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4790Viral Hepatitis as a Cause of Renal Disease

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  • claudine intexas
    Dec 2, 2000
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      Viral Hepatitis as a Cause of Renal Disease

      N. Kevin Krane, MD, Paul Gaglio, MD, Department of
      Medicine, Sections
      of
      Nephrology and Hepatology, Tulane University School of
      Medicine, New
      Orleans, La.
      [South Med J 92(4):354-360, 1999. � 1999 Southern
      Medical Association]


      Abstract
      Viral hepatitis has become a recognized cause of both
      acute and chronic
      renal disease. Acute and chronic viral infections may
      result in
      formation of
      immune complexes that can become deposited in the
      glomerular capillary
      basement membrane, stimulating both cytokine
      production and complement
      activation and producing a variety of glomerular
      lesions. Chronic viral
      infections may also result in production of mixed
      polyclonal IgG and
      monoclonal IgM cryoglobulins, which result in systemic
      vasculitic
      syndromes
      that also involve the kidney. Glomerular injury
      through these
      mechanisms may
      become clinically manifested as either acute
      glomerulonephritis or the
      nephrotic syndrome. Because of the worldwide
      prevalence of hepatitis B
      and C
      infections, they are important public health problems
      that may lead to
      a
      variety of important renal diseases. Further
      understanding of the
      mechanisms
      by which these viruses induce injury will allow more
      effective
      treatment
      strategies to reverse the renal diseases induced by
      hepatotropic viral
      infection.

      Introduction
      The association of viral hepatitis with both acute and
      chronic renal
      disease
      is increasingly being recognized. Progressive liver
      disease of any
      cause may
      be associated with significant fluid and electrolyte
      abnormalities,
      prerenal
      azotemia, and finally, the hepatorenal syndrome. In
      addition, specific
      hepatitis viruses may induce renal injury, resulting
      in acute and/or
      chronic
      renal insufficiency. Thus, because a significant
      percentage of the
      world's
      population suffers from hepatotropic viral infection,
      a similarly large
      number of patients are potentially susceptible to
      renal injury. As our
      understanding of the relationship between hepatitis
      viruses and renal
      disease advances, it becomes important to appreciate
      the mechanisms by
      which
      this phenomenon occurs. In this review, we will
      describe the mechanisms
      by
      which hepatitis may cause acute renal disease in
      patients with acute
      viral
      hepatitis, and then discuss the glomerular diseases,
      the associated
      vasculitic syndromes, and the immunologic mechanisms
      associated with
      hepatitis A, B, C, E, and G.


      Renal Disease and Acute Viral Hepatitis
      Acute renal failure is the most common renal syndrome
      associated with
      acute
      viral hepatitis and may be due to prerenal azotemia,
      in which renal
      perfusion is diminished, or intrinsic renal disorders,
      such as acute
      tubular
      necrosis (ATN), acute interstititial nephritis, or
      acute
      glomerulonephritis.
      Although acute viral hepatitis may result in acute
      renal failure
      through
      several mechanisms, most frequently this complication
      occurs in liver
      disease due to either prerenal azotemia or ATN.
      Patients with
      symptomatic
      acute viral hepatitis have constitutional symptoms
      that frequently
      result in
      anorexia, nausea, vomiting, or diarrhea and can result
      in reduced
      intravascular volume, decreased renal perfusion, and
      prerenal azotemia.
      Vomiting due to acute hepatitis also results in
      stimulation of the
      renin-angiotensin-aldosterone system, causing renal
      losses of potassium
      and
      the development of a metabolic alkalosis. On the other
      hand, diarrhea
      causes
      both potassium and bicarbonate loss and may result in
      a non-anion gap
      metabolic acidosis with hypokalemia. The diagnosis of
      prerenal azotemia
      can
      be established by a "benign" urinalysis and reduced
      fractional
      excretion of
      sodium (<1%). The BUN-creatinine ratio, which
      frequently increases in
      prerenal azotemia, may not change when significant
      liver injury
      prevents the
      generation of urea. Gastrointestinal bleeding is
      another important
      cause of
      prerenal azotemia in patients with liver disease,
      though it is more
      likely
      to occur in patients with cirrhosis and portal
      hypertension. Renal
      function
      in patients with prerenal azotemia improves with
      volume replacement.

