Serum levels of galactose-deficient IgA in children with IgA nephropathy and Henoch-Schönlein purpura

IgA nephropathy and Henoch-Schönlein purpura nephritis (HSPN) are related diseases characterized by deposits of IgA1-containing immune complexes in the renal mesangium. Adult patients with IgA nephropathy have aberrantly glycosylated IgA1 (galactose-deficient O-linked glycans) in the circulation and renal deposits. However, IgA1 glycosylation has not been studied in pediatric patients with IgA nephropathy. Using our quantitative lectin enzyme-linked immunosorbent assay (ELISA) test, we measured serum levels of galactose-deficient IgA1 of children with IgA nephropathy and HSPN and controls. Children with IgA nephropathy and HSPN had serum levels higher than those of healthy children or renal-disease controls with C1q nephropathy. Furthermore, lectin ELISA identified patients with HSPN whose clinical course mimicked that of IgA nephropathy. In summary, pediatric patients with IgA nephropathy and HSPN have an aberrancy in the glycosylation in IgA1 O-linked glycans that is similar to that in adults with IgA nephropathy.     

O-glycosylation of serum IgA1 antibodies against mucosal and systemic antigens in IgA nephropathy

In IgA nephropathy (IgAN), serum IgA1 with abnormal O-glycosylation deposits in the glomerular mesangium. The underlying mechanism of this IgA1 O-glycosylation abnormality is poorly understood, but recent evidence argues against a generic defect in B cell glycosyltransferases, suggesting that only a subpopulation of IgA1-committed B cells are affected. For investigation of whether the site of antigen encounter influences IgA1 O-glycosylation, the O-glycosylation of serum IgA1 antibodies against a systemic antigen, tetanus toxoid (TT), and a mucosal antigen, Helicobacter pylori (HP), was studied in patients with IgAN and control subjects. Serum IgA1 was purified from cohorts of patients with IgAN and control subjects with HP infection and after systemic TT immunization. The IgA1 samples were applied to HP- and TT-coated immunoplates to immobilize specific antibodies, and IgA1 O-glycosylation profiles were assessed by binding of the O-glycan-specific lectin Vicia villosa using a modified ELISA technique. Although total serum IgA1 had raised lectin binding in IgAN, the O-glycosylation of the specific IgA1 antibodies to TT and HP did not differ between patients and control subjects. In both groups, IgA1 anti-HP had higher lectin binding than IgA1 anti-TT. This study demonstrates that IgA1 O-glycosylation normally varies in different immune responses and that patients produce the full spectrum of IgA1 O-glycoforms. IgA1 with high lectin binding was produced in response to mucosal HP infection in all subjects. The raised circulating level of this type of IgA1 in IgAN is likely to be a consequence of abnormal systemic responses to mucosally encountered antigens rather than a fundamental defect in B cell O-glycosylation pathways.     

Properties of circulating IgA molecules in Henoch-Schonlein purpura nephritis with focus on neutrophil cytoplasmic antigen IgA binding (IgA-ANCA): new insight into a debated issue

Background: The presence and the pathogenetic role of circulating IgA reacting with neutrophil cytoplasmic antigens (IgA-ANCA) in patients with Henoch-Schonlein purpura (HSP) is still debated. This study was aimed to investigate some characteristics of serum IgA and macromolecular IgA in HSP patients, focusing on IgA-ANCA. Methods: Eighty-seven HSP patients with biopsy proved renal involvement (51 adults and 36 children) enrolled in a multicentre study of the Italian Group of Immunopathology were investigated. Results: Significantly high levels of IgA immune complexes were found in both adults (P <0.05) and children (P <0.01), while the binding of IgA to jacalin, was significantly low in children with HSP (P <0.01) only. Two series of ELISA were done for IgA-ANCA, in two different laboratories. Increased binding to PMN crude extracts (P <0.01) without any modification in IgA binding to proteinase 3 was found by either specific ELISA. Conversely, the binding of IgA to myeloperoxidase (MPO) was found to be significantly (P <0.05) increased with positive values in 25% of patients by one assay only. Three of four sera with positive IgA-MPO ANCA exhibited binding in Western-blot studies with the MPO preparation used in ELISA to a 28-kDa species. D-galactose and N-acetyl-glucosamine decreased the binding of serum IgA to MPO more in HSP than in controls (P <0.05). Conclusions: The conflicting reports on IgA-ANCA may reflect some atypical characteristics of the reaction which can be detected only by some ELISAs. We suggest that not an antigen-antibody reaction but a lectinic interaction due to abnormal composition of IgA carbohydrate side chains may account for the IgA-ANCA reaction in patients with HSP nephritis.     

