Mesangial proliferative glomerulonephritis in murine malaria parasite, Plasmodium chabaudi AS, infected NC mice.

BACKGROUND: Malaria is an important tropical disease and has remained a serious health problem in many countries. One of the critical complications of malarial infection is renal injury, such as acute renal failure and chronic glomerulopathy. Few animal models of nephropathy related to malarial infection have been reported. Therefore, we developed and investigated a novel malarial nephropathy model in mice infected by murine malaria parasites. METHODS: NC mice and C57BL/6J mice were infected with Ttwo different murine malaria parasites, Plasmodium (P.) chabaudi AS and P. yoelii 17X. After the infection, renal pathology and blood and urinary biochemistry were analyzed. RESULTS: NC mice infected by the murine malaria parasite P. chabaudi AS, but not P. yoelii 17X, developed mesangial proliferative glomerulonephritis with endothelial damage, and decreased serum albumin concentration and increased proteinuria. These pathological changes were accompanied by deposition of immunoglobulin G and complement component 3, mainly in the mesangium until day 4 and in the mesangium and glomerular capillaries from day 8. On day 21, renal pathology developed to focal segmental sclerosis according to light microscopy. In C57BL/6J mice, renal injuries were not observed from either parasite infection. CONCLUSION: The clinical and pathological features of P. chabaudi AS infection in NC mice might be similar to quartan malarial nephropathy resulting from human malaria parasite P. malariae infection. The NC mouse model might therefore be useful in analyzing the underlying mechanisms and developing therapeutic approaches to malaria-related nephropathy.

Activation of autophagy and nucleotide-binding domain leucine-rich repeat-containing-like receptor family, pyrin domain-containing 3 inflammasome during Leishmania infantum-associated glomerulonephritis.

Chronic kidney disease is a major contributor to human and companion animal morbidity and mortality. Renal complications are sequelae of canine and human visceral leishmaniasis (VL). Despite the high incidence of infection-mediated glomerulonephritis, little is known about pathogenesis of VL-associated renal disease. Leishmania infantum-infected dogs are a naturally occurring model of VL-associated glomerulonephritis. Membranoproliferative glomerulonephritis type I [24 of 25 (96%)], with interstitial lymphoplasmacytic nephritis [23 of 25 (92%)], and glomerular and interstitial fibrosis [12 of 25 (48%)] were predominant lesions. An ultrastructural evaluation of glomeruli from animals with VL identified mesangial cell proliferation and interposition. Immunohistochemistry demonstrated significant Leishmania antigen, IgG, and C3b deposition in VL dog glomeruli. Asymptomatic and symptomatic dogs had increased glomerular nucleotide-binding domain leucine-rich repeat-containing-like receptor family, pyrin domain containing 3 and autophagosome-associated microtubule-associated protein 1 light chain 3 associated with glomerular lesion severity. Transcriptional analyses from symptomatic dogs confirmed induction of autophagy and inflammasome genes within glomeruli and tubules. On the basis of temporal VL staging, glomerulonephritis was initiated by IgG and complement deposition. This deposition preceded presence of nucleotide-binding domain leucine-rich repeat-containing-like receptor family, pyrin domain containing 3-associated inflammasomes and increased light chain 3 puncta indicative of autophagosomes in glomeruli from dogs with clinical VL and renal failure. These findings indicate potential roles for inflammasome complexes in glomerular damage during VL and autophagy in ensuing cellular responses.

Catching the Worm Early: An Atypical Case of Bancroftian Filarial Nephropathy.

Filarial glomerular disease has been attributed to circulating immune complex deposition. We report here a rare manifestation of filarial nephropathy with microfilariae documented in glomerular capillaries in addition to immune complex glomerulonephritis, thus suggesting that direct toxicity may also contribute to the pathogenesis of this entity.

Ultrastructural pathological changes in mice kidney caused by Plasmodium berghei infection.

Malaria, a common health problem in certain parts of the world, has a considerable morbidity and mortality. This work reports under electron microscopy studies serious ultrastructural kidney damage such as extensive cytoplasmic vacuolation, vesiculation and autophagic vacuoles in proximal tubular cells. A thickened endothelial wall on peritubular capillary, interdigitation disorganization and significant decrease of their number in some areas were detected. Swollen rough endoplasmic reticulum, swollen mitochondria, and parasitized erythrocytes were observed. Many epithelial cells exhibited cytoplasmic areas of autophagia and a myelin-like form. A tubular cell presented severe cytoarchitecture alterations. Abundant lipid droplets were noticed. Almost total loss of interdigitations, rough endoplasmic reticulum vesiculation, peritubular capillaries with endothelial cells thickened cytoplasm, papillary processes projected to the lumen, and an inflammatory infiltrate of macrophages were also observed. These ultrastructural kidney changes could cause, on the basis of their clinical and pathologic expressions, a fat accumulation, an acute temporary reversible glomerulonephritis, a chronic progressive irreversible glomerulonephritis, and an acute renal failure (ARF).