      Prerenal azotemia as described occurs with variable
      frequency and is
      generally mild, self-limited, and easily reversible
      with appropriate
      fluid
      administration. On the other hand, acute renal failure
      frequently
      occurs in
      patients with acute fulminant hepatitis due to either
      hepatitis A, B,
      or
      C.[1] Prerenal azotemia should always be considered
      initially when
      patients
      with fulminant liver disease have acute renal failure;
      however,
      hepatorenal
      syndrome may also occur in this setting. This
      syndrome, which may
      complicate
      any form of severe liver disease, represents an
      extreme form of
      prerenal
      azotemia, typically manifested as oliguric acute renal
      failure in
      patients
      with severe liver failure. Hepatorenal syndrome must
      be differentiated
      from
      acute prerenal azotemia, since this irreversible
      complication portends
      an
      ominous prognosis in which liver transplantation is
      the only effective
      treatment for both the hepatic and the renal disease.
      The diagnosis of
      hepatorenal syndrome depends on showing a "benign"
      urinalysis with an
      extremely low urine sodium value (generally <5 mEq/L).
      Because it is a
      diagnosis of exclusion, intravascular volume
      contraction is the most
      important diagnosis to exclude. A full discussion of
      hepatorenal
      syndrome is
      beyond the scope of this discussion, and complete
      reviews are available
      elsewhere.[2,3]

      Acute tubular necrosis also occurs with greater
      frequency in patients
      with
      fulminant hepatitis because of renal ischemia from
      severe prerenal
      azotemia,
      exposure to tubular toxins (aminoglycosides,
      radiocontrast dye), or
      cholestasis leading to decreased peripheral vascular
      resistance and
      renal
      perfusion. The diagnosis of ATN is usually established
      clinically when
      urinalysis shows granular or "dirty brown casts" and
      the fractional
      excretion of sodium is >2%. Although supportive
      therapy with dialysis
      may be
      necessary, patients with acute renal failure due to
      ATN usually recover
      renal function. Another renal syndrome that can be
      difficult to
      distinguish
      from ATN is acute interstitital nephritis. While many
      drugs that may be
      administered to patients with acute viral hepatitis
      can cause acute
      interstitial nephritis, two cases have been attributed
      directly to
      hepatitis
      A infection. Renal biopsy is necessary to establish
      the diagnosis.[4,5]

      Acute renal failure due to hepatitis viruses is
      usually attributed to
      the
      mechanisms we have described. However, ATN directly
      attributed to
      hepatitis
      A has also been described in nonfulminant cases. Faust
      and Pimstone[6]
      reviewed 10 cases of ATN in nonfulminant hepatitis A,
      5 of them proven
      by
      renal biopsy. Eight patients required dialysis, with
      almost all
      patients
      recovering. In another recently reported case, the
      diagnosis was
      established
      on clinical grounds, and after a course of dialysis,
      renal function
      returned
      to baseline.[7] Mechanisms of acute renal failure that
      occur in
      patients
      without liver disease may be more likely to occur in
      patients with
      acute
      hepatitis A. The causes of renal disease associated
      with acute viral
      hepatitis are summarized in Table 1.

