Kidney transplantation from hepatitis B surface antigen-positive donors into hepatitis B surface antigen-positive recipients: preliminary findings

INTRODUCTION: The success of renal transplantation as a treatment for end-stage renal disease has created a chronic shortage of donor organs. We present our initial experience in transplanting kidneys from hepatitis B surface antigen (HbsAg)-positive donors into HbsAg-positive recipients. MATERIAL AND METHODS: From January 2002 to March 2004, 5 patients with end-stage renal disease, hepatitis B virus (HBV) infection, and HbsAg seropositivity underwent a kidney transplantation from a cadaveric HbsAg-positive donor. The median time on the waiting list was 8 months, compared with the median of 3 years on the national waiting list. RESULTS: One patient experienced an acute rejection; 1 patient had an increase in serum level of aspartate aminotransferase (AST)/alanine aminotransferase (ALT) with no signs of recurrence of hepatitis. Graft and patient survival at a median follow-up of 12 months was 100%. CONCLUSIONS: Although the number of patients is small and the follow-up is short, our results suggest that HbsAg-positive donors can be considered as an alternative donor source because their kidneys are allocated to the matched serology-positive recipients, shortening their time on the waiting list.     

Five-year follow-up of a hepatitis B virus-positive recipient of hepatitis B surface antigen-positive living donor liver graft.

The shortage of cadaveric donor organs has led to the use of living donors and marginal cadaveric donors. To date, there have been only 2 reports on the use of hepatitis B surface antigen (HBsAg)-positive liver grafts. Here we describe the 5-yr posttransplantation sequence of a hepatitis B virus (HBV)-positive recipient who received an HBsAg-positive living donor liver graft. A 43-yr-old HBV-positive patient with hepatorenal syndrome received a living donor liver graft in October 2000 from a 27-yr-old HBsAg-positive carrier with no clinical evidence of HBV infection other than the serologic markers. The recipient recovered slowly after liver transplantation (LT). Recipient serum HBsAg was continuously positive despite anti-HBV therapy with high-dose hepatitis B immunoglobulin (HBIG) and lamivudine. The patient was also treated with famciclovir and interferon; to date, a final regimen of lamivudine and adefovir has kept liver function stable for 20 months. The recipient has lived for 64 months after transplantation. The donor has not revealed any clinical evidence of active hepatitis during follow-up. In conclusion, our result implicates that a recipient of liver graft from an HBsAg-positive carrier may survive for a long period following antiviral therapy with lamivudine and adefovir. Considering this living donor case and previously reported cases, the use of an HBsAg-positive cadaveric liver graft may deserve attention when no other donor is available.     

Cadaveric renal transplantation in hepatitis B antigen-positive recipients using hepatitis B antigen-positive donor organs with lamivudine treatment

Although renal transplantation has been regarded as the best renal replacement therapy in end-stage renal disease patients, there have never been enough organ donors. Therefore, hepatitis B surface antigen (HBsAg)-negative patients are often given priority over HBsAg-positive patients. We performed cadaveric renal transplantation in six HBsAg-positive recipients given HBsAg-positive donor organs who were on lamivudine treatment. Donors were found to have normal renal function by serum and urine laboratory tests. All recipients underwent liver biopsies before transplantation; those with liver cirrhosis were excluded. All recipients were treated with 100 mg lamivudine once daily because of positive titers of hepatitis B viral (HBV) DNA (three patients), and increased levels of alanine aminotransferase (ALT) (three patients). During the follow-up period, one patient died from hepatic failure at 50 months after transplantation without deterioration of graft function. The remaining five patients showed sustained normal ALT levels. Decreases in HBV DNA titer were observed among patients who were positive before transplantation, but did not reverse to negative. Acute rejection developed in two patients: one was treated successfully with steroid pulse therapy, and the other had two bouts of acute rejection within a 33-month interval. The first was successfully treated with steroid pulse therapy, but the second failed. The four remaining patients have maintained normal renal function for a considerable time. HBsAg-positive donor organs must be used carefully in renal transplantation of HBsAg-positive recipients.     

