INTRODUCTION
Hepatitis C virus infection has been associated with the development of immune complex glomerular diseases, including MPGN and membranous nephropathy. In addition, HCV infection has been strongly linked with the pathogenesis of cryoglobulinemia. In this context, all HCV-infected patients are at increased risk to develop kidney disease and should be screened annually. In addition, patients with vasculitis or glomerular syndromes of uncertain etiology should be screened for HCV infection as part of the initial evaluation.
5.1 It is suggested that HCV-infected patients be tested at least annually for proteinuria, hematuria, and estimated GFR to detect possible HCV-associated kidney disease. (Weak)
5.2 It is suggested that a kidney biopsy be performed in HCVinfected patients with clinical evidence of GN. (Weak)
5.3 It is suggested that for patients with HCV-associated glomerular diseases, particularly MPGN, antiviral treatment as per Guideline 2.2 be considered. (Weak)
- It is suggested that immunosuppressive agents be considered for patients with cryoglobulinemic kidney diseases. (Weak)
BACKGROUND
Patients with long-standing HCV infection can develop chronic
hepatitis, liver cirrhosis, and hepatocellular carcinoma. Several
extrahepatic-including hematologic and dermatologic-
complications have also been associated with HCV infection,
as well as autoimmune and kidney diseases.353 There is an
increasing evidence for the association between HCV infection
and glomerular disease in both native and transplanted
kidneys. Type I MPGN associated with type II cryoglobulinemia
is the most common form of kidney disease associated
with HCV infection.354 Less frequently described lesions are
MPGN without cryoglobulinemia and membranous GN
(MGN). Also, occasional cases of focal segmental glomerulosclerosis,
thrombotic microangiopathy associated with anticardiolipin
antibodies, and fibrillary and immunotactoid
glomerulopathies have been reported.60,354-359
The presence of these renal manifestations of HCV
infection is not common and their exact prevalence remains
unknown because the available information is limited. Why
only some HCV-infected patients develop kidney lesions
has not been determined. However, consideration for the use
of antiviral therapy in these cases is important, as HCV
infection has been implicated in the pathogenesis of the
immune complex GN that sometimes develops.60 Establishment
of the correct histologic diagnoses in patients
with suspected HCV-induced GN is essential, as clearing of
HCV RNA with SVR can be obtained with the use
of appropriate antiviral strategies. In some patients with
histologically active lesions (for example, crescents, vasculitis),
combined antiviral and immunosuppressive therapies
may be effective and should be considered.360
RATIONALE
5.1 It is suggested that HCV-infected patients be tested at least
annually for proteinuria, hematuria, and estimated GFR to detect
possible HCV-associated kidney disease. (Weak)
HCV-infected patients, including those with kidney or liver
transplants, have an increased risk of glomerulopathy leading
to CKD.359 Glomerular lesions associated with HCV infection
have been described in the presence or absence of significant
liver disease; however, all patients with HCV-associated GN
are HCV RNA-positive in the serum.60,359,360
Epidemiologic studies reporting the actual prevalence
of CKD in patients with HCV infection are not available. It
has been demonstrated that the prevalence of HCV
seropositivity in case series of patients with MPGN is about
10 times greater than the reported prevalence of HCV
seronegativity.361 Furthermore, studies of both live and
autopsy series of individuals with HCV infection have shown
a higher prevalence of MPGN than those reported for the
general population.362,363 A recent cross-sectional analysis
of the NHANES III data demonstrated an age-dependent
association between HCV seropositivity and albuminuria
(adjusted odds ratio of 1.84 for ages 40-59 years and 1.27 for
age ≥60 years).32 In the ≥60-year age group, 46% of HCVseropositive
individuals had albuminuria compared with
24% of those who were HCV antibody-negative. Of interest,
the same study found no significant association between
HCV seropositivity and low estimated GFR. Similar findings
were reported in a recent study from Taiwan.31 In this crosssectional
analysis, nondiabetic subjects who were anti-HCVpositive
had an 8.3% prevalence of ≥1 positive dipstick
proteinuria compared with 5.1% in the seronegative group
(P=0.002). In multivariate analysis, the association between
anti-HCV-positive status and proteinuria had an odds ratio
of 1.84.
