PathPointers highlight important everyday teaching points when reviewing kidney histology. These brief and easy-to-read blog posts include real clinical images to demonstrate various biopsy findings.

In renal pathology, hump-like deposits are defined as large subepithelial deposits with a rounded shape by electron microscopy, and minimal associated basement membrane reaction. These deposits were historically associated with acute post-infectious glomerulonephritis (APIGN) in the setting of streptococcal infection in children. However, it is now recognized that these hump-like deposits are not specific to APIGN, and may be seen in other entities, particularly C3 glomerulopathy (C3GP).

In classic APIGN, infectious antigens and immune complexes result in the activation of the alternative complement pathway, leading to glomerular injury and low serum C3 level. It typically presents with a diffuse endocapillary proliferative and exudative pattern, as shown in figure 1A. Subepithelial humps are frequent and have been described as the hallmark of this disease (Figure 1C). They vary in size and number and are sometimes concentrated on the basement membrane overlying the mesangium. As the disease resolves, they become less electron-dense and scarce. On the trichrome stain, they may appear as red-orange subepithelial deposits. By immunofluorescence, subepithelial humps are identified as coarsely granular deposits along the glomerular capillary wall with a dominant C3 staining, sometimes associated with polyclonal IgG (Figure 1B). In APIGN, studies have demonstrated the colocalization of streptococcal antigen, C3 and IgG within the hump-like deposits.

Figure 1. Acute post-infectious glomerulonephritis. (A) Light microscopy shows a diffuse endocapillary proliferative pattern, (B) by immunofluorescence, C3 coarse granular staining (arrows), (C) typical hump-like deposits by electron microscopy (arrows).

In adults, non-streptococcal infection can result in a similar pattern of injury by light microscopy. Staphylococcal and Gram-negative infections, particularly in patients with diabetes, can precipitate acute proliferative GN with a characteristic dominant IgA staining. Interestingly, hump-like deposits can also be seen in IgA-dominant-infection related GN, although less consistently.

More recently, C3GP, including C3 glomerulonephritis and dense deposit disease (DDD), have also been associated with hump-like deposits. These glomerular diseases are characterized by dysregulation of the alternative complement pathway, genetic or acquired, and dominant C3 staining by immunofluorescence. C3GP usually show a membranoproliferative pattern, although  a mesangial proliferative pattern can also be seen. In addition to mesangial, subendothelial and intramembranous deposits, subepithelial hump-like deposits identical to those of APIGN can be seen on electron microscopy. For example, the prevalence of hump-like deposits in DDD is approximately 30%.

Data obtained from mass spectrometry in C3PG show the accumulation of alternative pathway and terminal complement complex proteins in the glomerular deposits. Panel D of Figure 2  below shows staining of hump-like deposits for C5b9. Similarities shared by APIGN and C3GP point toward a possible association between over-activation of the alternative complement pathway and the formation of hump-like deposits.

Figure 2. C3 glomerulonephritis. (A) Light microscopy shows a mesangial proliferative pattern with mesangial silver negative deposits; (B) hump-like deposits by electron microscopy (arrows), with a deposit at the mesangial waist (asterisk); (C) dominant C3 staining by immunofluorescence; (D) staining of hump-like deposits with C5b9 (arrows).

The presence of hump-like deposits should always be correlated with the light microscopic appearance, the immunofluorescence results, and importantly, with the clinical information. Their presence should prompt a clinical investigation for infection, especially when an endocapillary proliferative and exudative pattern is present. An evaluation of the alternative pathway should also be considered in cases with a membranoproliferative pattern or other features suggestive of C3GP (eg, immunofluorescence with C3 two orders of magnitude greater than any other stain), or where the proteinuria, hematuria, and impaired kidney function persist or worsen.

– Post prepared by Virginie Royal, AJKDBlog Contributor. Follow her @virginieroyal.