SEARCH

SEARCH BY CITATION

INTRODUCTION

  1. Top of page
  2. INTRODUCTION
  3. REFERENCES
  4. SCREENING OF DIALYSIS PATIENTS FOR HEPATITIS C VIRUS INFECTION
  5. REFERENCES
  6. MANAGEMENT OF HEPATITIS C IN DIALYSIS PATIENTS (METHODS, FREQUENCY OF BLOOD TESTS AND IMAGING STUDIES)
  7. REFERENCES
  8. INDICATIONS OF ANTIVIRAL THERAPIES IN DIALYSIS PATIENTS
  9. REFERENCES
  10. TREATMENT OF DIALYSIS PATIENTS BY ANTIVIRAL THERAPIES
  11. REFERENCES
  12. PREVENTION OF HCV INFECTION AT HEMODIALYSIS FACILITIES
  13. REFERENCES

Objectives of the preparation of the guidelines

The prevention, diagnosis, and treatment of hepatitis C Virus (HCV) infection are clearly important for the management of patients undergoing chronic hemodialysis, because (i) the HCV infection rate is high in dialysis patients; (ii) the outcome is poorer in HCV-infected than non-infected dialysis patients; and (iii) an improvement in the outcome can be expected by the prevention or diagnosis and treatment of HCV infection. Therefore, it was decided to prepare “guidelines for the treatment and management of hepatitis C at dialysis facilities by dialysis physicians and nephrologists in cooperation with hepatologists” by the instruction of Tadao Akizawa, Chairman of the Board of Directors of the Japanese Society for Dialysis Therapy, and Hideki Hirakata, Chairman of the Scientific Committee, and under the leadership of Tadashi Tomo, Chairman of the Committee for the Preparation of the Guidelines. In preparing the guidelines, it was agreed (i) that they would be applied to chronic dialysis patients; and (ii) that they would be used by physicians at dialysis facilities. They would also be prepared to inform hepatologists about the dose of interferon and the criteria for the introduction and reduction of interferon administration in dialysis patients. Their preparation was initiated at the first meeting of the Committee for the Preparation of Guidelines for the Treatment of Hepatitis C Virus Infection in Dialysis Patients on 6 January 2009.

Environment and history of the preparation of the guidelines

Prior to this, in April 2008, the Kidney Disease: Improving Global Outcomes (KDIGO) group presented the “KDIGO Clinical Practice Guidelines for the Prevention, Diagnosis, Evaluation, and Treatment of Hepatitis C in Chronic Kidney Disease” as the first guidelines by the KDIGO itself in Kidney International(1). The guidelines were a 107-page tour de force consisting of five chapters dealing with (i) detection and evaluation of HCV in CKD patients; (ii) treatment of HCV-infected CKD patients; (iii) prevention of HCV infection in the dialysis room; (iv) treatment of HCV infected patients before and after kidney transplantation; and (v) diagnosis and treatment of HCV-related retinopathy, were compiled under the supervision of Michel Jadoul and David Roth, and described the diagnosis, treatment, and prevention of HCV infection in patients with CKD in the maintenance period, dialysis patients, and patients undergoing kidney transplantation. The ISN informed its members of these guidelines and recommended to apply them in consideration of the state of each country, region, and facility (implantation), because they contained provisions not necessarily based on strong evidence.

Thus, the Working Group for the Preparation of the Guidelines for the Treatment of Hepatitis C Virus Infection decided to make the guidelines cover the (i) diagnosis, (ii) treatment, and (iii) prevention of HCV infection in dialysis patients, and (iv) their management before and after transplantation on the basis of the items of the KDIGO guidelines by securing the cooperation of experts in dialysis and HCV hepatitis. In addition, as the aminotransferase levels are low in dialysis patients, and as the method for the assessment of fibrosis was not established, some members considered it necessary to include test methods and diagnostic criteria, and the guidelines were decided to comprise five chapters dealing with (i) screening, (ii) management (methods and frequencies of blood tests and imaging studies), (iii) indications of antiviral therapies, (iv) treatment by antiviral therapies (including patients expected to receive kidney transplantation), and (v) prevention of HCV infection at hemodialysis facilities.

The references consisted primarily of English and Japanese literature published by the end of 2008, but domestic and overseas guidelines were also included.

Committee members involved in the preparation of the guidelines

Tadao Akizawa, Chairman, Board of Directors, Japanese Society for Dialysis Therapy
Hideki Hirakata, Chairman, Scientific Committee, Japanese Society for Dialysis Therapy
Tadashi Tomo, Chairman, Subcommittee for the Preparation of Guidelines of the Japanese Society for Dialysis Therapy
Working Group for the Preparation of Guidelines for the Treatment of Hepatitis C Virus Infection in Dialysis Patients
ChairmanTakashi Akiba (Tokyo Women's Medical University)
Vice-chairmanKazuhiko Hora (Hokushin General Hospital)
MembersMichio Imawari (Showa University)
Chifumi Sato (Tokyo Medical and Dental University)
Eiji Tanaka (Shinshu University)
Namiki Izumi (Musashino Red Cross Hospital)
Takashi Harada (Nagasaki Kidney Hospital)
Ryoichi Ando (Musashino Red Cross Hospital)
Kan Kikuchi (Tokyo Women's Medical University)

All members listed above have submitted a conflict of interest disclosure report to the General Affairs Committee.

Times and dates of meetings of the Committee for the Preparation of Guidelines for the treatment of hepatitis C virus infection in dialysis patients

1st Meeting6 January 200918:00–20:00Seiyoken, Nihonbashi
2nd Meeting17 June 200918:00–20:00Seiyoken, Nihonbashi
3rd Meeting30 September 200918:00–20:00Seiyoken, Nihonbashi
4th Meeting25 December 200918:00–20:00Seiyoken, Nihonbashi
5th Meeting5 February 201018:00–20:00Seiyoken, Nihonbashi
6th Meeting4 June 201018:00–20:00Seiyoken, Nihonbashi
55th Consensus Conference on Hepatitis C, Scientific Committee, Japanese Society for Dialysis Therapy20 June 201013:30–16:30Kobe International Conference Center, 1st Conference Room
7th Meeting6 August 201018:00–20:00Seiyoken, Nihonbashi
Public Hearing16 January 201113:00–15:00Clinical Lecture Hall, Tokyo Women's Medical University
8th Meeting4 February 201118:00–20:00Office Tokyo, 4F, Meeting Room A4

Evaluation of the evidence and recommendation levels

The evidence and recommendation levels were prepared on the basis of the position paper “Grading evidence and recommendations for clinical practice guidelines in nephrology”(2) issued by KDIGO in 2006 and the Working Group Report on the Grading of Evidence Levels and Degrees of Recommendation disclosed by the Japanese Society for Dialysis Therapy on 16 November 2009 (Table 1) (later published in the Journal of the Japanese Society for Dialysis Therapy with modifications) (3).

Table 1. Working Group Report on the grading of evidence levels and degrees of recommendation, 16 November 2009
Chairman of WG: Masashi Fukagawa
Members of WG: Kazutaka Kukita, Yusuke Tsukamoto, Tsubakihara Yoshiharu, Yoshizo Kaizu, Eiji Kusano, Masaaki Nakayama
Chairman, Subcommittee for the Preparation of Guidelines: Tadashi Tomo
Chairman, Scientific Committee: Hideki Hirakata
General Principles
(1) Considering the situation that various global and local guidelines have been issued, the following general principles are observed.
(2) The consistency of the style of the text of the guidelines will be evaluated in the future.
(3) After the report is submitted to and approved by the Board of Directors, its details will be published formally as a WG Report in the Journal of Japanese Society for Dialysis Therapy.
On the evaluation of evidence levels
(1) Basically, the current evidence grading method of KDIGO is followed (Kidney International, 2006, see the attached table).
(2) The following may be decided by the responsibility of the working group for each guideline. However, the criteria and reasons must be stated clearly.
 (a) Restriction of conditions for the adoption of research papers (size, period, etc.)
 (b) Upgrading and downgrading of evidence (depending on the situation, that the data are about Japanese subjects may be regarded as a condition of upgrading).
(3) Papers in Japanese may be adopted by the judgment of the WG if the evidence level can be evaluated.
 (a) If they are adopted, the reason for the adoption and the evaluation of the evidence level must be stated clearly.
 (b) Maximum support for publication in English must be provided until the Guidelines are published in English.
(4) Abstracts are not adopted, in principle.
On the recommendation level
(1) Graded into 2 levels (strong, weak)
(2) The following expressions are used.
 (a) It is recommended to . . . , It is recommended not to . . . (strong)
 (b) It is desirable to . . . , It is desirable not to . . . (weak)
 (c) Since negative sentences such as “It is disrecommended to . . . or it is undesirable to . . .” is a strong expression, “It is recommended not to . . . or it is desirable not to . . .” is used by attaching conditioning modifications such as “as a routine procedure”.
(3) Ungraded expert opinions may be attached to items lacking evidence. In this instance, only those agreed on by two thirds or more of the WG members are adopted.

Table of abbreviations

AFPα-fetoprotein
ALTalanine aminotransferase
ASTaspartate aminotransferase
AUCarea under the plasma concentration time curve
Ccrcreatinine clearance
Cmaxpeak serum concentration of a therapeutic drug
EIAenzyme-linked immunosorbent assay
EOB-MRIEOB-magnetic resonance imaging
EPOerythropoietin
ESAerythropoiesis stimulating agent
HAhyaluronate
HCVhepatitis C virus
IFNinterferon
KDIGOKidney Disease: Improving Global Outcomes
NIDDMnon-insulin-dependent diabetes mellitus
PCRpolymerase chain reaction
PEG-IFNpegylated interferon
PIVKA-IIproteins induced by vitamin K absence-II
PLPpyridoxal-5′-phosphate
PNALTpersistent normal ALT
ROC curvereceiver operating characteristic curve
RT-PCRreverse transcriptase PCR
RVRrapid virological response
SNMCstronger neo-minophagen C
SVRsustained virological response
Tmaxmaximum drug concentration time
TRXthioredoxin
UDCAursodeoxycholic acid
VRADvirus removal and eradication by double filtration plasma pheresis

REFERENCES

  1. Top of page
  2. INTRODUCTION
  3. REFERENCES
  4. SCREENING OF DIALYSIS PATIENTS FOR HEPATITIS C VIRUS INFECTION
  5. REFERENCES
  6. MANAGEMENT OF HEPATITIS C IN DIALYSIS PATIENTS (METHODS, FREQUENCY OF BLOOD TESTS AND IMAGING STUDIES)
  7. REFERENCES
  8. INDICATIONS OF ANTIVIRAL THERAPIES IN DIALYSIS PATIENTS
  9. REFERENCES
  10. TREATMENT OF DIALYSIS PATIENTS BY ANTIVIRAL THERAPIES
  11. REFERENCES
  12. PREVENTION OF HCV INFECTION AT HEMODIALYSIS FACILITIES
  13. REFERENCES
  • 1
    Kidney Disease: Improving Global Outcomes. KDIGO clinical practice guidelines for the prevention, diagnosis, evaluation, and treatment of Hepatitis C in chronic kidney disease. Kidney Int 2008;73(Suppl 109):S199.
  • 2
    Uhlig K, MacLeod A, Craig J et al. Grading evidence and recommendations for clinical practice guidelines in nephrology. A position statement from Kidney Disease: Improving Global Outcomes (KDIGO). Kidney Int 2006;70:205865.
  • 3
    Fukagawa M, Tsukamoto Y, Tsubakihara Y et al. On the evaluation of evidence levels and degrees of guideline recommendation. J Jpn Soc Dial Ther 2010;43:3479.

SCREENING OF DIALYSIS PATIENTS FOR HEPATITIS C VIRUS INFECTION

  1. Top of page
  2. INTRODUCTION
  3. REFERENCES
  4. SCREENING OF DIALYSIS PATIENTS FOR HEPATITIS C VIRUS INFECTION
  5. REFERENCES
  6. MANAGEMENT OF HEPATITIS C IN DIALYSIS PATIENTS (METHODS, FREQUENCY OF BLOOD TESTS AND IMAGING STUDIES)
  7. REFERENCES
  8. INDICATIONS OF ANTIVIRAL THERAPIES IN DIALYSIS PATIENTS
  9. REFERENCES
  10. TREATMENT OF DIALYSIS PATIENTS BY ANTIVIRAL THERAPIES
  11. REFERENCES
  12. PREVENTION OF HCV INFECTION AT HEMODIALYSIS FACILITIES
  13. REFERENCES

[Statements]

  • 1
    The serum aminotransferase levels are lower in dialysis patients than in individuals with normal renal function. (Evidence level: High, Recommendation level: Strong)
  • 2
    The serum aminotransferase levels are higher in HCV-antibody-positive than in negative dialysis patients, but the criteria for the general population cannot be applied to dialysis patients. (Evidence level: High, Recommendation level: Strong)
  • 3
    In dialysis patients, it is desirable to measure the serum aminotransferase levels at least once a month even if they are asymptomatic. (Evidence level: Low, Recommendation level: Weak)
  • 4
    It is recommended to perform the HCV antibody test and, if necessary, the HCV-RNA test at the introduction of dialysis and the acceptance of patients. (Evidence level: Low, Recommendation level: Strong)
  • 5
    In dialysis patients, it is desirable to perform the HCV antibody test at least once every 6 months even if HCV antibody is negative on the initial test. (Evidence level: Low, Recommendation level: Weak)
  • 6
    If the serum aminotransferase level increases with no clear cause, it is recommended to perform an ad hoc HCV-RNA or HCV core antigen test in addition to the HCV antibody test. (Evidence level: Low, Recommendation level: Strong)
  • 7
    If an HCV-positive patient considered to be due to nosocomial infection that has been detected, it is recommended to perform the HCV-RNA or HCV core antigen test in all dialysis patients who may have been exposed. (Evidence level: Very low, Recommendation level: Strong)

[Comments]

1. The serum aminotransferase level is lower in dialysis patients than in individuals with normal renal function.(Evidence level: High, Recommendation level: Strong)

Serum aminotransferase levels (AST, ALT) as indices of liver function have been reported to be lower in dialysis patients than in individuals with normal kidney function. There has been a report that the ALT level was 15.6 ± 12 IU/L in dialysis patients and 22.7 ± 18 IU/L in normal controls and that the upper limit of the normal range of ALT in dialysis patients was 27 IU/mL (1). Thus, if the upper limit of the normal range was set at 25 IU/L, then the ALT level was normal in 67% of dialysis patients (2). There is also a report that the AST levels in healthy individuals and dialysis patients were 22.3 (22.0 ± 22.7) and 20.6 (21.6 ± 23.6), respectively, that the ALT levels were 20.3 (19.9 ± 20.7) and 16.3 (15.3 ± 17.3), respectively, and that the cutoff values effective for the prediction of HCV infection were 18 for AST and 16 for ALT (3). Since the serum aminotransferase levels are lower in dialysis patients than the standards in the general population, their cutoff values for the prediction of HCV infection should be set at lower levels in these patients. It has been known that the serum aminotransferase levels in uremic patients are low and negatively correlate with the blood urea nitrogen level (4), and factors that inhibit the serum aminotransferase activities have been reported to accumulate in patients’ serum with elevations of the serum aminotransferase levels due to dialysis (5). However, the level of pyridoxal-5’-phosphate (PLP) is positively correlated with the AST and ALT levels. Additionally, serum aminotransferase levels were significantly lower in the PLP-deficient group than in the normal group, being 9.2 ± 0.3 vs. 13.4 ± 0.7 for AST and 8.6 ± 0.6 vs. 11.4 ± 0.9 for ALT. Also, as the AST and ALT levels were elevated by supplementation of PLP only in the PLP-deficient group, deficiency of PLP, which acts as a coenzyme of aminotransferases, has been suggested to partly explain the low aminotransferase levels in dialysis patients (6). There is also a report that, in uremia, the enzyme activity of PLP is lost as its lysine-binding site is carbamylated by cyanogen salts formed by urea (7). In contrast, it has also been reported that the Vitamin B6 and PLP levels are normal in dialysis patients and thus, the low serum aminotransferase levels cannot be explained by Vitamin B6 deficiency (8,9).

