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By Dr Saurav Deka , MBBS MD at 5:23 pm, Mar 03, 2012

Chronic viral hepatitis and chronic kidney disease

Elias C Chacko,1 Soondal Koomar Surrun,1 T P Mubarack Sani,2 Joseph M Pappachan3
1

Department of Internal Medicine, Singapore General Hospital, Singapore 2 Department of Community Medicine, Pariyaram Medical College, Kannur, South India 3 Department of Gastroenterology and Hepatology, Singapore General Hospital, Singapore Correspondence to Dr M J Pappachan, Department of Gastroenterology and Hepatology, Singapore General Hospital, Singapore 169608, Singapore; drpappachan@yahoo.co.in Received 16 October 2009 Accepted 17 May 2010

ABSTRACT Chronic kidney disease (CKD) has become a major public health problem worldwide over the past few decades because of the increasing prevalence of hypertension, diabetes mellitus, and elderly individuals in most countries. Chronic viral hepatitis (due to hepatitis B virus (HBV) and hepatitis C virus (HCV)) also poses signicant morbidity and mortality globally. Both these viruses can cause CKD and these infections can occur as a consequence of CKD management. CKD patients acquiring HBV or HCV infection have higher morbidity and mortality rates, and the management of these infections among CKD patients with antiviral agents is associated with high rates of adverse effects. The optimal management of CKD associated with HBV and HCV is not well dened because of insufcient data from clinical trials. This review discusses the pathogenesis, clinical characteristics and management issues related to chronic viral hepatitis and CKD.

with HBV or HCV infections and the management issues related to these infections among CKD patients.

HBV ASSOCIATED CKD

HBV, a common cause of liver disease and liver cancer, infects more than 300 million people worldwide.4 It has been known for the past few decades that there is a strong association between HBV and renal disease.8 The overall prevalence of HBV associated nephropathies is not known. However, children appear to be affected more commonly than adults.3 Various morphological forms of renal disease described among patients infected with HBV9 are listed in box 1.

Pathogenesis and pathology

Renal injury caused by HBV may be related to a direct cytopathic effect of the virus on cells of the kidney, glomerular deposition of immune complexes (viral antigen and host antibody), or virus induced specic immunological effector mechanisms (specic T lymphocyte or antibody), which damage the kidney, or indirect effects of virus induced cytokines/mediators on renal tissue.9 Some individuals with HBV infection may be genetically predisposed to develop nephropathy.10 Expression of HBV antigens (hepatitis B surface antigen (HBsAg) and hepatitis B core antigen (HBcAg)) in the renal tubular epithelial cells can upregulate complement mediated inammatory gene pathways that may contribute to the pathogenesis of nephropathy.11 Serum of patients with chronic HBV infection has been shown to induce apoptotic damage to the renal tubular cells.12 Membranous glomerulonephritis (MGN) is the most common HBV associated nephropathy and liver disease may be mild or absent in many of the patients with this condition.3 Membranoproliferative glomerulonephritis (MPGN) is characterised by the deposition of immune complexes in the mesangium and subendothelial space. Glomerular deposition of immunoglobulin G (IgG), complement C3, and HBsAg have been demonstrated in renal biopsies.13 Predominant deposition of immunoglobulin A (IgA) in the renal mesangium is seen in patients with HBV associated mesangial proliferative glomerulonephritis.14 Polyarteritis nodosa (PAN) usually occurs within 4 months of HBV infection. Classic PAN that affects the medium sized arteries is seen in most of the cases.15

INTRODUCTION
Chronic viral hepatitis is a major public health issue that affects about 500 million people worldwide. Among the viruses that cause hepatitis, only hepatitis B virus (HBV) and hepatitis C virus (HCV) usually become chronic. Chronic HBV and chronic HCV have signicant association with chronic kidney disease (CKD).1 2 Both HBV and HCV infections are well known causes of CKD and these infections may occur as a consequence of CKD management. Renal involvement is an uncommon extrahepatic manifestation of chronic HBV infection that can result in various morphological forms of CKD.3 4 When compared to chronic HBV, extrahepatic diseases are more common in patients with chronic HCV infection, and HCV associated CKD is an important clinical complication.5 6 Even with adequate precautionary measures, transmission of HBV and HCV infections are common among CKD patients on dialysis. The immune dysfunction caused by CKD makes patients more vulnerable to the cytopathic effects of HBV and HCV infections. The presence of HBV or HCV is an independent and signicant risk factor for death among CKD patients, and management of these infections is a challenge to clinicians because of the higher rates of toxicity of antiviral agents in CKD victims.7 Because of the rising global burden of CKD, and the high prevalence of chronic viral hepatitis worldwide, a thorough understanding of the relationship between these infections and CKD is warranted. This review discusses the pathophysiological mechanisms of CKD in patients infected
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Clinical presentation
A majority of children with MGN experience spontaneous remission, but about one third of adults can progress to renal failure, with as many as
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HBV infection among CKD patients

