hepatitis c virus & chronic kidney diseases

HCV & chronic renal diseases

Samir Haffar M.D.

Associate Professor of Gastroenetrology

Faculty of Medicine – Damascus – Syria

24th Congress of the SSGE – May 25-28, 2010 Dedeman Hotel – Lattakia – Syria.

HCV & chronic kidney diseases

• HCV diagnosis in CKD Patients

• HCV-related glomerulonephritis

• HCV in dialysis patients

• HCV and kidney transplantation

Testing of chronic hepatitis C

• anti-HCV (EIA*-3) Initially

• HCV RNA (RT-PCR**) Document viremia

• HCV genotyping Before treatment

* ELISA: Enzyme-Linked Immuno-Assay** RT-PCR: Real time Polymerase Chain Reaction

HCV diagnosis in dialysis patients2,653 patients

2 108 HD – 545 CAPD39 of 49 dialysis centers in the Netherlands

Anti-HCV (EIA-3)

79 patients +

HCV RNA +

57 patients +

2574 patients –

HCV RNA in pools of five

6 patients +

False negative 0.23%

Schneeberger PM et al. J Clin Microbiol 1998;36:1711–1715.

HCV-RNA test should be obtained prior to HD

• Heparin used during dialysis can interfere with the

PCR technique

• HD can lower HCV RNA by adsorption of HCV RNA

onto inner surface of dialyzers & destruction of viral

particles by hydraulic pressure exerted by blood

Okuda K et al. Lancet 1999;347:909–910.

Percutaneous liver biopsy in CHC with ESRD

Pawa S et al. Clin Gastroenterol Hepatol 2007;5:1316–20.

319 patients with CHC

Platelet, PT & PTTNo bleeding time

No arginine vasopressin

241 control patientsCHC without renal failure

5 complications3 severe2.1%

78 patients CHC & ESRD

1 complicationModerate

1.3%

Accuracy of fibrotest* in HD patients with CHC

*Noninvasive method to assess liver fibrosis in HCV on scale from 0 to 1Varaut A et al. Transplantation 2005 Dec 15;80:1550–5 .

110 CHC60 renal transplant recipients

50 hemodialysis patients

METAVIR scoreFibrotest

50 patients had fibrosis F2

AUROC for significant fibrosis Global population: 0.66

Hemodialysis patients: 0.47Renal transplant patients: 0.71

Liver stiffness for each Metavir stage in CHC

Box-and-whiskers plot

Vertical axis in logarithmic scale (wide range of F4 values)

Ziol M et al. Hepatology 2005 ; 41 : 48 – 54.

Prospective multicenter study 327 patients

Castera L et al. Gastroenterology 2005;128:343–350.

Prospective study 183 patients

HCV-related glomerulonephritis

• Membranoproliferative glomerulonephritis (MPGN)

• IgA nephropathy

• Postinfectious glomerulonephritis

• Membranous nephropathy

• Thrombotic microangiopathies

• Focal & segmental glomerulosclerosis

• Fibrillary glomerulopathy

Perico N et al. Clin J Am Soc Nephrol 2009;4:207–220.

Cryoglobulinemia Systemic vasculitis of small-calibre arteries & veins

Type Frequency Associated disease

Type ISingle

10 – 15 % Monoclonal Lymphoproliferative disorderIndistinguishable from MM, Waldenströ ِm, or CLL

Type IIMixed

50 – 60% MixedMonoclonal & polyclonal

HCV

Type IIIMixed


Connective tissue disease Autoimmune diseasesChronic bacterial infectionsChronic viral infections

Incidence of CHC in Mixed Cryoglobulinemia 40 – 100% 90% in Mediterranean basin

Sansonno D et al. Lancet Infect Dis 2005; 5: 227–36

Prevalence of cryoglobulinemia in CHCMeta-analysis

• No of studies 19 studies between 1994 & 2001

• No of patients 2 323 patients

• Cryoprecipitate 1 022 patients prevalence 44%

• Cirrhosis 40% of patients with cryoprecipitate

17% of patients without cryoprecipitate

OR for cirrhosis in CP*+: 4.87 (3.3-7.1)

* CP: CryoprecipitatesKayali Zeid et al. Hepatology 2002;36:978-985.

