Kidney International, Vol. 66 (2004), pp.
2472–2484
The changing face of schistosomal glomerulopathy
Principal discussant: RASHAD BARSOUM
Cairo Kidney Center and Cairo University, Cairo, Egypt
CASE PRESENTATION
A 47-year-old man from rural Egypt presented 2 years
ago with the complaint of general ill health, weight loss,
and swelling of his legs. His recent illness had started
3 years earlier, when a massive hematemesis originated
from severe antral gastritis with multiple erosions. As-
sessments showed evidence of schistosomal hepatic fi-
brosis, splenomegaly, and portal hypertension. He also
had serologic evidence of hepatitis C viral (HCV) infec-
tion with minimal impact on hepatocellular function. He
received multiple blood transfusions, was treated with
proton pump inhibitors, and was eventually discharged
in fair condition.
A few weeks later, he noticed recurrent swelling of his
legs, for which he received diuretics occasionally. Five
months before presentation, his edema worsened. His
general practitioner detected nephrotic-range protein-
uria and prescribed a small dose of corticosteroids for
1 month. He had another episode of hematemesis, for
which he received several pints of blood. However, he
remained pale and asthenic, had persistent diarrhea, and
The Nephrology Forum is funded in part by grants from Amgen, Incor-
porated; Merck & Co., Incorporated; and Dialysis Clinic, Incorporated.
Key words: schistosomiasis, salmonellosis, HCV, amyloidosis, glomeru-
lonephritis.


C 2004 by the International Society of Nephrology
2472
NEPHROLOGY FORUM
his lower limb edema increased. The physician noted im-
pairment of renal function and referred him to our facility.
The patient’s medical history featured Schistosoma
mansoni infection in 1982, for which he received intra-
venous injections; rheumatoid arthritis in 1990, for which
he was prescribed nonsteroidal anti-inflammatory agents
for a short while; persistent iron-deficiency anemia from
1999 onward; and a dark, interscapular, itchy, macular
skin lesion in 2002 that was identified histologically as
lichen amyloidosis.
On examination, he looked quite ill, strikingly pale, and
puffy. His weight was 68 kg (compared to 85 kg 6 months
earlier). His blood pressure was 210/110 mm Hg and pulse
rate was 120 beats/min. He was afebrile. His neck veins
were not congested; the thyroid gland was not palpable,
and neither were any lymph nodes. There was bilateral
gross soft edema of his lower limbs. The abdominal wall
recti were divaricated, and suprapubic hair distribution
was feminine. The liver was shrunken, firm, and irregu-
lar as felt in the middle line. The spleen was palpable 12
cm below the left costal margin. Moderate ascites was
detected by shifting dullness. No venous hums or perivis-
ceral rubs were detected. No physical abnormalities were
detected in the heart or lungs. There was a short stocking
of symmetrical hypesthesia in both legs, but no other neu-
rologic abnormalities were apparent. His skin was darkly
pigmented in the interscapular region, but he had no rash
and no cutaneous vasculitis. Joint examination revealed
no deformities, swelling, or tenderness.
Urinalysis on admission showed gross proteinuria
on the order of 8 to 9 g/24 hr with a few granular
and waxy casts in the sediment. Serum creatinine was
2.4 mg/dL. There were no abnormalities in serum elec-
trolytes or acid-base balance. The blood hemoglobin
was 8.8 g/dL, with hypochromic (mean corpuscular
hemoglobin, 26.7 g/dL), microcytic (mean corpuscular
volume, 87.5 fL) red cells.
Simultaneously, the reticulocytic count was 1%. The
total leukocytic count was 9200/mm3 with a normal dif-
ferential. Platelet count was 169,000/mm3 . Serum iron
was 32 lg/dL, and ferritin concentration was 515 ng/mL.
Bone marrow was slightly hypocellular, with a modest
normoblastic reaction. There were no abnormalities in
the myelocytic or the megakaryocytic series. Coomb’s test
 Nephrology Forum: Schistosomal glomerulopathy 2473

was negative, and haptoglobin concentration was normal

(194 mg/L).
Serum bilirubin was 1.3 mg/dL; AST, 62 IU/L; ALT,
81 IU/L; GGT, 135 IU/L; ALP, 280 IU/L. Serum to-
tal protein was 5.02 g/dL, 51.8% of which was albumin,
and the globulins showed a modest increase in the a2
and b fractions by electrophoresis. The c globulin region
showed a monoclonal band that subsequent immunoelec-
trophoresis revealed to be composed of IgM (714 mg/dL).
Serum IgG was 193 mg/dL, and IgA 135 mg/dL. Pro-
thrombin concentration was reduced to 70%. A test
for C-reactive protein was positive; C 3 was low normal
(76 mg/dL); C 4 was markedly reduced (2.6 mg/dL), with
a CH50 of 30%; rheumatoid factor (RF) was strongly
positive (titer 1/192); and ANCA, ANA, and anti-DNA
were negative. Cryoglobulin concentrations were 15, 2, 0,
and 18% on 4 occasions. HCV antibodies were detected
by ELISA, and PCR disclosed low viremia (600,000
copies). Antischistosomal antibodies were detected in the
serum by indirect hemagglutination (IHA) in a titer of
1/160.
Abdominal ultrasonographic examination displayed
reduction in the size of the liver, with a distinct hetero-
geneity and thickening of the portal tracts. The spleen was
“moderately” enlarged, and the portal vein was border-
line distended (14 mm wide). The kidneys were slightly
reduced in size (right, 10.1 × 4.3 × 4 cm; left, 11.6 × 4.9 ×
4.3 cm), with increased (grade II) echogenicity and resis-
tivity indices (right, 0.68; left, 0.66). There was moderate
ascites. A chest radiograph was normal. No radiographic
abnormalities were detected in the skull, spine, hands,
Fig. 1. Histopathologic features of the patient presented. Top:
or feet. No erosions were evident in the metacarpal, glomerulus, stained by Masson trichrome, showing amyloid deposits
metatarsal, or phalangeal bones. (A) (confirmed by green birefringence under polarized light of Congo
Rectal snip examination showed a few dead Schis- red stained sections and EM) amidst mesangiocapillary (membranopro-
liferative) GN (P). Note the capillary thrombi (T) and nuclear dust
tosoma mansoni ova. Renal biopsy (Fig. 1) showed a (D). Bottom right: immunoperoxidase stain showing IgM deposits in
mesangiocapillary glomerulonephritis with some nuclear the mesangium and subendothelium. Note the antibody uptake by the
dust, extensive AA-type amyloid deposits (abolished by amyloid material and the capillary thrombi. Bottom left: Amyloid de-
posits in the wall of an arteriole, stained with Congo red, and seen as
potassium permanganate oxidation), and hyaline cap- green birefringence under polarized light.
