Atypical postinfectious glomerulonephritis is associated with abnormalities in the alternative pathway of complement

Abstract

Postinfectious glomerulonephritis is a common disorder that develops following an infection. In the majority of cases, there is complete recovery of renal function within a few days to weeks following resolution of the infection. In a small percentage of patients, however, the glomerulonephritis takes longer to resolve, resulting in persistent hematuria and proteinuria, or even progression to end-stage kidney disease. In some cases of persistent hematuria and proteinuria, kidney biopsies show findings of a postinfectious glomerulonephritis even in the absence of any evidence of a preceding infection. The cause of such 'atypical' postinfectious glomerulonephritis, with or without evidence of preceding infection, is unknown. Here we show that most patients diagnosed with this 'atypical' postinfectious glomerulonephritis have an underlying defect in the regulation of the alternative pathway of complement. These defects include mutations in complement-regulating proteins and antibodies to the C3 convertase known as C3 nephritic factors. As a result, the activated alternative pathway is not brought under control even after resolution of the infection. Hence, the sequela is continual glomerular deposition of complement factors with resultant inflammation and development of an 'atypical' postinfectious glomerulonephritis.

Figure 1

Representative light microscopy, immunofluorescence microscopy and electron microscopy from 3 patients are shown. Each column represents one case. Light microscopy: (A) Patient # 8 shows a mesangial proliferative glomerulonephritis, (B) Patient # 9 shows a diffuse proliferative glomerulonephritis, (C) Patient # 7 shows a crescentic glomerulonephritis. (D–F) Bright C3 staining in the mesangium and along capillary walls. (G–I) Subepithelial hump-like deposits (black arrows) in all 3 cases on electron microscopy. Figure 1-I also shows an insert with a classic subepithelial-hump in patient #7.

Figure 2

Schematic representation of complement and ‘atypical’ post-infectious glomerulonephritis. Top panel shows normal balance of complement regulating proteins (red triangles) and complement factors (yellow oval structures). Following development of post-infectious glomerulonephritis, there is activation of the alternative pathway of complement represented by increase in complement factors. Following resolution of the infection, the complement cascade is quickly brought into control with restoration of balance. Lower panel showing atypical’ post-infectious glomerulonephritis due to the disruption of the complement cascade that results in a ‘persistent’ and ‘slowly resolving’ glomerulonephritis. Antibodies to complement regulating protein (inverted Y structures) or mutation/polymorphisms in complement regulating proteins (striped triangles) result in continual activation of the complement cascade following an infection. In case of ‘slowly resolving’ ‘atypical’ post-infectious glomerulonephritis the complement cascade is slowly brought under control, while in ‘persistent’ atypical post-infectious glomerulonephritis the complement cascade is continually activated, even after resolution of the infection.