Fulminant hepatitis in renal transplant recipients. The role of the delta agent

In a series of about 300 renal transplant patients followed from 1972 to 1983, 3 cases of fulminant hepatitis were observed in HBs Ag-positive patients. In the liver biopsies of 2/3 of them, the delta antigen was detected by direct immunofluorescence with a specific anti-delta serum. This result demonstrates the responsibility of the delta agent for the development of fulminant hepatitis, and emphasizes the possibility of delta infection in HBs Ag-positive transplant patients with severe hepatitis.     

Role of lamivudine in the posttransplant prophylaxis of chronic hepatitis B virus and hepatitis delta virus coinfection

BACKGROUND: Posttransplant combined lamivudine (LAM) and immunoglobulin (HBIg) prophylaxis is the gold standard in the case of single hepatitis B virus (HBV), but is still not recommended in the case of patients coinfected with hepatitis delta virus (HDV). METHODS: We compared two consecutive groups of chronic HDV carriers who survived >6 months after liver transplantation of the risk of recurrence, survival and HBIg requirements: 21 received passive prophylaxis (HBIg group) and 25 were treated with combined prophylaxis (LAM+HBIg group). The immunoprophylaxis schedule was the same in both groups: intramuscular HBIg targeted to maintain anti-HBs levels of >500 IU/L during the first 6 posttransplant months and >200 IU/L thereafter. RESULTS: The mean length of follow-up in the two groups was significantly different (133 vs. 40 months; P<0.001). None of the patients in either group developed recurrent hepatitis, and the 3-year actuarial survival rate was 100% in both groups. During the first 6 months, HBIg requirement was 38% lower in the LAM+HBIg group although similar anti-HBs target levels were maintained, leading to significantly lower costs (5,000 Euros in the first year and 500 Euros in the second). CONCLUSIONS: This is the first study of large and homogeneous cohort of long-term HDV coinfected liver transplant survivors showing the absence of HBV recurrence under combined prophylaxis. Although retrospective, our results suggest that combined anti-HBV prophylaxis should also be preferred to single immunoprophylaxis in patients with HDV coinfection because it allows significant cost savings in the first two posttransplant years.     

The incidence and clinical outcome of YMDD mutants in hepatitis B surface antigen-positive renal allograft recipients after prolonged lamivudine therapy

Although lamivudine (LAM) is a potent inhibitor of hepatitis B virus (HBV), prolonged therapy may induce the development of LAM-resistant strains, YMDD mutants. Although YMDD mutants have impaired replication that leads to a benign clinical course compared with wild-type virus, some immunosuppressive agents may enhance replication of YMDD mutants, causing a severe hepatitis flare. We retrospectively investigated the incidence and clinical outcomes of YMDD mutants in renal allograft recipients on immunosuppressive treatment. Clinical records of 25 renal allograft recipients, who underwent renal transplantation between December 1997 and February 2006 were hepatitis B surface antigen positive at the time of transplantation, were reviewed. All patients received LAM treatment after renal transplantation. Over 9 to 98 months of follow-up, 16 patients (64.0%) maintained undetectable HBV DNA levels; however, 9 patients (36.0%) showed persistent or increased levels of HBV DNA. Seven were identified as having developed YMDD mutants. Although genotypic analysis was not performed, YMDD mutants were strongly suspected in another two patients, who developed severe hepatic dysfunction combined with high levels of HBV viremia at close to 2 years of LAM therapy. One patient recovered after hepatic transplantation and another patient died of hepatic failure. In conclusion, the incidence of YMDD mutants was similar to that of nonimmunosuppressed individuals; however, the presence of these mutants made it more likely for severe liver disease to develop in renal transplant recipients. Therefore, close monitoring for the development of YMDD mutants should be performed during LAM treatment, especially in this group of patients.     

