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Nephrology 20 (2015) 40–43
Brief Communication
Outcomes in hepatitis B surface antigen-positive renal transplant recipients CAROLINE L CHEMBO, PAUL MANLEY and IAN DITTMER Department of Renal Medicine, Auckland City Hospital, Auckland, New Zealand Correspondence: Dr Ian Dittmer, Department of Renal Medicine, Auckland City Hospital, Level 15, Park Road, Auckland, New Zealand. Email: [email protected] Accepted for publication 24 September 2014. Accepted manuscript online 18 October 2014. doi:10.1111/nep.12344
BACKGROUND With the outcomes in dialysis patients remaining poor, renal transplantation remains the treatment of choice for patients with end-stage kidney disease. The prevalence of hepatitis B surface antigen (HBsAg)-positive patients on dialysis is declining; however, there remain a number of patients with HBsAg positivity who may benefit from renal transplantation.1 Hepatitis B infection is relatively common in the New Zealand Maori and Pacifica populations.2,3 Reports on renal and liver outcomes in patients receiving a renal transplant with pre-existing HBsAg positivity have demonstrated both favourable and unfavourable outcomes.4,5 A meta-analysis of some observational studies in 2005 showed increased mortality and increased graft loss in patients that were HBsAg positive prior to renal transplantation.6 Older studies reported poor outcomes while newer studies have reported comparable outcomes. This could be due to more focused and better follow-up in these patients. A review by Tsai et al.7 gives a comprehensive review of studies that have looked at hepatitis B infection and renal transplantation outcomes. With this background, we set out to review the renal and liver outcomes of all patients transplanted at Auckland City Hospital, New Zealand who were HBsAg positive pre-transplant.
METHODS
between 1981 and 2011 were identified from the Auckland City Hospital renal transplant database. Follow-up information on these patients was obtained from medical records and laboratories where the patient was being routinely followed up. Basic demographics included ethnicity, gender, age at transplant, primary renal disease and donor status. Follow-up data included renal function tests, liver function tests, viral DNA and PCR, and any form of liver imaging or biopsy.
Immunosuppression Induction therapy was not generally used except for a period in the late 1980s when an anti-lymphocyte agent was used for some recipients. Since 2010, basiliximab has been used as induction therapy in all recipients. Anti-lymphocyte preparations were only used to treat vascular or steroid-resistant rejection episodes. Patients received long-term triple immunosuppression with prednisone, a calcineurin inhibitor, and an anti-proliferative agent.
Liver assessments There were no standardized protocols for liver imaging, biopsy and follow-up until after 2000. No patients with cirrhosis were accepted for listing for kidney alone transplantation.
Ethics Ethics approval was obtained from the regional and hospital ethics committee.
Study population
Statistical analysis
The Auckland renal transplant unit caters for a large geographical area in the upper North Island of New Zealand, and long-term follow-up of distant patients is managed at their home centres. Ethics approval was obtained for this observational study. All patients who were HBsAg positive at the time of transplantation
Systat version 9.01 (Systat Software, Inc., Chicago, IL, USA) was used. The Kaplan–Meier method was used to derive survival curves for renal graft survival and overall survival. Graft survival was determined from date of transplant to date of return to dialysis or date of
40
© 2014 Asian Pacific Society of Nephrology
Outcomes in hepatitis B surface antigen-positive renal transplant recipients
33 potential patients identified 1 excluded because his/her transplant not done in Auckland
32 patients
8 patients excluded due to being hepatitis B core antibody positive only
24 patients left 3 patients excluded due to lack of follow-up information 1 excluded as he/she had combined liver and kidney transplant Fig. 1 Patient exclusion and final inclusion for study.
20 patients left in review
sustained eGFR of less than 15 mL/min/1.73 m2. Kaplan–Meier curves were also generated to assess overall survival with time from the date of transplant to date of death.
RESULTS Baseline characteristics Twenty patients were included in this review (Fig. 1 and Table 1). The median follow-up was 8 years (range 1.9–23.4 years). There was a male preponderance (75%) and the majority of the patients were Maori (60%). The mean age at transplant was 39 years (range 19–59). Primary glomerulonephritis was the single most common cause of primary renal disease. Sixty-five per cent received deceased donor transplants with 15 (75%) transplanted after 2005. Sixteen patients had hepatitis B e antigen (HBeAg) checked prior to transplant with five of these being positive. Viral load estimations were not performed on a routine basis, and routine genotype testing was not available for most of our patients.
