Deposition of the Membrane Attack Complex in Healthy and Diseased Human Kidneys.

Jacob J E Koopman,Aiko P J De Vries,Mieke F Van Essen,Cees Van Kooten,Helmut G Rennke

doi:10.3389/fimmu.2020.599974

Jacob J E Koopman, Aiko P J De Vries + Show 3 more

Open Access

https://doi.org/10.3389/fimmu.2020.599974

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Abstract

The membrane attack complex—also known as C5b-9—is the end-product of the classical, lectin, and alternative complement pathways. It is thought to play an important role in the pathogenesis of various kidney diseases by causing cellular injury and tissue inflammation, resulting in sclerosis and fibrosis. These deleterious effects are, consequently, targeted in the development of novel therapies that inhibit the formation of C5b-9, such as eculizumab. To clarify how C5b-9 contributes to kidney disease and to predict which patients benefit from such therapy, knowledge on deposition of C5b-9 in the kidney is essential. Because immunohistochemical staining of C5b-9 has not been routinely conducted and never been compared across studies, we provide a review of studies on deposition of C5b-9 in healthy and diseased human kidneys. We describe techniques to stain deposits and compare the occurrence of deposits in healthy kidneys and in a wide spectrum of kidney diseases, including hypertensive nephropathy, diabetic nephropathy, membranous nephropathy, IgA nephropathy, lupus nephritis, C3 glomerulopathy, and thrombotic microangiopathies such as the atypical hemolytic uremic syndrome, vasculitis, interstitial nephritis, acute tubular necrosis, kidney tumors, and rejection of kidney transplants. We summarize how these deposits are related with other histological lesions and clinical characteristics. We evaluate the prognostic relevance of these deposits in the light of possible treatment with complement inhibitors.

Highlights

The membrane attack complex is the end-product of the three complement pathways: the classical, lectin, and alternative pathway
C3 glomerulopathy is regarded a disease of an activated alternative pathway, characterized by deposition of C3 but no or scarce deposition of immunoglobulins or other complement factors
In kidney diseases due to deposition of immune complexes and kidney diseases due to activation of the alternative pathway, glomerular deposits of C5b-9 colocalized with immune deposits containing immunoglobulins or other complement factors (44, 57, 67, 73, 75, 81, 96, 126, 143, 218)

Summary

INTRODUCTION

The membrane attack complex is the end-product of the three complement pathways: the classical, lectin, and alternative pathway. In the few studies conducted on patients who had IgA vasculitis with nephritis, deposits of C5b-9 were present in the mesangium and capillary wall, colocalized with IgA and C3–containing immune complexes (52, 61, 75, 85, 99, 139), along the tubular basement membrane, and in the vascular wall (75, 96). Descriptive studies on mostly small numbers of patients reported ubiquitous deposits in the glomerulus (18, 46, 58, 72, 77, 81, 95, 96, 111, 119, 133, 139, 143, 170, 171)—both in the mesangium and along the capillary wall (18, 44, 57, 67, 75, 111, 172–174) and sometimes along Bowman’s capsule (119, 171) —, linearly or granularly along the tubular basement membrane (18, 44, 57, 67, 70, 72, 75, 95, 96, 119, 142, 151, 171), and in the vascular wall (18, 57, 67, 72, 95, 96, 119, 171). With similar clinical characteristics and serum complement levels, the successfully treated case differed only by exhibiting histological thrombotic microangiopathy (108)

Glomerulopathy

Findings

DISCUSSION