Schistosomal glomerulopathy

Kidney International, Vol. 16 (1979), pp. 23-29

Schistosomal glomerulopathy ZILTON A. ANDRADE and HEONIR ROCHA Departments of Pathology and Medicine, University of Bahia Medical School, Salvador, Bahia, Brazil

demic areas of schistosomiasis has yet to be determined. In one study, an attempt was made to corre-

Historical background

For some time clinicians in Brazil have suspected that renal involvement may occur in Schistosoma mansoni infection [1, 2]. In 1964, Lopes noted abnormal concentrations of protein and leucocytes in the urine of 26.7% of patients with the hepatosplenic form of schistosomiasis, as compared with 3.8% of patients with milder forms of the disease [1]. Moreover, Machado demonstrated that in the most advanced forms of schistosomiasis, large amounts of beta and gamma globulins, as well as lipoproteins, were present in the urine [21. When a cirrhotic glomerulosclerosis" [3, 41 or "hepatic glomerulosclerosis" [5] was described in the literature, it seemed plausible that at least some similar glomerular changes could be present also in advanced schistosomiasis, a chronic liver disease with prominent portal hypertension. A comparative histologic study then showed that glomeruloscierotic changes were indeed even more marked and frequent in hepatosplenic schistosomiasis than they were in active hepatic cirrhosis [6]. Membranous

late S. mansoni infection with proteinuria [17]. Higher concentrations of urinary protein were encountered in individuals with infections compared to those without infection. Because these authors only related spleen size with proteinuria, however, they were unable to assess the importance of advanced hepatic disease with portal hypertension to proteinuria. They found that 35.4% of infected individuals had splenic enlargement, a rate which exceeds the 4% of cases that normally go on to develop the hepatosplenic form [18, 19]. It has been demonstrated recently that schistosomal glomerulopathy is mediated via the glomerular deposition of immune complexes. Circulating

specific schistosomal antigen has been demonstrated in the serum [20], as well as in the urine, of heavily infected animals [21, 22]. Also, circulating immune-complexes have been detected in patients with S. mansoni infection [24]. More recently, some authors have identified specific schistosomal antigens deposited in glomerular capillary loops of animals [11, 13, 14] and patients [25, 26] with glomerulonephritis. Several questions, however, still remain to be answered. The true prevalence of renal involvement, the clinical course of the glomerulopathy, the nature of the antigen or antigens, as well as the nature of the immunologic factors rendering the host susceptible to this renal involvement are not well understood.

glomerular changes with fibrillar thickening and cellular proliferation of the mesangium were observed

in the kidneys of patients who had died of hepatosplenic schistosomiasis. The results of this study stimulated an investigation of the renal lesions in a larger number of patients. Histologic examination of 80 cases revealed that renal glomeruli were frequently altered in advanced schistosomiasis [7]. There were a variety of changes that included mesangial cell proliferation, increased mesangial matrix, focal sclerosis, and several types of glomerulonephritis. Reproduction of this glomerular involvement in S. mansoni-infected experimental animals came later. Renal lesions were demonstrated in several spe-

Clinical manifestations

Most patients diagnosed as having schistosomal

glomerulonephritis are young adults who come from an endemic area for schistosomiasis and ex-

cies of monkeys [8—li], mice [12—14], rabbits [15],

and hamsters [161 heavily infected either with S. mansoni or S. japonicum. The appearance of these lesions seemed to be similar to those found in humans. The prevalence of renal involvement in en-

Received for publication July 12, 1978

0085-2538/79/0016-0023 $01.40

© 1979 by the International Society of Nephrology 23

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Andrade and Rocha

hibit hepatosplenomegaly on physical examination. The liver is usually hard, with a prominent left lobe,

and has an irregular surface and sharp edge. The spleen is hard and rarely tender. The majority of patients have edema of the legs and some have ascites. In a study of 100 consecutive patients with hepatosplenic S. mansoni admitted to a general hos-

