Version May 2024
INTRODUCTION — Human schistosomiasis is caused by infection with Schistosoma haematobium, S. mansoni, S. japonicum, S. mekongi, or S. intercalatum. The three species most frequently infecting humans are S. mansoni, which is endemic in Latin America, S. japonicum in China and East Asia, and S. haematobium in Africa. The kidneys are important targets of schistosomal infection. There are several patterns of kidney involvement in schistosomiasis, including the upstream sequelae of lower urinary tract pathology [1], glomerulonephritis with different immune-mediated pathways [2], tubulointerstitial nephritis [3], and oxidant-stress-mediated tubular injury [4,5]. Glomerular disease associated with schistosomiasis will be discussed here. Other issues related to schistosomiasis are presented separately:
●(See "Schistosomiasis: Epidemiology and clinical manifestations".)
●(See "Schistosomiasis: Diagnosis".)
●(See "Schistosomiasis: Treatment and prevention".)
EPIDEMIOLOGY — Like many other helminthic diseases [6], schistosomiasis may produce a broad spectrum of glomerular pathology. The incidence is unknown since many cases are subclinical or resolve spontaneously. In a village in Upper Egypt, for example, where S. haematobium was newly introduced as a result of changing irrigation methods, the majority of those who acquired the infection developed self-limited nephrotic-range proteinuria with biopsy-confirmed mesangioproliferative glomerulonephritis [7,8]. Similar glomerular lesions have also been described with recent S. mansoni or S. japonicum infection and usually resolve with antiparasitic treatment.
By contrast, persistent or progressive glomerular disease develops in approximately 10 to 15 percent of patients who usually have hepatic fibrosis due to chronic infection with S. mansoni (and occasionally S. haematobium) [2,9-12]. Despite the global schistosomiasis control programs, new cases of schistosomal glomerulopathy continue to be reported [13,14].
PATHOGENESIS — Several observations support a pathogenic role for schistosomal infection in the development of glomerular disease:
●Glomerular lesions, similar to those described in humans, have been induced by experimental infection of many small and large animals [15,16].
●Antibodies against schistosomal antigens can often be eluted from the glomeruli of affected animals [15] and humans [17].
●Schistosomal antigens have been detected in the glomeruli by indirect immunofluorescence (in which fluoresceinated anti-schistosomal antibodies are incubated with the kidney tissue) [12].
●There are several observations of an association between schistosomal infection and clinical glomerular disease, as described above [2,7,9,11,12,18,19]. (See 'Epidemiology' above.)
A number of disease mechanisms are thought to contribute to the pathogenesis of schistosomal glomerular disease:
●Immune complex formation – Deposition in the mesangium of circulating antigens derived from the adult worm and eggs, with subsequent formation of immunoglobulin M (IgM) and G (IgG) immune complexes, is considered the main mechanism of glomerular disease. Schistosomiasis can produce hepatic fibrosis, which impairs the clearance of these antigens from the portal blood [20]. These find their way to the systemic circulation through intrahepatic and extrahepatic portosystemic shunts associated with hepatic fibrosis. This mechanism is thought to be responsible for the development of membranoproliferative glomerulonephritis in patients with schistosomal infection.
Treatment of the parasitic infection does not end the process of progression of the glomerular disease. Autoimmune factors may also be triggered and sustain the lesions. Because of this, infected patients as well as experimental animals may develop antinuclear antibodies (ANA), rheumatoid factor, cryoglobulins, and antiphospholipid antibodies [14,21].
●Direct podocyte injury – T cell dysfunction and the production of cytokines that promote podocyte injury are thought to play a role in the pathogenesis of nephrotic syndrome in patients with schistosomal infection [22].
●Immunoglobulin A (IgA) production – Schistosomiasis is associated with increased local production of mucosal IgA. In late stages of infection, interleukin (IL) 10 induces a significant increase in the expression of IgA on circulating B lymphocytes, which suggests a preferential switching of B lymphocyte generation to IgA predominance [23-25]. The circulating immunoglobulin profile is characterized by significant augmentation of IgA subsets [26]. Impaired clearance of IgA due to the associated hepatic fibrosis leads to an increase in circulating IgA [26]. (See "IgA nephropathy: Clinical features and diagnosis", section on 'Associated conditions'.)
