Glomerular galactose-deficient IgA1 expression analysis in pediatric patients with glomerular diseases

Abstract

Galactose-deficient IgA1 (Gd-IgA1) is important in the pathogenesis of IgA nephropathy (IgAN). A Gd-IgA1-specific monoclonal antibody (KM55) has revealed glomerular Gd-IgA1 deposition solely in patients with IgAN and IgA vasculitis with nephritis (IgAV-N). However, this specificity is controversial and has not been demonstrated in pediatric patients. Here, we conducted doubleimmunofluorescence staining of IgA and Gd-IgA1 in 60 pediatric patients with various glomerular diseases. We divided patients into four groups: (1) patients with IgAN and IgAV-N (n = 23); (2) patients with immunocomplex-mediated glomerulonephritis accompanied by IgA deposition, including lupus nephritis, membranoproliferative glomerulonephritis, and membranous nephropathy (n = 14); (3) patients with other glomerular diseases involving IgA deposition, including idiopathic nephrotic syndrome (INS), oligomeganephronia, Alport syndrome, dense deposit disease, and crescentic glomerulonephritis (n = 11); and (4) patients with IgA-negative diseases including INS, membranoproliferative glomerulonephritis, membranous nephropathy, oligomeganephronia, Alport syndrome, C3 glomerulonephritis, poststreptococcal acute glomerulonephritis, and hemolytic uremic syndrome (n = 12). KM55 staining revealed Gd-IgA1-positive findings in 23/23 patients in Group 1 and 13/14 patients in Group 2, but not in patients in Groups 3 or 4. Therefore, KM55 may detect incidental IgA deposition in pediatric patients. Gd-IgA1 may be involved in the pathogenesis of these immunerelated diseases; alternatively, KM55 may recognize IgA-related immunocomplexes in a non-specific manner. IgA nephropathy (IgAN) is a common type of primary glomerulonephritis in children. It was initially considered a benign condition, but extended follow-up studies indicated that IgAN was associated with a poor renal prognosis, with a renal survival probability of 79.8% at 20 years for Japanese patients with end-stage kidney disease 1. In most patients, IgAN is discovered as microscopic hematuria with or without proteinuria and is diagnosed by evaluation of renal biopsy specimens. IgAN is defined by mesangial proliferative nephritis with IgA-dominant or codominant mesangial glomerular deposits. Considerable advances in understanding the pathogenesis of IgAN have been made over the past two decades, and galactose-deficient IgA1 (Gd-IgA1) has been identified as an essential molecule in this process. However,

Associations of left renal vein entrapment with IgA nephropathy and Henoch–Schönlein purpura nephritis

“…In pediatric patients, Ishiko et al. reported Gd-IgA1 staining was positive in patients with LN ( n = 9) and MN ( n = 1), but negative in idiopathic nephrotic syndrome ( n = 6) and Alport syndrome ( n = 1) with IgA deposition [ 35 ]. Wang et al.…”

Glomerulonephritis with severe nephrotic syndrome induced by immune complexes composed of galactose-deficient IgA1 in primary Sjögren’s syndrome: a case report

“…The present case likewise showed a persistently elevated serum IgA and the existence of circulating IgA-CIC, in addition to Gd-IgA1 comparable with IgAN. Gd-IgA1 has been extensively investigated as a specific pathogen inducing IgAN and IgA vasculitis, [3] while some recent reports have documented that other kidney diseases also often show IC composed of Gd-IgA1 in the glomeruli such as lupus nephritis and primary MN [7,8]. Although the frequency and pathogenicity of Gd-IgA1 in pSS are unknown, aberrant IgA in pSS has been reported to be associated with augmentation of sialylated IgA1 and IgA2, as well as reduction of galactosylated IgA1 and IgA2 [4].…”

IgA vasculitis update: Epidemiology, pathogenesis, and biomarkers

“…Suzuki et al. found that Gd-IgA1 mesangial deposition was a typical manifestation of IgAN and IgAVN patients when they performed immunohistochemical analysis of renal biopsy specimens from those and patients with other secondary nephropathy by KM55 staining ( 57 ), which has also been confirmed in relevant studies on children ( 58 ). Gd-IgA1 levels in patients of IgAV with nephritis were similar to IgAN, while those without nephritis showed no statistical difference compared to healthy controls ( 58 ).…”

“…In addition, in 2020, Ishiko et al. found that patients with lupus nephritis and primary membranous nephropathy also had renal Gd-IgA1 deposition ( 58 ). These suggest that Gd-IgA1 alone is not a determinant of IgAV pathogenesis and that other triggers need to be considered.…”