Laboratory Investigation

Kidney International (1985) 27, 643–651; doi:10.1038/ki.1985.59

Role of terminal complement pathway in the heterologous phase of antiglomerular basement membrane nephritis

Gerald C Groggel, David J Salant, Christine Darby, Helmut G Rennke and William G Couser

The Evans Memorial Department of Clinical Research and the Department of Medicine, University Hospital, Boston University Medical Center, and the Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts; and the Division of Nephrology, Department of Medicine, University of Washington, Seattle, Washington, USA

Correspondence: Dr G C Groggel, Division of Nephrology, Department of Medicine, University of Utah Medical Center, Salt Lake City, Utah 84132, USA

Received 23 May 1984; Revised 2 October 1984.

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Abstract

Role of terminal complement pathway in the heterologous phase of antiglomerular basement membrane nephritis. Terminal complement components, including the membrane attack complex, have been demonstrated in glomeruli of patients with immune complex and anti-GBM nephritis. We recently demonstrated the functional significance of C6 in the mediation of experimental membranous nephropathy in rabbits. In the present study, the role of C6 was examined in the heterologous phase of rabbit anti-GBM nephritis by studying normal and C6-deficient (C6D) rabbits. In C6D rabbits, C6 hemolytic activity was less than 0.01% of control. All control rabbits became heavily proteinuric in the first 24 hr following injection of a standard dose of sheep anti-rabbit GBM antibody (mean, 42.0 plusminus 26.3; range, 18.4 to 83.5 mg protein/mg creatinine, N = 5). In contrast, C6D rabbits excreted a mean of only 5.1 plusminus 5.5 mg/mg creatinine (range, 0.06 to 14.4, N = 6, P = 0.002). Protein excretion in normal rabbits was less than 0.06 mg/mg creatinine. Both control and C6D rabbits had similar deposits of sheep anti-rabbit GBM IgG in glomeruli when measured by radiolabeling techniques (control 15.8 plusminus 2.71, N = 5; C6D 18.7 plusminus 1.99 microg of sheep IgG/104 glomeruli, N = 6, P > 0.05). Control rabbits had a greater rise in serum creatinine in the first 24 hr (1.74 plusminus 1.15 vs. 0.53 plusminus 0.44 mg/dl, P < 0.05). Both groups had similar deposits of sheep IgG and rabbit C3 by IF. By light microscopy at 4 and 24 hr, both groups had qualitatively similar proliferative changes and similar numbers of neutrophils infiltrating glomeruli. C6 is critical in the mediation of proteinuria and decreased renal function in the heterologous phase of anti-GBM nephritis in rabbits thus demonstrating a requirement for this terminal complement component for full expression of this form of glomerular injury.

Rôle de la voie terminale du complément dans la phase hétérologue de la néphrite anti-membrane basale glomérulaire. Les facteurs complémentaires terminaux dont le complexe d'attaque membranaire ont été démontrés dans les glomérules de malades atteints de néphrite à complexes immuns et anti-GBM. Nous avons récemment démontré la signification fonctionnelle du C6 dans la médiation d'une néphropathie extra-membraneuse expérimentale chez des lapins. Dans cette étude, le rôle du C6 a été examiné à la phase hétérologue d'une néphrite anti-GBM de lapin par l'étude de lapins normaux et déficients en C6 (C6D). Chez les lapins C6D, l'activité hémolytique du C6 était de moins de 0,01% du contrôle. Tous les lapins contrôles devenaient très protéinuriques dans les 24 premières heures après injection d'une dose standard d'anticorps de mouton anti-GBM de lapin (moyenne, 42,0 plusminus 26,3; extrêmes 18,4 à 83,5 mg protéine/mg créatinine, N = 5, P = 0,002). A l'opposé, les lapins C6D excrétaient une moyenne de seulement 5,1 plusminus 5,5 mg/mg créatinine (extrême 10,06 à 14,4, N = 6, P = 0,002). L'excrétion protéique de lapins normaux était de moins de 0,06 mg/mg créatinine. Les lapins contrôles et C6D avaient des dépôts semblables d'IgG de mouton anti-GBM de lapin dans leurs glomérules, mesurés par des techniques de radio-marquage (contrôles 15,8 plusminus 2,71, N = 5; C6D 18,7 plusminus 1,99 microg d'IgG de mouton/104 glomérules, N = 6, P > 0,05). Les lapins contrôles avaient une élévation plus forte de leur créatinine sérique lors des 24 premières heures (1,74 plusminus 1,15 contre 0,53 plusminus 0,44 mg/dl, P < 0,05). Les deux groupes avaient des dépôts d'IgG de mouton et de C3 de lapin identiques en IF. En microscopie optique à 4 et 24 heures, les deux groupes avaient des modification prolifératives qualitativement identiques, et des nombres de neutrophiles infiltrant les glomérules semblables. Le C6 est critique dans la médiation de la protéinurie et de la diminution de la fonction rénale au cours de la phase hétérologue de la néphrite anti-GBM de lapin, démontrant ainsi la nécessité de ce facteur terminal du complément pour une expression complète de cette forme d'atteinte glomérulaire.

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