Journal articles on the topic 'IgAN'
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1
Zhang, Xue, Xinfang Xie, Sufang Shi, Lijun Liu, Jicheng Lv, and Hong Zhang. "Plasma galactose-deficient immunoglobulin A1 and loss of kidney function in patients with immunoglobulin A vasculitis nephritis." Nephrology Dialysis Transplantation 35, no. 12 (August 3, 2019): 2117–23. http://dx.doi.org/10.1093/ndt/gfz151.
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Abstract Background Immunoglobulin A (IgA) vasculitis nephritis (IgAV-N) is the most common secondary IgA nephropathy (IgAN). Many studies have demonstrated that galactose-deficient IgA1 (Gd-IgA1) in the IgA1 hinge region is associated with the development and also progression of primary IgAN. In this study, we aimed to evaluate the roles of Gd-IgA1 in kidney disease progression in a large Chinese cohort of IgAV-N patients. Methods This cohort study enrolled 112 patients with IgAV-N, 15 patients with IgA vasculitis (IgAV) without kidney involvement and 108 patients with IgAN. Plasma IgA1 and Gd-IgA1 levels at kidney biopsy were measured by enzyme-linked immunosorbent assay. The primary endpoint was a 30% decline in estimated glomerular filtration rate or end-stage renal disease or death. Results The levels of Gd-IgA1 in IgAV-N and IgAN patients were higher than in healthy controls (mean ± SD, 302.86 ± 54.93 U/mL versus 303.16 ± 59.43 U/mL versus 281.30 ± 43.74 U/mL, respectively; P = 0.047), as well as compared with those with IgAV without kidney involvement (272.65 ± 53.14 U/mL; P = 0.036). After adjusting clinical data, higher levels of Gd-IgA1 were found to be independently associated with a greater risk for kidney failure [hazard ratio (HR) = 1.703 per 1 SD, 95% confidence interval (CI) 1.233–2.352; P = 0.001]. Compared with the first Gd-IgA1 quartile group (as reference), the fourth Gd-IgA1 quartile group retained a predictive value for poor renal outcome (HR = 3.740, 95% CI 1.204–11.619; P = 0.023). Conclusions These data indicate that Gd-IgA1 levels were similarly elevated in adult patients with IgAN and those with IgAV-N. Moreover, increased Gd-IgA1 levels were associated with both the development and progression of IgAV-N, as observed in IgAN.
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Khairwa, Anju. "Indian scenario of IgA nephropathy: a systematic review and meta-analysis." African Health Sciences 21, no. 1 (April 16, 2021): 159–65. http://dx.doi.org/10.4314/ahs.v21i1.21.
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Background: IgA nephropathy (IgAN) is most common primary glomerulopathy. There are variations in prevalence of IgAN and its clinical features in different studies from India.
Aim: To summarize overall scenario of IgAN in India.
Methods: In this systematic review, studies related to IgAN and related renal disease were included. Data searched were PubMed, EMBASE, Google scholar, and Cochrane Database from inception to 31st January 2019.
Results: Total 49 studies (N=2480) were included: 21studies (N=2309) of primary IgAN; 19 studies (N=21) of Secondary IgAN; four studies (N=133) of IgA vasculitis nephropathy (IgAVN); and five studies (N=17) of IgA dominant nephropathy (IgADN). Prevalence of IgAN was 16.5% in India. Age of affected persons was ranging from 27.2±16.7 to 48.6±21.3 years . Male female ratio was 1.8:1. Clinical features of Primary IgAN, IgAVN, IgADN & Secondary IgAN were microscopic hematuria (49.6%, 44.4%, 15.6% & 59.5%), macroscopic hematuria (5.1%, 0.4%,40.9%,& 35.7%), Subnephrotic proteinuria (42.1%, 29.4%, 23.2%, & 52.3%), nephrotic proteinuria (16.0%, 4.4%, 76.8%,& 47.6%), and hypertension (25.8%,18.3%, 35.5%,& 47.6%).. The 24 hours proteinuria was ranging from 2.6±1.5 to 4.7±2.3 gm/day and serum creatinine (mg/dl) was ranging from 0.9±0 to 3.5±3.9 mg/dl. Histolomorphologically, all type of IgAN showed mesangial hypercellularity and Immunofluorescence revealed IgA deposition.
Conclusion: The overall prevalence of primary IgAN in India was 16.5%. The subnephrotic proteinuria and microscopic hematuria were common clinical features.
Keywords: IgA Nephropathy; histomorphology; prevalence; India.
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Suzuki, Hitoshi, Landino Allegri, Yusuke Suzuki, Stacy Hall, Zina Moldoveanu, Robert J. Wyatt, Jan Novak, and Bruce A. Julian. "Galactose-Deficient IgA1 as a Candidate Urinary Polypeptide Marker of IgA Nephropathy?" Disease Markers 2016 (2016): 1–6. http://dx.doi.org/10.1155/2016/7806438.
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In patients with IgA nephropathy (IgAN), circulatory IgA1 and IgA1 in mesangial deposits contain elevated amounts of galactose-deficient IgA1 (Gd-IgA1). We hypothesized that a fraction of Gd-IgA1 from the glomerular deposits and/or circulation may be excreted into the urine and thus represent a disease-specific biomarker. Levels of urinary IgA and Gd-IgA1 were determined in 207 patients with IgAN, 205 patients with other renal diseases, and 57 healthy controls, recruited in USA, Japan, and Italy. Urinary IgA was similarly elevated in patients with IgAN and renal-disease controls compared with healthy controls. However, urinary Gd-IgA1 levels were higher in patients with IgAN (IgAN,28.0±17.9; disease controls,20.6±17.4units/mg urinary creatinine;P<0.0001). Lectin western blotting data confirmed these results. In IgAN patients, levels of urinary Gd-IgA1 correlated with proteinuria (P<0.001). When we purified IgA from serum and urine of an IgAN patient, the relative proportion of Gd-IgA1 to total IgA1 was higher in the urine compared with serum, suggesting selective excretion of Gd-IgA1 in IgAN. In summary, urinary excretion of Gd-IgA1 was elevated in patients with IgAN and the urinary Gd-IgA1 levels correlated with proteinuria. Urinary Gd-IgA1 may thus represent a disease-specific biomarker of IgAN.
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Irabu, Hitoshi, Masaki Shimizu, Shuya Kaneko, Natsumi Inoue, Mao Mizuta, Kazuhide Ohta, and Akihiro Yachie. "Clinical Significance of Serum Galactose-Deficient IgA1 Level in Children with IgA Nephropathy." Journal of Immunology Research 2020 (May 21, 2020): 1–10. http://dx.doi.org/10.1155/2020/4284379.
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This study was aimed at investigating the clinical significance of serum galactose-deficient IgA1 (Gd-IgA1) levels measured by a novel lectin-independent enzyme-linked immunosorbent assay (ELISA) using an anti-Gd-IgA1 monoclonal antibody (KM55) as a disease-specific biomarker for IgA nephropathy (IgAN) in children. Thirty-three children with IgAN, 40 with non-IgA glomerular diseases, and 38 age-matched healthy controls (HCs) were enrolled. Serum Gd-IgA1 levels were quantified by ELISA using KM55. Results were statistically compared with clinical features and pathological findings of IgAN. Serum Gd-IgA1 levels were significantly elevated in children with IgAN compared with children with non-IgA glomerular diseases and HCs. Serum Gd-IgA1 levels in children with IgAN were positively correlated with serum total IgA levels. However, the serum Gd-IgA1/total IgA ratio (Gd-IgA1/IgA) was also significantly elevated in children with IgAN. Serum Gd-IgA1 levels in children with IgAN increased in an age-dependent manner. The cutoff value of serum Gd-IgA1 levels for differentiating IgAN from non-IgA glomerular diseases was 3236 in children<12 years and 5284 in children≥12 years, respectively. In contrast, serum Gd-IgA1/IgA was age-independent. The cutoff value of serum Gd-IgA1/IgA for differentiating IgAN from non-IgA glomerular diseases was 0.2401. Serum Gd-IgA1 levels were negatively correlated with eGFR and positively correlated with mesangial IgA deposition. In contrast, serum Gd-IgA1/IgA levels were not correlated with any clinical parameters of IgAN. In conclusion, serum Gd-IgA1 levels were significantly elevated in children with IgAN. However, those levels were age-dependent; therefore, serum Gd-IgA1 levels classified by age and/or serum Gd-IgA1/IgA might have diagnostic values in children with IgAN.
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Li, Guanhong, Xiaoyan Wang, Zhe Yang, Qing Zhao, Yubing Wen, Xuemei Li, and Ruitong Gao. "Serum Levels of Joining Chain-Containing IgA1 Are Not Elevated in Patients with IgA Nephropathy." Disease Markers 2019 (July 2, 2019): 1–11. http://dx.doi.org/10.1155/2019/9802839.
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Background. It has been suggested that mesangial IgA deposits are dimeric or polymeric in IgA nephropathy (IgAN). However, evidence concerning the molecular form of serum IgA in IgAN is controversial. And there is no direct evidence that the serum levels of joining chain- (J chain-) containing IgA (J-IgA) are elevated in IgAN. In this study, we aimed to measure serum J-IgA and glomerular J chain deposition with anti-J chain monoclonal antibody in IgAN. Methods. BALB/c mice were immunized with human J chain-GST recombinant peptide to obtain anti-J chain monoclonal antibody. The levels of serum total IgA and J-IgA were measured by sandwich enzyme-linked immunosorbent assay in 115 patients with IgAN and 117 healthy volunteers. J chain deposition in kidney specimens was analyzed by immunohistochemistry staining. Results. Serum levels of total IgA1 were elevated in IgAN patients compared to healthy subjects. However, serum levels of IgA, J-IgA, and J chain-containing IgA1 (J-IgA1), the J-IgA to total IgA ratio, and the J-IgA1 to total IgA1 ratio were not significantly different between IgAN patients and healthy subjects. Western blot analysis and gel filtration analysis using purified IgA1 also showed that the proportion of J chain-containing polymeric IgA1 was lower in IgAN patients compared to healthy subjects. No correlation was found between serum J-IgA or J-IgA1 and clinical features in IgAN. Immunohistochemistry analysis showed that glomerular J chain was positive in 12 IgAN patients (57.1%). The values of the J-IgA to IgA ratio and J-IgA1 to IgA ratio were significantly higher in IgAN patients with glomerular J chain deposition than those without. However, the serum levels of J-IgA and J-IgA1 and the J-IgA1 to IgA1 ratio were not significantly higher in two subgroups. Conclusions. Although serum levels of total IgA1 were elevated in IgAN, the serum levels of J-IgA1 were not elevated. And serum J-IgA, serum J-IgA1, and J chain deposition were not correlated with disease severity in IgAN.
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Kim, Jin Sug, Hyeon Seok Hwang, Sang Ho Lee, Yang Gyun Kim, Ju-Young Moon, Ji Yoon Kong, and Kyung Hwan Jeong. "Clinical Relevance of Serum Galactose Deficient IgA1 in Patients with IgA Nephropathy." Journal of Clinical Medicine 9, no. 11 (November 4, 2020): 3549. http://dx.doi.org/10.3390/jcm9113549.
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New biomarkers of IgA nephropathy (IgAN) are needed for non-invasive diagnosis and appropriate treatment. There is emerging evidence that galactose deficient IgA1 (Gd-IgA1) is a pivotal molecule in the pathogenesis of IgAN. However, few studies have investigated the role of Gd-IgA1 as a biomarker in IgAN. In this study, we investigated the clinical relevance of serum Gd-IgA1 levels in patients with IgAN. Two hundred and thirty biopsy-proven IgAN patients, 74 disease controls (patients with non-IgAN nephropathy), and 15 healthy controls were enrolled in this study. Levels of serum Gd-IgA1 were measured using an ELISA kit in serum samples obtained the day of renal biopsy. We compared levels of serum Gd-IgA1 according to the type of glomerular disease and analyzed the association between Gd-IgA1 levels and clinical and pathological parameters in patients with IgAN. We then divided IgAN patients into two groups according to Gd-IgA1 level and investigated the predictive value of Gd-IgA1 for progression of chronic kidney disease (CKD). Serum Gd-IgA1 levels were significantly higher in IgAN patients than disease controls and healthy controls. In patients with IgAN, serum Gd-IA1 levels were significantly correlated with estimated glomerular filtration rate, serum IgA level, and tubular atrophy/interstitial fibrosis. CKD progression was more frequent in IgAN patients with higher serum Gd-IgA1 levels than in those with lower serum Gd-IgA1 levels. Cox proportional hazard models showed that high GdIgA1 level was an independent risk factor for CKD progression after adjusting for several confounders. Our results suggest that serum Gd-IgA1 level is a useful diagnostic and prognostic marker in IgAN patients. Further studies with a larger sample size and longer follow-up duration are needed.