The deposition of IgA is in mesangial, subendothelial, subepithelial, and peritubular locations, suggesting an important pathogenic role for this immunoglobulin (figure 1) [26,27].
●Coinfection – Coinfection with other microbial agents, particularly Salmonella and hepatitis B virus (HBV) and/or hepatitis C virus (HCV), enhances and modifies the glomerular structural and/or functional changes associated with schistosomiasis [19,28,29].
●Genetic factors – Genetics appear to be important in the susceptibility to schistosomal infection [30], progression to hepatic fibrosis [31], initiation of glomerulonephritis [32], and the pattern of glomerular lesions [33,34].
Differences in the schistosomal strains and the severity of infection may explain geographic variations in the prevalence of schistosomal glomerulopathy [35].
CLINICOPATHOLOGIC MANIFESTATIONS — The glomerular manifestations and histologic correlations are discussed in this section. Other clinical features associated with schistosomiasis are presented elsewhere. (See "Schistosomiasis: Epidemiology and clinical manifestations", section on 'Clinical manifestations'.)
Clinical features — As noted above, asymptomatic and self-limited glomerular disease may be relatively common in patients with schistosomal infection. (See 'Epidemiology' above.)
However, patients with schistosomal glomerulopathy can present with clinical and laboratory features that vary depending upon the glomerular histologic pattern of the patient. As an example, patients with membranoproliferative glomerulonephritis (class III), the most common histologic form (71 percent of cases in one series [14]), frequently present with features of both nephrotic and nephritic syndrome. Such patients generally have hematuria (82 percent), hypertension (71 percent), and low serum complement C3 levels (65 percent). (See 'Histologic classification' below.)
Nephrotic syndrome (without nephritic syndrome) can be the presentation in patients with a histologic pattern of focal segmental glomerulosclerosis (FSGS; class IV), or, less commonly, minimal change disease or membranous nephropathy [14,36].
Unlike other causes of nephrotic syndrome, despite severe hypoproteinemia, serum lipid concentrations are usually low due to associated nutritional deficiency and hepatic dysfunction. (See "Lipid abnormalities in nephrotic syndrome".)
Patients who do not have the common nephrotic-nephritic or nephrotic presentation mentioned above may present with other kidney manifestations, including (see 'Histologic classification' below):
●Isolated non-nephrotic proteinuria with normal glomerular filtration rate (GFR; such patients are asymptomatic and therefore incidentally identified); these patients will have class I by histology.
●Acute glomerulonephritis with hematuria and heavy proteinuria (such patients have been described with recent-onset S. haematobium infection); these patients will have class I or II by histology.
●Nephrotic syndrome in combination with systemic manifestations of coinfection with Salmonella (class II) or hepatitis C virus (HCV; class VI) [6].
●End-stage kidney disease (ESKD).
Most asymptomatic patients with incidentally discovered non-nephrotic proteinuria will recover with antiparasitic treatment. By contrast, most symptomatic patients will have progressive kidney disease and develop ESKD or die from severe nutritional deficiency, intercurrent infection, or other sequelae of hepatic fibrosis.
Coinfection — In regions where schistosomiasis is endemic, patients may be coinfected with other pathogenic organisms, leading to significant clinical sequelae. Infections that may modify the kidney manifestations of schistosomiasis include Salmonella, hepatitis B virus (HBV), HCV, and HIV. In addition, coinfection with papilloma virus seems to have a pathogenic role in schistosomal (bilharzial) bladder cancer [37]. Coinfection with tuberculosis [38], plasmodium [39,40], filarial [41], or other parasites may have important clinical implications, but kidney involvement with these organisms has not been reported [29].
Salmonella coinfection — Patients with Salmonella coinfection may present with an acute febrile illness, arthralgias, myalgias, rash, and other signs and symptoms of salmonellosis [30,42,43]. (See "Nontyphoidal Salmonella: Microbiology and epidemiology" and "Enteric (typhoid and paratyphoid) fever: Epidemiology, clinical manifestations, and diagnosis".)
