- Email: [email protected]
Hepatitis C virus and renal transplantation
Hepatitis C Virus and Renal Transplantation D.H. Van Thiel, A. Nadir, and N. Shah
I
T IS WELL RECOGNIZED that biochemical abnormalities of liver function occur in 7% to 24% of renal transplant (RTx) recipients.1 It is also well known that liver failure is the cause of death of 8% to 28% of long-term renal transplantation survivors.1 The pretransplantation prevalence of anti– hepatitis C virus (anti-HCV) positivity ranges from 11% to 49%.1 More importantly, the rate of post–renal transplantation liver disease varies markedly as a function of the pre–renal transplantation anti-HCV status of the population undergoing transplantation. For those, who are anti-HCV–negative, the rate is low, ranging from 2% to 19%.1 For those, who are anti-HCV–positive pretransplantation, the posttransplantation rate of recognized liver disease is much higher, ranging from 19% to 64%.1 The risk factors for anti-HCV positivity in patients with end-stage renal disease awaiting renal transplantation are well known and consist of the following (1) the number of transfusions the individual has received; (2) the duration of renal dialysis; (3) the type of dialysis; (4) the presence of a prior history of alcohol or drug abuse; and (5) the number of prior renal allografts the individual has received.2,3 A major problem with the recognition of HCV prevalence in patients with end-stage renal disease is the criterion used to define HCV disease. The specific criteria used to define HCV disease pretransplantation include the following: (1) anti-HCV testing; (2) the presence or absence of abnormal liver injury test results often requiring a two-fold or greater elevation for disease recognition; (3) HCV-RNA positivity by polymerase chain reaction (PCR); or (4) a liver biopsy sample documenting HCV disease. Obviously, the prevalence rates reported using these different methods for disease recognition vary markedly. Moreover, each can be criticized for one or more reasons related to their ability to recognize cases. One of the earlier studies of HCV infection in renal transplantation patients involved a population of 350 RTx recipients.3 Twenty-five percent were found to be antiHCV–positive and 88% of these cases were found to be HCV-positive prior to renal transplantation. Importantly, only 40% of these cases had an abnormality in any liver injury test parameter prior to renal transplantation and only 64% had an abnormality in a measured liver injury parameter either alanine aminotransferase (ALT), aspartate aminotransferase (AST) alkaline phosphatase, or total bilirubin level post–renal transplantation. Interestingly, 36% of those
with any abnormal test result present pretransplantation found that their abnormal test result returned to within a normal range posttransplantation even in the absence of any specific therapy directed at the HCV infection. In another large study of 598 posttransplantation patients, individuals with anti-HCV positivity pretransplantation were found to have lower pre–renal transplantation and post–renal transplantation AST abnormalities than did individuals with other forms of posttransplantation liver disease.2 Despite these lower values of AST, they had a higher rate of posttransplantation mortality as a result of their liver disease. In a study of 310 patients, 252 with a renal transplantation and 58 treated with dialysis, liver disease and deaths due to liver disease were substantially higher in individuals treated with transplantation than those treated with dialysis.4 In yet another study of 346 RTx recipients, 74 (21.4%) were found to be anti-HCV–positive pre–renal transplantation.5 Following renal transplantation, the hepatic histology of those with normal and abnormal serum ALT levels in the anti-HCV–positive group was compared. As might be expected, those with abnormal serum ALT levels had higher rates of histologic liver disease abnormalities, with 73% having documented chronic active hepatitis. However, many of those with normal ALT levels (32%) had chronic active hepatitis histologically as well. Others have reported that individuals who are anti-HCV–positive prior to renal transplantation are frequently HCV-RNA–positive as well with reported rates varying between 85% and 90% and that such hepatitis HCV-RNA positivity persists posttransplantation for prolonged, often indefinite periods, usually