Box 1 Morphological forms of hepatitis B virus associated chronic kidney diseases

< < < < < <

Membranous nephropathy Membranoproliferative glomerulonephritis Mesangial proliferative glomerulonephritis IgA nephropathy Focal segmental glomerulosclerosis Polyarteritis nodosa

10% requiring dialysis or renal transplant.4 Clinical manifestations of MGN differ among children and adults. Male preponderance, preservation of renal function in a vast majority, low incidence of hepatitis, and asymptomatic presentation are the classical features of paediatric cases, whereas many adults present with proteinuria and nephrotic syndrome.9 Hepatitis is also more common among adults. MPGN patients present with proteinuria, microscopic haematuria and mild or moderate renal impairment. Acute oliguric renal failure due to severe glomerular disease can occur in a few cases. PAN is a multisystemic vasculitis that can present with neurological, musculoskeletal, cutaneous, gastrointestinal, and renal disease.16 Vasculitis can lead to renal infarction, glomerular ischaemia and hypertension.

Management of HBV associated CKD

No randomised clinical trials have been conducted to date on the treatment of HBV associated CKD.2 Persistence of proteinuria in many patients, improvement of renal and liver disease with drug treatment, and a tendency for gradual deterioration of renal function in a small but signicant percentage of cases may form the rationale for treating patients with HBV associated CKD.9 Steroids were not found useful in the treatment of nephrotic syndrome in patients with HBV associated MGN.17 18 Use of corticosteroids and/or plasma exchange may be justied for a short period in cases of multisystemic vasculitis secondary to HBV associated PAN, though there is no clear-cut evidence to recommend this treatment option in all cases. The role of steroids and/or immunosuppressive agents in the treatment of other forms of HBV associated nephropathy is also unknown. There is inadequate clinical and experimental data to make recommendations regarding the rational use of antiviral therapy for patients with HBV associated nephropathy. However, some studies showed benet of using interferon a (IFNa) especially in patients with MGN.18 19 Improvement of proteinuria and seroconversion among a signicant number of patients in the treatment group, and lack of serious adverse effects, makes IFNa a treatment option for patients with HBV associated MGN.18 19 The oral antiviral agent lamivudine also has shown to improve renal outcomes and seroconversion rates in treatment groups (when compared to historic controls) among patients with HBV associated MGN.20 Newer antiviral agents like entecavir and tenofovir, that can provide improved viral suppression with lower rates of emerging resistance and less toxicity, are used by many experts as rst line drugs to treat chronic HBV infection because of the high rate of lamivudine resistance.21 These drugs may be useful as rst line agents to treat patients with HBV associated MGN. IFNa or oral antiviral treatment may be benecial among patients with other forms of HBV associated nephropathy as well, though there are no data to recommend the same.
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CKD has become a major public health problem in both the developed and developing countries because of the increasing prevalence of hypertension and diabetes mellitus, and the increasing population of elderly individuals in the world. Renal replacement therapies (RRT) like haemodialysis/peritoneal dialysis form the cornerstones of treatment of the majority of patients with advanced CKD because of the difculty in obtaining donor kidneys. CKD patients are at increased risk of acquiring HBV infection as a result of nosocomial spread or exposure to infected blood and blood products.22 HBV infection has been a major consequence of RRT among CKD patients; however, the introduction of rigorous infection control strategies, screening of patients and staff for HBV serologic markers, vaccination of susceptible patients and staff, and use of separate rooms and dedicated machines for dialysis of HBsAg positive patients have all led to a decline in the prevalence of HBV infection in recent years.7 Despite the awareness about the mode of transmission and the safety precautions, outbreaks of HBV infection have occurred recently even in the healthcare settings of developed countries, with 30.3% of such outbreaks occurring in dialysis units.23 Higher rates of transmission of HBV among patients on RRT can be anticipated in the developing countries because of the higher prevalence of HBV infection in these countries and less rigorous precautionary measures to prevent transmission in the dialysis units due to nancial constraints. The prevalence of HBV infection (HBsAg sera positive) among patients on maintenance haemodialysis in the developed world is currently low (0e10%) but remains higher (2e20%) in developing countries.24 HBV infection among CKD patients is associated with higher morbidity and mortality rates.7 24 Patients with CKD may be more likely to develop chronic infection once exposed to HBV.22

