Asunto(s)
Suero Antilinfocítico/uso terapéutico , Rechazo de Injerto/prevención & control , Inmunosupresores/uso terapéutico , Trasplante de Riñón/inmunología , Ácido Micofenólico/análogos & derivados , Adolescente , Adulto , Azatioprina/uso terapéutico , Biopsia , Cadáver , Femenino , Rechazo de Injerto/epidemiología , Rechazo de Injerto/patología , Humanos , Terapia de Inmunosupresión/métodos , Incidencia , Trasplante de Riñón/patología , Masculino , Ácido Micofenólico/uso terapéutico , Donantes de Tejidos , Trasplante HomólogoRESUMEN
Increased urinary excretion of C5b-9 distinguishes passive Heymann nephritis from other forms of experimental glomerulonephritis in the rat. In the passive Heymann nephritis (PHN) model of membranous nephropathy (MN) subepithelial deposits form from anti-Fx1A antibody reacting with antigen expressed on the glomerular epithelial cell membrane followed by membrane patching and shedding of immune complexes. Immune complex deposits are accompanied by deposits of C5b-9 which is required for the mediation of proteinuria. We tested the hypothesis that C5b-9 assembly on the epithelial cell membrane might result in C5b-9 excretion in the urine, which would distinguish this autoimmune mechanism of MN from other processes that result in subepithelial immune complex deposits. Using monoclonal antibodies developed to rat C6 and a rat C5b-9 neoantigen, in a sensitive ELISA assay, elevated urinary excretion of rat C5b-9 was documented in PHN associated with on-going glomerular immune deposit formation. No urinary C5b-9 was detectable in MN induced by an exogenous antigen (cationized IgG) despite equivalent glomerular C5b-9 deposits, or in models of nephrotoxic nephritis, subendothelial immune complex nephritis, anti-mesangial cell membrane antibody-induced nephritis or two non-immune nephropathies. Infusion of preformed C5b-9 in proteinuric animals excluded glomerular filtration of C5b-9 as a contributing mechanism to urinary C5b-9 excretion. We conclude that in the rat, increased urinary excretion of C5b-9 is a marker of MN induced by antibody to a glomerular epithelial cell antigen. Urine C5b-9 excretion reflects active glomerular immune deposit formation and distinguishes MN induced by this mechanism from other forms of MN as well as from other glomerular diseases with equivalent glomerular C5b-9 deposits.
Asunto(s)
Proteínas del Sistema Complemento/metabolismo , Glomerulonefritis/orina , Animales , Anticuerpos Monoclonales , Complejo Antígeno-Anticuerpo/inmunología , Complejo de Ataque a Membrana del Sistema Complemento , Ensayo de Inmunoadsorción Enzimática , Técnica del Anticuerpo Fluorescente , Glomerulonefritis/inmunología , Glomérulos Renales/inmunología , Masculino , RatasRESUMEN
To obtain a better understanding of the sequential development of sclerosis in immune glomerular disease, the authors induced experimental membranous nephropathy in unilaterally nephrectomized rats and evaluated the lesions that developed over a 35-week period. Serial renal biopsies were examined by light and immunofluorescence microscopy for IgG, C3, neoantigens of the membrane attack complex (MAC), and interstitial (Type III) and basement membrane (Type IV) collagen. Urinary protein excretion increased from 208 +/- 19 mg/day to 308 +/- 36 mg/day during the period of observation. Progressive mesangial sclerosis, crescent formation, and interstitial fibrosis developed in association with deposition of Type IV but not Type III collagen in the glomeruli. Capillary wall deposits of IgG, C3, and MAC gradually decreased, whereas coarse granular deposits of C3 and MAC were visible in sclerotic areas beginning at 8 weeks. The appearance of complement components in early sclerotic lesions raises the possibility that they are of pathogenetic importance. The absence of interstitial collagen in sclerotic glomeruli suggests that the components of the lesion are produced solely by glomerular cells.
Asunto(s)
Glomérulos Renales/patología , Animales , Técnica del Anticuerpo Fluorescente , Enfermedades Renales/patología , Microscopía Fluorescente , Ratas , Esclerosis , OvinosRESUMEN
The complement (C) system is an important mediator of glomerular injury both through its attraction of inflammatory cells and by a cell-independent effect on glomerular capillary wall permeability. We have postulated that the latter effect may be mediated by the terminal components of the C system, the membrane attack complex (MAC). We examined several models of immunologic renal injury in the rat by immunofluorescence for the presence of neoantigens of the MAC. Rats with experimental membranous nephropathy induced by antibody binding to a fixed glomerular antigen (passive Heymann nephritis, PHN) or a planted antigen (autologous phase of PHN) had moderate proteinuria and 1-2+ capillary wall deposits of IgG, rat C3, and MAC. C depletion with cobra venom factor (CVF) significantly decreased proteinuria and prevented deposition of C3 and MAC. Rats with active Heymann nephritis had similar capillary wall deposits of MAC. Rats with anti-glomerular basement membrane nephritis developed severe proteinuria which was not affected by CVF treatment and had no glomerular deposits of MAC. Rats with nonimmunologic proteinuria induced by aminonucleoside of puromycin also had no glomerular deposits of MAC. In rats unilaterally nephrectomized before the induction of PHN segmental glomerular sclerosis developed after 6 months with deposits of MAC in the sclerotic areas. The presence or absence of glomerular deposits of MAC in experimental renal disease correlates well with the pathogenetic role of C in the production of injury. These results support a role for the MAC in the mediation of several types of glomerular injury.