Renal Disease and Viral Hepatitis

Richard McCrory

Basic Virology

Hepatitis B

Hepadnavirus

• 4 serotypes, 8 genotypes (impact virulence)

Circular DNA Genome

• DNA →RNA →DNA

Hepatitis C

Flavivirus

• 7 genotypes but high rate of mutation

Single Strand positive RNA genome

Testing for HBVTest Result Typical interpretation

HBsAganti-HBcanti-HBs

negativenegativenegative

Susceptible (needs vaccination)

HBsAganti-HBcanti-HBs

negativepositivepositive

Resolved HBV infection

HBsAganti-HBcanti-HBs

negativenegativepositive

Vaccinated

HBsAganti-HBcanti-HBs

positivepositivenegative

Active HBV infection(usually chronic)

HBsAganti-HBcanti-HBs

negativepositivenegative

Various possibilities, including:

- distant resolved infection (most common)

- recovering from acute infection- false positive- 'occult' HBV ( +ve HBV DNA viral load)

Testing for HCV

HCV antibody (4-6 weeks to become +ve)

● May be negative in the first 6 weeks after exposure

● Does not distinguish between acute and chronic infection

● Low signal-to-cutoff ratio may be present during acute HCV infection

or represent a false-positive result

HCV RNA (10-14 days to become +ve)

● Viral fluctuations >log10 IU/mL may indicate acute HCV infection

● Alone does not distinguish between acute and chronic infection

Epidemiology

Hepatitis B

• Worldwide– 240-350 million HbSAg +ve

• 1:350 UK Population

Transmission– Blood or Contaminated

Equipment

– Sexual

– Vertically

Hepatitis C

• Worldwide– 135-200 million HCV Ab +ve

• 1 in 250 UK Population

Transmission– Blood or Contaminated

Equipment

– Sexual (less common)

The Many faces of Chronic HBV Infection

Associations of Viral Hepatitis with CKD / ESRD in Taiwan

HBV

HBV +ve prevalence >15% 1985

Incidence of ESRD in untreated chronic HBV cohort 2% (HR 3.85)

HCV

High HCV Prevalence

• Incidence of ESRD in chronic HCV patients 2.14 fold higher than age matched cohort

• Patients aged 50-59 had highest incidence

BUTTaiwan has high prevalence of Type 2 DiabetesAssociations between T2DM and both Hepatitis Viruses

Spectrum of Renal Disease Associated with Hepatitis Viruses

Membranous Nephropathy

MPGN

PolyarteritisNodosa

Sample Questions

A 41-year-old woman with a recent diagnosis of hepatitis C infection was

found to have a serum creatinine of 167 umol/L. Urine dipstick was

positive for 3+ protein and + blood

Other results are as follows:

24hr Urinary protein - 2.7 g/24 h

C4 - <0.14 g/L C3 - 0.23 g/L

Rheumatoid factor – Positive

ANCA / ANA / Anti-GBM - Negative

Light Immunoagainst IgG

EM

What is the most likely diagnosis?

A. IgA Nephropathy

B. Cryoglobulinemic Glomerulonephritis

C. Membranous Nephropathy

D. Thrombotic Microangiopathy

E. Crescentic Glomerulonephritis

Membranoproliferative GN

● Large glomeruli with accentuation of lobules

● Irregular thickening of glomerular basement membrane by interposition of mesangial cells between endothelium and basement membrane

● Causes tram track / double contour appearance (PAS or silver stain), crescents in 20%

Cryoglobulins in HCV

Type II cryoglobulins● IgM directed against Fc of IgG● Rheumatoid Factor behaviour

40-90% of patients with Chronic HCV have evidence of cryoglobulins● <10% of these will manifest with vasculitis

Cryoglobulinaemic Vasculitis

The patient was commenced on treatment for cyroglobulinaemicvasculitis and is discharged 10 days after admission. She presents at outpatient clinic 3 weeks later with increasing shortness of breath.

Blood Tests at date of admission and at 6 weeks are shown below:

Admission Week 5

Haemoglobin(g/L)

115 78

MCV 86 102

WCC 11.8 7.2

Platelets 242 196

What agent started at treatment is most likely to explain the patient’s shortness of breath?

A. CyclophosphamideB. Interferon-AlphaC. RibavirinD. Losartan

HCV Related Glomerular Disease

● Membranoproliferative GN● IgA Nephropathy● Post-infectious GN● Thrombotic Microangiopathy● FSGS● Fibrillary GN

Treatment of HCV-related renal disease

Patients with nephrotic-range proteinuria and/or progressive renal failure:

● Immunosuppressive plus antiviral treatmento Rituximab: 375 mg/m2 weekly for 4 wko Cyclophosphamide: 2 mg/kg per d for 2 to 4 monthso Methylprednisolone pulses: 0.5 to 1 g/d for three consecutive

days● RBV daily: initial dose according to GFR● Some newer agents do not require dose adjustment for GFR● Plasma exchange in case of high cryoglobulin levels

o 3 l of plasma three times per week for 2 or 3 wk

Antivirals for Hepatitis C

Virologic cure = Sustained Virological Response● Absence of detectable HCV RNA >12 weeks after

completion of therapy

Response depends heavily on Genotype● Genotype 1 - 40% response at 48 weeks● Genotype 2/3 - 80% response rate within 12 weeks

