Transcript of "Hepatitis B in Dialysis and Transplantation"
Hepatitis B in Dialysis and
Dr. Sandeep G. Huilgol
MBBS., DNB (Int.Med)., MMedSci (Nephro)
Hepatitis B virus (HBV) infection can lead
to acute or chronic hepatitis, cirrhosis, or
Despite the availability of effective
vaccines since 1982, HBV infection has
remained endemic in many localities, with
more than 350 million chronic HBV
HBV infection in dialysis
Immunosuppressive effect of renal failure.
The susceptibility for de novo infection
and nosocomial transmission,
The long-term implications on morbidity
and mortality, and
The change in clinical course after kidney
The majority of newly HBV-infected dialysis
patients have a relatively mild clinical course .
Infected patients are often asymptomatic, and
have normal or only slightly elevated serum
Data from patients on peritoneal dialysis showed
that the impact of HBV infection per se on the
survival of dialysis patients was relatively small
Significant risk of clinical deterioration in the HBV
infected renal transplant recipient.
The risk of severe life-threatening complications is
highest when de novo HBV infection occurs shortly
Hepatitic flares and liver-related complications can
occur at any time after kidney transplantation in
HBsAg-positive kidney transplant recipients, including
those who have been asymptomatic HBV carriers
Therefore, despite the relatively benign clinical
disease in dialysis patients, the importance of
preventing and treating HBV infection in dialysis
patients must be underscore
INCIDENCE AND PREVALENCE
Decreased due to various reasons
1 percent in United States
5.9 percent in Italy
12 percent in Brazil
1.3 to 14.6 percent in Asian Pacific countries
The prevalence of HBV in the dialysis
population in India is reported to range
between 3.4% and 42% ( S K Agarwal et al.)
Even in HBsAg-negative dialysis patients
with a history of resolved HBV
infection, minute amounts of
transcriptionally active HBV DNA can be
detected by polymerase chain reaction in
peripheral blood mononuclear cells and
serum samples from about 50 percent of
This phenomenon is associated with
deletions in the pre-S1 region of the viral
genome, which affected the S
promoter, thereby reducing the production
Patients on peritoneal dialysis have a
lower risk of acquiring HBV infection
compared to those on long-term
There is a reported 19-fold difference in
In the majority of dialysis patients, testing
for HBsAg is sufficient for the diagnosis of
Negative HBsAg test does not preclude
absolutely the presence of occult HBV
Occult HBV infection has been defined by
positivity in nested PCR assays with
sensitivity down to 10 copies/mL ( 9% in a
In addition to these standard precautions, measures
specific to hemodialysis units are also important to
prevent nosocomial HBV infection .
Wearing gloves before contact with patients or dialysis
Routine cleaning and disinfection procedures
Prohibition of sharing instruments or medications
Preparing and distributing medications from a
Avoiding the use of medication supply carts
Regular screening of HBsAg status in non-immune
Hepatitis B vaccination of patients and staff
Segregation and reuse of
Failure to segregate and use dedicated hemodialysis
machines for HBsAg positive patients is associated with
an increased incidence of HBV infection.
United States national surveillance in 1997 showed no
difference in the incidence of HBV infection between
centers that practiced segregation of dialysis rooms and
those that did not
Dialyzer reuse was also not associated with a higher
risk of HBV infection both in patients and in staff.
Nevertheless, the Centers for Disease Control (CDC)
recommended that dialyzers from HBsAg-positive
patients be excluded from reuse programs
Laboratory testing during the acute or chronic
phases of HBV infection can reveal elevations in the
concentration of alanine and aspartate
aminotransferase levels (ALT and AST).
Hypotransaminasemia is a well-recognized feature in
dialysis patients with or without liver disease.
The normal range of transaminases should be
adjusted downwards, otherwise the incidence or
severity of clinical liver disease might be
Levels of 24 IU/L and 17 IU/L have been
recommended as the upper limits of normal for AST
and ALT, respectively, in dialysis patients
Acute hepatitis B in dialysis patients is
more likely to result in chronic infection
compared to non immunosuppressed
Up to 80 percent of acutely infected
dialysis patients may become chronic
The manifestations of chronic hepatitis B
or HBV-induced cirrhosis in dialysis
patients are identical to those without
Aminotransferase levels indicate hepatitic
activity, but need to be interpreted
according to the adjusted normal ranges.