Cryoglobulins may be useful indicator

for increased risk of cirrh

osis in CHC

Signs & symptoms in mixed cryoglobulinemia• Skin Palpable purpura 90%

Leg ulcers 15%

Raynaud’s phenomenon 30%

Cold urticaria 10%• Liver Hepatomegaly 70%

Hypertransaminasaemia 50%• Kidney Microscopic hematuria 30%

Proteinuria 15%

Arterial hypertension 40%• MS system Arthralgia 70%

Asthenia 80%• NS Peripheral: Motor-sensory axonopathy 60%

Acute mononeuritis 5%

Central Neurocognitive impairment 25%

Sansonno D et al. Lancet Infect Dis 2005;5:227–36.

Any organ may be affected

Palpable purpura


Most frequent sign of MC: 90%

Usually the first sign of MC

Raise immediate suspicion of MC

Chronic leg ulcersRelatively frequent

Above the malleoli

Always associated with purpura

Absence of severe stasis dermatitis


Mixed Cryoglubulinemia in CHCMajority of patients have no or nonspecific symptoms

• Meltzer's triad (30%): purpura, asthenia, arthralgia

• Most frequent affected tissues: skin, nerves, & kidney

• Renal involvement (1/3 of patients)

Signs Proteinuria – microhematuria – RI – HTN

Diagnosis Positive anti-HCV & HCV RNA

Biopsy MPGN with immune complex deposition

Renal biopsy of cryoglobulinaemic patient

Immunohistochemical detection of HCV coreprotein in glomerular vascular structures


Association between HCV & ESRDRetrospective cohort study

Medicare, Department of Veterans Affairs, & US Renal Data SystemCreatinine measured between Oct 2000 & Sept 2001

2 352 584 patients

3 years follow-up – ESRD

Tsui JI et al.Arch Intern Med. 2007;167:1271-1276.

Anti-HCV –421 495patients (89%)

3.05/ 1000 person-years 95% CI: 2.96 – 3.14

Anti-HCV +52 874 patients (11%)

4.26 /1000 person-years95% CI: 3.97 – 4.57

anti-HCV test within 1 year of creatinine testing474 369 patients

Prevalence of HCV in long-term dialysis patients Developing countries

Country Anti-HCV positives Reference year

Brazil 16.4% (180/1095) 2007

Turkey 19% (83/437) 2005

Tunisia 20% (79/395) 2006

Sudan 23.7% (56/236) 2007

Iran 24.8% (74/298) 2005

Saudi Arabia 43.4% (86/198) 2004

Moldavia 75% (111/148) 1999

Morocco 76% (141/186) 2005

Egypt 80% (169/210) 2000Martin P et al. J Hepatol 2008;49:613–624.

DOPPSProspective observational study – Based on anti-HCV

• Facilities 308 representative dialysis facilities• Patients 8615 hemodialysis patients• Countries 7 countries from 3 continents

France, Germany, Italy, Japan, Spain, US

• Time 1997-98 to 2001• Prevalence Mean 13.5% (2.6 – 22.9%)• Seroconversion 56% of facilities: no seroconversion

44% of facilities: > 0 – 20%DOPPS: Dialysis Outcomes & Practice Patterns Study

Fissell RB et al. Kidney Int 2004;65:2335–2342.

HCV prevalence & time on dialysis


Impact of HCV on survival in dialysis patientsMeta-analysis

• No of studies 7 studies (5 cohorts – 2 case-controls)

• No of patients 11 589 patients on maintenance dialysis

• RR for death 1.34 (95% CI: 1.13-1.59)

Heterogeneity statistics, R(i) = 0.48

P-value by Q-test = 0.13

• Cause of death Liver cirrhosis & HCC more frequent

Fabrizi F et al J Viral Hepat 2007;14:697–703.

Excess risk of death in HCV-positive

patients on HD partially attributed to CLD

HCV & death risk in hemodialysis patients82 933 patients on MHD for at least 45 days

3 year period: 2001 – 2004580 outpatient dialysis facilities of DaVita Inc*

* DaVita Inc: Large dialysis organizationKalantar-Zadeh K et al. J Am Soc Nephrol 2007;18:584–1593.

anti-HCV EIA at least once

13 664 patients

1590 patients (12%)

anti-HCV +

Mortality Hazard Ratio: 1.25 95% CI: 1.12 – 1.39 (P < 0.001)Higher all-cause & CV mortality

Preventing HCV transmission in HD units

• Wear disposable gloves when caring for patient

Remove gloves & wash hands between each patient

• Use disposable items

Nondisposable items dedicated for use on single patient

Unused medications dedicated for use on single patient

• Separation of clean & contaminated areas

• Clean & disinfect dialysis station between patients

e.g., chairs, beds, tables, machines

Centers for Disease Control & Prevention MMWR Recomm Rep 2001;50:1-43.