Such patients frequently have a rapid-onset nephrotic syndrome and an active urine sediment, including red and white cell casts. The kidney function may be impaired due to sepsis and hypovolemia. Serum complement C3 is typically reduced due to alternative pathway activation by bacterial endotoxin. Patients may also have positive serological tests for syphilis, rheumatoid factor, antinuclear antibodies, and anti-DNA antibodies [18]. The disease is reversible with combined antiparasitic and antibiotic therapy [44].
The kidney histology in these patients is described below. (See 'Histologic classification' below.)
Hepatitis B virus (HBV) coinfection — Schistosoma and HBV coinfection has deleterious effects on the liver, leading to the rapid onset and progression of cirrhosis to hepatocellular failure or carcinoma. HBV infection produces kidney manifestations that may be superimposed upon those due to schistosomiasis. (See "Kidney disease associated with hepatitis B virus infection".)
Hepatitis C virus (HCV) coinfection — HCV coinfection is extremely common in patients with hepatosplenic schistosomiasis. In most patients, HCV infection seems to have been acquired via administration of unhygienic parenteral therapies for schistosomiasis. Like HBV, HCV accelerates the progression of cirrhosis and development of hepatocellular carcinoma (see "Overview of kidney disease associated with hepatitis C virus infection"). In addition, some of the kidney manifestations may be explained by superimposition and exacerbation of schistosomal and HCV-associated lesions [19]. (See 'Histologic classification' below.)
HIV coinfection — Schistosomiasis has been documented to increase the replication and infectivity of HIV [45] and augment its impact on kidney function [28]. However, the specific impact of HIV coinfection on schistosomal glomerular disease is unclear. (See "Schistosomiasis: Epidemiology and clinical manifestations".)
Histologic classification — The African Association of Nephrology (AFRAN) has endorsed a classification of schistosomal glomerulopathies into five categories based upon the prevailing histopathological lesions [2]; a sixth category was proposed later to encompass the lesions associated with HCV coinfection (picture 1) [19]:
●Class I is mesangial proliferative glomerulonephritis, resulting from deposition of parasitic antigens and antibodies. Patients with class I schistosomal glomerulopathy are most often asymptomatic and are discovered incidentally when a urinalysis reveals mild proteinuria and/or microhematuria. GFR is unaffected. Such patients usually have a benign, self-limited course upon eradication of infection.
●Class II is an exudative glomerulonephritis associated with Salmonella infection. Light microscopy shows neutrophils and monocytes in the glomerulus, and immunofluorescence microscopy reveals deposition of immunoglobulin G (IgG) and complement.
●Class III is a membranoproliferative glomerulonephritis (MPGN), usually reported in White patients, and class IV is a focal proliferative/sclerosing lesion typically seen in Black patients. These classes constitute the vast majority of the observed kidney lesions in patients with schistosomal glomerulopathy. They can occur in the hepatosplenic or intestinal form of the disease. Why Black patients preferentially develop the class IV sclerosing lesion is unclear, but it may be related to genetic factors such as polymorphisms in APOL1 [33,34]. (See "Noncirrhotic portal hypertension" and "Membranoproliferative glomerulonephritis: Classification, clinical features, and diagnosis" and "Focal segmental glomerulosclerosis: Clinical features and diagnosis".)
●Class V is renal amyloidosis of the AA type, which results from chronic inflammation due to persistent infection. Such patients present with significant proteinuria, including the nephrotic syndrome, and reduced GFR. The course and prognosis of this category are similar to those in secondary amyloidosis due to other causes. (See "Renal amyloidosis".)
●Class VI describes the extensive pathology in patients with Schistosoma/HCV coinfection. The glomerular lesion includes mesangial proliferation, amyloid deposition, fibrinoid necrosis, cellular apoptosis, and capillary thrombosis (all features present simultaneously). In addition, immune complexes and cryoglobulins are deposited in the glomeruli. Affected patients are grossly edematous, hypertensive, severely undernourished, and progress rapidly to ESKD. Many patients succumb to intercurrent infection even before reaching ESKD.