beyond the duration of the reported investigations typically 2 to 5 years.6 Interestingly, only 30% of HCV-RNA–positive anti-HCV–positive RTx recipients have an abnormal ALT level. Ninety-three percent of the chronic liver disease not due to chronic hepatitis B seen in RTx recipients in one study from Spain was due to chronic hepatitis C.7 Importantly, liver biopsy has been shown to be essential for the From the Division of Gastroenterology and Hepatology, Stritch School of Medicine, Loyola University of Chicago, Loyola University Medical Center, Maywood, Illinois. Address reprint requests to D.H. Van Thiel, MD, Building 114, Room 54, Loyola University Medical Center, 2160 South 1st Avenue, Maywood, IL 60153. E-mail: [email protected]
© 2002 by Elsevier Science Inc. 655 Avenue of the Americas, New York, NY 10010
0041-1345/02/$–see front matter PII S0041-1345(02)03168-8
Transplantation Proceedings, 34, 2433–2435 (2002)
2433
2434
detection of liver disease in anti-HCV–positive RTx recipients.8 Among those with any abnormalities of their liver injury tests, 74% were found to have histologic disease. Conversely, 60% of those with no abnormality of their various liver injury test results had histologic evidence of chronic liver disease. When the serum levels of ALT or AST are used alone to identify cases of liver disease, histologic liver disease can be documented in 71% of those with an abnormal value, whereas histologic liver disease can be found in 59% of those with normal ALT and AST levels. In renal transplantation candidates who are anti-HCV– positive and HCV-RNA–positive, 68% can be shown to have histologic liver disease; 55% of those with normal liver enzymes who are HCV-RNA–positive can be shown to have histologic liver disease.8 Regardless of the methods used to identify cases pre– renal transplantation, post–renal transplantation HCV is progressive and cirrhosis can develop in such cases with or without the development of abnormal serum ALT levels. In a unique study from China, it was demonstrated that the development of cirrhosis, hepatic decompensation, and death in RTx recipients was related more to the presence of a confounding hepatitis B virus (HBV) infection than it was to the HCV infection used to identify patients.9 This finding may be of importance in Asia and Africa where HBV infection is endemic. Regardless of the type of immune suppression used, the development of post–renal transplantation chronic liver disease is more common in males and those who have a confounding HBV infection, a history of alcohol or intravenous drug abuse, a higher serum ferritin level, a history of blood transfusion, and a longer duration of pretransplantation dialysis.10 Despite the consistent documentation of the presence of histologic liver disease in RTx recipients with HCV infection, it has not been possible to document a significant reduction in length of posttransplantation survival in such cases until at least 8 to 10 years post–renal transplantation.11–15 Conversely, when HCV-positive patients treated with dialysis are compared to RTx recipients, a significant reduction in the rate of survival in the group treated using dialysis can be seen after 18 to 24 months. More recently using better tools to identify cases of HCV before renal transplantation, the Medical College of Wisconsin has reported a significantly reduced 8 years’ post– renal transplantation survival among hepatitis C antibody– positive cases as compared to hepatitis C antibody–negative cases.16 In Boston, the New England Organ Bank has reported a 3.3-fold higher relative risk of death and a 9.9-fold risk of death due to sepsis in anti-HCV–positive RTx recipients as compared to anti-HCV–negative RTx recipients.17 They reported that infection was the leading cause of death in anti-HCV RTx recipients. Deaths due to liver disease in anti-HCV–positive RTx recipients are seen rarely prior to 5 years posttransplantation but increase steadily thereafter and can account for as many as 24% of
VAN THIEL, NADIR, AND SHAH