illary thrombi. Immunofluorescence revealed an abun-
dance of IgM and C 3 subendothelial deposits, along with
faint mesangial IgG. The capillary thrombi stained heav-
ily with IgM and fibrinogen. The arterioles were mod- lar hemodialysis. This goal was achieved by administering
erately sclerosed with amyloid deposits in the media. rofecoxib, 50 mg/day, along with ramipril, 10 mg/day. Pro-
Significant interstitial fibrosis was present. teinuria regressed to 5 g/24 hr; the serum creatinine rose
The patient was hospitalized, received salt-free al- to 3.7 mg/dL (Cockroft estimated clearance, 12 mL/min).
bumin and nutritional support, and his blood pressure Through daily albumin infusions (200 mL 20% salt-free
was controlled by an angiotensin-converting enzyme albumin), total parenteral nutrition, and hemodiafiltra-
(ACE) inhibitor (ramipril, 5 mg/day) and forced diuresis tion (removing ± 4 L of fluid daily), he ultimately lost
(furosemide, 250 mg/day). He also received intravenous 12 kg of his body weight in 2 weeks. He became symptom-
iron saccharate and erythropoietin. He was considered free, and his appetite improved enough for us to stop par-
too ill for interferon treatment, and its cost-benefit was enteral nutrition and to allow liberal calorie and protein
doubtful. However, he continued to lose large amounts intake. His blood pressure was controlled at 130/80 mm
of protein in the urine and stools, and his serum proteins Hg, edema almost disappeared, and he was discharged
remained alarmingly low. It was decided to deliberately 2 months after admission for regular hemodialysis as an
reduce his glomerular filtration rate, and he began regu- outpatient.
2474 Nephrology Forum: Schistosomal glomerulopathy
DISCUSSION
DR. RASHAD BARSOUM (Professor of Medicine, Cairo
University, Cairo Kidney Center, Cairo, Egypt): For many
thousands of years, schistosomiasis has been one of na-
ture’s tools for selection of the fittest. The human, the
snail, and the worm formed an efficient ecosystem that
maintained the parasite’s existence with relatively limited
human morbidity, except for certain genetically predis-
posed individuals, or those who had significant concomi-
tant disease. During the past century, humans decided
to eradicate schistosomiasis, the most effective means
being mass treatment campaigns. Until the mid 1980s,
this was partially achieved by parenteral injection of
antimony-containing preparations. Along with the anti-
mony, however, infected patients also received biologic
contaminants, most important of which, as we know
today, was the hepatitis C virus (HCV). This virus has
changed the present face of schistosomiasis.
Today’s patient reflects the interaction of concomitant
schistosomal and HCV infection at epidemiologic, clin-
icopathologic, and pathogenetic levels, and displays the
difficulties in the management of such cases. The diag-
nosis of rheumatoid arthritis, made in 1990, is very un-
likely to be correct, in view of the absence of any joint
deformities [1] or radiologic erosions [2] after many years
of strong rheumatoid factor (RF) seropositivity [3]. It is
noteworthy that both schistosomiasis [4, 5] and HCV [6]
have been associated with nonspecific RF seropositivity,
acquiring astronomically high levels in the latter [7]. This
has no relation to the musculoskeletal manifestations of
either disease [8].
Rheumatoid-like arthritis can be induced by experi-
mental infection of Swiss albino mice with S. mansoni
[9], and can occur early in the course of schistosomiasis
[10, 11]. In the majority of cases, schistosomal arthritis
affects the large joints—shoulders and hips—but some-
times is associated with small joint involvement as well
[12]. Hepatitis C virus is much more often associated with
symmetrical small joint arthritis, occurring in patients
with chronic active hepatitis, and constituting a true viral
arthritis [13]. Asymmetrical large joint disease can occur
as part of the Meltzer’s triad in patients with cryoglob-
ulinemia [14]. Accordingly, it is likely that the arthritis
encountered during the early stages of this patient’s ill-
ness was indeed a manifestation of schistosomiasis, HCV,
or both, rather than true rheumatoid arthritis.
Epidemiologic interaction
Schistosomiasis is a documented risk factor for the ac-
quisition of HCV infection in many endemic areas, partic-
ularly in Egypt [15]. It is generally accepted that the virus
is transmitted along with intravenous antimony therapy
for schistosomiasis [16], which was the standard treat-
ment until the late 1980s, when mass treatment strategies
moved to oral therapy. The contemporary poor hygienic
standards initially favored both HBV and HCV infec-
tions, yet the former gradually declined with mass vacci-
nation programs.
Preliminary evidence suggests that HCV might be
transmitted along with the helminthic infection itself. In
a recent study, HCV-RNA was detected by in situ hy-
bridization in schistosomal ova deposited in rectal tissue
[abstract; Labib B et al, VIII Cong Arab Soc Nephrol
Renal Transplant I:4–5, 2004]. It is unclear whether this
is attributed to infection of the adult worms residing in
the portal circulation of the infected host, or to random
contamination of the deposited ova with circulating vi-
ral particles. It is also uncertain whether the virus can
survive the subsequent phases of the life cycle, retaining
infectivity in subsequent generations.
These unfortunate patients constitute a large reser-
voir for the spread of HCV infection by different routes,
even to those without previous exposure to schistosomi-
asis. Living in Egypt, per se, thus has become a signif-
icant risk factor for acquisition of HCV infection [17];
the overall prevalence is around 20%, compared to 1%
to 2% in most other countries [18]. Consequently, the
prevalence of end-stage liver disease has dramatically in-
creased, and the incidence of hepatocellular carcinoma
also has risen strikingly over the past decade. Likewise,
the renal complications of schistosomiasis became con-
siderably confounded by the impact of HCV infection, as
demonstrated in today’s patient.
Clinicopathologic interaction
In addition to the typical confounding effect of HCV
infection on schistosomal liver disease, and the potential
role of either or both infections in the pathogenesis of
arthritis, anemia, and serologic abnormalities, the most
striking interaction in this patient was displayed in the
renal lesions. Although both infections induce glomerular
lesions, what was seen in our patient does not conform
to either alone, nor does it fit with superimposition of
independent lesions.
Schistosoma-associated glomerular disease. “Pure”
schistosomal glomerulopathy (SG) is a distinct disease
entity, the identity of which is based on experimental [19],
epidemiologic [20], post-mortem [21], and clinical [22] ev-
idence. In humans, it presents with a broad spectrum of
clinical manifestations extending from an asymptomatic
microalbuminuria to end-stage renal disease. This range
has led to a clinicopathologic classification known as
“AFRAN,” for the African Association of Nephrology,
which endorsed it in 1992 [22]. Accordingly, 5 classes
of schistosomal glomerulopathy are recognized (Fig. 2).
Switching from one class to another can occur as a result
of superimposed infections [23] or progression of associ-
ated hepatic pathology [24].
