CLINICAL NEPHROLOGY TEACHING CASE

Lupus Membranous Glomerulonephritis Mimicking Hepatitis

C–Associated Nephropathy
Farhad R. Danesh, MD, Patrick Lynch, MD, and Yashpal S. Kanwar, MD, PhD

● About 20% to 40% of hepatitis C virus (HCV)–infected patients have antinuclear antibody (ANA) seropositivity.
Despite the high prevalence of ANA seropositivity in HCV infection, only a few cases of systemic lupus erythemato-
sus (SLE) coinciding with HCV infection have been reported. This discrepancy may be the result of underdiagnos-
ing SLE in patients with chronic HCV infection. The possible underdiagnosis of SLE in HCV-infected patients may
be of great concern because interferon-based therapy should be avoided in patients with autoimmune diseases. We
report a case of a patient with chronic HCV infection who presented with nephrotic syndrome. She had no previous
history of SLE. A kidney biopsy specimen revealed characteristic lesions of lupus membranous nephritis. Further
serologic studies confirmed the diagnosis of SLE in this patient. Lupus nephropathy should be ruled out in patients
with chronic HCV infection who present with kidney disease and moderate-to-high titers of ANA seropositivity
because (1) the association between lupus nephritis and HCV infection may not be coincidental and (2) the
diagnosis of lupus nephritis has important therapeutic implications in HCV-infected patients.
© 2002 by the National Kidney Foundation, Inc.

INDEX WORDS: Systemic lupus erythematosus (SLE); membranous glomerulonephritis (GN); hepatitis C virus
(HCV); immunosuppression.

S YSTEMIC LUPUS erythematosus (SLE) is

a classic autoimmune disease that can affect
any organ in the body.1 Clinical and morphologic
involvement of the kidneys in SLE occurs in
about 60% of lupus patients during the course of
their disease.2 It is believed that the potential
mechanism of renal injury in lupus nephritis is
related to the deposits of immune complexes
composed of various antigens and autoantibod-
ies in the glomerular structures.3 Whether these
are derived from circulating complexes or from
the in situ combination of antigen and autoanti-
body is not defined.
Evidence has suggested that hepatitis C virus
(HCV) infection may trigger the formation of
various autoantibodies, such as cryoglobulins,
rheumatic factor, and antinuclear antibodies
(ANA).4 About 20% to 40% of HCV-infected
patients have ANA seropositivity.4,5 Despite a
high prevalence of ANA seropositivity in pa-
tients with chronic HCV infection, a search of
the medical literature shows that only a few cases
of lupus nephritis coinciding with HCV infection
have been reported.6,8 This discrepancy may be
the result of underdiagnosing SLE in patients
with chronic HCV infection because the high
prevalence of ANA seropositivity in these pa-
tients may have discouraged many physicians
from pursuing the diagnosis of SLE. SLE symp-
toms closely mimic symptoms related to HCV
infection, which may lower the clinical suspicion
for the diagnosis of SLE. The possible underdiag-
nosis of SLE in patients with HCV infection is of
concern because establishing the diagnosis of
lupus nephritis in HCV-infected patients has im-
portant therapeutic implications.
The association between lupus nephropathy
and chronic HCV infection may not be coinciden-
tal. Formation of various autoantibodies asso-
ciated with HCV infection could facilitate the
development of lupus nephritis by forming im-
mune complex deposits in the kidneys. The di-
agnosis of lupus nephropathy in patients with
chronic HCV infection who present with kidney
disease and mild-to-moderate titers of ANA sero-
positivity should alert physicians to rule out the
possibility of lupus nephritis as the underlying
kidney disease because (1) the association be-
tween lupus nephritis and HCV infection may
not be coincidental and (2) the diagnosis of lupus
From the Divisions of Nephrology/Hypertension, Gastro-
enterology/Hepatology, and Pathology, Northwestern Uni-
versity Medical School, Chicago, IL.
Received August 31, 2001; accepted in revised form
November 30, 2001.
Address reprint requests to Farhad R. Danesh, MD,
Northwestern University Medical School, Medical Science
Building, 400 East Ontario, Suite 229, Chicago, IL, 60611.
E-mail: f-rahimi@northwestern.edu
© 2002 by the National Kidney Foundation, Inc.
0272-6386/02/3903-0030$35.00/0
doi:10.1053/ajkd.2002.31430

