The changing face of schistosomal glomerulopathy

Abstract

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. Assessments showed evidence of schistosomal hepatic fibrosis, splenomegaly, and portal hypertension. He also had serologic evidence of hepatitis C viral (HCV) infection 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 proteinuria 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 his lower limb edema increased. The physician noted impairment of renal function and referred him to our facility. The patient's medical history featured Schistosoma mansoni infection in 1982, for which he received intravenous 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 irregular 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 perivisceral 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 neurologic 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 electrolytes 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 differential. Platelet count was 169,000/mm3. Serum iron was 32 μg/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 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 total protein was 5.02 g/dL, 51.8% of which was albumin, and the globulins showed a modest increase in the α2 and β fractions by electrophoresis. The γ globulin region showed a monoclonal band that subsequent immunoelectrophoresis revealed to be composed of IgM (714 mg/dL). Serum IgG was 193 mg/dL, and IgA 135 mg/dL. Prothrombin concentration was reduced to 70%. A test for C-reactive protein was positive; C3 was low normal (76 mg/dL); C4 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 heterogeneity and thickening of the portal tracts. The spleen was “moderately” enlarged, and the portal vein was borderline 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 resistivity 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, or feet. No erosions were evident in the metacarpal, metatarsal, or phalangeal bones. Rectal snip examination showed a few dead Schistosoma mansoni ova. Renal biopsy Figure 1 showed a mesangiocapillary glomerulonephritis with some nuclear dust, extensive AA-type amyloid deposits (abolished by potassium permanganate oxidation), and hyaline capillary thrombi. Immunofluorescence revealed an abundance of IgM and C3 subendothelial deposits, along with faint mesangial IgG. The capillary thrombi stained heavily with IgM and fibrinogen. The arterioles were moderately sclerosed with amyloid deposits in the media. Significant interstitial fibrosis was present. The patient was hospitalized, received salt-free albumin and nutritional support, and his blood pressure was controlled by an angiotensin-converting enzyme (ACE) inhibitor (ramipril, 5 mg/day) and forced diuresis (furosemide, 250 mg/day). He also received intravenous iron saccharate and erythropoietin. He was considered too ill for interferon treatment, and its cost-benefit was doubtful. However, he continued to lose large amounts of protein in the urine and stools, and his serum proteins remained alarmingly low. It was decided to deliberately reduce his glomerular filtration rate, and he began regular hemodialysis. This goal was achieved by administering rofecoxib, 50 mg/day, along with ramipril, 10 mg/day. Proteinuria regressed to 5 g/24 hr; the serum creatinine rose to 3.7 mg/dL (Cockroft estimated clearance, 12 mL/min). Through daily albumin infusions (200 mL 20% salt-free albumin), total parenteral nutrition, and hemodiafiltration (removing ± 4 L of fluid daily), he ultimately lost 12 kg of his body weight in 2 weeks. He became symptom-free, and his appetite improved enough for us to stop parenteral nutrition and to allow liberal calorie and protein intake. His blood pressure was controlled at 130/80 mm Hg, edema almost disappeared, and he was discharged 2 months after admission for regular hemodialysis as an outpatient. Dr. Rashad Barsoum (Professor of Medicine, Cairo University, Cairo Kidney Center, Cairo, Egypt): For many thousands of years, schistosomiasis has been one of nature'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 predisposed individuals, or those who had significant concomitant 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 antimony, 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, clinicopathologic, and pathogenetic levels, and displays the difficulties in the management of such cases. The diagnosis of rheumatoid arthritis, made in 1990, is very unlikely to be correct, in view of the absence of any joint deformities1Green M. Marzo-Ortega H. McGonagle D. et al.Persistence of mild, early inflammatory arthritis: The importance of disease duration, rheumatoid factor, and the shared epitope.Arthritis Rheum. 