OUTCOMES Patient and graft survival: Figure 2 Over a median follow-up time of 8 years (1.9–23.4 years), eight patients lost their renal allograft. One patient had acute kidney injury in the context of severe sepsis that required renal replacement therapy prior to their death. Overall death censored graft survival was 87% at 5 years and 56% at 10 years. © 2014 Asian Pacific Society of Nephrology
Table 1 Baseline patient characteristics Hepatitis B-positive recipients Total number Male (%) Age at transplant (mean years) Ethnicity Maori, n (%) Non Maori, n (%) Primary renal disease Glomerulonephritis, n (%) Diabetes mellitus, n (%) Others, n (%) Transplant period Prior to 2005, n (%) 2005–2011, n (%) Mean ALT at transplant Time on dialysis (years) Pre-emptive Median time Type of donor Deceased, n (%) Live, n (%)
20 15 (75) 39 (19–59) 12 (60) 8 (40) 9 (45) 3 (15) 8 (40) 5 (25) 15 (75) 32 U/L 2 3 13 (65) 7 (35)
ALT, alanine amino transferase.
Five patients died and all were transplanted prior to 2005. 5-year survival was 100% with a median survival of 9 years (5.5−23.4) One death was attributed to peritonitis associated with cirrhosis, while sepsis was the cause of death in the other four patients and this occurred some years after transplant.
Liver outcomes: Alanine amino transferase (ALT) levels were obtained at regular intervals. There were some non-sustained rises (less 41
CL Chembo et al.
Overall patient survival
1.0
1.0
0.8 Proportion still alive
Proportion with functioning grafts
Overall graft survival
0.6 0.4 0.2 0.0 0
10 20 Time in years
30
0.8 0.6 0.4 0.2 0.0 0
than twofold) in serum ALT levels in some patients. One patient had slightly raised ALT prior to transplant, which rose to 689U/L at 3 months but subsequently resolved. One patient developed liver cirrhosis 20 years after transplant. Ten (50%) patients had pre-transplant liver biopsies or scans and all had non-significant fibrosis or very mild hepatitis. Post-transplant liver scans in those patients who had them done did not show changes in the liver other than the one patient who developed cirrhosis. This patient died of sepsis because of spontaneous bacterial peritonitis. Therefore, only one patient had liver progression post-transplant. HBeAg was not performed or followed routinely.
Medication changes Eight of the 20 patients were on lamivudine and tenofovir (1) prior to transplant while post-transplant, 15 were on lamivudine and 2 were on adefovir and tenofovir. Treatment was altered when there was a rise in viral load, which signalled resistance. Four patients were not on any treatment pre- and post-transplant, three of these were transplanted prior to the availability of lamivudine.
DISCUSSION We report outcomes in pre-transplant HBsAg-positive renal transplant recipients at Auckland City Hospital from 1981 to 2011. Renal transplantation of HBsAg-positive recipients was uncommon prior to 2005. The 5-year renal allograft survival for this group of patients was 87% compared with 85.3% for those who were HBsAg negative at the same centre, and 5-year patient survival was 100%. Because of the small sample size, there is a possibility that our result shows favourable outcomes in HBsAg-positive recipients, but given that other people have also reported this before, we feel this is a true outcome. Sepsis was the predominant cause of death and occurred some years after transplant; in four cases after the renal transplant had failed and the patient had returned to dialysis therapy. 42
10 20 Time in years
30
Fig. 2 Overall patient survival and death censored graft survival.
