Mesangial IgA Research Articles

Analysis of renal impairment in children with Wilson’s disease

Since the diverse manifestations of renal impairment appear in different periods of Wilson's disease, misdiagnosis or missed diagnosis is not rare. This study was undertaken to find the clinical features of renal impairment in children with Wilson's disease or hepatolenticular degeneration (HLD). Eighty-five children with HLD who had been treated at our department between January 1991 and June 2006 were retrospectively studied. The clinical data of 25 patients with renal impairment were analyzed. In the 85 HLD patients, 34 had renal impairment. Nine of the 34 patients with D-penicillamine treatment were excluded. In the remaining 25 patients, 7 had initiated symptoms of renal impairment, 5 of them with edema, 1 with gross hematuria, and 1 with acute hemolysis and acute renal failure. Twelve of the 25 patients had proteinuria, 14 had hematuria, and 5 had both proteinuria and hematuria. Urine glucose was positive in 4 patients, urine N-acetyl-beta-D-glucosaminidase (NAG) increased in 5, and urine beta2-microglobulin increased in 6. Urine red blood cell (RBC) phase was detected in 7 patients, including glomerular hematuria in 5 patients and non-glomerular hematuria in 2. Blood urea nitrogen and creatinine increased in 1 patient. B-ultrasound revealed bilaterally enlarged kidneys in 3 patients. Kidney biopsy showed diffuse mesangial proliferation and IgA deposit in mesangial region in 1 patient. All of the 25 patients had cornea K-F ring and the level of ceruloplasmin decreased. Six patients had a family history of HLD. The manifestations of renal impairment with HLD are varied. HLD should be excluded from patients with unexplained renal impairment, while those with HLD should take examinations of the kidney to identify renal impairment. We propose that renal function and urinalysis should be checked regularly in patients receiving treatment of D-penicillamine.

Downregulated expression in high IgA (HIGA) mice and the renal protective role of meprinβ

This study discusses the critical role of the metalloproteinase meprinβ in the progression of glomerulonephritis. Using a microarray technique, the gene expression profiles in glomeruli isolated from high serum IgA (HIGA) mice with a purity of 97% or greater were examined. HIGA mice are a valid model of human IgA nephropathy (IgAN), with the typical pathological features of this condition, including a consistently high serum IgA level as well as dominant mesangial IgA deposition and mesangial enlargement. Among the many upregulated/downregulated genes after the development of IgAN, the downregulation of meprinβ was intriguing. The expression level of the meprinβ gene at 40 weeks of age was 52% of that observed at 8 weeks of age (prior to the development of IgAN), although in the control BALB/c mice, a 2.19-fold elevation was seen. These results were also confirmed by semi-quantitative RT-PCR and immunostaining analyses. As meprinβ is a subunit of metalloproteinase meprins (meprin A, meprin B) and meprins are capable of proteolytically degrading extracellular matrix (ECM) components and proteolytically processing bioactive peptides, the downregulation of meprinβ may contribute to the progression of glomerulonephritis and the eventual glomerular scarring. This working hypothesis was examined using an in vivo meprinβ inhibition study. The inhibition of meprins by actinonin exacerbated some parameters of renal injury in mice afflicted with anti-glomerular basement membrane (anti-GBM) antibody-associated nephritis. These in vitro and in vivo results suggest that meprinβ may play a protective role against the progression of renal injury through the degradation of ECM and bioactive peptides.

Protective role of anti-synthetic hinge peptide antibody for glomerular deposition of hypoglycosylated IgA1

The KM mouse lacks endogenous genes for immunoglobulins and carries the entire human IgH locus and the IgLk transgene. Therefore, human IgA1 does not provoke a hetero-immune response. We had observed mesangial IgA deposits in KM mice given desialo-degalacto (DeS/DeGal) IgA1. In this study, the mice were immunized with synthetic IgA1 hinge (glyco-)peptide before administration of DeS/DeGal IgA1, and the effects of the pre-immunization were evaluated. Mice were divided into sHP, 5GalNAc-sHP and non-immunization groups. In two pre-immunization groups, KLH-conjugated sHP or KLH-5GalNAc-sHP, which has five GalNAc residues, was subcutaneously given three times every 2 weeks. Two weeks after the final pre-immunization, DeS/DeGal IgA1 was administered daily for 5 weeks. Serial serum levels of anti-sHP and anti-IgA1 antibodies were evaluated by ELISA. On the day of the last administration of IgA1, renal biopsy was performed. Mesangial IgA deposits were observed in all non-immunized mice. In pre-immunized mice, IgA deposition was not detected in 6 of 13 sHP mice and 1 of 4 5GalNAc-sHP mice. The intensities of IgA deposits were significantly different between sHP groups and non-immunized (P = 0.003) groups. There was a significant inverse correlation between the intensities of IgA deposits and the anti-sHP antibody titers (P = 0.016). These results suggest that the anti-IgA1 hinge peptide antibody plays a role in the inhibition of glomerular IgA deposition.