1999; 42: 2184Crossref PubMed Scopus (164) Google Scholar or radiologic erosions2Lindqvist E. Jonsson K. Saxne T. Eberhardt K. Course of radiographic damage over 10 years in a cohort with early rheumatoid arthritis.Ann Rheum Dis. 2003; 62: 611-616Crossref PubMed Scopus (163) Google Scholar after many years of strong rheumatoid factor (RF) seropositivity3Cats A. Hazevoet H.M. Significance of positive tests for rheumatoid factor in the prognosis of rheumatoid arthritis: A follow-up study.Ann Rheum Dis. 1970; 29: 254Crossref PubMed Scopus (59) Google Scholar. It is noteworthy that both schistosomiasis4Arinola O.G. Salimonu L.S. Rheumatoid factor in sera of Nigerian school children with urinary schistosomiasis.Afr J Med Sci. 2000; 29: 329-300Google Scholar,5Barsoum R.S. Bassily S. 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A clinico-serological investigation of arthritis in patients with or without cryoglobulinemic syndrome.Reumatismo. 2002; 54: 316-323PubMed Google Scholar. Rheumatoid-like arthritis can be induced by experimental infection of Swiss albino mice with S. mansoni9Ismail H.I. Sallam F.A. Sheer H.A. The pathogenesis of arthropathy in experimental Schistosomiasis mansoni.J Egypt Soc Parasitol. 2000; 30: 943-949PubMed Google Scholar, and can occur early in the course of schistosomiasis10Abdel-Aaty H.E. Selim M.M. Abdel-Rehim H.A. Study of gamma-interferon in schistosomiasis mansoni, autoimmune diseases and schistosomal arthropathy.J Egypt Soc Parasitol. 1999; 29: 721-734PubMed Google Scholar,11Khalil H.M. el-Missiry A.G. Abdalla H.M. et al.Serum levels of tumour necrosis factor alpha in Schistosomiasis mansoni and their analogous changes in collagen diseases and schistosomal arthropathy.J Egypt Soc Parasitol. 1995; 25: 427-436PubMed Google Scholar. In the majority of cases, schistosomal arthritis affects the large joints—shoulders and hips—but sometimes is associated with small joint involvement as well12Atkin S.L. Kamel M. el-Hady A.M. et al.Schistosomiasis and inflammatory polyarthritis: A clinical, radiological and laboratory study of 96 patients infected by S. mansoni with particular reference to the diarthrodial joint.Q J Med. 1986; 59: 479-487PubMed Google Scholar. 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 arthritis13Cimmino M.A. Picciotto A. Sinelli N. et al.Has hepatitis C virus a specific tropism for the synovial membrane?.Br J Rheumatol. 1997; 36: 505-506Crossref PubMed Scopus (7) Google Scholar. Asymmetrical large joint disease can occur as part of the Meltzer's triad in patients with cryoglobulinemia14Olivieri I. Palazzi C. Padula A. Hepatitis C virus and arthritis.Rheum Dis Clin North Am. 2003; 29: 111-222Abstract Full Text Full Text PDF PubMed Scopus (56) Google Scholar. Accordingly, it is likely that the arthritis encountered during the early stages of this patient's illness was indeed a manifestation of schistosomiasis, HCV, or both, rather than true rheumatoid arthritis. Schistosomiasis is a documented risk factor for the acquisition of HCV infection in many endemic areas, particularly in Egypt15Gad A. Tanaka E. Orii K. et al.Relationship between hepatitis C virus infection and schistosomal liver disease: Not simply an additive effect.J Gastroenterol. 2001; 36: 753-758Crossref PubMed Scopus (25) Google Scholar. It is generally accepted that the virus is transmitted along with intravenous antimony therapy for schistosomiasis16Frank C. Mohamed M.K. Strickland G.T. et al.The role of parenteral antischistosomal therapy in the spread of hepatitis C virus in Egypt.Lancet. 2000; 355: 887-891Abstract Full Text Full Text PDF PubMed Scopus (826) Google Scholar, which was the standard treatment until the late 1980s, when mass treatment strategies moved to oral therapy. The contemporary poor hygienic standards initially favored both HBV and HCV infections, yet the former gradually declined with mass vaccination 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 hybridization 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 viral 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 reservoir for the spread of HCV infection by different routes, even to those without previous exposure to schistosomiasis. Living in Egypt, per se, thus has become a significant risk factor for acquisition of HCV infection17Di Bisceglie A.M. Hepatitis C.Lancet. 