RESUMEN
Interstitial injury is the hallmark of glomerulonephritis which is progressing to end-stage renal disease (ESRD). In humans and experimental animals, we have shown that interstitial disease is accompanied by up-regulation of complement components in tubular epithelial cells. Glomerulonephritis was induced in mice by the intraperitoneal injection of horse spleen apoferritin (HSA) and lipopolysaccharide (LPS). In addition to wild-type C57/B6 mice, animals in which the C5a receptor had been deleted (C5aR KO) were used. Animals were killed after 3 or 6 weeks, and kidneys harvested. At three weeks, both groups had evidence of mild mesangial matrix expansion and increased cellularity; there were no crescents, sclerotic lesions, or interstitial disease. At six weeks, glomerular lesions were advanced, but identical in the two groups. Both groups had evidence of an identical pattern of C3 gene expression in the tubular epithelium by in situ hybridization. There was a marked difference, however, in the extent of interstitial injury. Wild-type animals had significantly greater numbers of infiltrating interstitial cells, greater expansion of the peritubular space, more tubular atrophy, and more apoptotic tubular cells than did C5aR KOs. The anaphylotoxic fragment of C5, C5a, is not likely to be important in the glomerular component of this model of progressive glomerulonephritis. On the other hand, the interstitial component is markedly attenuated in knockout animals. These data support a role for complement in the interstitial component of this glomerulonephritis model. They are consistent with our hypotheses of a role for complement in the progression of some forms of glomerulonephritis to ESRD.
Asunto(s)
Glomerulonefritis/inmunología , Enfermedades del Complejo Inmune/inmunología , Animales , Animales Congénicos , Antígenos CD/genética , Antígenos CD/fisiología , Apoferritinas/toxicidad , Apoptosis , Atrofia , Activación de Complemento , Complemento C3/biosíntesis , Complemento C3/genética , Células Epiteliales/metabolismo , Regulación de la Expresión Génica , Glomerulonefritis/patología , Glomerulonefritis/orina , Hematuria/etiología , Caballos , Enfermedades del Complejo Inmune/patología , Enfermedades del Complejo Inmune/orina , Hibridación in Situ , Glomérulos Renales/patología , Túbulos Renales/metabolismo , Túbulos Renales/patología , Lipopolisacáridos/toxicidad , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Modelos Animales , Proteinuria/etiología , Receptor de Anafilatoxina C5a , Receptores de Complemento/deficiencia , Receptores de Complemento/genética , Receptores de Complemento/fisiologíaRESUMEN
Interleukin-1 is one of the most important pro-inflammatory cytokines whose role in the pathogenesis of glomerulonephritic process was proved in numerous studies. The aim of this study was to determine the urinary level of this cytokine in patients with primary immunocomplex glomerulonephritis and its significance in diagnosis of this disease. This prospective study comprised a total of 96 patients (84 males and 12 females) with primary immunocomplex glomerulonephritis. The elevated urinary IL-1 beta level was noticed in 43 (49.4%) patients with different histological forms of glomerulonephritis. The mean concentration was significantly higher in patient's group (57.7 +/- 120.7 pg/mg creatinine) (range 1.1-731) compared to control group (10.2 +/- 5.96 pg/mg creatinine) (range 1.6-25.4) (p < 0.05). There was no significant difference in the frequency of elevated urinary IL-1 beta concentration in different patients group based on histological type of glomerulonephritis (chi 2 = 6.377, p > 0.05). On the basis of our results we concluded that the elevated concentration of IL-1 beta in majority of patients with primary immunocomplex glomerulonephritis had suggested its role in the pathogenesis of glomerulonephritic process. The urinary level of IL-1 beta represents a novel, non-invasive parameter in the diagnosis of this disease, but its measurement is not useful in predicting the histological type of primary immunocomplex glomerulonephritis. The results of our study suggest the possibility that urinary IL-1 beta level reflects the activity of glomerulonephritic process and it could be useful in non-invasive monitoring of the disease progression.