Evaluation of IgA1 O-glycosylation in Henoch-Schönlein Purpura Nephritis Using Mass Spectrometry

BackgroundGlomerular deposition of IgA1 is a common feature of Henoch-Schönlein purpura nephritis (HSPN) and is indistinguishable from that seen in IgA nephropathy (IgAN). Serum IgA1 is abnormally O-glycosylated in IgA nephropathy, which may contribute to the development of glomerular injury. Abnormal O-glycosylated IgA1 was also detected in HSPN using lectin enzyme-linked immunosorbent assay; however, this method cannot provide the exact structural information of O-glycans. Mass spectrometry is an effective means of quantification of O-glycans, and there is no report to evaluate IgA1 O-glycans in HSPN using mass spectrometry.Materials and MethodsWe investigated O-glycosylation profile in serum IgA1 from 7 HSPN recipients, 26 IgAN recipients, 25 recipients with other kidney diseases (OKDs), and 26 normal healthy donors using mass spectrometry.ResultsOf the 14 GalNac-Gal combinations detected using mass spectrometry, the percentage of the only 6GalNAc-2Gal combination was significantly different between HSPN and IgAN. The percentage of GalNAc 3 in HSPN recipients was significantly higher than that in OKDs recipients and healthy donors (P = .0027 and P < .0001, respectively). Inversely, the percentage of GalNAc 5 in HSPN recipients was significantly lower than that in OKDs recipients and healthy donors (P = .0008, P < .0001, respectively). Moreover, the Gal content and the Gal/GalNAc ratio of HSPN recipients were significantly lower than OKDs recipients and healthy donors.ConclusionsExamination of Henoch-Schönlein purpura recipients revealed that the number of GalNAc fell and the Gal attachment to GalNAc was reduced compared to other kidney diseases and healthy donors. The IgA1 O-glycosylation profile of HSPN was very similar to that of IgAN.     

Mesangial IgA1 in IgA nephropathy exhibits aberrant O-glycosylation: observations in three patients

BACKGROUND: In IgA nephropathy (IgAN), circulating IgA1 molecules display an abnormal pattern of O-glycosylation. This abnormality may potentially contribute to mesangial IgA1 deposition, but this is unproven because the O-glycosylation of mesangial IgA1 has not been analyzed. METHODS: IgA1 was eluted from glomeruli isolated from the kidneys of three IgAN patients obtained after nephrectomy or at postmortem. Serum from these patients, other patients with IgAN, and controls was subjected to the same treatment as the glomerular eluates. The O-glycosylation of eluted and serum IgA1 was measured by lectin binding using an enzyme-linked immunosorbent assay-based system. RESULTS: In all three cases, the lectin binding of IgA1 eluted from the glomeruli of IgAN patients was markedly higher than that of the serum IgA1 of the same individual, and also all but one of a series of serum IgA1 samples from other patients and controls. CONCLUSIONS: The higher lectin binding of glomerular compared with serum IgA1 suggests that O-glycosylated IgA1 molecules abnormally and selectively deposit in the kidney. These results provide the first evidence that mesangial IgA1 is abnormally O-glycosylated, and support a direct role for abnormal IgA1 O-glycosylation in the mechanism of mesangial IgA deposition in IgAN.     