1998; 351: 351-355Abstract Full Text Full Text PDF PubMed Scopus (372) Google Scholar; the overall prevalence is around 20%, compared to 1% to 2% in most other countries18Strickland G.T. Elhefni H. Salman T. et al.Role of hepatitis C infection in chronic liver disease in Egypt.Am J Trop Med Hyg. 2002; 67: 436-442PubMed Google Scholar. Consequently, the prevalence of end-stage liver disease has dramatically increased, and the incidence of hepatocellular carcinoma also has risen strikingly over the past decade. Likewise, the renal complications of schistosomiasis became considerably confounded by the impact of HCV infection, as demonstrated in today's patient. 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. “Pure” schistosomal glomerulopathy (SG) is a distinct disease entity, the identity of which is based on experimental19Houba V. Experimental renal disease due to schistosomiasis.Kidney Int. 1979; 16: 30-43Abstract Full Text PDF PubMed Scopus (28) Google Scholar, epidemiologic20Ezzat E. Osman R.A. Ahmet K.Y. Soothill J.F. The association between Schistosoma hematobium infection and heavy proteinuria.Trans R Soc Trop Med Hyg. 1974; 68: 315-317Abstract Full Text PDF PubMed Scopus (26) Google Scholar, post-mortem21Andrade Z.A. Rocha H. Schistosomal glomerulopathy.Kidney Int. 1979; 16: 23-29Abstract Full Text PDF PubMed Scopus (67) Google Scholar, and clinical22Barsoum R. Schistosomal glomerulopathies.Kidney Int. 1993; 44: 1-12Abstract Full Text PDF PubMed Scopus (63) Google Scholar evidence. 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 199222Barsoum R. Schistosomal glomerulopathies.Kidney Int. 1993; 44: 1-12Abstract Full Text PDF PubMed Scopus (63) Google Scholar. Accordingly, 5 classes of schistosomal glomerulopathy are recognized Figure 2. Switching from one class to another can occur as a result of superimposed infections23Bassily S. Farid Z. Barsoum R.S. et al.Renal biopsy in schistosoma-salmonella associated nephrotic syndrome.J Trop Med Hyg. 1976; 79: 256-258PubMed Google Scholar or progression of associated hepatic pathology24Barsoum R. Sersawy G. Haddad S. et al.Hepatic macrophage function in schistosomal glomerulopathy.Nephrol Dial Transplant. 1988; 3: 612-616Crossref PubMed Scopus (13) Google Scholar. Class I is histologically defined as axial mesangial proliferative glomerulonephritis, and is associated with deposition of immune complexes containing schistosomal antigens, IgM, and C325Sobh M. Moustafa F. el-Arbagy A. et al.Nephropathy in asymptomatic patients with active Schistosoma mansoni infection.Int Urol Nephrol. 1988; 22: 37-43Crossref Scopus (20) Google Scholar. It is a fairly benign condition, 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 animals21Andrade Z.A. Rocha H. Schistosomal glomerulopathy.Kidney Int. 1979; 16: 23-29Abstract Full Text PDF PubMed Scopus (67) Google Scholar. The clinical presentation is usually limited to sub-nephrotic proteinuria, although frank nephrotic syndrome occurs in as many as 15% of patients22Barsoum R. Schistosomal glomerulopathies.Kidney Int. 1993; 44: 1-12Abstract Full Text PDF PubMed Scopus (63) Google Scholar. Under certain epidemiologic conditions, the acute nephritic syndrome is encountered20Ezzat E. Osman R.A. Ahmet K.Y. Soothill J.F. The association between Schistosoma hematobium infection and heavy proteinuria.Trans R Soc Trop Med Hyg. 1974; 68: 315-317Abstract Full Text PDF PubMed Scopus (26) Google Scholar, 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 antihelminthic drugs, corticosteroids, or immunosuppressive agents. Class II is defined as an exudative glomerulonephritis, with many neutrophils, monocytes, and eosinophils invading the mesangium23Bassily S. Farid Z. Barsoum R.S. et al.Renal biopsy in schistosoma-salmonella associated nephrotic syndrome.J Trop Med Hyg. 1976; 79: 256-258PubMed Google Scholar. Subendothelial and mesangial C3 deposits are characteristic of this class, often associated with IgG and IgM. It occurs with concomitant infection by either Schistosoma hematobium or S. mansoni, and salmonella species, usually Salmonella paratyphi A23Bassily S. Farid Z. Barsoum R.S. et al.Renal biopsy in schistosoma-salmonella associated nephrotic syndrome.J Trop Med Hyg. 1976; 79: 256-258PubMed Google Scholar. Dual infection is well documented in the Egyptian medical literature26Hathout S.E. El. Ghaffar Awny A.Y. Chronic salmonellosis complicating schistosomiasis in Egypt.Am J Trop Med Hyg. 1967; 16: 462PubMed Google Scholar. Schistosomal salmonella infection, also observed in Brazil, induces a similar glomerular lesion27Martinelli R. Pereira L.J. Brito E. Rocha H. Renal involvement in prolonged Salmonella bacteremia: The role of schistosomal glomerulopathy.Rev Inst Med Trop Sao Paulo. 