A Case of Adult onset Henoch-Schönlein Purpura with Acute Renal Failure

Henoch-Schnlein purpura (HSP) is a leukocytoclastic vasculitis of small vessels with deposition of IgA, commonly resulting in skin, joint, gastrointestinal, and kidney involvement. HSP is an uncommon disorder in adults and accounts for 0.6% to 2% of adult nephropathy. We report a case of HSP with acute renal failure successfully treated with corticosteroid. In this case, the patient presented with vasculitic purpuric rash on lower extremity, arthralgia in the wrist, abdominal pain, hematochezia, oliguria and azotemia. Abdominal CT showed wall thickening of the small and large bowels. Skin biopsy revealed leukocytoclastic vasculitis. Percutaneous renal biopsy showed no crescent formation, but mesangial IgA and deposits were observed by immunofluorescence. The patient was treated with corticosteroid (1mg/kg per day) and hemodialysis. After treatment, renal function improved and purpuric lesion, arthralgia and abdominal pain disappeared. Thus, when adults present with purpuric rash and rapidly progressive glomerulonephritis (RPGN), HSP should be a diagnostic consideration.

Significance of plasma von Willebrand factor level and von Willebrand factor-cleaving protease activity in patients with chronic renal diseases

von Willebrand factor (vWF) mediates the initial capture of platelets to vascular subendothelium and is essential for platelet aggregation under high fluid shear stress as in arterial stenosis. On release from endothelial cells, vWF is rapidly cleaved by ADAMTS13/vWF-cleaving protease (vWF-CP). We investigated the clinical significance of changes in plasma vWF and vWF-CP activities in chronic renal disease. Plasma vWF and vWF-CP activities were measured using enzyme-linked immunosorbent assay (ELISA) and residual collagen binding assay respectively in patients with lupus nephritis (n = 31), primary nephritic syndrome (n = 25), diabetic nephropathy (n = 45), chronic glomerulonephritis (n = 38) and 40 normal controls. The relation of their levels with pathological and renal status was analyzed. In all diseased patients the levels of vWF were significantly higher and vWF-CP activity significantly lower than the controls (both P < 0.01). vWF in the four subgroups did not correlate with the stage of disease but correlated negatively with vWF-CP activity. vWF-CP activity was not changed two weeks after renal transplantation. Renal biopsy demonstrated that the vWF level in stage IV was higher than in stages II and III while vWF-CP activity was lower in patients with lupus nephritis. After eight-week treatment, the vWF level significantly decreased and the vWF-CP activity significantly increased in systemic lupus erythema, disease activity index < 9, but not with index = 9. Even though the vWF-CP activity was significantly lower in membranous nephropathy than in minimal change disease, mesangial proliferative glomerulonephritis or IgA glomerulonephritis, the vWF level was not significantly different. The alterations of plasma vWF and vWF-CP activities were associated with different renal pathologies. Injury to endothelial cells and autoantibodies against vWF-CP activity may result in higher vWF level and lower vWF-CP activity in chronic renal disease and thus a mechanism for worsening of chronic renal disease and thrombosis.

Steroid Responsive Nephrotic Syndrome in IgA Nephropathy With FSGS

IgA nephropathy (IgAN) and focal segmental glomerulosclerosis (FSGS) are common chronic glomerulopathies that are usually not responsive to corticosteroids treatment. We describe a young African-American patient with nephrotic syndrome, whose renal biopsy showed mesangial IgA deposition and focal segmental sclerosis. Her clinical course resembles minimal change disease.

