Further Evidence for the Mucosal Origin of Pathogenic IgA in IgA Nephropathy

Cheung, Chee Kay; Barratt, Jonathan

doi:10.1681/asn.2022020201

Cited by 11 publications

(5 citation statements)

References 9 publications

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“…It was confirmed that the intestinal mucosa, especially the terminal ileum mucosa, was closely associated with IgA nephropathy in patients with CD. It was a similar mechanism in previous studies finding Peyer's patches at the end of the ileum causing proteinuria and renal function damage [ 25 – 27 ]. Based on this mechanism, the targeted release preparation of budesonide was designed by improving TARGIT starch capsule technology, which locally released active compounds in the distal ileum and the proximal colon.…”

Section: Discussionsupporting

confidence: 81%

The pathological and outcome characteristics of renal lesions in Crohn’s disease

Zhang

Dong

et al. 2022

BMC Nephrol

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Background The inflammatory bowel disease, containing Crohn’s disease and ulcerative colitis, was rare in the population, especially in the complication of kidney disease. A few studies had found proteinuria played a potential indicator of inflammatory bowel disease occurrence and activity. This study aimed to better define the histopathologic spectrum and study the outcome of renal disease in Crohn’s disease. Methods A retrospective study of 3557 Crohn's disease from January 1st, 2016 to July 1st, 2021 in the Sixth Affiliated Hospital of Sun Yat-sen University identified 20 (0.56% [20/3557]) patients who underwent kidney biopsy. All biopsy specimens were examined by standard procedures containing light microscopy, immunofluorescence, and electron microscopy. Results Twenty cases were shown in this review study. Subnephrotic proteinuria (30% [6 of 20]), persistent hematuria and proteinuria (25% [5 of 20]), and isolated hematuria with acanthocytes (25% [5 of 20]) were the main indications for kidney biopsy. The most common diagnosis was IgA nephropathy (70% [14/20]), followed by minimal change disease (10% [2/20]), acute interstitial nephritis (5% [1/20]), granulomatous interstitial nephritis (5% [1/20]), non-IgA mesangial proliferative nephritis (5% [1/20]) and thin basement membrane nephropathy (5% [1/20]). The Lee classification of IgA nephropathy was mostly II or III level. Glomerular mesangial hyperplasia was the most common pathologic manifestation according to the MEST-C Sore. After twelve-month treatment, the majority of patients turned to complete remission of renal disease by measuring proteinuria, while 3 patients still stayed in the relapse stage and 6 patients turned to partial remission by measuring hematuria. Conclusions IgA nephropathy is the most common kidney biopsy diagnosis in Crohn's disease. Renal damage in Crohn's disease mainly involves the glomerulus, especially the mesangial matrix. After the treatment, proteinuria might be in remission, but hematuria remains.

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Section: Discussionsupporting

confidence: 81%

The pathological and outcome characteristics of renal lesions in Crohn’s disease

Zhang

Dong

et al. 2022

BMC Nephrol

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“…The first hit in the pathogenesis of IgA nephropathy is the systemic accumulation of Gd-IgA1, thought to be secreted by gut or respiratory tract-homing Gd-IgA1(+) B cells with spillover from mucosal sites or from B cells that have mishomed to systemic sites. 9 The finding of increased circulating levels of intestinal-activated Gd-IgA1(+) B lymphocytes and Gd-IgA1(+) plasma cells 10,11 also supports this hypothesis. The second hit is the development of autoantibodies directed against the poorly galactosylated region of IgA1.…”