Clinical implications
Patients with CKD are more prone to develop infections because uraemia is associated with dysfunction of the immune system. Uraemia represents a unique clinical condition of immune dysregulation associated with phagocyte derived oxidative stress and sustained monocyte activation.25 Haemodialysis exacerbates the oxidative stress that may be a consequence of recurrent activation of neutrophils during blood passage through the dialysis circuits.26 27 Depressed peripheral lymphocyte count, impaired granulocyte phagocytic activity, anaemia, and malnutrition are other factors which immunocompromise uraemic patients.28 Because of the immune dysfunction, acute HBV infection is often mild or asymptomatic in CKD patients and, in contrast to normal adults, the majority of them become chronic carriers due to impaired viral clearance.28 29 Liver disease can progress with modest hepatic inammation and prominent brosis.7 Rarely, a fatal condition called brosing cholestatic hepatitis, in which unchecked viral replication leads to an extremely high viral load and cytopathic hepatic damage, can occur in CKD patients infected with HBV.30 Renal allograft recipients usually require long term immunosuppression to prevent rejection episodes and HBV reactivation can occur in these individuals. Reactivation is characterised by an abrupt reappearance or a rise in HBV DNA levels in the serum of patients with previously inactive or resolved HBV infection and may be accompanied by reappearance of disease activity or are up of hepatitis.31 HBV infection is also associated with decreased survival after renal transplantation and a more
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frequent need for re-transplantation.32 Hence, all renal allograft recipients with HBV infection should receive long term antiviral treatment.31

Pathogenesis and pathology

Various mechanisms have been proposed to explain the renal injury caused by HCV infection. Mixed essential cryoglobulinaemia (MC) is a systemic vasculitic syndrome that is most strongly associated with HCV infection.2 6 Overt cryoglobulinaemic syndrome develops in 5e20% of HCV infected patients.44 Renal involvement can occur in up to 60% of these patients and MPGN is the most common form of kidney disease among these cases.6 Pronounced leucocyte inltration of glomerular capillaries and the precipitation of immune complexes/cryoglobulins are seen among these patients.45 Glomerular deposition of HCV proteins were demonstrable in 67% of renal biopsies from patients with cryoglobulinaemic MPGN.46 However, HCV associated CKD is reported to be less common among patients in the UK (prevalence 1.77%).47 Non-cryoglobulinaemic MPGN has also been reported among patients with HCV infection in which mesangial and capillary wall deposition of IgM, IgG, and C3 are frequently but not invariably demonstrated.39 48 Other forms of immune complex mediated glomerular diseases like MGN, IgA nephropathy and focal segmental glomerulosclerosis (FSGS) described among HCV infected individuals may have similar pathogenic mechanisms as their idiopathic counterparts.45

Management of HBV infection in CKD patients

The overall long term effect of antiviral therapy in changing the outcome of HBV infection among patients with CKD is not well established.22 IFNa has little role in treating patients with advanced CKD because of its lower efcacy and frequent side effects.28 33 Nucleoside antiviral agents like lamivudine, adefovir and entecavir have been used successfully in patients with chronic hepatitis B on dialysis or after renal transplantation, although antiviral resistance in this situation may be common.22 Dose modication of all nucleosides is required in patients with CKD. The recent guidelines of the US National Institute of Health recommend antiviral therapy for CKD patients with chronic HBV infection.22 Thus, all patients with positive HBsAg >6 months, HBV DNA load >105 copies/ml, persistent/intermittent elevation of aminotransferase (ALT/AST) concentrations, and/or liver biopsy evidence of chronic hepatitis, are candidates for antiviral treatment. Prevention of HBV infection is crucial in the management of all patients with CKD. HBV vaccination is one of the most important measures in prevention of the nosocomial transmission of HBV infection among CKD patients on dialysis.28 The immunogenicity and efcacy of standard doses and regimen of HBV vaccine is subnormal among patients with advanced CKD.34 Higher doses and increased frequency of vaccination by the intramuscular route, or an intra-dermal route of vaccination, may help to resolve this problem.35 36

