Dng hbv -kidney disease

HBV- ASSOCIATED KIDNEY
DISEASES
By
Mohamed Abd El-Maksoud
Assistant Prof. of Tropical Medicine

History
5th century
B.C
Hepatitis was first described
1883 First blood borne outbreak occurred in Bremen, Germany
after receiving small pox vaccine
1947 McCallum and Bauer introduced the term hepatitis B
1965 Blumberg discovered the protein antigen (Australia
antigen) (HBsAg)
1970 Dane Cameron discovered the complete hepatitis B or
Dane particle
1972 Magnus and Espmark described HBeAg
Early
1980
The genome had been sequenced and the first vaccines
were being tested

Hepatitis B virus
 Member of hepadnaviridae
 Enveloped partially dsDNA virus
 100 times infectious than HIV
 Able to survive in dried blood for longer than 1week

VIROLOGY
 The infectious hepatitis B virion,
is composed of lipid envelope
containing:
 Viral glycoproteins
- Constitute HBsAg.
 Nucleocapsid (icosahedral)
-Composed of HBcAg
-Encloses partially double-
stranded circular HBV DNA and
the HBV DNA polymerase
• The partially double-stranded, relaxed-circular (rc) DNA
features 4 open reading frames (4 genes) encoding 7 proteins:

Genomic structure of HBV
Gene Region Gene product
S S Major protein (S)
S + Pre S2 Middle protein (M) HBsAg
S + Pre
S1&S2
Large protein (L)
C C HBcAg
C + Pre C HBeAg
P DNA polymerase
X HBxAg which contribute to
carcinogenesis

HBV Life cycle
1- Initial attachment of the virus to a cellular receptor
and its internalization.
2- In the cytoplasm → virus uncoating →nucleocapsid
is transported to the nucleus
3- In the nucleus → The viral genome is released under
its relaxed circular form (rcDNA) → converted into
a covalently closed circular DNA (cccDNA) which
serves as a transcription template for all viral
transcripts that are translated into the different viral
proteins

4- The viral RNAs transfer to the cytoplasm for translation of
the different viral proteins or for subsequent reverse
transcription of the pregenomic RNA
5-The DNA containing nucleocapsids in cytoplasm are either:
- Recycled into the nucleus to maintain cccDNA reservoir or
- Enveloped and secreted via the endoplasmic reticulum
6-In addition to complete infectious virions, infected cells
produce a large excess of genome-free, non-infectious
sub-viral spherical or filamentous particles.

Why genotype is important?
 Risk of cirrhosis
B/C higher risk of cirrhosis (C > B)
D: also high risk
 Risk of HCC
B/C highest risk of HCC
D: HCC at younger age, absence of cirrhosis
 Response to treatment
A: most responsive to IFN

Hepatitis B in the world
 2 billion people have been
infected (1 out of 3 people)
 350- 400 million people are
chronically infected
 700.000 deaths annually from
liver related complication

Concentration of HBV in various
body fluid
High Moderate Low/not detected
• Blood
• Serum
• Wound
exudate
• Semen
• Vaginal discharge
• Saliva
• Sweet
• Urine
• Feces
• Tears
• Breast milk

Transmission
1) Percutaneous:
100 times more infectious than HIV
2) Perinatal:
 Without prophylaxis, the risk of HBV vertical
transmission is high.
 HBeAg-positive mothers : 70%–90% risk
 HBeAg-negative mothers: 10%–30% risk
3) Sexual

In high-prevalence areas:
 South East Asia
-Perinatal transmission is common (50 %) (higher
prevalence of HBeAg in female carriers of childbearing
age
 Sub-Saharan Africa,
- Horizontal transmission
- Most children infected by the age of 5 years.
In low-prevalence areas:
- Hepatitis B is a disease of young adults
- High-risk behavior such as sexual promiscuity, drug
abuse ,high-risk occupations.

Pathogenesis of HBV
 Disease is immune mediated
 Hepatocyte carry viral antigen
 Nk cell and cytotoxic T cell attack
 In the absence of the adequate immune
response, HBV infection may not cause
hepatitis, but lead to carrier state

 Chronic HBV infection is a dynamic process reflecting
the interaction between HBV replication and the host
immune response
 Divided into five phases, taking into account :
- Presence of HBeAg
- HBV DNA levels
- ALT values
- Presence or absence of liver inflammation
Phases of chronic HBV Infection

Natural history of HBV
HBeAg positive
Chronic
infection
HBeAg positive
Chronic hepatitis
HBeAg negative
Chronic
infection
HBeAg negative
Chronic hepatitis
Old
terminology
Immune
tolerant
Immune reactive Inactive carrier Reactivation
HBsAg High High/Intermediate Low Intermediate
HBeAg Positive Positive Negative Negative
HBV DNA >10 7 IU/mL 10 4-10 7 IU/mL <2,000 IU/mL°° >2,000 IU/mL
ALT Normal Elevated Normal Elevated*
Liver disease None/minimal Moderate/severe None Moderate/severe

