2002/01/01 by Israel Nussenzveig, I Nussenzveig, Thales de Brito +5
Immunology and Microbiology · Medicine · #Liver Disease and Transplantation #Pancreatitis Pathology and Treatment #Parasites and Host Interactions
paper · pdf · doi:10.1093/ndt/17.1.4
openalex publication_date 2002/01/01 · openalex created_date 2025/10/10 · openalex updated_date 2026/07/30
A recent immuno‐electron microscopy (IM‐EM) study was conducted on a series of patients with [1] schistosomal glomerulopathy (SG) using a monoclonal anti‐Schistosoma mansoni antibody obtained from adult worms. IM‐EM allows precise localization of schistosomal antigen deposits in glomerular structures. Based on this work and on the experience accumulated along the years with this disease at the Institute of Tropical Medicine and at the Nephrology Division of the ‘Hospital das Clinicas’ (São Paulo University Medical School), we review here the difficulties involved in diagnosing SG and emphasize some differences from the Egyptian equivalent reviewed by Barsoum et al. [2,3]. In his editorial review, Barsoum [2] suggested the classification of SG into five histopathological categories: mesangio‐proliferative glomerulonephritis (GN), membrano‐proliferative glomerulonephritis, focal and segmental glomerulosclerosis (FSGS), exudative glomerulonephritis and amyloidosis. Exudative glomerulonephritis was associated with chronic salmonellosis, amyloidosis and with both recurrent salmonellosis and persistent Escherichia coli urinary tract infections, but was not related to mansonian schistosomal infection. Earlier studies have suggested mesangio‐proliferative glomerulonephritis and membrano‐proliferative glomerulonephritis type I to be the more common forms of SG [1,4,5]. Clinically, patients with this disease may either be asymptomatic, with only minor urinary alterations like mild proteinuria or haematuria, or may manifest a nephrotic syndrome which may evolve to end‐stage renal failure [6]. Membrano‐proliferative glomerulonephritis is often marked by hypo‐complementaemia, with low CH50, C3 and C4 levels, suggesting complement activation by the classical pathway. Membrano‐proliferative glomerulonephritis type III is found infrequently, and was associated with concomitant hepatitis B by Barsoum [2]. De Brito et al. [7] documented the transformation of mesangio‐proliferative glomerulonephritis into membrano‐proliferative glomerulonephritis. The factors involved in this evolution are unknown. It seems that mesangio‐proliferative glomerulonephritis, with glomerular IgM and C3 usually detected by immunofluorescence microscopy (IF), is probably the earlier and most frequent histopathological pattern of schistosomal‐associated glomerulopathy. Experimental models using various animal species [8] are compatible with findings in humans, thus strongly suggesting that the mesangial area is the first and principal target of parasitic antigen(s). Schistosomal glomerulopathy was initially described in patients with the hepato‐splenic form of the disease. However, a biopsy study by Sobh et al. [6] of 15 patients who presented with only proteinuria revealed six cases of focal mesangio‐proliferative glomerulonephritis, three of them with the hepato‐splenic and three with the hepato‐intestinal forms of the disease. Abensur et al. [10] reported 24 patients with the hepato‐intestinal form of the disease whose kidney biopsies showed various histopathological lesions clinically manifesting as nephrotic syndrome. Therefore, the existence of portal hypertension and porto‐systemic shunts is important but not essential for the development of nephrotic syndrome in SG. In the differential diagnosis of SG it is of importance to exclude hepatitis B and C. In hepatitis B‐associated glomerulopathy, which frequently is accompanied by nephrotic syndrome, the pattern is often of membranous glomerulonephritis. However, there are references to mesangio‐proliferative and membrano‐proliferative glomerulonephritis in association with this disease [11]. Immuno‐fluorescence shows glomerular deposits of IgG, IgM and C3. Therefore, neither light nor IF microscopy can distinguish SG from hepatitis B virus‐associated glomerulopathy. Transmission electron microscopy seldom shows virus‐like microtubular structures in glomerular endothelial cells in these cases. With specific sera, IF can detect antigens such as HBs, HBe and HBc in glomeruli. The simultaneous finding of schistosomal antigen(s) in the glomeruli of these patients might suggest either a double aetiology for the glomerular changes or a passive trapping of one of the antigens in a previously damaged glomerulus. Regarding hepatitis C, the most frequent renal manifestation is ‘cryoglobulinaemic glomerulopathy’, which presents as a nephrotic syndrome in most patients, and usually has the histopathologic pattern of membrano‐proliferative glomerulonephritis type I or type III and infrequently of mesangio‐proliferative glomerulonephritis and membranous glomerulopathy. Along with clinical manifestations of cryoglobulinaemia, glomeruli with a large number of leukocytes— most of them macrophages—are seen on renal biopsy [12]. Intraluminal thrombi are found in more than one third of the cases of cryoglobulinaemic nephropathy, a finding not described in schistosomal glomerulopathy. IF shows IgG, IgM and C3 in the mesangium, capillary walls and thrombi. Johnson et al. [12] reported that in 30–40% of patients the C virus‐induced glomerulopathy may be present without cryoglobulinaemia. European nephrologists, however, exclude this possibility [13–15]. De Brito et al. [16] encountered a false positive reaction to S. mansoni antigen by IM‐EM in one patient with hepatitis C whose epidemiology, clinical and laboratory data permitted the exclusion of schistosomiasis. The possibility was raised of a correlation of false positive serologic tests for hepatitis C with high IgG concentrations and circulating immune complexes, conditions which are common in patients with schistosomiasis [17,18]. Therefore, if hepatitis C virus‐induced glomerulopathy without cryoglobulinaemia occurs, it will be impossible to distinguish this condition from SG by IM‐EM in schistosomal