Therefore, based on the clinical observations to date and abnormalities of enzyme activities in uremic patients, serum aminotransferase levels are considered to be lower in dialysis patients than in people with normal kidney function.

2. The serum aminotransferase levels are higher in HCV-antibody-positive than in negative dialysis patients, but the criteria for the general population cannot be applied to dialysis patients.(Evidence level: High, Recommendation level: Strong)

The serum aminotransferase levels are normal in dialysis patients regardless of whether they are negative or positive for HCV antibody. However, the ALT level is higher in HCV antibody positive dialysis patients than in HCV antibody negative dialysis patients (2.7 ± 20.0 and 12.5 ± 8.8, respectively) (10). Particularly, the simultaneous detection of HB antigen and HCV-RNA has been related to ALT elevation. Also, it has been reported that the ALT level was 32.4 ± 24.2 and 33.7 ± 27.2 in male and female HCV-antibody-positive dialysis patients, respectively, but 17.0 ± 11.4 and 13.9 ± 6.1 in male and female HCV-antibody-negative patients, respectively. The ALT level was also reported to be higher in HCV-RNA-positive than in HCV RNA negative patients. However, the ALT level was not related to the HCV genotype (11). In HCV-antibody-positive, HCV-antibody-negative, HCV-RNA-positive, and HCV-antibody-negative dialysis patients, the ratio of ALT/upper limit of the normal range was 0.77 ± 0.57, 0.38 ± 0.23, 0.81 ± 0.57, and 0.37 ± 0.23, respectively. The cutoff value of ALT for being HCV-antibody-positive as determined from the receiver operating characteristic (ROC) curve was 50% of the upper limit of the normal range (sensitivity: 67%, specificity: 83%) and that for being HCV-RNA-positive was 45% (sensitivity: 71%, specificity 80%). Also, the observed value/upper limit of normal range of ALT was clearly higher in HCV-RNA-positive than in HCV-RNA-negative dialysis patients (12). Moreover, this value was reported not to differ in the group without hepatitis but to be higher in the group with hepatitis compared with the group without hepatitis, suggesting that the ALT level of HCV-RNA-positive dialysis patients may be useful as a marker of liver disorder obtained by liver biopsy (13). However, histological findings obtained by liver biopsy were reported to be milder, and the ALT level to be lower, in HCV-positive dialysis patients than in HCV-positive individuals with normal kidney function (14,15).

Therefore, the serum aminotransferase levels are considered to be higher in HCV-antibody-positive dialysis patients than in those negative, but the criteria for the general population are not considered to be applicable to dialysis patients.

3. In dialysis patients, it is desirable to measure the serum aminotransferase levels at least once a month even if they are asymptomatic.(Evidence level: Low, Recommendation level: Weak)

While there is no evidence concerning the frequency of measurement of the serum aminotransferase levels in dialysis patients, there have been reports that the serum aminotransferase levels and the ratio of ALT/upper limit of the normal range has been reported to be higher in HCV-antibody-positive and HCV-RNA-positive patients than in negative patients (10–12,16). Although the ALT level was elevated in only 51% of the HCV-RNA-positive patients after kidney transplantation, but that the ALT level was correlated with the degree of liver tissue damage evaluated by liver biopsy, and that ALT can serve as a marker of liver tissue damage in HCV-RNA-positive recipients of kidney transplantation (13). Therefore, observation of changes in ALT levels by regular examinations may lead to the early detection of HCV infection, and the possibility of HCV infection must always be considered even if the serum aminotransferase levels are within the normal ranges.

Liver function tests are usually performed once a month in dialysis patients. It is desirable to measure the serum aminotransferase levels at least once a month even in asymptomatic patients.

4. It is recommended to perform the HCV antibody test and, if necessary, the HCV-RNA test at the introduction of dialysis and the acceptance of patients.(Evidence level: Low, Recommendation level: Strong)

In HCV-positive chronic nephritis, there has been a report that membranoproliferative glomerulonephritis was the most frequent, accounting for 54%, that cryoglobulinemia was noted in 54% of the patients, and that HCV-RNA was detected in 66% on cryoprecipitation and 22% of frozen sections (17). Immunocomplexes are noted in the glomeruli by kidney biopsy, and they have been shown to be a cause of chronic nephritis such as membranoproliferative glomerulonephritis in which factors such as cryoglobulin are involved (18–21). The HCV antibody-positive rate is 7.9% in patients with kidney diseases compared with 1.03% in healthy individuals and is particularly high (16.6%) in patients with glomerulonephritis. This rate is higher in those patients with a Ccr level of less than 30 mL/min than in patients with a Ccr level of 30 mL/min or higher (13% vs. 2.7%). Furthermore, HCV infection has been reported to be involved in the etiology of glomerulonephritis (22). There has also been a report that HCV was positive in 3.9% of the 1041 CKD patients, and that 95% of HCV-positive patients showed viremia, and that the HCV-positive rate is high in CKD patients (23). It has also been reported that HCV antibody was positive in 12.7% of dialysis patients, and that of the dialysis patients, the HCV-antibody-positive rate was higher in those with non-insulin dependent diabetes mellitus (NIDDM) (20.8%) than in those with no diabetes mellitus (DM) (10%) (24), and that the HCV-positive rate in NIDDM patients was high at 19.5% (25). Based on these reports, HCV infection is likely to be involved in the pathogenesis of chronic kidney diseases. Therefore, the HCV-antibody-positive rate has been reported to be high at 7.3% (26) or 14.4% (27) in dialysis patients at the introduction of dialysis therapy. Moreover, according to the Dialysis Outcomes and Practice Patterns Study (DOPPS), the HCV-positive rate varied from 2.6% to 22.9% among the participating countries, and its increases were related to the dialysis period, male gender, black race, diabetes status, HBV infection, kidney transplantation, and alcohol and drug dependence. Many other studies have clarified the wide differences in the HCV-antibody-positive rate and the HCV-antibody-positive-conversion rate among dialysis patients at different facilities (28,29). Particularly, the HCV-positive-conversion rate has been reported to be high at facilities with a high HCV-positive rate (30). Therefore, it is recommended to perform HCV antibody or HCV-RNA test at the introduction of dialysis therapy or at transfer of patients to another hospital.

5. In dialysis patients, it is desirable to perform the HCV antibody test at least once every 6 months even if HCV antibody is negative on the initial test. (Evidence level: Low, Recommendation level: Weak)

While there is no evidence concerning the frequency of HCV antibody test in dialysis patients, HCV positivity was reported to be detected in 70 days (36–210 days) by second-generation enzyme immunoassay (EIA) and in 49 days (27–119 days) by the third generation EIA from the detection of abnormality of ALT. In patients with acute HCV hepatitis, HCV-RNA becomes detectable in 1–2 weeks after HCV infection, and chronic HCV hepatitis is diagnosed when HCV-RNA persists for 6 months or longer. The chronicity rate is 55–85%. In acute HCV hepatitis cases, the ALT level begins to increase 2–8 weeks after infection. Symptoms usually appear 3–12 weeks (mean 7 weeks) after infection, and HCV antibody become positive simultaneously or with a slight delay. If the infection takes a chronic course, the ALT level increases and changes. Some immune-deficient individuals remain HCV-antibody-negative even after HCV infection (31). In a previous study, the HCV-RNA-positive-rate increased from 12.9% to 15.7% after a 4-year follow-up, de novo HCV infection was observed in one patient during this period with an HCV-positive-conversion rate of 0.33%/year, and the initial examination is considered to have been made during the window period in five of the patients, so that it was concluded that the HCV-RNA test must be performed once a month to reduce nosocomial HCV infection (32).

Also, there is a report that the HCV-antibody positive conversion rate was 0.44%/year when examined at 6-month intervals while observing the CDC standard preventive measures (33). Therefore, the KDIGO guidelines recommend to perform the HCV antibody test in HCV-antibody-negative patients once every 6–12 months (intermediate recommendation level) (34). The KDIGO also recommends testing by the enzyme antibody method at facilities with a low HCV infection rate and by the nucleic acid amplification technique at those with a high HCV infection rate (intermediate recommendation level) (34).

Based on these observations, it is considered desirable to perform the HCV antibody test at least once every 6 months in dialysis patients even if the HCV antibody were negative on the initial test.

6. If the serum aminotransferase level increases with no clear cause, it is recommended to perform an ad hoc HCV-RNA test or HCV core antigen test in addition to the HCV antibody test.(Evidence level: Low, Recommendation level: Strong)

If the serum aminotransferase level has increased with no obvious reason, there is the possibility of HCV infection. It has been reported that 9% of dialysis patients were HCV-RNA-positive even if they were HCV-antibody-negative, and the viral level is considered to have been low in such patients. Caution is needed in immune-deficient individuals such as dialysis patients because of a low viral level (35). Therefore, HCV infection cannot be excluded on the basis of a negative HCV antibody test, the HCV-RNA test must be performed when considered necessary. For the HCV-RNA assay, real-time PCR is recommended because of its high sensitivity (36,37). It has also been reported that patients become positive for the HCV core antigen 2 days after HCV infection but do not become positive for the HCV antibody until 50.8 days after infection. Thus a high-sensitivity assay for the HCV core antigen that is an inexpensive and quick method for the judgment of HCV infection, is useful for the diagnosis of HCV infection and is used during the window period until HCV antibody becomes positive (38,39). KDIGO recommends that the HCV test by a nucleic acid amplification technique should be carried out if the serum aminotransferase level has increased with no clear reason (strong recommendation) (34). Also, the determination of the viral level and HCV genotype by the HCV-RNA assay contributes to the evaluation of responses to interferon therapy (36). Thus if the serum aminotransferase level has increased with no clear cause, it is recommended to perform the HCV-RNA or HCV core antigen test ad hoc in addition to the HCV antibody test.

7. If an HCV-positive patient considered to be due to nosocomial infection has been detected, it is recommended to perform the HCV-RNA or HCV core antigen test in all dialysis patients who may have been exposed.(Evidence level: Very low, Recommendation level: Strong)

If a patient is judged to be newly positive on the HCV antibody test, the possibility of a nosocomial outbreak of HCV infection must be examined. As mentioned in the comment for Statement 6, the possibility of HCV infection cannot be excluded in patients who may have been exposed even if they are HCV-antibody-negative. Also, to fill the window period of HCV infection, a test for HCV-RNA or HCV core antigen must be performed. KDIGO recommends that surveillance to examine whether nosocomial infection has not occurred by the HCV-RNA test using a nucleic acid amplification technique be carried out if an HCV-positive patient considered to be due to nosocomial infection has been detected (strong recommendation). In addition, KDIGO recommends re-examination within 2–12 weeks after an initial negative examination (weak recommendation) (34).

Therefore, if an HCV-positive patient considered to be due to nosocomial infection has been detected, it is recommended to carry out the HCV-RNA or HCV core antigen test in all dialysis patients who may have been exposed.