Secondary IgA Nephropathy

IgA nephropathy (IgAN) is the most common pattern of primary glomerulonephritis seen in the Western world. In the majority of cases the cause remains unknown. Cases of familial IgAN and secondary IgAN have been reported and these have provided insights into underlying genetic and environmental triggers for this common glomerular disease. Secondary IgAN is seen most commonly in patients with liver disease or mucosal inflammation, in particular affecting the gastrointestinal tract. A number of dietary and microbial antigens have been identified in circulating IgA immune complexes and mesangial IgA deposits, suggesting that environmental factors may play a role in the pathogenesis of IgAN. There is an increasing literature reporting associations between IgAN and other diseases. Whether these reports represent chance associations or genuine shared pathophysiology is discussed.

Hemorrhagic Fever in Schoenlein Henoch Purpura.

Schoenlein Henoch Purpura (SHP) may show a cohort of symptoms such as: a palpable purpuric rash where lesions may be prominent mostly on lower extremities, abdominal pain, arthritis and nephritis. It is an inflammatory disorder characterized by an IgA-mediated vasculitis with immune complexes deposition in smaller veins, capillaries and arterioles which often occur as a response to infections (mycoplasma, streptococcus group A, Campylobacter enteritis, Helycobacter, Herpes virus, Parvovirus B19, Epstein-Barr virus), or to an exposure to allergens, drugs, some particular food, cold, or even insect bites. Symptoms are often dramatic at the onset, and the exitus occurs sadly between 30 – 50% of the patients, despite the therapeutic support, for this reason the diagnosis and the therapy should be precocious. Clinically we can observe multi organ failure, hypotension, flushing, capillary leak haemorrhage secondary to thrombocytopenia, platelet dysfunction, disseminated intravascular coagulation, shock. We have studied a young boy (19 years old) with an urticarial wheals, erythematous maculo-papules, purple spots, and larger petechiae, migrant arthritis and arthralgia, renal disease (low grade hematuria with proteinuria), weakness, necrotic and hemorrhagic plaques, with haematemesis, diarrhoea, abdominal pain, fever (38.5°/39.5° C), and increased blood level of human Parvovirus-B19 NS1-gene component. We performed a skin biopsy of SHP that showed: leukocytoclastic vasculitis, with angiocentric neutrophilic infiltrate, fibrin deposition and focal fibrinoid necrosis. We also evaluated a kidney biopsy which showed: mild increase of mesangial cellularity, with segmental capillary luminal leukocytes and scattered capillary wall fuchsinophilic deposit, while the diagnostic finding is constituted by granular mesangial IgA with C3. The management is based on support therapy, with plenty of haemotrasfusions, and immunosuppressive therapy (prednisone 40 mg os/die, and cyclophosphamide100–200 mg/daily/os for 30–60 days (may decrease inflammation, capillary permeability and suppressing granulocytes activity and migration. The prognosis is usually excellent when the syndrome is self-limited and resolves spontaneously often 4/8 weeks without recurrence. Sometimes the diagnostic investigation may show an elevated level of vascular IgA deposition (direct immunofluorescence), elevated plasma levels of C3 and C4, elevated levels of IgA, ANCA (antineutrophil cytoplasmic antibodies: pANCA anti-MPO, cANCA anti-PR3), CRP, fibrinogen, ICAM-1, and increase of TNF, IL-1, IL-6, TGF-beta that reflect endothelial cell damage and dysfunction.

Minimal change variants with mesangial IgA deposits

Minimal change variants with mesangial IgA deposits

Analysis of MPO-ANCA subtypes in a patient with propylthiouracil-induced vasculitis with multiple complications