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Sanders, John T., M. Colleen Hastings, Zina Moldoveanu, Jan Novak, Bruce A. Julian, Zoran Bursac, and Robert J. Wyatt. "Serial Galactose-Deficient IgA1 Levels in Children with IgA Nephropathy and Healthy Controls." International Journal of Nephrology 2017 (2017): 1–5. http://dx.doi.org/10.1155/2017/8210641.
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Galactose-deficient IgA1 (Gd-IgA1) is a key pathogenic factor for IgA nephropathy (IgAN) and a potential biomarker for the disease. This study examined serial serum Gd-IgA1 levels over 1 year in 13 children with IgAN and 40 healthy children, to determine whether or not serum Gd-IgA1 levels changed over time. Subjects were younger than 18 years of age. Follow-up measurements were scheduled 6 and/or 12 months later. Analysis of variance and regression models for repeated measures were used to estimate group and time effects. Serum Gd-IgA1 level was higher in initial samples for IgAN patients compared to those of healthy children (P<0.0001). Serum Gd-IgA1 levels did not change over time for healthy controls but increased for IgAN patients (P=0.001). Serum Gd-IgA1 level was elevated for 9 children with IgAN at study entry and remained elevated. Two of the 4 IgAN patients with initially normal Gd-IgA1 levels had a subsequent elevated level. The persistent elevation of the serum Gd-IgA1 level in children with IgAN enhances its utility as a potential diagnostic test for IgAN.
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Fukao, Yusuke, Hitoshi Suzuki, Jin Sug Kim, Kyung Hwan Jeong, Yuko Makita, Toshiki Kano, Yoshihito Nihei, et al. "Galactose-Deficient IgA1 as a Candidate Urinary Marker of IgA Nephropathy." Journal of Clinical Medicine 11, no. 11 (June 2, 2022): 3173. http://dx.doi.org/10.3390/jcm11113173.
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In patients with IgA nephropathy (IgAN), circulatory IgA1 and IgA1 in the mesangial deposits contain galactose-deficient IgA1 (Gd-IgA1). Some of the Gd-IgA1 from the glomerular deposits is excreted in the urine and thus urinary Gd-IgA1 may represent a disease-specific marker. We recruited 338 Japanese biopsy-proven IgAN patients and 120 patients with other renal diseases (disease controls). Urine samples collected at the time of renal biopsy were used to measure Gd-IgA1 levels using a specific monoclonal antibody (KM55 mAb). Urinary Gd-IgA1 levels were significantly higher in patients with IgAN than in disease controls. Moreover, urinary Gd-IgA1 was significantly correlated with the severity of the histopathological parameters in IgAN patients. Next, we validated the use of urinary Gd-IgA1 levels in the other Asian cohorts. In the Korean cohort, urinary Gd-IgA1 levels were also higher in patients with IgAN than in disease controls. Even in Japanese patients with IgAN and trace proteinuria (less than 0.3 g/gCr), urinary Gd-IgA1 was detected. Thus, urinary Gd-IgA1 may be an early disease-specific biomarker useful for determining the disease activity of IgAN.
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Cho, Won-Hee, Seon-Hwa Park, Seul-Ki Choi, Su Woong Jung, Kyung Hwan Jeong, Yang-Gyun Kim, Ju-Young Moon, et al. "Characterization of IgA Deposition in the Kidney of Patients with IgA Nephropathy and Minimal Change Disease." Journal of Clinical Medicine 9, no. 8 (August 12, 2020): 2619. http://dx.doi.org/10.3390/jcm9082619.
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Approximately 5% of patients with IgA nephropathy (IgAN) exhibit mild mesangial lesions with acute onset nephrotic syndrome and diffuse foot process effacement representative of minimal change disease (MCD). It is not clear whether these unusual cases of IgAN with MCD (IgAN-MCD) are variant types of IgAN or coincidental deposition of IgA in patients with MCD. In a retrospective multicenter cohort study of 18 hospitals in Korea, we analyzed 46 patients with IgAN-MCD. Patients with endocapillary proliferation, segmental sclerosis, and crescent were excluded, and the clinical features and prognosis of IgAN-MCD were compared with those of pure MCD. In addition, we performed galactose-deficient IgA1 (KM55) staining to characterize IgAN-MCD. Among the 21,697 patients with glomerulonephritis enrolled in the database, 46 patients (0.21%) were diagnosed with IgAN-MCD, and 1610 patients (7.4%) with pure MCD. The 46 patients with IgAN-MCD accounted for 0.6% of primary IgAN patients (n = 7584). There was no difference in prognosis between patients with IgAN-MCD and those with only MCD. IgA and KM55 showed double positivity in all patients with IgAN-MCD (n = 4) or primary IgAN (n = 5) under double immunofluorescent staining. However, in four patients with lupus nephritis, mesangial IgA was deposited, but galactose-deficient-IgA1 (Gd-IgA1) was not. These findings suggest that IgAN-MCD is a dual glomerulopathy in which MCD was superimposed on possibly indolent IgAN. We confirmed by KM55 staining that IgAN-MCD is true IgAN, enabling better characterizations of the disease. Furthermore, IgAN-MCD shows a good prognosis when treated according to the usual MCD treatment modality.
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Rizk, Dana V., Manish K. Saha, Stacy Hall, Lea Novak, Rhubell Brown, Zhi-Qiang Huang, Huma Fatima, Bruce A. Julian, and Jan Novak. "Glomerular Immunodeposits of Patients with IgA Nephropathy Are Enriched for IgG Autoantibodies Specific for Galactose-Deficient IgA1." Journal of the American Society of Nephrology 30, no. 10 (August 23, 2019): 2017–26. http://dx.doi.org/10.1681/asn.2018111156.
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BackgroundIgA nephropathy (IgAN) is the leading primary GN worldwide. The disease is thought to result from glomerular deposition of circulating immune complexes of IgG bound to galactose-deficient IgA1 (Gd-IgA1). However, routine immunofluorescence microscopy fails to detect IgG in many kidney biopsies from patients with IgAN and the specificity of IgG in immunodeposits has not been tested.MethodsWe used remnant frozen kidney-biopsy specimens from 34 patients with IgAN; 14 were IgG-positive and 20 were IgG-negative by routine immunofluorescence microscopy. Six patients with primary membranous nephropathy (MN) and eight with lupus nephritis (LN) served as controls. IgG in the kidney tissue was extracted and its amount determined by ELISA. IgG molecular integrity was assessed by SDS-PAGE immunoblotting. Antigenic specificity of extracted IgG was determined by ELISA using phospholipase A2 receptor (PLA2R) or Gd-IgA1 as antigen. In addition, ten other IgAN cases, six IgG-positive and four IgG-negative by routine immunofluorescence, were used for colocalization studies by confocal microscopy.ResultsIgG extracted from MN but not IgAN immunodeposits reacted with PLA2R. Conversely, IgG extracted from IgAN but not MN or LN immunodeposits reacted with Gd-IgA1. Even IgAN kidney-biopsy specimens without IgG by routine immunofluorescence microscopy had IgG specific for Gd-IgA1. Confocal microscopy confirmed the presence of IgG in the IgAN biopsies with colocalization of glomerular IgA and IgG.ConclusionsThese results reveal for the first time that IgAN kidney biopsies, with or without IgG by routine immunofluorescence, contain Gd-IgA1–specific IgG autoantibodies. These findings support the importance of these autoantibodies in the pathogenesis of IgAN.
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Pillebout, Evangeline. "IgA Vasculitis and IgA Nephropathy: Same Disease?" Journal of Clinical Medicine 10, no. 11 (May 25, 2021): 2310. http://dx.doi.org/10.3390/jcm10112310.
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Many authors suggested that IgA Vasculitis (IgAV) and IgA Nephropathy (IgAN) would be two clinical manifestations of the same disease; in particular, that IgAV would be the systemic form of the IgAN. A limited number of studies have included sufficient children or adults with IgAN or IgAV (with or without nephropathy) and followed long enough to conclude on differences or similarities in terms of clinical, biological or histological presentation, physiopathology, genetics or prognosis. All therapeutic trials available on IgAN excluded patients with vasculitis. IgAV and IgAN could represent different extremities of a continuous spectrum of the same disease. Due to skin rash, patients with IgAV are diagnosed precociously. Conversely, because of the absence of any clinical signs, a renal biopsy is practiced for patients with an IgAN to confirm nephropathy at any time of the evolution of the disease, which could explain the frequent chronic lesions at diagnosis. Nevertheless, the question that remains unsolved is why do patients with IgAN not have skin lesions and some patients with IgAV not have nephropathy? Larger clinical studies are needed, including both diseases, with a common histological classification, and stratified on age and genetic background to assess renal prognosis and therapeutic strategies.
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Ohyama, Yukako, Matthew B. Renfrow, Jan Novak, and Kazuo Takahashi. "Aberrantly Glycosylated IgA1 in IgA Nephropathy: What We Know and What We Don’t Know." Journal of Clinical Medicine 10, no. 16 (August 5, 2021): 3467. http://dx.doi.org/10.3390/jcm10163467.
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IgA nephropathy (IgAN), the most common primary glomerular disease worldwide, is characterized by glomerular deposition of IgA1-containing immune complexes. The IgA1 hinge region (HR) has up to six clustered O-glycans consisting of Ser/Thr-linked N-acetylgalactosamine usually with β1,3-linked galactose and variable sialylation. Circulating levels of IgA1 with abnormally O-glycosylated HR, termed galactose-deficient IgA1 (Gd-IgA1), are increased in patients with IgAN. Current evidence suggests that IgAN is induced by multiple sequential pathogenic steps, and production of aberrantly glycosylated IgA1 is considered the initial step. Thus, the mechanisms of biosynthesis of aberrantly glycosylated IgA1 and the involvement of aberrant glycoforms of IgA1 in disease development have been studied. Furthermore, Gd-IgA1 represents an attractive biomarker for IgAN, and its clinical significance is still being evaluated. To elucidate the pathogenesis of IgAN, it is important to deconvolute the biosynthetic origins of Gd-IgA1 and characterize the pathogenic IgA1 HR O-glycoform(s), including the glycan structures and their sites of attachment. These efforts will likely lead to development of new biomarkers. Here, we review the IgA1 HR O-glycosylation in general and the role of aberrantly glycosylated IgA1 in the pathogenesis of IgAN in particular.
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Reily, Colin, Hiroyuki Ueda, Zhi-Qiang Huang, Jiri Mestecky, Bruce A. Julian, Christopher D. Willey, and Jan Novak. "Cellular Signaling and Production of Galactose-Deficient IgA1 in IgA Nephropathy, an Autoimmune Disease." Journal of Immunology Research 2014 (2014): 1–10. http://dx.doi.org/10.1155/2014/197548.
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Immunoglobulin A (IgA) nephropathy (IgAN), the leading cause of primary glomerulonephritis, is characterized by IgA1-containing immunodeposits in the glomeruli. IgAN is a chronic disease, with up to 40% of patients progressing to end-stage renal disease, with no disease-specific treatment. Multiple studies of the origin of the glomerular immunodeposits have linked elevated circulating levels of aberrantly glycosylated IgA1 (galactose-deficient in someO-glycans; Gd-IgA1) with formation of nephritogenic Gd-IgA1-containing immune complexes. Gd-IgA1 is recognized as an autoantigen in susceptible individuals by anti-glycan autoantibodies, resulting in immune complexes that may ultimately deposit in the kidney and induce glomerular injury. Genetic studies have revealed that an elevated level of Gd-IgA1 in the circulation of IgAN patients is a hereditable trait. Moreover, recent genome-wide association studies have identified several immunity-related loci that associated with IgAN. Production of Gd-IgA1 by IgA1-secreting cells of IgAN patients has been attributed to abnormal expression and activity of several key glycosyltransferases. Substantial evidence is emerging that abnormal signaling in IgA1-producing cells is related to the production of Gd-IgA1. As Gd-IgA1 is the key autoantigen in IgAN, understanding the genetic, biochemical, and environmental aspects of the abnormal signaling in IgA1-producing cells will provide insight into possible targets for future disease-specific therapy.