REFERENCES

  1. Top of page
  2. INTRODUCTION
  3. REFERENCES
  4. SCREENING OF DIALYSIS PATIENTS FOR HEPATITIS C VIRUS INFECTION
  5. REFERENCES
  6. MANAGEMENT OF HEPATITIS C IN DIALYSIS PATIENTS (METHODS, FREQUENCY OF BLOOD TESTS AND IMAGING STUDIES)
  7. REFERENCES
  8. INDICATIONS OF ANTIVIRAL THERAPIES IN DIALYSIS PATIENTS
  9. REFERENCES
  10. TREATMENT OF DIALYSIS PATIENTS BY ANTIVIRAL THERAPIES
  11. REFERENCES
  12. PREVENTION OF HCV INFECTION AT HEMODIALYSIS FACILITIES
  13. REFERENCES

MANAGEMENT OF HEPATITIS C IN DIALYSIS PATIENTS (METHODS, FREQUENCY OF BLOOD TESTS AND IMAGING STUDIES)

  1. Top of page
  2. INTRODUCTION
  3. REFERENCES
  4. SCREENING OF DIALYSIS PATIENTS FOR HEPATITIS C VIRUS INFECTION
  5. REFERENCES
  6. MANAGEMENT OF HEPATITIS C IN DIALYSIS PATIENTS (METHODS, FREQUENCY OF BLOOD TESTS AND IMAGING STUDIES)
  7. REFERENCES
  8. INDICATIONS OF ANTIVIRAL THERAPIES IN DIALYSIS PATIENTS
  9. REFERENCES
  10. TREATMENT OF DIALYSIS PATIENTS BY ANTIVIRAL THERAPIES
  11. REFERENCES
  12. PREVENTION OF HCV INFECTION AT HEMODIALYSIS FACILITIES
  13. REFERENCES

[Statements]

  • 1
    Similar to patients with normal renal function, liver biopsy is the most reliable method to evaluate the liver disease of HCV-infected dialysis patients. It is mostly recommended, when transplantation is considered. (Evidence level: Low, Recommendation level: Weak)
  • 2
    The prognosis is significantly worse in HCV-infected dialysis patients than in uninfected dialysis patients. (Evidence level: High, Recommendation level: None)
  • 3
    It is recommended to periodically follow-up HCV-infected dialysis patients to screen for liver cirrhosis and early detection of hepatocellular carcinoma. (Evidence level: High, Recommendation level: Strong)
  • 4
    Iron has hepatocyte toxicity, and excessive hepatic iron deposition is an exacerbating factor of chronic hepatitis C and promotes hepatocarcinogenesis. In consideration of these facts, it is desirable to avoid iron overload in HCV-infected dialysis patients. (Evidence level: Low, Recommendation level: Weak)

[Comments]

1. Evaluation of the liver disease in HCV-infected dialysis patients

Similar to HCV-infected patients with normal renal function, liver biopsy is the most reliable method to evaluate the liver disease in HCV-infected dialysis patients. It is mostly recommended when kidney transplantation is considered. (Evidence level: Low, Recommendation level: Weak)

In dialysis patients, the aminotransferase levels are often low even when they are infected with HCV, and liver biopsy is the most reliable method to evaluate the liver disease of HCV-infected dialysis patients as well as HCV-infected patients with normal renal function.

Concerning histological changes of the liver, there have been many reports that inflammation and fibrosis are observed less frequently in HCV-infected dialysis patients than in HCV-infected patients with normal renal function (1–5). Cotler et al. (3) showed that HCV-infected dialysis patients had less inflammatory activity and a lower proportion of bridging fibrosis or cirrhosis than in hepatitis C patients with normal renal function. In addition, as a histological finding by liver biopsy, Shiavon et al. (4) and Hu et al. (6) reported that HCV-infected dialysis patients showed stage III and IV severe fibrosis significantly less frequently than those with normal renal function. Also, Sterling et al. (7) noted that the severity of liver fibrosis and liver cirrhosis was similar to that in hepatitis C patients with normal renal function showing a normal ALT level but was milder than in those showing a high ALT level. There is also a report that the progression rate of liver fibrosis corrected for the infected period was relatively slow (8). However, de Paula Farah et al. (9) have reported that histological findings of both fibrosis and inflammation are comparable between HCV-infected dialysis patients and HCV-infected patients with normal renal function.

On histological examination of the liver in HCV-infected dialysis patients before kidney transplantation, severe liver fibrosis or cirrhosis was noted in 5.5–32%, and liver cirrhosis was noted in 0–24% (2,3,5–8,10,11). The survival rate of dialysis patients with biopsy-proven cirrhosis during 10 years after transplantation was low at 26%, indicating that liver cirrhosis is an independent risk factor of poor prognosis, and liver cirrhosis is a contraindication for kidney transplantation (12). It has also been clarified that the prevalence of liver disorders after transplantation increases markedly (five times) if there is HCV infection before transplantation (13), and that the progression of hepatic lesions is faster in HCV-infected kidney transplantation patients than in HCV-infected patients with normal kidney function (14). Since the results of blood tests are not correlated with these histological changes of the liver, it is necessary to evaluate histological changes by liver biopsy before kidney transplantation (5,7,10,11,15,16).

In dialysis patients, it has been reported that percutaneous liver biopsy can be performed safely (17), but it generally increases the risk of hemorrhage. Transjugular liver biopsy is safer but is not performed widely.

2. Prognosis of HCV-infected patients

The prognosis is significantly worse in HCV-infected dialysis patients than in uninfected dialysis patients. (Evidence level: High, Recommendation level: None)

In 90% or more of dialysis patients, HCV infection leads to chronic hepatitis (18). The effects of HCV infection on the prognosis of dialysis patients have become an important issue due to the increase in patients with longer dialysis duration.

Many studies have indicated that the prognosis of HCV-infected dialysis patients is significantly worse than that of uninfected dialysis patients (19–25). According to meta-analysis by Fabrizi et al. (26), adjusted relative risk of all-cause mortality in HCV-infected dialysis patients was 1.34 on the basis of seven clinical studies involving 11 589 patients. Causes of death related to liver diseases such as hepatocellular carcinoma and liver cirrhosis were 5.89 times more frequent in the former group.

The incidence of liver cirrhosis in HCV-infected dialysis patients varies among reports from 1.3–12.5% (10,11,16,27). According to the investigation by Akiba et al. (28), the incidence of liver cirrhosis in HCV-antibody-positive dialysis patients was 8.57/1000/year.

There have been a few reports that the prognosis of liver disease is better in HCV-infected dialysis patients than in patients with normal renal function. Okuda et al. (29) reported that none of the 189 patients with HCV-infected dialysis patients showed progression to liver cirrhosis. Also, Ishida et al. (30) showed by a questionnaire survey of 6366 dialysis patients that hepatocellular carcinoma and liver cirrhosis were observed in 1.8% and 8.6%, respectively, which were lower than the percentages in patients with normal renal function. However, reports regarding the progression of liver diseases have been inconsistent, with an 8-year prospective cohort study by Espinosa et al. (31) showing the rapid progression to liver cirrhosis in dialysis patients, being observed after a median of 7 years from the initial elevation in ALT, which is in contrast to the general population.

Generally, the incidence of hepatocellular carcinoma in HCV-infected patients is proportionate to the severity of liver fibrosis, and its incidence in patients with liver cirrhosis showing severest fibrosis is reported to be about 8%/year (32). However, there is no detailed report on the incidence of hepatocellular carcinoma in HCV-infected dialysis patients. Nakayama et al. (20) followed up 276 HCV-antibody-positive dialysis patients over 6 years and reported liver cirrhosis in 30 and hepatocellular carcinoma in eight at the end of the follow-up period. If most hepatocellular carcinomas are assumed to have occurred in liver cirrhosis, the annual rate of progression from liver cirrhosis to hepatocellular carcinoma is considered to be at least 4%. The finding that liver cirrhosis was noted in 30 (13.2%) of the 276 patients suggests that the progression rate to liver cirrhosis is nearly the same as that in non-dialysis patients.

In dialysis patients, the incidence of, and mortality due to, cancers have often been reported to be higher than in the general population. According to a report from Italy, the incidence of hepatocellular carcinoma is 2.41 times higher in dialysis patients than in those with normal renal function (33). According to a study in Okinawa, Japan, the incidence of cancer in dialysis patients was 2.48 times higher in males and 3.99 times higher in females than that in the general population, but the incidence of hepatocellular carcinoma was similar in males and lower in females compared with that in the general population (34). In a prospective study of a cohort of 233 HCV-infected dialysis patients, hepatocellular carcinoma was observed in three patients during 10 years (0.53%/year) (35). According to a questionnaire survey of 67 970 patients, the incidence of hepatocellular carcinoma was reported to be 3.87/1000 HCV-infected dialysis patients/year during a 3-year period (28).

At the end of 1999, the prevalence of liver cirrhosis was 8.25% and 11.84% in HCV-antibody-positive patients and HCV-RNA-positive dialysis patients, respectively, and that of hepatocellular carcinoma was 2.16% and 2.59%, respectively. In those coinfected with HBV and HCV, the prevalences of liver cirrhosis and hepatocellular carcinoma were 12.2% and 2.7%, respectively (36). In patients coinfected with HBV and HCV, liver damage is notable even in those with normal renal function. However, as the same is observed also in HCV-infected dialysis patients (8), particularly close follow-up is needed.

To date, there has been no control study comparing the prognosis between HCV-infected dialysis patients and HCV-infected patients with normal renal function. This comparison may be difficult because of the reduced life expectancy in dialysis patients.

There has been no report on the prognosis-improving effect of therapeutic intervention in HCV-infected dialysis patients.

Reports on the viral load level in dialysis patients have been inconsistent: It has been reported to be low by some (37,38), not to differ by others (2,39), and to be high in still others (6). The HCV RNA levels were reported to decrease in dialysis patients but not to change in the control group during a 3-year follow-up by Furusyo et al. (38) and during a 10-year follow-up by Okuda et al. (29), respectively.

In a comparison concerning comobidities, hypertension, hepatitis B, liver cirrhosis, wasting, anemia, and HIV infection were more prevalent, but coronary artery disease and stroke were less prevalent in 5737 HCV-infected dialysis patients than in 11 228 uninfected dialysis patients matched for the time at which dialysis was initiated. On the other hand, there is also a report that coronary artery disease was more prevalent in HCV-infected dialysis patients (40).

3. Follow-up

It is recommended to periodically follow-up HCV-infected dialysis patients for the diagnosis of liver cirrhosis and early detection of hepatocellular carcinoma. (Evidence level: High, Recommendation level: Strong)

HCV-infected dialysis patients develop liver cirrhosis or hepatocellular carcinoma more frequently than uninfected dialysis patients, and periodic follow-up for the diagnosis of liver cirrhosis and early detection of hepatocellular carcinoma is necessary.

Follow up testing to evaluate the progression of liver disease (liver fibrosis, liver cirrhosis, hepatocellular carcinoma) include blood tests of AST, ALT, γ-GTP, total bilirubin, albumin, platelet count, and AST/platelet ratio and imaging techniques such as abdominal ultrasonography and contrast-enhanced CT.

Since the AST and ALT levels are low in dialysis patients regardless of the presence or absence of liver disease, blood tests of liver fibrosis are necessary as well as those of AST and ALT for the follow-up of dialysis patients. In patients with chronic hepatitis C, in general, the platelet count has been reported to reflect liver fibrosis (41). The platelet count is also useful as a marker of liver fibrosis in dialysis patients (4). In HCV-infected dialysis patients, it has been reported that platelets decrease with time compared with uninfected dialysis patients and that the increases in ALT and decreases in the platelet count are related (42).

Generally, a high AST level as well as a low platelet count is related to liver fibrosis, and the AST (IU/L)/platelet count (×104/µL) ratio is useful as a marker of liver fibrosis. This marker is also useful in dialysis patients, indicating no fibrosis when it is less than 0.40 but fibrosis when it is 0.95 or higher (4,7).

In dialysis patients with liver cirrhosis, a high ALT level and low albumin, total cholesterol, and white blood cell count have been reported in addition to a low platelet count (36).

Ultrasonography is also considered useful for the dialysis of liver disorders in dialysis patients, and ultrasound findings are correlated with the hyaluronic acid level and platelet count (35).

The concentrations of α-fetoprotein and PIVKA-II, which are markers of hepatocellular carcinoma, can be interpreted in dialysis patients similar to patients with normal renal function (43,44).

Since some dialysis patients as well as patients with normal renal function are positive for HCV antibody but negative for HCV-RNA, the HCV-RNA test is necessary if HCV antibody is positive.

There is no evidence concerning the frequency of follow-up tests.

In Japan, there was a nationwide survey of the state of execution of tests for viral hepatitis in dialysis patients, particularly those for the detection of hepatocellular carcinoma, in 2009 (45). According to this survey, periodic follow-up using imaging techniques including ultrasonography and CT are performed in patients positive for hepatitis virus at 80% of the facilities, and the frequency of the follow-up was less than once a year in 5.4%, once a year in 56.5%, two times a year in 28.8%, and three or more times a year in 9.3%. Tumor markers were measured periodically at only 48.9% of the facilities, and the establishment of follow-up plans and systems according to the guidelines is anticipated.

The KDIGO guidelines recommend that follow up testing for HCV-related comobidities (such as liver cirrhosis and hepatocellular carcinoma) should be performed every 6 months in patients with liver cirrhosis and every year in those without liver cirrhosis (46).

However, the working group proposes the more close follow-up plan for the detection of hepatocellular carcinoma on the basis of the follow-up plan for patients with chronic hepatitis C recommended by the Japan Society of Hepatology (47).

  • Patients with chronic hepatitis, patients with a platelet count of 105/µL or higher

  • Tests: AFP, PIVKA-II, abdominal ultrasonography (about once every 6 months-1 year)

  • Liver cirrhosis patients, patients with a platelet count of less than 105/µL

  • Tests: AFP, PIVKA-II, abdominal US (about once every 3 months), contrast-enhanced CT (about once every 6 months)

If contrast-enhanced CT cannot be performed, or if the diagnosis is difficult, MRI using EOB containing a small amount of gadolinium, which, in principle, should be substituted for another test in dialysis patients, should be considered.

A test of the AFP-L3 fraction must be considered when the AFP level is high.

4. Administration of iron preparations

Iron has hepatocyte toxicity, and excessive hepatic iron deposition is an exacerbating factor of chronic hepatitis C and promotes hepatocarcinogenesis. In consideration of these facts, it is desirable to avoid iron overload in HCV-infected dialysis patients. (Evidence level: Low, Recommendation level: Weak)

Iron is a trace element indispensable for hemoglobin synthesis. Iron stored in the liver is released into blood when necessary. It has been shown that iron has hepatocyte toxicity and that excessive hepatic iron deposition is an exacerbating factor of chronic hepatitis C and promotes hepatocarcinogenesis. Patients with chronic hepatitis C show excessive iron deposition in liver tissue, and iron-dependent oxidative stress has been suggested to be involved in various stages including hepatocyte damage, fatty degeneration, fibrosis, and carcinogenesis. Iron deposition in the liver has also been reported to be related to hyporesponsiveness to interferon therapy in patients with normal renal function (48). Moreover, iron depletion therapy has been reported to significantly lower the risk of hepatocellular carcinoma in hepatitis C patients (49).