Clinical presentation
Nephrotic range proteinuria with oedema, hypertension and hypocomplementaemia occur in a quarter of cases of HCV associated MPGN.6 Mild haematuria, proteinuria and renal insufciency are characteristic of a signicant proportion of cases. The course of renal disease may be variable among patients with HCV associated CKD. In about one third of cases renal function may be maintained stable for many years, 20% may have recurrent episodes of nephritic syndrome, and about 15% may become dialysis dependent.6 MC may sometimes present early with proteinuria and renal dysfunction in the absence of symptoms of liver disease and extrahepatic manifestations of cryoglobulinaemia. Up to 90% of patients with MC can have anti-HCV antibodies49 and MPGN is a serious renal complication of MC. Therefore, all persons with proteinuria and cryoglobulinaemia should be screened for HCV infection even if they lack clinical and/or biochemical evidence of liver disease.50 Remissions and exacerbations are common in mixed cryoglobulinaemia and the exacerbation of systemic manifestations may often be associated with a are up of renal disease.42 51 The prognosis of patients with cryoglobulinaemic renal disease may be poor owing to the high incidence of infections and cardiovascular disease.51 Cardiovascular events were the most common cause of death among these patients (62%) followed by hepatic failure, infections, and neoplastic disease.42

HCV ASSOCIATED CKD

HCV is responsible for over one million deaths from cirrhosis and liver cancer every year, and more than 170 million people worldwide are chronically infected with the virus.5 Extrahepatic manifestations are more common with HCV infection than with HBV infection. Renal failure is an important extrahepatic complication of HCV infection and liver disease in these patients may be mild or even clinically absent.37 Probable association between HCV infection and renal disease was rst reported in 1990.38 Subsequently, Johnson et al demonstrated a strong association between HCV infection and MPGN.39 Various other forms of renal disorders have been described in subsequent studies.40e42 Autopsy studies of patients with HCV infection showed that in the presence of cirrhosis, 59.2% had evidence of glomerulonephritis whereas only 32.3% had renal involvement in the absence of cirrhosis.43 The morphological forms of HCV associated CKD are listed in box 2.

Management of HCV associated CKD

Box 2 Morphological types of hepatitis C virus associated chronic kidney diseases

< < < < < < <

Membranoproliferative glomerulonephritis Membranous nephropathy IgA nephropathy Focal segmental glomerulosclerosis Polyarteritis nodosa Fibrillar glomerulonephritis Immunotactoid glomerulopathy