Henoch-Schonlein nephritis: diagnosis and prognosis problems in childhood

Henoch-Schonlein purpura (HSP) is the most common vasculitis in childhood and is characterized by sistemic leukocytoclastic angiitis, mainly affecting small vessels of the skin, joints, gastro-intestinal tract and kidneys. Renal involvement is the most important cause of morbidity and mortality in patients with HSP. The aim of this study was to evaluate renal involvement in children with HPS and the prognoses of short- and long-term outcome of patients diagnosed with HS nephritis. MATERIAL AND METHOD: We conducted a retrospective study based on observation files of hospitalized children with Henoch-Schonlein purpura admitted in the Nephrology Department" Sf. Maria" Hospital, during 20 years. RESULTS: The results showed that the prognosis of Henoch-Schonlein nephritis is relatively good and long-time morbidity is predominantly associated with initial presentation and renal involvement.     

Methodological approaches to the analysis of IgA1 O-glycosylation in IgA nephropathy.

IgA nephropathy (IgAN) is a common form of glomerulonephritis in which IgA1 molecules deposit in the renal mesangium, leading to progressive glomerular inflammatory injury in a significant proportion of patients. The mechanisms underlying the pathogenesis of IgAN remain poorly understood, but altered O-glycosylation, a physicochemical abnormality of IgA1 observed in these patients, may be a contributory factor. Although many studies have reported aberrant IgA1 O-glycosylation in IgAN, the precise structural nature of the defect remains to be fully characterised, and analysis of IgA1 O-glycans has proved technically challenging. Three main strategies have been employed: lectin binding to the O-glycans in situ on the whole IgA1 molecule; mass spectroscopy of isolated O-glycosylated glycopeptides; and size/charge separation of free O-glycans released from IgA1. In this review, the basic principles, strengths and weaknesses of each of these methodological approaches are considered, together with a summary of the data obtained from their use. One of the common criticisms of many studies of IgA1 O-glycosylation is the method of IgA1 purification employed, and therefore, this issue is also critically discussed.     

Discriminant analysis of clinical markers before renal biopsy in patients with IgA nephropathy

Discriminant analysis of clinical markers before renal biopsy in patients with IgA nephropathy is described. Sixty eight patients with IgA nephropathy (IgA nephropathy group) and 66 patients with other chronic glomerulonephritis (non-IgA nephropathy group) were examined. The discriminant analysis was applied to separate those two groups by using twenty clinical parameters as well as binding capacity of serum IgA to the glomeruli of renal specimens. Binding of serum IgA of patients to the glomeruli obtained from patients with IgA nephropathy was performed using avidin-biotin immunofluorescence. Among twenty clinical markers, the levels of serum IgA and creatinine, and degree of microhematuria in IgA nephropathy group were significantly higher than those in non-IgA nephropathy group Furthermore, the positive incidence of serum IgA binding of IgA nephropathy group was significantly higher than that of serum IgA binding of non-IgA nephropathy group. The correct classification rate were 79.10% using five clinical markers including serum IgA, microhematuria, serum C4, quantitation of proteinuria and degree of proteinuria. It is indicated that the levels of serum IgA and the binding of serum IgA to the glomeruli were considered to be major markers for clinical diagnosis of patients with IgA nephropathy It was concluded that the discriminant analysis before renal biopsy was useful for diagnosis of IgA nephropathy.     

Evidence-based assessment of treatment options for children with IgA nephropathies

We present an evidence-based evaluation of published data on therapy for children with various presentations of the IgA nephropathies--idiopathic IgA nephropathy (IgAN) and Henoch-Schonlein purpura nephritis (HSPN). Particular attention has been paid to the outcome markers used in the studies reviewed, with the best evidence provided by markers highly associated with progressive renal failure. No treatment modality for either IgAN or HSPN in pediatric patients has been shown to be effective by a properly designed and administered randomized controlled trial (i.e., the highest level of evidence--level 1). Lower levels of evidence support the use of a variety of corticosteroid regimens, often in combination with other agents, although there are some conflicting studies in this area. No convincing evidence has been published to date to support the use of fish oil, angiotensin-converting enzyme inhibitors or tonsillectomy for the treatment of children with IgAN or HSPN. Well designed randomized controlled trials in children with the IgA nephropathies need to be undertaken.     