Immune complex-mediated glomerulopathy in Barbus graellsi infected with Myxobolus spp.

Membranous glomerulonephritis caused in Barbus graellsi by myxosporidian infections have been studied by electron microscopy and immunoelectron microscopy techniques. This study indicates that Myxosporidian infection produces a chronic severe aggression. Spores reach the spleen, the kidney and the liver, where they are trapped and phagocyted by Melano Macrophage Centres. Consequently, the commencement of a immunological response to myxosporidian is evident. Our results show the presence of immunodeposits in the basement membrane of the glomeruli, suggesting that they might initiate glomerulonephritis. The lesion was markedly similar to immune complex-mediated glomerulonephritis disease in higher vertebrates.

Human schistosomiasis: Schistosoma mansoni antigen detection in renal glomeruli.

Twelve kidney, five biopsy and seven necropsy specimens, all from schistosomiasis mansoni patients were studied by light and immunoflurescent microscopy in an attempt to detect antigen in the glomerular walls. Deposits of IgM, IgG,I gA, IgE, complement C3 and fibrinogen were observered in most cases. Antigen was successfully detected in two cases(one biopsy and one necropsy specimen), both exhibiting proliferative glomerulonephritis. The only clinical manifestation was a slight proteinuria. IgG antibodies eluted from the sutopsy kidney homogenates showed specific binding mostly to Schistosoma mansoni gut, thus spggesting that the fixed antibodies (eluates) are, at least partially, consituted by antibodies similar to the anti-circulating antigen. These data reinfroce the hypothesis that renal injury in schistosomiasis is mediated through an immune complex disease.

Histological assessment of tissue repair after treatment of human schistosomiasis.

Schistosomiasis is one of the main health problems hindering socio-economic development in Egypt. It affects millions at an early age, diminishing productivity and exerting a significant socio-economic impact. Schistosomiasis endemicity in Egypt varies in different areas. Schistosoma mansoni, with a prevalence generally ranging between 20 to 40%, has replaced Schistosoma haematobium in the Nile Delta, and the latter is now localized to upper Egypt with low endemicity levels (5-10%). The pathology of schistosomiasis consists essentially of a series of chronic inflammatory lesions produced in and around blood vessels by eggs or their products and sometimes by dead adult worms. If the ova continued to be deposited in sufficient numbers and over several years, they would ultimately lead to progressive fibrosis of the portal tracts and urinary bladder, or may be carried in blood and become trapped in the lungs, gastro-intestinal and genital tracts with only occasional association with other organs. The etiology of human pipe-stem fibrosis is still not understood. The host immune response and frequency of exposure and the time of re-infection interval appear to be involved in the overall process of fibrosis. Additional factors are probably involved in the human disease as genetic host susceptibility, malnutrition, repeated infections and repeated treatment, mixed infections including hepatitis, tuberculosis and typhoid. Reversibility of the fibrosis might be related to the proportion of the collagen types present. Immuno-histopathological demonstration of various types of collagen confirms the importance of time for administration of the treatment and period of follow-up. According to previous studies, the timing for treatment affects the reversibility of liver fibrosis emphasizing the importance of early treatment of schistosomiasis to prevent complications.

Kidney ultrastructural lesions in dogs experimentally infected with Dirofilaria immitis (Leidy, 1856).

Kidneys of 16 beagles with experimentally induced heartworm (Dirofilaria immitis) infections and 4 heartworm-nai;ve dogs were studied by light and electron microscopy. The infections were induced either by subcutaneous injection of infective larvae or by the transplantation of adult parasites, and infection periods varied from 111 to 818 days and 365 to 923 days, respectively. One control group of heartworm-naïve dogs and four groups of heartworm-infected dogs, which were divided according to the type and the length of infection, were used. In the infected dogs, thickening of the glomerular basement membrane (GBM), the presence of dense deposits in the GBM, and foot process effacement were the most frequent lesions observed. In some dogs, electron dense deposits were seen in the GBM and the mesangium and/or enlargement of the mesangial matrix could be characterized. The longer the infection period, the thicker the GBM and the more common the occurrence of foot process effacement. In general, these alterations were more evident in animals that had been infected for more than 1 year, had high microfilaremia, and had 14 or more parasites in the main pulmonary artery and its branches. The presence of dense deposits suggests that the pathogenesis of kidney disease in dirofilariasis is associated with deposits of immune complexes in the membrane. The finding of ultrastructural changes in dogs with early prepatent infections suggests that immature heartworms, as well as microfilariae and possibly adult worms, contribute to the glomerulonephropathy.