Management of patients with HCV associated CKD is challenging. Currently recommended therapy for chronic HCV infection is the combination of a pegylated interferon a (pegIFNa) and ribavirin.50 The kidney plays a role in the catabolism and ltration of both interferon and ribavirin.50 Renal clearance of peg-IFNa is reduced in persons with CKD. Because ribavirin is ltered by the kidneys, its clearance is impaired in persons with advanced CKD and the drug is not removed by dialysis. Severe haemolytic anaemia can complicate the treatment of CKD patients with ribavirin.50 Hence, as the renal function deteriorates, the concentration of both drugs must be reduced. Even low dose regimens are associated with a high rate of
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adverse events and such treatment requires extremely close monitoring.50 Peg-IFNa in combination with ribavirin appears to be the treatment of choice for patients with symptomatic essential mixed cryoglobulinaemia with or without glomerulonephritis.52 Treatment usually leads to disappearance of cryoglobulinaemia along with a sustained virological response. Interferon therapy may result in exacerbation of vasculitis, and therefore treatment should be restricted to those with overt symptoms, with careful monitoring of renal function to avoid worsening of CKD.50 Immunosuppressive therapy with cyclophosphamide or rituximab, as well as plasmapheresis and pulsed steroids, should be instituted in patients with progressive renal failure due to vasculitis.53 Because most of the studies on treatment of HCV associated CKD have been small and uncontrolled trials, evidence is inadequate to make rm recommendations and guidelines. Patients with moderate proteinuria and slowly progressive kidney disease can be treated for 12 months either with standard interferon or with reduced doses of peg-IFNa and ribavirin.50 Patients with mixed cryoglobulinaemia, pronounced proteinuria and evidence of worsening renal damage or acute extensive cryoglobulinaemic vasculitis can be managed with rituximab or cyclophosphamide plus methylprednisolone, or plasma exchange followed by interferon based treatment once the acute illness has improved.50 Though the above mentioned regimens may be used generally to manage patients with HCV associated CKD, an individualised treatment plan has to be adopted by the clinician while managing these patients with due consideration to the clinical subtype of the disease, degree of derangement of renal function, and availability and cost of the therapeutic agents in the country of his/her clinical practice. RRT have an increased risk of mortality compared with HCV negative patients.57 Hepatocellular carcinoma and liver cirrhosis were signicantly more frequent among HCV positive cases, and the excess risk of death among CKD patients may be at least partially attributed to chronic liver disease with its associated complications. A 6 year follow-up study of CKD patients on haemodialysis showed that 15% of HCV positive cases died of cirrhosis or hepatocellular carcinoma in contrast to only 0.4% of the HCV negative cases.58 Alanine aminotransferase (ALT) values may not be a useful indicator of liver damage among CKD patients with HCV infection, and despite histological evidence of liver inammation, ALT values in these cases may be normal.50 59 Suppression of ALT synthesis in hepatocytes, inhibition of its release into the bloodstream and accelerated clearance from serum have been proposed as probable mechanisms of low ALT values in CKD patients with HCV infection.60 Hence, liver biopsy may be required for CKD patients with HCV infection to assess the degree of liver damage and to plan antiviral therapy. Though the risk of bleeding is theoretically high among uraemic patients because of platelet dysfunction, the guidelines for liver biopsy are not different for CKD patients when compared with nonCKD cases.50 61 Transjugular liver biopsy is safer and may be an alternative option among CKD patients. Transient elastography is a novel ultrasound based technique that can be performed with high diagnostic accuracy for the diagnosis of increased liver stiffness.62 This technique may be useful for the non-invasive assessment of liver damage among CKD patients with bleeding risk. Few studies showed that renal transplant recipients with HCV infection had higher mortality rates.63 64 Their long term mortality rates (relative risk (RR) 2.23) and graft losses were higher (RR 1.96) when compared to uninfected individuals.63 Liver failure was a frequent cause of death among renal allograft recipients with HCV infection.64 Immunosuppressive therapy used to prevent renal allograft rejection may accelerate the liver disease in these patients. Risk for development of post-transplant diabetes mellitus and MGN was also higher among HCV infected individuals.50 However, HCV infection was not found to be a signicant risk factor for death among renal transplant recipients in other studies.65 66 Cardiovascular events were reported to be the major cause of death among renal transplant recipients in Scandinavia, although pre-transplant transfusion was also a risk factor.67 Although viral reactivation and progression to liver failure can occur among transplant recipients, HCV infection is not an absolute contraindication for renal transplantation.5 The quality of life and survival rates are better among renal transplant recipients than those patients remaining on dialysis.

HCV infection among CKD patients

HCV infection is a common complication of the treatment of CKD patients and poses a major medical and epidemiologic challenge in those with end stage renal disease on RRT with dialysis or transplantation.5 The reported prevalence of HCV infection in haemodialysis units of developed countries has ranged from 2.6e22.9% (with a mean of 13.5%) in a recent multinational cohort study.54 But prevalence may be as high as 70% in developing countries.55 The high rate of HCV transmission among CKD patients may be due to direct exposure to infectious blood and/or blood products because of inadequate infection control. Crosscontamination between patients can occur in dialysis units because of lack of disinfection of commonly utilised medication equipment and supplies, the use of shared vials of heparin, and blood spills which are not immediately cleaned.50 Therefore, the prevention of transmission requires strict adherence to infection control measures.