Only two patients had significant elevations in serum ALT; one had a transient rise while the other later developed cirrhosis 20 years after transplant and later died from chronic liver disease-related complications. Previous studies have shown poor overall and renal outcomes in HBsAg-positive patients compared with HBsAgnegative patients receiving renal transplants. Reported 5-year graft survival in pre-transplant HBsAg-positive patients ranges from 70 to around 75% while 10-year graft survivals are around 40%.8 Our 5- and 10-year graft survival was 87% and 56%, respectively, which is comparable with what is reported in the literature. This observational study demonstrates that transplantation is a good treatment for HBsAg-positive dialysis patients. Poor liver outcomes have also been previously reported and hence these patients need hepatology follow-up after transplant. One death in our cohort was related to chronic liver disease complications. This patient had only been on monotherapy with lamivudine. Apart from this reported case of liver complications, the other observed liver outcomes in our patients were encouraging, although we acknowledge that some have only had a relatively short period of followup. Other than serological tests, ultrasound and liver biopsies are part of the assessment and surveillance of the liver. Practice was varied in this cohort as assessment changed over the years of the study. A uniform and structured approach to management would probably be useful. Lamivudine use in pre-transplant HBsAg-positive patients has increased the 5- and 10-year overall graft survival and also improved liver outcomes and change is indicated in drug resistance cases, which is not restricted to the post-transplant group only.8–12 Other antiretroviral medications were used in light of viral resistance.
CONCLUSION The overall survival in pre-transplant hepatitis B-positive patients in our cohort was comparable with those who were negative prior to transplant. Poor liver outcomes were reported in the past but with widespread use of reverse © 2014 Asian Pacific Society of Nephrology
Outcomes in hepatitis B surface antigen-positive renal transplant recipients
transcriptase inhibitors and good hepatology follow-up, these outcomes are now improved. Our study shows that the renal allograft survival was not too dissimilar to the survival in the whole Auckland transplant population. Though the liver outcomes were acceptable, there is need for robust guidelines on follow-up of such patients. Viral load testing and liver imaging guidelines that are now in place guide clinicians especially in remote areas for appropriate follow-up of such patients.
8.
REFERENCES
9.
1. Edey M, Barraclough K, Johnson DW. Review article: Hepatitis B and dialysis. Nephrology (Carlton) 2010; 15: 137–45. 2. Robinson T, Bullen C, Humphries W, Hornell J, Moyes C. The New Zealand Hepatitis B Screening Programme: Screening coverage and prevalence of chronic hepatitis B infection. N. Z. Med. J. 2005; 118 (1211): U1345. 3. Gane E. Chronic hepatitis B virus infection in south Auckland. N. Z. Med. J. 1998; 111 (1063): 120–3. 4. Patel HV, Kute VB, Vanikar AV et al. Clinical outcome of renal transplantation in end-stage renal disease patients with positive pretransplantation hepatitis B surface antigen. Transplant. Proc. 2012; 44 (1): 72–4. 5. Reddy PN, Sampaio MS, Kuo HT, Martin P, Bunnapradist S. Impact of pre-existing hepatitis B infection on the outcomes of
© 2014 Asian Pacific Society of Nephrology
6.
7.
10.
11.
12.
kidney transplant recipients in the United States. Clin. J. Am. Soc. Nephrol. 2011; 6 (6): 1481–7. Fabrizi F, Martin P, Dixit V, Kanwai F, Dulai G. HBsAg seropositive status and survival after renal transplantation: Meta-analysis of observational studies. Am. J. Transplant. 2005; 5: 2913–21. Tsai MC, Chen YT, Chien YS, Chen TC, Hu TH. Hepatitis B virus infection and renal transplantation. World J. Gastroenterol. 2010; 16: 3878–87. Ahn HJ, Kim MS, Kim YS et al. Clinical outcome of renal transplantation in patients with positive pre-transplant hepatitis B surface antigen. J. Med. Virol. 2007; 79: 1655–63. Park SK, Yang WS, Lee YS et al. Outcome of renal transplantation in hepatitis B surface antigen-positive patients after introduction of lamivudine. Nephrol. Dial. Transplant. 2001; 16: 2222–8. Park KS, Han DJ, Park JB, Park JS, Park S. Long-term outcome of Hepatitis B-positive renal allograft recipients after development of antiviral treatment. Clin. Nephrol. 2012; 78: 391–8. Filik L, Karakayali H, Moray G et al. Lamivudine therapy in kidney allograft recipients who are seropositive for hepatitis B surface antigen. Transplant. Proc. 2006; 38: 496–8. Fabrizi F, Dulai G, Dixit V, Bunnapradist S, Martin P. Lamivudine for the treatment of hepatitis B virus-related liver disease after renal transplantation: Meta-analysis of clinical trials. Transplantation 2004; 77: 859–64.