Use of aortic valve allografts from hepatitis B surface antigen-positive donors

Over a 28-month period, 31 patients undergoing aortic valve replacement received valve allografts from hepatitis B surface antigen-positive, hepatitis B e antigen-negative donors. At the time of operation, 22 recipients were immune to hepatitis B infection; 19 had antibodies to hepatitis B surface antigen, and 3 were hepatitis B surface antigen positive. Nine patients were regarded as being susceptible to hepatitis B; 7 lacked hepatitis B markers, and records of serological status could not be found for the other 2. Four of the susceptible patients received hepatitis B immunoglobulin postoperatively, and 1 of them also received one 10-micrograms dose of hepatitis B vaccine. The 9 susceptible patients underwent hepatitis B serological studies a mean of 17 months (range, 4 to 31 months) postoperatively. In only 1 patient, tested 29 months after operation, had antibodies to hepatitis B surface, hepatitis B core, and hepatitis B e antigens developed. He had not experienced a clinical episode of hepatitis, and results of liver function tests were normal. He had not received prophylaxis. Because hepatitis B virus may be transmitted by hepatitis B surface antigen-positive, hepatitis B e antigen-negative valves, prophylaxis should be given whenever they are used and follow-up serological studies undertaken.     

Outcome of renal transplantation in hepatitis B surface antigen-positive patients after introduction of lamivudine.

BACKGROUND: In end-stage renal disease patients with hepatitis B surface antigen (HBsAg), the risk of hepatic dysfunction after immunosuppression represents a large barrier in renal transplantation. Lamivudine is a potent inhibitor of hepatitis B virus (HBV) replication. We retrospectively investigated the outcome of HBsAg-positive renal transplantation recipients after lamivudine had become available. METHODS: From July 1994 to August 2000, seventeen HBsAg-positive patients (M:F=15:2) received renal allografts (13:4=living:cadaveric donors). Liver function tests at the time of transplantation were normal in all patients. Pre-transplant liver biopsies performed in 15 patients demonstrated minimal inflammatory histology, except in three patients showing pathological and clinical signs of active hepatitis. Lamivudine was started pre-operatively in these three subjects. Another seven patients were treated with lamivudine for post-operative hepatic dysfunction. The remaining seven patients did not develop hepatic dysfunction after transplantation. RESULTS: Lamivudine was initially effective in decreasing serum HBV DNA titres, and in normalizing hepatic enzymes. Lamivudine was well tolerated without significant side effects for 35.5+/-8.9 months after initiation of treatment. HBV DNA became negative in nine patients but remained positive in one patient. Among the nine patients with initial negative conversion of HBV DNA, two developed transient positive conversion of HBV DNA and two demonstrated persistent positive conversion. Among the patients with normal liver histology in the pre-transplant period, 41.6% (5/12) developed liver pathology progression after immunosuppression. All 17 patients had functioning grafts, except for one patient who developed relapsed IgA nephropathy. CONCLUSIONS: Our data showed relatively favourable outcomes in hepatitis B-positive renal transplant recipients receiving lamivudine treatment, even though two patients developed lamivudine resistance.     

Use of hepatitis B core antibody-positive liver allograft in hepatitis C virus-positive and -negative recipients with use of short course of hepatitis B immunoglobulin and Lamivudine