 Nephrology Forum: Schistosomal glomerulopathy
Fig. 2. Schistosomal glomerulopathy. Class I, H&E stain (A). Class II,
H&E stain (B). Class III, H&E stain (C). Class III, IgA deposits by
immunofluorescence (D). Class IV, Masson trichrome stain (E). Class
V, Congo red stain under polarized light (F).
Class I is histologically defined as axial mesangial pro-
liferative glomerulonephritis, and is associated with de-
position of immune complexes containing schistosomal
antigens, IgM, and C 3 [25]. It is a fairly benign condi-
tion, analogous to that seen in many other microbial and
helminthic infections. It is associated with infection by
any of the human-pathogenic schistosomal species and is
the typical lesion seen in experimental infection of small
laboratory animals [21]. The clinical presentation is usu-
ally limited to sub-nephrotic proteinuria, although frank
nephrotic syndrome occurs in as many as 15% of patients
[22]. Under certain epidemiologic conditions, the acute
nephritic syndrome is encountered [20], but this seems
to require a heavy infection with specific strains. Class
I schistosomal nephropathy is self-limited and tends to
abate spontaneously in the majority of patients; hence the
difficulty in evaluating the effect of treatment with anti-
helminthic drugs, corticosteroids, or immunosuppressive
agents.
Class II is defined as an exudative glomerulonephritis,
with many neutrophils, monocytes, and eosinophils in-
vading the mesangium [23]. Subendothelial and mesan-
gial C 3 deposits are characteristic of this class, often
associated with IgG and IgM. It occurs with concomi-
tant infection by either Schistosoma hematobium or
S. mansoni, and salmonella species, usually Salmonella
paratyphi A [23]. Dual infection is well documented
in the Egyptian medical literature [26]. Schistosomal
salmonella infection, also observed in Brazil, induces a
similar glomerular lesion [27]. Dual infection is not a sim-
ple coincidence; the bacteria live in symbiosis within the
parasite’s integument, taking advantage of the protective
layer of the host’s native proteins, which schistosomes use
for evading the host’s immune surveillance. The clinical
2475
presentation in such cases is dominated by a febrile ill-
ness, toxic manifestations of salmonella infection, and a
rapidly developing nephrotic syndrome [28]. Complete
recovery occurs with combined antihelminthic and an-
tibacterial treatment.
Classes III and IV constitute the majority of pa-
tients with progressive disease. Both are encountered
mostly with S. mansoni infection, feature significant hep-
atic pathology [21, 24, 28], and are often associated
with abnormalities in serum IgA components [29], as
well as glomerular and peritubular IgA deposits [24].
Class III is a mesangiocapillary glomerulonephritis, often
occurring in non-black populations; Class IV is a focal-
segmental proliferative/sclerosing lesion, seen preferen-
tially in blacks [30]. In both classes, there is considerable
impairment of the hepatic macrophage function [24] due
to fibrosis and/or portosystemic shunting. This leads to
margination of the liver as a sieve for schistosomal egg
antigens drained from the gut mucosa [29], adult worm
gut antigens released into the portal blood, and mucosal
IgA produced within the context of local inflammation.
Glomerular lesions are associated with the mesangial and
subendothelial deposition of schistosomal immune com-
plexes and IgA, the latter being associated with progres-
sion in 70% of cases as compared to 29% in those with
non-progressive disease [24]. Mesangial cell prolifera-
tion and matrix expansion are typical light microscopic
findings in the majority of cases. Subepithelial deposits
also occur in less than 10% of cases, and lead to type III
mesangiocapillary glomerulonephritis (MCGN). It is not
clear why black patients tend to develop focal segmental
glomerulosclerosis (FSGS), but this seems to be a racial
characteristic regardless of the cause of renal injury. The
susceptibility to FSGS is probably attributed to the low
nephron number associated with low birth weight and
consequent glomerular hyperfiltration [31].
Classes III and IV present with proteinuria, usually
within the nephrotic range [22], although subnephrotic
proteinuria occurs in 10% to 20% of patients. Hyperten-
sion occurs in about one-half of the cases, and progressive
renal insufficiency is the rule in those who survive cir-
rhosis, hematemesis, and hepatocellular carcinoma. The
disease cannot be modified by any current treatment,
including antihelminthic drugs, corticosteroids, and im-
munosuppressive agents [32].
Class V is the renal component of a generalized re-
sponse to chronic inflammation, namely systemic amy-
loidosis [27]. Amyloidosis occurs with prolonged active
infection with either S. hematobium or S. mansoni in hu-
mans, as it does in several animal models [33]. Like other
inflammation-associated amyloids, AA beta-pleated fib-
rils are deposited preferentially in the kidney, liver, subcu-
taneous fat, and gums. Glomerular amyloid deposits are
usually seen near the vascular poles, and often involve the
arterial walls. In some cases, where immune complexes
2476 Nephrology Forum: Schistosomal glomerulopathy
are also deposited, mesangial proliferation can be seen
concomitantly with amyloidosis [28]. The clinical presen-
tation is similar to that of renal amyloidosis in general,
with proteinuria and progressive renal insufficiency. Hy-
pertension is unusual. The kidneys are shrunken in 25%
of patients, in whom there is associated schistosomal in-
terstitial fibrosis. No evidence indicates that the course
of schistosoma-associated amyloidosis can be modified
by any form of treatment [33].
HCV-associated renal disease. The frequency of HCV-
associated nephropathy varies in different geographic
locations. The incidence in Egypt is unknown, as no sys-
tematic epidemiologic studies have addressed this issue.
A recent study demonstrated evidence of HCV infection
in 38% of patients with mesangiocapillary glomeru-
lonephritis, compared to 19% in healthy blood donors
[34]. About one-seventh of patients with HCV disease
develop either type II or type III secondary cryoglobu-
linemia [35], thereby constituting the main bulk of HCV
nephropathy.
The most common glomerular lesion is mesangiocapil-
lary type I (MCGN-I), with mesangial and subendothelial
immune complex deposition, hypercellularity, and matrix
expansion with subendothelial interposition. HCV-RNA
is present in the glomerular deposits [36], and virus-like
particles can be detected by electron microscopy [37].
IgG and/or IgM are encountered in the glomerular de-
posits, depending on the presence and nature of circu-
lating cryoglobulins. Despite the associated liver disease,
IgA deposits are unusual. Complement deposits are often
seen, particularly in the presence of cryoglobulinemia.
MCGN-I is also the typical lesion seen in recurrence of
HCV nephropathy in renal allografts. It is also the most
common form of de novo glomerulonephritis developing
in HCV-infected recipients [38].
