Nephrol Dial Transplant (1996) 11: 1342-1345

Nephrology
Dialysis
Case Report Transplantation

Hepatitis C virus infection complicating lupus nephritis

Ma. D. Albero1, F. Rivera1, E. Merino1, Ma. T. Gil1, L. A. Jimenez1,1. Aranda2 and J. Olivares1
'Nephrology and 2Pathology Services, University General Hospital and Department of Internal Medicine, Alicante, Spain

Key words: hepatitis C virus; lupus nephritis Case reports

Case 1. A 50-year-old woman had a diagnosis of

Introduction systemic lupus erythematosus in 1976 when she pre-
sented polyarthritis, malar erythema, photosensitivity,
A certain prevalence of hepatitis C virus (HCV) anti- Raynaud's phenomenon, alopecia, and positive anti-

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bodies has been found in patients with chronic 'prim- nuclear and double-stranded DNA antibodies. The
ary' glomerulonephritis (GN). However there are patient received antimalarial drugs and aspirin with
scarce and conflicting data describing the prevalence good response. Twelve years later she developed
of anti-HCV antibodies in patients with GN. Although nephrotic syndrome without renal failure or arterial
HCV-associated GN seems to be infrequent in France hypertension. Renal biopsy showed focal proliferative
[ 1 ], Spain [2], and Hong Kong [3], others investigators glomerulonephitis (type III WHO) with active lesions.
have found a high prevalence of anti-HCV antibodies She was treated with prednisone plus azathioprine and
in patients with biopsy-proven GN in Italy [4] and in 6 months later nephrotic range proteinuria decreased
Japan [5]. to 0.5 g/24 h. With these medications she remained
HCV infection is associated with membranopro- well for 5 years. Afterwards she presented a relapse of
liferative type I GN [6-8] and membranous GN [9,10]. nephrotic syndrome with decreased renal function
The pathogenesis of HCV-associated GN is complex (serum creatinine 176.8 umol/1), microscopic haemat-
and unclear. HCV-associated membranoproliferative uria and elevated blood 'pressure. In a second renal
type I GN seems to be related to the deposition of biopsy diffuse proliferative glomerulonephitis (type
circulating immune complexes containing HCV, anti- IV WHO) was diagnosed (Figure 1). Simultaneously
HCV IgG and monoclonal rheumatoid factors; in she had elevation of liver enzymes values (GOT 72
contrast, it is possible that HCV-associated membran- U/L, GPT 94 U/l) and cryoglobulins were not pres-
ous GN could be related to antibodies cross-reacting ent. HCV serum antibodies were detected using the
with glomerular antigens [6,11-16]. However several second-generation HCV enzyme-linked immunoassay
important questions need further investigations: nature (Monolisa, Sanofi Diagnostics PasteurTM) and
of inciting antigens, composition of circulating and recombinant immunoblot assay (RIBA2, Immunoblot
deposited immune complexes, host predisposition and Ortho DiagnosticTM). Viral HCV RNA was detected
HCV genotypes [17]. Although a variety of extrahep-
atic immunologically mediated syndromes were recog-
nized to complicate HCV infection [14,15,17] the
development of systemic lupus erythematosus has not
been described previously in detail, but it is possible
that the deterioration of immune response in lupus
patients can increase the likelihood of HCV infection
[18].
We report two cases with severe lupus nephritis
(LN) and HCV infection with liver damage. Although
this association is probably not cause-effect related, it
offers the opportunity to discuss the evolution and
management of these conditions.

Correspondence and offprint requests to: Dr Francisco Rivera

Departamento de Medicina, Apartado de Correos 374, 03080 Fig. 1. Cellular proliferation with nuclear debris, and markedly
Alicante, Spain. thickened peripheral vascular loops (H & E x400).

O 1996 European Dialysis and Transplant Association-European Renal Association

Hepatitis C virus infection complicating lupus nephritis 1343

in serum by polymerase chain reaction (RT-PCR

RealTM-Durviz). Hepatic biopsy revealed chronic hep-
atitis with minor piecemeal necrosis (Figure 2). She
was treated with prednisone on a dose of 1 mg/kg per
24 h for 8 weeks and afterwards this dose was gradually
reduced; moreover six monthly pulses of intravenous
cyclophosphamide (0.75 g/m2 s.c.) were added. Three
months later there was a complete remission of
nephrotic proteinuria and the renal insufficiency
remained stable. To date, three years on from this
relapse, serum transaminase concentrations are slightly
elevated. HCV antibodies have been persistently
detected and LN is still in complete remission, con-
trolled with low doses of prednisone.
Case 2. A 46-year-old woman was diagnosed as Fig. 3. Diffuse thickening of the glomerular basement membrane,
having systemic lupus erythematosus in 1991 when she and cellular proliferation (H & Ex200).
presented migratory arthralgias, pancytopenia, low
serum complement concentration and positive antinuc-
lear and double-stranded DNA antibodies. Elevated
concentrations of IgM antiphospholipid antibodies