Higher Incidence of Renal Allograft Glomerulonephritis in Living-Related Donor Kidney Transplantation

Glomerulonephritis recurrence has emerged as one of the leading causes of allograft loss. We aimed to investigate the effect of living-related and deceased donation on the incidence of renal allograft glomerulonephritis and its effect on renal allograft survival.

Henoch-Schonlein nephritis

Henoch-Schonlein purpura is a clinical syndrome characterized by the association of skin, joint, and gastrointestinal symptoms. Henoch-Schonlein purpura is characterized by wide-spread vasculitis. Although the clinical symptoms of this disease are characteristic, the diagnosis is not always easy to establish because other forms of systemic vasculitis - mainly the microscopic form of periarteritis nodosa - may mimic the disease. In addition, in contrast to systemic lupus erythematosus, there are no biological tests that can identify Henoch-Schonlein purpura with certainty. Immunofluorescence microscopic techniques have made an important contribution to both the diagnosis and the study of the pathogenesis of the disease, particularly since they have demonstrated the presence of IgA deposits in the glomeruli and in the vessel walls. These findings not only confirmed the immunologic nature of the pathologic lesions but also drew attention to the remarkable similarity between Henoch-Schonlein purpura nephritis and IgA nephropathy.     

Evolution of IgA nephropathy into anaphylactoid purpura in six cases—further evidence that IgA nephropathy and Henoch–Schonlein purpura nephritis share common pathogenesis

Background

As the morphological and immunohistochemical manifestations of immunoglobulin A (IgA) nephropathy and Henoch–Schonlein purpura nephritis (HSPN) are very similar, they are considered to share a common pathogenesis. Although HSPN usually develops after the appearance of anaphylactoid purpura, we have encountered patients whose renal symptoms preceded purpura.

Methods

We reviewed the clinical courses of patients who were first diagnosed with IgA nephropathy, but developed purpura later, at the National Center for Child Health and Development in Tokyo, Japan.

Results

Of the 53 patients who were diagnosed with primary IgA nephropathy at our institute during the study period (March 2002 to July 2015), six (11 %) developed anaphylactoid purpura after the diagnosis of primary IgA nephropathy and therefore met the inclusion criteria. Duration between the onset of nephritis and subsequent appearance of purpura ranged from 5 months to 14 years. One patient reached end-stage renal failure due to IgA nephropathy and developed purpura after renal transplantation. All renal biopsies performed before the appearance of purpura showed mesangial proliferation with predominant IgA deposits. Urinary findings deteriorated in three patients after the appearance of purpura, including one patient who developed rapidly progressive glomerulonephritis. Renal biopsy findings worsened in two patients. At the last observation, two patients showed mild renal insufficiency.

Conclusions

Our clinical experience and previous reports support the argument that IgA nephropathy and HSPN are different manifestations of a single disease. Hence, it is acceptable to consider that they are variants of a single disease.

     

Adult-onset IgA vasculitis (Henoch-Schönlein): Update on therapy

Immunoglobulin A vasculitis (IgAV, formerly Henoch-Schönlein purpura) is a systemic inflammatory disease affecting small vessels. While it is common and usually benign in childhood, in adults it is rarer has a more severe course. Its main manifestations are cutaneous purpura, arthralgias or arthritis, acute enteritis and glomerulonephritis. Renal involvement is associated with a poor prognosis in adults. The treatment of adult-onset IgAV is still a matter of debate: although in patients with a non-severe phenotype remission can occur spontaneously, more severe cases may need immunosuppressive therapy. There are some areas of uncertainty with respect to the efficacy of immunosuppressive regimens: almost all data come from studies performed in children or from patients with IgA nephropathy and/or IgA-crescentic glomerulonephritis. The only randomised study performed in adults with IgAV and renal involvement showed that immunosuppressive therapy with cyclophosphamide did not improve renal outcome nor did it affect patient survival. The possible efficacy of other drugs is reported only in small case series. Recent evidences show that rituximab could be an effective therapeutic option for adult-onset IgAV, but this also needs to be confirmed in controlled trials. In this review, we focus on therapeutic options for adult-onset IgAV treatment, and discuss the main results of the studies performed so far.     