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Zhang, Kai, Qiongqiong Li, Yaru Zhang, Wenya Shang, Li Wei, Hongfen Li, Shan Gao, et al. "Clinical Significance of Galactose-Deficient IgA1 by KM55 in Patients with IgA Nephropathy." Kidney and Blood Pressure Research 44, no. 5 (2019): 1196–206. http://dx.doi.org/10.1159/000502579.
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Background: Aberrant galactose-deficient IgA1 molecules (Gd-IgA1) are important causal factors in IgA nephropathy (IgAN); however, the detection of Gd-IgA1 in IgAN is complicated and instable. A monoclonal antibody, KM55, which specifically recognizes Gd-IgA1 has been developed. In the present study, we further explored the clinical significance of Gd-IgA1 using KM55. Methods: In this study, we enrolled 75 patients with IgAN and 80 healthy controls and detected the plasma Gd-IgA1 levels using the KM55 ELISA method. We also stained mesangial Gd-IgA1 deposition using KM55. Results: We observed that the levels of plasma Gd-IgA1 in IgAN patients were elevated compared to the corresponding levels of healthy controls. Patients were divided into 2 groups based on the median of Gd-IgA1. Patients with high Gd-IgA1 levels had significantly higher levels of uric acid (UA) and IgA. The other clinical manifestations demonstrated that there were no differences in age, sex, blood pressure, initial proteinuria, hematuria, estimated glomerular filtration rate and Oxford pathological classification between the 2 groups of patients. In addition, positive correlations were observed between Gd-IgA1 and Bb, C3a, C4d and MAC. Mesangial Gd-IgA1 was positive in IgAN but negative in the normal renal tissue adjacent to neoplasm. We next analyzed the correlation between plasma Gd-IgA1 and mesangial Gd-IgA1 deposition. The results showed that a high level of plasma Gd-IgA1 was related to the deposition of mesangial Gd-IgA1, although the difference was not significant. Conclusion: We verified the elevated level of plasma and mesangial Gd-IgA1 in patients with IgAN by KM55, which provided an alternative, easy, and reliable tool for diagnosis and activity assessment of IgAN. The level of plasma Gd-IgA1 positively correlated with levels of UA, total IgA levels, and complement activation products.
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ALLEN, ALICE C., ELAINE M. BAILEY, JONATHAN BARRATT, KATHARINE S. BUCK, and JOHN FEEHALLY. "Analysis of IgA1 O-Glycans in IgA Nephropathy by Fluorophore-Assisted Carbohydrate Electrophoresis." Journal of the American Society of Nephrology 10, no. 8 (August 1999): 1763–71. http://dx.doi.org/10.1681/asn.v1081763.
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Abstract. Abnormal O-glycosylation of IgA1 may contribute to pathogenic mechanisms in IgA nephropathy (IgAN). Observations of altered lectin binding to IgA1 in IgAN suggest that the O-glycan chains may be undergalactosylated, but precise structural definition of the defect has proved technically difficult, and it remains unconfirmed. This is the first study using fluorophore-assisted carbohydrate electrophoresis (FACE) to analyze IgA1 O-glycans in IgAN and controls. IgA1 was purified from serum, and the intact O-glycans were released by hydrazinolysis at 60°C. After re-N-acetylation, the glycans were fluorophore-labeled and separated by polyacrylamide gel electrophoresis. Sequential exoglycosidase digestions of IgA1 allowed identification of the different O-glycan bands on FACE gels, and their relative frequencies in IgA1 samples were measured by ultraviolet densitometry. Lectin binding of the IgA1 samples was also measured. In some patients with IgAN, FACE analysis demonstrated a significant increase in the percentage of IgA1 O-glycan chains consisting of single N-acetyl galactosamine (GalNAc) units rather than the more usual galactosylated and sialylated forms. This finding was confirmed using both desialylated IgA1 and enzymatically released O-glycans. Good correlation was also found between O-glycan agalactosylation on FACE analysis and IgA1 lectin binding in IgAN, supporting the value of lectins as tools for detection of this abnormality. This is the first study in which all of the predicted O-glycan forms of IgA1 have been analyzed simultaneously, and demonstrates that in IgAN, the IgA1 O-glycan chains are truncated, with increased terminal GalNAc. This abnormality has the potential to significantly affect IgA1 behavior and handling with pathogenic consequences in IgAN.
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Uenoyama, Yuta, Atsushi Matsuda, Kazune Ohashi, Koji Ueda, Misaki Yokoyama, Takuya Kyoutou, Kouji Kishi, et al. "Development and Evaluation of a Robust Sandwich Immunoassay System Detecting Serum WFA-Reactive IgA1 for Diagnosis of IgA Nephropathy." International Journal of Molecular Sciences 23, no. 9 (May 5, 2022): 5165. http://dx.doi.org/10.3390/ijms23095165.
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Aberrant glycosylation of IgA1 is involved in the development of IgA nephropathy (IgAN). There are many reports of IgAN markers focusing on the glycoform of IgA1. None have been clinically applied as a routine test. In this study, we established an automated sandwich immunoassay system for detecting aberrant glycosylated IgA1, using Wisteria floribunda agglutinin (WFA) and anti-IgA1 monoclonal antibody. The diagnostic performance as an IgAN marker was evaluated. The usefulness of WFA for immunoassays was investigated by lectin microarray. A reliable standard for quantitative immunoassay measurements was designed by modifying a purified IgA1 substrate. A validation study using multiple serum specimens was performed using the established WFA-antibody sandwich automated immunoassay. Lectin microarray results showed that WFA specifically recognized N-glycans of agglutinated IgA1 in IgAN patients. The constructed IgA1 standard exhibited a wide dynamic range and high reactivity. In the validation study, serum WFA-reactive IgA1 (WFA+-IgA1) differed significantly between healthy control subjects and IgAN patients. The findings indicate that WFA is a suitable lectin that specifically targets abnormal agglutinated IgA1 in serum. We also describe an automated immunoassay system for detecting WFA+-IgA1, focusing on N-glycans.
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Liu, Youxia, Jie Zheng, Na Zhao, Junya Jia, and Tiekun Yan. "ELL2 Is Downregulated and Associated with Galactose-Deficient IgA1 in IgA Nephropathy." Disease Markers 2019 (June 4, 2019): 1–7. http://dx.doi.org/10.1155/2019/2407067.
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Background. Galactose-deficient IgA1 (Gd-IgA1) is an important causal factor in IgA nephropathy; however, the underlying mechanism for the production of Gd-IgA1 is unknown. The elongation factor for RNA polymerase II (ELL2), which encoded a key component of the superelongation complex (SEC), drives secretory-specific Ig mRNA production. Methods. We enrolled 21 patients with IgAN, 18 healthy controls, and 20 patients with non-IgAN glomerulonephritis. The differential expression of ELL2 was compared using publically available data from Gene Expression Omnibus (GEO) datasets. The relationship between ELL2 expressions and galactose-deficient IgA1 (Gd-IgA1) levels in serum were also studied. At last, the results were validated by shELL2 treatment experiment. Results. We found that the number of CD19+ B cells was increased in IgAN patients compared to healthy controls. The expression level of ELL2 in patients with IgAN was significantly lower than that of healthy control and disease control. Consistent with present results, the lower ELL2 expression in IgAN patients was observed in microarray expression profiles from GEO datasets. Pearson correlation analysis showed that ELL2 expression negatively correlated with Gd-IgA1 levels. Furthermore, in an in vitro experiment, we found that loss of ELL2 function in human B lymphoma DAKIKI cells, an IgA1-producing cell line, increased the levels of Gd-IgA1, which confirmed that ELL2 modulated the levels of Gd-IgA1. Conclusion. Our findings implied that decreased ELL2 expression was negatively correlated with the numbers of B cells and aberrant glycosylation of IgA1 in IgAN.
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Mizerska-Wasiak, Małgorzata, Emilia Płatos, Karolina Cichoń-Kawa, Urszula Demkow, and Małgorzata Pańczyk-Tomaszewska. "The Usefulness of Vanin-1 and Periostin as Markers of an Active Autoimmune Process or Renal Fibrosis in Children with IgA Nephropathy and IgA Vasculitis with Nephritis—A Pilot Study." Journal of Clinical Medicine 11, no. 5 (February 25, 2022): 1265. http://dx.doi.org/10.3390/jcm11051265.
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This study aimed to evaluate the usefulness of vanin-1 and periostin in urine as markers of the autoimmune process in kidneys and renal fibrosis in IgA nephropathy (IgAN) and IgA vasculitis with nephritis (IgAVN). From a group of 194 patients from the Department of Pediatrics and Nephrology, who were included in the Polish Pediatric Registry of IgAN and IgAVN, we qualified 51 patients (20 with IgAN and 31 with IgAVN) between the ages of 3 and 17, diagnosed based on kidney biopsy, for inclusion in the study. All of the patients received glucocorticosteroids, immunosuppressive drugs, or renoprotective therapy. The control group consisted of 18 healthy individuals. The concentration of vanin was significantly higher in the IgAN and IgAVN groups than in the control group. The concentration of vanin/creatinine correlates positively with the level of IgA and negatively with the serum level of C3 at the end of the observation. Urinary vanin-1 concentration may be useful as a marker of the active autoimmune process in IgAN and IgAVN in children, but the study needs confirmation on a larger group of children, along with evaluation of the dynamics of this marker. Urinary periostin is not a good marker for children with IgAN and IgAVN, especially in stage 1 and 2 CKD.
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Juan, Yun-Ting, Wen-Chih Chiang, Wei-Chou Lin, Cheng-Wen Yang, San-Fang Chou, Ruo-Wei Hung, and Yen-Ling Chiu. "Associations between Biomarkers of Complement Activation, Galactose-Deficient IgA1 Antibody and the Updated Oxford Pathology Classification of IgA Nephropathy." Journal of Clinical Medicine 11, no. 14 (July 21, 2022): 4231. http://dx.doi.org/10.3390/jcm11144231.
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Our prior study indicates a close relationship between alternative complement pathway activation, galactose-deficient IgA1 (Gd-IgA1) concentration and clinical severity of IgA nephropathy (IgAN). Nonetheless, the relationship between complement factors and the updated Oxford classification of IgAN remains unclear. This study enrolled eighty-four previously untreated, biopsy-diagnosed IgAN patients. The clinical and laboratory findings were collected at the time of biopsy. Plasma levels of complement factor C5a, factor Ba and Gd-IgA1 were measured and analyzed. It was found that the levels of proteinuria positively correlated with the updated Oxford classification of mesangial hypercellularity (M), endocapillary hypercellularity (E), tubular atrophy/interstitial fibrosis (T) and crescents (C). In addition, plasma Gd-IgA1 titer was significantly elevated in IgAN patients with tubular atrophy/interstitial fibrosis (T). In separate multivariable logistic regression models, both Gd-IgA1 and factor Ba independently predict higher T scores. The results indicate that both the levels of Gd-IgA1 antibody and biomarkers of the alternative complement pathway activation reflect the Oxford classification of IgAN. Whether these biomarkers can be used to guide therapeutic decisions requires further study.
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Tanaka, Mototsugu, George Seki, Tomonosuke Someya, Michio Nagata, and Toshiro Fujita. "Aberrantly Glycosylated IgA1 as a Factor in the Pathogenesis of IgA Nephropathy." Clinical and Developmental Immunology 2011 (2011): 1–7. http://dx.doi.org/10.1155/2011/470803.