INTRODUCTION: With the shortage of donor organs, increasing number of hepatitis B core antibody (HBcAb)-positive [HBcAb(+)] liver allografts are being used for liver transplantation (LTx) in patients who are HBcab-negative [HBsAb(-)]. This study was aimed at assessing outcomes for hepatitis C virus (HCV)-positive [HCV(+)] and HCV-negative [HCV(-)] patients who received HBcAb(+) liver grafts from deceased donors and also received a short course of hepatitis B immunoglobulin (HBIg) with long-term lamivudine therapy after LTx. MATERIALS AND METHODS: From February 1995 through February 2003, 28 patients (mean age 53.8 +/- 10.2 years, 19 men and nine women, 16 HCV[-]; 12 HCV[+]) received HbcAb(+) liver allografts. All recipients received a short course of HBIg prophylaxis (10,000 units/day for 4 days) and long-term lamivudine 100 mg/d after LTx in addition to a tacrolimus-based immunosuppressive regimen. RESULTS: Seven (25%) of the 28 recipients died during follow-up and three recipients required retransplantation. Three recipients (10.7%) developed HBV infection during follow-up, one of whom died 36 months after LTx and the other two had YMDD mutant HBV. The overall 6-year actuarial patient survival after transplantation was 74.4% and those for HCV(-) and HCV(+) recipients were 81.3% and 66.6%, respectively (P = .46). The overall 6-year actuarial graft survival was 63.9% and those for HCV(+) and HCV(-) recipients were 68.8% and 57.1%, respectively (P = .6). CONCLUSION: We conclude that HBcAb(+) liver grafts can be used for both HCV(+) patients and HCV(-) patients who are critically ill, have early hepatocellular carcinoma, or have been exposed to HBV in the past. A short course of HBIg-lamivudine combination therapy provides effective prophylaxis against HBV infection in 89% of recipients of HBcAb(+) grafts.     

乙型肝炎表面抗原阳性供肝肝移植的临床疗效分析

目的  探讨乙型肝炎表面抗原（HBsAg）阳性供肝在成人肝移植应用的临床疗效。方法  回顾性分析2012年7月至2015年10月28例接受HBsAg阳性供肝肝移植的乙型病毒性肝炎（乙肝）相关性肝病受者的临床疗效,总结受者预后、并发症发生情况,了解血清HBsAg及乙型肝炎病毒（HBV）DNA变化特点。结果  28例受者术后单药口服恩替卡韦预防乙肝复发。围手术期死亡2例,分别死于脓毒症和急性心力衰竭,2例随访期内因肝细胞癌（肝癌）复发死亡。另24例受者随访12~26个月,随访期间血清HBsAg持续阳性,经治疗HBV DNA滴度逐月下降,至术后12个月受者HBV DNA＜1×10² copies/mL。24例存活受者均未发生因乙肝复发导致的移植物失功。结论  作为边缘供肝,HBsAg阳性供肝可安全用于乙肝相关性肝病的肝移植受者,术后需加强抗HBV治疗并密切随访。     

Use of hepatitis B core antibody-positive donor kidneys in hepatitis B surface antibody-positive and -negative recipients

INTRODUCTION: The rate of hepatitis B virus transmission via organs from with isolated hepatitis B virus core antibody-positive (HBcAb+) donors in kidney transplant recipients seems very low. PATIENTS AND METHODS: Over 4 years, we performed 36 transplants from Ig HBcAb+, hepatitis B surface antigen (HBsAg)-negative donors into recipients with a history of prior hepatitis B virus (HBV) infection or reported vaccination (28 patients) and in recipients who were not immunized and received a pretransplant prophylaxis with hepatitis B immunoglobulins. We examined the HBV-related outcomes in these 36 patients in comparison with 40 recipients of allografts from HBcAb- donors. RESULTS: No patient receiving an allograft from an HBcAb+ donor developed clinical HBV infection or HBSAg positivity. The rate of seroconversion was 14.2% in immunized patients, 12.5% in nonimmunized patients, and 0% in the control group. The 17.8% of immunized patients developed elevated transaminases after transplant, in comparison with 25% and 10% in the nonimmunized patients and the control group, respectively. Graft and patient survival was 93% and 93% for immunized patients, 100% and 100% for nonimmunized patients, and 98% and 95% for the control group, respectively. CONCLUSION: The use of anti-HBc antibody-positive kidneys was associated with no risk of transmission of HBV infection, without affecting graft and patient survival, and could be considered a safe way to expand the donor pool. Our preliminary results suggest that such kidneys could be safely transplanted even in not immunized patients who underwent a prophylaxis with hepatitis B immunoglobulins.     

