the donor (84,110,113). Consequently, some transplant centers have adopted a policy of allocating kidneys from HBsAg-positive donors into recipients who are immune to HBV.

Because current data indicate that the risk of HBV transmission is specifically associated with the use of organs from donors who are concurrently HBsAg- and HBeAg-positive (106,107), kidneys from HBsAg-positive donors, who are HBeAg-negative could probably be used safely under certain circumstances. Indeed, there is evidence to prove that a policy of transplanting kidneys from HBsAg-positive, HBeAg-negative donors in HBsAg-negative recipients who are immune to HBV is reasonable and safe (84,111,112). In such cases, hyperimmune gammaglobulin was administered to all patients at the time of transplantation (sometimes simultaneously with a booster dose of recombinant hepatitis B vaccine) and again 3 months later (84,111,112).

Noteworthy, HBeAg-negative status does not always rule out viral replication and high degree of infectivity. Viral replication and high levels of HBV DNA can occur in the absence of HBe antigenemia if the infection is caused by a precore mutant of hepatitis B virus because these mutants are unable to secrete HBeAg (114).

Use of kidneys from HBsAg-positive donors in HBsAg-positive recipients. Another way to eliminate the waste of kidneys from HBsAg-positive donors is allocating these kidneys to HBsAg-positive recipients. This practice has received a special consideration, again, in geographic areas endemic for HBV and has been adopted by some transplant centers. As an example, in one study from Taiwan, there was no statistically significant difference between HBsAg-positive recipients of kidneys from HBsAg-positive donors and HBsAg-positive recipients of kidneys from HBsAg-negative donors with respect to the number of episodes of hepatitis (109). Among recipients from living-related donors, the HBsAg status of the donor had no impact on 1- and 5-year patient survival. In contrast, among recipients from cadaveric donors, recipients of kidneys from HBsAg-negative donors had significantly higher 1- and 5-year patient survival rates than recipients of kidneys from HBsAg-positive donors.

Use of kidneys from HBsAg-negative, anti-HBc-positive donors. There is a concern about the risk of HBV transmission by organs procured from donors who have a serologic profile exhibiting evidence of past HBV infection, i.e., HBsAg-negative, anti-HBc-positive, HBsAb-positive or negative (115, 116, 117). However, a single anti-HBc positive result should be interpreted with caution and confirmed by repeat testing as some of the anti-HBc immunoassays have demonstrated poor specificity and generate a very high percentage of false-positive results (116).

Use of kidneys from HBsAg-negative, anti-HBc-positive, HBsAb-positive donors. Donors with serologic profiles negative for HBsAg but positive for anti-HBc and HBsAb can transmit HBV to liver transplant recipients (118). However, such donors have failed to transmit HBV to kidney transplant recipients as demonstrated by absence of HBV DNA and HBsAg in the serum and lack of liver enzyme abnormalities in the posttransplantation period. Hence, it appears that HBsAg-negative/anti-HBc-positive/HBsAb-positive donor kidneys can be safely used for transplantation (118).

Use of kidneys from donors with isolated presence of anti-HBc (i.e., HBsAg-negative, anti-HBc-positive, HBsAb-negative). The risk of HBV transmission by using kidneys from donors with serologic profiles notable for isolated presence of anti-HBc (i.e., HBsAg-negative, anti-HBc-positive, HBsAb-negative) has not been exactly defined, but appears to be organ-specific. As an example, in one retrospective study the rate of HBV transmission with use of organs from HBsAg-negative, anti-HBc-positive, IgM anti-HBc-negative donors was high (50%) among liver recipients (three of the six liver transplant recipients became HBsAg-positive), but very low (2.4%) among kidney recipients (only one of 42 kidney transplant recipients converted to HBsAg-positive status), and zero among heart recipients (none of the seven heart transplant recipients acquired HBsAg after transplantation) (119). Another retrospective study also reported that kidneys from HBsAg-negative, anti-HBc-positive donors did not transmit HBV to their recipients who were HBsAg-negative, HBsAb-negative, anti-HBc-negative or positive (120). Likewise, in a small study, kidneys from donors with isolated presence of IgG anti-HBc did not transmit HBV infection to any of three recipients with negative HBV serologies (121). Consequently, it appears that the use of kidneys from
HBsAg-negative, anti-HBc-positive (IgM anti-HBc-negative) donors are associated with a very low or no risk of HBV transmission. However, in order to be overly cautious, some authors advise to use kidneys from such donors preferably for transplantation into recipients whose serologic status discloses immunity to HBV from prior HBV infection or HBV vaccination (119,122). In support, a recent study reported no cases of HVB transmission with the use of kidneys from anti-HBc-positive donors in recipients who tested positive for HBsAb at the time of transplantation (123). While this practice appears particularly safe, it has been emphasized that antibody titers are subjected to time-dependent decay and consequently some renal transplant candidates may lack HBsAb and anti-HBc in immediate pretransplantation sera despite a prior exposure to HBV. Therefore, some investigators have suggested a policy of performing annual quantitative HBsAb determinations in vaccinated patients on the transplant waiting list and accepting anti-HBc-positive kidneys only for those patients whose annual HBsAb titers exceed 10 IU/mL (122).