Other forms of glomerulonephritis associated with
HCV [39] include membranous glomerulonephritis,
particularly as a de novo disease in transplanted
kidneys; FSGS, which is often of the collapsing vari-
ety; and, very rarely, immunotactoid glomerulonephri-
tis [40]. Patients who develop a lymphoma as a compli-
cation of HCV disease [41] can develop AL-type renal
amyloidosis.
HCV cryoglobulins activate complement via the clas-
sic [42] and/or the lectin [43] pathways, the latter being
attributed to the carbohydrate motif in the vicinity of the
heavy-chain regions of individual immunoglobulin com-
ponents. This leads to very low C 4 levels, often approach-
ing zero. C 3 also can be consumed in the process, but its
blood level is often modestly depressed.
HCV cryoglobulinemia typically is associated with the
Meltzer triad, comprising purpura, arthralgia, and myal-
gia. The skin lesion is a leukocytoclastic vasculitis, which
also can be seen in other tissues and organs, particularly
the kidneys. It is associated with all the glomerular le-
sions described, although more often with MCGN-I. The
arterioles exhibit extensive intimal proliferation and me-
dial round cell infiltration, and their lumena can be filled
with hyaline thrombi. Fibrinoid necrosis of the glomeruli
often occurs. Crescents can develop in severe cases when
the glomerular capillaries are damaged. C 3 and fibrin are
seen in all these lesions, and IgM is typically found in
Brouet type II cases. Large casts, also staining for IgM,
are often seen within the dilated renal tubules, which
show ischemic changes as a consequence of upstream
pathology.
Glomerular lesions in concomitant schistosomal HCV
infection. Today’s patient displays a glomerular pathol-
ogy that does not fit with either infection alone. It would
not fit with any of the schistosomal classes as described,
in view of the presence of hyaline thrombi and depo-
sition of the “wrong” immunoglobulin, that is, IgM. It
would not fit with HCV glomerulopathy either, in view
of the extensive AA-type amyloid deposition. The con-
comitant helminthic and viral infection likely has pro-
voked a unique immune response that modified the
glomerular pathology, much as salmonella does in class II
pathology.
Pathogenetic interaction
Schistosomes and HCV primarily target the splanchnic
compartment of the immune system. S. mansoni ova are
deposited in the intestinal walls and the hepatic peripor-
tal tracts, where they provoke a relentless inflammatory
process following the usual rules of antigen presentation,
chemokine and cytokine secretion, and proliferation of
committed lymphocyte clones (Fig. 3). In the meantime,
adult worms live in the portal tracts for many years, even
decades, pouring their gut juices into the bloodstream,
which carries these fluids to the hepatic sinusoids. They
are taken up by the von Kupffer cells, which initiate a
similar cascade of reactions. The key player in both sites
is the macrophage, which acts as a phagocytic as well as
an antigen-presenting cell.
Throughout their life cycle in a human, a pair of worms
produces well over 100 known antigenic molecules. These
are categorized, according to their origin, into those pro-
duced by the ova, and those present in the cercarial,
schistosomular, and adult worm integument, tissues, and
gut secretions. Most of these antigens have been char-
acterized, encoded, sequenced, and prepared by recom-
binant techniques (reviewed in [44]). The infected host
is initially exposed to the integument antigens, a com-
plex set of proteins and glycoproteins that have a lim-
ited role in the pathogenesis of host morbidity, despite
being of crucial importance in immunity to infection
and reinfection, and consequently in the development
of anti-schistosomal vaccines [45]. Eggs deposited in the
host tissue release several antigens that diffuse through
 Nephrology Forum: Schistosomal glomerulopathy 2477

LPS
LPS MIF
TLR4 Direct killing

Ag Ag
Salmonella Pituitary Sm-PEPCK
CD40
Hepatocyte IL-12,18 Uptake -
IFG IL-6 IL-10
HCV Ag
AA
NKC Th0
IL-1 IL-4
Apoptosis TGF
Somatostatin CXC

IL-2
CD8 Th1 Th2
+ CDCC
N
IL-6 IL-13
AGR IL-4 ECF-p
CD81
CD40L ECF
+
IL-10 E ADCC
B B
Ig

LPS
Immune
Complexes
MBP C1q PB

Cryoglobulins
Complement C5a
Chemotaxis

Fig. 3. Immune mechanisms involved in schistosomal glomerulopathy. Oval and worm antigens (top right) are taken by the macrophage, which
can directly kill the younger stages of the parasite. Innate immune mechanisms are shown in dashed lines, involving natural killer cells (NKC),
alternative complement protein activation (PB), leading to chemotaxis of neutrophils (N), eosinophils (E), basophils (B), and generation of amyloid
(AA) protein. Specific immune mechanisms are shown in continuous lines, involving the commitment of naive (T 0 ) lymphocytes to become T-helper
1 (TH 1 ) cells, which interact with B-lymphocytes (B) and killer (CD8) cells. B-lymphocytes produce antibodies (Ig), which form immune complexes
that activate the complement system via the classic pathway (C1q). Along with chronicity of infection, the macrophages switch under the influence
of parasitic and host factors into the alternative mode, as shown by dotted arrows. TH 2 cells and cytokines preferentially supervene, particularly
IL-10, which favors IgA switching and suppresses the macrophages. In concomitant salmonella infections, endotoxin (LPS) leads to the release of
macrophage inhibitory factor (MIF), which up-regulates the toll-like receptors (TLR4) on the APCs, thereby sensitizing them to LPS. The latter
also activates PB and the lectin (MBP) pathways of complement. Concomitant HCV (dark solid lines) activates the APC and directly invades the
B lymphocytes via the CD81 receptor. This generates a clone of IgM-bearing lymphocytes that produce cryoglobulins, which activate complement
via C1q as well as MBP.

micropores in the eggshell into the surrounding tissue
fluids. The most immunogenic are a peptide called Sm-
p40, which induces a predominantly Th 1 response, and 2
more recently identified antigens, S. mansoni phospho-
enolpyruvate carboxykinase (Sm-PEPCK) and thiore-
doxin peroxidase-1 (Sm-TPx-1), which induce a balanced
Th 1 /Th 2 response. Egg antigens are mainly involved in
the pathogenesis of local granulomata and might be
carcinogenic.
Adult worm tissue antigens present in the parasite’s mi-
crosomes and smooth muscles are species-specific, hence
their importance in epidemiologic research. Although
they are markers of active infection, they are of limited
pathogenetic importance because they are hidden from
the host’s immune surveillance by a layer of host proteins
that impregnate the worm’s surface. The principal host
proteins identified in this context are immunoglobulins
and MHC and ABO antigens. Gut-associated antigens,
released by regurgitation of the worm’s digestive juices,
constitute the main component of circulating schistoso-
mal antigens in vivo. Of about 6 such antigens identified
in vitro, at least 2 are involved in the pathogenesis of
2478 Nephrology Forum: Schistosomal glomerulopathy
immune complex–mediated lesions [46]. These are a pro-
teoglycan that migrates to the anode in an electrical field,
hence the name “circulating anodic antigen (CAA),” and
a glycoprotein that migrates to the cathode, “circulating
cathodal antigen (CCA).”