Cryoglobulins containing HCV RNA can be detected in
up to 50% of patients with HCV-associated MPGN, but
generally at very low levels (cryocrit o3%).364 Symptomatic
cryoglobulinemia occurs in about 1% of patients with HCV
infection, generally in association with high levels of
cryoglobulins and rheumatoid factor. Only a small number
of patients with cryoglobulinemia develop kidney disease or
other systemic vasculitis symptoms.365 The prevalence of
MPGN in patients with cryoglobulinemia associated with
HCV infection is o10%,358 and, in some series of kidney
biopsies of different lesions, only MPGN was clearly
associated with HCV infection.361 For other lesions, such as
MPGN without cryoglobulinemia or MGN, the prevalence of
HCV infection is in the range of 1-10%.366-368 Membranous
nephropathy has been described occasionally in
HCV-infected patients.369,370 In a study from Japan,
evidence for HCV infection was found in 2 of 24
patients with apparent idiopathic membranous nephropathy.
371 In an autopsy series of 188 consecutive patients
with HCV infection, the authors reported that MPGN was
present in 11%, membranous nephropathy in 2%, mesangial
proliferative GN in 17%, and 45% of the kidneys showed no
evidence of GN.372
The principal clinical manifestations of glomerular disease
in HCV-infected patients are the presence of proteinuria and
microscopic hematuria with or without impaired kidney
function. Screening for urinary abnormalities and alterations
of kidney function in all HCV-positive patients is recommended,
particularly in those with cryoglobulinemia. Early
diagnosis and treatment of HCV-associated glomerulopathy
may improve clinical outcomes. Supporting this proposition
is a prospective study of hepatitis C-infected patients with
end-stage cirrhosis undergoing liver transplantation,373 in
which renal biopsies obtained at transplant surgery demonstrated
that most patients (25 of 30) had immune complexmediated
GN. The majority of these were MPGN, and most
glomerular disease was clinically not apparent before biopsy.
This study indicates a potentially large and unrecognized
reservoir of kidney diseases in HCV-infected patients,
particularly those with advanced liver disease, that could
contribute to CKD in conjunction with other kidney injuries
such as those consequent to liver transplantation.
5.2. It is suggested that a kidney biopsy be performed in
HCV-infected patients with clinical evidence of GN. (Weak)
HCV infection has been associated with glomerular lesions in
native and transplanted kidneys.32,60,359 In HCV-infected
patients with proteinuria and/or hematuria, a kidney biopsy
is necessary to determine the histologic pattern of glomerular
injury present. Although several glomerular lesions have been
described, the most important one is MPGN usually, but not
invariably, in the context of cryoglobulinemia. HCV infection
is the major cause of mixed cryoglobulinemia, a systemic
vasculitis characterized by arthralgias, arthritis, Raynaud's
phenomena, purpura, peripheral neuropathy, hypocomplementemia,
and kidney disease.356 Cryoglobulins and HCV
RNA are usually present. Hypocomplementemia and positive
rheumatoid factor can also be observed. Some patients exhibit
normal ALT/AST levels or only a mild elevation of liver
enzymes (60-70% of cases). Manifestations of kidney involvement
include nephrotic or non-nephrotic proteinuria, hematuria,
and variable degrees of reduced GFR. Acute nephritic
syndrome and nephrotic syndrome can be a presenting feature
in 25 and 20% of these patients, respectively.60
Pathologic findings of cryoglobulinemic GN typically
include evidence of immune complex deposition in the
glomeruli and changes of type I MPGN. Glomeruli may
demonstrate prominent hypercellularity as a result of massive
infiltration of glomerular capillaries with mononuclear and
polymorphonuclear leukocytes. Glomeruli show accentuation
of lobulation of the tuft architecture and may have a
combination of increased matrix and mesangial cells,
capillary endothelial swelling, splitting of capillary basement
membrane, intracapillary thrombi, and accumulation of
eosinophilic material representing precipitated immune
complexes or cryoglobulins. Vasculitis of the small- and
medium-sized renal arteries can also be present. On electron
microscopy, subendothelial immune complexes are usually
seen and may have a fibrillar or immunotactoid pattern
suggestive of cryoglobulin deposits.60,358
It is important to note that the presence of massive
intraluminal thrombi, vasculitis, or both is more commonly
observed in patients with acute nephritic syndrome and rapid
progression to kidney failure. Histologic findings of exudative
MPGN or lobular MPGN are associated with the
presence of nephrotic and/or nephritic syndromes, whereas
mesangioproliferative GN is associated with proteinuria and
microscopic hematuria with preserved kidney function.60
In noncryoglobulinemic MPGN, the clinical picture,
pathologic features, and laboratory data are indistinguishable
from idiopathic type 1 MPGN,358 but are characterized by
the presence of HCVantibodies and HCV RNA in the serum.