1992; 34: 193-198Crossref PubMed Google Scholar. Dual infection is not a simple 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 presentation in such cases is dominated by a febrile illness, toxic manifestations of salmonella infection, and a rapidly developing nephrotic syndrome28Barsoum R. Bassily S. Soliman M. et al.Renal amyloidosis and schistosomiasis.Trans R Soc Trop Med Hyg. 1979; 73: 367-374Abstract Full Text PDF PubMed Scopus (19) Google Scholar. Complete recovery occurs with combined antihelminthic and antibacterial treatment. Classes III and IV constitute the majority of patients with progressive disease. Both are encountered mostly with S. mansoni infection, feature significant hepatic pathology21Andrade Z.A. Rocha H. Schistosomal glomerulopathy.Kidney Int. 1979; 16: 23-29Abstract Full Text PDF PubMed Scopus (67) Google Scholar, 24Barsoum R. Sersawy G. Haddad S. et al.Hepatic macrophage function in schistosomal glomerulopathy.Nephrol Dial Transplant. 1988; 3: 612-616Crossref PubMed Scopus (13) Google Scholar, 28Barsoum R. Bassily S. Soliman M. et al.Renal amyloidosis and schistosomiasis.Trans R Soc Trop Med Hyg. 1979; 73: 367-374Abstract Full Text PDF PubMed Scopus (19) Google Scholar, and are often associated with abnormalities in serum IgA components29Barsoum R. Nabil M. Saady G. et al.Immunoglobulin A and the pathogenesis of schistosomal glomerulopathy.Kidney Int. 1996; 50: 920-928Abstract Full Text PDF PubMed Scopus (24) Google Scholar, as well as glomerular and peritubular IgA deposits24Barsoum R. Sersawy G. Haddad S. et al.Hepatic macrophage function in schistosomal glomerulopathy.Nephrol Dial Transplant. 1988; 3: 612-616Crossref PubMed Scopus (13) Google Scholar. Class III is a mesangiocapillary glomerulonephritis, often occurring in non-black populations; Class IV is a focal-segmental proliferative/sclerosing lesion, seen preferentially in blacks30Lopes A.A. Martinelli R.P. Silveira M.A. Rocha H. Racial differences between patients with focal segmental glomerulosclerosis and membranoproliferative glomerulonephritis from the State of Bahia.Rev Assoc Med Bras. 1999; 45: 115-120Crossref PubMed Scopus (5) Google Scholar. In both classes, there is considerable impairment of the hepatic macrophage function24Barsoum R. Sersawy G. Haddad S. et al.Hepatic macrophage function in schistosomal glomerulopathy.Nephrol Dial Transplant. 1988; 3: 612-616Crossref PubMed Scopus (13) Google Scholar 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 mucosa29Barsoum R. Nabil M. Saady G. et al.Immunoglobulin A and the pathogenesis of schistosomal glomerulopathy.Kidney Int. 1996; 50: 920-928Abstract Full Text PDF PubMed Scopus (24) Google Scholar, 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 complexes and IgA, the latter being associated with progression in 70% of cases as compared to 29% in those with non-progressive disease24Barsoum R. Sersawy G. Haddad S. et al.Hepatic macrophage function in schistosomal glomerulopathy.Nephrol Dial Transplant. 1988; 3: 612-616Crossref PubMed Scopus (13) Google Scholar. Mesangial cell proliferation 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 hyperfiltration31Forrester T. Historic and early life origins of hypertension in Africans.J Nutr. 2004; 134: 211-216PubMed Google Scholar. Classes III and IV present with proteinuria, usually within the nephrotic range22Barsoum R. Schistosomal glomerulopathies.Kidney Int. 1993; 44: 1-12Abstract Full Text PDF PubMed Scopus (63) Google Scholar, although subnephrotic proteinuria occurs in 10% to 20% of patients. Hypertension occurs in about one-half of the cases, and progressive renal insufficiency is the rule in those who survive cirrhosis, hematemesis, and hepatocellular carcinoma. The disease cannot be modified by any current treatment, including antihelminthic drugs, corticosteroids, and immunosuppressive agents32Sobh M.A. Moustafa F.E. Sally S.M. et al.Effect of antischistosomal treatment on schistosoma-specific nephropathy.Nephrol Dial Transplant. 