Macrophages are charged with the tasks of recogni-
tion of these different antigens and appropriately trigger-
ing the immune response. The dendritic cells of the skin
identify the cercarial integument antigens and respond by
directly killing the parasite by phagocytosis or by release
of reactive oxygen species (ROS) or lysozymes. A similar
reaction occurs when macrophages in different tissues are
exposed to schistosomulae as they migrate in the blood-
stream through the lungs, liver, spleen, and other tissues.
This innate host response is responsible for killing more
than 90% of the parasitic load.
Other innate mechanisms involved in this process in-
clude activation of the natural killer cells, which produce
cytokines (for example, interferon-c) that up-regulate the
antigen-presenting cells (APCs), and complement activa-
tion (via the “alternative pathway”), which is important
for chemotaxis and subsequent complement-dependent
cytotoxicity. Specific immune response to the invading
parasitic strain is also controlled by the macrophage,
which expresses the relevant antigens along with class II
MHC antigens, thereby initiating a classic TH1 response
(Fig. 3). This is essentially an inflammatory reaction, char-
acterized by cellular recruitment and activation, which
involves almost all types of leukocytes. The ultimate tar-
get is to recruit and up-regulate enough eosinophils that
have sufficient artillery to damage eggshells, parasite in-
tegument, and the like. The main weapons the eosinophil
uses in this battle are the eosinophil basic protein and
ROS. The eosinophil-parasite interaction requires IgE in
a process called antibody-dependent cell-mediated cyto-
toxicity (ADCC). This florid cellular response to schis-
tosomiasis occurs around tissue-deposited ova or worms
in the form of granulomata, as well as in the vicinity of
deposited immune complexes in the renal glomeruli in
class I and II lesions.
As with many other helminthic infections, persistence
of antigenic stimulation is followed by a phenotypic
change in the APCs, with a parallel switch of their
cytokine profile to a TH 2 mode. Studies in schistosomi-
asis have attributed this change to variations in the par-
asitic antigens (for example, “late egg antigens”) [47],
the synthesis of modulatory humoral polypeptides with
somatostatin-like activity [48], excessive formation of
TGF-b by the host’s cells [49], and possibly other me-
diators. The result of this “alternative APC activation”
is the release of “late cytokines” as IL-4, IL-10, and IL-
13, which modulate the inflammatory response. The same
cytokines also lead to switching of the B-lymphocyte C
gene, thereby favoring IgA production at the expense of
the typical parasite-associated IgM [50]. This switching
explains the predominance of IgA-bearing lymphocytes
[51] and the progression of glomerular lesions in classes
III and IV. In addition, late cytokines might be respon-
sible for impairment of the macrophage’s AA protein
scavenger function, thereby favoring the development of
amyloidosis, as in class V schistosomal glomerulopathy
[28].
This scenario can be critically modified by a con-
comitant infection. The clinical impact of superimposed
salmonellosis has been established since the early 1970s
[23], although the precise pathogenetic mechanisms in-
volved have been understood only recently. It is now
known that salmonella endotoxin is attracted to lig-
ands in the brain, mostly in the pituitary region, thereby
provoking the release of macrophage inhibitory factor
(MIF) [52]. This up-regulates a macrophage receptor
known as the toll-like receptor-4 (TLR-4), which is sensi-
tive to ultra-small amounts of circulating endotoxin [53].
Increased activation of the APCs leads to a florid inflam-
matory response that is clinically expressed in the con-
stitutional manifestations and the exudative glomerular
lesions of class II schistosomal glomerulopathy. “Prim-
ing” of the glomeruli by the immune response to schisto-
somiasis seems crucial; the glomerular lesions in typhoid
fever in otherwise normal individuals are much less florid,
and their clinical expression usually is mild or even sub-
clinical [54].
The impact of HCV is different. Although the pre-
cise immunologic events of the combination of HCV
and schistosomiasis have not been studied, it is possi-
ble to speculate on them on the basis of available data
on each infection separately. HCV has the potential to
intercept the schistosomal scenario at 3 levels: hepato-
cytes, macrophages, and lymphocytes. Hepatocellular in-
jury is associated with the release of many acute-phase
reactants, particularly when provoked by IL-1 and IL-6.
Relevant to the current scenario is the potential of in-
creased AA protein release as an important chemoattrac-
tant. Hepatic macrophages, already depressed in chronic
schistosomal infection and set to the “alternative activa-
tion mode” with a predominantly TH 2 cytokine profile,
now face a new antigenic challenge imposed by the viral
proteins and products of hepatocellular injury. The latter
would restore the depressed “classic activation mode”
and promote a new TH1 clone largely through the local
production of interferons [55].
The same APC should be able to express both schis-
tosomal and HCV antigens simultaneously. Its response
would quantitatively and qualitatively depend on the
relative concentrations of antigens, as well as the super-
vening cytokine profile in its micro-environment. The
subsequent steps in the immune response in general,
and their reflection on the glomerular lesions, would
exhibit considerable variability between individuals, as
well as in different phases of disease evolution within
 Nephrology Forum: Schistosomal glomerulopathy
the same individual. One striking option is the devel-
opment of amyloidosis, where the “classic” APC acti-
vation, privileged by viral interferon, favors the forma-
tion of AA protein by the hepatocytes as well as the
macrophages, while the modulatory cytokine-rich micro-
environment generated by schistosomiasis would inhibit
its uptake. This kind of “commitment” or “exhaustion” of
the macrophages is typically blamed in the pathogenesis
of amyloidosis in horses used for the production of anti-
sera, as well as that associated with chronic bacterial and
parasitic infections in humans [28]. The effect of brain
TH 2 cytokines in this context has been clearly demon-
strated in several recent studies on Alzheimer’s disease
[56].
Lymphocytes constitute a third target for HCV infec-
tion in schistosomiasis. The virus invades the lymphocytes
in its vicinity, presumably those in the hepatic periportal
tracts, through its affinity to CD81 receptors [57]. Infected
B-lymphocyte clones respond by proliferation and secre-
tion of their most “primitive” immunoglobulin, IgM, in a
nonspecific and uncontrolled fashion. This often acquires
an extremely high rheumatoid activity factor, which par-
ticipates in the formation of cryoglobulins when com-
bined with viral proteins and complement [58]. Patients
with combined schistosomal and HCV infection, there-
fore, would have at least 2 active and proliferating B-
lymphocyte clones, surface-marked by IgA and IgM, re-
spectively. Again, the relative predominance of these 2
clones depends on the intensity and phase of evolution
of either infection, as well as potential host factors deter-
mining the immune response in general.