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Predominant or codominant immunoglobulin (Ig) A deposition in the glomerular mesangium characterizes IgA nephropathy (IgAN). Accumulated glomerular IgA is limited to the IgA1 subclass and usually galactose-deficient. This underglycosylated IgA may play an important role in the pathogenesis of IgAN. Recently, antibodies against galactose-deficient IgA1 were found to be well associated with the development of IgAN. Several therapeutic strategies based on corticosteroids or other immunosuppressive agents have been shown to at least partially suppress the progression of IgAN. On the other hand, several case reports of kidney transplantation or acquired IgA deficiency uncovered a remarkable ability of human kidney to remove mesangial IgA deposition, resulting in the long-term stabilization of kidney function. Continuous exposure to circulating immune complexes containing aberrantly glycosylated IgA1 and sequential immune response seems to be essential in the disease progression of IgAN. Removal of mesangial IgA deposition may be a challenging, but fundamental approach in the treatment of IgAN.
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Monteiro, Renato C., Dina Rafeh, and Patrick J. Gleeson. "Is There a Role for Gut Microbiome Dysbiosis in IgA Nephropathy?" Microorganisms 10, no. 4 (March 22, 2022): 683. http://dx.doi.org/10.3390/microorganisms10040683.
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Immunoglobulin A nephropathy (IgAN) is the most common primary glomerulonephritis and one of the leading causes of renal failure worldwide. The pathophysiology of IgAN involves nephrotoxic IgA1-immune complexes. These complexes are formed by galactose-deficient (Gd) IgA1 with autoantibodies against the hinge region of Gd-IgA1 as well as soluble CD89, an immune complex amplifier with an affinity for mesangial cells. These multiple molecular interactions result in the induction of the mesangial IgA receptor, CD71, injuring the kidney and causing disease. This review features recent immunological and microbiome studies that bring new microbiota-dependent mechanisms developing the disease based on data from IgAN patients and a humanized mouse model of IgAN. Dysbiosis of the microbiota in IgAN patients is also discussed in detail. Highlights of this review underscore that nephrotoxic IgA1 in the humanized mice originates from mucosal surfaces. Fecal microbiota transplantation (FMT) experiments in mice using stools from patients reveal a possible microbiota dysbiosis in IgAN with the capacity to induce progression of the disease whereas FMT from healthy hosts has beneficial effects in mice. The continual growth of knowledge in IgAN patients and models can lead to the development of new therapeutic strategies targeting the microbiota to treat this disease.
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Cheng, Wenrong, Guoqin Wang, Weiyi Guo, Lijun Sun, Xiaoyi Xu, Hongrui Dong, Suhua Ye, Yanqiu Geng, and Hong Cheng. "Glomerular Galactose-Deficient IgA1(KM55) Positive May Predict Poorer Prognosis in Coexisting Primary Membranous Nephropathy and IgA Nephropathy Patients." Cells 12, no. 1 (December 28, 2022): 116. http://dx.doi.org/10.3390/cells12010116.
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Primary membrane nephropathy (PMN) and IgA nephropathy (IgAN) are the most common glomerular diseases in China. Because of different pathogenesis, prognosis is significantly different. When the two diseases coexist (PMN/IgAN), the clinicopathological manifestations and prognosis remain unclear. In the present study, we analyzed the clinicopathological characteristics of PMN/IgAN patients, with only IgA deposition (PMN/IgA deposition) patients as controls. Galactose-deficient IgA1(KM55) and M-type Phospholipase A2 Receptor(PLA2R), both in circulation and renal tissues, were detected. Furthermore, prognosis of PMN/IgAN was explored. We found that PMN/IgAN also had some clinical features of IgAN in addition to PMN, such as higher serum albumin, along with a similar heavy proteinuria and lower titers of serum anti-PLA2R antibody. The positive rate of glomerular KM55 in PMN/IgAN was 23.5% (20/85), and 0% (0/29) in PMN/IgA deposition. Among those glomerular KM55 positive patients, KM55 and IgA colocalized mainly along the glomerular mesangial and capillary areas. Unfortunately, there was no significant difference in serum level of Gd-IgA1 between KM55+ and KM55− subgroups in PMN/IgAN patients, similar to the PMN/IgA deposition group. Notably, glomerular KM55 positive may predict a poorer prognosis in PMN/IgAN patients. In conclusion, our study suggested that, when glomerular KM55 staining was positive, this special coexisting PMN/IgAN disorder was prone to have more characteristics of IgAN besides PMN, and may predict poorer prognosis, while the mechanism requires further investigation.
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Wang, Cheng, Hui Peng, Hua Tang, Xun Liu, Zhujiang Chen, Tanqi Lou, and Xueqing Yu. "Serum IgA1 from IgA nephropathy patients induces apoptosis in podocytes through direct and indirect pathways." Clinical & Investigative Medicine 30, no. 6 (December 1, 2007): 240. http://dx.doi.org/10.25011/cim.v30i6.2952.
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Purpose: To investigate apoptosis of podocytes induced by IgA1 isolated from IgA nephropathy (IgAN) patients through direct and indirect pathways.
Methods: Jacalin affinity chromatography and Sephacryl S-200 molecular sieve chromatography were used to isolate IgA1 from blood of IgAN patients made as aggregated IgA1 (aIgA1). Podocytes were incubated with aIgA1 or special treated medium from mesangial cells after co-incubation with aIgA1 from IgAN patients. Apoptosis of podocytes was assessed by TUNEL staining and flow cytometry. Real-time PCR was used to detect the mRNA expression of Bcl-2, Bax, Fas and Fas-L.
Results: AIgA1 from IgAN patients induced more apoptosis of podocytes by both time and concentration-dependent patterns than control (30.5±5.4% vs 20.5±4.5, respectively, P < 0.05). The percentage of apoptotic podocytes exposed to treated medium was higher than control (28.5±5.9 % vs 20.5±4.5%, respectively, P < 0.05). The level of normalized Fas mRNA expression in podocytes exposed to aIgA1 was 2.4-fold higher than control (P < 0.05), while the level in podocytes exposed with treated medium was 1.89-fold higher than control (P < 0.05), and the level of normalized Bcl-2 mRNA expression in this group was 72% lower than control (P < 0.05)
Conclusion: IgA1 from IgAN patients may induce apoptosis of podocytes through direct and indirect pathways. IgA1 may accelerate progression of IgAN by inducing apoptosis of podocytes.
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Levanon, S., V. Gotlieb, Y. Kraus, I. Novofastovski, S. Brikman, A. Fawaz, M. Aghbariyya, et al. "POS0831 IgA VASCULITIS IN ADULTS, PEDIATRICS AND NON-VASCULITIC IgA NEPHROPATHY." Annals of the Rheumatic Diseases 81, Suppl 1 (May 23, 2022): 706.2–707. http://dx.doi.org/10.1136/annrheumdis-2022-eular.3368.
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BackgroundIgA vasculitis (IgAV) has been extensively studied in children, while its natural history remains poorly studied in adults. Sparse data comparing childhood and adult-onset disease has shown significant differences in their clinical presentation, especially in the severity of renal involvement, which accounts for the major long-term morbidity. IgAV shares similar renal histologic features with IgA nephropathy (IgAN), while clinically IgAN is a chronic kidney disease which may lead to end stage renal disease and dialysis. The extent of kidney injury among adults with IgAV is still a matter of uncertainty.ObjectivesWe aimed to evaluate clinical manifestations, laboratory data, treatment patterns and long-term outcomes of pediatric and adult-onset IgAV in comparison to IgAN.MethodsThis retrospective collaborative study examined medical records of adults and children with IgAV and IgAN adult patients admitted to rheumatology clinic and in hospital pediatric departments in a 13-year period (2007-2019). Diagnosis of adults with IgAV relied on the Ankara criteria and was confirmed by a consistent skin biopsy with positive IgA staining by immunofluorescence. Children with IgAV were included in our study on a clinical basis. All IgAN patients had a kidney biopsy proven disease. We analyzed and compared frequencies of clinical manifestations, laboratory findings, treatment regimens and long-term outcomes at one year follow-up. Finally, we assessed long term outcomes, such as time to dialysis and all-cause mortality, till the end of the follow-up time.ResultsA total of 60 adult IgAV, 60 pediatric IgAV and 45 IgAN patients were included in our study. There were significantly more males in the IgAN group compared to the adult and pediatric IgAV groups (77.8%, 41.7% and 55% respectively, p=0.01). Adult IgAV patients were significantly older than IgAN patients (53.1±17.4 years vs. 45.1±15.7 years, p=0.02) and had significantly higher rates of diabetes (43.3% vs. 24.4%, p=0.05) and ischemic heart disease (18.3% vs. 4.4%, p=0.03). The pediatric IgAV group had a statistically higher rate of previous infection compared to the adult IgAV group (44.8% vs. 20%, p=0.02). At one year follow-up, IgAN patients had higher levels of serum creatinine compared to the adult IgAV group (2.002 vs. 1.100, p<0.01). Data observed until the end of the follow-up time showed no difference in time to dialysis (IgAV adults: 9.8-12.4 years, IgAN: 5.0-6.6 years, p>.41). Nevertheless, IgAV adult patients had significantly shorter survival time (5.5 years, 95% CI: 4.8-6.2 years) than IgAN patients (7.0 years, 95% CI: 6.6-7.5 years, p<.01).ConclusionThis retrospective study demonstrates that IgAV in adults presents substantial clinical manifestations, including high risk of progression to persistent renal impairment and possesses higher mortality rate in comparison with pediatric-onset disease and IgAN.References[1]Blanco R, Martínez-Taboada VM, Rodríguez-Valverde V, García-Fuentes M, González-Gay MA. Henoch-Schönlein purpura in adulthood and childhood: two different expressions of the same syndrome. Arthritis Rheum. 1997 May;40(5):859-64. doi: 10.1002/art.1780400513. PMID: 9153547.[2]Nossent J, Raymond W, Isobel Keen H, Preen D, Inderjeeth C. Morbidity and mortality in adult-onset IgA vasculitis: a long-term population-based cohort study. Rheumatology (Oxford). 2021 Dec 24;61(1):291-298. doi: 10.1093/rheumatology/keab312. PMID: 33779729.Figure 1.Disclosure of InterestsNone declared
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Liang, Ying, Qin Zeng, Xin-Hui Wang, Lei Yan, and Ren-Huan Yu. "Mechanism of Yiqi Yangying Heluo Formula in the Treatment of IgA Nephropathy by Affecting Gd-IgA1 Based on BAFF Molecular Level and T Lymphocyte Immunity." BioMed Research International 2023 (January 10, 2023): 1–9. http://dx.doi.org/10.1155/2023/5124034.
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Background. Galactose-deficient IgA1 (Gd-IgA1) is a critical initiating factor in the pathogenesis of IgA nephropathy (IgAN), which plays an important role in the diagnosis and evaluation of this disease. Moreover, the whole pathogenesis process has an intimate association with the immune response of T and B lymphocytes and their inflammatory factors. There is no specific therapy for IgAN at present. Yiqi Yangyin Formula can significantly reduce urinary protein and hematuria in patients with IgAN. Yiqi Yangying Heluo Formula (YYHF) is optimized on the basis of the above prescription, but its specific mechanism remains to be further studied. Methods. The effect of YYHF on urinary protein and urinary red blood cell count in patients with IgAN was observed by a self-controlled clinical study before and after treatment. On this basis, flow cytometry was used to detect the proportion of T lymphocyte subsets in peripheral blood of patients with IgAN before and after treatment and healthy controls. Meanwhile, the levels of Gd-IgA1, B cell activation factor (BAFF), and their cytokines (IL-4, IL-6, and IL-17) in peripheral blood were detected by enzyme-linked immunosorbent assay. The changes in mechanism-related indicators of the two groups were observed and subject to correlation analysis. Results. (1) Compared with the levels before treatment, 24-hour urinary protein content decreased by 47.7% and urinary red blood cell number decreased by 67% in patients with IgAN intervened by YYHF after 48 weeks of follow-up. (2) Compared with the healthy control group, patients with IgAN showed a significantly increased proportion of Th1 cells, Th17 cells, Th1/Th2, Th1/Treg, Th2/Treg, and Th17/Treg, obviously reduced proportion of Th2 cells and Treg cells, and evidently elevated levels of Gd-IgA1, BAFF, and their cytokines (IL-4, IL-6, and IL-17) in the peripheral blood. (3) Following 48 weeks of follow-up after intervention treatment with YYHF, the levels of Gd-IgA1, BAFF, IL-6, and IL-17 were significantly lower, but the level of IL-4 was higher in peripheral blood of patients with IgAN than those before treatment and after 24 weeks of treatment; simultaneously, the proportion of Th1 cells, Th17 cells, Th1/Th2, Th1/Treg, Th2/Treg, and Th17/Treg decreased while that of Th2 cells and Treg cells increased after 48 weeks of follow-up compared with that before treatment in peripheral blood of patients with IgAN. (4) The results of correlation analysis revealed that the level of Gd-IgA1 in peripheral blood of patients with IgAN was positively correlated with the level of BAFF, as well as the proportion of Th1 cells, Th17 cells, Th1/Th2, IL-6, and IL-17 levels, and negatively correlated with the proportion of Treg cells. In addition, the level of Gd-IgA1 in peripheral blood was positively correlated with proteinuria, yet without correlation with hematuria. Conclusion. YYHF can reduce the quantitative level of 24 h urinary protein and urinary red blood cell count in patients with IgAN. Patients with IgAN have obvious T cell immune imbalance. YYHF can significantly reduce the level of Gd-IgA1 in patients with IgAN, and its mechanism may be explained by the reduced level of BAFF in peripheral blood and improved immune balance of T cells.