Some patients with schistosomiasis and heavy proteinuria are found to have membranous nephropathy (MN) [46]. However, this has not been included in the AFRAN classification owing to the lack of evidence for a pathogenic link [12,47].
DIAGNOSIS — This section presents the diagnosis of schistosomal glomerulopathy. The diagnosis of schistosomiasis in general and the evaluation of infected patients are discussed elsewhere. (See "Schistosomiasis: Diagnosis" and "Schistosomiasis: Epidemiology and clinical manifestations".)
The diagnosis of schistosomal glomerulopathy begins with clinical suspicion in a patient presenting with kidney disease who has known S. mansoni infection, exposure to an endemic area, or clinical evidence of chronic hepatosplenic schistosomiasis. If an exposed patient is not known to have acquired infection, schistosomiasis should be documented. Patients with schistosomiasis and kidney disease sparing the lower urinary tract should have a kidney biopsy. In addition, it is important to evaluate these patients for coinfection with Salmonella, hepatitis C virus (HCV), and hepatitis B virus (HBV). (See "Nontyphoidal Salmonella: Microbiology and epidemiology" and "Overview of kidney disease associated with hepatitis C virus infection".)
Even with documentation of schistosomal infection and a kidney biopsy consistent with schistosomal glomerulopathy, the diagnosis is essentially circumstantial. A definitive diagnosis, which is rarely obtained, requires identification of parasitic antigens in the glomeruli. Glomerular staining for schistosomal antigens is only available in specialized laboratories and is therefore primarily a research technique.
Documentation of schistosomal infection — Stool and/or urine microscopy is rarely useful in making the diagnosis of schistosomiasis in patients with kidney disease since glomerulopathy is a late complication that usually occurs after the worms have ceased laying eggs. Rather, infection is typically diagnosed in such patients with either serology or a rectal submucosal biopsy (or liver biopsy if indicated for another reason). However, in a study of 24 patients with glomerulopathy associated with schistosomiasis, diagnosis of the parasite in nearly all patients was possible by finding eggs in the stool [14]. Highly specific nucleic acid tests (NATs) are available in research laboratories but are awaiting clinical application in endemic areas.
There are many clinically applicable serological tests with variable sensitivity and specificity [48]. These target either circulating antibodies or parasitic antigens. The most reliable serological test detects circulating antibodies against schistosomal microsomal antigens by an enzyme-linked immunosorbent assay using the Falcon assay screening test (FAST-ELISA) [49]. Microsomal antigens are species specific and can therefore differentiate S. mansoni adult worm microsomal antigens (MAMAs) from those of S. hematobium (HAMAs) or S. japonicum (JAMAs).
Circulating schistosomal antigens can be directly detected by monoclonal antibodies. The most frequently targeted are the schistosomal gut antigens, which are responsible for the glomerular immune deposits [50]. In contrast to antibody-based tests, detection of circulating parasitic antigens indicates ongoing active infection.
Laboratories that lack the facilities to perform serologic tests often use a high rectal submucosal biopsy to demonstrate S. mansoni ova. Old, trapped eggs may be seen and are often calcified (picture 2).
Role of kidney biopsy — A kidney biopsy is usually necessary unless the kidney disease is mild and stable:
●A kidney biopsy may be deferred in a patient who presents with mild proteinuria (eg, less than 1 g/day), with or without hematuria, a normal glomerular filtration rate (GFR), and known schistosomiasis. Such patients should be reevaluated after antiparasitic therapy, and a kidney biopsy may be performed if the kidney disease is persistent or progressive.
●Other patients with suspected schistosomal glomerulopathy should undergo kidney biopsy to exclude other forms of glomerular disease. In addition, a kidney biopsy is useful for classification (as noted above), which may influence management and inform prognosis (picture 1). (See 'Differential diagnosis' below and 'Histologic classification' above.)