The renal lesion in today’s patient neatly reflects these
events, particularly the association of mesangial prolifer-
ation, apoptotic transit cellular infiltrations, amyloidosis,
and cryoglobulin deposition. While the relative pre-
dominance of these different pathologic components is
expected to vary from one patient to another, their as-
sembly within the same glomerulus as a consequence of
a unique immunologic response to a combined helminthic
and viral infection justifies their categorization as a new
class, for which I propose the name class VI schistosomal
glomerulopathy.
QUESTIONS AND ANSWERS
DR. JOHN T. HARRINGTON (Dean Emeritus, Tufts Uni-
versity School of Medicine, Boston, Massachusetts): How
did the parenteral antimony preparation become contam-
inated with hepatitis C virus? Was there a contemporary
large viral reservoir?
DR. BARSOUM: I do not think anybody knows how it
started. The virus was discovered in the late 1980s, when
it had already been widely spread. But it is noteworthy
that it took only a single infected patient to transmit the
2479
disease to a whole group lining up for treatment, through
the then-prevailing highly unhygienic procedure of in-
travenous administration. At that time, one or two glass
or metal syringes and a few needles were used for tens
of patients. Each syringe was rinsed in boiling water be-
tween one patient and the other for “sterilization.” And
every patient was supposed to return for 10 or more visits
to complete the course of antimony treatment. One can
imagine how a critical viral reservoir can be generated in
any community under those circumstances.
DR. HARRINGTON: Are you aware of any other com-
bined viral/helminthic infections?
DR. BARSOUM: A couple of decades ago, hepatitis B
virus was the most common infection associated with
schistosomiasis; both were transmitted by intravenous in-
jections. Hepatitis B confounded the hepatic pathology,
and it was blamed for a lot of ANCA-negative vasculitis
among Egyptian patients. Yet the incidence of HBV in-
fection has remarkably regressed since mass vaccination
programs were adopted.
Hepatitis B virus remains the most common cause
of membranous nephropathy in black African children,
but the relation of this pathology to concomitant schis-
tosomiasis is unclear in the published reports. Other
viral infections associated with schistosomiasis include
the human papilloma virus in 25% of Egyptian patients
who develop bilharzial bladder cancer [59], and Epstein-
Barr virus in Brazilian patients with Burkitt’s lymphoma
[60].
DR. C. M. MATHEW (Al Qassimi Hospital, Sharjah,
United Arab Emirates): My question concerns the asso-
ciation of HCV and schistosoma. It is difficult for me to
believe that this relationship is entirely due to parenteral
therapy. We do not see this association in other chronic
diseases requiring parenteral therapy, like rheumatic
heart disease—patients receive penicillin monthly for
years in a similar geographic distribution. Are there any
animal models showing the transmission of HCV from
infected schistosomal ova?
DR. BARSOUM: Your point is very well taken. But
please consider the route and frequency of drug adminis-
tration. The chances of contaminating glass syringes are
much higher when they are used for intravenous rather
than for intramuscular or subcutaneous injections. Rel-
evant to your question is a study, published in Egypt in
the 1990s, which compared the incidence of HCV infec-
tion in 4 groups of adolescents receiving multiple injec-
tions for different chronic diseases [61]. The infection rate
among those who had received intravenous therapy for
schistosomiasis was about 40%, close to that seen in tha-
lassemic patients exposed to multiple transfusions. Juve-
nile diabetics treated by insulin at home exhibited less
than one-half this frequency. None of the patients receiv-
ing monthly penicillin in hospitals or district health units
had evidence of HCV infection.
2480 Nephrology Forum: Schistosomal glomerulopathy
I alluded in my presentation to the possibility of vi-
ral transmission along with the initial acquisition of the
helminthic infection itself, on the basis of demonstrating
viral RNA in tissue-deposited ova. But there is no clini-
cal or experimental evidence as yet that the virus remains
viable and infectious all the way through the subsequent
stages of the life cycle.
DR. ABEL MEGUID EL NAHAS (Professor of Renal
Medicine, Sheffield Kidney Institute, Sheffield, United
Kingdom): You showed us an association between
salmonella and schistosoma infections leading to an ex-
udative (class II) schistosoma nephropathy. You put for-
ward a new class VI of schistosomal nephropathy when
the patient is co-infected with HCV. Isn’t it more likely
that MCGN (class III) is the nephropathy strongly influ-
enced by HCV? At the time of your definition of the schis-
tosomal nephropathy classes, we were not fully aware of
the high prevalence of HCV infection in Egypt and its
association with MCGN.
DR. BARSOUM: This is unlikely in view of the different
clinicopathologic profiles. Unlike co-infection with HCV,
typical class III schistosomal nephropathy does not ex-
hibit any cutaneous vasculitis, hepatocellular functions
are not significantly affected, serum complement levels
are not depressed, the renal lesions do not show any mani-
festations of cryoglobulinemia, and IgA, rather than IgM,
deposits are seen in most patients. It is true that HCV
can cause class III-type lesions in the absence of cryo-
globulinemia, but that is quite unusual, and there is no
reason why such an exception would prevail in patients
with hepatosplenic schistosomiasis. We have shown that
patients with non-schistosomal chronic hepatitis cluster
quite differently from class III patients regarding pro-
teinuria associated with the same degree of macrophage
dysfunction, the pattern of glomerular immune-complex
deposits, and relevant serologic abnormalities.
DR. OMAR ABBOUD (Consultant Nephrologist,
Hamad Medical Corporation, Qatar): Does the pres-
ence of HCV in the schistosomal worm and ova shield
HCV from treatment in a similar way to the insulation
salmonella (typhoid) enjoys when it infects the schis-
tosomal worm? Following on this: if we control the 2
infections—the schistosomiasis and HCV—can we use
immunosuppressive agents to control the immunologic
manifestations, as in cryoglobulinemia and hepatitis C
virus?
DR. BARSOUM: I am not sure. In class II, the bug is
trapped within the schistosomal integument. So killing
the worm exposes the bacteria. This is not the case with
HCV, which does not seem to biologically interact with
the worm. Even if it turns out that the virus actually in-
fects the worm, the viral load still exists in the hepatocytes
and lymphocytes, and this would not be affected by erad-
ication of the parasite.
As to your follow-up question, I have not seen any
problems while immunosuppressing patients with HCV
for severe cryoglobulinemic vasculitis. I usually combine
immunosuppressive therapy with ribavirin as a tempo-
rary measure until the patient’s condition permits the ad-
dition of interferon. Schistosomicidal treatment does not
help in this context.
DR. JORGE CANNATA-ANDIA (Professor of Medicine,
Hospital Central de Asturias, Oviedo, Spain): Could you
please further comment about the medium- and long-
term evolution of the joint involvement, and also whether
a relationship exists between this evolution and the dif-
ferent classes (I to VI) that you described?