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were also present. At that time there were no signs of
renal damage and blood pressure was normal. She was
treated with hydroxychloroquine and during sub-
sequent follow-ups was asymptomatic. Several months
later she developed hepatomegaly and slightly raised
of liver enzymes. HCV infection was diagnosed with
the same techniques (ELISA, RIBA2 and PCR)
described in Case 1. As an epidemiological antecedent
she had received a blood transfusion 17 years earlier
as treatment of a complicated spontaneous abortion.
She remained well for 2 years. Afterwards proteinuria
(1 g/24 h) and marginally decreased renal function
(serum creatinine 141.4 umol/1) were detected. Blood Fig. 4. Chronic active hepatitis with hepatocellular necrosis and
pressure was normal. Renal biopsy showed diffuse sinusoidal inflammation (H & Ex400).
proliferative glomerulonephritis (Figure 3). Further-
more she developed peripheral oedema, ascites, she received prednisone at a dose of 1 mg/kg per 24 h
increase in the serum concentrations of transaminases for 8 weeks which was later gradually reduced. During
(GOT 64 U/l, GPT 51 U/l), hypergammaglobulinae- subsequent follow-ups proteinuria and renal function
mia, and signs of portal hypertension. HCV antibodies were stabilized but hepatic damage progressed to hep-
were present and PCR were positive. Cryoglobulins atic insufficiency. The patient died 8 months later as a
were not present. Transjugular hepatic biopsy revealed consequence of gastrointestinal bleeding and hepatic
chronic hepatitis with periportal necrosis, intralobular encephalopathy.
degeneration and focal necrosis (Figure 4). Due to LN

Discussion

We report two cases with HCV infection and severe

Fig. 2. Portal inflammation with minor piecemeal necrosis. Hepatic
architecture is preserved (H & E x 200).
LN with liver damage. Although, in our opinion, a
clear causal relationship does not exist between HCV
infection and LN, this association might be not coincid-
ental. Several extrahepatic immunologically mediated
syndromes complicate HCV infection [17], and many
autoantibodies—including antinuclear antibodies—
are frequently shown in chronic HCV-infected patients
[19]. On the other hand, the prevalence of HCV
infection in patients with cryoglobulinaemia is seen in
81-91% [17]. Further, the association of IgA nephro-
pathy and HCV infection and cryoglobulinaemia has
been recently observed [20]. In our patients tests for
cryoglobulins were negative but we have not performed
sequential measurements over time, and we should not
1344
exclude the participation of HCV and cryoglobulins
in LN.
It is possible that the altered immune response of
systemic lupus could facilitate HCV infection. Indeed
in both cases systemic lupus seems to precede the
diagnosis of HCV infection. Garcia-Valdecasas et al.
[18] found an increased prevalence of HCV infection
in patients with chronic nephropathies before the onset
of end-stage renal failure and chronic GN was the
most important epidemiological factor in relation to
HCV infection. In fact, cell mediated immunity plays
an important role in controlling HCV infection and the
percentage of chronicity of HCV infection is higher in
immunosuppressed patients compared with immuno-
competent individuals [21]. Thus, HCV infection could
very well have been the cause of the abnormal liver
function tests in lupus patients because serological
assays and PCR for detection of HCV infection have
been widely available since 1989 and 1992 respectively.
One would expect this association—systemic lupus and
HCV—to be more common, considering the extent of
both situations. It is possible that several cases with
subclinical hepatic manifestations escape diagnosis.
Our dilemma was how to manage LN and HCV
hepatitis at the same time. Treatment of severe LN
with steroids and cyclophosphamide improves the renal
damage and its efficacy is well demonstrated [22]. On
the other hand in patients with chronic VHC infection,
immunosuppressive regimens may be detrimental for
liver disease [23] and induce a rapid increase in circulat-
ing HCV RNA levels [15,24], In renal immuno-
suppressed transplant patients HCV hepatitis could
play a role in the progression of liver disease [25]. The
effect of increased HCV on the underlying liver and
kidney disease remains unknown but it seems that it
could aggravate hepatic damage because viral cytotox-
icity can increase during immunosuppression. Recently
Arend et al. [26] reported a patient with cANCA
vasculitis and chronic HCV infection reactivated by
cyclophosphamide. Finally, it has been stated that
relative short-term courses of a-interferon can be useful
in patients with HCV infection and hepatic and/or
renal damage [27,28], but this therapy should be
avoided in patients with clinically manifest auto-
immune diseases [29]. Indeed, systemic lupus can be
induced by recombinant a-interferon prescribed for
VHC chronic hepatitis [30].
Taking into account the different hepatic damage in
our patients we applied a different approach of treat-
ment that assesses the result of hepatic biopsy [31]. In
case 1 we decided to treat it with steroids and cyclopho-
sphamide in spite of hepatic damage, because renal
damage was severe whereas HCV hepatitis was not
evolved. We prescribed lower doses of cyclophospham-
ide than recommended for severe LN [22] and during
this treatment we watched out for the evolution of
liver enzymes or other signs of hepatic damage. We
did not find any worsening of liver disease, and renal
damage improved dramatically. In case 2 the severity
of the hepatic damage and persistent HCV replication
meant that it was not advisable for it to be treated
M. D. Albero et al.
with immunosuppressive drugs; moreover, the pro-
gnosis in this patient was determined by hepatic
damage more than renal disease and administration of
cyclophosphamide could have deteriorated further the
HCV hepatitis. In fact, the patient died from hepatic
failure without renal complications.
We conclude: (i) rising liver enzyme values in sys-
temic lupus should alert the physician to the possibility
of HCV infection; (ii) those patients with lupus and
HCV hepatitis should be proposed for liver biopsy;
(iii) this particular association modifies the therapeutic
approach to lupus erythematosus with nephritis or
other systemic affectations; and (iv) epidemiological,
clinical and experimental data are needed to clarify the
possible association between HCV infection and sys-
temic lupus erythematosus.
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Received for publication: 30.10.95
Accepted in revised form: 21 2.96