43
Nephrology 20 (2015) 40–43
Brief Communication
Outcomes in hepatitis B surface antigen-positive renal transplant recipients CAROLINE L CHEMBO, PAUL MANLEY and IAN DITTMER Department of Renal Medicine, Auckland City Hospital, Auckland, New Zealand Correspondence: Dr Ian Dittmer, Department of Renal Medicine, Auckland City Hospital, Level 15, Park Road, Auckland, New Zealand. Email: [email protected] Accepted for publication 24 September 2014. Accepted manuscript online 18 October 2014. doi:10.1111/nep.12344
BACKGROUND With the outcomes in dialysis patients remaining poor, renal transplantation remains the treatment of choice for patients with end-stage kidney disease. The prevalence of hepatitis B surface antigen (HBsAg)-positive patients on dialysis is declining; however, there remain a number of patients with HBsAg positivity who may benefit from renal transplantation.1 Hepatitis B infection is relatively common in the New Zealand Maori and Pacifica populations.2,3 Reports on renal and liver outcomes in patients receiving a renal transplant with pre-existing HBsAg positivity have demonstrated both favourable and unfavourable outcomes.4,5 A meta-analysis of some observational studies in 2005 showed increased mortality and increased graft loss in patients that were HBsAg positive prior to renal transplantation.6 Older studies reported poor outcomes while newer studies have reported comparable outcomes. This could be due to more focused and better follow-up in these patients. A review by Tsai et al.7 gives a comprehensive review of studies that have looked at hepatitis B infection and renal transplantation outcomes. With this background, we set out to review the renal and liver outcomes of all patients transplanted at Auckland City Hospital, New Zealand who were HBsAg positive pre-transplant.
METHODS
between 1981 and 2011 were identified from the Auckland City Hospital renal transplant database. Follow-up information on these patients was obtained from medical records and laboratories where the patient was being routinely followed up. Basic demographics included ethnicity, gender, age at transplant, primary renal disease and donor status. Follow-up data included renal function tests, liver function tests, viral DNA and PCR, and any form of liver imaging or biopsy.
Immunosuppression Induction therapy was not generally used except for a period in the late 1980s when an anti-lymphocyte agent was used for some recipients. Since 2010, basiliximab has been used as induction therapy in all recipients. Anti-lymphocyte preparations were only used to treat vascular or steroid-resistant rejection episodes. Patients received long-term triple immunosuppression with prednisone, a calcineurin inhibitor, and an anti-proliferative agent.
Liver assessments There were no standardized protocols for liver imaging, biopsy and follow-up until after 2000. No patients with cirrhosis were accepted for listing for kidney alone transplantation.
Ethics Ethics approval was obtained from the regional and hospital ethics committee.
Study population
Statistical analysis
The Auckland renal transplant unit caters for a large geographical area in the upper North Island of New Zealand, and long-term follow-up of distant patients is managed at their home centres. Ethics approval was obtained for this observational study. All patients who were HBsAg positive at the time of transplantation
Systat version 9.01 (Systat Software, Inc., Chicago, IL, USA) was used. The Kaplan–Meier method was used to derive survival curves for renal graft survival and overall survival. Graft survival was determined from date of transplant to date of return to dialysis or date of
40
© 2014 Asian Pacific Society of Nephrology
Outcomes in hepatitis B surface antigen-positive renal transplant recipients
33 potential patients identified 1 excluded because his/her transplant not done in Auckland
32 patients
8 patients excluded due to being hepatitis B core antibody positive only
24 patients left 3 patients excluded due to lack of follow-up information 1 excluded as he/she had combined liver and kidney transplant Fig. 1 Patient exclusion and final inclusion for study.
20 patients left in review
sustained eGFR of less than 15 mL/min/1.73 m2. Kaplan–Meier curves were also generated to assess overall survival with time from the date of transplant to date of death.
RESULTS Baseline characteristics Twenty patients were included in this review (Fig. 1 and Table 1). The median follow-up was 8 years (range 1.9–23.4 years). There was a male preponderance (75%) and the majority of the patients were Maori (60%). The mean age at transplant was 39 years (range 19–59). Primary glomerulonephritis was the single most common cause of primary renal disease. Sixty-five per cent received deceased donor transplants with 15 (75%) transplanted after 2005. Sixteen patients had hepatitis B e antigen (HBeAg) checked prior to transplant with five of these being positive. Viral load estimations were not performed on a routine basis, and routine genotype testing was not available for most of our patients.