[The Queixadinha Project: morbidity and control of schistosomiasis in an endemic area in the northeast of Minas Gerais, Brazil]. / O Projeto Queixadinha: a morbidade e o controle da esquistossomose em área endêmica no nordeste de Minas Gerais, Brasil.

In an endemic area for schistosomiasis in the northeast of the state of Minas Gerais in Brazil 516 individuals have been submitted to clinical and laboratory examination, ultrasonography of the abdomen and dopplerecocardiography in order to define the morbidity of schistosomiasis before and after treatment. A high prevalence of schistosomiasis (66.3%) and of severe disease (9.5% with palpable spleens) were recorded. Ultrasonography classified liver periportal fibrosis as light (19.4%), moderate (27.6%) and intense (6.8%), and 46.0% presented no periportal fibrosis. Twenty one out of the 53 individuals (39.6%) with palpable spleens did not present liver fibrosis on ultrasound. Periportal lymph nodes were described in 33.8% of the population and anti-KLH antibodies were found in the serum of 40.7%. Urinary alterations compatible with the glomerulopathy of schistosomiasis were observed in 4.5% of the population, and 11.7% of the individuals examined by dopplerecocardiography had pulmonary hypertension. Twelve months after treatment for schistosomiasis the prevalence of the disease dropped from 66.3% to 25.0%. In Queixadinha, a profile of the morbidity of schistosomiasis has just been established.

Schistosoma mansoni: kinetics of glomerulonephritis in Mongolian gerbils and its correlation with intensity and duration of infection.

The frequent occurrence of glomerular lesions in schistosomiasis patients has been reported, although appropriate animal models for the study of schistosomal glomerulonephritis have not been developed. To analyze the relationship between glomerulonephritis and Schistosoma mansoni infection, gerbils, Meriones unguiculatus, were infected with different number of cercariae and sacrificed at different weeks of post infection. Fifty cercariae were the optimum dose to produce the disease, glomerulonephritis, without early death of the animal. Infected gerbils showed heterogeneous types of glomerular lesions with increased serum creatinine level. Immune complex deposition was not detected at glomeruli of infected gerbils even by means of immunuofluorescence and also by transmission electron microscopy. However, infiltration of mononuclear cells in and around some of the altered glomeruli was observed. Immunohistochemical staining, using monoclonal antibody (HUSM-M.g. 15) specific to gerbil's T-cells, revealed significant infiltration of T-cells. These findings suggest that T-cells might be involved in the development of glomerulonephritis. Gerbil could be a useful model to clarify the role of T-cells in the development of glomerulonephritis of schistosomiasis.

Fine structure of Sarcocystis singaporensis merogony stages preceding sarcocyst formation in the rat.

The fine structure of merogony stages of Sarcocystis singaporensis (Zaman and Colley, 1975) is described from experimentally infected laboratory rats, 10 days after being fed sporocysts obtained from naturally infected Python reticulatus from Singapore. Infection was shown to consist exclusively of S. singaporensis. Parasites developed in the endothelial cells of the lungs, brain, kidney and heart. Infection comprised meronts prior to division, dividing and divided meronts, and dispersed merozoites. Undivided meronts developed deep pellicular invaginations and extensions of the nucleus toward the cell boundary, seemingly to sustain metabolic exchange. The course of merogonous development was the same in all organs. Hypertrophy of the endothelium induced by invading merozoites appeared to lead to obstruction of the capillary lumen.

Surface antigen detected by a Schistosoma mansoni monoclonal antibody in worm extracts and kidney deposits of infected mice and hamsters.

Four monoclonal antibodies (MAbs) derived from a Schistosoma mansoni-infected mouse reacted against the tegument or the cell layer of the digestive tract of the adult worm. They also showed similar patterns of immunofluorescence staining when schistosomula were used as antigens. Two of the MAbs (4A10 and 4D3) recognized immune complexes deposited in the kidneys of infected mice and hamsters as detected by indirect and direct immunofluorescence reactions. When adsorbed to polystyrene beads, both MAbs allowed the quantitative detection of antigen by an enzyme immunoassay. 125I-labeled 4A10 binding to live schistosomula and corresponding inhibition assay ruled out the possibility that this binding could be through its Fc fragment. The same MAb detected an antigen migrating as an 80-kilodalton protein by Western blot analysis of soluble worm antigen preparation after sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Use of MAb 4A10 may help to elucidate mechanisms of renal pathology and also be of value in the development of immunodiagnostic assays.

Factors influencing the passage of Onchocerca volvulus microfilariae into the urine.