In hemodialysis patients, also, the serum ferritin level shows significant positive correlations with the AST and ALT levels in those positive for HCV antibody (50). There has been no large-scale clinical study evaluating the effects of iron administration on the liver in HCV-infected dialysis patients. Kurihara et al. (51) administered an intravenous iron preparation to HCV-antibody-positive dialysis patients for one year with a target serum ferritin level of 200–300 ng/mL, though the number of patients was small, observed changes in the liver function, and compared them with those in HCV-antibody-negative dialysis patients. According to this study, the AST and ALT levels increased in two of the seven HCV-antibody-positive patients but could be controlled by the administration of stronger neo-minophagen C, no change was observed in other markers such as the viral level, cholinesterase level, and platelet count, and the administration of an iron preparation to HCV-antibody-positive patients was safe. In their study, however, no histological evaluation was made, and long-term consequences are unknown. Kato et al. (52) showed that the oxidative stress marker levels were high in HCV-infected dialysis patients and were increased further by the administration of an iron preparation.

On the other hand, HCV-infected dialysis patients have been shown to have a high endogenous erythropoietin concentration and need a lower dose of erythropoietin (53). This is considered to be due to an increase in the erythropoietin production by hepatocytes in the process of hepatocyte regeneration. The same report showed that they also require a lower dose of iron. This is considered to be due to the release of iron stored in hepatocytes induced by inflammation, causing an increase in ferritin.

From these observations, caution to avoid iron overload is necessary in administering iron preparations to HCV-infected dialysis patients. Therefore, in HCV-infected dialysis patients, iron supplementations should be restricted to anemia not responding even to the maximum dose of an ESA preparation (54).

Package inserts mention severe liver disorder as a contraindication of intravenous iron preparations.

REFERENCES

  1. Top of page
  2. INTRODUCTION
  3. REFERENCES
  4. SCREENING OF DIALYSIS PATIENTS FOR HEPATITIS C VIRUS INFECTION
  5. REFERENCES
  6. MANAGEMENT OF HEPATITIS C IN DIALYSIS PATIENTS (METHODS, FREQUENCY OF BLOOD TESTS AND IMAGING STUDIES)
  7. REFERENCES
  8. INDICATIONS OF ANTIVIRAL THERAPIES IN DIALYSIS PATIENTS
  9. REFERENCES
  10. TREATMENT OF DIALYSIS PATIENTS BY ANTIVIRAL THERAPIES
  11. REFERENCES
  12. PREVENTION OF HCV INFECTION AT HEMODIALYSIS FACILITIES
  13. REFERENCES
  • 1
    Espinosa M, Martin-Malo A, Alvarez de Lara MA, Soriano S, Aljama P. High ALT levels predict viremia in anti-HCV-positive HD patients if a modified normal range of ALT is applied. Clin Nephrol 2000;54:1516.
  • 2
    Alric L, Di-Martino V, Selves J et al. Long-term impact of renal transplantation on liver fibrosis during hepatitis C virus infection. Gastroenterology 2002;123:14949.
  • 3
    Cotler SJ, Diaz G, Gundlapalli S et al. Characteristics of hepatitis C in renal transplant candidates. J Clin Gastroenterol 2002;35:1915.
  • 4
    Schiavon LL, Schiavon JL, Filho RJ et al. Simple blood tests as noninvasive markers of liver fibrosis in hemodialysis patients with chronic hepatitis C virus infection. Hepatology 2007;46:30714.
  • 5
    Trevizoli JE, de Paula Menezes R, Ribeiro Velasco LF et al. Hepatitis C is less aggressive in hemodialysis patients than in nonuremic patients. Clin J Am Soc Nephrol 2008;3:138590.
  • 6
    Hu KQ, Lee SM, Hu SX, Xia VW, Hillebrand DJ, Kyulo NL. Clinical presentation of chronic hepatitis C in patients with end-stage renal disease and on hemodialysis versus those with normal renal function. Am J Gastroenterol 2005;100:20108.
    Direct Link:
  • 7
    Sterling RK, Sanyal AJ, Luketic VA et al. Chronic hepatitis C infection in patients with end stage renal disease: characterization of liver histology and viral load in patients awaiting renal transplantation. Am J Gastroenterol 1999;94:357682.
    Direct Link:
  • 8
    Becker VR, Badiani RG, Lemos LB et al. Factors associated with the progression of hepatic fibrosis in end-stage kidney disease patients with hepatitis C virus infection. Eur J Gastroenterol Hepatol 2009;21:13959.
  • 9
    de Paula Farah K, Carmo RA, de Figueiredo Antunes CM et al. Hepatitis C, HCV genotypes and hepatic siderosis in patients with chronic renal failure on haemodialysis in Brazil. Nephrol Dial Transplant 2007;22:202731.
  • 10
    Martin P, Carter D, Fabrizi F et al. Histopathological features of hepatitis C in renal transplant candidates. Transplantation 2000;69:147984.
  • 11
    Pol S, Romeo R, Zins B et al. Hepatitis C virus RNA in anti-HCV positive hemodialyzed patients: significance and therapeutic implications. Kidney Int 1993;44:1097100.
  • 12
    Mathurin P, Mouquet C, Poynard T et al. Impact of hepatitis B and C virus on kidney transplantation outcome. Hepatology 1999;29:25763.
  • 13
    Gentil MA, Rocha JL, Rodríguez-Algarra G et al. Impaired kidney transplant survival in patients with antibodies to hepatitis C virus. Nephrol Dial Transplant 1999;14:245560.
  • 14
    Zylberberg H, Nalpas B, Carnot F et al. Severe evolution of chronic hepatitis C in renal transplantation: a case control study. Nephrol Dial Transplant 2002;17:12933.
  • 15
    Caramelo C, Ortiz A, Aguilera B et al. Liver disease patterns in hemodialysis patients with antibodies to hepatitis C virus. Am J Kidney Dis 1993;22:8228.
  • 16
    Al-Wakeel J, Malik GH, Al-Mohaya S et al. Liver disease in dialysis patients with antibodies to hepatitis C virus. Nephrol Dial Transplant 1996;11:22658.
  • 17
    Pawa S, Ehrinpreis M, Mutchnick M, Janisse J, Dhar R, Siddiqui FA. Percutaneous liver biopsy is safe in chronic hepatitis C patients with end-stage renal disease. Clin Gastroenterol Hepatol 2007;5:131620.
  • 18
    Simon N, Couroucé AM, Lemarrec N, Trépo C, Ducamp S. A twelve year natural history of hepatitis C virus infection in hemodialyzed patients. Kidney Int 1994;46:50411.
  • 19
    Kalantar-Zadeh K, Kilpatrick RD, McAllister CJ et al. Hepatitis C virus and death risk in hemodialysis patients. J Am Soc Nephrol 2007;18:158493.
  • 20
    Nakayama E, Akiba T, Marumo F, Sato C. Prognosis of anti-hepatitis C virus antibody-positive patients on regular hemodialysis therapy. J Am Soc Nephrol 2000;11:1896902.
  • 21
    Stehman-Breen CO, Emerson S, Gretch D, Johnson RJ. Risk of death among chronic dialysis patients infected with hepatitis C virus. Am J Kidney Dis 1998;32:62934.
  • 22
    Pereira BJ, Natov SN, Bouthot BA et al. Effects of hepatitis C infection and renal transplantation on survival in end-stage renal disease. The New England Organ Bank Hepatitis C Study Group. Kidney Int 1998;53:137481.
  • 23
    Goodkin DA, Bragg-Gresham JL, Koenig KG et al. Association of comorbid conditions and mortality in hemodialysis patients in Europe, Japan, and the United States: the Dialysis Outcomes and Practice Patterns Study (DOPPS). J Am Soc Nephrol 2003;14:32707.
  • 24
    Di Napoli A, Pezzotti P, Di Lallo D, Petrosillo N, Trivelloni C, Di Giulio S, Lazio Dialysis Registry. Epidemiology of hepatitis C virus among long-term dialysis patients: a 9-year study in an Italian region. Am J Kidney Dis 2006;48:62937.
  • 25
    Nakai S, Shinzato T, Sanaka T et al. The Current State of Chronic Dialysis Treatment in Japan (as of December 31, 2000). Ther Apher Dial 2002;7:335.
  • 26
    Fabrizi F, Takkouche B, Lunghi G, Dixit V, Messa P, Martin P. The impact of hepatitis C virus infection on survival in dialysis patients: meta-analysis of observational studies. J Viral Hepat 2007;14:697703.
  • 27
    Al Meshari K, al Ahdal M, Alfurayh O, Ali A, De Vol E, Kessie G. New insights into hepatitis C virus infection of hemodialysis patients: the implications. Am J Kidney Dis 1995;25:5728.
  • 28
    Akiba T, Kawaguchi Y, Kuroda M et al. Investigation of the real state of HCV infection at Japanese dialysis facilities. J Jpn Soc Dial Ther 1994;27:277782.
  • 29
    Okuda K, Yokosuka O. Natural history of chronic hepatitis C in patients on hemodialysis: case control study with 4–23 years of follow-up. World J Gastroenterol 2004;10:220912.
  • 30
    Ishida H, Agishi T, Koyama I et al. Hemodialysis paradox: survey on the incidence rate of hepatocellular carcinoma in antihepatitis virus C-antibody-positive chronic hemodialysis patients. Artif Organs 2001;25:5860.
  • 31
    Espinosa M, Martin-Malo A, Alvarez de Lara MA, Aljama P. Risk of death and liver cirrhosis in anti-HCV-positive long-term haemodialysis patients. Nephrol Dial Transplant 2001;16:166974.
  • 32
    Yoshida H, Shiratori Y, Moriyama M et al. Interferon therapy reduces the risk for hepatocellular carcinoma: national surveillance program of cirrhotic and noncirrhotic patients with chronic hepatitis C in Japan. IHIT Study Group. Inhibition of Hepatocarcinogenesis by Interferon Therapy. Ann Intern Med 1999;131:17481.
  • 33
    Buccianti G, Maisonneuve P, Ravasi B, Cresseri D, Locatelli F, Boyle P. Cancer among patients on renal replacement therapy: a population-based survey in Lombardy, Italy. Int J Cancer 1996;66:5913.
  • 34
    Iseki K, Osawa A, Fukiyama K. Evidence for increased cancer deaths in chronic dialysis patients. Am J Kidney Dis 1993;22:30813.
  • 35
    Furusyo N, Hayashi J, Kanamoto-Tanaka Y et al. Liver damage in hemodialysis patients with hepatitis C virus viremia: a prospective 10-year study. Dig Dis Sci 2000;45:22218.
  • 36
    Japanese Society for Dialysis Therapy. Present state of chronic dialysis therapy in Japan (as of December 31, 1999). 2001;34:131.
  • 37
    Rampino T, Arbustini E, Gregorini M et al. Hemodialysis prevents liver disease caused by hepatitis C virus: role of hepatocyte growth factor. Kidney Int 1999;56:228691.
  • 38
    Furusyo N, Hayashi J, Ariyama I et al. Maintenance hemodialysis decreases serum hepatitis C virus (HCV) RNA levels in hemodialysis patients with chronic HCV infection. Am J Gastroenterol 2000;95:4906.
    Direct Link:
  • 39
    Azevedo HA, Villela-Nogueira CA, Perez RM et al. Similar HCV viral load levels and genotype distribution among end-stage renal disease patients on hemodialysis and HCV-infected patients with normal renal function. J Nephrol 2007;20:60916.
  • 40
    Butt AA, Evans R, Skanderson M, Shakil AO. Comorbid medical and psychiatric conditions and substance abuse in HCV infected persons on dialysis. J Hepatol 2006;44:8648.
  • 41
    Matsumura H, Moriyama M, Goto I, Tanaka N, Okubo H, Arakawa Y. Natural course of progression of liver fibrosis in Japanese patients with chronic liver disease type C—a study of 527 patients at one establishment. J Viral Hepat 2000;7:26875.
  • 42
    Nishida C, Uto H, Oketani M et al. Clinical significance of alanine aminotransferase levels and the effect of ursodeoxycholic acid in hemodialysis patients with chronic hepatitis C. J Gastroenterol 2010;45:32634.
  • 43
    Odagiri E, Jibiki K, Takeda M et al. Effect of hemodialysis on the concentration of the seven tumor markers carcinoembryonic antigen, alpha-fetoprotein, squamous cell carcinoma-related antigen, neuron-specific enolase, CA125, CA19-9 and CA15-3 in uremic patients. Am J Nephrol 1991;11:3638.
  • 44
    Kato A, Yasuda H, Togawa A et al. Measurement of des-gamma-carboxy prothrombin levels in hemodialysis patients positive for anti-hepatitis virus C antibody. Clin Nephrol 2002;58:296300.
  • 45
    Ando R, Akiba T. Present state of preventive measures against nosocomial hepatitis virus infections at hemodialysis facilities. J Jpn Soc Dial Ther 2009;42:42333.
  • 46
    Gordon CE, Balk EM, Becker BN et al. KDOQI US commentary on the KDIGO clinical practice guideline for the prevention, diagnosis, evaluation, and treatment of hepatitis C in CKD. Am J Kidney Dis 2008;52:81125.
  • 47
    Japan Society of Hepatology, ed. Guidelines for the Treatment of Chronic Hepatitis 2008. Tokyo: Bunkodo, 2008.
  • 48
    Clemente MG, Congia M, Lai ME et al. Effect of iron overload on the response to recombinant interferon-alfa treatment in transfusion-dependent patients with thalassemia major and chronic hepatitis C. J Pediatr 1994;125:1238.
  • 49
    Kato J, Miyanishi K, Kobune M et al. Long-term phlebotomy with low-iron diet therapy lowers risk of development of hepatocellular carcinoma from chronic hepatitis C. J Gastroenterol 2007;42:8306.
  • 50
    Caramelo C, Albalate M, Bermejillo T et al. Relationships between plasma ferritin and aminotransferase profile in haemodialysis patients with hepatitis C virus. Nephrol Dial Transplant 1996;11:17926.
  • 51
    Kurihara I, Saito T. Significance of intravenous iron injection therapy in HCV-antibody-positive dialysis patients. J Jpn Soc Nephrol 2002;44:38995.
  • 52
    Kato A, Odamaki M, Nakamura H, Yodoi J, Hishida A. Elevation of blood thioredoxin in hemodialysis patients with hepatitis C virus infection. Kidney Int 2003;63:22628.
  • 53
    Altintepe L, Kurtoglu E, Tonbul Z, Yeksan M, Yildiz A, Türk S. Lower erythropoietin and iron supplementation are required in hemodialysis patients with hepatitis C virus infection. Clin Nephrol 2004;61:34751.
  • 54
    Japanese Society for Dialysis Therapy. 2008 edition of the Guidelines for the Treatment of Renal Anemia in Patients with Chronic Kidney Disease, Japanese Society for Dialysis Therapy. J Jpn Soc Dial Ther 2008;41:661716.