pital in an endemic area, 9 patients had nephrotic syndrome, 6 had only proteinuria, and 3 patients had arterial hypertension. The urinary protein of these patients had low selectivity [271 or was nonselective [281; this corresponds to the detection of 1gM, alpha-2 macroglobulins, and lipoproteins in the urine. A peculiarity of the nephrotic syndrome observed in association with schistosomiasis is the concomitant finding of increased plasma globulin concentrations and normal cholesterol concentrations in one-third of such patients. The 15% in-

cidence of overt renal disease in hepatosplenic schistosomiasis observed in this study [291 may not

reflect the true prevalence of this condition. This survey was conducted in a hospital with an interest in schistosomal nephropathy, and this fact might have been responsible for selection of patients. This figure, however, is similar to the 12% incidence of glomerulonephritis described in patients with hepa-

tosplenic schistosomiasis autopsied in the same hospital [71.

Very little is known about the natural history of schistosomal glomerulopathy. In an endemic area, some patients with hepatosplenic S. mansoni admitted for splenectomy or ligation of esophageal varices exhibited only proteinuria and microscopic hematuria, but they developed the nephrotic syndrome, with or

without arterial hypertension, 10 to 12 years later. Of 15 patients with hepatosplenic S. mansoni who had no clinical evidence of glomerular disease when subjected to renal (surgical) biopsy at the time of splenectomy, 6 patients had glomerular lesions [301.

The lesions were usually mild, but 1 patient had membranoproliferative glomerulonephritis, and another had focal glomerular sclerosis. These findings suggest that glomerular lesions antedate overt clinical manifestations and that the evolution of the gbmerular disease is slow and probably takes years to

become clinically apparent. Thus far, there is no

conclusive test to detect preclinical renal involvement in this disease. Recently, however, it has been demonstrated that low levels of f3-l-C are correlated with the histologic finding of glomerulone-

phritis in hepatosplenic patients without clinical renal involvement, but this finding is still preliminary (Martinelli et al, to be published).

Diagnosis

Several factors should be considered in the clinical diagnosis of schistosomal glomerulopathy: (1) Patients are usually young adults, more frequently male than female (2:1), and come from an endemic area for schistosomiasis. The finding of viable worm eggs in stool specimens is diagnostic of the parasitic infection. Rarely is the stool examination negative,

and in such cases, the diagnosis can be made by rectal and/or liver biopsy. In the biopsy specimens,

granulomas containing the eggs are seen. (2) Patients exhibit an enlarged liver with a prominent left lobe, and in most cases, an enlarged spleen; the majority have esophageal varices. (3) Nephropathy is

usually manifested by a nephrotic syndrome. The only peculiarity is the finding of high serum globulin levels and normal serum cholesterol levels in a third of such cases. Some patients may show only a mild persistent proteinuria. (4) Other causes of nephrotic

syndrome, such as disseminated lupus erythematosus, malaria, syphilis, diabetes mellitus, streptococcal glomerulonephritis, and any indication of previous episodes of gbomerulonephritis should be considered in the differential diagnosis. Although there is no reliable way to rule out unrelated renal pathology, it is reasonable to assume, however, with the accumulated evidence available, that the major etiology of the glomerular disease in these cases is related to the S. mansoni infection. Pathologic features

In good correlation with the clinical picture of nephrotic syndrome, the majority of human cases studied histologically conform to a diagnosis of chronic diffuse membranoproliferative glomerulonephritis, frequently with lobular accentuation [7, 27, 30, 31]. This picture is also in keeping with the observation that the mesangium is the area that is most altered in schistosomal gbomerubopathy. Since the initial studies, both in humans [6, 7, 27, 30, 31J

and in experimental animals [8, 9, 121, the most prominent finding has been mesangial expansion, which is seen best at the glomerular vascular pole. This was described as a fibrillar, PAS-positive thickening, with a mild to moderate increase in cellularity. In what appeared to be very early cases of renal involvement and with no clinical manifesta-

tion of renal disease, mesangial cell proliferation was so outstanding that a diagnosis of mesangial glomerulonephritis seemed justified [31]. On the other hand, Brito et al [301 refer to a patient who progressed from a predominant membranous type