HBV Associated Membranous (HBV-MN)

Children● Strong (>80%) Male Preponderance● Commonly presents with nephrotic

syndrome or microscopic haematuria

● Often don’t have overt liver disease

● Remission correlates with viral clearance

Adults● Less favourable prognosis● Proteinuria + Hypertension

In high titre HBsAg Patients● Nephrotic Syndrome + Abnormal

LFTs = >50% RRT at 3yrs

HBeAg / Anti-HBe immune complexes likely culprit for sub-epithelial deposit substrate

HBV DNA can be detected in glomerular & interstitial tissues

Treatment of HBV-MN

Don’t forget measures utilised for other proteinuricdisease!

Immunosuppression monotherapy● Causes more harm than good● Increases viral replication, accelerates

progressionAntivirals

● Suppresses viral load, facilitates clearance of antigen

Interferon● Helps accelerate seroconversion

Antivirals in Hepatitis B

• Aim of therapy – to promote seroconversion• No new drugs in Phase 3 trials presently

• Nucleoside Analogues– Lamivudine

• Cheaper• Mutation Resistance increases with treatment duration

– Entecavir• More Expensive• <1% resistance rate at three years treatment

• Interferon– Finite duration of treatment– No mutation resistance– Side effects can be difficult to manage

A 45 year old man presents with a 10 week history of intermittent abdominal pain after eating and weakness in his legs. Blood Pressure is elevated at 190/110 mmHg and examination confirms a right foot drop. You have been asked to consult due to elevated serum creatinine.

Urine dipstick notes 1+ protein and 2+blood

Hb 110g/L WCC 7.5 CRP 25 mg/LCoagulation Screen - Normal Thrombophilia Screen - NegativeCreatinine 220 umol/L Urine ACR - 30 mg/mmolHIV Antibodies - Negative HBsAg - Positive HBeAg - PositiveANA / ANCA / Anti-GBM - Negative C3 - 0.39 g/L C4 - 0.15 g/L

CT Brain - NormalUltrasound Renal Tracts - No obstruction, Left Kidney 10cm, Right Kidney 10.5cm

Which of the following would be the best investigationto perform next?

A. Renal BiopsyB. Mesenteric AngiographyC. CT Abdomen with ContrastD. Sural Nerve BiopsyE. Gastroscopy

“Testing is Cheap,Treatment is not”

Viral Hepatitis & Dialysis

DOPPS (2004)● HCV prevalence ranged from 3-23% HD units

over 3 continents● HBV from 0-5%

● Prevalences in Developing World– 18-80%

Vaccinating CKD Patients against HBV

Why not?

– Reduced efficacy of the vaccine

– The low rate of hepatitis B infection

CDC Position (2012)

“The cost of vaccinating patients is mitigated by the reduced need for monthly surveillance of antigen and antibody status”

Use of HBV Vaccines as treatment for HBV?

“Third generation” vaccines show increased immunogenic response in CKD patients

Chronic HBV and Pre-RT evaluation

Involve a Hepatologist!HBeAg status and HBV DNA copy load can help

determine risk of reactivation post-TxHBsAg +ve patients routinely need liver biopsy

Are they a candidate for combined liver-kidney transplant?

Hepatitis B & Renal Transplantation

The HBsAg Positive Donor Kidney● Should not be transplanted into HBV-naive

recipients except in urgent scenario● Risk of de novo infection reduced if donor

anti-HBc positive

General Rules for Recipients with HBV

HBsAg +ve Recipients● Lifelong anti-viral therapy

Anti-HBc +ve(or -ve) / anti-HBs +ve Recipients● No prophylaxis immediately needed, may

need vaccine booster if titre <10IU/ml, need antiviral until anti-HBs >10IU/ml

● HBV DNA monitoring (NICE guidance)

Hepatitis C & Renal Transplantation

The HCV +ve donor kidneyGood experience of transplanting into HCV+ve

recipientsTransplantation confers survival advantage over

staying on waiting listBUT Higher rates of Graft Loss, Rejection

Episodes, NODAT, CMV Disease

Potential KT Recipients with HCV

Sustained virological response preferable to be achieved pre-transplant

Immunosuppression encourages HCV reactivation even if SVR initially achieved

Recommendations on Treatment of Hepatitis C (2014)● Suggest IFN-free regime pre-Tx Regimens of anti-HCV

therapy post transplant similar to non-transplanted patients (without IFN)

● Newer agents not yet extensively investigated

“New Drugs; New Interactions”

Don’t Forget...

● HCC Screening (USS & AFP) (HBV/HCV)● Monitoring blood glucose for development of

NODAT (HCV)

Take Home Points

Testing & Prevention is CheapBurden of Disease & Treatment is Costly

Hepatitis B● Preventing Transmission & Vaccination Works

Hepatitis Co “On the Cusp of Change” with new antivirals