Management of HCV infection in CKD patients

CKD patients with HCV infection have a higher risk for cardiovascular as well as all-cause mortality. In maintenance haemodialysis patients, the mortality hazard ratio associated with the infection had been estimated to be 1.25.68 Because of the high prevalence of the infection, its deleterious effects, and higher risk for mortality, all CKD patients should be tested for HCV infection in order to plan their management. Initial screening of CKD patients for HCV infection is by antiHCV antibodies. Those tested positive should have an estimation of the highly sensitive HCV RNA values.69 All CKD patients should be tested for serum HCV RNA before the start of haemodialysis and also before and after renal transplantation.50 Maintenance haemodialysis patients with
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Clinical implications
Acquisition of HCV infection implies a serious risk to the health of persons with CKD. A recent study from the USA showed that HCV seropositive individuals <70 years of age had more than a twofold increase in risk for developing end stage renal disease (ESRD) compared with HCV seronegative patients.56 Patients with HCV infection are more likely to have glomerular hyperltration in the early stages of CKD and they experience rapid decline in renal function. A meta-analysis of seven studies involving 11 589 patients on maintenance dialysis showed that HCV positive patients on
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abnormal liver function tests and those with likely nosocomial exposure to HCV also should be tested. Monthly estimation of ALT values and estimation of anti-HCV antibodies every 6 months (if abnormal, HCV RNA testing to conrm new infection) is recommended in these patients.69 Because both IFNa and ribavirin are cleared by the kidneys, dose modication is mandatory in CKD patients according to the degree of renal impairment. Patients with a glomerular ltration rate (GFR) >60 ml/min can be managed with the same regimen (combination of peg-IFNa and ribavirin) as used for those without CKD according to the viral genotype.69 Dosage modication of both the drugs and careful monitoring are required for those with more severe renal impairment and without dialysis support.50 Few small studies demonstrated benecial effects of combination therapy in patients on dialysis, but the side effects of drugs were reported very high, often necessitating growth factor treatment for anaemia and neutropenia.70 71 Discontinuation of therapy due to side effects and high relapse rates after completion of treatment were the other problems encountered among these patients. Standard IFNa (instead of peg-IFNa) without the addition of ribavirin has fewer side effects and equal efcacy in treating HCV infection among haemodialysis patients, and has been recommended by an international group of experts.69 However, a recent meta-analysis of studies using both agents showed comparable benecial effects of conventional as well as pegylated IFNa in haemodialysis patients.72 Though some small studies among renal transplant recipients with HCV infection73 74 have shown the efcacy of IFNa and/or ribavirin, routine antiviral treatment is not recommended in such patients.50 Poor response to antiviral treatment and high rate of allograft rejection were common among the infected patients. Fibrosing cholestatic hepatitis, a potentially lethal condition observed among some patients infected with HCV following solid organ transplantation, is probably a denite indication for treatment with IFNa in renal allograft recipients.50 75

Main messages
< Chronic viral hepatitis (hepatitis B virus (HBV) and hepatitis C

< <

<

<

< <

virus (HCV)) can be the cause or consequence of chronic kidney disease (CKD). Chronic HBV or HCV infections carry higher morbidity and mortality rates among CKD patients. Interferon a (IFNa) or nucleoside antiviral agents (lamivudine, tenofovir or entecavir) are useful for treating patients with HBV associated membranous nephropathy. Membranoproliferative glomerulonephritis (MPGN) secondary to mixed essential cryoglobulinaemia is a common extrahepatic manifestation of HCV infection. Liver biopsy may be necessary to plan antiviral treatment as alanine aminotransferase (ALT) levels may be normal in many CKD patients. Combination of pegylated interferon a (peg-IFNa) and ribavirin is used for treating patients with HCV associated CKD. Standard IFNa is used for treating HCV patients with advanced CKD.

Precautionary measures
Prevention of HCV infection among CKD patients on dialysis requires strict adherence to infection control precautions recommended for all haemodialysis patients. Isolation of HCV infected patients is not recommended, but routine testing for ALT and anti-HCV for monitoring transmission among patients should be done to ensure that appropriate precautions are being properly and consistently used.76 HCV is less contagious than HBV and transmission through occupational exposures is less likely. Thus, reprocessing dialysers from HCV positive patients should not place staff members at increased risk of infection.76 Co-infection with hepatitis A virus (HAV)77 or HBV78 in patients with HCV infection may carry a worse prognosis. Similarly, alcohol can worsen HCV associated liver disease. Hence, patients with HCV infection should be tested for antibodies to HAV and HBV and those tested negative should be offered vaccination against these viral infections.50 So, CKD patients with HCV infection, being at high risk for hepatic complications, should be vaccinated against hepatitis A and B, and they should strictly avoid alcohol consumption.

course in children, but can progress to renal failure in a signicant percentage of adults. Though there is no denite consensus regarding management because of the paucity of clinical trial based evidence, antiviral therapy with IFNa or oral agents like lamivudine, entecavir and tenofovir may be justied in these patients to reduce adverse renal outcomes. The majority of CKD patients acquiring HBV infection become chronic carriers and hepatic disease can progress in some of them. Renal transplant recipients have higher risks of hepatitis are up, allograft rejection and mortality due to HBV infection. Treatment of HBV infection in advanced CKD involves mainly administration of nucleoside antiviral agents such as lamivudine, with appropriate dose reduction according to the degree of renal impairment. HBV vaccination and strict infection control measures are crucial in preventing the infection among CKD patients. MPGN associated with mixed essential cryoglobulinaemia is the most common form of HCV associated CKD, although other forms of renal diseases are also frequently seen. Even if there are no denite recommendations from professional bodies regarding management, combination therapy with IFNa and ribavirin may be justied with the appropriate use of immunosuppressive agents whenever necessary because of high morbidity and mortality among these patients. HCV infection is a serious consequence of RRT among patients with CKD and carries higher risks for hepatic complications, worsening of renal function, reduced renal allograft survival and overall mortality.