25

Schistosomal glomerulopathy

of lesion to a definite lobular pattern during a period of 7 years. The second most common type of glomerular lesion observed in biopsy material is focal glomerular sclerosis [7, 27, 31]. In necropsy material, however, almost all histologic types of glomerulonephritis can be observed in patients dying with renal disease and

advanced hepatic schistosomiasis [7]. In our own patients' biopsy specimens, although the membranoproliferative form occurs in about 50% of the total,

there are cases of acute diffuse proliferative gbmerulonephritis, rapidly progressive glomerulonephritis, focal glomerular sclerosis, membranous gbomerulopathy, and end-stage kidney disease. In a case of membranous glomerubopathy, observed in a 13-year-old boy with massive schistosome infection [32], there was a moderate mesangial cell prolifera-

tion besides the basement membrane thickening with silver-positive 'spikes." Electron microscopic studies [9, 12, 18, 29, 33, 34] have shown the presence of electron-dense deposits both in the basement membrane near the mesangial cells and in the mesangial area itself (Figs. 1 and 2). In this area, the presence of large, laminated, electron-dense bodies was sometimes noted. Patho genesis and immunopathology

There is good evidence that schistosomal glomerubopathy results from deposition of immune complexes in the glomeruli of the affected host. Immunofluorescent studies have revealed IgG, 1gM, IgE, occasionally IgA and -1-C protein in glomerular deposits along the glomerular basement membrane

-

CL

I.

tt$1.

J

Fig. 1. Electron-dense deposits (D) in basement membrane (BM) and especially in the mesangium (M) in the glomerulus of a 23-year-old woman with glomerulopathy and schistosomal hepatosplenic disease (X12,000).

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Andrade and Rocha

Fig. 2. A picture similar to Fig. 1, with electron-dense deposits in mesangial area (probably immune-complex deposits), in the renal glomerulus of a mouse infected 64 days before with 100 S. mansoni cercariae (x25,650).

and mesangial areas of heavily infected experimental animals [9, 11-14] and humans [25, 26, 30, 33, 34J. Also, electron micrography of the glomerular

tegument or the intestinal lining. In 1961, Okabe and Tanaka [21j documented the presence of a

lesions reveal electron-dense deposits within the mesangium and along the endothelial side of the basement membrane. This latter finding supports the concept that the renal damage of schistoso-

the urine of rabbits and humans. Later, a schistosome antigen was detected in the serum [201 and urine [221 of mice and hamsters heavily infected with S. mansoni. This antigen was later character-

miasis is of immunologic origin. The true nature of these immune complexes, and more important, of their antigenic component, however, is not understood. Initially it was thought that they were formed by antigens from the worm or its products and antibodies produced by the host. This hypothesis progressively received strength from several studies. More than 60 immunogenic constituents have been extracted from adult worms, cercariae, and schistosomula [35j. Only few of them, however, appear

ized as a high-molecular-weight polysaccharide [36]

on exposed sites of the adult worms, such as the

culating worm antigens have been well character-

dialyzable and thermostable schistosome antigen in

and was found only in the intestinal lining of the adult worm [371. This location is important because the worm regurgitates the antigen along with ingested blood into the circulation of the host. This anti-

gen also has been demonstrated in the primordial esophagus of cercarie and in the developing intestinal tube of the schistosomule [381, and this finding may explain the early detection of this material in the serum of infected animals. Several other cir-

27

Schistosomal glomerulopathy

ized in infected animals. Recently, Deelder et al [39] characterized a low-molecular-weight substance in

the serum and urine of hamsters heavily infected with S. mansoni as well as in secretory products of

the adult worm. Thus far, this purified polysaccharide antigen could not be made immunogenic

for rabbits, and its role in the pathogenesis of the glomerulopathy is unknown. It may be related to the M antigen detected in the urine of infected patients [231. Besides the adult worm antigens, the eggs are another important source of schistosomal antigens. A soluble egg antigen (SEA) plays a major

role in the periovular granulomatous reaction, but so far SEA has not been implicated in the pathogenesis of the glomerular lesions in schistosoma-infected hosts. Antibodies to several antigenic fractions of the schistosome worm or its products can be detected in infected animals and humans [40, 41]. These serum antibodies react with several antigenic fractions derived from mature eggs, cercaria, schistosomula, and from living and dead worms. Schistosomal antigens and antibodies have been detected in the milk of mothers with S. mansoni infection [421.

