BackgroundImmunoglobulin (Ig) A nephropathy (IgAN) is characterized by mesangial deposits of IgA1 and C3, often with co-deposits of IgG. We attempted to clarify the clinical significance of mesangial IgG deposition in patients with IgAN.MethodsWe retrospectively reviewed 57 patients who were diagnosed with IgAN on the basis of pathological examination of renal biopsy specimens obtained between October 2006 and December 2010. Subjects were divided into two groups: IgA+IgG deposition (IgA-IgG) group (n = 29) and IgA deposition alone (IgA) group (n = 28). The study outcome was complete remission (CR), defined as negative proteinuria by dipstick urinalysis and urinary erythrocytes of less than 1–4/high-power field.ResultsProteinuria was greater in the IgA-IgG group than the IgA group (1.1 ± 0.8 vs. 0.7 ± 0.6 g/day, Mann–Whitney U test, P = 0.042). Capillary wall IgA deposits were noted more frequently in the IgA-IgG group than the IgA group (59 vs. 11 %, Fisher’s exact test, P = 0.014). During the median follow-up period of 33.3 months (range 6–55 months) in the 57 patients, we observed CR in 24 cases (42.1 %). After the start of treatment, urinary abnormalities disappeared earlier in the IgA group than in the IgA-IgG group (log rank test, P = 0.012). Cox’s regression model showed that IgG deposition reduced the hazard ratio for CR (hazard ratio 0.35; 95 % confidence interval 0.14–0.82, P = 0.014). Therefore, IgG deposition is a risk factor for persistent urinary abnormalities.ConclusionMesangial IgG deposition is associated with more severe clinical features in patients with IgAN.
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.
The phospholipase A2 receptor (PLA2R) is the major target antigen (Ag) in idiopathic membranous nephropathy (IMN). Recently, several types of immunoassay systems for anti-PLA2R antibody (Ab) have been developed. However, the correlation of serum anti-PLA2R Abs and glomerular expression of PLA2R Ag, and their association with clinicopathological characteristics have yet to be proven in Japanese patients. We examined serum anti-PLA2R Abs by both ELISA and cell-based indirect immunofluorescence assay (CIIFA), and glomerular PLA2R expression by immunofluorescence (IF) in 59 biopsy-proven MN patients including IMN (n = 38) and secondary MN (SMN) (n = 21). In this study, anti-PLA2R Abs were present in 50% of IMN patients, but was absent in SMN patients. The concordance rate between ELISA and CIIFA was 100%. Serum IgG levels were significantly lower in anti-PLA2R Ab-positive patients. Serum albumin levels correlated inversely with serum anti-PLA2R Ab titers. The prevalence and intensity of glomerular staining for IgG4 by IF were significantly higher in anti-PLA2R Ab-positive patients than in -negative patients. Glomerular PLA2 Ag expression evaluated by IF was positive in 52.6% of IMN patients, but was absent in SMN patients. The concordance rate between the prevalence of glomerular PLA2R Ag expression and anti-PLA2R Ab was 84.2%. The prevalence of anti-PLA2R Abs measured by ELISA/CIIFA was equivalent to previous Japanese studies evaluated using Western blotting. These analyses showed an excellent specificity for the diagnosis of IMN, and anti-PLA2R positivity was associated with some clinicopathological features, especially glomerular IgG4-dominant deposition.
Background In people with SLE and in the MRL-Fas lpr lupus mouse model, macrophages and autoantibodies are central to lupus nephritis. IL-34 mediates macrophage survival and proliferation, is expressed by tubular epithelial cells (TECs), and binds to the cFMS receptor on macrophages and to a newly identified second receptor, PTPRZ. Methods To investigate whether IL-34-dependent intrarenal and systemic mechanisms promote lupus nephritis, we compared lupus nephritis and systemic illness in MRL-Fas lpr mice expressing IL-34 and IL-34 knockout (KO) MRL-Fas lpr mice. We also assessed expression of IL-34 and the cFMS and PTPRZ receptors in patients with lupus nephritis. Results Intrarenal IL-34 and its two receptors increase during lupus nephritis in MRL-Fas lpr mice. In knockout mice lacking IL-34, nephritis and systemic illness are suppressed. IL-34 fosters intrarenal macrophage accumulation via monocyte proliferation in bone marrow (which increases circulating monocytes that are recruited by chemokines into the kidney) and via intrarenal macrophage proliferation. This accumulation leads to macrophage-mediated TEC apoptosis. We also found suppression of circulating autoantibodies and glomerular antibody deposits in the knockout mice. This is consistent with fewer activated and proliferating intrarenal and splenic B cells in mice lacking IL-34, and with our novel discovery that PTPRZ is expressed by macrophages, B and T cells. These findings appear translatable to human patients with lupus nephritis, whose expression of IL-34, cFMS, and PTPRZ is similar to that seen in the MRL-Fas lpr lupus mouse model. Moreover, expression of IL-34 in TECs correlates with disease activity. Conclusions IL-34 is a promising novel therapeutic target for patients with lupus nephritis.
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