INDICATIONS OF ANTIVIRAL THERAPIES IN DIALYSIS PATIENTS

  1. Top of page
  2. INTRODUCTION
  3. REFERENCES
  4. SCREENING OF DIALYSIS PATIENTS FOR HEPATITIS C VIRUS INFECTION
  5. REFERENCES
  6. MANAGEMENT OF HEPATITIS C IN DIALYSIS PATIENTS (METHODS, FREQUENCY OF BLOOD TESTS AND IMAGING STUDIES)
  7. REFERENCES
  8. INDICATIONS OF ANTIVIRAL THERAPIES IN DIALYSIS PATIENTS
  9. REFERENCES
  10. TREATMENT OF DIALYSIS PATIENTS BY ANTIVIRAL THERAPIES
  11. REFERENCES
  12. PREVENTION OF HCV INFECTION AT HEMODIALYSIS FACILITIES
  13. REFERENCES

[Statements]

  • 1
    Performance of antiviral therapy in HCV-infected dialysis patients is recommended if the prognosis is expected to be improved. (Evidence level: Very low, Recommendation level: Strong)
  • 2
    Performance of antiviral therapy in HCV-infected dialysis patients is recommended in case of expecting kidney transplantation. (Evidence level: High, Recommendation level: Strong)
  • 3
    If a dialysis patient has contracted acute HCV infection and the virus cannot be eliminated within 12 weeks spontaneously, performance of antiviral therapy is desirable. (Evidence level: High, Recommendation level: None)

[Comments]

1. Performance of antiviral therapy in HCV-infected dialysis patients is recommended if the prognosis is expected to be improved. (Evidence level: Very low, Recommendation level: Strong)

Dialysis patients are at high-risk of HCV infection, and many patients are suffering from chronic hepatitis C. Patients with chronic hepatitis C tend to develop liver cirrhosis and hepatocellular carcinoma during its long-term course (1,2). While HCV infection has been reported to increase the mortality due to liver cirrhosis and/or hepatocellular carcinoma in dialysis patients, prognosis of HCV-infected dialysis patients is known to be poor regardless of the presence or absence of liver disease (3–5). In Japan, patients who are undergoing dialysis for 20 years or longer are not rare (6), and thus the management of HCV infection, which affects the prognosis, is important.

HCV can be eliminated by antiviral therapy using interferon (IFN), and viral elimination contributes to the control of hepatitis and prevention of its progression to liver cirrhosis or hepatocellular carcinoma. In the past, introduction of antiviral therapy tended to be uncertain in dialysis patients with HCV infection, while recently, we came to consider that antiviral therapy should be performed aggressively in dialysis patients in whom long-time survival is expected. According to a survey by the Japanese Society for Dialysis Therapy, 48% of the anti-HCV-positive dialysis patients are HCV RNA-positive (7), and many of these HCV RNA-positive patients are considered to have indications of antiviral therapy. Antiviral therapy not only improves the prognosis of the HCV-infected patients themselves but also reduces sources of infection to other patients. Presently, most new HCV infections in dialysis patients are considered to be nosocomial ones (8). Thus, antiviral therapy should further be considered in HCV-infected patients.

A basic consensus has been made concerning the indications of antiviral therapy for chronic hepatitis C in patients with normal renal function (9,10). Guidelines for antiviral therapy for chronic hepatitis C patients with reduced renal function, which must be evaluated individually, have not been issued for a long time. Recently, guidelines for the treatment of hepatitis C in patients with chronic kidney disease (11) have been proposed by KDIGO (Kidney Disease: Improving Global Outcomes), and patients whose prognosis is expected to be improved are considered to have indications for aggressive antiviral therapy. The KDIGO Guideline defines patients whose prognosis is expected to be improved as young patients who have no severe cardiovascular complication and are expected to live for at least 5 years. The Japanese guideline is created along with this proposal.

In selecting patients with indications for antiviral therapy, the severity of liver disorder, age, comobidities, and tolerability to treatment are important factors, and candidates are selected in consideration of the therapeutic effect and the patient's condition (12,13). Particularly, patients in whom IFN is expected to be effective from the viewpoint of cost-effectiveness are optimal candidates for aggressive treatment. Among the predictive factors of the effectiveness of IFN accumulated in non-dialysis patients, those that predict marked response to IFN, i.e. SVR (sustained virological response) are: (i) As factors of HCV, (1) a low viral load and (2) HCV genotypes other than 1a and 1b; (ii) as host factors, (1) no advanced fibrosis (≤F3 according to the New Inuyama Classification), (2) age under 45 years, (3) a 5-year or shorter infection period, (4) no obesity, and (5) a low γGTP level (14,15). According to data in Japan, IFN therapy is expected to suppress hepatocarcinogenesis even if SVR cannot be achieved (15). Incidentally, liver biopsy is reliable for the evaluation of liver fibrosis, but liver fibrosis can also be estimated to an extent from the platelet count, liver fibrosis markers, AST/platelet count ratio, and findings on abdominal ultrasonography (16).

The present consensus is that there is no age restriction for administering antiviral therapy, but as the response rate to IFN is low, and the frequency of the occurrence of adverse effects is high, in patients aged 65 years or older, whether they should be treated aggressively needs careful evaluation in considering their prognosis. Also, severe complications, e.g., psychiatric disorders such as depression, severe hypertension, heart failure, significant coronary artery disease, poorly controlled diabetes, chronic obstructive pulmonary disease, untreated thyroid disease, uncompensated liver cirrhosis, and active or suspected malignancy, are contraindications for the treatment (12,13). Patients with poor compliance and children are also excluded. In antiviral therapy for patients with normal renal function, peginterferon (PEG-IFN) and ribavirin are usually used in combination. However, ribavirin is contraindicated, in principle, because it causes hemolytic anemia that can be particularly dangerous in dialysis patients and cannot be eliminated by dialysis, so the treatment using PEG-IFN alone is generally recommended. The SVR rate achieved by PEG-IFN in dialysis patients is similar to or better than that in non-dialysis patients, but the frequency of adverse effects and dropout rate of the therapy are slightly higher (17–19).

Recently, antiviral therapy has become recommended in HCV carriers with normal renal function showing persistently normal ALT (PNALT) (20), because it has been learned that the risk of progression of liver fibrosis (i.e. hepatocarcinogenesis) is high in many patients with a platelet count of 150 000/mm3 or below regardless of the ALT level (21). In Japan, a treatment guideline setting an ALT of 30 IU/mL and a platelet count of 150 000/µL as cut-off values (22) for PNALT patients has already been prepared. The ALT level is significantly lower in dialysis patients than in patients with normal renal function, and patients with a low ALT level may have liver disorders. Therefore, antiviral therapy should be considered regardless of the ALT level.

2. Performance of antiviral therapy in HCV-infected dialysis patients is recommended in case of expecting kidney transplantation. (Evidence level: High, Recommendation level: Strong)

Many patients waiting for kidney transplantation are young, have few serious complications, and are expected to survive over a long period. Further, the prognosis is expected to be more favorable in patients after successful kidney transplantation than in dialysis patients. Therefore, antiviral therapy is positively recommended to patients waiting for kidney transplantation.

In HCV-antibody-positive recipients of kidney transplantation, both the survival rate and graft survival rate are reported to be lower than in HCV-antibody-negative recipients (23,24). In principle, antiviral therapy is not recommended after kidney transplantation, because it may induce rejection or exacerbate liver disorders. However, elimination of HCV by antiviral therapy from patients waiting for kidney transplantation is expected to not only prevent the exacerbation of hepatitis after transplantation, avoid graft loss by preventing hepatitis C-related nephropathy and acute rejection, and suppress the occurrence of new diabetes but also improve the prognosis (25,26).

3. If a dialysis patient has contracted acute HCV infection and the virus cannot be eliminated within 12 weeks spontaneously, performance of antiviral therapy is desirable. (Evidence level: High, Recommendation level: None)

The therapeutic effect of IFN in patients with acute hepatitis C is higher than in those with chronic hepatitis C. IFN therapy is particularly effective if conducted early after the onset of acute hepatitis, and as high as over 80% of SVR rate can be expected (27,28). However, acute hepatitis C cures spontaneously in some patients within 12 weeks after the onset (29), and the possibility of spontaneous HCV RNA clearance in the general population has been reported to be 30–50% (29,30). However, 12 or more weeks after the onset, the disease rarely cures spontaneously and often takes a chronic course. Therefore, IFN therapy is recommended to be initiated as early as possible in patients not showing sero-clearance of HCV-RNA within 12 weeks after the onset. Early initiation of treatment is particularly necessary in genotype 1 (28). If the treatment is initiated after 20 weeks, the condition approaches chronic hepatitis, and the SVR rate declines (28). The SVR rate improves with the duration of IFN therapy, and the administration should be continued for 24 weeks in patients with genotype 1 and for 8–12 weeks in those with other genotypes (31). The incidence of acute hepatitis C is high in dialysis patients, and its spontaneous cure rate is 5–30% (1), which is lower than in the general population. Therefore, IFN therapy for acute hepatitis C should be conducted more actively in patients on dialysis than in those not on it. There have been some reports indicating that SVR rate tends to be lower in dialysis patients than in patients with normal renal function (32,33). However, it is generally considered that antiviral therapy such as IFN therapy is useful for the treatment of acute hepatitis C even in patients on hemodialysis.

REFERENCES

  1. Top of page
  2. INTRODUCTION
  3. REFERENCES
  4. SCREENING OF DIALYSIS PATIENTS FOR HEPATITIS C VIRUS INFECTION
  5. REFERENCES
  6. MANAGEMENT OF HEPATITIS C IN DIALYSIS PATIENTS (METHODS, FREQUENCY OF BLOOD TESTS AND IMAGING STUDIES)
  7. REFERENCES
  8. INDICATIONS OF ANTIVIRAL THERAPIES IN DIALYSIS PATIENTS
  9. REFERENCES
  10. TREATMENT OF DIALYSIS PATIENTS BY ANTIVIRAL THERAPIES
  11. REFERENCES
  12. PREVENTION OF HCV INFECTION AT HEMODIALYSIS FACILITIES
  13. REFERENCES
  • 1
    Seeff LB. Natural history of hepatitis C. Hepatology 2002;36:S35S46.
  • 2
    Kiyosawa K, Sodeyama T, Tanaka E et al. Interrelationship of blood transfusion, non-A, non-B hepatitis and hepatocellular carcinoma: analysis by detection of antibody to hepatitis C virus. Hepatology 1990;12:6715.
  • 3
    Nakayama E, Akiba T, Marumo F, Sato C. Pathogenesis of anti-hepatitis C virus antibody-positive patients on regular hemodialysis therapy. J Am Soc Nephrol 2000;11:1896902.
  • 4
    Espinosa M, Martin-Malo A, Alvarez de Lara MA, Aljama P. Risk of death and liver cirrhosis in anti-HCV-positive long-term haemodialysis patients. Nephrol Dial Transplant 2001;16:166974.
  • 5
    Fabrizi F, Takkouche B, Lunghi G, Dixit V, Messa P, Martin P. The impact of hepatitis C virus infection on survival in dialysis patients: meta-analysis of observational studies. J Viral Hepat 2007;14:697703.
  • 6
    Statistical Investigation Committee, Japanese Society for Dialysis Therapy. State of chronic dialysis therapy in Japan, illustrated (as of December 31, 2008). 22, 2009.
  • 7
    Statistical Investigation Committee, Japanese Society for Dialysis Therapy. State of chronic dialysis therapy in Japan, illustrated (as of December 31, 1999). 13, 2000. (In Japanese)
  • 8
    Kobayashi M, Tanaka E, Oguchi H, Hora K, Kiyosawa K. Prospective follow-up study of hepatitis C virus infection in patients undergoing maintenance hemodialysis: comparison among hemodialysis units. J Gastroenterol Hepatol 1998;13:6049.
  • 9
    Patel KP, Muir AJ, McHutchinson JG. Diagnosis and treatment of chronic hepatitis C infection. BMJ 2006;332:10137.
  • 10
    Shamoun DK, Anania FA. Which patients with hepatitis C virus should be treated? Semin Gastrointest Dis 2000;11:8495.
  • 11
    KDIGO Clinical practice guidelines for the prevention, diagnosis, evaluation, and treatment of hepatitis C in chronic kidney disease. Kidney Int 2008;73(Suppl 109):S205.
  • 12
    Girndt M. Viral hepatitis in elderly haemodialysis patients: current prevention and management strategies. Drugs Aging 2008;25:82340.
  • 13
    Pol S, Vallet-Pichard A, Fontane H, Lebray P. HCV infection and hemodialysis. Semin Nephrol 2002;22:3319.
  • 14
    Matsumoto A, Tanaka E, Suzuki T, Ogata H, Kiyosawa K. Viral and host factors that contribute to efficacy of interferon-alpha 2a therapy in patients with chronic hepatitis C. Dig Dis Sci 1994;39:127380.
  • 15
    Yoshida H, Shirotori Y, Moriyama M et al. Interferon therapy reduces the risk for hepatocellular carcinoma: National surveillance program of cirrhotic and noncirrhotic patients with chronic hepatitis C in Japan. Ann Intern Med 1999;131:17481.
  • 16
    Strader DB, Wright T, Thomas DL, Seeff LB American Association for the Study of Liver Diseases. Diagnosis, management, and treatment of hepatitis C. Hepatology 2004;39:114771.
  • 17
    Russo MW, Goldsweig CD, Jacobson IM, Brown RS Jr. Interferon monotherapy for dialysis patients with chronic hepatitis C: an analysis of the literature on efficacy and safety. Am J Gastroenterol 2003;98:16105.
    Direct Link:
  • 18
    Fabrizi F, Dixit V, Messa P, Martin P. Interferon monotherapy of chronic hepatitis C in dialysis patients: meta-analysis of clinical trials. J Viral Hepatol 2008;15:7988.
  • 19
    Gordon CE, Uhlig K, Lau J, Schmid CH, Levey AS, Wong JB. Interferon treatment in hemodialysis patients with chronic hepatitis C virus infection: a systemic review of the literature and meta-analysis of treatment efficacy and harms. Am J Kidney Dis 2008;51:2637.
  • 20
    Okanoue T, Makiyama A, Nakayama M et al. A follow-up study to determine the value of liver biopsy and need for antiviral therapy for hepatitis C virus carries with persistently normal serum aminotransferase. J Hepatol 2005;43:599605.
  • 21
    Okanoue T, Itoh Y, Minami M et al. Guidelines for the antiviral therapy of hepatitis C virus carriers with normal serum aminotransferase based on platelet counts. Hepatol Res 2008;38:2736.
  • 22
    Treatment Standardization Committee. Guidelines for the treatment of chronic hepatitis C. Ministry of Health, Labour and Welfare. Tokyo, 2008.
  • 23
    Mathurin P, Mouquet C, Poynard T. Impact of hepatitis B and C virus on kidney transplant outcome. Hepatology 1999;29:25763.
  • 24
    Fabrizi F, Martin P, Dixit V, Bunnapsdist S, Dulai G. Hepatitis C virus antibody status and survival after renal transplantation: meta-analysis of observational studies. Am J Transplant 2005;5:145261.
  • 25
    Cruzado JM, Casanovas-Taitavull T, Torras J. Pretransplant interferon prevents hepatitis C virus-associated glomerulonephritis in renal allografts by HCV-RNA clearance. Am J Transplant 2003;3:35760.
  • 26
    Gursoy M, Guvener N, Koksal R. Impact of HCV infection in development of posttransplantation diabetes mellitus in renal allograft recipients. Transplant Proc 2000;32:5612.
  • 27
    Nomura H, Sou S, Tanimoto H et al. Short-term interferon-alpha therapy for acute hepatitis C: a randomized controlled trial. Hepatology 2004;39:12139.
  • 28
    Kamal SM, Fouly AE, Kamel RR et al. Peginterferon alfa-2b therapy in acute hepatitis C: impact of onset of therapy on sustained virologic response. Gastroenterology 2006;130:6328.
  • 29
    Gerlach JT, Diepolder HM, Zachoval R et al. Acute hepatitis C: high rate of both spontaneous and treatment-induced viral clearance. Gastroenterology 2003;125:808.
  • 30
    Tanaka E, Kiyosawa K. Natural history of acute hepatitis C. J Gastroenterol Hepatol 2000;15:E97104.
  • 31
    Kamal SM, Moustafa KN, Chen J et al. Duration of peginterferon therapy in acute hepatitis C: a randomized trial. Hepatology 2006;43:92331.
  • 32
    Urbanek P, Tesar V, Prochazkova-Francisi E, Lachmanova J, Marecek Z, Svobodnik A. Treatment of early diagnosed HCV infection in hemodialyzed patients with interferon-alpha. Treatment of hepatitis C. Blood Purif 2004;22:34450.
  • 33
    Rocha CM, Perez RM, Narciso JL et al. Interferon-alpha therapy within the first year after acute hepatitis C infection in hemodialysis patients: efficacy and tolerance. Eur J Gastroenterol Hepatol 2007;19:11923.