DR. BARSOUM: Arthritis can occur in classes I, II,
and the proposed class VI schistosomal glomerulopathy.
Class I lesions can occur early enough to coincide with
true schistosomal arthritis, which tends to recover spon-
taneously without any long-term sequelae. In class II,
the concomitant salmonella infection can be responsible
for reactive polyarthritis (Reiter’s syndrome) or spondy-
larthritis. Both patterns are self-limited, although they
can follow a protracted course even after control of the in-
fection. Arthritis in class VI is attributed to its HCV com-
ponent. Most of the musculoskeletal manifestations of
this infection are extra-articular; true synovitis occurs in a
minority of cases. The latter is usually transient, although
it can be progressive and deforming. In such cases, HCV
synovitis can be confused with classic rheumatoid disease,
particularly in view of the associated serum rheumatoid
factor reactivity. Distinction can be made by the pres-
ence of other HCV extrahepatic manifestations, partic-
ularly in the skin, the absence of subcutaneous nodules,
and negative serology for antikeratin antibodies and IgA-
rheumatoid factor.
DR. ASSEM EL SHERIF (Professor of Nephrology, King
Khaled University, Kingdom of Saudi Arabia): My ques-
tion relates to the quality of evidence; we need to make
the distinction between what is evidence and what is
speculation. What are the minimal criteria for diagnos-
ing schistosomal nephropathy?
DR. BARSOUM: You are quite right. As you know, the
identity of schistosomal glomerulopathy as a distinct syn-
drome is based on hard experimental and epidemiologic
evidence. Yet at an individual patient level, the diagno-
sis is largely based on circumstantial evidence. A patient
with documented schistosomal hepatic fibrosis who de-
velops glomerular disease is a potential candidate for the
diagnosis if the histologic and immunofluorescence find-
ings are compatible. The pathognomonic criterion, which
is detection of schistosomal antigens in the glomeru-
lar deposits, is only possible in class I patients who are
rarely subjected to renal biopsy. Unfortunately, this ev-
idence cannot be obtained in any of the other classes
owing to the intervention of other pathogenetic factors.
 Nephrology Forum: Schistosomal glomerulopathy
Schistosomal glomerulopathy is not unique in this re-
spect; it is the collateral evidence associated with compat-
ible glomerular lesions that makes the diagnosis of lupus
glomerulonephritis, post-infectious glomerulonephritis,
and many other glomerulopathies.
DR. EL SHERIF: What is peculiar to the kidney that fa-
cilitates the development of amyloid tissue? We don’t of-
ten see amyloid deposits in other organs, such as the liver,
spleen, and intestine, in association with schistosoma.
DR. BARSOUM: I concur with your comment, and I
presume that hemodynamic, immunologic, and metabolic
factors explain this peculiarity. We know that AA protein
is a local chemoattractant produced by macrophages in
the schistosomal granulomata, as well as an acute-phase
reactant nonspecifically released from the hepatocytes in
many long-standing inflammatory diseases, such as schis-
tosomiasis. Regardless of the site of synthesis, excess AA
protein spills over into the circulation as soluble AA.
It is likely that the latter circulates through the mesan-
gial matrix within the context of macromolecular traf-
ficking, while the mesangial cells are unable to clear it,
being committed in the immune response to schistoso-
mal antigens. Subsequently, AA protein would integrate
with proteoglycans as decorin and biglycan, which are
known constituents of the amyloid fibrils [62].
DR. MOHAMED HELMY ABOU ZEID (Professor of
Medicine, Kasr El Aini, Cairo University, Cairo, Egypt):
The full-blown clinical picture in this patient can be
explained by HCV alone, and schistosoma could have
no role in the pathogenesis of the disease. What is your
opinion?
DR. BARSOUM: The main reason why the glomerular
lesions in this patient cannot be exclusively attributed to
HCV is the presence of AA amyloid deposits. HCV is
not associated with AA amyloid. The only association
that I am aware of is the occurrence of AL amyloidosis in
mice, when such infection is complicated by a malignant
lymphoma [63].
DR. ZEID: As you know, the histopathologic renal le-
sion depends on the size and charge of the antigen, and
you mentioned many kinds of antigens produced by schis-
tosoma. Is there any correlation between the kind of anti-
gen and each of the histologic types you mentioned?
DR. BARSOUM: This is an interesting hypothesis that
has not been addressed in patients or animal models.
While there is evidence that host factors are very im-
portant in defining the glomerular lesions, agent factors
might play a significant role, particularly in experimental
models, where the spectrum of deposited antigens seems
to exceed that in humans [19].
DR. G. H. MALIK (Security Forces Hospital, Riyadh,
KSA): Class II glomerulonephropathy associated with
schistosomiasis was mentioned as being precipitated
by salmonella. However, Salmonella typhi also causes
2481
glomerulonephritis (even without schistosoma), which is
attributed to immune-complex injury. How can we differ-
entiate the two?
DR. BARSOUM: Although glomerular involvement oc-
curs in about 50% of cases of typhoid fever, the only
clinical findings in the majority of patients are transient
proteinuria and microhematuria. Clinically overt disease
occurs in about 5% of patients, usually in the form of an
acute nephritic syndrome. Nephrotic-range proteinuria,
like that in class II, is extremely rare and generally lim-
ited to an occasional case report [64]. So it seems that the
integrated immunologic insult caused by schistosomes
and salmonella, as I described earlier in my presentation,
is crucial for the development of significant glomerular
injury.
DR. PETER MATHESON (Professor of Renal Medicine,
University of Bristol, United Kingdom): Your patient was
treated for schistosomiasis more than 20 years before he
developed severe renal failure. Could he have been re-
infected, and would there have been any value in retreat-
ing him, or are the eggs as much trouble “dead” as they
are “alive?”
DR. BARSOUM: Dead ova can be detected with active
as well as inactive infection, whereas live eggs indicate the
contemporary presence of fertile female worms. Trapped
ova that fail to reach fresh water within a few days must
die, but they can remain in the tissues for many months
or years after eradication of the infection. What further
complicates matters is that a pair of worms can live and
reproduce for many years; 20 years is not a terrible ex-
ception. So it is difficult to say whether this patient was
re-infected.
Treatment is indicated whenever live eggs are detected.
But when they are dead, serologic tests can help in mak-
ing the decision. It would not do any harm to treat such
patients with a safe drug like praziquantel, although treat-
ment at this point, even in the presence of an active in-
fection, would not modify the renal pathology.
DR. MOHAMED BEN HAMIDA (Professor of Nephrol-
ogy, Hedi Chaken University Hospital, Sfan, Tunisia):
What is the mechanism of the persistent overt and
sometimes life-threatening proteinuria in patients with
amyloidosis, despite end-stage renal disease and low
GFR?
