Clinical significance of serum and mesangial galactose-deficient IgA1 in patients with IgA nephropathy

Abstract

IntroductionGalactose-deficient IgA1 (Gd-IgA1) is a critical pathogenic factor for IgA nephropathy (IgAN), but its value as a disease-specific biomarker remains controversial. We aimed to clarify the clinical significance of Gd-IgA1 in patients with IgAN.MethodsWe retrospectively reviewed 111 patients who were diagnosed with IgAN based on the findings of renal biopsies (RB) at Showa University Hospital since 2007. Serum Gd-IgA1 (s-Gd-IgA1) at the time of RB was compared among 111 IgAN patients, 18 Henoch-Schönlein purpura nephritis (HSPN) patients, 29 lupus nephritis (LN) patients, 28 ANCA-associated vasculitis (AAV) patients, and 13 minimal change disease (MCD) patients using ELISA with an anti-human Gd-IgA1-specific monoclonal antibody (KM55). We also immunohistochemically stained paraffin-embedded sections for mesangial Gd-IgA1 (m-Gd-IgA1) deposition using KM55.ResultsAlthough levels of s-Gd-IgA1 were comparable among IgAN and HSPN, s-Gd-IgA1 levels were significantly elevated in patients with IgAN compared with LN, AAV and MCD (IgAN vs. HSPN, LN, AAV, and MCD: 16.2 ± 9.1 vs. 14.2 ± 10.8, p = 0.263; 12.7 ± 9.4, p = 0.008; 13.1 ± 7.3, p = 0.059; and 8.2 ± 4.8 μg/mL, p<0.001, respectively). Mesangial-Gd-IgA1 deposition was specifically detected in IgAN or HSPN. The increase in s-Gd-IgA1 significantly correlated with m-Gd-IgA1 positivity in patients with IgAN, and s-Gd-IgA1 elevation and m-Gd-IgA1 deposition were evident in patients with histopathologically advanced IgAN. Moreover, s-Gd-IgA1 levels were significantly higher in IgAN patients with glomerular sclerosis and tubulo-interstitial lesions. Mesangial-Gd-IgA1 intensity negatively correlated with eGFR in IgAN. Multivariate analysis selected s-Gd-IgA1 elevation as a significant risk factor for a 30%-reduction in eGFR in IgAN (HR, 1.37; 95% CI, 1.02–1.89; p = 0.038).ConclusionsAlthough IgAN and HSPN remain difficult to differentiate, s-Gd-IgA1 elevation and m-Gd-IgA1 deposition are reliable diagnostic factors that reflect IgAN severity. Serum-Gd-IgA1 could serve as a predictor of renal outcomes in IgAN. Thus, Gd-IgA1 could be significant biomarker for patients with IgAN.

A cross-sectional analysis of clinicopathologic similarities and differences between Henoch-Schönlein purpura nephritis and IgA nephropathy

“…With respect to a difference in Gd-IgA1 between the 2 diseases, our findings were consistent with previous reports [25,26,28]. Assessing Gd-IgA1 alone was not enough to distinguish between these 2 diseases.…”

“…Similar results were obtained in other recent studies [27,28]. Additionally, glomerular-Gd-IgA1 (g-Gd-IgA1)-deposition, assessed by immunofluorescence (IF) or immunohistochemistry (IHC) with KM55, was specific to patients with HSPN and IgAN [25,26]. Taken together, HSPN and IgAN have similar pathologic and biological abnormalities and are closely related.…”

“…We performed a cross-sectional study of 80 adult (�18 years) patients with HSPN (n = 24) or IgAN (n = 56) who underwent a renal biopsy (RB) between April 2008 and December 2018 at Showa University Hospital. Data for some patients with HSPN or IgAN were previously described in our historical cohort study [26]. Furthermore, 6 patients with lupus nephritis (LN), 10 with ANCA-associated vasculitis (AAV), and 6 with minimal change disease (MCD) were enrolled as positive or negative controls for ELISA measurements.…”

“…Gd-IgA1 deposition in glomeruli was examined by IHC staining as described elsewhere [26,39,40]. Briefly, dewaxed paraffin sections were heated with Histofine (Nichirei, Tokyo, Japan) in an autoclave at 121˚C for 30 min for antigen retrieval.…”

“…Moreover, recent studies noted that these 2 diseases share the feature of Gd-IgA1-oriented pathogenesis [25,26]. In our recent report, serum Gd-IgA1 (s-Gd-IgA1) levels, quantified by a novel lectin-independent enzyme-linked immunosorbent assay (ELISA) using an anti-Gd-IgA1 monoclonal antibody (KM55) [27], were significantly elevated in patients with HSPN or IgAN compared to other kidney diseases [26]. Similar results were obtained in other recent studies [27,28].…”