We report a 16 year-old girl with propylthiouracil (PTU)-induced antineutrophil cytoplasmic antibody (ANCA)-positive glomerulonephritis combined with Henoch-Schönlein purpura nephritis (HSPN) and antiphospholipid syndrome (APS). The patient had Graves' disease and had been treated with PTU for about 6 years. She complained of arthralgia, epigastralgia, purpura of the lower extremities, anemia, and abnormal urinalysis. Lupus anticoagulant was positive. Additionally, a high level of anti-myeloperoxidase (MPO) antibodies (IgG) and a low level of coagulation factor XIII were recognized. She had several complications including lung bleeding, lacuna infarctions of the right frontal and parietal brain lobes, and deep vein thrombosis of the left lower extremity. We studied tissue histology and carried out MPO-ANCA subtype analysis by immunofluorescence and flow cytometry and MPO-ANCA epitope analysis. Histologically, purpura showed leukocytoclastic vasculitis with perivascular depositions of IgA and complement C3. Renal biopsy showed necrotizing glomerulonephritis with crescents and mesangial IgA deposits. Notably, IgG, IgM, and IgA ANCA were detected in the patient's serum by flow cytometry and immunofluorescence. We diagnosed an overlap syndrome of ANCA-positive vasculitis, HSPN, and APS. A change in the reactivity of MPO-ANCA from recognition of only the Hg epitope in the C-terminal region to recognition of multiple MPO epitopes was accompanied by a remission of symptoms. This report may provide a very rare description of an overlap syndrome of PTU-induced ANCA vasculitis, HSPN, and APS in which not only IgG ANCA but also IgA and IgM ANCA were found. Epitope analysis may be a useful marker for disease-monitoring of PTU-induced ANCA-positive vasculitis. This case may provide insight into the pathological mechanism underlying each of these diseases.

Aberrantly Glycosylated IgA1 in Glomerular Immune Deposits of IgA Nephropathy

In IgA nephropathy, abnormal O-glycosylation of IgA1 molecules contributes to mesangial IgA1 deposition and the development of glomerular injury; however, direct in situ demonstration of aberrantly O-glycosylated IgA1 within glomerular immune deposits has not been reported. This study investigated the presence of abnormally glycosylated IgA1 in situ and its spatial relationship with complement within the immune deposits and correlated these features with glomerular lesion severity. Immunofluorescence and confocal microscopy were used to evaluate 19 consecutive renal biopsies, and the severity of glomerular lesions were also scored. Aberrantly glycosylated IgA was observed within the immune deposits, and its amount was found to correlate with both the severity of glomerular lesions and the amount of C3c on the surface of the deposits. These results demonstrate that qualitative and quantitative evaluation of aberrantly glycosylated IgA can be performed on routine renal biopsy samples. Its presence in immune deposits likely influences the spatial organization of IgA and C3c, thereby contributing to the glomerular inflammatory response in IgA nephropathy.

Recurrence of IgA Nephropathy With Crescents in Kidney Transplants

Crescentic IgA nephropathy is an uncommon finding in native kidneys (3%–5%) and in renal transplants. This study was performed to determine the frequency of relapsing crescentic IgA nephropathy after kidney transplantation. Over a 15-year period, 42 patients (25 men, 17 women) of age range 17 to 59 years with biopsy-proven IgA nephropathy in their native kidneys were entered into this retrospective study, because they had undergone kidney transplantation and had sequential allograft biopsies during their follow-up. Mean follow-up after transplantation was 8.9 years (range, 1–15 years). In their native kidneys, 5 patients (12%) had more than 20% crescents, and only 2 (5%) had more than 50% of glomeruli involved. As expected, 52.4% of recipients showed recurrent mesangial IgA deposits in their kidney grafts. The 2 patients with diffuse crescentic IgA nephropathy in their native kidneys experienced acute graft dysfunction at 15 and 47 months. Graft biopsy showed recurrent IgA deposits with cellular crescents in 30% and 20% of glomeruli, respectively. Despite corticosteroid pulse therapy, graft failures occurred 2 and 27 months later. No crescentic proliferation was observed during follow-up in any other case. Only 5 other grafts failed because of chronic allograft nephropathy, without any relationship to the relapse of IgA deposits. These data suggested for the first time that only diffuse crescentic IgA nephropathy in the native kidneys was associated with the occurrence of crescents in the kidney transplants, a finding that raises the possibility of a particular subgroup of IgA nephropathies.

Immunopathogenesis of IgAN

The defining hallmark of IgA nephropathy (IgAN) is deposition of polymeric IgA1 in the glomerular mesangium accompanied by a mesangial proliferative glomerulonephritis. The mechanisms involved in mesangial polymeric IgA1 deposition and the initiation of inflammatory glomerular injury remain unclear. This lack of a complete understanding of the pathogenesis of IgAN has meant that there is still no treatment known to modify mesangial deposition of IgA. Increasing evidence, however, supports the importance of IgA-containing immune complex formation as a pivotal factor driving mesangial IgA deposition and triggering of glomerular injury. A number of potentially important changes to the IgA1 molecule have been identified in IgAN, which may contribute to immune complex formation. These changes suggest that the polymeric IgA1 that deposits in IgA nephropathy is derived from mucosally primed plasma cells. The presence of this IgA in the circulation reflects displacement of mucosal B lineage cells to systemic sites and may be the result of mishoming of lymphocytes trafficking along the mucosa-bone marrow axis.