American Journal of Kidney Diseases, Vol 39, No 3 (March), 2002: E19 1

2 DANESH ET AL
nephritis has important therapeutic implications
in HCV-infected patients.
We present a patient with chronic HCV infec-
tion who presented with nephrotic syndrome.
She had no previous history of SLE. A kidney
biopsy specimen revealed characteristic lesions
of lupus membranous nephritis. Further sero-
logic studies confirmed the diagnosis of SLE in
this patient.
CASE REPORT
A 42-year-old black woman with a history of chronic
HCV infection presented with hypertension, bilateral leg
edema, and fatigue of 6 weeks’ duration. Past medical
history was remarkable for drug abuse and multiple sexual
partners. There was no family history of autoimmune dis-
ease.
Four years before presentation, a life insurance health
examination showed elevated liver enzymes and seropositiv-
ity for HCV antibody. A liver biopsy was recommended to
the patient at that time, but she refused. She had no history of
hypertension, and her last employee physical examination
10 months previously showed a blood pressure of 110/70
mm Hg with a serum creatinine of 0.9 mg/dL.
Physical examination revealed blood pressure, 140/100
mm Hg; pulse, 70 beats/min; respiratory rate, 14 breaths/
min; and anicteric sclera. Heart sounds were regular; no
murmurs or gallops were detected. Lungs were clear. The
liver was enlarged with a span of 13 cm. There was bilateral
lower extremity edema to the knees. Laboratory evaluation
showed white blood cell count of 3,600/␮L with 48%
neutrophils, 39% lymphocytes, 10% monocytes, and 3%
eosinophils. Hematocrit was 34%, and platelets were 288/
␮L. Blood urea nitrogen was 6 mg/dL; serum creatinine, 0.6
mg/dL; glucose, 110 mg/dL; sodium, 138 mEq/L; potas-
sium, 4.3 mEq/L; carbon dioxide, 29 mEq/L; albumin, 1.8
g/dL; total protein, 7.9 g/dL; alanine aminotransferase, 83
U/L (normal range, 0 to 48 U/L); and aspartate aminotrans-
ferase, 97 U/L (normal range, 0 to 40 U/L). Urinalysis
showed specific gravity of 1020; pH 6.5; protein, 100
mg/dL; 0 to 5 red blood cells/high-powered field; 0 to 5
white blood cells/high-powered field; and a few oval fat
bodies/high-powered field. A 24-hour urinary protein re-
vealed a protein of 3.6 g and a creatinine clearance of 138
mL/min. The following serologies were negative: rapid
plasma reagin, hepatitis B surface antigen, human immuno-
deficiency virus (HIV), and serum cryoglobulins. C3 and C4
serum levels were depressed slightly. C3 was 57 mg/dL
(normal range, 79 to 165 mg/dL), C4 was 12 mg/dL (normal
range, 14 to 43 mg/dL), and CH50 was 43 mg/dL (normal
range, 63 to 145 mg/dL). Rheumatoid factor was 122 IU/
mL; ANA, 1:1280 and speckled; Anti-dDNA, 1:80 (mea-
sured by Crithidia assay); anti-Smith antibodies (sm), 93
(normal, ⬍20); RNP/SM, 208 (⬍20); SSA (Ro), 139 (⬍20);
and SSB (La), 32 (⬍20). HCV antibody was positive, and
the blood viral load of HCV as measured by polymerase
chain reaction was greater than 660,000 copies/mL. The
HCV genotype was type Ia. Renal ultrasonography showed
normal-sized kidneys. Simultaneous liver and kidney biop-
sies were performed.
Biopsy Findings
On light microscopic examination, 20 glomeruli were
identified. The glomeruli showed varying degrees of mesan-
gial cell hypercellularity with thickening of mesangial matri-
ces. Podocytes (visceral glomerular epithelial cells) were
prominent (Fig 1A). The tubules revealed mild degenerative
changes and contained periodic acid–Schiff–positive absorp-
tion droplets. Immunofluorescence microscopy revealed me-
sangiocapillary granular deposits of IgG, IgA, IgM, C1q,
and C3 (Fig 1B). Electron microscopy revealed marked
effacement of the visceral epithelial foot process and pre-
dominant subepithelial electron-dense deposits (Fig 1C). A
few mesangial deposits also were present. Tubuloreticular
elements were seen in the glomerular (Fig 1C) and extraglo-
merular endothelial cells. The liver biopsy specimen re-
vealed a focal lymphocytic infiltrate (Fig 1D), consistent
with chronic hepatitis, grade 2.
DISCUSSION
We have presented a case of a 42-year-old
black woman with a history of chronic HCV
infection who presented with proteinuria, hypo-
complementemia, and hypertension. The kidney
biopsy findings were consistent with the diagno-
sis of lupus membranous nephropathy. Lesions
of lupus membranous nephropathy (World Health
Organization class V) are similar in many ways
to HCV-associated membranous nephropathy
with subepithelial glomerular immune depos-
its.2,3 There typically is a thickening of the glo-
merular capillary walls and spike formation. Lu-
pus nephritis is one of the few renal diseases in
which immune deposits can be found in glomer-
ular and extraglomerular compartments. The im-
munoglobulin deposits are polyclonal and are
seen not only as subepithelial deposits, but also
in subendothelial and mesangial locations.3 C3
and C1q are identified commonly, and staining
for C1q may be particularly intense.
Chronic HCV infection has been linked to
multiple patterns of glomerular injury. Two large
studies conducted in the United States and Italy
found a high prevalence of HCV infection in
patients with type II cryoglobulinemia.9,11 On
histologic examination, these patients show a
pattern resembling type 1 mesangioproliferative
glomerulonephritis (MPGN). MPGN type 1 is
not the only pattern of glomerular disease seen in
patients with HCV infection. Other glomerulopa-
thies associated with HCV include acute exuda-
tive glomerulonephritis, MPGN type 3 fibrillary
LUPUS NEPHRITIS AND CHRONIC HEPATITIS C 3