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Maixnerova, Dita, Delphine El Mehdi, Dana V. Rizk, Hong Zhang, and Vladimir Tesar. "New Treatment Strategies for IgA Nephropathy: Targeting Plasma Cells as the Main Source of Pathogenic Antibodies." Journal of Clinical Medicine 11, no. 10 (May 16, 2022): 2810. http://dx.doi.org/10.3390/jcm11102810.
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Immunoglobulin A nephropathy (IgAN) is a rare autoimmune disorder and the leading cause of biopsy-reported glomerulonephritis (GN) worldwide. Disease progression is driven by the formation and deposition of immune complexes composed of galactose-deficient IgA1 (Gd-IgA1) and Gd-IgA1 autoantibodies (anti-Gd-IgA1 antibodies) in the glomeruli, where they trigger complement-mediated inflammation that can result in loss of kidney function and end-stage kidney disease (ESKD). With the risk of progression and limited treatment options, there is an unmet need for therapies that address the formation of pathogenic Gd-IgA1 antibody and anti-Gd-IgA1 antibody-containing immune complexes. New therapeutic approaches target immunological aspects of IgAN, including complement-mediated inflammation and pathogenic antibody production by inhibiting activation or promoting depletion of B cells and CD38-positive plasma cells. This article will review therapies, both approved and in development, that support the depletion of Gd-IgA1-producing cells in IgAN and have the potential to modify the course of this disease. Ultimately, we propose here a novel therapeutic approach by depleting CD38-positive plasma cells, as the source of the autoimmunity, to treat patients with IgAN.
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Xie, Lin-Shen, Wei Qin, Jun-Ming Fan, Jun Huang, Xi-Sheng Xie, and Zi Li. "The role of C1GALT1C1 in lipopolysaccharide-induced IgA1 aberrant O-glycosylation in IgA nephropathy." Clinical & Investigative Medicine 33, no. 1 (February 1, 2010): 5. http://dx.doi.org/10.25011/cim.v33i1.11832.
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Purpose: IgA1 aberrant O-glycosylation is one of the main pathogenetic features of IgA nephropathy (IgAN). This study attempted to determine the role of C1GALT1C1 in aberrant IgA1 O-glycosylation induced by lipopolysaccharide (LPS) and identify potential therapeutic targets in IgAN. Methods: Lymphocytes isolated from 22 patients with IgAN and 17 normal controls were cultured for 3 to 7 days with or without LPS and 5-azacytidine (5-AZA). Expression levels of C1GALT1C1 mRNA and protein were measured by real-time PCR and Western blot analysis, respectively. Concentration of IgA1 and level of O-glycosylation were determined by ELISA and Vicia villosa (VV) lectin-binding assay. Correlation analysis was performed between the expression of C1GALT1C1 protein and IgA1 O-glycosylation. Results: Lymphocytes from patients with IgAN secreted more IgA1 than that from normal controls after LPS stimulation (P=0.26, 0.002 and 0.005 on the 3rd, 5th and 7th day, respectively) which could be inhibited by 5-AZA (P=0.001, 0.025 and 0.001 on the 3rd, 5th and 7th day, respectively). Moreover, LPS stimulation could obviously inhibit C1GALT1C1 expression in patients with IgAN (decreased by 71%, 82% and 92% on the 3rd, 5th and 7th day, respectively; P < 0.001), and cause a significant decrease of IgA1 O-glycosylation compared with normal controls (P=0.004, 0.003 and 0.03 on the 3rd, 5th and 7th day, respectively). When 5-AZA was added, the level of C1GALT1C1 expression increased dramatically (1.98, 5.53 and 8.97 times on the 3rd, 5th and 7th day, respectively; P < 0.001) along with an increase of IgA1 O-glycosylation (P=0.295, 0.09 and 0.003 on the 3rd, 5th and 7th day, respectively). However, normal controls showed no significant change in C1GALT1C1 expression and IgA1 O-glycosylation after LPS stimulation (P > 0.05). Conclusion: LPS induced IgA1 aberrant O-glycosylation and suppressed C1GALT1C1 expression in patients with IgAN. Upregulation of C1GALT1C1 expression by 5-AZA could reverse the IgA1 aberrant O-glycosylation. These results suggest that C1GALT1C1 may play a key role in the regulation of IgA1 O-glycosylation.
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Tam, Ka Ying, Joseph C. K. Leung, Loretta Y. Y. Chan, Man Fai Lam, Sydney C. W. Tang, and Kar Neng Lai. "In vitro enhanced chemotaxis of CD25+ mononuclear cells in patients with familial IgAN through glomerulotubular interactions." American Journal of Physiology-Renal Physiology 299, no. 2 (August 2010): F359—F368. http://dx.doi.org/10.1152/ajprenal.00664.2009.
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Tubulointerstitial infiltration of immunocompetent cells is often associated with a more rapid progression in IgA nephropathy (IgAN). Using an in vitro Transwell coculture system, we examined the chemotactic response of peripheral blood mononuclear cells to proximal tubular epithelial cells (PTEC) following activation by conditioned medium prepared from mesangial cells cultured with macromolecular IgA1 from 60 patients with multiplex familial IgAN (MpIgAN) and 91 of their asymptomatic relatives; 43 patients with sporadic IgAN (SpIgAN) and 90 of their asymptomatic relatives; and 43 healthy subjects. Compared with SpIgAN patients, PTEC activated by conditioned medium from patients with MpIgAN had elevated gene expression of a spectrum of C-C, C-X-C chemokines and proinflammatory cytokines, with prominent expressions of interleukin-6, interleukin-8, and tumor necrosis factor-α. In response to conditioned medium from patients with familial IgAN, there was a significant increase in chemotaxis of CD45+ cells, CD3+, CD4+, CD8+, CD20+ lymphocytes, and monocytes with CD25 expression. Our findings suggest that compared with SpIgAN patients, macromolecular IgA1 taken from MpIgAN patients is more pathogenic to cultured PTEC through a glomerulotubular interaction. A long-term follow-up is needed to better define the prognostic course for familial IgAN and to clarify the risk of developing IgAN in initially asymptomatic relatives from a multiplex IgAN family.
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Wang, Chang, Muyao Ye, Qiulan Zhao, Ming Xia, Di Liu, Liyu He, Guochun Chen, Youming Peng, and Hong Liu. "Loss of the Golgi Matrix Protein 130 Cause Aberrant IgA1 Glycosylation in IgA Nephropathy." American Journal of Nephrology 49, no. 4 (2019): 307–16. http://dx.doi.org/10.1159/000499110.
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Background: Aberrant O-glycosylation IgA1 production is a major factor in the pathogenesis of IgA nephropathy, but the underlying mechanism is still unclear. IgA1 glycosylation modification is in Golgi, and downregulation of the Golgi peripheral membrane protein Golgi matrix protein 130 (GM130) could lead to glycosylation deficiency. In this study, we aimed to explore the role of GM130 in glycosylate deficiency IgA1 (Gd-IgA1) production. Methods: We enrolled 27 IgA nephropathy patients, 12 patients with chronic tonsillitis, 15 non-IgAN chronic kidney disease patients, and 15 healthy volunteers as healthy control. We explored GM130 expression in Tonsillar tissue by immunofluorescence staining and Western blotting and expression in peripheral blood mononuclear cells (PBMCs) by flow cytometry. The concentration of IgA1 and level of O-glycosylation were determined by ELISA and Vicia Villosa lectin-binding assay. Real-time PCR and Western blot were used to analyze the levels of β1,3-Gal transferase (C1GALT1) and ST6GalNAC2, respectively. To explore the contribution of GM130 in IgA1 O-glycosylation modification, cells were subjected to experiments for evaluation of GM130 silencing by GM130-siRNA transfection. Results: GM130 expression was significantly decreased in tonsil tissues and PBMC of IgAN patients; the expression of C1GALT1 decreased and Gd-IgA1 level increased significantly in patients with IgAN patients. The expression of GM130 was negatively related to Gd-IgA1 production. By siRNA transfection, our results clearly indicated that the downregulation of GM130 can increase IgA1 O-glycosylation deficiency, which is thought to reduce C1GALT1 expression but not affect the expression of ST6GalNAC2. Conclusion: We identified and demonstrated that GM130 plays an important role in IgA1 O-glycans deficiency in IgAN patients, by negatively regulating C1GALT1 expression. We believe that this finding will provide theoretical foundations for a new mechanism of Gd-IgA1 production in IgAN patients.
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Cassol, Clarissa A., Cherri Bott, Gyongyi M. Nadasdy, Valeria Alberton, Ana Malvar, Haikady N. Nagaraja, Tibor Nadasdy, Brad H. Rovin, and Anjali A. Satoskar. "Immunostaining for galactose-deficient immunoglobulin A is not specific for primary immunoglobulin A nephropathy." Nephrology Dialysis Transplantation 35, no. 12 (August 1, 2019): 2123–29. http://dx.doi.org/10.1093/ndt/gfz152.
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Abstract Background Primary immunoglobulin A nephropathy (IgAN) is characterized by IgA1-dominant or codominant glomerular deposits, postulated to be galactose deficient (Gd). However, glomerular IgA deposition can also occur in nonrenal diseases such as liver cirrhosis, psoriasis and inflammatory bowel disease (‘secondary IgAN’) or be an incidental finding in biopsies with other pathologies. A glomerulonephritis resembling IgAN can develop in patients with bacterial, mainly staphylococcal infections [staphylococcal infection-associated glomerulonephritis (SAGN)]. There are no specific histological features to distinguish between these, but differentiation is critical for appropriate management. The aim of this study was to investigate whether a recently described antibody to Gd-IgA1 (KM-55) could aid in differentiating primary IgAN from other conditions with glomerular IgA deposition, especially SAGN. Methods We performed a retrospective cohort study of patients who underwent kidney biopsy for clinical indications and were found to have glomerular IgA deposits. Results We evaluated 100 biopsies, including primary IgAN (n = 44), secondary IgAN (n = 27), SAGN (n = 13), incidental IgA deposition (n = 8) and lupus nephritis (n = 8). There was no difference in Gd-IgA staining intensity or the proportion of positive cases between primary and secondary IgAN. SAGN and cases with incidental IgA deposits had significantly lower Gd-IgA staining intensity than primary IgAN, but up to 69% of SAGN cases were positive (albeit weaker). Conclusions Gd-IgA staining is present not only in primary IgAN, but also in biopsies with secondary IgAN, SAGN and incidental IgA. Weak or negative staining may favor SAGN, especially in the setting of infection, or incidental IgA in the absence of nephritic symptoms or in the presence of other unrelated glomerular pathologies. However, positive staining for Gd-IgA alone is not specific enough for a diagnosis of primary IgAN.
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AMORE, ALESSANDRO, PAOLA CIRINA, GIOVANNI CONTI, PAOLA BRUSA, LICIA PERUZZI, and ROSANNA COPPO. "Glycosylation of Circulating IgA in Patients with IgA Nephropathy Modulates Proliferation and Apoptosis of Mesangial Cells." Journal of the American Society of Nephrology 12, no. 9 (September 2001): 1862–71. http://dx.doi.org/10.1681/asn.v1291862.