TREATMENT OF DIALYSIS PATIENTS BY ANTIVIRAL THERAPIES

  1. Top of page
  2. INTRODUCTION
  3. REFERENCES
  4. SCREENING OF DIALYSIS PATIENTS FOR HEPATITIS C VIRUS INFECTION
  5. REFERENCES
  6. MANAGEMENT OF HEPATITIS C IN DIALYSIS PATIENTS (METHODS, FREQUENCY OF BLOOD TESTS AND IMAGING STUDIES)
  7. REFERENCES
  8. INDICATIONS OF ANTIVIRAL THERAPIES IN DIALYSIS PATIENTS
  9. REFERENCES
  10. TREATMENT OF DIALYSIS PATIENTS BY ANTIVIRAL THERAPIES
  11. REFERENCES
  12. PREVENTION OF HCV INFECTION AT HEMODIALYSIS FACILITIES
  13. REFERENCES

[Statements]

  • 1
    It is recommended that for dialysis patients with HCV infection, interferon of antiviral therapy is the first choice.
  • 2
    In dialysis patients, the response rate of interferon therapy is comparable or superior to that in patients with normal renal function, but as the frequency of adverse effects is also high, sufficient observation is recommended. (Evidence level: Low, Recommendation level: Strong)
  • 3
    Since the blood levels of both standard interferon α and pegylated interferon α increase excessively in dialysis patients if they are administered at standard dose, an adjusted dose reduction to the level of renal function is recommended. (Evidence level: High, Recommendation level: Strong)
  • 4
    It is recommended not to use ribavirin contraindicated in dialysis patients. (Evidence level: High, Recommendation level: Strong)
  • 5
    The therapeutic guidelines for patients with normal renal function mention the selection of drugs depending on the viral level and viral type and whether ribavirin should be used concomitantly. However, there is no recommendation for the selection of drugs according to the viral level or viral type for dialysis patients, in whom ribavirin administration is a contraindication.
  • 6
    In dialysis patients, treatment with pegylated interferon α monotherapy is more effective and less frequently causes adverse effects than treatment with standard interferon α monotherapy. (Evidence level: High, Recommendation level: Strong)
  • 7
    Interferon β can be used in dialysis patients at the standard dose
    • • 
      However, as its intravenous injection over a short period may cause adverse effects due to a rapid increase in its plasma concentration, it is recommended to administer it by intravenous drip infusion over 30–60 min for dialysis patients. (Evidence level: High, Recommendation level: Strong)
  • 8
    It is recommended that HCV-infected dialysis patients accepted for kidney transplantation be treated before transplantation. (Evidence level: High, Recommendation level: Strong)
  • 9
    It is recommended that treatment of HCV-infected kidney transplant recipients be considered only when the benefits of treatment clearly outweigh the risk of allograft rejection due to interferon therapy. (Evidence level: High, Recommendation level: Strong)

[Comments on treatments for HCV-infected dialysis patients]

1. Treatment with interferon (IFN) monotherapy

Monotherapy with standard interferon.  Many of the studies of IFN therapy for dialysis patients have been case reports of a small number of patients, making its evaluation difficult. According to the reports of a relatively large number of patients published since 2000, the sustained virological response (SVR) rate varies widely from 19% to 62% (1–5).

The results of meta-analyses of treatments using IFNα monotherapy including these reports are reviewed. In the reports by Fabrizi et al., which covered 28 studies and 645 dialysis patients, the SVR rate by treatment using IFNα monotherapy was 39%, and the dropout rate from the treatment was 19% (6). According to the report by Gordon et al., which reviewed 20 studies and 459 dialysis patients, the SVR rate by IFNα monotherapy was 41%, and the dropout rate was 26% (7). Important factors that contributed to SVR were the administration of IFNα at 3 MU or above 3 or more times/week, a low HCV-RNA level, mild liver fibrosis, and a genotype other than genotype 1. In all meta-analyses, the effectiveness of IFN was similar or superior, but the dropout rate due to adverse effects was higher, in dialysis patients compared with patients with normal renal function. Since the treatment is discontinued more frequently due to cytopenia and psychiatric symptoms in dialysis patients than in patients with normal renal function, sufficient observation and management are needed.

Also, concerning the pharmacokinetics of IFNα2b, the AUC and Cmax are about two times higher, and the half-life is also prolonged in dialysis patients compared with patients with normal renal function. In dialysis patients, the dose must be reduced to a half of the usual dose for patients with normal renal function or below (8).

Monotherapy with IFNβ.  As for studies on treatments using IFNβ monotherapy, there are data of 20 patients reported by Zeniya et al. in Japan. These patients, consisting of 60% genotype 1 (12/20) and 40% genotype 2 (8/20), in whom the HCV-RNA level was 15–150 KIU/mL, showed a high SVR rate of 90% (18/20) with no serious adverse effect such as depression during administration (9). There has been no other report of a large number of dialysis patients who underwent IFNβ therapy, and the SVR rate in dialysis patients is unclear. In Japan, however, IFNβ has been used widely in patients with normal renal function, and both its efficacy and safety are established.

Concerning the pharmacokinetics of IFNβ, the peak plasma concentration is higher in dialysis patients than in patients with normal renal function, but its half-life in dialysis patients does not differ markedly compared with that in patients with normal renal function, and there is no tendency for accumulation. Therefore, it is considered possible to administer IFNβ to dialysis patients at the same dose as in patients with normal renal function. Except, in dialysis patients, its intravenous injection over a short period has been reported to induce adverse effects such as headache, nausea, and a decrease in the blood pressure due to a rapid increase in its plasma concentration. Therefore, in dialysis patients, it is recommended to conduct IFNβ therapy by intravenous drip infusion over about 30–60 min (10–14).

2. Treatment with pegylated interferon (pegIFN) monotherapy

Effects of treatment with pegIFN monotherapy.  There are 11 reports on treatment of dialysis patients using pegIFN monotherapy published by 2009, consisting of nine on pegIFN α-2a and 2 on pegIFN α-2b. The initial administration of pegIFN α-2a was made subcutaneously at 135–180 µg once a week, the SVR rate was 14–75%, and the dropout rate was 0–73% (15–25). Major adverse effects were fever, reduced appetite, malaise, cytopenia, and depression. The dropout rate was low in reports with a high SVR rate but high in those with a low SVR rate.

Comparison of effectiveness between standard IFNα monotherapy and pegIFNα monotherapy.  A randomized controlled trial comparing standard IFNα monotherapy and pegIFNα monotherapy has been reported (25). Fifty hemodialysis patients were randomized to pegIFNα-2a and IFNα-2a therapies, the administration of pegIFNα-2a at 135 µg/week and IFNα-2a at 3 MU×3/week was continued for 24 weeks, and the results were evaluated by an intention-to-treat (ITT) analysis. In the pegIFNα-2a and IFNα-2a groups, the SVR rate was 48% and 20% (P = 0.07), fever was observed in 12% and 44% (P = 0.03), and dropout rate was 0% and 20% (P = 0.04), respectively, showing that pegIFN α-2a was more effective and less frequently caused adverse effects than the conventional preparation. Multivariate analysis indicated the use of a pegIFN α-2a preparation (P = 0.02) and an HCV-RNA level of less than 800 KIU/mL as factors contributing to SVR. Also, the SVR rate was 65% in the group that showed a rapid virological response (RVR) and 0% in the non-RVR group (P < 0.001). It was shown that SVR cannot be attained in patients in whom early negative conversion of HCV-RNA cannot be achieved either by pegIFN α-2a or IFN α-2a.

Pharmacokinetics.  The pharmacokinetics after a single subcutaneous administration of pegIFN α-2a at 90 µg in patients with a creatinine clearance of 20 mL/min or above was the same as in healthy adults. However, when pegIFN α-2a was administered once subcutaneously at 45, 90, 135, and 180 µg, its plasma concentration increased in a dose-related manner, and the pharmacokinetics in dialysis patients after the administration at 135 µg was similar to that in healthy adults after the administration at 180 µg (26).

In a report about patients in Japan, Cmax and Tmax after a single administration of pegIFN α-2a at 90 µg were similar to those in healthy adults after the administration at 180 µg, but the disappearance of the drug from blood was delayed. The increase in the plasma concentration was insufficient by a single administration of pegIFN α-2a at 45 µg. Also, the pharmacokinetics on repeated administrations of pegIFN α-2a at 90 µg were similar to those in healthy adults at 180 µg (27). Therefore, the dose of pegIFN α-2a in dialysis patients must be reduced to 90–135 µg.

3. Treatment with combination of pegIFN and ribavirin

There were four reports on treatment of dialysis patients with a combination of pegIFN and ribavirin by 2009 (28–31). pegIFN α-2a was administered initially at 135 µg once a week, and pegIFN α-2b was administered at 50 µg once a week, by subcutaneous injection. The SVR rate was 29–97%, the dropout rate was 0–71%, and the treatment was often discontinued due to severe anemia requiring transfusion. However, in reports with a high SVR rate, the dropout rate was low, and modifications such as an increase in the dose of an erythropoiesis stimulating agent (ESA) and the administration of ribavirin every other day were made.

Also, there is a report that ribavirin is excreted through the kidneys, that its AUC increases three times or more in patients with a creatinine clearance of less than 30 mL/min compared with patients with normal renal function, and that it cannot be eliminated efficiently by hemodialysis (32), so its administration to dialysis patients is a contraindication.

4. Guidelines for IFN therapy in dialysis patients
  • 1
    Drugs and administration methods
    • • 
      Subcutaneous injection of pegIFN α-2a at 90–135 µg once a week over 24–48 weeks
    • • 
      Subcutaneous or intramuscular injection of natural IFN α or recombinant IFN α-2b at 3–6 million units once a day, 3 times a week, over 24–48 weeks
    • • 
      Intravenous drip infusion (30–60 min) of natural IFN β at 3–6 million unites once a day, 3 times a week, over 24–48 weeks
  • 2
    Comments about the guidelines

In dialysis patients undergoing IFN therapy, the SVR rate is similar to, or higher than, in patients with normal renal function, but the dropout rate from the treatment is also high. Factors important for achieving SVR are a low viral level, a genotype other than genotype 1, use of pegIFN, rapid virological response, and no marked liver fibrosis.

While the SVR rate is high in patients in whom the treatment could be continued, the dropout rate is higher in dialysis patients than in patients with normal renal function because of cytopenia and psychiatric symptoms. For achieving SVR, it is important to complete the treatment by promptly using an ESA preparation at a high dose in patients showing anemia and by concomitantly using granulocyte colony stimulating factor (G-CSF) and reducing the dose of IFN in patients showing neutropenia.