乙型肝炎病毒阳性供肝的规范化临床应用

慢性乙型肝炎是全球肝病的最重要原因之一,中国是乙型肝炎病毒(hepatitis B virus,HBV)的流行区,大约8600万人是慢性乙肝表面抗原(hepatitis B surface antigen,HBsAg)携带者[1]。未经治疗的慢性乙肝患者肝硬化的5年累积发生率为8%~20%,估计每年有超过50万人死于肝细胞癌和肝功能失代偿的并发症[2-3]。     

Survival outcome after hepatic retransplantation for hepatitis C virus-positive and -negative recipients

INTRODUCTION: Hepatitis C virus (HCV)-related liver disease is the most common indication for liver transplantation in the United States. Recurrence of HCV infection in these recipients is almost uniform. The currently available antiviral treatment is known to cause significant side effects, and the rate of sustained viral response is low. There is still controversy about whether such patients should undergo subsequent transplantations for HCV disease. This study compared outcomes for hepatic retransplantation performed in HCV(+) and HCV(-) recipients at a single center. PATIENTS AND METHODS: From December 1994 through November 2003, 68 patients at our institution received a second liver allograft. Nineteen of the recipients were HCV(+) (group A) and 49 were HCV(-) (group B). All patients were followed until January 2004. The mean follow-up time after initial retransplantation was 37 +/- 29 months. Patient and graft survival for the two groups were compared. RESULTS: Seven recipients in group A (36.8%) and 22 recipients in group B (44.9%) died during follow-up. The actuarial 3-year patient survival after initial retransplantation for groups A and B were 61.7% and 51.6%, respectively. Nine patients required a second retransplantation, 3 (15.8%) in group A and 6 (12.2%) in group B. The actuarial 3-year graft survival from initial retransplantation for groups A and B were 56.3% and 45.7%, respectively. CONCLUSION: We observed slightly better patient and graft survivals at 3 years from initial retransplantation in HCV(+) recipients compared to HCV(-) recipients. This may be due to younger donor age and better selection of HCV(+) recipients in this series.     

The role of hepatitis B surface antigen in the pathogenesis of glomerulopathies.

The frequency of hepatitis B surface antigen (HBsAg) has been studied in the sera and renal biopsies of 276 patients with various forms of glomerulonephritis (GN), the nephrotic syndrome and other nephropathies. Using a modified Hepanosticon method, HBs antigenemia was detected in 32 of 196 patients (16.3%) with immune complex (IC) GN and the nephrotic syndrome. Indirect immunofluorescence revealed HBsAg in 33 renal biopsy tissue specimens (16.8%). HBsAg was found in the sera of four of the 80 remaining patients with other renal diseases (5%), and in the renal biopsy tissues of another four (5%). Antibody against HBsAg could only be demonstrated in the serum of one glomerulonephritic patient. The sera of 18,799 normal blood donors were used as controls; of these 186 (0.99%) had positive tests for HBsAg. It is concluded that, in some patients with GN and the nephrotic syndrome, HBsAg-containing IC may be implicated in the development and/or progression of the disease.     

Transplantation of ABO group A2 kidneys from living donors into group O and B recipients.

Fifteen blood group O and B recipients have been transplanted with kidneys from subtype A2 living donors since April 1992. ABO red cell grouping was performed by local licensed blood banks with A2 subtype determined using an anti-A1 lectin and, retrospectively, by a polymerase chain reaction (PCR)-based molecular method. All grafts functioned immediately and no patient has required dialysis. Three patients each experienced one reversible rejection episode. With the exception of one cardiac death at 9months and one patient with profound toxicity to calcineurin inhibitors, all allografts continue to function normally. One donor, mistyped as a group A2 using lectin, was by PCR typing an A1O1 nonsecretor; the graft continues to function normally at 30 months. Transplantation of living donor A2 renal allografts into non-A recipients produces excellent long-term allograft survival and expands the potential living donor pool for nonblood group A recipients.