Both subendothelial and mesangial immune complexes can
be identified by electron microscopy typically without a
distinctive substructure. In both forms of HCV-associated
MPGN, immunofluorescence usually demonstrates deposition
of IgM, IgG, and C3 in the mesangium and capillary
walls.358
MGN is also associated with HCV infection. The clinical
presentation, outcome, and pathologic findings are similar to
those of idiopathic MGN.365,367 On light microscopy, the
characteristic finding is a diffuse and uniform thickening of
the glomerular basement membrane without mesangial
proliferation. Diffuse subepithelial immune deposits can be
identified by electron microscopy, and immunofluorescence
reveals diffuse and granular deposits of IgG, C3, and IgA.
The pathogenesis of MGN in HCV-infected patients may
be related to the deposition of immune complexes containing
HCV proteins in the glomerular basement membrane. Viral
antigens have been detected by immunohistochemistry,374
and by in situ hybridization.375 It has been also reported that
laser microdissection is a useful method for measuring HCV
RNA genomic sequences and HCV core protein in kidney
structures, such as glomeruli and tubules, in patients with
HCV-related GN.376 However, these reports of localization of
either HCV mRNA or proteins still await confirmation.
Of interest, a recent study found that Toll-like receptor 3
messenger RNA expression was elevated in mesangial cells in
HCV-associated GN and was associated with enhanced
proinflammatory cytokines. The authors hypothesized that
immune complexes containing RNA activate mesangial Tolllike
receptor 3 during HCV infection, inducing chemokine
and cytokine release and affecting proliferation and apoptosis.
The authors suggest a novel role for Toll-like receptor 3 in
HCV-associated GN that could establish a link between viral
infections and GN.377
Other glomerular diseases that have been occasionally reported in association with HCV infection include acute diffuse proliferative GN,358,362 focal segmental glomerulosclerosis, 358 rapidly progressive GN,378 IgA nephropathy,358 thrombotic microangiopathy,355 fibrillary GN, and immunotactoid glomerulopathy.357
5.3 It is suggested that for patients with HCV-associated glomerular diseases, particularly MPGN, antiviral treatment as per Guideline 2.2 be considered. (Weak)
- It is suggested that immunosuppressive agents be considered for patients with cryoglobulinemic kidney diseases. (Weak)
Antiviral therapy targeted at achieving clearance of HCV RNA with SVR has been used in patients with HCVassociated GN to treat the underlying kidney disease.Unfortunately, there are limited data regarding antiviral treatment in HCV-associated GN, and the impact of antiviral
therapy on long-term outcomes of kidney disease is not well known (Tables 25-28).