The level of serum secretory IgA of patients with IgA nephropathy is elevated and associated with pathological phenotypes

Mucosal infection associated episodic macroscopic haematuria is observed in many patients with IgA nephropathy (IgAN), however, the mechanism has not been elucidated. Recent study suggested that secretory IgA (SIgA) might play an important role in the pathogenesis of IgAN. The aim of this study is to investigate the level of serum SIgA and the deposition of SIgA in glomeruli in IgAN patients with different pathological phenotypes. The levels of serum SIgA were detected in 57 patients with IgAN and 48 normal controls. The associations between the levels of SIgA and the pathological phenotypes of IgAN as well as clinical parameters were investigated. Frozen renal sections from 34 of the 57 patients without IgM deposition were immunofluorescence stained and examined by confocal microscopy to detect the co-deposition of IgA and secretory component (SC). The association between deposition of SIgA and the level of serum SIgA was analysed. The level of serum SIgA in patients with IgAN was significantly higher than that of normal controls. The level of serum SIgA in patients with focal proliferative sclerosing IgAN (fpsIgAN) was much higher than that in patients with mild mesangial proliferative IgAN (mIgAN) (P<0.001). The level of serum SIgA correlated with the level of serum creatinine (R=0.509, P<0.001), degree of proteinuria (R=0.643, P<0.001) and creatinine clearance (R= -0.454, P=0.002) in patients with IgAN. Significant co-deposition of SC and IgA were found in 11 of the 34 patients. Although the level of serum SIgA in patients with SC deposits was higher than those without SC deposits, the difference was not significant. It was concluded that mesangial IgA, at least partly, was originated from mucosal immune sites. The levels of serum SIgA were significantly increased in patients with IgAN and were closely associated with pathological phenotypes.

Synthesis of TNF- by mesangial cells cultured with polymeric anionic IgA role of MAPK and NF- B

Deposition of polymeric IgA1 (pIgA) in kidney mesangium is the hallmark of IgA nephropathy (IgAN). Current consensus is that a fraction of IgA1 molecules in the circulation of IgAN patients exhibit aberrant structures or properties that may lead to their deposition. Our previous findings suggest that the anionic property of IgA1 may play a role in mesangial IgA1 deposition in patients with IgAN. In the present study, the functional consequences of the binding of anionic polymeric IgA1 to human mesangial cells (HMCs) were investigated. Anionic polymeric IgA1 from IgAN patients and healthy subjects was isolated by sequential jacalin affinity chromatography, size exclusion chromatography using size exclusion and MonoQ ion exchange chromatography. HMCs were cultured with purified anionic polymeric IgA1 and the release of tumour necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) was examined by enzyme-linked immunosorbent assay. The signalling pathways involved in anionic pIgA-mediated HMC activation were examined by immunoblotting. Standard electrophoretic mobility shift assay (EMSA) was used to further examine whether the transcriptional factor NF-kappaB is associated in the signalling process. To define the mechanism of TNF-alpha and IL-6 production, HMCs were cultured with anionic pIgA in the presence or absence of p42/p44 mitogen-activated protein kinase (MAPK) inhibitor (PD98059), NF-kappaB inhibitor pyrrolidine dithiocarbamate (PDTC) or NF-kappaB blocking permeable peptides. Compared with less anionic pIgA or monomeric IgA1 (mIgA), anionic pIgA from patient with IgAN significantly increased cell proliferation (P<0.05) when cultured with HMC. These anionic pIgA significantly increased the synthesis of TNF-alpha (P<0.05) and IL-6 (P<0.05) in a dose and time-dependent manner. Furthermore, the increased synthesis of IL-6 and TNF-alpha by anionic pIgA in HMC was significantly diminished (P<0.01) in the presence of NF-kappaB inhibitor pyrrolidine dithiocarbamate and NF-kappaB blocking permeable peptides SN50 (P<0.01). The increased synthesis of IL-6 by anionic pIgA in HMC was reduced by inhibitor to NF-kappaB or p42/p44 MAPK and was abolished by the simultaneous presence of inhibitors to p42/p44 MAPK and NF-kappaB. The up-regulation of TNF-alpha was partially suppressed by inhibitor to NF-kappaB but not PD98059. Our results suggest that polymeric anionic IgA1 could activate HMC and increase the synthesis of TNF-alpha and IL-6. While both the p42/p44 MAPK and NF-kappaB pathways are essential in regulating the anionic pIgA-induced synthesis of IL-6, TNF-alpha synthesis mediated by anionic pIgA is partly dependent on NF-kappaB.