Current research questions

< Role of antiviral therapy for patients with HBV associated CKD

CONCLUSIONS
Both HBV and HCV can cause distinct types of CKD, and patients with CKD are at high risk of acquiring these chronic viral infections as a sequel of RRT. MGN, the most common form of HBV associated nephropathy, usually runs a benign
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other than membranous nephropathy needs further investigations. < Utility of transient elastography for non-invasive assessment of liver damage among HBV/HCV positive CKD patients should be further studied. < Role of antiviral therapy among renal allograft recipients with HCV infection needs to be investigated further in large controlled trials.

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Hepatitis B virusassociated polyarteritis nodosa: clinical characteristics, outcome, and impact of treatment in 115 patients. Medicine (Baltimore) 2005;84:313e22. Semple D, Keogh J, Forni L, et al. Clinical review: vasculitis on the intensive care unitepart 1: diagnosis. Crit Care 2005;9:92e7. Pena A, Debora MJ, Melgosa M, et al. Membranous nephropathy associated with hepatitis B in Spanish children. Clin Nephrol 2001;55:25e30. Lin CY. Treatment of hepatitis B virus-associated membranous nephropathy with recombinant alpha-interferon. Kidney Int 1995;47:225e30. Bhimma R, Coovadia HM, Kramvis A, et al. Treatment of hepatitis B virus-associated nephropathy in black children. Pediatr Nephrol 2002;17:393e9. Tang S, Lai FM, Lui YH, et al. Lamivudine in hepatitis B-associated membranous nephropathy. Kidney Int 2005;68:1750e8. Cooke GS, Main J, Thursz MR. Treatment for hepatitis B. BMJ 2010;340:b5429. doi:10.1136/bmj.b5429. Peters MG. Special populations with hepatitis B virus infection. Hepatology 2009;49(5 Suppl):S146e55. Lanini S, Puro V, Lauria FN, et al. Patient to patient transmission of hepatitis B virus: a systematic review of reports on outbreaks between 1992 and 2007. BMC Med 2009;7:15. Fabrizi F, Messa P, Martin P. Hepatitis B virus infection and the dialysis patient. Semin Dial 2008;21:440e6. ` Capeillere-Blandin C, Gausson V, Nguyen AT, et al. Respective role of uraemic toxins and myeloperoxidase in the uraemic state. Nephrol Dial Transplant 2006;21:1555e63. Descamps-Latscha B, Drueke T, Witko-Sarsat V. Dialysis-induced oxidative stress: biological aspects, clinical consequences, and therapy. Semin Dial 2001;14:193e9. Witko-Sarsat V, Rieu P, Descamps-Latscha B, et al. Neutrophils: molecules, functions and pathophysiological aspects. Lab Invest 2000;80:617e53. Wong P, Mak S, Wong AK. Management of chronic hepatitis B infection in patients with end-stage renal disease and dialysis. Hep B Annual 2006;3:76e105. London WT, Drew JS, Lustbader ED, et al. Host responses to hepatitis B infection in patients in a chronic hemodialysis unit. Kidney Int 1977;12:51e8. Wong PN, Fung TT, Chan AN, et al. Unusual case of hepatitic cholestasis resembling brosing cholestatic hepatitis in a dialysis patient with chronic hepatitis B infection. J Gastroenterol Hepatol 2006;21:1635e7. Hoofnagle JH. Reactivation of hepatitis B. Hepatology 2009;49(5 Suppl):S156e65. Lopez-Alcorocho JM, Barril G, Ortiz-Movilla N, et al. Prevalence of hepatitis B, hepatitis C, GB virus C/hepatitis G and TT viruses in predialysis and hemodialysis patients. J Med Virol 2001;63:103e7. Girndt M, Kohler H. Hepatitis B virus infection in hemodialysis patients. Semin Nephrol 2002;22:340e50. Stevens CE, Alter HJ, Taylor PE, et al. Hepatitis B vaccine in patients receiving hemodialysis. Immunogenicity and efcacy. N Engl J Med 1984;311:496e501. Micozkadioglu H, Zumrutdal A, Torun D, et al. Low dose intradermal vaccination is superior to high dose intramuscular vaccination for hepatitis B in unresponsive hemodialysis patients. Ren Fail 2007;29:285e8. Barraclough KA, Wiggins KJ, Hawley CM, et al. Intradermal versus intramuscular hepatitis B vaccination in hemodialysis patients: a prospective open-label randomized controlled trial in nonresponders to primary vaccination. Am J Kidney Dis 2009;54:95e103. Radhakrishnan J, Uppot RN, Colvin RB. Case records of the Massachusetts General Hospital. Case 5-2010. A 51-year-old man with HIV infection, proteinuria, and edema. N Engl J Med 2010;362:636e46. Pascual M, Perrin L, Giostra E, et al. Hepatitis C virus in patients with cryoglobulinemia type II. J Infect Dis 1990;162:569e70. Johnson RJ, Gretch DR, Yamabe H, et al. Membranoproliferative glomerulonephritis associated with hepatitis C virus infection. N Engl J Med 1993;328:465e70. Stehman-Breen C, Alpers CE, Couser WG, et al. Hepatitis C virus associated membranous glomerulonephritis. Clin Nephrol 1995;44:141e7. Sabry AA, Sobh MA, Irving WL, et al. A comprehensive study of the association between hepatitis C virus and glomerulopathy. Nephrol Dial Transplant 2002;17:239e45. Roccatello D, Fornasieri A, Giachino O, et al. Multicenter study on hepatitis C virusrelated cryoglobulinemic glomerulonephritis. Am J Kidney Dis 2007;49:69e82. Arase Y, Ikeda K, Murashima N, et al. Glomerulonephritis in autopsy cases with hepatitis C virus infection. Intern Med 1998;37:836e40.