Monotherapy with IFN alfa has been used in cryoglobulinemic
GN with complete clearance of HCV RNA and
improved kidney function; however, recurrence of viremia
and relapses of kidney disease were universally observed after
IFN was discontinued.367,379 The use of steroid pulses and
cytotoxic agents, with or without plasma exchange, can be
useful in some patients with cryoglobulinemic GN and
systemic manifestations of mixed cryoglobulinemia, but can
be associated with a high rate of severe complications such as
infection, increased viral replication, and death.360
Combination therapy with pegylated IFN and ribavirin to
treat HCV-associated GN has been reported in isolated cases
and uncontrolled studies with small numbers of patients.
The most recent experience shows promising results with
this combination. SVR, decreased HCV RNA viral titers,
and improved kidney function and proteinuria have been
demonstrated in some patients.380-383 However, IFN has
been reported to exacerbate proteinuria in some patients
with underlying glomerulopathies.336 Monitoring ribavirin
dosage is essential to circumvent ribavirin-induced hemolytic
anemia. Ribavirin is not recommended in patients with a
creatinine clearance <50 ml per min per 1.73m2.360 Recently,
the anti-CD20 monoclonal antibody rituximab, an agent that
selectively targets B cells, has been used in a few noncontrolled
studies of cryoglobulinemic MPGN associated with
HCV infection.360,384-386 Preliminary results are encouraging.
Rituximab has not been associated with enhanced viral
replication and the side effects of cytotoxic agents such as
cyclophosphamide.360,387 In fact, the preferential use of
rituximab has been recommended by some in spite of the
absence of controlled trials. However, a point of caution is
important, as the use of rituximab may be associated with the
activation of various viral infections, including HCV.388-391
It is clear that prospective multicenter RCTs are mandatory
to establish evidence-based recommendations to treat
glomerular lesions associated with HCV infection. However,
until this information is available, it is suggested that two
possible regimens should be considered for the treatment
of cryoglobulinemic MPGN, depending on the severity of
proteinuria and kidney failure:
- First, in patients with moderate proteinuria and slow but progressive loss of kidney function, therapy for 12 months with standard IFN or pegylated IFN alfa-2a (135 μg week-1 SQ in patients with reduced creatinine clearance) or pegylated IFN alfa-2b (1.5 μg kg-1 week-1 SQ) plus ribavirin (not recommended for a GFR <50 ml per min per 1.73m2), with or without erythropoietin support depending on the level of hemoglobin.
- Second, in patients with nephrotic-range proteinuria and/or rapidly progressive loss of kidney function and an acute flare of cryoglobulinemia, it is recommended to consider the use of either plasma exchange (3 l of plasma thrice weekly for 2-3 weeks), rituximab (375 mg m-2 week-1 for 4 weeks), or cyclophosphamide (2 mg kg-1 day-1 for 2-4 months) plus methylprednisolone pulses 0.5-1 g day-1 for 3 days.360 After control of the vasculitic syndrome has been achieved, attention should be focused on treating the HCV infection directly with the antiviral therapy outlined above. In cases of early relapse of viremia, consideration should be given to further treatment with rituximab (375 mg m-2 week-1 for 4 weeks) with or without IFN for a longer duration (minimum of 18 months treatment).
- Finally, and in all cases, treatment including diuretics and antihypertensive agents should be used to achieve recommended target blood pressure goals of patients with CKD (see KDOQI Hypertension Guidelines). Additionally, antiproteinuric agents such as ACEI alone or in combination with ARBs should be used to maximally reduce urinary protein losses.
In patients with noncryoglobulinemic MPGN and
MGN associated with HCV infection, the use of IFN
monotherapy or combination treatment with pegylated IFN
plus ribavirin, as outlined above, could be useful. Another
possibility could be monotherapy with standard IFN or
pegylated IFN alone and the use of ribavirin only in patients
remaining HCV RNA-positive after 3 months of therapy with
IFN. Symptomatic therapy is also important in these cases,
particularly that of antiproteinuric agents to decrease
proteinuria.