Practice of hand hygiene in HD unitsOne person observed the staff in 9 dialysis units during 1 month

495 randomly distributed 30 min observation periodsCovered all steps of hemodialysis session

Dolores Arenas M et al. Nephrol Dial Transplant 2005;20:1164–1171.

977 opportunities to wear gloves & wash hands following activity

Gloves used in 93% Hands washed in 36%

1902 opportunities to wash hands before activity

Hands washed in 148%

Higher patient-to-nurse ratio influenced hand washing before& after patient contact

Universal precautions prevent HCV transmission 963 patients – 15 Belgian units

No isolation of anti-HCV patientsAnti-HCV (EIA 2 or 3) every 18 m for 54 m

Jadoul M et al. Kidney Int 1998;53:1022-1025.

488 patients available

Drop-up from death or RT

1st 18 month (May 91 – Nov 92): 1.41 %

HCV seroconversion

2nd 18 month (Nov 92 – May 94): 0.56 %

Reinforced precautions

3rd 18 month (May 94 – Nov 95): 0 %

P=0.04

Kidney transplantation for HD patients with CHC

Anti-HCV positive patient on dialysis0

HCV RNA –

Waiting list for KT

Normal LFTs



Liver failure

Liver & kidney transplantation


Chronic hepatitis

IFN

HCV RNA – HCV RNA +


Cirrhosis


HCV RNA +

Liver biopsy

Waiting list for KT

Normal

Thank You

HCV genome

Sansonno D et al. Lancet Infect Dis 2005 ; 5 : 227 – 36.

• Anti-HCV (ELISA)

1st generation Frequent false-negative results

2nd generation Frequent false-negative results

3rd generation Rare false-negative results

(6/2576 pts - 0.23% )• RIBA testing Surpassed by PCR technology• HCV-RNA Obtained prior to HD procedure• Heparin can interfere with PCR

technique

Schneeberger PM et al. J Clin Microbiol 1998 ; 36 : 1711 – 1715.

KDIGOKidney Disease: Improving Global Outcomes

Epidemiology of HCV in dialysis population

Serological tests of chronic HCV infection

Rodés J et all. Textbook of hepatology: from basic science to clinical practice.Blackwell Publishing, Oxford, UK, 3rd edition, 2007

Cryoglobulinemia

Type Frequency Associated disease

Type ISingle

10 – 15 % Monoclonal Lymphoproliferative disorderIndistinguishable from MM, Waldenströ ِm, or CLL

Type IIMixed


HCV

Type IIIMixed

30 – 40% MixedPolyclonal & monoclonal

Connective tissue disease Autoimmune diseasesChronic bacterial infectionsChronic viral infections

Incidence of HCV infection in EMC 40–100% 90% in Mediterranean basin

Mixed Cryoglobulinemia

Josephsen G. N Engl J Med 2005;352:2627.

38-year-old woman

CHC treated with IFN- several years ago

Palpable lesions on legs & feet

HBsAg – & anti-HCV +

Acute renal failure & pancytopenia

Improvement with plasmapheresis


CirrhosisChronic hepatitis

IFN

HCV RNA – HCV RNA +


HCV RNA –

Waiting list for KT

Normal LFTs

Liver failure


HCV RNA +

Liver biopsy

Normal

Increased risk of HCV in HD patients

• Longer time on dialysis• Male gender• Black race• Diabetes• HBV infection• Prior renal transplantation• Alcohol or substance abuse in previous 12 month


Proposed model of cryoprecipitating immune complex in HCV-related cryoglobulinemia


Practice of hand hygiene in hemodialysis units

• One person observed health care staff in 9 dialysis units495 randomly distributed 30 min observation periodsCovered all steps of hemodialysis session


Tests no longer needed

• RIBA: Recombinant Immuno-Blot Assay

• Qualitative HCV RNA by PCR

Practice of hand hygiene in hemodialysis units

• One person observed health care staff in 9 dialysis units495 randomly distributed 30 min observation periodsCovered all steps of hemodialysis session

• 1902 opportunities to wash hands before patient contact• 977 opportunities to wear gloves •


HCV & death risk in hemodialysis patients

Kalantar-Zadeh K et al. J Am Soc Nephrol 2007;18:584–1593.

hepatitis c virus & chronic kidney diseases

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