Abstract
Purpose The ocular fundi of many patients with membranoproliferative glomerulonephritis type II (MPGN-II) are characterised by the presence of deposits within Bruch's membrane that resemble drusen, hallmark lesions associated with age-related macular degeneration (AMD). Glomerulonephritis (GN)-associated drusen appear at a younger age, however, than do drusen in individuals with AMD. In light of recent evidence that immune-mediated events participate in drusen biogenesis and AMD, we examined the structure and composition of drusen in eyes obtained from human donors with two distinct glomerulopathies, both of which involve complement deposition within glomeruli. These features were compared with those of drusen from patients with clinically documented AMD.
Methods Eyes obtained from two human human donors diagnosed with membranous and post-streptococcal GN, respectively, were analysed histochemically, immunohistochemically and ultrastructurally.
Results Subretinal pigment epithelial (RPE) deposits in both types of GN are numerous and indistinguishable, both structurally and compositionally, from drusen in donors with AMD. GN-associated drusen exhibit sudanophilia, bind filipin, and react with antibodies directed against vitronectin, complement C5 and C5b-9 complexes, TIMP-3 and amyloid P component. Drusen from the membranous GN donor, but not the post-streptococcal GN donor, reacted with peanut agglutinin and antibodies directed against MHC class II antigens and IgG. The ultrastructural characteristics of these deposits were also identical with those of AMD-associated drusen.
Conclusions The composition and structure of ocular drusen associated with membranous and post-streptococcal/segmental GN are generally similar to those of drusen in individuals with AMD. In view of the recent data supporting the involvement of complement activation in drusen biogenesis and the pathobiology of AMD, further studies of the biological relationships between AMD and diseases associated with complement activation are warranted.
Similar content being viewed by others
Article PDF
References
Bird AC, Bressler NM, Bressler SB, Chisholm IH, Coscas G, Davis MD, et al. An international classification and grading system for age-related maculopathy and age-related macular degeneration. The International ARM Epidemiological Study Group. Surv Ophthalmol 1995;39:367–74.
Sarks SH . Drusen patterns predisposing to geographic atrophy of the retinal pigment epithelium. Aust J Ophthalmol 1982;10:91–7.
Gass JDM . Stereoscopic atlas of macular diseases: diagnosis and treatment. St Louis: CV Mosby, 1987.
Bressler NM, Bressler SB, Seddon JM, Gragoudas ES, Jacobson LP . Drusen characteristics in patients with exudative versus non-exudative age-related macular degeneration. Retina 1988;8:109–14.
Bressler SB, Maguire G, Bressler NM, Fine SL . Relationship of drusen and abnormalities of the retinal pigment epithelium to the prognosis of neovascular macular degeneration. Arch Ophthalmol 1990;108:1442–7.
Pauleikhoff D . Drusen in Bruch's membrane: their significance for the pathogenesis and therapy of age-associated macular degeneration. Ophthalmologe 1992;89:363–86.
Holz FG, Wolfensberger TJ, Piguet B, Gross-Jendroska M, Wells JA, Minassian DC, et al. Bilateral macular drusen in age-related macular degeneration: prognosis and risk factors. Ophthalmology 1994;101:1522–8.
Risk factors for choroidal neovascularization in the second eye of patients with juxtafoveal or subfoveal choroidal neovascularization secondary to age-related macular degeneration. Macular Photocoagulation Study Group. Arch Ophthalmol 1997;115:741–7.
Gorin MB, Jackson KE, Ferrell RE, Sheffield VC, Jacobson SG, Gass JD, et al. A peripherin/retinal degeneration slow mutation (Pro-210-Arg) associated with macular and peripheral retinal degeneration. Ophthalmology 1995;102:246–55.
Piguet B, Heon E, Munier FL, Grounauer PA, Niemeyer G, Butler N, et al. Full characterization of the maculopathy associated with an Arg-172-Trp mutation in the RDS/ peripherin gene. Ophthalmic Genet 1996;17:175–86.
Stone EM, Lotery AJ, Munier FL, Heon E, Piguet B, Guymer RH, et al. A single EFEMP1 mutation associated with both Malattia Leventinese and Doyne honeycomb retinal dystrophy. Nature Genet 1999;22:199–202.
Duvall-Young J, MacDonald MK, McKechnie NM . Fundus changes in (type II) mesangiocapillary glomerulonephritis simulating drusen: a histopathological report. Br J Ophthalmol 1989;73:297–302.
Raines MF, Duvall-Young J, Short CD . Fundus changes in mesangiocapillary glomerulonephritis type II: vitreous fluorophotometry. Br J Ophthalmol 1989;73:907–10.
Duvall-Young J, Short CD, Raines MF, Gokal R, Lawler W . Fundus changes in mesangiocapillary glomerulonephritis type II: clinical and fluorescein angiographic findings. Br J Ophthalmol 1989;73:900–6.
Leys A, Michielsen B, Leys M, Vanrenterghem Y, Missotten L, Van Damme B . Subretinal neovascular membranes associated with chronic membranoproliferative glomerulonephritis type II. Graefes Arch Clin Exp Ophthalmol 1990;228:499–504.
Leys A, Vanrenterghem Y, Van Damme B, Syners B, Pirson Y, Leys M . Fundus changes in membranoproliferative glomerulonephritis type II: a fluorescein angiographic study of 23 patients. Graefes Arch Clin Exp Ophthalmol 1991;229:406–10.
O'Brien C, Duvall-Young J, Brown M, Short C, Bone M . Electrophysiology of type II mesangiocapillary glomerulonephritis with associated fundus abnormalities. Br J Ophthalmol 1993;77:778–80.