Fig 1. (A) Photomicrograph of a glomerulus with thickening of the peripheral capillary wall, accompanied by
mesangial widening and prominent podocytes (arrow). (H&E, original magnification ⴛ100.) (B) Immunofluores-
cence showed strong glomerular capillary wall staining of 3ⴙ intensity for IgG. Peripheral granular deposition of
immunoglobulins occurs in an irregular fashion throughout all of the capillary loops. (C) Electron micrograph
shows diffuse irregular thickening of the basement membrane with subepithelial electron-dense deposits (arrow).
Tubuloreticular elements were seen in glomerular and extraglomerular endothelia (arrowhead). (D) Liver biopsy
revealed chronic lymphocytic infiltrates (arrow) without fibrosis.

glomerulonephritis, and membranous glomerulo-
nephritis.12
In many instances, the differential diagnosis
between lupus membranous nephritis and HCV-
associated membranous nephritis is challenging.
There are a few clues, however, to the diagnosis
of lupus nephritis. Lupus membranous nephritis
often is associated with hypocomplementemia
and moderate-to-high titers of ANA seropositiv-
ity. On the kidney biopsy specimen, the presence
of polyclonal immunoglobulin deposits in all
four compartments of the kidney is typical of
lupus nephritis. Tubuloreticular elements in glo-
merular and extraglomerular endothelium are
characteristic, although not pathognomonic, of
lupus nephritis because the same inclusion bod-
ies could be seen with HIV and hepatitis ne-
phropathies.3 HCV-associated membranous glo-
merulonephritis often is seen without evidence
of hypocomplementemia, or anti-sm autoantibod-
ies, and usually with lower titers of ANA. On
the kidney biopsy specimen, in contrast to lupus
membranous glomerulonephritis, there is no evi-
dence of subepithelial and mesangial deposits.
Multiple immune phenomena have been de-
scribed in HCV, including autoimmune thyroid-
itis, vasculitis, Sjögren’s syndrome, polyarteritis
nodosa, and cryoglobulinemia.4 The principal
mechanisms by which these autoimmune mani-
festations develop are unknown, however. The
virus itself may be the triggering antigen, or it
may modulate the immune response indirectly
by releasing endogenous interferon. HCV infec-
tion also has been associated with a broad range
of autoimmune responses, including the pres-
ence of ANA, anticardiolipin antibodies, rheuma-
toid factor, antithyroidal antibodies, anti-SMA,
and anti–liver/kidney/microsomal (anti-LKM) au-
toantibodies (Table 1).4,5,13 About 20% to 40%
of chronic HCV patients have ANA seropositiv-
4 DANESH ET AL
Table 1. Prevalence of Autoantibodies in Hepatic C
Virus Infection
Autoantibodies Prevalence (%)
Antinuclear antibodies 20-40
Anti–smooth muscle antibodies 20-22
Antithyroid antibodies 8-12
Anticardiolipin antibodies 20-22
Anti–liver/kidney/microsomal antibodies 5-10
Rheumatic factor 50-70
Cryoglobulins 30-40
ity.4,5 The percentage of ANA-positive patients
who have HCV antibodies still is unclear, but it
has been estimated to be around 15% to 20%. It
is of concern that despite the association between
ANA seropositivity and HCV infection, only a
few cases of lupus nephritis coinciding with
HCV infection have been reported.6,7,14 This
discrepancy may be the result of underdiagnos-
ing SLE in patients with chronic HCV infection
because many symptoms of SLE may mimic HCV
symptoms closely. Because of the high prev-
alence of ANA seropositivity in HCV-infected
patients, many physicians may not pursue the
diagnosis of SLE in HCV-infected patients with
positive ANA. The possible underdiagnosis of
