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Nature Reviews. Disease Primers Nov 2023IgA nephropathy (IgAN), the most prevalent primary glomerulonephritis worldwide, carries a considerable lifetime risk of kidney failure. Clinical manifestations of IgAN... (Review)
Review
IgA nephropathy (IgAN), the most prevalent primary glomerulonephritis worldwide, carries a considerable lifetime risk of kidney failure. Clinical manifestations of IgAN vary from asymptomatic with microscopic or intermittent macroscopic haematuria and stable kidney function to rapidly progressive glomerulonephritis. IgAN has been proposed to develop through a 'four-hit' process, commencing with overproduction and increased systemic presence of poorly O-glycosylated galactose-deficient IgA1 (Gd-IgA1), followed by recognition of Gd-IgA1 by antiglycan autoantibodies, aggregation of Gd-IgA1 and formation of polymeric IgA1 immune complexes and, lastly, deposition of these immune complexes in the glomerular mesangium, leading to kidney inflammation and scarring. IgAN can only be diagnosed by kidney biopsy. Extensive, optimized supportive care is the mainstay of therapy for patients with IgAN. For those at high risk of disease progression, the 2021 KDIGO Clinical Practice Guideline suggests considering a 6-month course of systemic corticosteroid therapy; however, the efficacy of systemic steroid treatment is under debate and serious adverse effects are common. Advances in understanding the pathophysiology of IgAN have led to clinical trials of novel targeted therapies with acceptable safety profiles, including SGLT2 inhibitors, endothelin receptor blockers, targeted-release budesonide, B cell proliferation and differentiation inhibitors, as well as blockade of complement components.
Topics: Humans; Glomerulonephritis, IGA; Antigen-Antibody Complex; Galactose; Immunoglobulin A
PubMed: 38036542
DOI: 10.1038/s41572-023-00476-9 -
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 -
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 -
Acta Physiologica (Oxford, England) Oct 2023When discussing glomerular function, one cell type is often left out, the mesangial cell (MC), probably since it is not a part of the filtration barrier per se. The MCs... (Review)
Review
When discussing glomerular function, one cell type is often left out, the mesangial cell (MC), probably since it is not a part of the filtration barrier per se. The MCs are instead found between the glomerular capillaries, embedded in their mesangial matrix. They are in direct contact with the endothelial cells and in close contact with the podocytes and together they form the glomerulus. The MCs can produce and react to a multitude of growth factors, cytokines, and other signaling molecules and are in the perfect position to be a central hub for crosstalk communication between the cells in the glomerulus. In certain glomerular diseases, for example, in diabetic kidney disease or IgA nephropathy, the MCs become activated resulting in mesangial expansion. The expansion is normally due to matrix expansion in combination with either proliferation or hypertrophy. With time, this expansion can lead to fibrosis and decreased glomerular function. In addition, signs of complement activation are often seen in biopsies from patients with glomerular disease affecting the mesangium. This review aims to give a better understanding of the MCs in health and disease and their role in glomerular crosstalk and inflammation.
Topics: Humans; Endothelial Cells; Glomerular Mesangium; Kidney Glomerulus; Diabetic Nephropathies; Podocytes
PubMed: 37658606
DOI: 10.1111/apha.14045 -
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 -
Clinical Journal of the American... Dec 2023IgA nephropathy is the most common primary GN worldwide, with dominant deposition of IgA and co-deposits of complement component 3 (C3). Phenotypes and progression of...
BACKGROUND
IgA nephropathy is the most common primary GN worldwide, with dominant deposition of IgA and co-deposits of complement component 3 (C3). Phenotypes and progression of IgA nephropathy varies among different ethnic populations, while patients with IgA nephropathy from Asia showed more severe clinical phenotypes, active kidney lesions, and rapid progression. Our previous genome-wide association study identified complement factor H ( CFH ) variant rs6677604, tightly linked with the deletion of CFH -related protein 3 and CFH -related protein 1 genes ( ΔCFHR3-1 ), as IgA nephropathy susceptible variant, and additionally revealed its effect on complement regulation in IgA nephropathy.
METHODS
To further explore the effect of rs6677604 on IgA nephropathy progression, here we enrolled a Chinese IgA nephropathy cohort of 1781 patients with regular follow-up for analysis. The rs6677604 genotype was measured, and the genotype-phenotype correlation was analyzed using the t test, the chi-squared test, or the nonparametric test, and the association between rs6677604 genotype or mesangial C3 deposition and IgA nephropathy prognosis was analyzed using Kaplan-Meier analysis and Cox regression.
RESULTS
We found that patients with rs6677604-GG genotype had a stronger intensity of mesangial C3 deposition than those with the rs6677604-AA/AG genotype. Patients with IgA nephropathy who had stronger intensity of C3 deposition manifested with more severe clinical and pathological manifestations, including lower eGFR and higher Oxford-M/S/T/C (mesangial hypercellularity, endocapillary cellularity, segmental sclerosis, interstitial fibrosis/tubular atrophy, and crescent) scores. In the survival analysis, stronger intensity of mesangial C3 deposition, but not rs6677604-GG genotypes, was associated with poor long-term kidney outcome in IgA nephropathy.
CONCLUSIONS
We found that in Chinese patients with IgA nephropathy, variant rs6677604 was associated with mesangial C3 deposition, and mesangial C3 deposition, but not rs6677604, was associated with IgA nephropathy severity and progression.
Topics: Humans; Disease Progression; Genome-Wide Association Study; Glomerular Mesangium; Glomerulonephritis, IGA; Kidney; Prognosis; Complement Factor H
PubMed: 37651123
DOI: 10.2215/CJN.0000000000000290 -
Kidney International Nov 2023
Topics: Animals; Humans; Mesangial Cells; Diabetic Nephropathies; Glomerular Mesangium; Diabetes Mellitus, Experimental
PubMed: 37863632
DOI: 10.1016/j.kint.2023.03.033