Factors affecting progression to
complication
Host factors Viral factors
• Older age > 40 ys
• Male sex
• African or Asian race
• Fibrosis , Cirrhosis
• Alcohol abuse
• Chronic co-infections
• Diabetes or metabolic syndrome
• Active smoking
• Positive family history
• High HBV DNA
• High HBsAg levels
• Genotype C > B
• Precor and core promoter
mutations.
• Prolonged time to
HBe Ag seroconvertion
• Development of Hbe Ag
hepatitis

Renal involvement in hepatitis B
1) Renal disease associated with Hepatitis B
2) HBV in dialysis and renal transplant.
3) Renal dysfunction associated with HBV
antiviral drugs
4) Renal dysfunction in hepatitis B cirrhosis.

RENAL DISEASE ASSOCIATED WITH
HEPATITIS B
 HBV is associated with various extrahepatic
manifestation
 Globally, HBV infection is the most common cause of
viral nephropathy
 Renal involvement is linked to epidemiology of HBV:
- Occur in 3%–5%
- Common in endemic areas.
- More common in children than adults
- Men than women.

Mechanisms of renal involvement in
HBV infection
 The exact mechanism is not known.
 Not likely due to cytopathic effect of HBV.
 Immunologic response plays a role:
a) Circulating immune complex deposition
b) In situ immune complex formation in glomeruli
c) Complement activation
Glomerular damage
Various forms of glomerulonephritis

 Viral genotype:
-Has an impact on HBV-related glomerular involvement.
-Genotype A have the highest risk of MN or MPGN.
 Mutations of the HBV x gene (84%)
 HLA associations
Association of HLA DQB1*0603 and DQB1*0303, with
the disease.

 The morphologic classification of HBV-
glomerular injury depends on:
- Site of immune complex deposition
- Type of immune complex deposition

1)Membranous nephropathy
 Most common pattern of
injury in HBV-related renal
disease
 HBeAg and anti‐HBe
immune complexes
in subepithelial region of
glomeruli
 Predominance of IgG , C3
 Stiff and thick appearance
of capillary loops

Clinical presentation
Features Children Adults
Gender M>F( >80%) M>F
Presentation Nephrotic
syndrome
Nephrotic /nephritic
syndrome
History of prior liver
disease
Uncommon Hepatitis flares
present
Spontaneous
remission
Common Uncommon
Progression to
renal failure
Rare In 30% of patients

2) MPGN
 The second most common GN
 Type 1 and type 3 MPGN
 HBsAg with IgG deposition in
the subendothelial space
 Typical lobular appearance of
the glomerulus with splitting of
the basement membrane and
mesangial, subendothelial,
and even subepithelial
deposits.

Clinical presentation:
 Haematuria
 Proteinuria of variable degrees
 ↓ GFR
 Hypertension.

 An additional cause of type 1 MPGN in HBV carriers .
 75% presented after >10 years of HBV infection
 Predominantly type 3 cryoglobulinemia (polyclonal IgM –
polyclonal IgG).
 HBV patients with cryoglobulinemia may present with:
- Nephrotic syndrome
- AKI
- Systemic vasculitis
- Low C4 (92%) and low C3 (58%).
Mixed cryoglobulinemia.

 HBV is not lymphotropic, it is not known how HBV
induces B cell cryoglobulin production.
 Therefore, it is essential to exclude coinfection with
hepatitis C as a cause of MPGN in HBV carriers
because up to 10% of patients worldwide carry both viral
infections and the treatment will be dictated by which
infection is causing the renal lesion.

 It is a necrotizing vasculitis affecting small‐ and
medium‐sized blood vessels producing multiorgan
involvement.
 HBV was account for up to 30% of PAN cases, but now
it represent < 8% of all cases
 Renal involvement in 11-66% of patients with PAN
 Deposition of circulating antigen‐antibody immune
complexes in the vessel wall triggers inflammatory
processes.
3)Polyarteritis nodosa (PAN)

 Similar to idiopathic PAN.
 Typical features include
 Arthralgias.
 Fever.
 Rash,
 Abdominal pain.
 Renal disease.
 Hypertension
 Mononeuritis multiplex
 CNS abnormalities.
Clinical manifestation

Diagnosis of HBV‐associated renal
disease :
 Diagnosis of HBV‐associated renal disease is important
because therapy with corticosteroids and cytotoxic
agents, which are common therapies for idiopathic forms
may lead to reactivation of HBV replication, hepatitis
flares and liver failure.
1) HBV DNA testing :to confirm active viral replication.
2) Concurrent infection with HCV should be excluded
3) Renal biopsy : confirm diagnosis.