Comparison of clinical,pathological and long-term renal outcomes of children with Henoch–Schonlein purpura nephritis and IgA nephropathy

International Urology and Nephrology - To compare clinical, pathological, and long-term renal outcomes of children with Henoch–Schonlein purpura nephritis (HSPN) and IgA nephropathy (IgAN)....     

Long-term prognosis of Henoch-Schonlein nephritis in adults and children

Background: The aim of this multicentre collaborative study was to compare the progression of renal disease in children and adults with Henoch-Schonlein purpura (HPS) nephritis selected on the basis of IgA-dominant renal deposits and biopsy material available for review. Methods: The analysis was performed in 152 patients (95 adults and 57 children <16 years old at diagnosis) with a follow-up (⩽1 year up to 20 years (4.9±3.4 years in adults and 4.8±3.9 years in children). Results: Renal histology and clinical presentation were similar in both age groups: crescents were found in 36% of adults and 34.6% of children (in only 2.7% of adults and 1.9% of children involving >50% of glomeruli), nephrotic-range proteinuria in 29.5% of adults and 28/.1% of children and functional impairment in 24.1% of adults and 36.9% of children. The outcome was similar for both age groups (remission, 32.5% of adults and 31.6% of children; renal function impairment, 31.6% of adults and 24.5% of children). End-stage renal disease was observed in 15.8% of adults and in 7% of children. Renal function survival at 5 years was not significantly different in the two groups (85% in adults and 95% in children) and at 10 years it was approximately 75% in both groups. None of the children died and adult survival was 97% at 5 years. In adults at presentation, renal function impairment (P <0.02) as well as proteinuria higher than 1.5 g/day (P <0.02) and hypertension (P <0.001) were negative prognostic factors. Multivariate analysis stressed the main statistical relevance of proteinuria (relative risk 2.37, P <0.02). Conversely, in children no definite level of proteinuria, hypertension or other data were found to be associated with poor prognosis. Conclusion: Among patients with a clinical presentation which warrants renal biopsy, HSP nephritis has a similar prognosis in children and adults. The evolution is more predictable in adults than in children.     

Spectrum of biopsy-proven kidney diseases in northwest China: a review of 30 years of experiences

Purpose

Large-scale, contemporary studies assessing the spectrum of kidney diseases in northwest China are lacking. Therefore, we aimed to assess the profile of 30-year temporal changes in biopsy-proven kidney diseases in northwest China.

Methods

This cross-sectional study included all patients with a native kidney biopsy specimen in the First Affiliated Hospital of Xi'an Jiaotong University between 1989 and 2018. Data on demographic characteristics and pathological diagnosis were extracted from medical records and pathological reports. Changing patterns of kidney diseases over the study period and disease distributions in different gender and age groups were examined.

Results

This study included 13,620 patients with a mean age of 38.5?±?16.5 years and included 58.2% of men. Primary glomerulonephritis (PGN), second glomerulonephritis (SGN), tubulointerstitial disease, and other renal diseases accounted for 79.1, 18.3, 2.4, and 0.2% of all kidney diseases, respectively. In PGN, IgA nephropathy (IgAN) (25.1%) was the most common type, followed by non-IgA mesangial proliferative glomerulonephritis (MsPGN) (24.9%) and membranous nephropathy (MN) (17.4%). The frequency of MN dramatically increased (p?<?0.001) over the course of the study. Lupus nephritis (6.2%) and Henoch-Schönlein purpura nephritis (HSPN) (4.9%) were leading SGN diagnosis. The frequencies of IgAN, non-IgA MsPGN, and HSPN declined, while those of ANCA/pauci-immune glomerulonephritis and diabetic nephropathy significantly increased.