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Abstract. Abnormalities in circulating IgA1 have been demonstrated in patients with IgA nephropathy (IgAN). This study addresses the question of the functional significance of this alteration in creating mesangial injury. Biologic effects of selected IgA glycoforms isolated from serum of IgAN patients and controls and in vitro deglycosylated normal IgA were tested on cultured human mesangial cells (MC). IgA glycoforms, ranging from 250 to 500 kD molecular weight, were isolated by lectin affinity chromatography followed by HPLC. IgA and IgG content was measured by enzyme-linked immunosorbent assay. HPLC fractions were incubated with MC to evaluate proliferation and apoptosis rates and nitric oxide synthesis. Moreover, MC were conditioned with in vitro desialylated and degalactosylated normal IgA. Patients with IgAN displayed increased levels of IgA glycoforms exposing sialic acid in α2,6 linkage with N-acetylgalactosamine (Neu5Acα2,6GalNAc) (P < 0.02) and GalNAc (P < 0.05), indicating truncation of O-linked glycans of IgA1. Moreover, IgA glycoforms with increased exposure of mannose were observed (P < 0.03), suggesting a defective N-linked glycosylation. No modification in IgG glycosylation was detected. When incubated with MC, the IgA glycoforms isolated from patients with increased exposure of GalNAc, Neu5Acα2,6GalNAc, or mannose, significantly depressed the proliferation and increased the apoptotic rate and nitric oxide synthesis activity of cultured MC, in comparison with fractions isolated from controls. Similarly, in vitro desialylated and degalactosylated IgAs significantly depressed the proliferation and enhanced the apoptosis rates of MC. In conclusion, a significant modulation of several human MC functions exerted by serum IgA with increased exposure of GalNAc, Neu5Acα2,6GalNAc, and mannose residues isolated from IgAN patients is reported for the first time.
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Ye, Zeng-chun, Cheng Wang, Ying Tang, Xun Liu, Hui Peng, Hui Zhang, and Tan-qi Lou. "Serum IgA1 from patients with IgA nephropathy up-regulates integrin-linked kinase synthesis and inhibits adhesive capacity in podocytes through indirect pathways." Clinical & Investigative Medicine 32, no. 1 (February 1, 2009): 20. http://dx.doi.org/10.25011/cim.v32i1.5083.
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Purpose: To investigate the influence of IgA1 isolated from IgA nephropathy (IgAN) patients on integrin-linked kinase (ILK) synthesis and adhesive capacity of podocytes through indirect pathways. Methods: IgA1 was isolated from healthy control or IgAN patients’ sera using jacalin affinity chromatography and S-200 chromatography. Podocytes were treated with medium from mesangial cells incubated with aggregated IgA1 (aIgA1, 100 ?g/ml), in the presence or absence of valsartan (10-5M) or neutralizing antibodies of tumor necrosis factor-? (TNF-?, 50 ng/ml). Adhesive capacity of podocytes was assessed by cell counting manually and hexosaminidase assay. Real-time PCR and western blotting were used to detect the expression of ILK. Results: Medium from mesangial cells incubated with aIgA1 from IgAN patients reduced podocyte adhesion to collagen compared with medium from mesangial cells incubated with control medium(RPMI-1640 with 0.5% FBS) (35.0±4.8% vs. 60.0±2.0%; P < 0.05). While medium from mesangial cells incubated with aIgA1 from IgAN patients upregulated ILK expression in podocytes at mRNA and protein levels compared with medium from mesangial cells without aIgA1 incubated (1.6-fold and 1.38-fold higher than control, respectively, P < 0.05). Defects in podocyte adhesion and up-regulation of ILK synthesis induced by medium from mesangial cells incubated with aIgA1 from IgAN patients can be partially reversed by the pre-treatment for 1 hour with valsartan(P < 0.05), while pre-treatment with neutralizing antibodies of TNF-? produced no protective effect on podocytes (P > 0.05). Conclusion: Serum IgA1 from IgAN patients may inhibit adhesive capacity and up-regulate ILK synthesis in podocytes through indirect pathways.
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Ye, Muyao, Youming Peng, Chan Liu, Wenzhe Yan, Xiaofei Peng, Liyu He, Hong Liu, and Fuyou Liu. "Vibration Induces BAFF Overexpression and Aberrant O-Glycosylation of IgA1 in Cultured Human Tonsillar Mononuclear Cells in IgA Nephropathy." BioMed Research International 2016 (2016): 1–8. http://dx.doi.org/10.1155/2016/9125960.
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Objective. To investigate the influence ofin vitrovibratory stimulation of human tonsillar mononuclear cells (TMCs).Methods. Fourteen IgA nephropathy (IgAN) patients with chronic tonsillitis (CT) and 12 CT patients with no renal pathology were enrolled. Group A TMCs were collected after 24 hours of culture and used to determine baseline levels. TMCs in groups B, C, D, E, and F were exposed to vibratory stimulation (60 Hz) for 0 (as the control group), 1, 3, 5, and 10 minutes, respectively.Results. Baseline concentrations of B-cell-activation factor (BAFF) and IgA1, BAFF mRNA expression, and aberrant O-glycosylation IgA1 level were higher in the IgAN group as compared to that in the CT group, and all increased after vibratory stimulation. Baseline mRNA expressions of coreβ1,3-galactosyltransferase (C1GALT1) and coreβ1,3GalT-specific molecular chaperone (Cosmc) were lower in the IgAN group; the levels decreased further after vibratory stimulation.Conclusion. In patients with IgAN, vibratory stimulation of TMCs appears to induce IgA1 secretion through activation of BAFF release and to aberrant O-glycosylation IgA1 by suppressing C1GALT1 and Cosmc expression.In vitrovibratory stimulation of human TMCs mimics the vibratory simulation of palatine tonsils produced by vocal cords during phonation.
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Zhang, Lei, Dan Kong, Hongxue Meng, Changsong Han, Jiang Zhu, Juanjuan Qiao, Yan He, et al. "Plasma Gelsolin Promotes Proliferation of Mesangial Cell in IgA Nephropathy." Cellular Physiology and Biochemistry 40, no. 6 (2016): 1473–86. http://dx.doi.org/10.1159/000453199.
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Background/Aims: Plasma gelsolin (pGSN) is an actin-binding protein that plays a critical role in the pathogenesis of rheumatoid arthritis. However, whether pGSN is involved in other immunological diseases remains unknown. This study focused on the relationship between pGSN and immunoglobulin A (IgA) nephropathy (IgAN). Methods: Two hundred patients with IgAN, 200 patients each with several other types of nephropathy and healthy controls (HCs) who underwent kidney biopsies between 2000 and 2014 were enrolled in the study. The Oxford classification system was used to predict the risk of disease progression. Serum and renal tissue were used to detect pGSN, and the correlations between pGSN and IgA, galactose-deficient IgA1 (Gd-IgA1), transforming growth factor beta1 (TGF-β1), fibronectin (FN) content, clinical symptoms, and kidney function were analyzed. Results: We found that the pGSN levels were significantly decreased in sera from IgAN patients compared to sera from patients with other forms of glomerular nephritis and HCs. Furthermore, the serum pGSN levels were negatively correlated with the serum IgA1, FN, and TGF-β1 levels, and positively correlated with the estimated glomerular filtration rate. Conversely, the glomerular pGSN content was significantly elevated in the IgAN patients and was positively correlated with TGF-β1 and FN levels. In renal tissue, the pGSN levels were significantly higher in IgAN patients with M1 and S1 compared to patients with M0 and S0 (p < 0.05). Meanwhile, pGSN promoted human mesangial cell (HMC) proliferation by facilitating cell mitosis in vitro. pGSN also promoted integrin α2β1 expression in HMCs and enhanced the integrin α2β1-pGSN interaction. Conclusion: Our study suggested that pGSN may play an important role in the development of IgAN by promoting the proliferation of mesangial cells and that serum and glomerular pGSN levels may be new markers for predicting IgAN progression and prognosis.
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Wehbi, Batoul, Virginie Pascal, Lina Zawil, Michel Cogné, and Jean-Claude Aldigier. "History of IgA Nephropathy Mouse Models." Journal of Clinical Medicine 10, no. 14 (July 16, 2021): 3142. http://dx.doi.org/10.3390/jcm10143142.
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IgA nephropathy (IgAN) is the most common primary glomerulonephritis in the world. It was first described in 1968 by Jean Berger and Nicole Hinglais as the presence of intercapillary deposits of IgA. Despite this simple description, patients with IgAN may present very broad clinical features ranging from the isolated presence of IgA in the mesangium without clinical or biological manifestations to rapidly progressive kidney failure. These features are associated with a variety of histological lesions, from the discrete thickening of the mesangial matrix to diffuse cell proliferation. Immunofluorescence on IgAN kidney specimens shows the isolated presence of IgA or its inconsistent association with IgG and complement components. This clinical heterogeneity of IgAN clearly echoes its complex and multifactorial pathophysiology in humans, inviting further analyses of its various aspects through the use of experimental models. Small-animal models of IgAN provide the most pertinent strategies for studying the multifactorial aspects of IgAN pathogenesis and progression. Although only primates have the IgA1 subclass, several murine models have been developed in which various aspects of immune responses are deregulated and which are useful in the understanding of IgAN physiopathology as well as in the assessment of IgAN therapeutic approaches. In this manuscript, we review all murine IgAN models developed since 1968 and discuss their remarkable contribution to understanding the disease.
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Hiki, Y., A. Tanaka, T. Kokubo, H. Iwase, J. Nishikido, K. Hotta, and Y. Kobayashi. "Analyses of IgA1 hinge glycopeptides in IgA nephropathy by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry." Journal of the American Society of Nephrology 9, no. 4 (April 1998): 577–82. http://dx.doi.org/10.1681/asn.v94577.
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This study was performed to analyze the structural variety of O-glycans on the IgA1 hinge in IgA nephropathy (IgAN). The IgA1 fragments containing the hinge glycopeptide (33-mer hinge peptide core (HP) + O-glycans) were separated from 13 IgAN patients, eight healthy control subjects, and 11 patients with other primary glomerulonephritides by pyridylethylation, trypsin treatment, and Jacalin affinity chromatography. Because of the use of Jacalin, only the Gal beta 1-3GalNAc residue containing IgA was analyzed. The molecular weights (MW) of the IgA1 fragments treated by the following sequential treatment by exoglycosidases were estimated using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry: (1) Sialidase treatment: the MW of the two observed peaks A and B were compatible with (A) HP + 4GalNAc + 4Gal and (B) HP + 5GalNAc + 4Gal. (2) Sialidase and galactosidase: the MW of the two identified peaks a and b were consistent with (a) HP + 4GalNAc and (b) HP + 5GalNAc. (3) Sialidase, galactosidase, and alpha-N-acetylgalactosaminidase. All subjects revealed one peak, indicating the 33-mer IgA1 hinge peptide core. The intensity rate of peak B/A was significantly decreased in the IgAN group (mean +/- SD, 1.01 +/- 0.08) compared with the negative control subjects (healthy group, 1.15 +/- 0.06, P = 0.0048; other glomerulonephritis group, 1.13 +/- 0.10, P = 0.0049; Scheffe's F test). These results suggested the presence of a defect in the Gal and/or GalNAc residues in the IgA1 hinge glycopeptides in IgAN.
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Chen, Yun-Sung, Cheng-Wen Yang, Chien-Chen Tsai, Min-De Ang, San-Fang Chou, Wen-Chih Chiang, and Yen-Ling Chiu. "Newly-diagnosed immunoglobulin A nephropathy with increased plasma galactose-deficient-IgA1 antibody associated with mRNA COVID-19 vaccination: a case report." Journal of International Medical Research 50, no. 10 (October 2022): 030006052211296. http://dx.doi.org/10.1177/03000605221129674.