Section: Introductionmentioning

confidence: 67%

Treatment of IgA Nephropathy: A Rapidly Evolving Field

El Karoui,

Fervenza,

De Vriese

2023

JASN

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The pivotal event in the pathophysiology of IgA nephropathy is the binding of circulating IgA-containing immune complexes to mesangial cells, with secondary glomerular and tubulointerstitial inflammation and fibrosis. The paramount difficulty in the management of IgA nephropathy is the heterogeneity in its clinical presentation and prognosis, requiring an individualized treatment approach. Goal-directed supportive care remains the bedrock of therapy for all patients, regardless of risk of progression. SGLT2 inhibitors and sparsentan should be integral to contemporary supportive care, particularly in patients with chronic kidney damage. Pending the development of reliable biomarkers, it remains a challenge to identify patients prone to progression due to active disease and most likely to derive a net benefit from immunosuppression. The use of clinical parameters, including the degree of proteinuria, the presence of persistent microscopic hematuria and the rate of eGFR loss, combined with the MEST-C score, is currently the best approach. Systemic glucocorticoids are indicated in high-risk patients, but the beneficial effects wane after withdrawal and come at the price of substantial treatment-associated toxicity. Therapies with direct impact on disease pathogenesis are increasingly becoming available. While targeted release budesonide has garnered the most attention, anti-B cell strategies and selective complement inhibition will most likely prove their added value. We propose a comprehensive approach that tackles the different targets in the pathophysiology of IgA nephropathy according to their relevance in the individual patient.

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“…Several lines of evidence support a mucosal source for the increased circulating Gd-IgA1 in IgAN ( 2 , 45 – 47 ; Figure 1 ). The majority of human IgA is produced by plasma cells residing in mucosal-associated lymphoid tissue (MALT), and two major regions are implicated in IgAN: the gut-associated lymphoid tissue (GALT) and nasopharynx-associated lymphoid tissue (NALT) ( 46 , 48 ).…”

Section: Pathogenesis and The Four-hit Hypothesismentioning

confidence: 91%

“…Immunoglobulin A nephropathy (IgAN), characterized by mesangial deposition of immune complexes containing galactosedeficient-IgA1 (Gd-IgA1) and associated autoantibodies, is the most common primary glomerulonephritis worldwide (1)(2)(3)(4). However, its true prevalence is uncertain, and estimates are confounded by varying access to healthcare, quality of data capture, and heterogeneity in screening practices and in thresholds to perform a kidney biopsy between centers worldwide (5,6).…”

Section: Introductionmentioning

confidence: 99%

The role of BAFF and APRIL in IgA nephropathy: pathogenic mechanisms and targeted therapies

Cheung,

Barratt,

Liew

et al. 2024

Front. Nephrol.

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Immunoglobulin A nephropathy (IgAN), characterized by mesangial deposition of galactose-deficient-IgA1 (Gd-IgA1), is the most common biopsy-proven primary glomerulonephritis worldwide. Recently, an improved understanding of its underlying pathogenesis and the substantial risk of progression to kidney failure has emerged. The “four-hit hypothesis” of IgAN pathogenesis outlines a process that begins with elevated circulating levels of Gd-IgA1 that trigger autoantibody production. This results in the formation and deposition of immune complexes in the mesangium, leading to inflammation and kidney injury. Key mediators of the production of Gd-IgA1 and its corresponding autoantibodies are B-cell activating factor (BAFF), and A proliferation-inducing ligand (APRIL), each playing essential roles in the survival and maintenance of B cells and humoral immunity. Elevated serum levels of both BAFF and APRIL are observed in patients with IgAN and correlate with disease severity. This review explores the complex pathogenesis of IgAN, highlighting the pivotal roles of BAFF and APRIL in the interplay between mucosal hyper-responsiveness, B-cell activation, and the consequent overproduction of Gd-IgA1 and its autoantibodies that are key features in this disease. Finally, the potential therapeutic benefits of inhibiting BAFF and APRIL in IgAN, and a summary of recent clinical trial data, will be discussed.

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Further Evidence for the Mucosal Origin of Pathogenic IgA in IgA Nephropathy

Cited by 11 publications

References 9 publications

The pathological and outcome characteristics of renal lesions in Crohn’s disease

The pathological and outcome characteristics of renal lesions in Crohn’s disease

Treatment of IgA Nephropathy: A Rapidly Evolving Field

The role of BAFF and APRIL in IgA nephropathy: pathogenic mechanisms and targeted therapies

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