      Glomerulonephritis is another mechanism by which renal
      disease may
      develop
      in patients with acute hepatitis. Despite minimal
      urinary
      abnormalities,
      Eknoyan et al[8] did renal biopsies in[7] patients (4
      with hepatitis B
      infection) to determine whether acute viral hepatitis
      can cause renal
      disease. They found glomerular involvement as shown by
      immune complex
      deposition and cytoplasmic inclusions in the
      glomerular basement
      membrane.
      In a subsequent retrospective study of 59 patients who
      died of either
      acute
      fulminant hepatitis or subacute hepatitis (most of
      whom had hepatitis
      B),
      glomerular deposits were found in 15% of the renal
      tissue specimens
      examined.[9] Symptomatic glomerulonephritis has been
      reported in one
      case of
      postinfectious glomerulonephritis associated with
      acute hepatitis B
      virus
      infection.[10] Another case of acute renal failure due
      to mesangial
      proliferative glomerulonephritis has been reported in
      a patient with
      acute
      hepatitis A infection,[11] whereas several other
      reports describe
      patients
      with either clinical evidence or renal biopsy evidence
      of glomerular
      disease
      without acute renal failure in hepatitis A
      infection.[12-14]


      Mechanisms of Glomerular Injury Due to Hepatitis
      Viruses
      Acute and chronic viral infections are invariably
      associated with
      immune
      complex formation.[15] These immune complexes,
      composed of viral
      antigens
      and host antibody, become deposited in the glomerular
      capillary bed and
      mesangium and can be shown by immunofluorescense or
      immunoperoxidase
      microscopy.[16] Immune complex deposition in
      association with cytokine
      production and complement activation may induce a wide
      variety of
      glomerular
      lesions, including membranous glomerulonephritis,
      mesangiocapillary or
      membranoproliferative glomerulonephritis, mesangial
      proliferative
      glomerulonephritis, and crescentic glomerulonephritis.
      Glomerular
      damage may
      result in a nephrotic syndrome with proteinuria,
      hematuria, and/or
      variable
      degrees of reduction in glomerular filtration rate. In
      patients with
      nephrotic syndrome, glomerular involvement is
      recognized clinically by
      the
      development of edema, hypoalbuminemia,
      hypercholesterolemia, and
      urinary
      excretion of more than 3.5 g of protein per 24 hours.
      Glomerular
      involvement
      may also occur without overt clinical manifestations,
      whereby patients
      will
      exhibit significant proteinuria discovered by
      urinalysis without other
      clinical symptoms.

      Chronic viral infection may induce the formation of
      cryoglobulins.
      These
      immunoglobulins are classified as mixed -- ie, a
      combination of type II
      (polyclonal IgG, monoclonal IgM) and type III
      (polyclonal IgG and IgM).
      The
      majority of mixed cryoglobulinemias are associated
      with connective
      tissue
      disorders; however, when the etiology is unclear,
      these mixed
      cryoglobulinemias are called essential. Mixed
      essential
      cryoglobulinemia
      (MEC) is a multisystem syndrome characterized by
      arthralgia, palpable
      purpura, vasculitis, and neuropathy. Up to 50% of
      patients with MEC
      have
      renal disease, manifested as membranoproliferative
      glomerulonephritis,
      diffuse, focal, or mesangial proliferative
      glomerulonephritis.[17] In
      addition, granulomatous vasculitis of small and
      moderate sized renal
      arteries may be present in patients with mixed
      cryoglobulinemia. When
      MEC is
      associated with renal disease, the prognosis is
      significantly worse
      than in
      patients without renal involvement.[18] The glomerular
      diseases
      associated
      with viral hepatitis infection are shown in Table 2.