Screening — Patients with chronic hepatosplenic schistosomiasis and hepatic fibrosis are at high risk for developing glomerulopathy, even after effective antiparasitic therapy (figure 2). (See 'Pathogenesis' above.)
Thus, although data are few, we suggest that such patients without known kidney disease be screened, on an annual basis, with urine dipstick testing (for proteinuria and hematuria) and measurement of serum creatinine. If an abnormal urine dipstick is confirmed after repeat testing, the urine sediment should be examined and proteinuria should be quantified with a urine protein-to-creatinine ratio.
DIFFERENTIAL DIAGNOSIS — Because the kidney presentation of schistosomal glomerulopathy is variable and nonspecific, the differential diagnosis includes many primary and secondary glomerular diseases. (See "Glomerular disease: Evaluation and differential diagnosis in adults".)
Schistosomal glomerulopathy is usually distinguished by the documentation of schistosomiasis combined with consistent histologic findings. However, the kidney biopsy may suggest that the kidney disease is not due to schistosomiasis. In addition, abnormal serologic tests (such as low complement levels) are uncommon in patients with schistosomal glomerulopathy unless there is coinfection with Salmonella, hepatitis C virus (HCV), or hepatitis B virus (HBV).
Schistosomal glomerulopathy may also be confused with cirrhotic glomerulopathy (usually characterized by mild microhematuria and proteinuria) and with primary IgA nephropathy; both disorders, like schistosomal glomerulopathy, are characterized by glomerular IgA deposition [51]:
●Although patients with cirrhotic glomerulopathy have chronic liver disease, they rarely develop nephrotic syndrome, seldom progress to end-stage kidney disease (ESKD), and do not have extrahepatic manifestations of chronic schistosomal disease. In addition, subendothelial IgA deposits are frequent in cirrhotic glomerulopathy but are rarely seen in schistosomal glomerulopathy [51].
●Although primary IgA nephropathy can result in the nephrotic syndrome and ESKD, such patients do not have hepatic fibrosis.
THERAPY AND PROGNOSIS — Therapy of schistosomiasis-associated glomerular disease centers around treatment of the underlying helminthic infection as well as coinfections. Other factors contributing to the patient's morbidity, such as undernutrition and intercurrent infection, must be addressed. However, the prognosis varies according to the histologic class. (See 'Histologic classification' above.)
Immunosuppressive therapy is not warranted in most patients with this disease [42,49], except in some patients with class VI disease who have life-threatening cryoglobulinemia. (See 'Class VI' below.)
Class I — Class I disease may remain subclinical, regress either spontaneously or with antiparasitic treatment, or progress by transformation into other classes depending upon the presence of coinfections (ie, transformation into class II or VI), the presence of hepatic fibrosis (ie, transformation into class III or IV), or presence of certain genetic polymorphisms [2].
Class I schistosomal glomerular disease, particularly in the presence of living ova in stools or rectal snip, should be treated by praziquantel [52] or an alternative in resistant cases. Treatment of schistosomiasis, including its use in pregnant women, is discussed elsewhere. (See "Schistosomiasis: Treatment and prevention".)
Class II — Class II disease is reversible with simultaneous treatment of schistosomiasis (with praziquantel) and Salmonella (with an antibiotic such as ampicillin, trimethoprim-sulfamethoxazole [49], or ciprofloxacin [53]). Therapy against Salmonella alone is not effective, since these bacteria firmly attach to the schistosomal worms and hide under a protective layer of host proteins that covers the worms [44].
Classes III to V — These classes of the disease progress relentlessly to end-stage kidney disease (ESKD) over four to six years in 37 to 75 percent of cases, regardless of therapy [14,42,54]. However, active schistosomal infection should be treated with an antiparasitic, although such therapy is unlikely to improve kidney disease. Immunosuppressive drugs are not indicated. The effect of antiinflammatory and investigational therapies that are used for the treatment of secondary amyloidosis (class V disease) is unknown in patients with schistosomiasis. (See "Treatment of AA (secondary) amyloidosis".)