1988; 3: 744-751PubMed Google Scholar. Class V is the renal component of a generalized response to chronic inflammation, namely systemic amyloidosis27Martinelli R. Pereira L.J. Brito E. Rocha H. Renal involvement in prolonged Salmonella bacteremia: The role of schistosomal glomerulopathy.Rev Inst Med Trop Sao Paulo. 1992; 34: 193-198Crossref PubMed Google Scholar. Amyloidosis occurs with prolonged active infection with either S. hematobium or S. mansoni in humans, as it does in several animal models33Sobh M. Moustafa F. Hamed S. Ghoneim M. Effect of colchicine on schistosoma-induced renal amyloidosis in Syrian golden hamsters.Nephron. 1995; 70: 478-485Crossref PubMed Google Scholar. Like other inflammation-associated amyloids, AA beta-pleated fibrils are deposited preferentially in the kidney, liver, subcutaneous 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 are also deposited, mesangial proliferation can be seen concomitantly with amyloidosis28Barsoum R. Bassily S. Soliman M. et al.Renal amyloidosis and schistosomiasis.Trans R Soc Trop Med Hyg. 1979; 73: 367-374Abstract Full Text PDF PubMed Scopus (19) Google Scholar. The clinical presentation is similar to that of renal amyloidosis in general, with proteinuria and progressive renal insufficiency. Hypertension is unusual. The kidneys are shrunken in 25% of patients, in whom there is associated schistosomal interstitial fibrosis. No evidence indicates that the course of schistosoma-associated amyloidosis can be modified by any form of treatment33Sobh M. Moustafa F. Hamed S. Ghoneim M. Effect of colchicine on schistosoma-induced renal amyloidosis in Syrian golden hamsters.Nephron. 1995; 70: 478-485Crossref PubMed Google Scholar. The frequency of HCV-associated nephropathy varies in different geographic locations. The incidence in Egypt is unknown, as no systematic epidemiologic studies have addressed this issue. A recent study demonstrated evidence of HCV infection in 38% of patients with mesangiocapillary glomerulonephritis, compared to 19% in healthy blood donors34Sabry A.A. Sobh M.A. Irving W.L. et al.A comprehensive study of the association between hepatitis C virus and glomerulopathy.Nephrol Dial Transplant. 2002; 17: 239-245Crossref PubMed Scopus (76) Google Scholar. About one-seventh of patients with HCV disease develop either type II or type III secondary cryoglobulinemia35Gad A. Tanaka E. Matsumoto A. et al.Factors predisposing to the occurrence of cryoglobulinemia in two cohorts of Egyptian and Japanese patients with chronic hepatitis C infection: ethnic and genotypic influence.J Med Virol. 2003; 70: 594-599Crossref PubMed Scopus (21) Google Scholar, thereby constituting the main bulk of HCV nephropathy. The most common glomerular lesion is mesangiocapillary 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 deposits36Sansonno D. Gesualdo L. Manno C. et al.Hepatitis C virus-related proteins in kidney tissue from hepatitis C virus-infected patients with cryoglobulinemic membranoproliferative glomerulonephritis.Hepatology. 1997; 25: 1237-1244Crossref PubMed Scopus (150) Google Scholar, and virus-like particles can be detected by electron microscopy37Pucillo L.P. Agnello V. Membranoproliferative glomerulonephritis associated with hepatitis B and C viral infections: From viruslike particles in the cryoprecipitate to viral localization in paramesangial deposits, problematic investigations prone to artifacts.Curr Opin Nephrol Hypertens. 1994; 3: 465-470Crossref PubMed Scopus (22) Google Scholar. IgG and/or IgM are encountered in the glomerular deposits, depending on the presence and nature of circulating 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 recipients38Hammoud H. Haem J. Laurent B. et al.Glomerular disease during HCV infection in renal transplantation.Nephrol Dial Transplant. 1996; 11: 54-55Crossref PubMed Scopus (49) Google Scholar. Other forms of glomerulonephritis associated with HCV39Sinico R.A. Fornasieri A. D'Amico G. Renal manifestations associated with hepatitis C virus.Ann Med Interne (Paris). 2000; 151: 41-45PubMed Google Scholar include membranous glomerulonephritis, particularly as a de novo disease in transplanted kidneys; FSGS, which is often of the collapsing variety; and, very rarely, immunotactoid glomerulonephritis40Markowitz G.S. Cheng J.T. Colvin R.B. et al.Hepatitis C viral infection is associated with fibrillary glomerulonephritis and immunotactoid glomerulopathy.J Am Soc Nephr