      Hepatitis A

      Only five cases in the literature document immune
      complex deposition
      with
      glomerular involvement associated with hepatitis A
      virus (HAV)
      infection.[19] Renal biopsy in these patients showed
      immune complex
      deposition of IgG, IgA, IgM, C3, and Clq. Mesangial
      hypercellularity
      has
      also been reported, as well as one case of mesangial
      proliferative
      glomerulonephritis.[11] This patient had nephrotic
      syndrome, which
      resolved
      after recovery from the HAV infection. Dialysis and
      plasmapheresis have
      been
      recommended in HAV-infected patients with renal
      failure, though
      spontaneous
      recovery of renal function usually occurs.[20,21]

      Hepatitis B

      Hepatitis B virus (HBV) poses a greater threat to
      public health than
      HAV
      infection, because HBV has a predilection for
      chronicity. It has been
      reported that persistent infection develops in 0.1% to
      15.0% of the 50
      million people infected each year with HBV. Thus, the
      global prevalence
      of
      HBV chronic carriers may be as high as 300 million
      people.[22] The
      potential
      worldwide threat of HBV-associated renal disease is
      therefore
      significant,
      though the risk of glomerular disease may depend on
      age at the time of
      infection, particularly where HBV is endemic and
      infection is thus
      frequently neonatal.

      Hepatitis B viral infection is associated with a
      variety of
      immunologically
      mediated disorders. In the acute setting, a serum
      sickness syndrome
      manifested by fever, rash, and arthritis has been
      reported in 10% to
      25% of
      patients. Transient microscopic hematuria,
      proteinuria, and sterile
      pyuria
      have also been reported.[23] In contrast, vasculitis
      and glomerular
      disease
      occur more commonly in patients with chronic HBV
      infection. In this
      setting,
      polyarteritis nodosa (PAN) (systemic necrotizing
      vasculitis), a
      multisystem
      process associated with fibrinoid necrosis and
      perivascular
      infiltration of
      medium and small arteries and arterioles by leukocytes
      may occur.
      Polyarteritis nodosa usually presents itself weeks to
      months after the
      initial HBV infection. Early manifestations include
      fever, arthralgias
      and/or arthritis, and a vasculitis that may involve
      any organ. Clinical
      sequelae may include skin rash, mononeuritis
      multiplex, and urticaria.
      Patients with HBV-associated PAN generally have only
      mildly elevated
      values
      on liver function tests and serologic evidence of
      chronic hepatitis
      with
      positive HBsAg, HBeAg, and anti-HBc antibodies. Most
      patients will have
      a
      negative test for perinuclear antineutrophilic
      cytoplasmic antibody
      (p-ANCA).[24] Renal manifestations include membranous
      glomerulonephritis
      (MGN); diffuse proliferative, membranoproliferative,
      and mesangial
      proliferative GN with hematuria; proteinuria; and red
      blood cell
      casts.[25]
      Ischemic damage of the renal tubules may also occur in
      PAN and show
      manifestations similar to those of ATN. The diagnosis
      should be
      suspected in
      any HBV-infected patient with evidence of skin lesions
      or other
      symptoms of
      vasculitis. Confirmation is necessary by biopsy of
      skeletal muscle,
      peripheral nerve, or testicle. The highest diagnostic
      yield is obtained
      by
      renal or celiac angiography, which will show
      medium-sized aneurysmal
      dilatation.[26]

      Hepatitis B viral infection is also associated with a
      variety of
      glomerular
      diseases that are manifested as either nephrotic or
      nephritic
      syndromes.
      Minimal-change disease, mesangial proliferative
      glomerulonephritis,
      membranoproliferative glomerulonephritis, and IgA
      nephropathy have all
      been
      described in patients with hepatitis B virus
      infection, though in
      several
      studies, HBV antigens could not be shown in
      association with these
      glomerular lesions.[27] A clear association has been
      established,
      however,
      between HBV infection and mesangial proliferative
      glomerulonephritis
      and
      membranous glomerulopathy. While several reports
      describe the
      occurrence of
      these last two disorders in patients with HBV,
      membranous
      glomerulopathy is
      clearly the most frequently occurring renal disease in
      patients with
      HBV.

