Mesangial C4d deposition at diagnosis in childhood immunoglobulin A nephropathy

Abstract

Background Immunoglobulin A nephropathy (IgAN) is a major cause of end‐stage renal disease. Complement activation via the lectin pathway influences outcomes in IgAN. We examined the association of glomerular C4d deposition with clinicopathological severity at diagnosis and the disappearance of proteinuria in Japanese pediatric IgAN patients. Methods We retrospectively analyzed 25 children newly diagnosed with IgAN at Hokkaido University Hospital. We evaluated glomerular C4d immunofluorescent staining at diagnosis. We compared clinical findings, pathological findings (based on Oxford classification), and the disappearance of proteinuria within 24 months after renal biopsy between C4d‐positive and C4d‐negative patients. Results Glomerular C4d staining was observed in 14 patients (56.0%). C4d‐positive patients had significantly higher proteinuria at diagnosis than C4d‐negative patients (2.03 g/gCr vs 0.78 g/gCr; P = 0.005). The number of glomeruli with segmental glomerulosclerosis or adhesion (8.0% vs 0.0%; P = 0.046) and the extent of tubular atrophy/interstitial fibrosis (9.46% vs 2.86%; P = 0.031) were significantly increased in C4d‐positive patients compared with C4d‐negative patients. Further, the proportion of patients with modified T1 (>10%) was significantly higher in the C4d‐positive group than the C4d‐negative group. There was no significant difference, however, in the disappearance rate of proteinuria at 24 months after renal biopsy between groups (64% vs 82%; P = 0.149). Conclusions Glomerular C4d deposition was associated with clinicopathological severity at diagnosis in Japanese pediatric patients with IgAN. Glomerular C4d deposition, however, was not a predictor of the disappearance of proteinuria within 24 months after diagnosis in Japanese pediatric patients with IgAN.

The Role of Immune Modulation in Pathogenesis of IgA Nephropathy

“…The possible underlying mechanism is that the risk of infection is increased in patients with MBL deficiency, and infection may induce impaired mucosal immune regulation, which promotes the progression of IgAN (136). The findings of many studies have suggested that the activated fragments of C4 deposited in the glomerular mesangium of patients with IgAN are more likely to be produced by the MBL pathway (137,138). Mesangial deposition of C4d has been identified as a significant risk factor for worsening renal function (139)(140)(141).…”

Glomerular C4d Deposition and Kidney Disease Progression in IgA Nephropathy: A Systematic Review and Meta-analysis

“…A total of 12 studies 8 , 9 , 10 , 11 , 12 , 13 , 14 , 16 , 20 , 21 , 22 , 23 with 1,251 patients were included. Reasons for exclusion are listed in Fig 1 .…”

“…The studies involved 7 cohort and 5 cross-sectional studies. Nine studies 9 , 10 , 11 , 12 , 13 , 14 , 16 , 21 , 22 described the definition of glomerular C4d deposition, but the definition was inconsistent: “C4d positive” was defined as C4d deposition in >25% of nonsclerotic glomeruli in 3 studies, 12 , 14 , 21 >50% in 4 studies, 10 , 11 , 16 , 22 >75% in 1 study, 13 or greater than any 1 of nonsclerotic glomeruli in another study. 9 Four studies 10 , 11 , 21 , 23 (n = 484) recruited patients from Asian populations, including Japanese and Korean patients, and 8 studies 8 , 9 , 12 , 13 , 14 , 16 , 20 , 22 (n = 767) mainly recruited from European and South American populations.…”

“…Nine studies 9 , 10 , 11 , 12 , 13 , 14 , 16 , 21 , 22 described the definition of glomerular C4d deposition, but the definition was inconsistent: “C4d positive” was defined as C4d deposition in >25% of nonsclerotic glomeruli in 3 studies, 12 , 14 , 21 >50% in 4 studies, 10 , 11 , 16 , 22 >75% in 1 study, 13 or greater than any 1 of nonsclerotic glomeruli in another study. 9 Four studies 10 , 11 , 21 , 23 (n = 484) recruited patients from Asian populations, including Japanese and Korean patients, and 8 studies 8 , 9 , 12 , 13 , 14 , 16 , 20 , 22 (n = 767) mainly recruited from European and South American populations. Five of the 7 cohort studies 12 , 13 , 16 , 21 , 22 (n = 817) with a mean follow-up of 5.7 years provided 199 composite kidney events and 126 ESKD events; these 5 studies were used to analyze the predictive value of C4d deposition to kidney event.…”

“… 5 , 6 Several studies have proved that lectin pathway activation is associated with serious clinical and pathologic presentations and poor long-term renal survival in both children and adults. 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 C4d is the cleavage product of C4, which covalently binds to the cell surface through thioester bonds, 17 , 18 and a common downstream marker of the lectin and classical pathways. Because the classical pathway is not involved in the pathogenesis of IgAN, C4d deposition is thought to be associated with activation of the lectin pathway.…”