A pediatric occurrence of crescentic glomerulonephritis associated with antineutrophil cytoplasmic antibodies and mesangial IgA deposits

Antineutrophil cytoplasmic antibody-(ANCA) associated glomerulonephritis usually shows histopathologic features of pauciimmune crescentic glomerulonephritis and occurs late in life. We report a 14-year-old Japanese girl presenting with proteinuria, hematuria and mildly elevated serum creatinine. A renal biopsy specimen demonstrated crescentic glomerulonephritis, immunofluorescence showed mesangial IgA staining. Electron microscopic examination disclosed paramesangial deposits. Serum ANCA against myeloperoxidase (MPO) were detected at high titers. Myeloperoxidase-ANCA-related nephritis accompanied by IgA nephropathy is considered rare in childhood and teen years. Yet, if ANCA assays and detailed electron microscopic examination of renal specimens were performed routinely in patients with rapidly progressive glomerulonephritis, the diagnosis might be more frequent in young patients.

IgA nephropathy: Immune mechanisms beyond IgA mesangial deposition

IgA nephropathy is attributable to mesangial IgA immune complex deposition. The pathogenic potential of frequently colocalized IgG deposits may depend on polarized T-helper cytokines that modulate Fcgamma receptors of infiltrating macrophages, leading to either activation or inhibition that determines glomerular injury.

Underglycosylation of IgA in IgA nephropathy: More than a diagnostic marker?

Moldoveanu et al. present a diagnostic test for IgA nephropathy based on the presence of undergalactosylated IgA in serum. This underglycosylated IgA appears to be overrepresented in serum of IgA nephropathy patients and is most likely related to mesangial IgA deposition. Further studies on the nature, production, regulation, and cellular and molecular interactions of this undergalactosylated IgA may facilitate disease diagnosis and provide further insight into the pathogenesis of this important disease.

56-Year-Old Man With Rash, Abdominal Pain, and Arthralgias

56-Year-Old Man With Rash, Abdominal Pain, and Arthralgias

The pathogenic role of IgA1 O‐linked glycosylation in the pathogenesis of IgA nephropathy (Review Article)

SUMMARY: Numerous abnormalities of the IgA immune system have been reported in IgAN but the most consistent finding remains aberrant IgA1 O‐linked glycosylation of the IgA1 hinge region. The defect comprises reduced galactosylation of O‐linked N‐acetylgalactosamine residues with or without changes in the terminal sialylation of the O‐linked sugars. Aberrant O‐galactosylation has been found in serum IgA1, in IgA1 isolated from tonsillar lymphocytes, and in IgA1 eluted from mesangial deposits. There is evidence that changes in IgA1 O‐galactosylation lead to IgA immune complex formation and mesangial IgA deposition. Mesangial cells exposed to these IgA immune complexes proliferate and adopt a pro‐inflammatory phenotype; they secrete cytokines, chemokines, growth factors and extracellular matrix components promoting glomerular inflammation and glomerulosclerosis. Recent evidence suggests that the control of IgA1 O‐glycosylation is linked to class switching from IgD to IgA1 synthesis and that the pattern of IgA1 O‐glycosylation may be programmed at the time of initial antigen encounter. IgA1 glycosylation varies between systemic and mucosal sites and the association of aberrant IgA1 galactosylation with low affinity, polymeric IgA1 antibodies against mucosal antigens suggests undergalactosylated IgA1 may in fact be a mucosal glycoform of IgA1. Although suited to the mucosal compartment, when these IgA1 glycoforms enter the systemic circulation in appreciable quantities they deposit in the mesangium and trigger glomerular inflammation. This review will discuss the evidence for the role of IgA1 O‐glycosylation in the pathogenesis of IgAN and propose an explanation for the presence of aberrantly O‐glycosylated IgA1 in the circulation of patients with IgAN.