ORAL DRUGS USED FOR HEPATITIS B
six oral agents have been licensed for the treatment
of chronic HBV infection:
3 nucleoside
• Lamivudine
• Telbivudine
• Entecavir
3 nucleotide
• Adefovir
• Tenofovir fumarate (TDF)
• Tenofovir alafenamide
(TAF)

Entecavir
• Lactic
acidosis
Adefovir and
Tenofovir
• Nephrotoxicity
• Proximal tubular
damage
• Fanconi syndrome
• Osteomalacia.
Telbivudine
• Myopathy,
• Increase creatine
kinase,
• Peripheral
neuropathy
Extrahepatic effects of nucleos(t)ide
analogues

The recommended NA dosages according to the
renal function
Creatinine
clearance
(mL/min)
Lamivudine Adefovir Entecavir ( Telbivudine Tenofovir
≥50 100 mg daily 10 mg daily 0.5 mg daily 600 mg daily 300 mg daily
30‐49 100 mg
loading
dose—50 mg
daily
10 mg every
2nd day
0.25 mg daily
or 0.5 mg
every 2nd
day
400 mg daily
or 600 mg
every 2nd
day
300 mg
every 2nd
day
10‐29 100 mg
loading
dose—25 mg
daily
10 mg every
3rd day
0.15 mg daily
or 0.5 mg
every 3rd day
200 mg daily
or 600 mg
every 3rd day
300 mg
every 3rd day
HDa <35 mg
loading
dose—10 mg
daily
(<5 CrCl)
10 mg once
weekly
0.05 mg daily
or 0.5 mg
once weekly
600 mg once
every
96 hours
300 mg
once weekly

 No dose adjustment tenofovir alafinamide (TAF), but it should
not be used if the estimated creatinine clearance is
<15 mL/min.
 The main advantage of (TAF) over TDF is its more‐favourable
effects on markers of kidney and bone function, which may
be particularly important in older patients or those who have
pre‐existing renal insufficiency or osteopaenia/osteoporosis.
 In NA‐naïve patients with renal dysfunction at baseline
(creatinine clearance <50‐60 mL/min), entecavir may be
preferred over tenofovir

Treatment of HBV‐associated renal
disease
 Therapy for HBV-related renal disease
may include:
-Therapy targeted at the HBV infection
-Therapy targeting renal disease
-Combination of both

 Immunosuppressive therapy without the use of
antivirals may not be recommended as there is an
associated concern of HBV reactivation.
 Combination of antivirals and immunosuppression
led to significant improvement in proteinuria and
serum albumin levels amongst patents with HBV
related glomerular disease

1)Pegylated Interferon alfa
 Preferred in children and young adults
 48 weeks in both HBeAg+VE and HBeAg‐VE patients.
2)Nucleoside/nucleotide analog:
 Entecavir is preferred (efficacy and low resistance).
 Adefovir and to a lesser extent, tenofovir not preferred
 In HBeAg +ve patients, treatment is continued for at
least 12 months after seroconversion
 In HBeAg -ve patients, treatment often require lifelong

3)Immunosuppression (with or without
plasmapheresis)
 Used in combination with antiviral therapy in
patients who have:
- -Rapidly progressive glomerulonephritis
- - PAN with severe manifestations.

 In patients who are to receive immuno-modulatory or
immunosuppressive therapy, use of drugs with high
genetic barrier to resistance like entecavir and tenofovir
is preferred to other drugs as some patients may be
inherently resistant to lamivudine or may develop
resistant strains while on therapy.
 The antivirals should ideally begin prior to initiation of
immunosuppressive treatment and continue for 6
months after discontinuation of immunosuppression (12
months for B cell depleting agents).

 All in all, an approach in setting of HBV-related renal
disease would be to initiate treatment with antiviral
drugs alone (preferably entecavir or tenofovir) and
to add immunosuppressive agents in case of
worsening of renal function or lack of response.
 This will also provide time for the potent anti-viral
drugs to control the HBV infection and avoid any
HBV reactivation where immunosuppression is

5)Concomitant HCV infection
NAs for HBV and directly acting antivirals
(DAA) for HCV.

 Hepatitis B virus (HBV) infection is a global public health
problem
 The global prevalence of chronic HBV infection varies among
different geographical areas
 The risk of chronicity after primary HBV infection varies and
depends on the age and immune status at the time of
infection
 The natural course of HBV infection is complex and variable
CONCLUSION

 Renal involvement in HBV is seen in a minority of
patients and is likely to occur in patients who remain
infected.
 Nucleos(t)ide analogues are cleared by the kidneys
and therefore their dosage has to be adjusted in all
patients with impaired renal function.

 It seems logical to first treat the HBV infection in case of
stable and non-life threatening disease, and keep the
patient on regular follow up.
 However, life threatening renal involvement in the form
of rapidly progressive glomerulonephritis and
severe form of PAN may necessitate addition of
immunosuppressive drug treatment with or without
plasmapheresis

Dng hbv -kidney disease

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