the deaths at 5 years, a rate 8-fold greater than that seen in anti-HCV–negative cases. Not only do deaths occur at an increased rate and as a result of liver disease, but they also occur as a result of an increase rate for sepsis in anti-HCV– positive cases.18 Moreover, this difference in death rate does not take 5 to 10 years to be manifest, but can be seen as early as 1 year post–renal transplantation.19 As a result of these factors, liver disease and sepsis in individuals who undergo renal transplantation and are anti-HCV–positive result in both reduced graft and patient survival rates. As a consequence of data like that presented above, many centers have taken the approach that anti-HCV– positive patients with renal disease awaiting renal transplantation should be selected for renal transplantation only if they do not have evidence for significant liver disease or cirrhosis with portal hypertension. Those with evidence of liver disease are segregated into those with advanced disease, who should not undergo transplantation, and those with lessor degrees of liver disease, who can be treated with interferon ␣ (IFN) prior to renal transplantation. The concept has been accepted widely. More recently, attention has shifted away from the liver disease and toward the characteristics of the underlying renal disease in anti-HCV–positive individuals pre–renal transplantation and post–renal transplantation.20 In a large study of 399 RTx recipients, 29% could be shown to be anti-HCV–positive. Of the 15 cases with membranoproliferative glomerulonephritis, 55% were anti-HCV–positive. Importantly, the degree of posttransplantation proteinuria has been shown to be a major determinant of RTx graft survival and the progress of the post–renal transplantation renal disease particularly in cadaveric grafts obtained from anti-HCV–positive donors. Grafts obtained from HLA DR3–positive recipients have the shortest length of survival post–renal transplantation. The treatment of HCV–positive RTx recipients with IFN is highly controversial. The initial reports of such therapy were associated with high rates of graft loss as a result of putative IFN-induced acute cellular rejection (ACR) in individuals who prior to the use of IFN were free of ACR.21 Despite these widely reported negatives studies, a few studies documenting improvement in the hepatic disease of IFN-treated RTx recipients have been reported.22 A final issue to be addressed in this presentation is the use of cadaveric kidneys obtained from anti-HCV–positive donors. This is an important issue because of the very great need for donor organs and the large fraction of the population (donor pool) that is identified as being anti-HCV– positive. As a consequence of considerable debate and a review of some data, the existing policy at most centers is to use such kidneys exclusively in recipients who are antiHCV–positive.19 This policy produces the greatest total life quality in adjusted life years post–renal transplantation at an intermediate cost in terms of the numbers of organs being wasted. Much remains to be learned about HCV infections in patients with renal disease, those requiring immunosup-
HCV AND RENAL TRANSPLANTATION
pression and particularly RTx recipients. The preceding has been a synopsis of the currently available data relating to the complex problem of HCV infection and renal transplantation. REFERENCES 1. Pereira BJ, Levey AS: Kidney Int 51:981, 1997 2. Stempel CA, Lake J, Kuo G, et al: Transplantation 55:273, 1993 3. Rostaing L, Izopet J, Cisterne JM, et al: Am J Nephrol 17:46, 1997 4. Kazi S, Prasad S, Pollak R, et al: Dig Dis Sci 39:961, 1994 5. Cisterne JM, Rostaing L, Izopet J, et al: Nephrol Dial Transplant 11:46, 1996 6. Chan TM, Lok AS, Cheng IK, et al: Gastroenterology 104: 862, 1993 7. Genesca J, Vila J, Cordoba J, et al: J Hepatol 22:272, 1995 8. Boletis J, Delladetsima J, Psimenou E, et al: Transplant Proc 27:945, 1995 9. Huang CC, Liaw YF, Lai MK, et al: Transplantation 53:763, 1992
2435 10. Berthoux F: Nephrology 71:386, 1995 11. Ynares C, Johnson HK, Kerlin T, et al: Transplant Proc 25:1466, 1993 12. Roth D, Zucker K, Cirocoo R, et al: Kidney Int 45:238, 1994 13. Orloff SL, Stempel CA, Wright TL, et al: Clin Transplant 9:119, 1995 14. Pouteil-Noble C, Maiza H, Donia A, et al: Transplant Proc 29:791, 1997 15. Legendre C, Garrique V, LeBihan C, et al: Transplantation 65:667, 1998 16. Fritsche C, Brandes JC, Delaney SR, et al: Transplantation 55:1283, 1993 17. Pereira BJ: Transplant Proc 30:2070, 1998 18. Kirk AD, Heisey DM, D’Alessandro AM, et al: Transplantation 62:1758, 1996 19. Hanafusa T, Ichikawa Y, Yazawa K, et al: Transplant Proc 30:122, 1998 20. Hammond H, Haem J, Laurent B, et al: Nephrol Dial Transplant 11:54, 1996 21. Rostaing L, Modesto A, Baron E, et al: Nephron 74:512, 1996 22. Chan TM, Lok ASF, Cheng IKP, et al: Transplantation 56:1095, 1993