      The association between HBV and MGN was first
      illustrated by Combes et
      al[28] when HBV specific antigens were found in the
      glomerulus of a
      patient
      with membranous glomerulopathy. Membranous
      glomerulonephritis occurs in
      patients who are chronic hepatitis B surface antigen
      carriers. These
      patients present clinically with nephrotic syndrome
      occurring at least
      6
      months after the initial episode of hepatitis. They
      generally are not
      hypertensive, and impairment of renal function is
      variable.
      Transaminase
      values are generally mildly elevated; however, liver
      biopsy typically
      shows
      evidence of chronic hepatitis. Progression to
      end-stage renal disease
      is
      rare; spontaneous remission occurs in up to 85% of
      patients. In some
      patients with asymptomatic HBV infection, renal
      disease may be the
      initial
      clinical manifestation. These patients have a clinical
      presentation of
      either nephrotic syndrome or heavy proteinuria
      discovered incidentally
      on
      urinalysis. Therefore, serologic studies in the
      evaluation of new onset
      proteinuria can lead to the discovery of hepatitis B
      antigenemia.

      The treatment of both the glomerulopathy and
      vasculitis associated with
      HBV
      infection is predicated on an understanding of the
      pathobiology of this
      condition. It has been established that various
      HBV-associated
      antigens, ie,
      surface antigen, e antigen, and core antigen, induce
      an antibody
      response
      with the formation of circulating immune complexes.
      These complexes
      become
      deposited in arterioles and the glomeruli and evoke
      complement
      activation
      and cytokine production, with subsequent inflammatory
      response.[29]
      Thus,
      mechanisms that modify the immune response, including
      high dose
      corticosteroids, immunosuppresive agents
      (cyclophosphamide), and plasma
      exchange, have been used to treat patients with
      PAN.[30] Early
      protocols for
      treatment of membranous glomerulopathy have relied on
      corticosteroids,
      though therapy should be reserved for high-risk
      populations (ie, those
      with
      heavy proteinuria or progressive renal insufficiency)
      because many
      patients
      have spontaneous remission. Unfortunately, these
      therapies have limited
      benefit and may paradoxically be harmful, since both
      corticosteroids
      and
      immunosuppressive agents enhance HBV replication and
      may exacerbate the
      underlying liver disease.[24]

      At present, optimal therapy for HBV-associated
      vasculitis and
      glomerulopathy
      has not been established, though it is intuitive that
      eradicating or
      minimizing HBV viral replication would be of benefit.
      Further support
      for
      this concept is based on the observation that
      spontaneous hepatitis B e
      antigen (HBeAg) clearance is associated with
      resolution of the
      nephrotic
      syndrome associated with HBV infection.[31]

      Unfortunately, studies investigating the effect of
      antiviral therapy on
      HBV-associated vasculopathy and glomerulopathy have
      not provided
      consistent
      results. Treatment with with interferon alfa and
      adenine arabinoside
      has
      proved efficacious in PAN.[32] In contradistinction,
      several
      investigators
      have documented that clearance of HBeAg using
      interferon alfa was
      associated
      with resolution of MGN, while others have shown only
      modest benefit
      with
      antiviral therapy.[33,34] Reverse transcriptase
      inhibitors
      (lamivudine/3TC),
      which more specifically inhibit HBV replication, are
      more likely to be
      effective than previously available antiviral agents.

      Hepatitis C

      Although the association of HBV with renal disease has
      been appreciated
      for
      more than a quarter of a century, the role of HCV in
      renal disease has
      only
      recently been acknowledged. Hepatitis C virus is now
      recognized as the
      responsible agent in the majority of cases of non-A,
      non-B
      hepatitis.[35]
      Most patients are minimally symptomatic when acutely
      infected;
      nonetheless,
      more than 85% have chronic viral infection. Nearly 85%
      of untreated
      HCV-infected patients have chronic hepatitis, 20% of
      infected patients
      progress to cirrhosis after 20 years, and up to 10%
      have hepatocellular
      carcinoma.[36]