OUTCOMES Patient and graft survival: Figure 2 Over a median follow-up time of 8 years (1.9–23.4 years), eight patients lost their renal allograft. One patient had acute kidney injury in the context of severe sepsis that required renal replacement therapy prior to their death. Overall death censored graft survival was 87% at 5 years and 56% at 10 years. © 2014 Asian Pacific Society of Nephrology
Table 1 Baseline patient characteristics Hepatitis B-positive recipients Total number Male (%) Age at transplant (mean years) Ethnicity Maori, n (%) Non Maori, n (%) Primary renal disease Glomerulonephritis, n (%) Diabetes mellitus, n (%) Others, n (%) Transplant period Prior to 2005, n (%) 2005–2011, n (%) Mean ALT at transplant Time on dialysis (years) Pre-emptive Median time Type of donor Deceased, n (%) Live, n (%)
20 15 (75) 39 (19–59) 12 (60) 8 (40) 9 (45) 3 (15) 8 (40) 5 (25) 15 (75) 32 U/L 2 3 13 (65) 7 (35)
ALT, alanine amino transferase.
Five patients died and all were transplanted prior to 2005. 5-year survival was 100% with a median survival of 9 years (5.5−23.4) One death was attributed to peritonitis associated with cirrhosis, while sepsis was the cause of death in the other four patients and this occurred some years after transplant.
Liver outcomes: Alanine amino transferase (ALT) levels were obtained at regular intervals. There were some non-sustained rises (less 41
CL Chembo et al.
Overall patient survival
1.0
1.0
0.8 Proportion still alive
Proportion with functioning grafts
Overall graft survival
0.6 0.4 0.2 0.0 0
10 20 Time in years
30
0.8 0.6 0.4 0.2 0.0 0
than twofold) in serum ALT levels in some patients. One patient had slightly raised ALT prior to transplant, which rose to 689U/L at 3 months but subsequently resolved. One patient developed liver cirrhosis 20 years after transplant. Ten (50%) patients had pre-transplant liver biopsies or scans and all had non-significant fibrosis or very mild hepatitis. Post-transplant liver scans in those patients who had them done did not show changes in the liver other than the one patient who developed cirrhosis. This patient died of sepsis because of spontaneous bacterial peritonitis. Therefore, only one patient had liver progression post-transplant. HBeAg was not performed or followed routinely.
Medication changes Eight of the 20 patients were on lamivudine and tenofovir (1) prior to transplant while post-transplant, 15 were on lamivudine and 2 were on adefovir and tenofovir. Treatment was altered when there was a rise in viral load, which signalled resistance. Four patients were not on any treatment pre- and post-transplant, three of these were transplanted prior to the availability of lamivudine.
DISCUSSION We report outcomes in pre-transplant HBsAg-positive renal transplant recipients at Auckland City Hospital from 1981 to 2011. Renal transplantation of HBsAg-positive recipients was uncommon prior to 2005. The 5-year renal allograft survival for this group of patients was 87% compared with 85.3% for those who were HBsAg negative at the same centre, and 5-year patient survival was 100%. Because of the small sample size, there is a possibility that our result shows favourable outcomes in HBsAg-positive recipients, but given that other people have also reported this before, we feel this is a true outcome. Sepsis was the predominant cause of death and occurred some years after transplant; in four cases after the renal transplant had failed and the patient had returned to dialysis therapy. 42
10 20 Time in years
30
Fig. 2 Overall patient survival and death censored graft survival.