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Newly-diagnosed or relapses of immunoglobulin A nephropathy (IgAN) have been associated with COVID-19 vaccination in the literature. Most reported cases were mild clinical diseases characterized by microscopic haematuria and do not require dialysis treatment. This current case report describes a 55-year-old male patient that presented to the emergency department with acute kidney injury after receiving the first dose of the mRNA-1273 COVID-19 vaccine. After admission, his renal function deteriorated rapidly, and then he developed uraemic encephalopathy. He underwent emergency haemodialysis with a rapid improvement in his mental status. Renal biopsy showed newly-diagnosed IgA nephropathy along with markedly elevated plasma level of galactose-deficient-IgA1 (Gd-IgA1) antibody. The patient did not receive immunosuppressive treatment and is now dialysis-free. Immune activation is considered an essential factor in developing or exacerbating IgAN following COVID-19 vaccination. This current case report demonstrates that elevated Gd-IgA1 antibody may be the potential mechanistic link between COVID-19 vaccination and IgAN.
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Du, Yating, Tingzhu Cheng, Chenxuan Liu, Tingting Zhu, Chuan Guo, Shen Li, Xiangrong Rao, and Jinpu Li. "IgA Nephropathy: Current Understanding and Perspectives on Pathogenesis and Targeted Treatment." Diagnostics 13, no. 2 (January 13, 2023): 303. http://dx.doi.org/10.3390/diagnostics13020303.
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Immunoglobulin A nephropathy (IgAN) is the most common primary glomerulonephritis worldwide, with varied clinical and histopathological features between individuals, particularly across races. As an autoimmune disease, IgAN arises from consequences of increased circulating levels of galactose-deficient IgA1 and mesangial deposition of IgA-containing immune complexes, which are recognized as key events in the widely accepted “multi-hit” pathogenesis of IgAN. The emerging evidence further provides insights into the role of genes, environment, mucosal immunity and complement system. These developments are paralleled by the increasing availability of diagnostic tools, potential biomarkers and therapeutic agents. In this review, we summarize current evidence and outline novel findings in the prognosis, clinical trials and translational research from the updated perspectives of IgAN pathogenesis.
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Nagasawa, Yasuyuki, Taro Misaki, Seigo Ito, Shuhei Naka, Kaoruko Wato, Ryota Nomura, Michiyo Matsumoto-Nakano, and Kazuhiko Nakano. "Title IgA Nephropathy and Oral Bacterial Species Related to Dental Caries and Periodontitis." International Journal of Molecular Sciences 23, no. 2 (January 10, 2022): 725. http://dx.doi.org/10.3390/ijms23020725.
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A relationship between IgA nephropathy (IgAN) and bacterial infection has been suspected. As IgAN is a chronic disease, bacteria that could cause chronic infection in oral areas might be pathogenetic bacteria candidates. Oral bacterial species related to dental caries and periodontitis should be candidates because these bacteria are well known to be pathogenic in chronic dental disease. Recently, several reports have indicated that collagen-binding protein (cnm)-(+) Streptococcs mutans is relate to the incidence of IgAN and the progression of IgAN. Among periodontal bacteria, Treponema denticola, Porphyromonas gingivalis and Campylobacte rectus were found to be related to the incidence of IgAN. These bacteria can cause IgAN-like histological findings in animal models. While the connection between oral bacterial infection, such as infection with S. mutans and periodontal bacteria, and the incidence of IgAN remains unclear, these bacterial infections might cause aberrantly glycosylated IgA1 in nasopharynx-associated lymphoid tissue, which has been reported to cause IgA deposition in mesangial areas in glomeruli, probably through the alteration of microRNAs related to the expression of glycosylation enzymes. The roles of other factors related to the incidence and progression of IgA, such as genes and cigarette smoking, can also be explained from the perspective of the relationship between these factors and oral bacteria. This review summarizes the relationship between IgAN and oral bacteria, such as cnm-(+) S. mutans and periodontal bacteria.
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Sendic, Senka, Ladan Mansouri, Sigrid Lundberg, Anna Nopp, Stefan H. Jacobson, and Joachim Lundahl. "B cell and monocyte phenotyping: A quick asset to investigate the immune status in patients with IgA nephropathy." PLOS ONE 16, no. 3 (March 19, 2021): e0248056. http://dx.doi.org/10.1371/journal.pone.0248056.
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Background IgA nephropathy (IgAN) advances from multiple pathogenic “hits” resulting in poorly O-galactosylated IgA1 glycoforms (Gd-IgA1), production of antibodies and glomerular deposition of immune complexes. A sequence of immune responses arising from plasma cells, T cells and antigen presenting cells (APCs), causes glomerular injury. This study was designed to phenotype subsets of B cells, monocytes and T cells in the peripheral circulation and their association with inflammatory cytokines and kidney function in patients with IgAN, healthy controls (HC) and disease controls with autosomal dominant polycystic kidney disease (ADPKD). Methods Patients with IgAN (n = 13), median estimated glomerular filtration rate (eGFR) of 57 ml/min/1.73m2 (IQR 42–84), patients with ADPKD (n = 13) matched for kidney function, gender and age and gender and age-matched HC (n = 13) were recruited. CD3+ and CD3- peripheral blood mononuclear cells were isolated and profiled based on their specific surface markers for different subsets of monocytes, B and T cells and analyzed by flow cytometry. Cytokines were analyzed by ELISA. Results We observed a significant decrease in the proportion of pre-switched B cells and plasmablasts, but an increase in long-lived plasma cells in the peripheral circulation of IgAN patients compared to HC. The proportion of non-classical monocytes was significantly higher in IgAN patients compared to both HC and ADPKD. We also report an association between sCD40L levels and the proportion of pre-switched B cells, as well as sCD40L and MCP-1 levels and albuminuria in IgAN patients. Conclusions We applied an easy-access method to analyze subsets of immune cells as well as relevant inflammatory mediators in IgAN patients. Our data demonstrate an altered B cell profile that indicates a pathophysiological role of the B cell lineage and an increased proportion of non-classical monocytes that suggests their role in the disease process.
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Al Harash, Abdalhamid, Stephanie Saeli, Michael Lucke, and Swati Arora. "IgA Vasculitis Nephritis: A Case Series and Comparison of Treatment Guidelines." Case Reports in Rheumatology 2020 (December 2, 2020): 1–5. http://dx.doi.org/10.1155/2020/8863858.
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Immunoglobulin A (IgA) vasculitis nephritis (IgAVN) and IgA nephropathy (IgAN) share many pathological parallels and are viewed as related diseases by many groups. Current treatment guidelines remain vague, controversial, and without consensus, especially regarding the role of immunosuppressive medications. We present five cases of IgAVN encountered at our tertiary care center between 2016 and 2020, which were treated with different immunosuppression regimens. Infection was the leading cause of death in this series. These cases provide evidence that IgAVN should be distinguished from IgAN on a spectrum of IgA-associated glomerulonephritis. The outcomes presented herein suggest that the morbidity and systematic involvement IgAVN is greater than previously believed and that these substantial risks should be reflected in contemporary treatment guidelines.
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Yano, Naohiro, Kumiko Asakura, Masayuki Endoh, Yoshifumi Abe, Yasuo Nomoto, Hideto Sakai, Kiyoshi Kurokawa, and Hideo Tsukamoto. "Polymorphism in the Iα1 Germ-Line Transcript Regulatory Region and IgA Productivity in Patients with IgA Nephropathy." Journal of Immunology 160, no. 10 (May 15, 1998): 4936–42. http://dx.doi.org/10.4049/jimmunol.160.10.4936.
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Abstract Enhanced in vivo and in vitro production of IgA has been reported in patients with IgA nephropathy (IgAN) and their family members. It is generally considered that IgA1 is a prominent subclass of IgA in IgAN. Although genetic mechanisms of IgA class switch recombination in IgAN have been studied enthusiastically, the critical factors that induce IgA1-specific class switching in IgAN have yet to be elucidated. A large body of data indicates that the germ-line transcript of Ig constant region (CH) genes that precedes actual class switching has regulatory effects on class switch recombination. To analyze structural abnormalities in the Iα1 germ-line transcript regulatory gene, a region about 1000 bp long located upstream of Iα1 exons was surveyed by the PCR-single strand conformation polymorphism method, and the polymorphism detected was confirmed by subsequent DNA sequencing. Three hot spots for point mutation were detected upstream of the promoter region of the Iα1 germ-line transcript, and the mutations were observed more frequently in patients than in controls. Patients with the mutations showed higher levels of serum IgA and higher in vitro IgA synthesis. In the luciferase assay, the regulatory gene with the mutations showed a potent effect for induction of the Iα1 germ-line transcript. The polymorphism in the Iα1 regulatory region possibly causes enhanced IgA production in some patients with IgAN.
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Zhao, Yuhong, Youngki Kim, Milind Junghare, Viral Vakil, Xuesong Su, Faqian Li, and Lihong Bu. "Galactose-Deficient IgA1 Deposits in Clear Cell Renal Cell Carcinoma-Related Henoch–Schönlein Purpura Nephritis." Case Reports in Nephrology 2020 (August 24, 2020): 1–7. http://dx.doi.org/10.1155/2020/8828336.
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Recent studies suggest that galactose-deficient IgA1 (Gd-IgA1) plays a role in the pathogenesis of primary IgA nephropathy (IgAN) and Henoch–Schönlein purpura nephritis (HSPN). Furthermore, immunostaining of KM55, an antibody that identifies Gd-IgA1, may be helpful to differentiate primary IgAN and HSPN from secondary causes of glomerular IgA deposition. We report sequential kidney biopsies of a malignancy-associated HSPN, showing intense glomerular mesangial IgA deposition at the initial kidney biopsy and dramatic decrease in disappearance of glomerular deposits after tumor removal. We demonstrate that the glomerular IgA deposition contains Gd-IgA1, detected by immunostaining of KM55, with similar distribution and intensity to IgA. This suggests that renal Gd-IgA1 deposition may play a role in the pathogenesis of malignancy-associated HSPN.
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Zhu, Li, and Hong Zhang. "The Genetics of IgA Nephropathy: An Overview from China." Kidney Diseases 1, no. 1 (2015): 27–32. http://dx.doi.org/10.1159/000381740.
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Background: IgA nephropathy (IgAN) is the most common type of primary glomerulonephritis worldwide. Highly variable data for disease prevalence and reports of familial clustering suggest the involvement of genetic factors in IgAN. As China is an area with a high prevalence of IgAN, Chinese scholars have made a considerable effort to reveal the underlying genetic architecture of IgAN. Summary: In this review, we summarize recent achievements in the genetic studies of IgAN, focusing mainly on studies undertaken in China. Early association studies followed a population-based design and focused on a single variant or single gene. Subsequently, family-based designs and genetic interactions applied by Chinese scholars revealed an association of variants in MEGSIN and glycosyltransferase genes with IgAN. Recently, genome-wide association studies (GWAS) have been used to identify multiple susceptibility loci for IgAN, and they have, for the most part, been validated in Chinese populations. Key Messages: More efforts should be made to explore the underlying genetic mechanisms of GWAS-identified variants. In future studies in IgAN, the application of a systems genetics approach would be helpful and productive. Facts from East and West: The reported prevalence of IgAN is higher in Asia than in Europe and North America. However, differences in use of biopsy for the diagnosis of IgAN should be taken into account in analyzing data from both East and West. In Europe, IgAN affects men more frequently than women; this is not the case in Asia. Familial IgAN has been more frequently reported in Europe than in Asia. Within Europe, familial IgAN is more evident in southern than in northern populations. Changes in the pattern of serum IgA1 O-glycosylation is a common finding in IgAN patients in the East and West. SNPs within the gene coding for the enzyme C1GALT1 have been reported in Chinese and European patients. However, there is no evidence for a role of gene polymorphism of the C1GALT1 chaperone cosmc in Europeans. Genetic variants in the HLA gene family have been observed in populations from the East and West. Associations between IgAN and variants of the TAP1/PSMB and DEFA genes were observed in Asian but not in Western patients. Association with the angiotensin-converting enzyme gene was seen only in Asian patients.
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Park, Sehoon, Seung Hee Yang, Chang Wook Jeong, Kyung Chul Moon, Dong Ki Kim, Kwon Wook Joo, Yon Su Kim, Jae Wook Lee, and Hajeong Lee. "RNA-Seq profiling of microdissected glomeruli identifies potential biomarkers for human IgA nephropathy." American Journal of Physiology-Renal Physiology 319, no. 5 (November 1, 2020): F809—F821. http://dx.doi.org/10.1152/ajprenal.00037.2020.