SLE in patients with chronic HCV and nephrop-
athy may have important consequences because
the management of these patients may be af-
fected considerably. Ramos-Caslas et al14 stud-
ied the correlation between HCV infection and
SLE in 134 patients in Spain. These authors
recommended that HCV testing be considered in
patients with SLE, especially in patients with
lower titers of autoantibodies.
The association between lupus nephropathy
and chronic HCV infection may not be coinciden-
tal. It is possible that the HCV antigens induce an
autoimmune response with the subsequent pre-
cipitation of antigen antibodies in the glomeruli.
Although it also could be argued that the associa-
tion between lupus nephropathy and HCV infec-
tion may be sporadic and simply indicates an
increased incidence of HCV infection in patients
with autoimmune kidney disease, other emerg-
ing case reports documenting the occurrence of
HCV infection before the development of autoim-
mune disease suggest a potential role for HCV
antigens in individuals who may be predisposed
to the development of autoimmunity and possi-
bly autoimmune kidney disease.15 Our patient
did not have any prior evidence of SLE or lupus
nephritis. Temporally the development of protein-
uria could have been secondary to HCV-associ-
ated nephropathy or lupus nephritis. The typical
pattern of lupus membranous glomerulonephritis
in the kidney biopsy specimen in addition to
consistent serology supports the diagnosis of
lupus nephritis in this patient, however. Further
studies are needed to establish an association
between lupus nephritis and chronic HCV infec-
tion. The presence of nephropathy in HCV-
infected patients with ANA seropositivity should
alert physicians to obtain a kidney biopsy speci-
men to rule out the possibility of lupus nephritis
as the underlying kidney disease rather than
HCV-associated nephropathy.
The challenge in these cases is to manage
lupus membranous nephritis in patients with HCV
infection. Treatment of lupus nephritis with ste-
roids and cyclophosphamide has been shown to
improve renal survival, and its efficacy is well
established.16 Although patients with lupus mem-
branous nephritis usually are treated less inten-
sively than patients with proliferative nephritis,
Sloan et al17 reported that lupus membranous
nephropathy is associated with an increased risk
of end-stage renal disease or death. In patients
with HCV infection, however, immunosuppres-
sive treatment may be ultimately detrimental for
the liver by increasing HCV viral load. In immu-
nosuppressed kidney transplant patients, HCV
hepatitis could be aggravated because of in-
creased viral cytotoxicity. Treatment with inter-
feron alfa can be useful in patients with HCV
hepatitis and renal disease but should be avoided
in patients with autoimmune diseases. SLE can
be induced by recombinant interferon alfa pre-
scribed for chronic HCV infection. Given the
absence of hepatic fibrosis and the potential risk
of exacerbating the patient’s underlying lupus,
interferon-based therapy was not initiated in this
patient. We decided to treat the proteinuria ini-
tially with an angiotensin-converting enzyme
inhibitor, ramipril. Ramipril decreased signifi-
cantly the amount of proteinuria to less than 1
g/24 h. Considering the patient’s response to the
angiotensin-converting enzyme inhibitor and her
normal kidney function, we are continuing with
conservative management.
LUPUS NEPHRITIS AND CHRONIC HEPATITIS C
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