Only two patients had significant elevations in serum ALT; one had a transient rise while the other later developed cirrhosis 20 years after transplant and later died from chronic liver disease-related complications. Previous studies have shown poor overall and renal outcomes in HBsAg-positive patients compared with HBsAgnegative patients receiving renal transplants. Reported 5-year graft survival in pre-transplant HBsAg-positive patients ranges from 70 to around 75% while 10-year graft survivals are around 40%.8 Our 5- and 10-year graft survival was 87% and 56%, respectively, which is comparable with what is reported in the literature. This observational study demonstrates that transplantation is a good treatment for HBsAg-positive dialysis patients. Poor liver outcomes have also been previously reported and hence these patients need hepatology follow-up after transplant. One death in our cohort was related to chronic liver disease complications. This patient had only been on monotherapy with lamivudine. Apart from this reported case of liver complications, the other observed liver outcomes in our patients were encouraging, although we acknowledge that some have only had a relatively short period of followup. Other than serological tests, ultrasound and liver biopsies are part of the assessment and surveillance of the liver. Practice was varied in this cohort as assessment changed over the years of the study. A uniform and structured approach to management would probably be useful. Lamivudine use in pre-transplant HBsAg-positive patients has increased the 5- and 10-year overall graft survival and also improved liver outcomes and change is indicated in drug resistance cases, which is not restricted to the post-transplant group only.8–12 Other antiretroviral medications were used in light of viral resistance.
CONCLUSION The overall survival in pre-transplant hepatitis B-positive patients in our cohort was comparable with those who were negative prior to transplant. Poor liver outcomes were reported in the past but with widespread use of reverse © 2014 Asian Pacific Society of Nephrology
Outcomes in hepatitis B surface antigen-positive renal transplant recipients
transcriptase inhibitors and good hepatology follow-up, these outcomes are now improved. Our study shows that the renal allograft survival was not too dissimilar to the survival in the whole Auckland transplant population. Though the liver outcomes were acceptable, there is need for robust guidelines on follow-up of such patients. Viral load testing and liver imaging guidelines that are now in place guide clinicians especially in remote areas for appropriate follow-up of such patients.
8.
REFERENCES
9.
1. Edey M, Barraclough K, Johnson DW. Review article: Hepatitis B and dialysis. Nephrology (Carlton) 2010; 15: 137–45. 2. Robinson T, Bullen C, Humphries W, Hornell J, Moyes C. The New Zealand Hepatitis B Screening Programme: Screening coverage and prevalence of chronic hepatitis B infection. N. Z. Med. J. 2005; 118 (1211): U1345. 3. Gane E. Chronic hepatitis B virus infection in south Auckland. N. Z. Med. J. 1998; 111 (1063): 120–3. 4. Patel HV, Kute VB, Vanikar AV et al. Clinical outcome of renal transplantation in end-stage renal disease patients with positive pretransplantation hepatitis B surface antigen. Transplant. Proc. 2012; 44 (1): 72–4. 5. Reddy PN, Sampaio MS, Kuo HT, Martin P, Bunnapradist S. Impact of pre-existing hepatitis B infection on the outcomes of
© 2014 Asian Pacific Society of Nephrology
6.
7.
10.
11.
12.
kidney transplant recipients in the United States. Clin. J. Am. Soc. Nephrol. 2011; 6 (6): 1481–7. Fabrizi F, Martin P, Dixit V, Kanwai F, Dulai G. HBsAg seropositive status and survival after renal transplantation: Meta-analysis of observational studies. Am. J. Transplant. 2005; 5: 2913–21. Tsai MC, Chen YT, Chien YS, Chen TC, Hu TH. Hepatitis B virus infection and renal transplantation. World J. Gastroenterol. 2010; 16: 3878–87. Ahn HJ, Kim MS, Kim YS et al. Clinical outcome of renal transplantation in patients with positive pre-transplant hepatitis B surface antigen. J. Med. Virol. 2007; 79: 1655–63. Park SK, Yang WS, Lee YS et al. Outcome of renal transplantation in hepatitis B surface antigen-positive patients after introduction of lamivudine. Nephrol. Dial. Transplant. 2001; 16: 2222–8. Park KS, Han DJ, Park JB, Park JS, Park S. Long-term outcome of Hepatitis B-positive renal allograft recipients after development of antiviral treatment. Clin. Nephrol. 2012; 78: 391–8. Filik L, Karakayali H, Moray G et al. Lamivudine therapy in kidney allograft recipients who are seropositive for hepatitis B surface antigen. Transplant. Proc. 2006; 38: 496–8. Fabrizi F, Dulai G, Dixit V, Bunnapradist S, Martin P. Lamivudine for the treatment of hepatitis B virus-related liver disease after renal transplantation: Meta-analysis of clinical trials. Transplantation 2004; 77: 859–64.
43