Conclusion

PGN continues to be the predominant kidney disease in northwest China, and IgAN is the most common type. The frequencies of MN and diabetic nephropathy significantly increased. These findings might be explained by behavioral and environmental exposures and provide implications on future hypothesis-driven research.

     

Occurrence of anti-C1q antibodies in IgA nephropathy

Background: The pathogenic mechanisms and the antigens involved in the establishment and progress of IgA nephropathy are unknown. As antibodies against C1q have been reported to correlate with SLE nephritis, we analysed the occurrence of these antibodies in IgA nephropathy in order to investigate the possibility of pathogenetic similarities in these renal disorders. Methods: The occurrence of IgA- and IgG anti-C1q antibodies (anti-C1q) were determined by ELISA in patients with IgA nephropathy (n=36) and SLE nephritis (n=37), diseases both known to be associated with circulating immune complexes. Levels of these antibodies were also determined in two other glomerular diseases, i.e. idiopathic membranous glomerulo-nephritis (n=7) and minimal change disease (n=2), in which circulating immune complexes are usually not present, and in 40 healthy controls. Results: IgA anti-C1q was observed in increased titres in 11/36 of the patients with IgA nephropathy, in 2/37 of the patients with SLE nephritis (both with proliferative disease) and in 1/9 of the patients with membranous and minimal change disease (P<0.001). Increased titres of IgG anti-C1q were observed in 1/36 of the patients with IgA nephropathy, in 17/37 of the patients with SLE nephritis and in 0/9 of the patients with membranous and minimal change disease (P<0.001). There were no correlations between the levels of anti-C1q antibodies and clinical parameters such as degree of proteinuria, haematuria, or renal function. Nor was there any correlation to the concentration of C3a and the terminal complement complex (TCC) in patients with IgA nephropathy. Conclusions: The occurrence of anti-C1q antibodies in both IgA nephropathy and SLE nephritis, albeit of different predominating isotypes, indicates the possibility of a similar pathogenic mechanism involved in these renal disorders. The occurrence of IgA anti-C1q antibodies in patients with IgA nephropathy has to our knowledge not previously been reported.     

Clinicopathological correlation of young onset chronic glomerulonephritis

In a retrospective analytical study involving 98 children with primary glomerulonephritis who were seen by us at our hospital during a 2-year period from 1984 through 1985 and who had renal biopsy performed previously, attempts were made to correlate pathological findings with both clinical findings and prognosis. The results are summarized as follows: 1) Of 87 patients with asymptomatic chronic glomerulonephritis, glomerular findings were those of minimal change lesion, mesangial proliferative nephritis, MPGN, membranous nephropathy and FGS or sclerosing nephritis in 29.9%, 51.7%, 13.8%, 1.1% and 3.5%, respectively. Among the other 11 patients in whom the diagnosis was made after manifesting the nephritic symptoms, minimal change was noted less frequently and MPGN was detected more frequently than in the aforementioned asymptomatic group. IgA nephropathy was estimated to account for 44.2% of cases of asymptomatic chronic nephritis. 2) Mild mesangial proliferation was observed relatively frequently and severe mesangial proliferation or MPGN rather infrequently in hematuria cases without proteinuria while in those with severe proteinuria minimal change lesion was uncommon and severe mesangial proliferative changes, MPGN or FGS were relatively frequent. 3) In 22 patients with IgA nephropathy and 11 with non-IgA nephritis the severity of glomerular changes was related to the intensity of proteinuria at the time of renal biopsy. 4) A 3 to 5 years' follow-up study of patients with mesangial proliferative nephritis inclusive of IgA nephropathy disclosed that 26-28% of patients became free from urinary abnormalities, 27-37% had persistent hematuria without proteinuria and 24-32% still had proteinuria of 2 plus or above. Patients with milder glomerular changes had a definitely better prognosis than those with severe glomerular lesions.