The level of gamma
glutamyltranspeptidase may be
increased, which could signify bile duct
Progression of liver disease manifests as
hypoalbuminemia, coagulopathy, and
development of complications such as
hypersplenism, ascites, esophageal
varices, or hepatic encephalopathy.
Considerations for combined liver and renal
transplantation may be warranted in dialysis
patients with severe irreversible liver disease.
Co-infection with the hepatitis D virus can
lead to more severe liver disease, and needs
to be investigated when clinically indicated.
Clinical course of HBV infection in dialysis patients
appears less severe.
The aim of management is to minimize the
progression of liver disease and for the early detection
of liver complications including hepatocellular
Treatment is indicated in HBsAg-positive patients with
evidence of disease activity, as indicated by viral
replication and abnormal transaminase
levels, preferably corroborated by examination of liver
A level of 4 to 5 log10 copies/mL for HBV DNA is
usually taken as the threshold to start treatment.
With the advent of more sensitive
quantitative assays, it remains to be
investigated whether the treatment level
needs to be adjusted downwards.
HBeAg can be negative in patients with
precore- or core promotor-mutant infection
despite active disease.
In view of the side effects of interferon in
patients on dialysis, nucleotide or
nucleoside analogues are better choices.
Entecavir is the recommended first-line
oral therapy in patients with kidney
The doses of all medications must be
adjusted appropriately according to renal
Hep B and renal Transplantation
Among HBsAg positive patients, reactivation of
HBV replication is variably defined by the
appearance of HBV DNA in a patient who has
had undetectable HBV DNA previously, or by a
>1 to 2 log increase in HBV DNA.
Among HBsAg negative, anti-HBc positive
patients, reactivation is defined by the
reappearance of HBsAg or HBV DNA or an
increase in HBV DNA in those with detectable
HBV DNA prior to start of immunosuppressive
The risk of reactivation of HBV
replication following transplantation is
related to the status of serologic and
virologic markers at the time of kidney
Patients who are HBsAg positive have
higher risk than patients who are HBsAg
negative, anti-HBc positive.
Among those who are HBsAg
positive, patients who are HBeAg positive
or have high levels of HBV DNA in serum
have higher risk.
Reactivation can also occur in patients
who were HBeAg negative or had
undetectable serum HBV DNA prior to
Reactivation of HBV replication has also
been reported in those who were HBsAg
negative but anti-HBc positive
Risk factors for liver failure among
Immunosuppression can accelerate progression of
HBV-related liver disease.
Hepatitis associated with HBV reactivation can lead to
liver failure; the risk is higher in patients with cirrhosis.
Among HBsAg positive patients, a liver
biopsy, performed prior to and, if indicated, after renal
transplant, can help determine the stage of liver
disease and assess the risk of liver failure.
Administration of prophylactic or pre-emptive antiviral
therapy - liver failure should be very low
Risk factors for de novo HBV infection
De novo infection may occur through receipt of a kidney from
an infected donor.
The kidney from an HBsAg positive donor must not be
transplanted into an HBsAg-negative and anti-HBs-negative
There is a low risk of transmission of HBV infection from
HBsAg-negative, anti-HBc positive donors to HBsAg negative
The risk is even lower if the recipient is anti-HBs positive
EVALUATION PRIOR TO TRANSPLANT
All patients who are being evaluated
for renal transplantation should be
tested for HBV infection.
Standard tests in the evaluation of
potential kidney transplant recipients
kidney donors include HBsAg and
anti-HBs, and if both are negative antiHBc should be tested.
Alternatively, all three markers can be
tested at the same time
Chronic HBV infection is not a contraindication to
HBV-infected patients should be further evaluated
prior to transplantation.
Patients should be tested for HBeAg and serum
HBV DNA in order to determine the risk for
reactivation of HBV infection.
Patients who are HBeAg-positive or have high
levels of HBV DNA prior to transplantation are at
higher risk for reactivation.
It is advisable that HBsAg-positive patients
undergo liver biopsy to determine whether
cirrhosis is present.
Patients with cirrhosis are at higher risk for
hepatic failure following transplantation
because of the immunosuppressive
therapy that is used to prevent rejection.
Such patients used to be ineligible for
renal transplantation because of an
unacceptably high rate of liver-related
Patients with cirrhosis may be
considered for kidney
transplantation, providing cirrhosis is
compensated (ie, without
complications and providing there is
no evidence of portal hypertension
indicated by hepatic venous pressure
reading or reduced platelet count.