Key references
< Molino C, Fabbian F, Cozzolino M, et al. The management of

10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21.

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viral hepatitis in CKD patients: an unresolved problem. Int J Artif Organs 2008;31:683e96. Bhimma R, Coovadia HM. Hepatitis B virus-associated nephropathy. Am J Nephrol 2004;24:198e211. Galossi A, Guarisco R, Bellis L, et al. Extrahepatic manifestations of chronic HCV infection. J Gastrointestin Liver Dis 2007;16:65e73. Ghany MG, Strader DB, Thomas DL, et al. American Association for the Study of Liver Diseases. Diagnosis, management, and treatment of hepatitis C: an update. Hepatology. 2009;49:1335e74. Kidney disease: improving global outcomes (KDIGO). KDIGO clinical practice guidelines for the prevention, diagnosis, evaluation, and treatment of hepatitis C in chronic kidney disease. Kidney Int Suppl 2008;109:S1e99.

Antiviral therapy with a combination of peg-IFNa and ribavirin is recommended, with appropriate dose modication according to the degree of renal impairment for patients not on dialysis. Standard IFNa without ribavirin is the recommended treatment for those on haemodialysis. There is no role for antiviral agents among renal allograft recipients with HCV infection except in those with brosing cholestatic hepatitis. Strict adherence to infection control precautions is the most effective measure in preventing this serious infection among patients with CKD.

22. 23. 24. 25. 26. 27. 28. 29. 30. 31. 32. 33. 34. 35. 36.

SELF ASSESSMENT QUESTIONS (TRUE (T)/FALSE (F); ANSWERS AFTER THE REFERENCES)
1. Steroids are useful in the treatment of nephrotic syndrome among patients with hepatitis B associated membranous nephropathy. 2. Patients with chronic kidney disease acquiring hepatitis B viral infection are more prone to become chronic carriers. 3. Extrahepatic manifestations are more common among patients with hepatitis B than those with hepatitis C. 4. Recommended therapy for chronic hepatitis C virus infection is a combination of pegylated interferon a and ribavirin. 5. Dose modication of interferon a and ribavirin is necessary in patients with advanced renal impairment and chronic hepatitis.
Competing interests None. Provenance and peer review Not commissioned; externally peer reviewed.

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ANSWERS 1. F: steroids are not useful in the treatment of nephrotic syndrome among patients with hepatitis B associated membranous nephropathy 2. T 3. F: extrahepatic manifestations are more common in patients with hepatitis C 4. T 5. T

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Chronic viral hepatitis and chronic kidney disease

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