Circulating antigen-antibody complexes have been demonstrated in experimental animals and hu-

mans with schistosomiasis [24, 43, 441, and the highest titers of complexes were found in patients having the hepatosplenic form of the disease or as-

sociated nephropathy [45]. The reasons why the glomerular involvement in schistosomiasis appears to be limited to the hepatosplenic form of the disease deserve a special comment. (1) It seems important that the polysaccharide antigen described has been detected only in serum and urine of heavily infected hosts. Normally, as has been suggested [9, 14, 461, this polysaccharide antigen is removed from the circulation by reticuloendothelial cells (similarly to other high-molecular-weight poiysaccharides), and only when the RES is saturated does the antigen appear in the circulation. In this respect, it is important that patients with the hepatosplenic form of schistosomiasis generally have a greater parasitic load. (2) It has been shown that the induction of colateral portal circulation by partial portal vein ligation resulted in greater deposition of immunoglobulins and complement in the glomeruli of mice infected with S. mansoni [14]. This finding suggested that diversion of immune complexes from filtration by the Kupifer cells results in a greater op-

portunity for them to reach the kidneys and other organs of the systemic circulations. It is of interest that in hepatosplenic schistosomiasis there is a col-

lateral circulation due to pre sinusoidal portal vein obstruction in practically all cases. (3) Finally, it is of interest that occurrence of glomerular lesions are

related to the development of the hepatosplenic form of the disease. It has been shown that baboons infected with S. mansoni do not develop portal fibrosis, and, in this species, even heavy infections do not result in glomerular lesions [47]. Likewise, in

humans heavily infected with S. haematobium, liver damage is less severe, and the disease is accompanied rarely by glomerulopathy [481. Definite evidence that schistosome antigen or antigens are present in the immune-complex glomerular disease observed in humans and animals has appeared only recently. Earlier studies probably failed

to demonstrate specific antigens in the glomeruli, because of the lack of a potent antischistosomal sera. More recently, Tada et al [11] were able to demonstrate the presence of coarse granular deposition of IgG, 1gM, IgA, and IgE, together with /3-1-C mainly in mesangial area in monkeys heavily

infected with S. japonicum. Schistosoma antigens were also detected in the mesangium and along the glomerular capillary wall. The authors pointed out the unique feature of IgE deposition in this nephritis. All these findings have been duplicated in human patients [25, 26]. Immunoglobulins which react

with the intestinal lining and tegument of adult S. mansoni have been eluted from the kidneys of patients with schistosomal glomerulopathy [49]. Therapy

Treatment of patients with schistosomal glomerulopathy has been disappointing. Patients having the

nephrotic syndrome with membranoproliferative glomerulonephritis or focal glomerular sclerosis often do not respond to therapy with corticosteroids

and or cyclophosphamide [50]. The use of antischistosomal drugs alone or in association with corticosteroids and immunosuppressors also does not

improve the results. The few cases that have responded well to therapy have been followed for 2 and 3 years, without recrudescence, but more eval-

uation is needed. Thus far, the use of antischistosomal drugs such as oxamniquine or hycan-

thone does not seem to have had any immediate deleterious effect on renal function of the patients, as judged by lack of changes in proteinuria, urea and creatinine levels, and creatinine clearences. In any case, it seems logical to use antischistosomal drugs in patients with schistosomal glomerulopathy. Elimination of the worms and their antigens in

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Andrade and Rocha

early glomerular involvement could be curative, but this awaits a well-documented proof. Acknowledgments

This work was supported by grants (SIP 08/126 and PDE 06/2/04) from the Conselho Nacional de Desenvolvimento Cientifico e Technolçgico CNPq. Reprint requests to Dr. Z. A. Andrade, Department of Pathology, University of Bahia Medical School, Salvador, Bahia, Bra-

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