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Clinical Kidney Journal Jul 2023Immunoglobulin A (IgA) nephropathy (IgAN) is the most common primary glomerulonephritis worldwide and it is characterized by mesangial IgA deposition. Asymptomatic... (Review)
Review
Immunoglobulin A (IgA) nephropathy (IgAN) is the most common primary glomerulonephritis worldwide and it is characterized by mesangial IgA deposition. Asymptomatic hematuria with various degrees of proteinuria is the most common clinical presentation and up to 20%-40% of patients develop end-stage kidney disease within 20 years after disease onset. The pathogenesis of IgAN involves four sequential processes known as the "four-hit hypothesis" which starts with the production of a galactose-deficient IgA1 (gd-IgA1), followed by the formation of anti-gd-IgA1 IgG or IgA1 autoantibodies and immune complexes that ultimately deposit in the glomerular mesangium, leading to inflammation and injury. Although several key questions about the production of gd-IgA1 and the formation of anti-gd-IgA1 antibodies remain unanswered, a growing body of evidence is shedding light on the innate and adaptive immune mechanisms involved in this complex pathogenic process. Herein, we will focus on these mechanisms that, along with genetic and environmental factors, are thought to play a key role in disease pathogenesis.
PubMed: 37398689
DOI: 10.1093/ckj/sfad025 -
Wiener Klinische Wochenschrift Aug 2023Immunoglobulin A nephropathy (IgAN) is the most common glomerulonephritis. It leads to end-stage kidney disease in about a third of the patients within 10 to...
Immunoglobulin A nephropathy (IgAN) is the most common glomerulonephritis. It leads to end-stage kidney disease in about a third of the patients within 10 to 20 years. The pathogenesis of IgAN is incompletely understood. It is believed that a dysregulation of the mucosal immune system leads to undergalactosylation of IgA, followed by formation of IgG autoantibodies against undergalactosylated IgA, circulation of these IgG-IgA immune complexes, deposition of the immune complexes in the mesangium, ultimately resulting in glomerular inflammation. IgAN can occasionally be triggered by other diseases, these secondary causes of IgAN should be identified or ruled out (chronic inflammatory bowel disease, infections, tumors, rheumatic diseases). Characteristic findings of IgAN of variable extent are a nephritic urinary sediment (erythrocytes, acanthocytes, erythrocyte casts), proteinuria, impaired renal function, arterial hypertension, or intermittent painless macrohematuria, especially during infections of the upper respiratory tract. However, the diagnosis of IgAN can only be made by a kidney biopsy. A histological classification (MEST‑C score) should always be reported to be able to estimate the prognosis. The most important therapeutic measure is an optimization of the supportive therapy, which includes, among other things, a consistent control of the blood pressure, an inhibition of the RAS, and the administration of an SGLT2 inhibitor. A systemic immunosuppressive therapy with corticosteroids is discussed controversially, should be used restrictively and only administered after an individual benefit-risk assessment under certain conditions that speak for a progressive IgAN. New promising therapeutics are enteral Budesonide or the dual angiotensin-II-receptor- and endothelin-receptor-antagonist Sparsentan. Rapidly progressive IgAN should be treated with corticosteroids and cyclophosphamide like ANCA-associated vasculitis.
Topics: Humans; Glomerulonephritis, IGA; Antigen-Antibody Complex; Autoantibodies; Immunoglobulin A; Immunoglobulin G
PubMed: 37728647
DOI: 10.1007/s00508-023-02257-6 -
Medical Science Monitor : International... Jan 2024The clinical association of purpura, arthralgia, and arthritis was first described in 1837 in a publication by Johann Lukas Schönlein, a German physician. In 1874,... (Review)
Review
The clinical association of purpura, arthralgia, and arthritis was first described in 1837 in a publication by Johann Lukas Schönlein, a German physician. In 1874, Eduard Henoch, a student of Schönlein, reported cases of children with purpura, abdominal pain, bloody diarrhea, and joint pain. IgA vasculitis, or Henoch-Schönlein purpura, is a systemic hypersensitivity vasculitis caused by the deposition of immune complexes in small blood vessels, including the renal glomeruli and mesangium. In the skin, the presentation is with non-thrombocytopenic purpura or urticaria. Worldwide, IgA nephropathy is the most common cause of primary glomerulonephritis. Detection of IgA deposition in small blood vessels and the renal glomeruli is diagnostic in most cases. This article aims to review the history, current classification, epidemiology, presentation, and diagnosis of IgA vasculitis and nephropathy, disease associations or trigger factors, including infections, vaccines, and therapeutic agents, and highlights some future approaches to improve diagnosis and clinical management.