Non-invasive assessments of liver fibrosis and cirrhosis
with panels of routine laboratory tests or special
biomarkers such as FibroTest, and with measurement of
liver stiffness using ultrasound.
These tests have been validated in patients with
hepatitis C, and are more accurate in detecting cirrhosis
than in differentiating different stages of hepatic fibrosis.
The validity of these tests in patients with hepatitis
B, particularly those with kidney failure or kidney
transplantation is less certain, however.
PREVENTION OF REACTIVATION OF HBV
REPLICATION AFTER TRANSPLANTATION
HBsAg positive patients
Prophylactic strategy: antiviral agents are
administered to all patients.
Preemptive approach: transplant recipients are
periodically (ie, at least every two months for the
first year and every six months thereafter)
monitored for viremia using the polymerase chain
reaction (PCR) assay to permit prompt treatment
after the detection of HBV DNA in a patient who
previously had undetectable serum HBV DNA or
a marked increase (eg, 10-fold or 1 log) in serum
HBV DNA in a patient who previously had a low
serum HBV DNA level
Reduction of immunosuppression
For patients at risk for reactivation of HBV replication, use
lowest level of immunosuppression that is necessary to
prevent rejection of the transplanted kidney.
The specific immunosuppressive regimen varies between
centers and depending upon individual patient characteristics
such as immunologic risk for rejection, tolerance to specific
immunosuppression medications, and the absence or
presence of prior antibody induction therapy.
For patients who are at low risk for rejection, aim to reduce
the dose of prednisone to 5 mg daily or below.
The 2009 KDIGO clinical practice guidelines suggest, among
patients who are at low-immunologic risk and who also
receive induction therapy, glucocorticoids may be
discontinued during the first week after transplantation
All HBV-infected transplant recipients who
have an increase in HBV DNA concentration
either with or without abnormal ALT, should
be treated with an antiviral agent.
Antiviral therapies are effective in treating
reactivation of HBV infection among
transplant recipients, even when there is
evidence of hepatic failure (ie, when used as
However, antiviral therapy is less effective
when administered as salvage treatment.
The optimal antiviral agent depends upon the preventive
Entecavir for both prophylaxis and for treatment of
reactivation of HBV replication in lamivudine-naïve patient.
Although most of the experience in renal transplant patients is
with lamivudine, lamivudine is associated with a high rate of
Entecavir is among the most potent agents, has a low rate of
resistance with long-term treatment (approximately 1 percent
after five years of therapy), and is not nephrotoxic compared
with adefovir or tenofovir.
Tenofovir may be an acceptable alternative particularly in
patients with lamivudine resistance, but it has been
associated with nephrotoxicity.
For patients who have been treated with prophylactic
lamivudine and have developed resistance, adefovir or
tenofovir (preferred to adefovir in countries where this is
available) can be added to lamivudine (rather than stopping
lamivudine), since combination therapy may reduce the
development of resistance to the second drug.
These patients may respond to entecavir, but lamivudineresistant HBV is less sensitive to entecavir compared with
wildtype HBV (without lamivudine-resistant mutations).
Despite the use of a higher dose of entecavir, the rate of
entecavir resistance is higher in patients with prior lamivudine
resistance compared with patients who have not been
exposed to lamivudine.
The addition of adefovir or tenofovir is thus preferred in
patients with lamivudine-resistant HBV
How does the Fibroscan device work?
The Fibroscan device (Echosens) works by measuring
In this technique, a 50-MHz wave is passed into the
liver from a small transducer on the end of an
ultrasound probe .
The probe also has a transducer on the end that can
measure the velocity of the shear wave (in meters per
second) as this wave passes through the liver.
The shear wave velocity can then be converted into
liver stiffness, which is expressed in kilopascals.
FibroTest involves assessment of alpha-2macroglobulin, alpha-2-globulin
(haptoglobin), gammaglobulin, apolipoprotein
A1, GGT, and total bilirubin
Patient's age, and sex.
Results from the individual assays are combined and
are used to classify patients having mild fibrosis (F0F1), significant fibrosis (F2-F4), or an indeterminate
stage of fibrosis.
The sensitivity and specificity for detection of
significant fibrosis are approximately 75 and 85
ActiTest is a modification of the FibroTest
that incorporates ALT and reflects both
liver fibrosis and necroinflammatory
ActiTest appears to improve identification
of more advanced fibrosis associated with
Reference : Uptodate.com