I
T IS WELL RECOGNIZED that biochemical abnormalities of liver function occur in 7% to 24% of renal transplant (RTx) recipients.1 It is also well known that liver failure is the cause of death of 8% to 28% of long-term renal transplantation survivors.1 The pretransplantation prevalence of anti– hepatitis C virus (anti-HCV) positivity ranges from 11% to 49%.1 More importantly, the rate of post–renal transplantation liver disease varies markedly as a function of the pre–renal transplantation anti-HCV status of the population undergoing transplantation. For those, who are anti-HCV–negative, the rate is low, ranging from 2% to 19%.1 For those, who are anti-HCV–positive pretransplantation, the posttransplantation rate of recognized liver disease is much higher, ranging from 19% to 64%.1 The risk factors for anti-HCV positivity in patients with end-stage renal disease awaiting renal transplantation are well known and consist of the following (1) the number of transfusions the individual has received; (2) the duration of renal dialysis; (3) the type of dialysis; (4) the presence of a prior history of alcohol or drug abuse; and (5) the number of prior renal allografts the individual has received.2,3 A major problem with the recognition of HCV prevalence in patients with end-stage renal disease is the criterion used to define HCV disease. The specific criteria used to define HCV disease pretransplantation include the following: (1) anti-HCV testing; (2) the presence or absence of abnormal liver injury test results often requiring a two-fold or greater elevation for disease recognition; (3) HCV-RNA positivity by polymerase chain reaction (PCR); or (4) a liver biopsy sample documenting HCV disease. Obviously, the prevalence rates reported using these different methods for disease recognition vary markedly. Moreover, each can be criticized for one or more reasons related to their ability to recognize cases. One of the earlier studies of HCV infection in renal transplantation patients involved a population of 350 RTx recipients.3 Twenty-five percent were found to be antiHCV–positive and 88% of these cases were found to be HCV-positive prior to renal transplantation. Importantly, only 40% of these cases had an abnormality in any liver injury test parameter prior to renal transplantation and only 64% had an abnormality in a measured liver injury parameter either alanine aminotransferase (ALT), aspartate aminotransferase (AST) alkaline phosphatase, or total bilirubin level post–renal transplantation. Interestingly, 36% of those
with any abnormal test result present pretransplantation found that their abnormal test result returned to within a normal range posttransplantation even in the absence of any specific therapy directed at the HCV infection. In another large study of 598 posttransplantation patients, individuals with anti-HCV positivity pretransplantation were found to have lower pre–renal transplantation and post–renal transplantation AST abnormalities than did individuals with other forms of posttransplantation liver disease.2 Despite these lower values of AST, they had a higher rate of posttransplantation mortality as a result of their liver disease. In a study of 310 patients, 252 with a renal transplantation and 58 treated with dialysis, liver disease and deaths due to liver disease were substantially higher in individuals treated with transplantation than those treated with dialysis.4 In yet another study of 346 RTx recipients, 74 (21.4%) were found to be anti-HCV–positive pre–renal transplantation.5 Following renal transplantation, the hepatic histology of those with normal and abnormal serum ALT levels in the anti-HCV–positive group was compared. As might be expected, those with abnormal serum ALT levels had higher rates of histologic liver disease abnormalities, with 73% having documented chronic active hepatitis. However, many of those with normal ALT levels (32%) had chronic active hepatitis histologically as well. Others have reported that individuals who are anti-HCV–positive prior to renal transplantation are frequently HCV-RNA–positive as well with reported rates varying between 85% and 90% and that such hepatitis HCV-RNA positivity persists posttransplantation for prolonged, often indefinite periods, usually beyond the duration of the reported investigations typically 2 to 5 years.6 