D'Souza Y, Duvall-Young J, McLeod D, Short C, Roberts ISD, Bonshek RE . Ten year review of drusen-like lesions in mesangiocapillary glomerulonephritis-II. Invest Ophthalmol Vis Sci (Suppl) 2000;41:S164.
Couser WG . Glomerulonephritis. Lancet 1999;353:1509–15.
Framme C, Herboth T, Roider J, Laqua H . [Subretinal neovascular membranes in membranoproliferative glomerulonephritis type II]. Klin Monatsbl Augenheilkd 1998;213:252–3.
Hageman GS, Mullins RF, Russell SR, Johnson LV, Anderson DH . Vitronectin is a constituent of ocular drusen and the vitronectin gene is expressed in human retinal pigmented epithelial cells. FASEB J 1999;13:477–84.
Russell SR, Mullins RF, Schneider BL, Hageman GS . Basal laminar drusen are indistinguishable in location, substructure, and composition from drusen associated with aging and age-related macular degeneration. Am J Ophthalmol 2000;129:205–14.
Mullins RF, Johnson LV, Anderson DH, Hageman GS . Characterization of drusen-associated glycoconjugates. Ophthalmology 1997;104:288–94.
Mullins RF, Hageman GS . Human ocular drusen possess novel core domains with a distinct carbohydrate composition. J Histochem Cytochem 1999;47:1533–9.
Hageman GS, Mullins RF . Molecular composition of drusen as related to substructural phenotype. Mol Vis 1999;5:28.
Mullins RF, Anderson DH, Russell SR, Hageman GS . Ocular drusen contain proteins common to extracellular deposits associated with atherosclerosis, elastosis, amyloidosis, and dense deposit disease. FASEB J 2000;14:835–46.
Curcio CA, Millican CL, Bailey T, Kruth HS . Accumulation of cholesterol with age in human Bruch's membrane. Invest Ophthalmol Vis Sci 2001;42:265–74.
Sarks SH, Sarks JP, ??, In: Ryan S, editor. The retina. St Louis: CV Mosby, 1989.
Wolter JR, Falls HF . Bilateral confluent drusen. Arch Ophthalmol 1962;68:219–26.
Farkas TG, Sylvester V, Archer D, Altona M . The histochemistry of drusen. Am J Ophthalmol 1971;71:1206–15.
Pauleikhoff D, Zuels S, Sheraidah GS, Marshall J, Wessing A, Bird AC . Correlation between biochemical composition and fluorescein binding of deposits in Bruch's membrane. Ophthalmology 1992;99:1548–53.
Fariss RN, Apte SS, Olsen BR, Iwata K, Milam AH . Tissue inhibitor of metalloproteinases-3 is a component of Bruch's membrane of the eye. Am J Pathol 1997;150:323–8.
Vranka JA, Johnson E, Zhu X, Shepardson A, Alexander JP, Bradley JM, et al. Discrete expression and distribution pattern of TIMP-3 in the human retina and choroid. Curr Eye Res 1997;16:102–10.
Hellmark T, Burkhardt H, Wieslander J . Goodpasture disease: characterization of a single conformational epitope as the target of pathogenic autoantibodies. J Biol Chem 1999;274:25862–8.
Mullins RF, Speth CR, Schneider BL, Hageman GS . Compositional and ultrastructural analyses suggest a role for a cell-mediated process in drusen biogenesis. Exp Eye Res (Suppl) 1998;67:S101.
Anderson DH, Hageman GS, Mullins RF, Neitz M, Neitz J, Ozaki S, et al. Vitronectin gene expression in the adult human retina. Invest Ophthalmol Vis Sci 1999;40:3305–15.
Johnson LV, Ozaki S, Staples MK, Erickson PA, Anderson DH . A potential role for immune complex pathogenesis in drusen formation. Exp Eye Res 2000;70:441–9.
Jahn B, Von Kempis J, Kramer KL, Filsinger S, Hansch GM . Interaction of terminal complement components C5b-9 with synovial fibroblasts: binding to the membrane surface leads to increased levels of collagenase-specific mRNA. Immunology 1993;78:329–34.
Kilgore KS, Schmid E, Shanley TP, Flory CM, Maheswari V, Tramontini NL, et al. Sublytic concentrations of the membrane attack complex of complement induce endothelial interleukin-8 and monocyte chemoattractant protein-1 through nuclear factor-kappa B activation. Am J Pathol 1997;150:2019–31.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Mullins, R., Aptsiauri, N. & Hageman, G. Structure and composition of drusen associated with glomerulonephritis: Implications for the role of complement activation in drusen biogenesis. Eye 15, 390–395 (2001). https://doi.org/10.1038/eye.2001.142
Issue Date:
DOI: https://doi.org/10.1038/eye.2001.142
This article is cited by
-
Ocular retinal findings in asymptomatic patients with antiphospholipid syndrome secondary to systemic lupus erythematosus
Clinical Rheumatology (2023)
-
Stages, pathogenesis, clinical management and advancements in therapies of age-related macular degeneration
International Ophthalmology (2023)
-
Retinal drusen in glomerulonephritis with or without immune deposits suggest systemic complement activation in disease pathogenesis
Scientific Reports (2022)
-
Retinal drusen counts are increased in inflammatory bowel disease, and with longer disease duration, more complications and associated IgA glomerulonephritis
Scientific Reports (2022)
-
Increased retinal drusen in IgA glomerulonephritis are further evidence for complement activation in disease pathogenesis
Scientific Reports (2022)