Asunto(s)
Glomerulonefritis/orina , Enfermedades del Complejo Inmune/orina , Interleucina-1/orina , Biomarcadores/orina , Biopsia con Aguja , Creatinina/orina , Femenino , Glomerulonefritis/diagnóstico , Glomerulonefritis/inmunología , Glomerulonefritis/patología , Humanos , Enfermedades del Complejo Inmune/diagnóstico , Enfermedades del Complejo Inmune/inmunología , Riñón/patología , MasculinoRESUMEN
Biochemical changes in plasma and urine were monitored in six cats before and during the induction of immune complex-mediated glomerulonephritis (ICGN) by daily intravenous administration of human serum albumin (HSA). The earliest indication of renal dysfunction in the cats was hypoalbuminaemia, which occurred as early as 13 weeks before cats developed clinical signs of renal disease. Proteinuria occurred 2 to 3 weeks before clinical disease, but was sensitive in predicting renal pathology in two cats that did not develop clinical signs of disease. In addition, increased activities of several urinary enzymes were detected in affected cats, with measurement of N-acetyl-beta-D-glucosaminidase and gamma-glutamyl transferase providing the earliest and most sensitive indication of renal damage. These plasma and urine measurements correlated more closely with the renal pathology, observed at postmortem, than clinical assessment of disease. It was concluded that ICGN in the cat could be diagnosed earliest by measurement of plasma protein concentration, whilst disease progress could be effectively monitored by including assays to measure urine protein and urine enzymes.
Asunto(s)
Enfermedades de los Gatos/sangre , Glomerulonefritis/veterinaria , Enfermedades del Complejo Inmune/veterinaria , Animales , Enfermedades de los Gatos/enzimología , Enfermedades de los Gatos/orina , Gatos , Glomerulonefritis/sangre , Glomerulonefritis/enzimología , Glomerulonefritis/orina , Enfermedades del Complejo Inmune/sangre , Enfermedades del Complejo Inmune/enzimología , Enfermedades del Complejo Inmune/orina , Proteinuria/veterinariaRESUMEN
Immunohistochemical methods were used to investigate the role of macrophages in the progression of proliferative immune complex glomerulonephritis. The mononuclear cell component of glomerular inflammation was analysed in three different stages of chronic serum sickness, each of which was clearly distinguished by criteria of kidney function. Urinary excretion of the macrophage secretory products interleukin-1 and tumour necrosis factor was also evaluated in relation to the functional severity of kidney disease. T lymphocytes and macrophages began to accumulate in glomeruli at the onset of proteinuria, but not before. Urinary excretion of interleukin-1 also began with proteinuria. Proteinuria increased in direct correlation with increases in the number of glomerular macrophages. Development of the most severe stage of glomerulonephritis, characterized by cachexia, declining kidney function, and necrotizing glomerular pathology, was accompanied by the disappearance of T cells from glomeruli and the expression of highly abnormal phenotypes by most macrophages. In addition, there was a switch from urinary excretion of interleukin-1 to excretion of tumour necrosis factor. The progression of proliferative immune complex glomerulonephritis was associated with qualitative as well as quantitative changes in glomerular macrophage populations. Differentiation and/or activation of those glomerular macrophages may have resulted from local T cell-mediated immunoregulation. Measurements of urinary cytokine excretion provided a reliable means of monitoring disease progression. The local action of tumour necrosis factor probably contributed to declining kidney function in the most severe stage of disease.