Class VI — Patients with schistosomal and hepatitis C virus (HCV) coinfection who have severe mixed cryoglobulinemia syndrome should be treated similarly to other patients with mixed cryoglobulinemia, including the use of immunosuppression, if needed. Anti-HCV therapy should be provided according to the degree of kidney dysfunction [55] (see "Mixed cryoglobulinemia syndrome: Treatment and prognosis" and "Treatment of chronic hepatitis C infection in adults with kidney function impairment"). Although such patients are unlikely to have active parasitic infection at this stage, those with positive serology should receive antiparasitic treatment.
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Glomerular disease in adults".)
SUMMARY AND RECOMMENDATIONS
●Epidemiology – Human schistosomiasis is caused by infection with Schistosoma haematobium, S. mansoni, S. japonicum, S. mekongi, or S. intercalatum. Schistosomiasis may produce a broad spectrum of glomerular pathology. Many cases are subclinical or resolve spontaneously. By contrast, persistent or progressive glomerular disease develops in approximately 10 to 15 percent of patients who usually have hepatic fibrosis due to chronic infection with S. mansoni (and occasionally S. haematobium). (See 'Epidemiology' above.)
●Pathogenesis – The immune response to the parasite appears to be important in the development of glomerulonephritis. The initial glomerular injury is thought to be a consequence of antigens released by schistosomal worms in the portal vein tributaries. However, progression to advanced pathological lesions and eventually glomerulosclerosis involves other disease mechanisms (even after effective antiparasitic treatment) (figure 2). (See 'Pathogenesis' above.)
●Clinical features – Asymptomatic and self-limited glomerular disease may be relatively common in patients with schistosomal infection. Symptomatic patients with schistosomal glomerulopathy most frequently present with nephrotic syndrome or nephrotic-nephritic syndrome, and such patients typically have hepatosplenic schistosomiasis with hepatic fibrosis resulting from S. mansoni infection. Less commonly, affected patients may have isolated non-nephrotic proteinuria with a normal glomerular filtration rate (GFR), acute glomerulonephritis, nephrotic syndrome in combination with systemic manifestations of Salmonella or HCV (eg, fever, arthralgias, muscle aches, rash), or end-stage kidney disease (ESKD). (See 'Clinical features' above.)
Asymptomatic patients with incidentally discovered non-nephrotic proteinuria may recover with antiparasitic treatment. By contrast, most symptomatic patients will have progressive kidney disease and develop ESKD or die from other sequelae of hepatic fibrosis. (See 'Clinical features' above.)
●Histologic classification – The African Association of Nephrology (AFRAN) has endorsed a classification of schistosomal glomerulopathies into five categories based upon the prevailing histopathological lesions; a sixth category has been subsequently appended to encompass the lesions associated with HCV coinfection (picture 1) (see 'Histologic classification' above).
●Diagnosis – The diagnosis of schistosomal glomerulopathy begins with clinical suspicion in a patient presenting with kidney disease who has known S. mansoni infection, exposure to an endemic area, or clinical evidence of chronic hepatosplenic schistosomiasis. If the patient is not known to have schistosomiasis, schistosomal infection should be documented. Most patients with schistosomiasis and kidney disease should have a kidney biopsy. In addition, it is important to evaluate these patients for coinfection with Salmonella and HBV or HCV in endemic areas. (See 'Diagnosis' above.)
●Screening – Patients with chronic hepatosplenic schistosomiasis and hepatic fibrosis are at high risk for developing glomerulopathy, even after effective antiparasitic therapy (figure 2). In patients with chronic hepatosplenic schistosomiasis who do not have known kidney disease, screening for kidney disease on an annual basis with urine dipstick testing (for proteinuria and hematuria) and a serum creatinine may identify individuals with schistosomal glomerulopathy. (See 'Screening' above.)
●Treatment and prognosis – Therapy for schistosomal glomerulopathy is treatment of the underlying helminthic infection and, if present, the bacterial or viral coinfection. Immunosuppressive therapy is not warranted in most patients. The prognosis varies according to the histologic class. (See 'Therapy and prognosis' above.)
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Rashad Barsoum, MD, FRCP, FRCPE (deceased), who contributed to earlier versions of this topic review.
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