      Because of the relatively asymptomatic nature of
      infection and the
      prolonged
      period before diagnosis, many patients infected with
      HCV have
      significant
      hepatocellular disease when initially diagnosed. In
      addition, since the
      majority of patients who contract HCV remain viremic,
      the potential for
      immunologically mediated disease is great. Indeed,
      patients with HCV
      viremia
      are often found to have circulating
      autoantibodies,[37] and several
      immune-mediated extrahepatic manifestations of HCV
      have been reported,
      including polyarteritis nodosa, thyroiditis, anemia,
      dermatitis, sicca
      syndrome, and non-Hodgkin's lymphoma.[38] The
      extrahepatic
      manifestations
      that are most clearly associated with HCV infection
      are
      glomerulonephritis
      and mixed essential cryoglobulinemia.

      Membranoproliferative glomerulonephritis is the most
      common glomerular
      disease associated with HCV infection, but membranous
      glomerulopathy,
      fibrillary glomerulonephritis, rapidly progressive
      glomerulonephritis,[39]
      and IgA nephropathy[40] have been reported. The
      glomerulopathy
      associated
      with HCV may occur in the presence[41] or the absence
      of MEC.[42]
      Despite
      the presence of cryoglobulinemia, extrarenal
      manifestations of MEC are
      noted
      in the minority of patients at initial presentation,
      though as the
      disease
      progresses, up to 50% of patients manifest extrarenal
      complications.[43] In
      addition, while the minority of affected patients have
      physical
      evidence of
      chronic liver disease, 70% to 75% of patients will
      have elevated serum
      transaminase values and manifest chronic hepatitis on
      liver biopsy.[44]

      The renal manifestations of HCV-associated
      glomerulopathy include
      nephrotic
      or non-nephrotic range proteinuria, modest azotemia,
      renal
      insufficiency,
      and occasional hypertension. Renal biopsies often show

      membranoproliferative
      glomerulonephritis type I, while MPGN type III with
      subepithelial,
      subendothelial, and mesangial immune deposits,
      proliferative and
      exudative
      nephritis, and arteritis are present in the minority
      of patients. Light
      microscopy shows both mesangial proliferation and
      thickening of the
      basement
      membrane, and IgM and IgG are often present in a
      granular pattern on
      immunofluorescence. Electron microscopy often reveals
      electron dense
      deposits in a subendothelial location, and
      intraluminal thrombi and C3
      may
      be found. The capillary lumen may also contain a
      fibrillar or
      crystaloid
      structure.

      The pathogenesis of HCV-associated renal disease is
      not fully
      understood. It
      is clear that HCV is linked to MEC, since 80% of
      patients with MEC are
      infected with HCV, and HCV RNA is specifically
      concentrated in
      cryoglobulins. Various investigators have proposed
      that
      cryoglobulinemia
      occurs as a result of antibody response to HCV, with
      subsequent
      formation of
      immune complexes and rheumatoid factors.[45] These
      immune complexes and
      cryoglobulins are then deposited in various tissues,
      thus inducing
      end-organ
      manifestations such as arthralgia, vasculitis,
      purpura, and neuropathy.
      The
      deposition of these immune complexes and cryoglobulins
      in the
      subendothelium
      and mesangium of glomerular capillaries induces local
      cellular
      proliferation
      and leukocyte infiltration, with resultant
      glomerulonephritis.
      Glomerular
      deposition of immune complexes made up of HCV and
      antibody may also
      occur
      without cryoglobulinemia.[44] More recently, two cases
      of thrombotic
      microangiopathy associated with HCV infection,
      cryoglobulinemia, and
      MPGN
      have also been reported.[46]