Asunto(s)
Factores Biológicos/orina , Glomerulonefritis/inmunología , Enfermedades del Complejo Inmune/inmunología , Glomérulos Renales/inmunología , Macrófagos/fisiología , Animales , Citocinas , Femenino , Glomerulonefritis/orina , Enfermedades del Complejo Inmune/orina , Interleucina-1/orina , Activación de Macrófagos , Ratas , Ratas Endogámicas Lew , Índice de Severidad de la Enfermedad , Linfocitos T/fisiología , Factor de Necrosis Tumoral alfa/orinaRESUMEN
Indomethacin has been used to lower proteinuria in human glomerular diseases with controversial results. The mechanism of indomethacin beneficial effects has not been established. A possible explanation is that indomethacin reduces proteinuria by inhibiting the synthesis of renal prostaglandins (PGs); however, appropriate studies to address this issue have never been done. The objectives of the present study were: to investigate whether indomethacin influences protein excretion in an experimental model of immunologically-mediated glomerular disease; to establish if the possible favorable effect of indomethacin on proteinuria is related to a reduction in glomerular filtration rate (GFR); to establish the possible association between the antiproteinuric effect of indomethacin and its inhibitory effect on arachidonic acid (AA) metabolites of renal or extrarenal origin; and to further investigate the relationship between proteinuria and renal thromboxane (Tx) synthesis previously demonstrated in experimental models of nephrotoxic nephritis and adriamycin (ADR) nephrosis. To this purpose we used an experimental immune-complex disease, passive Heymann nephritis (PHN) which was induced in the rat by a single intravenous (i.v.) injection of heterologous serum directed against a brush border component (gp 330 antigen). Indomethacin at a dose of 6 mg/kg intraperitoneally (i.p.) administered for four consecutive days to PHN animals during the period of heavy proteinuria, effectively reduced urinary protein excretion. The reduction in proteinuria does not appear to be a consequence of a reduction in GFR as documented by inulin clearance. Glomerular synthesis and urinary excretion of vasodilatory prostacyclin (PGI2) and PGE2 were decreased or unchanged in PHN animals in respect to control animals.(ABSTRACT TRUNCATED AT 250 WORDS)
Asunto(s)
Glomerulonefritis/tratamiento farmacológico , Enfermedades del Complejo Inmune/orina , Indometacina/uso terapéutico , Proteinuria , Animales , Dinoprostona , Glomerulonefritis/metabolismo , Glomerulonefritis/patología , Imidazoles/farmacología , Enfermedades del Complejo Inmune/fisiopatología , Técnicas In Vitro , Pruebas de Función Renal , Glomérulos Renales/efectos de los fármacos , Glomérulos Renales/metabolismo , Glomérulos Renales/fisiopatología , Masculino , Microvellosidades/inmunología , Prostaglandinas E/metabolismo , Prostaglandinas E/orina , Ratas , Ratas Endogámicas , Tromboxano B2/biosíntesis , Tromboxano B2/orina , Factores de TiempoRESUMEN
An experimental glomerulonephritis was produced in mice by an injection with a sub-nephrotoxic dose of nephrotoxic serum after immunization with rabbit IgG. In order to examine the susceptibility of disease, we tested the onset of nephritis in 6 different strains (ICR,C57BL/6,C3H,DBA/2, nu/nu and DDY) of mice. Strain C57BL/6 mice indicated the highest susceptibility to the disease with a high degree of reproducibility. The excretion of protein in urine, the elevation of serum cholesterol and blood urea nitrogen level and the decrease of serum albumin were observed in nephritic mice. Typical histopathological changes in the kidney were crescent formation in glomeruli, thickening of glomerular basement membrane and cast of urinary tubuli. Cyclophosphamide, at doses of 5 and 10 mg/kg, inhibited the development of nephritis in C57BL/6 mice. These results suggest that the experimental glomerulonephritis model in C57BL/6 mice is useful for immunopharmacological studies of nephritis.