There has also been a report that a low dropout rate and a high SVR rate were obtained in dialysis patients by ribavirin combination therapy with reduced dose and number of administrations. This approach is likely to be effective in patients treated again after no response to IFN monotherapy and genotype 1 patients showing a high viral level. However, as ribavirin accumulates and cannot be eliminated by hemodialysis, the drug is contraindicated for dialysis patients by its package insert, and we recommend not administering it to dialysis patients.

Therefore, we recommend IFNα or IFNβ monotherapy as an antiviral therapy for dialysis patients. Regarding the drug selection for antiviral therapy using IFNα alone, the results of an RCT that the SVR rate was high, that adverse effects were infrequent, and that dropout rate was low with a pegIFNα preparation have been reported. We recommend using pegIFNα for treating dialysis patients. Although there are pegIFNα-2a and pegIFNα-2b, treatment using pegIFNα-2a monotherapy is covered by medical insurance in Japan.

5. Other treatments

Drugs of suppressing inflammation in the liver.  In patients with normal renal function, Stronger Neo-Minophagen C (SNMC) or ursodeoxycholic acid (UDCA, Urso) are administered as drugs of suppressing inflammation to those with liver dysfunction in whom IFN therapy cannot be performed or has been ineffective. RCTs and prospective studies in patients with normal renal function have provided little evidence of suppression of death and liver cirrhosis or liver cancer (33,34), and there is no evidence in dialysis patients. In addition, as no antiviral effect is observed in drugs of suppressing inflammation, they are administered with the objective of reducing ALT in patients with liver dysfunction.

Administration methods

  • 1
    Stronger Neo-Minophagen injection, intravenous injection at 40–100 mL per injection, at each dialysis
  • 2
    Urso (100 mg), 6–9 tablets/day, daily oral administration t.i.d.

Virus removal and eradication by DFPP (VRAD).  VRAD is covered by insurance in patients receiving re-treatment with IFN, those with genotype 1B, and those with an HCV-RNA level of 100 KIU/mL or higher up to five times (there is no evidence regarding the amount of treated plasma or duration, interval, or number of VRAD).

A multi-facility collaborative prospective study in non-dialysis patients is in progress, and SVR is compared between groups undergoing PEG-IFN plus ribavirin (30 patients) and PEG-IFN plus ribavirin plus DFPP (74 patients) (35). In the patients in whom SVR could be evaluated, SVR was observed in 50.0% (29/58) in the PEG-IFN plus ribavirin group and 70.8% (17/24) in the PEG-IFN plus ribavirin plus DFPP group. While the SVR rate was higher in the group treated by combinations including DFPP, the increase was not significant. There is no report comparing SVR between IFN therapy and a combination therapy including DFPP in dialysis patients, and there is no evidence. However, ribavirin administration to dialysis patients is a contraindication, and as VRAD is expected to be effective as a concomitant treatment in re-treatment using IFN, evaluation by accumulation of clinical research is necessary for the future.

[Comments concerning HCV-infected recipients of kidney transplantation]

1. HCV infection and kidney transplantation

Fabrizi et al. performed meta-analysis of 10 clinical studies and 2502 kidney transplantation patients and reported the incidences of diabetes after kidney transplantation in HCV-antibody-positive and -negative patients (36). The incidence of diabetes in HCV-antibody-positive patients varied from 7.9–50.0% among reports but was significantly higher than in negative patients with an odds ratio of 3.97 (95% confidence interval = 1.83–8.61, P-value = 0.047). The authors suggested the possibility that this is related to the kidney graft survival rate in HCV-antibody-positive patients.

Mathurin et al. reported the survival rate and graft survival rate 10 years after kidney transplantation in 834 patients (128 were HBs-antigen-positive, 216 were HCV-antibody-positive) (37). The survival rate 10 years after kidney transplantation was 65 ± 5% in HCV-antibody-positive patients and 80 ± 3% in HCV-antibody-negative patients (P < 0.001), and the graft survival rate was 49 ± 5% and 63 ± 3% (P < 0.0001), respectively, both being lower in the HCV-antibody-positive patients.

2. IFN therapy before transplantation

Kamar et al. performed standard IFN therapy in five HCV-antibody-positive and HCV-RNA-positive hemodialysis patients (38). SVR was observed in 21 (38%), and 16 (76%) of them underwent kidney transplantation. All patients continued to be HCV-RNA-negative throughout an observation period of 22.5 months (2–88 months), with none having developed post-transplantation diabetes.

Cruzado et al. evaluated the occurrence of post-transplantation nephritis in 78 HCV-antibody-positive dialysis patients after kidney transplantation (IFN therapy was performed before transplantation in 15 and not in 63) (39). In those who underwent IFN therapy, 10/15 (67%) showed SVR, and only one patient (6.7%), who could not attain SVR, developed post-transplantation nephritis. In those who did not undergo IFN therapy, 12/63 (19%) developed post-transplantation nephritis. The frequency of post-transplantation nephritis was reduced by IFN therapy before transplantation.

Mahmoud et al. reported the effects of IFN therapy before transplantation on rejection and renal function after transplantation in 50 HCV-RNA-positive kidney transplantation patients (40). The patients consisted of 18 who underwent IFN therapy and 32 who did not, and the percentage of those who showed chronic rejection was significantly higher, and the renal function 5 years after transplantation was significantly lower, in the non-IFN therapy group.

Interferon therapy before transplantation is important to improve the kidney graft survival rate.

3. IFN therapy after transplantation

Fabrizi et al. carried out a meta-analysis concerning 12 studies (102 patients) in which standard IFN therapy and standard IFN plus ribavirin therapy were performed after kidney transplantation (41). The SVR rate was 18.0% (95% CI: 7.0–29.0%), and the dropout rate was 35.0% (95% CI: 20–50%). The most frequent adverse effect was kidney graft dysfunction. IFN therapy after transplantation was unsatisfactory in both efficacy and safety.

4. Guidelines for IFN therapy in kidney transplanted patients

In HCV-infected recipients of kidney transplantation, the post-transplantation incidence of diabetes is high, and the graft survival rate and survival rate are low. IFN therapy before transplantation reduces the incidences of post-transplantation diabetes, post-transplantation nephritis, and chronic rejection. However, IFN therapy after kidney transplantation is associated with a low SVR rate and a high dropout rate, and induces rejection of the kidney graft.

Therefore, in HCV-infected dialysis patients expecting kidney transplantation, IFN therapy should be performed before transplantation. Also, in HCV-infected recipients of kidney transplantation, IFN therapy is likely to induce rejection and should be performed only when the necessity surpasses the risk (fibrosing cholestatic hepatitis [FCH] etc.).

REFERENCES

  1. Top of page
  2. INTRODUCTION
  3. REFERENCES
  4. SCREENING OF DIALYSIS PATIENTS FOR HEPATITIS C VIRUS INFECTION
  5. REFERENCES
  6. MANAGEMENT OF HEPATITIS C IN DIALYSIS PATIENTS (METHODS, FREQUENCY OF BLOOD TESTS AND IMAGING STUDIES)
  7. REFERENCES
  8. INDICATIONS OF ANTIVIRAL THERAPIES IN DIALYSIS PATIENTS
  9. REFERENCES
  10. TREATMENT OF DIALYSIS PATIENTS BY ANTIVIRAL THERAPIES
  11. REFERENCES
  12. PREVENTION OF HCV INFECTION AT HEMODIALYSIS FACILITIES
  13. REFERENCES
  • 1
    Casanovas-Taltavull T, Baliellas C, Benasco C et al. Efficacy of interferon for chronic hepatitis C virus-related hepatitis in kidney transplant candidates on hemodialysis: results after transplantation. Am J Gastroenterol 2001;96:11707.
  • 2
    Degos F, Pol S, Chaix ML et al. The tolerance and efficacy of interferon-alpha in hemodialysis patients with HCV infection: a multicentre, prospective study. Nephrol Dial Transplant 2001;16:101723.
  • 3
    Rocha CM, Perez RM, Ferreira AP et al. Efficacy and tolerance of interferon-alpha in the treatment of chronic hepatitis C in end-stage renal disease patients on hemodialysis. Liver Int 2006;26:30510.
  • 4
    Buargub M, El Huni S, Tagdi M. Tolerance and efficacy of interferon-alpha in hemodialysis patients in Tripoli. Saudi J Kidney Transplant 2006;17:33843.
  • 5
    Yildirim B, Durak H, Ozaras R et al. Liver steatosis in hepatitis C positive hemodialysis patients and factors affecting IFN-2a treatment. Scand J Gastroenterol 2006;41:123541.
  • 6
    Fabrizi F, Dixit V, Messa P, Martin P. Interferon monotherapy of chronic hepatitis C in dialysis patients: meta-analysis of clinical trials. J Viral Hepat 2008;15:7988.
  • 7
    Gordon CE, Uhlig K, Lau J, Schmid CH, Levey AS, Wong JB. Interferon treatment in hemodialysis patients with chronic hepatitis C virus infection: a systematic review of the literature and meta-analysis of treatment efficacy and harms. Am J Kidney Dis 2008;51:26377.
  • 8
    Uchihara M, Izumi N, Sakai Y et al. Interferon therapy for chronic hepatitis C in hemodialysis patients: increased serum levels of interferon. Nephron 1998;80:516.
  • 9
    Zeniya M, Yokoyama K, Imamura N et al. Significance of interferon-β for the treatment of hepatitis C virus infection in hemodialyzed patients. Hepatol Res 2010;40:8629.
  • 10
    Nakayama H, Shiotani S, Akiyama S, Gotoh H, Tani M, Akine Y. Pharmacokinetic study of human natural beta-interferon in patients with end-stage renal failure. Clin Nephrol 2001;56:3826.
  • 11
    Nakajima F, Fukii M, Kitamura T et al. A case report of interferon beta monotherapy for high hepatitis C viral load in dialysis patients. Ther Apher Dial 2007;11:3068.
  • 12
    Umeda S, Minami H, Izumi N, Yamamoto M, Kanno T, Ozaki Y. Treatment of a hemodialysis patient with hepatitis C using interferon β. J Jpn Soc Dial Ther 1994;27:638.
  • 13
    Tachibana N, Ako S, Deura T et al. A dialysis patient treated with interferon β for chronic hepatitis C: Pharmacokinetic evaluation of IFNβ. J Jpn Soc Dial Ther 2000;33:617.
  • 14
    Araoka T, Takeoka H, Nishioka K et al. Evaluation of safe and effective interferon β therapy for maintenance hemodialysis patients with chronic hepatitis C. J Jpn Soc Dial Ther 2009;42:393402.
  • 15
    Teta D, Luscher BL, Gonvers JJ, Francioli P, Phan O, Burnier M. Pegylated interferon for the treatment of hepatitis C virus in haemodialysis patients. Nephrol Dial Transplant 2005;20:9913.
  • 16
    Sporea I, Popescu A, Sirli R et al. Pegylated-interferon alpha 2a treatment for chronic hepatitis C in patients on chronic haemodialysis. World J Gastroenterol 2006;12:41914.
  • 17
    Covic A, Maftei ID, Mardare NG et al. Analysis of safety and efficacy of pegylated-interferon alpha-2a in hepatitis C virus positive hemodialysis patients: results from a large, multicenter audit. J Nephrol 2006;19:794801.
  • 18
    Kokoglu OF, Ucmak H, Hosoglu S et al. Efficacy and tolerability of pegylated-interferon alpha-2a in hemodialysis patients with chronic hepatitis C. J Gastroenterol Hepatol 2006;21:57580.
  • 19
    Chan TM, Ho SK, Tang CS et al. Pilot study of pegylated interferon-alpha 2a in dialysis patients with chronic hepatitis C virus infection. Nephrology (Carlton) 2007;12:117.
  • 20
    Casanovas-Taltavull T, Baliellas C, Llobet M et al. Preliminary results of treatment with pegylated interferon alpha 2A for chronic hepatitis C virus in kidney transplant candidates on hemodialysis. Transplant Proc 2007;39:21257.
  • 21
    Ayaz C, Celen MK, Yuce UN, Geyik MF. Efficacy and safety of pegylated-interferon alpha-2a in hemodialysis patients with chronic hepatitis C. World J Gastroenterol 2008;14:2559.
  • 22
    Akhan SC, Kalender B, Ruzgar M. The response to pegylated interferon alpha 2a in haemodialysis patients with hepatitis C virus infection. Infection 2008;36:3414.
  • 23
    Russo MW, Ghalib R, Sigal S, Joshi V. Randomized trial of pegylated interferon alpha-2b monotherapy in haemodialysis patients with chronic hepatitis C. Nephrol Dial Transplant 2006;21:43743.
  • 24
    Tan SS, Abu Hassan MR, Abdullah A et al. Treatment of hemodialysis (HD) patients with chronic hepatitis C (CHC) using an escalating dose regimen of pegylated interferon (PEG-IFN) alpha-2b. Hepatology 2007;46:363a4a.
  • 25
    Liu CH, Liang CC, Lin JW et al. Pegylated interferon alpha-2a versus standard interferon alpha-2a for treatment-naive dialysis patients with chronic hepatitis C: a randomized study. Gut 2007;57:52530.
  • 26
    Chugai Pharmaceutical. Pegasys Drug Interview Form (10th revised edition). p23, 2008.
  • 27
    Akiba T, Kikuchi K. A study of the efficacy and administration method of peg-interferon-α-2a preparations in patients with chronic hepatitis C undergoing chronic hemodialysis. A Grant-in-Aid by the Ministry of Health, Labour and Welfare for research regarding the epidemiology of hepatitis B and C and measures to control hepatitis including mass screening, a research project on emergency measures to conquer hepatitis and other diseases. 2005 Assigned Research Report; 511, 2006.
  • 28
    Bruchfeld A, Lindahl K, Reichard O, Carlsson T, Schvarcz R. Pegylated interferon and ribavirin treatment for hepatitis C in haemodialysis patients. J Viral Hepat 2006;13:31621.
  • 29
    Rendina M, Schena A, Castellaneta NM et al. The treatment of chronic hepatitis C with peginterferon alfa-2a (40kDa) plus ribavirin in haemodialysed patients awaiting renal transplant. J Hepatol 2007;46:76874.
  • 30
    van Leusen R, Adang RP, de Vries RA et al. Pegylated interferon alfa-2a (40kD) and ribavirin in haemodialysis patients with chronic hepatitis C. Nephrol Dial Transplant 2008;23:7215.
  • 31
    Carriero D, Fabrizi F, Uriel AJ, Park J, Martin P, Dieterich DT. Treatment of dialysis patients with chronic hepatitis C using pegylated interferon and low-dose ribavirin. Int J Artif Organs 2008;31:295302.
  • 32
    MSD. Rebetol Drug Interview Form (3rd revised edition). p2, 2005.
  • 33
    Kumada H. Long-term treatment of chronic hepatitis C with glycyrrhizin [stronger neo-minophagen C (SNMC)] for preventing liver cirrhosis and hepatocellular carcinoma. Oncology 2002;62:94100.
  • 34
    Omata M, Yoshida H, Toyota J et al. Japanese C-Viral Hepatitis Network. A large-scale, multicentre, double-blind trial of ursodeoxycholic acid in patients with chronic hepatitis C. Gut 2007;56:174753.
  • 35
    Fujiwara K, Kaneko S, Kakumu S et al. The Virus Reduction Therapy Study Group. Double filtration plasmapheresis and interferon combination therapy for chronic hepatitis C patients with genotype 1 and high viral load. Hepatol Res 2007;37:70110.
  • 36
    Mathurin P, Mouquet C, Poynard T. Impact of hepatitis B and C virus on kidney transplant outcome. Hepatology 1999;29:25763.
  • 37
    Fabrizi F, Martin P, Dixit V, Bunnapradist S, Kanwal F, Dulai G. Post-transplant diabetes mellitus and HCV seropositive status after renal transplantation: meta-analysis of clinical studies. Am J Transplant 2005;5:243340.
  • 38
    Kamar N, Toupance O, Buchler M et al. Evidence that clearance of hepatitis C virus RNA after alpha-interferon therapy in dialysis patients is sustained after renal transplantation. J Am Soc Nephrol 2003;14:20928.
  • 39
    Cruzado JM, Casanovas-Taitavull T, Torras J. Pretransplant interferon prevents hepatitis C virus-associated glomerulonephritis in renal allografts by HCV-RNA clearance. Am J Transplant 2003;3:35760.
  • 40
    Mahmoud IM, Sobh MA, El-Habashi AF et al. Interferon therapy in hemodialysis patients with chronic hepatitis C: study of tolerance, efficacy and post-transplantation course. Nephron Clin Pract 2005;100:1339.
  • 41
    Fabrizi F, Lunghi G, Dixit V, Martin P. Meta-analysis: anti-viral therapy of hepatitis C virus-related liver disease in renal transplant patients. Aliment Pharmacol Ther 2006;24:141322.