DR. BARSOUM: Persistence of proteinuria in advanced
chronic kidney disease often reflects maintained perfu-
sion of the pathologic glomeruli, which are prevented
from shrinkage by stable deposits. This typically occurs
in amyloidosis, as well as in diabetes, nodular glomeru-
lopathy, and some cases of mesangiocapillary glomeru-
lonephritis.
DR. BEN HAMIDA: Why is renal involvement so rare in
other North African endemic parasitic diseases, namely,
hydatid disease?
2482 Nephrology Forum: Schistosomal glomerulopathy
DR. BARSOUM: I am not sure whether parasitic renal
disease is rare or is under-reported in that region. Sev-
eral papers have described small numbers of patients with
echinococcal, leishmanial, schistosomal, and other para-
sitic nephropathies. I do not know of any epidemiologic
studies that describe the prevalence of these conditions
in North Africa.
DR. M. SHERIF EL HAMMADY (Medical Military
Academy, Egypt): Do you think that this novel class-VI
type of schistosomal glomerulopathy would describe a
mix of schistosomal nephropathy and HCV nephropa-
thy, or of schistosomal nephropathy and cryoglobuline-
mic nephropathy, whatever its cause? If the cause of
cryoglobulinemia was Epstein-Barr virus, for example,
or even the essential type, would that produce the same
described type?
DR. BARSOUM: This kind of lesion seems to require
dual activation of the APCs and direct B-lymphocyte ac-
tivation. Such a scenario is readily bestowed by combined
infection with schistosomiasis and HCV, but I do not see
why the same thing would not happen with other combi-
nations, including Epstein-Barr virus.
DR. KECHRID MOHAMED (Security Forces Hospital,
Riyadh): What is the prognosis for this 47-year-old man
with schistosoma- and HCV-related end-stage renal dis-
ease?
DR. BARSOUM: Quite poor, I am afraid. We had to sub-
ject him to medical nephrectomy and put him on dialysis
to save his life. His advanced cirrhosis and persistent ele-
vation of the hepatic transaminases, active HCV disease,
no possibility of interferon therapy, esophageal varices,
and severe undernutrition make his chances for medium-
term survival very meager.
DR. MAGDI FRANCIS (Professor of Pathology, Kasr El
Aini Faculty of Medicine, Cairo, Egypt): The concept of
overproduction of IgA from the gut in IgA nephropa-
thy has evolved to an overproduction from bone marrow.
Are we going to adapt this to the theory of schistosomal
nephropathy? What is the origin of the IgA glomerular
deposits? Does hepatic macrophage dysfunction still play
a primordial role?
DR. BARSOUM: Although there is evidence of IgA
overproduction from the gut and impaired hepatic clear-
ance, the B-lymphocytes in patients with schistosomal
glomerulopathy are switched to preferentially secrete
IgA in response to many extrinsic and intrinsic antigens,
even those unrelated to schistosomiasis. A study of the
serum immunoglobulin profile in those patients disclosed
a significant increase in IgA rheumatoid factor and IgA
anti-DNA in addition to IgA antigliadin antibodies [29].
Thus it appears that, as in primary IgA nephropathy,
switching is a generalized phenomenon attributed to IL-
10 excess and is not restricted to the mucosal compart-
ment. To answer your question about the source of IgA
glomerular deposits, we need to study whether they are
mostly composed of IgA1 or IgA2, which we have not be
able to do so far for logistic reasons.
DR. AHMED ADEL HASSAN (Professor of Medicine,
Zagazig University, Egypt): Does the genetic background
play a role in schistosomiasis patients who develop hep-
atosplenomegaly and glomerulopathy?
DR. BARSOUM: Genetics play an important role in the
predisposition to schistosomal infection and complica-
tions. There is considerable variability among laboratory
animal species and strains as regards susceptibility to
experimental infection. In humans, certain MHC hap-
lotypes seem to confer susceptibility to infection. For
example, HLA-Dw12-DR2-DQwl haplotype is required
for the in vitro proliferative response of T-lymphocytes
to schistosomal antigens [65]. HLA-B8 has been associ-
ated with intestinal polyposis; HLA-A1, -B5 (reviewed
in [22]), and certain DRB1 and DQB1 alleles with hep-
atosplenic disease [66]; and HLA-28 [22] with glomeru-
lopathy. All these associations, however, are based on
small series of cases and require confirmation.
DR. HARRINGTON: Why was there no IgA in the
glomeruli of this patient? Is the patient unique? Do you
or others have comparable patients with your new class
VI schistosomal glomerulopathy?
DR. BARSOUM: Although IgA deposits are seen in
more than two-thirds of our patients with “pure” schis-
tosomal glomerulopathy, there is still a considerable
proportion of patients in our, as well as others’, expe-
rience who do not have IgA deposits. The mechanism of
progression in those cases is unknown, although some
data point to an autoimmune response, as evidenced
by the presence of circulating anti-DNA, anti-idiotypic,
and anti-GBM antibodies. In patients with associated
HCV disease, the expanded B-lymphocyte clones pref-
erentially produce IgM, thereby disturbing the typical
IgA predominance seen in schistosomal glomerulopa-
thy [51]. Simple quantitative immunoglobulin imbalance,
blockade of IgA mesangial binding sites, or other mech-
anisms might explain the dearth of IgA in the glomerular
deposits.
This patient is not unique. The trouble lies in the very
broad range of lesions encountered in patients with con-
comitant schistosomal and HCV infection, depending on
multiple agent and host factors. The new class would ac-
commodate all those patients, despite the intraclass vari-
ability. Without such a slot in the classification, we cannot
build an adequate information database for further re-
finement and expansion of our knowledge.
ACKNOWLEDGMENTS
The Principal Discussant would like to acknowledge the help of Prof.
Magdy R. Francis, Professor of Pathology, Cairo University, who has
kindly prepared and interpreted the histopathology material and re-
vised the relevant text, as well as the efforts of his collaborators, who
put together the clinical and investigative data related to the patient pre-
sented in this Forum, particularly Dr. Nasr Tawfik, Dr. Sawssan Halim,
 Nephrology Forum: Schistosomal glomerulopathy
Dr. Marian Fouad, Dr. Sally Sami, and Dr. Rene Abdel-Malak. He
also thanks Dr. Soha Sobhy, his office manager, for preparation of the
manuscript. Dr. Barsoum also acknowledges the generous support of
the Egyptian Society of Nephrology by including this Forum in its an-
nual congress. Prof. Magdy Soliman, President of the Congress, and
Prof. Assem El-Sherif, Chairman of the Scientific Program Committee,
were most helpful.
Reprint requests to Dr. R. Barsoum, The Cairo Kidney Centre, P.O.
Box 91, Bab-El-Louk, 11513 Cairo, Egypt.
E-mail: rbarsoum@msn.com
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