Interestingly, only 30% of HCV-RNA–positive anti-HCV–positive RTx recipients have an abnormal ALT level. Ninety-three percent of the chronic liver disease not due to chronic hepatitis B seen in RTx recipients in one study from Spain was due to chronic hepatitis C.7 Importantly, liver biopsy has been shown to be essential for the From the Division of Gastroenterology and Hepatology, Stritch School of Medicine, Loyola University of Chicago, Loyola University Medical Center, Maywood, Illinois. Address reprint requests to D.H. Van Thiel, MD, Building 114, Room 54, Loyola University Medical Center, 2160 South 1st Avenue, Maywood, IL 60153. E-mail: [email protected]
© 2002 by Elsevier Science Inc. 655 Avenue of the Americas, New York, NY 10010
0041-1345/02/$–see front matter PII S0041-1345(02)03168-8
Transplantation Proceedings, 34, 2433–2435 (2002)
2433
2434
detection of liver disease in anti-HCV–positive RTx recipients.8 Among those with any abnormalities of their liver injury tests, 74% were found to have histologic disease. Conversely, 60% of those with no abnormality of their various liver injury test results had histologic evidence of chronic liver disease. When the serum levels of ALT or AST are used alone to identify cases of liver disease, histologic liver disease can be documented in 71% of those with an abnormal value, whereas histologic liver disease can be found in 59% of those with normal ALT and AST levels. In renal transplantation candidates who are anti-HCV– positive and HCV-RNA–positive, 68% can be shown to have histologic liver disease; 55% of those with normal liver enzymes who are HCV-RNA–positive can be shown to have histologic liver disease.8 Regardless of the methods used to identify cases pre– renal transplantation, post–renal transplantation HCV is progressive and cirrhosis can develop in such cases with or without the development of abnormal serum ALT levels. In a unique study from China, it was demonstrated that the development of cirrhosis, hepatic decompensation, and death in RTx recipients was related more to the presence of a confounding hepatitis B virus (HBV) infection than it was to the HCV infection used to identify patients.9 This finding may be of importance in Asia and Africa where HBV infection is endemic. Regardless of the type of immune suppression used, the development of post–renal transplantation chronic liver disease is more common in males and those who have a confounding HBV infection, a history of alcohol or intravenous drug abuse, a higher serum ferritin level, a history of blood transfusion, and a longer duration of pretransplantation dialysis.10 Despite the consistent documentation of the presence of histologic liver disease in RTx recipients with HCV infection, it has not been possible to document a significant reduction in length of posttransplantation survival in such cases until at least 8 to 10 years post–renal transplantation.11–15 Conversely, when HCV-positive patients treated with dialysis are compared to RTx recipients, a significant reduction in the rate of survival in the group treated using dialysis can be seen after 18 to 24 months. More recently using better tools to identify cases of HCV before renal transplantation, the Medical College of Wisconsin has reported a significantly reduced 8 years’ post– renal transplantation survival among hepatitis C antibody– positive cases as compared to hepatitis C antibody–negative cases.16 In Boston, the New England Organ Bank has reported a 3.3-fold higher relative risk of death and a 9.9-fold risk of death due to sepsis in anti-HCV–positive RTx recipients as compared to anti-HCV–negative RTx recipients.17 They reported that infection was the leading cause of death in anti-HCV RTx recipients. Deaths due to liver disease in anti-HCV–positive RTx recipients are seen rarely prior to 5 years posttransplantation but increase steadily thereafter and can account for as many as 24% of
VAN THIEL, NADIR, AND SHAH