      Historically, treatment protocols for
      glomerulonephritis relied on
      immunosuppressive therapy with corticosteroids,
      cytotoxic medication,
      and
      plasmapheresis, which was thought to be effective in
      removal of
      circulating
      cryoglobulins. More recently, strategies to suppress
      HCV with antiviral
      therapy have been implemented to determine the effect
      on MPGN
      associated
      with HCV infection. In a study by Johnson et al,[43]
      34 patients with
      MPGN
      associated with HCV infection were treated with
      interferon alfa. It was
      shown that if HCV could be cleared from the serum,
      proteinuria
      diminished;
      however, both viremia and proteinuria recurred when
      interferon therapy
      was
      discontinued. There was no significant improvement in
      renal function.
      In
      patients in whom viremia could not be suppressed,
      there was no
      significant
      improvement in either renal function or
      proteinuria.[43] In another
      recent
      study, Misiani et al[41] treated 53 HCV-infected
      patients with
      cryoglobulinemia in a randomized prospective trial
      using interferon
      alfa. In
      15 of 25 treated patients, HCV levels became
      undetectable. These
      patients
      had a significant improvement in cutaneous vasculitis
      and mild
      improvement
      in renal function; however, when therapy was
      discontinued, HCV viremia,
      cryoglobulinemia, and renal dysfunction recurred.[41]
      It is anticipated
      that
      more effective antiviral agents or combinations of
      antiviral agents
      will
      more effectively suppress HCV replication, diminish
      cryoglobulinemia,
      and
      display greater efficacy in treating HCV-associated
      MPGN.

      Hepatitis E and G

      Hepatitis E, an enterically transmitted virus, has
      been associated with
      outbreaks of acute hepatitis in developing countries,
      particularly the
      Indian subcontinent, Asia, and Africa. Although
      usually self-limited,
      HEV
      infection has been associated with a high mortality
      rate during
      pregnancy.[47] Infection with HEV does not induce
      chronic liver
      disease, and
      there is no evidence of an association between HEV
      infection and
      chronic
      renal disease.[48] Infection with HEV may cause acute
      renal failure
      through
      the same indirect mechanisms as other hepatitis
      viruses, though acute
      renal
      failure/ ATN has been reported in one patient with
      acute hepatitis due
      to
      HEV infection.[49]

      At present, hepatitis G (HGV) infection has been
      documented in 3% to
      19% of
      chronic hemodialysis patients.[50,51] Despite the
      relatively high
      prevalence
      of infection in this population, there is no evidence
      that HGV
      contributes
      to renal failure.[52] A recent report documented that
      87% of
      HGV-positive
      chronic dialysis and renal transplant patients were
      coinfected with
      HCV.[53]
      It could be postulated that in these co-infected
      patients, HCV and not
      HGV
      infection induces renal dysfunction.


      Conclusions
      Hepatitis A, B, and C viruses are important etiologic
      agents in that
      they
      induce renal disease through several mechanisms.
      Hepatitis B and C
      viruses
      are important causative agents in membranous
      glomerulopathy and
      membranoproliferative glomerulonephritis,
      respectively. Both of these
      viruses have been associated less commonly with other
      glomerular
      diseases,
      while the association of HCV with mixed essential
      cryoglobulinemia is
      increasingly being recognized. Hepatitis viruses may
      also be associated
      with
      systemic disorders that result in renal injur y,
      primarily through
      immunologically mediated mechanisms. On a worldwide
      basis, HBV and HCV
      are
      important causes of morbidity and mortality, largely
      due to the renal
      disease they initiate. Glomerulonephritis that had
      previously been
      considered "idiopathic" may actually be initiated by
      underlying
      infectious
      agents. The discovery and understanding of the
      mechanisms by which HBV
      and
      HCV initiate glomerulonephritis will allow the
      development of more
      effective
      preventive and treatment strategies for these
      important infections.
      Although
      HEV infection may induce acute renal dysfunction,
      there is no evidence
      that
      HEV or HGV infection is associated with chronic renal
      disease.
      Reprint requests to N. Kevin Krane, MD, Tulane
      University School of
      Medicine, Office of Academic Affairs, SL77, 1430
      Tulane Ave, New
      Orleans, LA
      70112.


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