The effect of various substances on the output of Onchocerca volvulus microfilariae in the urine was investigated in volunteers infected with the Cameroon forest and Sudan-savanna strains of the parasite. Output of microfilariae in the urine tended to be higher during periods of normal activity than during sleep. During waking hours, the rate of output remained generally steady, but in some patients occasional showers of microfilariae appeared in the urine, possibly associated with the intake of food and drink. Drinking 1.2-2.5 litres water produced a shower of microfilariae in the urine of some subjects. This began within an hour of drinking and its onset preceeded that of the diuresis. Thiazide diuretics, acting on the convoluted tubules, produced no increase in microfilaruria. In savanna subjects intravenous injection of DT TAB vaccine caused pyrexia, and simultaneously large numbers of microfilariae appeared in the urine. There was no associated diuresis, and no increase in the concentration of microfilariae in the venous blood. In forest subjects DT TAB caused no increase in microfilaruria. In all subjects 25-50 mg diethylcarbamazine (DEC) caused large numbers of microfilariae to appear in the urine on day 0, within a few hours of the first dose; and there was an increased output of urine over the first 24 hours. Microfilaruria declined sharply on day 1 of treatment, but in subjects developing a high microfilaraemia, it rose again on day 2, and declined more slowly thereafter. Betamethazone, given in conjunction with DEC, appeared to slow the rate of destruction of microfilariae in the skin and lymph glands, and to prolong the duration of microfilaraemia and microfilaruria. The findings suggest that there is a reservoir of microfilariae in the glomerular capillaries, which fills slowly by accumulating microfilariae from the circulating blood. The microfilariae probably enter the urine by penetrating the glomerular capillary.

Modification by a latent contaminant of glomerular pathology in mice infected with Plasmodium berghei.

This study was designed to determine, by means of electron microscopy, the effect of latent contaminants-which are associated with the syringe passage of the parasite-on the findings in the glomeruli of P. berghei-infected mice. A rapid alteration of the glomerular basement membrane was observed in mice infected with the syringe-transmitted N strain, but not in those infected with the cyclically passaged Nig strain. Glomerular changes were also seen in mice inoculated with nonparasitized blood from normal mice, obtained after 16 passages by syringe. It appears that these changes were provoked by a latent contaminant that had proliferated after passages of the parasite through mice, and that they constitute a secondary immune reaction.

[Coincidental appearance of PKD and Sphaerospora sp. (Myxosporidia) in stock of Salmo gairdneri (Osteichthyes)]. / Koinzidentes Auftreten von PKX und Sphaerospora sp. (Myxosporidia) in Beständen von Salmo gairdneri (Osteichthyes).

For the first time in Europe simultaneous occurrence of PKX and Sphaerospora sp. is recorded in Salmo gairdneri. Myxosporidian (?) forms hitherto not described have been observed in the kidney interstitium and the epithelium of the renal tubules, sporadically also in the swimbladder wall and the intestinal wall, besides the typical PKX organism in the kidney interstitium. Sporogonic stages and spores of a Sphaerospora species have been found in the lumen of the renal tubules. Neither the exact identification of the Sphaerospora species has been possible, nor the final proof, whether the luminal form, the hitherto undescribed extraluminal forms and PKX belong to one another.

Characterisation of kidney lesions in early schistosomal-specific nephropathy.

In this work 42 patients with active Schistosoma mansoni infection and renal involvement were examined. Of these, 16 had asymptomatic proteinuria (group I) and 26 had the nephrotic syndrome (group II). Fifteen nonschistosomal patients with idiopathic nephrotic syndrome were included as control cases (group III). Renal biopsy specimens were obtained from all patients and controls. These were examined by light microscopy (LM), by direct immunofluorescence microscopy using antisera against human IgG, IgM, IgA, C3, C4, C1q, and fibrinogen, and by indirect immunofluorescence microscopy using monoclonal antibodies directed against the circulating schistosome antigens, circulating anodic antigen (CCA) and circulating cathodic antigen (CCA). Schistosomal-specific deposits were seen in the renal glomeruli in 24 of the 42 schistosomal patients but in none of the 15 control patients. Although schistosomal-specific deposits were seen in seven of the 16 patients presenting with asymptomatic proteinuria, no morphological changes could be seen by LM. On the other hand, schistosomal-specific deposits could be seen in the kidneys of 17 of the 26 patients presenting with the nephrotic syndrome. All but one specimen showed morphological changes when examined by LM. These were consistent with mesangioproliferative glomerulonephritis in seven, focal segmental glomerulosclerosis in five, mesangiocapillary glomerulonephritis in two, membranous glomerulonephritis in one, and focal segmental hyalinosis in one patient. The present study clearly suggests that (a) schistosomal-specific nephropathy does exist in human settings, (b) it is an immune complex disease, and (c) CAA and CCA are major responsible antigens.