Asunto(s)
Glomerulonefritis/inmunología , Enfermedades del Complejo Inmune/etiología , Animales , Nitrógeno de la Urea Sanguínea , Ciclofosfamida/uso terapéutico , Glomerulonefritis/tratamiento farmacológico , Glomerulonefritis/orina , Enfermedades del Complejo Inmune/tratamiento farmacológico , Enfermedades del Complejo Inmune/orina , Inmunización , Masculino , Ratones , Ratones Endogámicos , Ratones Desnudos , Proteinuria/metabolismo , Especificidad de la EspecieAsunto(s)
Glomerulonefritis/etiología , Enfermedades del Complejo Inmune/etiología , Riñón/efectos de la radiación , Animales , Femenino , Glomerulonefritis/patología , Glomerulonefritis/orina , Enfermedades del Complejo Inmune/patología , Enfermedades del Complejo Inmune/orina , Riñón/inmunología , Riñón/patología , Corteza Renal/efectos de la radiación , Médula Renal/efectos de la radiación , Túbulos Renales/efectos de la radiación , Nefroesclerosis/etiología , Nefroesclerosis/patología , Nefroesclerosis/orina , Tamaño de los Órganos , Vacuna contra la Tos Ferina , Ratas , Rayos XRESUMEN
Urine from eight normal controls in whom an influenza-like illness developed contained high concentrations of fibrin-degradation products (F.D.P.), IgG, and C3. The study was carried out when influenza A was prevalent in the community. However, a wide range of serological investigations revealed no evidence for influenza A or other viruses. The infection may have been caused by other viruses which produce upper-respiratory-tract infections and which are not readily diagnosed by serology. Urinary fibrin-degradation products are a well-known marker of glomerulonephritic activity and viral antigens may have induced an immune-complex glomerulonephritis in the 8 controls in whom an influenza-like disease developed. A larger normal population should be investigated during a virus epidemic.
Asunto(s)
Complemento C3/análisis , Proteínas del Sistema Complemento/análisis , Productos de Degradación de Fibrina-Fibrinógeno/orina , Inmunoglobulina G/orina , Gripe Humana/orina , Virosis/orina , Ritmo Circadiano , Glomerulonefritis/etiología , Glomerulonefritis/inmunología , Glomerulonefritis/orina , Humanos , Enfermedades del Complejo Inmune/etiología , Enfermedades del Complejo Inmune/orina , Gripe Humana/complicaciones , Gripe Humana/inmunología , Proteinuria/orina , Virosis/complicaciones , Virosis/inmunologíaRESUMEN
The quantity of urinary proteins and their molecular weight composition was analyzed in different experimental glomerulopathies using the SDS-PAA-electrophoresis. Masugi nephritis, heterologous and autologous immune complex nephritis as well as D-penicillamine induced glomerulonephritis were studied in rabbits, guinea pigs and rats. The procedure allows (1) to distinguish physiological from low grade glomerular proteinuria by their respective characteristic patterns in early disease stages (2) to follow up the disease course of individual animals without sacrifice and (3) to discriminate species specificity of physiological urinary proteins. It is recommended to use this technique of urinary protein analysis in experimental conditions, where mild glomerular damage is expected.
Asunto(s)
Glomerulonefritis/orina , Proteinuria , Animales , Enfermedades Autoinmunes/orina , Modelos Animales de Enfermedad , Electroforesis en Gel de Poliacrilamida , Glomerulonefritis/etiología , Cobayas , Enfermedades del Complejo Inmune/orina , Peso Molecular , Penicilamina , Proteinuria/diagnóstico , Conejos , Ratas , Especificidad de la EspecieRESUMEN
The altered functional properties of the glomerular capillary wall in a model of autologous immune complex disease (Heymann's nephritis) was studied by electron microscopy using intravenously injected protein tracers of varying molecular weight. There was an increase in the permeability of the glomerular basement membrane (GBM) itself to large molecules; this change was focal and was found in those areas where the GBM contained immune complex deposits. Both ferritin and catalase, tracers normally restricted from passing the glomerular filter, were present in the urinary space within minutes of injection. No evidence was obtained for increased glomerular epithelial transport in this disease. Foot process swelling and "close" junction formation was moderate, even in animals with marked degrees of proteinuria. Indirect evidence, therefore, makes an alteration in the slit pore complex likely. In addition, there was immediate and selective concentration of all tracers within deposits, though ferritin was partially excluded from some deposits. This phenomenon may be of significance in the perpetuation of the disease.