the deaths at 5 years, a rate 8-fold greater than that seen in anti-HCV–negative cases. Not only do deaths occur at an increased rate and as a result of liver disease, but they also occur as a result of an increase rate for sepsis in anti-HCV– positive cases.18 Moreover, this difference in death rate does not take 5 to 10 years to be manifest, but can be seen as early as 1 year post–renal transplantation.19 As a result of these factors, liver disease and sepsis in individuals who undergo renal transplantation and are anti-HCV–positive result in both reduced graft and patient survival rates. As a consequence of data like that presented above, many centers have taken the approach that anti-HCV– positive patients with renal disease awaiting renal transplantation should be selected for renal transplantation only if they do not have evidence for significant liver disease or cirrhosis with portal hypertension. Those with evidence of liver disease are segregated into those with advanced disease, who should not undergo transplantation, and those with lessor degrees of liver disease, who can be treated with interferon ␣ (IFN) prior to renal transplantation. The concept has been accepted widely. More recently, attention has shifted away from the liver disease and toward the characteristics of the underlying renal disease in anti-HCV–positive individuals pre–renal transplantation and post–renal transplantation.20 In a large study of 399 RTx recipients, 29% could be shown to be anti-HCV–positive. Of the 15 cases with membranoproliferative glomerulonephritis, 55% were anti-HCV–positive. Importantly, the degree of posttransplantation proteinuria has been shown to be a major determinant of RTx graft survival and the progress of the post–renal transplantation renal disease particularly in cadaveric grafts obtained from anti-HCV–positive donors. Grafts obtained from HLA DR3–positive recipients have the shortest length of survival post–renal transplantation. The treatment of HCV–positive RTx recipients with IFN is highly controversial. The initial reports of such therapy were associated with high rates of graft loss as a result of putative IFN-induced acute cellular rejection (ACR) in individuals who prior to the use of IFN were free of ACR.21 Despite these widely reported negatives studies, a few studies documenting improvement in the hepatic disease of IFN-treated RTx recipients have been reported.22 A final issue to be addressed in this presentation is the use of cadaveric kidneys obtained from anti-HCV–positive donors. This is an important issue because of the very great need for donor organs and the large fraction of the population (donor pool) that is identified as being anti-HCV– positive. As a consequence of considerable debate and a review of some data, the existing policy at most centers is to use such kidneys exclusively in recipients who are antiHCV–positive.19 This policy produces the greatest total life quality in adjusted life years post–renal transplantation at an intermediate cost in terms of the numbers of organs being wasted. Much remains to be learned about HCV infections in patients with renal disease, those requiring immunosup-
HCV AND RENAL TRANSPLANTATION
pression and particularly RTx recipients. The preceding has been a synopsis of the currently available data relating to the complex problem of HCV infection and renal transplantation. REFERENCES 1. Pereira BJ, Levey AS: Kidney Int 51:981, 1997 2. Stempel CA, Lake J, Kuo G, et al: Transplantation 55:273, 1993 3. Rostaing L, Izopet J, Cisterne JM, et al: Am J Nephrol 17:46, 1997 4. Kazi S, Prasad S, Pollak R, et al: Dig Dis Sci 39:961, 1994 5. Cisterne JM, Rostaing L, Izopet J, et al: Nephrol Dial Transplant 11:46, 1996 6. Chan TM, Lok AS, Cheng IK, et al: Gastroenterology 104: 862, 1993 7. Genesca J, Vila J, Cordoba J, et al: J Hepatol 22:272, 1995 8. Boletis J, Delladetsima J, Psimenou E, et al: Transplant Proc 27:945, 1995 9. Huang CC, Liaw YF, Lai MK, et al: Transplantation 53:763, 1992
2435 10. Berthoux F: Nephrology 71:386, 1995 11. Ynares C, Johnson HK, Kerlin T, et al: Transplant Proc 25:1466, 1993 12. Roth D, Zucker K, Cirocoo R, et al: Kidney Int 45:238, 1994 13. Orloff SL, Stempel CA, Wright TL, et al: Clin Transplant 9:119, 1995 14. Pouteil-Noble C, Maiza H, Donia A, et al: Transplant Proc 29:791, 1997 15. Legendre C, Garrique V, LeBihan C, et al: Transplantation 65:667, 1998 16. Fritsche C, Brandes JC, Delaney SR, et al: Transplantation 55:1283, 1993 17. Pereira BJ: Transplant Proc 30:2070, 1998 18. Kirk AD, Heisey DM, D’Alessandro AM, et al: Transplantation 62:1758, 1996 19. Hanafusa T, Ichikawa Y, Yazawa K, et al: Transplant Proc 30:122, 1998 20. Hammond H, Haem J, Laurent B, et al: Nephrol Dial Transplant 11:54, 1996 21. Rostaing L, Modesto A, Baron E, et al: Nephron 74:512, 1996 22. Chan TM, Lok ASF, Cheng IKP, et al: Transplantation 56:1095, 1993