patients positive for hepatitis C virus. The third histopathological pattern proposed for SG is FSGS. This lesion has been noted in experimental conditions in baboons and hamsters [8,19]. In humans the incidence of FSGS varies from 11.2 to 38% of cases of SG [2]. Abensur et al. (10) found FSGS in 25% of their SG patients. Light and IF microscopy showed findings similar to those of idiopathic FSGS. FSGS was present in two of the nine patients of De Brito et al. [1]: in one with deposits of C3 and in the other with IgM and C3 in the mesangium. There are two possible explanations for FSGS in schistosomiasis. There currently is no way to distinguish between the two possibilities. (A) ‘Primary’ FSGS: in this circumstance schistosomiasis should be included among the aetiologies of FSGS (in the same category as HIV). (B) Secondary FSGS: the lesions must be regarded as secondary to the cicatrization of focal mesangio‐proliferative glomerulonephritis. Two patients in the series described by De Brito et al. [1] had membranous nephropathy and minimal‐change disease, respectively. Membranous nephropathy does not feature in the histopathological classification suggested by Barsoum [2], and this pattern is not seen in experimental models of mansonian schistosomiasis [8]. Among the 17 human cases described by Sobh et al. [6], however, four exhibited membranous glomerulopathy. Abensur et al. [10] found two cases of membranous glomerulopathy among a total of 24 schistosomotic patients (8.3%). An 18‐year‐old white male with glomerular deposits of schistosomal antigen was found to have a normal kidney on IM‐EM, except for slight mesangial proliferation detected by light microscopy, and repeatedly negative findings by IF [1]. That patient had hepato‐intestinal schistosomiasis, nephrotic syndrome and normal renal function. In this patient glomerular schistosomal antigenic deposits were present in the absence of immunoglobulins and complement. Treated with prednisone as minimal‐change disease case, the patient progressed to a complete remission, which has lasted for about 5 years. Houba [8] described similar findings in baboons experimentally infected with S. mansoni and suggested that antigens may be deposited (‘planted’) directly in the glomeruli. Taken together, these findings might suggest that different patterns of glomerulopathies may be related to S. mansoni infections (Fig. 1). It should be kept in mind, however, that schistosomiasis is a disease with chronic antigenaemia, and that the worm survives in the human host for 15–20 years. Therefore, it is possible that schistosomal antigens might passively impregnate (so‐called non‐immunological trapping) glomerular structures previously injured by other agents. If so, glomerulopathies like membranous glomerulopathy and minimal‐change disease, albeit already having been described in conjunction with infectious diseases [20–23], might be idiopathic, with passive antigen deposits in the glomerulus. Sobh et al. [6] also suggested that an associated nephropathy of non‐schistosomotic aetiology might have been present in those of their patients whose kidney biopsies were negative for CAA and CCA antigens. IM‐ME contributes to the understanding of some pathogenic mechanisms, but does not rule out concurrent glomerular pathologies. Suggested pathogenesis of the glomerulopathies associated with mansonian schistosomiasis. The association of amyloidosis and SG was addressed specifically in a paper by Sadigursky and Andrade [24], who reviewed 53 autopsies of patients with hepatosplenic schistosomiasis and did not find renal amyloidosis in any of them. In their review of SG, Andrade and van Marck [5] did not mention an association of schistosomiasis with amyloidosis. Moreover, in a review of biopsy and autopsy cases in the Department of Pathology (São Paulo Medical School, Brazil) this association was mentioned only once [25]. Therefore, here in Brazil, amyloidosis is not a frequent finding in schistosomiasis mansoni patients. Glomerular deposits of IgA were described by Barsoum et al. [3] in patients with advanced schistosomal glomerulopathy and their role in the progression of the disease was discussed. Our experience in Brazil has shown, however, that glomerular IgA deposits are scarce and found infrequently. De Brito et al. [17] mentioned only deposits of IgG, IgM, and C3 in their study of eleven schistosomotic patients with advanced glomerular lesions. Among the nine cases described by De Brito et al. [1], only the patient with membranous glomerulopathy showed Ig A (+), and Ig G (++), IgM (+) and C3 (+) in the glomeruli. El‐Sherif and Befus [26] infected mice using cercariae from Puerto Rico and demonstrated a predominance of IgA in glomerular deposits, thus giving experimental support to Barsoum's contentions. As a whole, these data might suggest geographical differences in some pathogenetic mechanisms of SG. Clinical, epidemiological, pathological and experimental data suggest that mesangio‐proliferative and membrano‐proliferative glomerulonephritis are more commonly associated with mansonian schistosomiasis. They also are frequently associated with other infections like hepatitis, which suggests that a similar pathogenetic pathway may be present. However, the precise diagnosis of SG and also of hepatitis‐associated glomerulopathies is complicated by the possibility that passive trapping of antigens may occur in a previously damaged glomerulus. In the differential diagnosis of SG, infectious diseases such as hepatitis B and C should be excluded. It is possible that there are geographical differences between the Brazilian and Egyptian diseases, for amyloidosis and glomerular IgA deposits are usually absent in Brazilian patients. There is insufficient data, so far, relevant to the specificity of the histopathological patterns seen in human S. mansoni‐associated glomerulopathy. Correspondence and offprint requests to: Dr Israel Nussenzveig, Hospital das Clinicas da FMUSP, Divisão de Nefrologia, Av. Dr. Enéas de Carvalho Aguiar 255, 05403‐000, São Paulo, SP, Brazil. Email: [email protected] Financial support for this project was provided by CNPq (300857/94–2‐NV) and LIM 06.