Clinico-Pathogenic Similarities and Differences between Infection-Related Glomerulonephritis and C3 Glomerulopathy

Abstract

Recently, the comprehensive concept of "infection-related glomerulonephritis (IRGN)" has replaced that of postinfectious glomerulonephritis (PIGN) because of the diverse infection patterns, epidemiology, clinical features, and pathogenesis. In addition to evidence of infection, hypocomplementemia particularly depresses serum complement 3 (C3), with endocapillary proliferative and exudative GN developing into membranoproliferative glomerulonephritis (MPGN); also, C3-dominant or co-dominant glomerular immunofluorescence staining is central for diagnosing IRGN. Moreover, nephritis-associated plasmin receptor (NAPlr), originally isolated from the cytoplasmic fraction of group A Streptococci, is vital as an essential inducer of C3-dominant glomerular injury and is a key diagnostic biomarker for IRGN. Meanwhile, "C3 glomerulopathy (C3G)", also showing a histological pattern of MPGN due to acquired or genetic dysregulation of the complement alternative pathway (AP), mimics C3-dominant IRGN. Initially, C3G was characterized by intensive "isolated C3" deposition on glomeruli. However, updated definitions allow for glomerular deposition of other complement factors or immunoglobulins if C3 positivity is dominant and at least two orders of magnitude greater than any other immunoreactant, which makes it challenging to quickly distinguish pathomorphological findings between IRGN and C3G. As for NAPlr, it was demonstrated to induce complement AP activation directly in vitro, and it aggravates glomerular injury in the development of IRGN. A recent report identified anti-factor B autoantibodies as a contributing factor for complement AP activation in pediatric patients with PIGN. Moreover, C3G with glomerular NAPlr deposition without evidence of infection was reported. Taken together, the clinico-pathogenic features of IRGN overlap considerably with those of C3G. In this review, similarities and differences between the two diseases are highlighted.

Keywords: C3 glomerulopathy; complement alternative pathway; infection-related glomerulonephritis; membranoproliferative glomerulonephritis; nephritis-associated plasmin receptor.

Figure 1

Characteristic pathological findings of C3-dominant infection-related glomerulonephritis (IRGN) and of C3 glomerulonephritis (C3GN). Representative photos of C3-dominant IRGN (A–D) and C3GN (E–H) diagnosed in our hospital. (A,E): The glomerulus shows endocapillary and mesangial proliferative change (periodic acid-Schiff stain; original magnification ×400). (B,F) immunofluorescence (IF) staining for C3 shows strong positivity, mainly on capillary walls and partially in the mesangial area (original magnification ×400). (C,G) IF staining for IgG shows weak positivity or negative on capillary walls (original magnification ×400). (D,H) Electron microscopy shows scattered small-sized subepithelial electron-dense deposits (EDDs) in C3 dominant IRGN and different-size EDDs in the subendothelial and paramesangial area in C3GN (original magnification ×1000).

Figure 2

A simple classification of MPGN based on the findings of IF staining and the difference in the state of complement activation. The MPGN pattern detected by light microscopy is divided into immunoglobulin-positive or immunoglobulin-negative on IF staining. It is suspected that immunoglobulin-positive MPGN is induced by classical pathway activation. Immunoglobulin-negative C3-positive MPGN is categorized as C3G due to dysregulation of the alternative pathway. C3G is further subdivided into C3GN and DDD. C3G: C3 glomerulopathy, DDD: dense deposit disease, IF: immunofluorescence, and MPGN: membranoproliferative glomerulonephritis.

Figure 3

A schematic diagram showing an approach to classifying the morphological changes in glomerulonephritis with dominant C3. The morphological changes are divided into C3G, Postinfectious GN, and MGRS. C3G is further subdivided into C3GN and DDD, and then categorized into each group in detail according to the etiology. C3GN: C3 glomerulonephritis, DDD: dense deposit disease, MGRS: monoclonal gammopathy of renal significance, and Postinfectious GN: postinfectious glomerulonephritis.

Figure 4

Histological staining for C3, NAPlr, and plasmin activity in the glomeruli of a patient with IRGN induced by streptococci, Neisseria gonorrhoeae, and Chlamydia. (A) Double IF staining for NAPlr (fluorescein isothiocyanate, green) and C3 (Alexa Fluor 594, red) with nuclear staining for DAPI (blue) show glomerular deposition, and different distributions of NAPlr and C3. (B) Glomerular plasmin activity assessed by in situ zymography using plasmin-sensitive synthetic peptide on a serial section demonstrates an approximately similar distribution as NAPlr deposition.

Figure 5

Summary of the concept of this review. Clinico-pathogenic features of IRGN overlap considerably with those of C3G. IRGN: infection-related glomerulonephritis, C3G: C3 glomerulopathy, IC: immune complex, C3GN: C3 glomerulonephritis, DDD: dense deposit disease, MPGN: membranous proliferative glomerulonephritis, LM: light microscopy, EDDs: electron-dense deposits, AP: alternative complement pathway, C3NeF: C3 nephritic factor, FB: factor B, NAPlr: nephritis-associated plasmin receptor, and PA: plasmin activity.