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Few studies have examined gene expression changes occurring in the glomeruli of IgA nephropathy (IgAN) using a sensitive transcriptomic profiling method such as RNA sequencing (RNA-Seq). We collected glomeruli from biopsy specimens from patients with IgAN with relatively preserved kidney function (estimated glomerular filtration rate ≥ 60 mL·min−1·1.73 m−2 and urine protein-to-creatinine ratio < 3 g/g) and from normal kidney cortexes by hand microdissection and performed RNA-Seq. Differentially expressed genes were identified, and gene ontology term annotation and pathway analysis were performed. Immunohistochemical labeling and primary mesangial cell cultures were performed to confirm the findings of RNA-Seq analysis. Fourteen patients with IgAN and ten controls were included in this study. Glomerulus-specific genes were highly abundant. Principal component analysis showed clear separation between the IgAN and control groups. There were 2,497 differentially expressed genes, of which 1,380 were upregulated and 1,117 were downregulated (false discovery rate < 0.01). The enriched gene ontology terms included motility/migration, protein/vesicle transport, and immune system, and kinase binding was the molecular function overrepresented in IgAN. B cell signaling, chemokine signal transduction, and Fcγ receptor-mediated phagocytosis were the canonical pathways overrepresented. In vitro experiments confirmed that spleen tyrosine kinase (SYK), reported as upregulated in the IgAN transcriptome, was also upregulated in glomeruli from an independent set of patients with IgAN and that treatment with patient-derived IgA1 increased the expression of SYK in mesangial cells. In conclusion, transcriptomic profiling of the IgAN glomerulus provides insights in the intraglomerular pathophysiology of IgAN before it reaches profound kidney dysfunction. SYK may have a pathogenetic role in IgAN.
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Yamaguchi, Hiroki, Shin Goto, Nao Takahashi, Masafumi Tsuchida, Hirofumi Watanabe, Suguru Yamamoto, Yoshikatsu Kaneko, et al. "Aberrant mucosal immunoreaction to tonsillar microbiota in immunoglobulin A nephropathy." Nephrology Dialysis Transplantation 36, no. 1 (October 25, 2020): 75–86. http://dx.doi.org/10.1093/ndt/gfaa223.
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Abstract Background Immunoglobulin A nephropathy (IgAN) is the most common glomerulonephritis worldwide, characterized by mesangial polymeric IgA1 deposition. IgAN is believed to develop owing to aberrant mucosal immunoreaction against commensals in the tonsils. However, the exact interrelation between pathogenic IgA and mucosal microbiota in IgAN patients is unclear. Methods Biopsy-proven IgAN or recurrent tonsillitis (RT) patients who had undergone tonsillectomy were enrolled. We used 16S ribosomal RNA gene amplicon sequencing with a flow cytometry-based bacterial cell sorting technique) and immunoglobulin repertoire sequencing of the IgA heavy chain to characterize IgA-coated bacteria of the tonsillar microbiota (IgA-SEQ) and their corresponding IgA repertoire. Furthermore, we fractionated patient serum using gel-filtration chromatography and performed flow cytometry-based analysis of IgA binding to bacteria cultured from incised tonsils. Results Tonsillar proliferation-inducing ligand and B-cell activating factor levels were significantly higher in IgAN than in RT patients. IgA-SEQ for tonsillar microbiota revealed the preferential binding ability of IgA to Bacteroidetes in IgAN tonsils compared with those from RT patients. Expression of immunoglobulin heavy (IGH) constant alpha 1 with IGH variable 3–30 was significantly higher in IgAN than that in RT, and positively correlated with the IgA-coated enrichment score of Bacteroidetes. Serum polymeric IgA, comprising high levels of GdIgA1, exhibited considerable binding to Bacteroidetes strains cultured from the tonsils of IgAN patients. Conclusions These findings provide evidence that aberrant mucosal immune responses to tonsillar anaerobic microbiota, primarily consisting of members of the phylum Bacteroidetes, are involved in IgAN pathophysiology.
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Gutiérrez, Eduardo, Fernando Carvaca-Fontán, Leonella Luzardo, Enrique Morales, Marina Alonso, and Manuel Praga. "A Personalized Update on IgA Nephropathy: A New Vision and New Future Challenges." Nephron 144, no. 11 (2020): 555–71. http://dx.doi.org/10.1159/000509997.
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IgA nephropathy (IgAN) is the most common primary glomerulonephritis in the world among patients undergoing renal biopsy. Approximately 30% of patients with IgAN develop end-stage kidney disease 20 years after renal biopsy. It is a glomerulopathy with a very broad clinical presentation, making it difficult to stratify and treat. IgAN is characterized by dysregulation of the immune system, which causes an abnormal synthesis of IgA1 that is deglycosylated causing its mesangial deposition. IgAN pathogenesis is incompletely understood; the current multi-hit hypothesis of IgAN pathogenesis does not explain the range of glomerular inflammation and renal injury associated with mesangial IgA deposition. Although associations between IgAN and glomerular and circulating markers of complement activation are established, the mechanism of complement activation and contribution to glomerular inflammation and injury are not defined. On the other hand, the renal-gut connection can also play an important role in the pathogenesis of IgAN with possible therapeutic implications. In order to standardize the histological findings, the Oxford Classification has allowed clarifying renal lesions that confer potential risk of progression. Currently, except for the blockade of the renin-angiotensin-aldosterone system, no other therapies are available in clinical setting for the treatment of IgAN, although the range of new drugs under investigation is extensive. The incorporation in the next trials of clinical parameters such as the amount of hematuria and histological lesions may allow more personalized therapeutic approaches. To summarize, in recent years, several important efforts have taken place in the understanding of IgAN, but still, further studies are warranted to elucidate the best therapeutic strategies according to the risk to improve the prognosis of this entity.
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Zhang, Minfang, Wenyan Zhou, Shaojun Liu, Liyin Zhang, Zhaohui Ni, and Chuanming Hao. "KM55 Monoclonal Antibody Staining in IgA-Dominant Infection-Related Glomerulonephritis." Nephron 145, no. 3 (2021): 225–37. http://dx.doi.org/10.1159/000513269.
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<b><i>Introduction:</i></b> IgA-dominant infection-related glomerulonephritis (IgA-IRGN) is a unique form of IRGN, which needs to be distinguished from IgA nephropathy (IgAN), due to overlapping clinical and pathological features. The key factor in the pathogenesis of IgAN is galactose-deficient IgA1 (Gd-IgA1). However, the mechanism of glomerular IgA deposition in patients with IgA-IRGN is unclear. Therefore, we evaluated whether Gd-IgA1 could be a useful biomarker to distinguish between these 2 diseases. <b><i>Methods:</i></b> A case-control study was conducted to analyze the clinical and pathological characteristics of 12 patients with IgA-IRGN. The intensity and distribution of glomerular Gd-IgA1 (KM55) staining in renal biopsies were assessed. The control group consisted of 15 patients diagnosed with IgAN and an additional 17 patients with glomerulopathy involving IgA deposition. <b><i>Results:</i></b> The main clinical manifestations of patients with IgA-IRGN were nephrotic-range proteinuria, hematuria, acute renal injury, and hypocomplementemia. Active lesions were the leading pathological feature, while focal segmental sclerosis was rare. Half of the patients exhibited hump-shaped subepithelial deposits. Glomerular KM55 staining was negative in 7 patients, trace in 4 patients, and 2+ in 1 patient. The median intensity of KM55 staining in IgA-IRGN patients was 0 (range 0∼2+), which was significantly lower than that of primary IgAN patients (median 2+, range 1+∼3+). The receiver operating characteristic analysis demonstrated that the optimal cutoff level to identify these 2 diseases was 0.5+. <b><i>Conclusions:</i></b> Glomerular KM55 staining intensity might be helpful to distinguish IgA-IRGN from primary IgAN. Weak or negative staining may favor IgA-IRGN. In addition, integrated analysis including clinical data, pathological findings, and prognostic information would further improve the differential diagnosis.
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Feehally, John, and Jonathan Barratt. "The Genetics of IgA Nephropathy: An Overview from Western Countries." Kidney Diseases 1, no. 1 (2015): 33–41. http://dx.doi.org/10.1159/000381738.
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Background: IgA nephropathy (IgAN) is the commonest primary glomerulonephritis worldwide and a significant cause of chronic kidney disease and end-stage renal disease. It is widely accepted that genetic factors play a role in the pathogenesis of IgAN. However, the identity of these genetic factors remains uncertain. Summary: Critical to all genetic studies is a precise phenotypic definition of the disease. It is well recognised that IgAN displays striking phenotypic variation, raising the possibility that it may not be a single disease and it may not be the same disease in different parts of the world. In this review, we discuss the challenges that this phenotypic variation poses to interpreting genetic data and the current evidence for specific gene involvement in IgAN, focusing particularly on data from European IgAN cohorts. Key Messages: With advances in genetic techniques, in particular next-generation sequencing, and an increased understanding of the importance of copy number variations, epigenetics and transcriptomics, it is likely that we will gain a greater understanding of the genetic basis for IgAN. However, due to the lack of consistency in epidemiological clinicopathological studies both within and between continents, this will only be achieved if we are able to more precisely phenotype IgAN populations. Facts from East and West: The reported prevalence of IgAN is higher in Asia than in Europe and North America. However, differences in use of biopsy for the diagnosis of IgAN should be taken into account in analysing data from both East and West. In Europe, IgAN affects men more frequently than women; this is not the case in Asia. Familial IgAN has been more frequently reported in Europe than in Asia. Within Europe, familial IgAN is more evident in southern than in northern populations. Changes in the pattern of serum IgA1 O-glycosylation is a common finding in IgAN patients in the East and West. SNPs within the gene coding for the enzyme C1GALT1 have been reported in Chinese and European patients. However, there is no evidence for a role of gene polymorphism of the C1GALT1 chaperone cosmc in Europeans. Genetic variants in the HLA gene family have been observed in populations from the East and West. Associations between IgAN and variants of the TAP1/PSMB and DEFA genes were observed in Asian but not in Western patients. Association with the angiotensin-converting enzyme gene was seen only in Asian patients.
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Ai, Zhen, Ming Li, Wenting Liu, Jia-Nee Foo, Omniah Mansouri, Peiran Yin, Qian Zhou, et al. "Low α-defensin gene copy number increases the risk for IgA nephropathy and renal dysfunction." Science Translational Medicine 8, no. 345 (June 29, 2016): 345ra88. http://dx.doi.org/10.1126/scitranslmed.aaf2106.
Full textAbstract:
Although a major source of genetic variation, copy number variations (CNVs) and their involvement in disease development have not been well studied. Immunoglobulin A nephropathy (IgAN) is the most common primary glomerulonephritis worldwide. We performed association analysis of the DEFA1A3 CNV locus in two independent IgAN cohorts of southern Chinese Han (total of 1189 cases and 1187 controls). We discovered three independent copy number associations within the locus: DEFA1A3 [P = 3.99 × 10−9; odds ratio (OR), 0.88], DEFA3 (P = 6.55 × 10−5; OR, 0.82), and a noncoding deletion variant (211bp) (P = 3.50 × 10−16; OR, 0.75) (OR per copy, fixed-effects meta-analysis). While showing strong association with an increased risk for IgAN (P = 9.56 × 10−20), low total copy numbers of the three variants also showed significant association with renal dysfunction in patients with IgAN (P = 0.03; hazards ratio, 3.69; after controlling for the effects of known prognostic factors) and also with increased serum IgA1 (P = 0.02) and galactose-deficient IgA1 (P = 0.03). For replication, we confirmed the associations of DEFA1A3 (P = 4.42 × 10−4; OR, 0.82) and DEFA3 copy numbers (P = 4.30 × 10−3; OR, 0.74) with IgAN in a Caucasian cohort (531 cases and 198 controls) and found the 211bp variant to be much rarer in Caucasians. We also observed an association of the 211bp copy number with membranous nephropathy (P = 1.11 × 10−7; OR, 0.74; in 493 Chinese cases and 500 matched controls), but not with diabetic kidney disease (in 806 Chinese cases and 786 matched controls). By explaining 4.96% of disease risk and influencing renal dysfunction in patients with IgAN, the DEFA1A3 CNV locus may be a potential therapeutic target for developing treatments for this disease.