Ribavirin monotherapy has been used in a few cases of
HCV-associated GN with consequent decreased proteinuria,
although no improvement in viremia was achieved.360 In
patients with reduced kidney function, ribavirin should be
administered with caution because of the risk of hemolytic
anemia. Its use is not recommended in patients with a
creatinine clearance of <50 ml per min per 1.73m2. Owing
to the limited data available, more information is needed
before the use of ribavirin monotherapy can be recommended
in HCV-associated GN.
Summary of recommendations
- Patients with acute flares of cryoglobulinemia and MPGN should be treated with plasma exchange, immunosuppressive drugs, and antiviral therapy.
- Immunosuppressive drugs include steroids, cyclophosphamide, or rituximab.
- Antiviral therapy with standard IFN or pegylated IFN plus ribavirin for at least 12 months is recommended.
- Patients with cryoglobulinemia without systemic disease and MPGN may be treated with standard IFN or pegylated IFN plus ribavirin without immunosuppressive agents.
- Patients with noncryoglobulinemic MPGN and MGN may be treated with standard IFN, pegylated IFN, or IFN plus ribavirin.
- SVR after antiviral therapy, change in kidney function, evolution of proteinuria, and side effects of therapy must be carefully monitored.
- Relapses of systemic cryoglobulinemia and MPGN may be treated with additional doses of rituximab.
- Relapses of HCV infection may be treated with standard or pegylated IFN. Patients who received monotherapy with standard IFN as initial therapy should be considered for treatment with pegylated IFN plus ribavirin if the creatinine clearance is >50 ml per min per 1.73m2.
- Ribavirin is not recommended in patients with impaired kidney function (creatinine clearance <50 ml per min per 1.73m2) to avoid anemia from hemolysis. If ribavirin is used in patients with CKD Stages 3-5, extreme caution must be used and close monitoring for worsening anemia is required.
- Patients with HCV-associated glomerulopathy should receive therapy with antiproteinuric agents, including ACEI and/or ARBs to reduce proteinuria and antihypertensive treatment to achieve target blood pressure and proteinuria goals established for patients with CKD.
LIMITATIONS
- Limited studies are available; most studies are retrospective analyses with small sample sizes.
- Most of the published literature comes from studies of patients referred with significant proteinuria, hematuria, or reduced kidney function. More thorough screening of the HCV-infected population will likely identify larger numbers of patients with earlier evidence of kidney disease who might have other histologic forms of injury.
- The measure of response to therapy varies significantly across the studies making it difficult to have valid comparisons of outcomes (for example, changes in proteinuria and kidney function).
- Long-term studies of patient and kidney outcomes after treatment of HCV associated glomerular disease are lacking.
RESEARCH RECOMMENDATIONS
- Large epidemiologic studies are needed to determine the prevalence and types of glomerular lesions in HCV-infected patients.
- Epidemiologic studies should be performed to examine the prevalence, risk factors, and outcomes of cryoglobulinemic MPGN.
- Epidemiologic studies are needed to determine whether acute diffuse proliferative GN, focal segmental glomerulosclerosis, rapidly progressive GN, and IgA nephropathy represent a true association or a coincidental association with HCV infection.
- Development of reagents that reliably test the presence of HCV virions, peptides, or RNA in tissues is needed to better understand the pathogenesis of glomerular disease associated with HCV infection.
- Further analyses should be conducted on the cytopathic effect of HCV and its possible interaction with cell-surface receptors such as Toll-like receptor 3.
- The role of HCV quasispecies evolution in promoting the development of cryoglobulinemia, GN, or in modulating the response of patients to various treatment regimens needs to be defined.
- Prospective multicenter RCTs are needed to establish the most efficacious treatment of HCV-associated glomerulopathy.
- Controlled trials of pegylated IFN should be performed to determine the dose and duration of therapy that is most effective with minimal adverse effects.
- Prospective controlled trials are needed to define the role of rituximab in cryoglobulinemic MPGN, and to determine dosage, safety, and effect on kidney disease.
- Controlled trials should be performed to determine the most effective therapy for relapses of cryoglobulinemia and HCV replication after a successful initial course of treatment.