Topics: Child; Humans; IgA Vasculitis; Immunoglobulin A; Glomerulonephritis, IGA; Vasculitis; Kidney Glomerulus; Hypersensitivity
PubMed: 38281080
DOI: 10.12659/MSM.943912 -
Nephrology, Dialysis, Transplantation :... Sep 2023This review summarizes the pathomorphological sequences of nephron loss in human diabetic nephropathy (DN). The relevant changes may be derived from two major... (Review)
Review
This review summarizes the pathomorphological sequences of nephron loss in human diabetic nephropathy (DN). The relevant changes may be derived from two major derangements. First, a failure in the turnover of the glomerular basement membrane (GBM) based on an increased production of GBM components by podocytes and endothelial cells leading to the thickening of the GBM and accumulation of worn-out GBM in the mesangium. This failure may account for the direct pathway to glomerular compaction and sclerosis based on the continuous deposition of undegraded GBM material in the mesangium. Second, an increased leakiness together with an increased propensity of glomerular capillaries to proliferate leads to widespread plasma exudations. Detrimental are those that produce giant insudative spaces within Bowman's capsule, spreading around the entire glomerular circumference and along the glomerulo-tubular junction onto the tubule resulting in tubular obstruction and retroactively to glomerulosclerosis. Tubular atrophy and interstitial fibrosis develop secondarily by transfer of the glomerular damage onto the tubule. Interstitial fibrosis is locally initiated and apparently stimulated by degenerating tubular epithelia. This leads to a focal distribution of interstitial fibrosis and tubular atrophy accompanied by a varying interstitial mononuclear cell infiltration. Spreading of fibrotic areas between intact nephrons, much less to the glomerulus, has not been encountered.
Topics: Humans; Diabetic Nephropathies; Endothelial Cells; Glomerular Basement Membrane; Fibrosis; Atrophy; Diabetes Mellitus
PubMed: 36918205
DOI: 10.1093/ndt/gfad052 -
Frontiers in Nephrology 2023Immunoglobulin A nephropathy (IgAN), characterized by mesangial deposition of galactose-deficient-IgA1 (Gd-IgA1), is the most common biopsy-proven primary... (Review)
Review
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.
PubMed: 38362118
DOI: 10.3389/fneph.2023.1346769 -
Aging Jan 2024Immunoglobulin A nephropathy (IgAN), one type of glomerulonephritis, displays the accumulation of glycosylated IgA in the mesangium. Studies have demonstrated that both... (Review)
Review
Immunoglobulin A nephropathy (IgAN), one type of glomerulonephritis, displays the accumulation of glycosylated IgA in the mesangium. Studies have demonstrated that both genetics and epigenetics play a pivotal role in the occurrence and progression of IgAN. Post-translational modification (PTM) has been revealed to critically participate in IgAN development and progression because PTM dysregulation results in impaired degradation of proteins that regulate IgAN pathogenesis. A growing number of studies identify that PTMs, including sialylation, o-glycosylation, galactosylation, phosphorylation, ubiquitination and deubiquitination, modulate the initiation and progression of IgAN. Hence, in this review, we discuss the functions and mechanisms of PTMs in regulation of IgAN. Moreover, we outline numerous compounds that govern PTMs and attenuate IgAN progression. Targeting PTMs might be a useful strategy to ameliorate IgAN.
Topics: Humans; Glomerulonephritis, IGA; Glycosylation; Phosphorylation; Protein Processing, Post-Translational
PubMed: 38175721
DOI: 10.18632/aging.205406 -
Cell Reports Feb 2024Recent regenerative studies using human pluripotent stem cells (hPSCs) have developed multiple kidney-lineage cells and organoids. However, to further form functional...
Recent regenerative studies using human pluripotent stem cells (hPSCs) have developed multiple kidney-lineage cells and organoids. However, to further form functional segments of the kidney, interactions of epithelial and interstitial cells are required. Here we describe a selective differentiation of renal interstitial progenitor-like cells (IPLCs) from human induced pluripotent stem cells (hiPSCs) by modifying our previous induction method for nephron progenitor cells (NPCs) and analyzing mouse embryonic interstitial progenitor cell (IPC) development. Our IPLCs combined with hiPSC-derived NPCs and nephric duct cells form nephrogenic niche- and mesangium-like structures in vitro. Furthermore, we successfully induce hiPSC-derived IPLCs to differentiate into mesangial and erythropoietin-producing cell lineages in vitro by screening differentiation-inducing factors and confirm that p38 MAPK, hypoxia, and VEGF signaling pathways are involved in the differentiation of mesangial-lineage cells. These findings indicate that our IPC-lineage induction method contributes to kidney regeneration and developmental research.
Topics: Humans; Animals; Mice; Induced Pluripotent Stem Cells; Kidney; Cell Lineage; Regeneration; Erythropoietin
PubMed: 38237600
DOI: 10.1016/j.celrep.2023.113602