PREVENTION OF HCV INFECTION AT HEMODIALYSIS FACILITIES

  1. Top of page
  2. INTRODUCTION
  3. REFERENCES
  4. SCREENING OF DIALYSIS PATIENTS FOR HEPATITIS C VIRUS INFECTION
  5. REFERENCES
  6. MANAGEMENT OF HEPATITIS C IN DIALYSIS PATIENTS (METHODS, FREQUENCY OF BLOOD TESTS AND IMAGING STUDIES)
  7. REFERENCES
  8. INDICATIONS OF ANTIVIRAL THERAPIES IN DIALYSIS PATIENTS
  9. REFERENCES
  10. TREATMENT OF DIALYSIS PATIENTS BY ANTIVIRAL THERAPIES
  11. REFERENCES
  12. PREVENTION OF HCV INFECTION AT HEMODIALYSIS FACILITIES
  13. REFERENCES

[Statements]

  • 1
    It is recommended to apply and implement a strict infection control procedure to prevent blood-borne infection of pathogens including HCV at hemodialysis facilities. (Evidence level: Very low, Recommendation level: Strong)
  • 2
    In addition to a strict infection control procedure, it is recommended to identify or isolate HCV-infected patients and to use special dialysis instruments (consoles) for them. (Evidence level: Very low, Recommendation level: Strong)
  • 3
    It is recommended that the infection control procedure includes hygienic cautions to effectively prevent direct transmission of pathogens between patients through blood or body fluid or via contaminated gloves, medical materials, or instruments. (Evidence level: Very low, Recommendation level: Strong)
  • 4
    In evaluating the results of HCV infection prevention measures at hemodialysis facilities, it is recommended to include observation of the state of implementation of infection control measures, periodic surveillance of the state of infection, and review of infection control measures depending on the state of infection. (Evidence level: Very low, Recommendation level: Strong)

[Comments]

1. It is recommended to apply and implement a strict infection control procedure to prevent blood-borne infection of pathogens including HCV at hemodialysis facilities.(Evidence level: Very low, Recommendation level: Strong)

The occurrence of nosocomial infection of HCV in dialysis facilities has been documented by epidemiological and viral molecular biological researches (1,2). The most frequent patient-to-patient transmission of HCV is caused by contamination of the drugs administered and the surface of instruments and materials in the dialysis facility including gloves due to manipulations violating the infection control procedure (1,2). With the current equipment, transmission of infection in the dialysis instruments is unlikely (3). Other causes of nosocomial infection include direct contact between patients and medical actions outside the dialysis facility such as transfusion (4), but their frequency is considered to be low. Therefore, for the prevention of HCV infection, it is required to determine and observe effective infection control procedures and to periodically review them and make necessary modifications (5–8). In Japan, the Manual Regarding the Standard Dialysis Procedure and Prevention of Nosocomial Infections in Dialysis Medicine (7) prepared with a Grant-in-Aid for Health and Welfare Science by the Ministry of Health, Labour and Welfare is used widely as a manual of infection control procedures at dialysis facilities.

2. In addition to a strict infection control procedure, it is recommended to identify or isolate HCV-infected patients and to use special dialysis instruments (consoles) for them.(Evidence level: Very low, Recommendation level: Strong)

Since infection experiments cannot be performed due to ethical restrictions, we must depend primarily on the results of observational studies. In Japan, the prevalence of HCV infection is clearly higher than in Western countries (9). On the basis of the results of a multi-facility observational study (9) that the incidence of new HCV infection is high at facilities with a high prevalence of HCV infection and that it is lower at facilities with a larger number of stations for isolated dialysis and the results of an observational study (10) that infection is less frequent at facilities that isolate HCV-infected patients than at those that do not isolate them, we recommend isolation of HCV-infected patients or the use of dedicated HD machines. While this statement differs from the CDC guidelines of the United States (5), these are considered to be necessary infection control measures from the high prevalence of HCV infection in Japan, poorer prognosis of HCV-positive dialysis patients (11), and statement of the German clinical nephrology working group in 2006 (8).

3. It is recommended that the infection control procedure includes hygienic cautions to effectively prevent direct transmission of pathogens between patients through blood or body fluid or via contaminated gloves, medical materials, or instruments.(Evidence level: Very low, Recommendation level: Strong)

According to the Ministry of Health, Labour and Welfare, each hospital must have an “Infection Control Manual” independently prepared by the Infection Control Committee. However, it is difficult for a small facility to prepare a manual, survey the state of infection, and continue its modification. Therefore, the “Manual Regarding the Standard Dialysis Procedure and Prevention of Nosocomial Infections in Dialysis Medicine”(7) was prepared with a Grant-in-Aid for Health and Welfare Science by the Ministry of Health, Labour and Welfare and with the cooperation of the Japanese Association of Dialysis Physicians, Japanese Society for Dialysis Therapy, Japan Association for Clinical Engineering Technologists, and Japan Academy of Nephrology Nursing as a manual of infection control procedure at dialysis facilities (8) and is used as a model of individual hospital manuals (12). In addition, there has been a report of the observation that the incidence of new HCV infection was reduced by its implementation (13).

There are reports that the risk of infection does not increase by the reuse of the dialyzer if it is handled by a professional agent or dedicated machines are operated by strict observance of reliable infection control procedures. In Japan, however, there is no professional agent or dedicated machine, and dialyzers, the cost of which is covered by insurance, are not permitted to be reused. Since infection is expected to increase unless dialyzers are reused with sufficient caution under these conditions (10), it is recommended not to reuse them.

4. In evaluating the results of HCV infection prevention measures at hemodialysis facilities, it is recommended to include observation of the state of implementation of infection control measures, periodic surveillance of the state of infection, and review of infection control measures depending on the state of infection.(Evidence level: Very low, Recommendation level: Strong)

According to the results of inspection of the dialysis operation at nine dialysis facilities in Spain in November 2003, the staff of the dialysis facilities wore gloves in 93% of the manipulations requiring gloves, but the hands were washed 36% of the times after, and only 14% of the times before, contact with patients (14). On direct observation of how infection control manipulations were implemented after an outbreak (15), problems including (i) poor compliance with hand-washing, (ii) poor compliance with glove changes particularly in emergency hemostasis of arteriovenous fistula, (iii) carrying a channel contaminated with blood in the dialysis room without containing it in a bag, (iv) neglect of periodic decontamination of blood-contaminated dialysis system, and (v) neglect of replacement of a contaminated pressure transducer protector were revealed, but these problems are hardly detected by interviews with the staff (16).

In evaluating the results of HCV infection prevention measures at hemodialysis facilities, it is recommended to observe the state of implementation of infection control measures, periodically survey the state of infection, and review infection control measures depending on the state of infection.

REFERENCES

  1. Top of page
  2. INTRODUCTION
  3. REFERENCES
  4. SCREENING OF DIALYSIS PATIENTS FOR HEPATITIS C VIRUS INFECTION
  5. REFERENCES
  6. MANAGEMENT OF HEPATITIS C IN DIALYSIS PATIENTS (METHODS, FREQUENCY OF BLOOD TESTS AND IMAGING STUDIES)
  7. REFERENCES
  8. INDICATIONS OF ANTIVIRAL THERAPIES IN DIALYSIS PATIENTS
  9. REFERENCES
  10. TREATMENT OF DIALYSIS PATIENTS BY ANTIVIRAL THERAPIES
  11. REFERENCES
  12. PREVENTION OF HCV INFECTION AT HEMODIALYSIS FACILITIES
  13. REFERENCES
  • 1
    Kokubo S, Horii T, Yonekawa O, Ozawa N, Mukaide M. A phylogenetic-tree analysis elucidating nosocomial transmission of hepatitis C virus in a haemodialysis unit. J Viral Hepat 2002;9:4504.
  • 2
    Furusyo N, Kubo N, Nakashima H, Kashiwagi K, Etoh Y, Hayashi J. Confirmation of Nosocomial Hepatitis C Virus Infection in a hemodialysis unit. Infect Control Hosp Epidemiol 2004;25:58490.
  • 3
    Noiri E, Nakao A, Oya A, Fujita T, Kimura S. Hepatitis C virus in blood and dialysate in hemodialysis. Am J Kidney Dis 2001;37:3842.
  • 4
    Stramer SL, Glynn SA, Kleinman SH et al. National Heart, Lung, and Blood Institute Nucleic Acid Test Study Group. Detection of HIV-1 and HCV infections among antibody-negative blood donors by nucleic acid-amplification testing. N Engl J Med 2004;351:7608.
  • 5
    Alter HJ, Aragon T, AuBuchon JP et al. Recommendations for prevention and control of hepatitis C virus (HCV) infection and HCV-related chronic disease. MMWR 1998;47(RR19):139.
  • 6
    Bailey JL, Balter P, Berns J et al. Recommendations for preventing transmission of infection among chronic hemodialysis patients. MMWR 2004;50(RR05):143.
  • 7
    Manual Regarding the Standard Dialysis Procedure and Prevention of Nosocomial Infections in Dialysis Medicine (3rd revised edition). Research Project on Emergency Measures to Overcome Hepatitis and Other Diseases on a Grant-in-Aid for Health, Labour and Welfare Science 2007, Tokyo, 2007
  • 8
    Deutschen Arbeitsgemeinschaft für Klinische Nephrologie e.V. in Zusammenarbeit mit dem Verband Deutscher Nierenzentren der DD nÄ e.V. sowie der Arbeitsgemeinschaft für Pädiatrische Nephrologie (APN). Dialysestandard 2006.
  • 9
    Fissell RB, Bragg-Gresham JL, Woods JD et al. Patterns of hepatitis C prevalence and seroconversion in hemodialysis units from three continents: the DOPPS. Kidney Int 2004;65:233542.
  • 10
    dos Santos JP, Loureiro A, Cendoroglo Neto M, Pereira BJ. Impact of dialysis room and reuse strategy on the incidence of hepatitis C virus infection in haemodialysis units. Nephrol Dial Transplant 1996;11:201722.
  • 11
    Nakayama E, Akiba T, Marumo F, Sato C. Prognosis of anti-hepatitis C virus antibody-positive patients on regular hemodialysis therapy. J Am Soc Nephrol 2000;11:1896902.
  • 12
    Ando R, Akiba T. Present state of preventive measures against nosocomial infection of viral hepatitis at hemodialysis facilities. J Jpn Soc Dial Ther 2009;42:42333.
  • 13
    Tsuruta Y, Watanabe U, Yamazaki C, Maeda K. Present state of hepatitis B and C infection at dialysis facilities in Aichi Prefecture (Part 2). J Jpn Assoc Dial Physicians 2002;17:4229.
  • 14
    Arenas MD, Sanchez-Paya J, Barril G et al. A multicentric survey of the practice of hand hygine in haemodialysis units: factors affecting compliance. Nephrol Dial Transplant 2005;20:116471.
  • 15
    Delarocque-Astagneau E, Baffoy N, Thiers V et al. Outbreak of hepatitis C virus infection in a hemodialysis unit: potential transmission by the hemodialysis machine? Infect Control Hosp Epidemiol 2002;23:32834.
  • 16
    Izopet J, Pasquier C, Sandres K, Puel J, Rostaing L. Molecular evidence for nosocomial transmission of hepatitis C virus in a French hemodialysis unit. J Med Virol 1999;58:13944.