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Clinical Journal of the American... Apr 2017IgA nephropathy (IgAN) is a leading cause of CKD and renal failure. Recent international collaborative efforts have led to important discoveries that have improved our... (Review)
Review
IgA nephropathy (IgAN) is a leading cause of CKD and renal failure. Recent international collaborative efforts have led to important discoveries that have improved our understanding of some of the key steps involved in the immunopathogenesis of IgAN. Furthermore, establishment of multicenter networks has contributed to rigorous design and execution of clinical trials that have provided important insights regarding immunotherapy in IgAN. In this article, we review emerging developments in clinical and translational IgAN research and describe how these novel findings will influence future strategies to improve the outcome of patients with IgAN.
Topics: Adrenal Cortex Hormones; Conservative Treatment; Drug Therapy, Combination; Glomerulonephritis, IGA; Hematuria; Humans; Immunologic Factors; Mycophenolic Acid; Phenotype; Proteinuria; Renal Insufficiency, Chronic; Rituximab
PubMed: 28159829
DOI: 10.2215/CJN.07420716 -
Clinical and Experimental Rheumatology Apr 2023Anti-glomerular basement membrane (anti-GBM) disease is a rare life-threatening small vessel vasculitis that typically affects the capillaries of kidneys and lungs, with... (Review)
Review
Anti-glomerular basement membrane (anti-GBM) disease is a rare life-threatening small vessel vasculitis that typically affects the capillaries of kidneys and lungs, with most of patients developing rapidly progressive crescentic glomerulonephritis, and 40%-60% concomitant alveolar haemorrhage. It is caused by the deposition in alveolar and glomerular basement membrane of circulating autoantibodies directed against antigens intrinsic to the basement membrane. The exact mechanism that induces the formation of autoantibodies is unknown, but probably environmental factors, infections or direct damage to kidneys and lungs may trigger the autoimmune response in genetically susceptible individuals. Initial therapy includes corticosteroids and cyclophosphamide to prevent autoantibodies production, and plasmapheresis to remove the circulating autoantibodies. Good renal outcomes may be achieved by a prompt treatment initiation. However, when patients present with severe renal failure requiring dialysis or with a high proportion of glomerular crescents at biopsy, renal outcomes are bad. Relapses are rare and when renal involvement is present, the suspect of concomitant diseases, such as ANCA-associated vasculitis and membranous nephropathy, should be raised. Imlifidase is showing promising results, which if confirmed will cause a paradigm shift in the treatment of this disease.
Topics: Humans; Anti-Glomerular Basement Membrane Disease; Kidney; Autoantibodies; Hemorrhage; Kidney Glomerulus; Nephritis
PubMed: 36995324
DOI: 10.55563/clinexprheumatol/tep3k5 -
Kidney International Jul 2023The biology and diversity of glomerular parietal epithelial cells (PECs) are important for understanding podocyte regeneration and crescent formation. Although protein...
The biology and diversity of glomerular parietal epithelial cells (PECs) are important for understanding podocyte regeneration and crescent formation. Although protein markers have revealed the morphological heterogeneity of PECs, the molecular characteristics of PEC subpopulations remain largely unknown. Here, we performed a comprehensive analysis of PECs using single-cell RNA sequencing (scRNA-seq) data. Our analysis identified five distinct PEC subpopulations: PEC-A1, PEC-A2, PEC-A3, PEC-A4 and PEC-B. Among these subpopulations, PEC- A1 and PEC-A2 were characterized as podocyte progenitors while PEC-A4 represented tubular progenitors. Further dynamic signaling network analysis indicated that activation of PEC-A4 and the proliferation of PEC-A3 played pivotal roles in crescent formation. Analyses suggested that upstream signals released by podocytes, immune cells, endothelial cells and mesangial cells serve as pathogenic signals and may be promising intervention targets in crescentic glomerulonephritis. Pharmacological blockade of two such pathogenic signaling targets, proteins Mif and Csf1r, reduced hyperplasia of the PECs and crescent formation in anti-glomerular basement membrane glomerulonephritis murine models. Thus, our study demonstrates that scRNA-seq-based analysis provided valuable insights into the pathology and therapeutic strategies for crescentic glomerulonephritis.
Topics: Mice; Animals; Endothelial Cells; Epithelial Cells; Kidney Glomerulus; Podocytes; Glomerulonephritis; Proteins; Kidney Diseases
PubMed: 37100348
DOI: 10.1016/j.kint.2023.03.036 -
Science Translational Medicine Aug 2022Crescentic glomerulonephritis is characterized by vascular necrosis and parietal epithelial cell hyperplasia in the space surrounding the glomerulus, resulting in the...
Crescentic glomerulonephritis is characterized by vascular necrosis and parietal epithelial cell hyperplasia in the space surrounding the glomerulus, resulting in the formation of crescents. Little is known about the molecular mechanisms driving this process. Inducing crescentic glomerulonephritis in two Pax2Cre reporter mouse models revealed that crescents derive from clonal expansion of single immature parietal epithelial cells. Preemptive and delayed histone deacetylase inhibition with panobinostat, a drug used to treat hematopoietic stem cell disorders, attenuated crescentic glomerulonephritis with recovery of kidney function in the two mouse models. Three-dimensional confocal microscopy and stimulated emission depletion superresolution imaging of mouse glomeruli showed that, in addition to exerting an anti-inflammatory and immunosuppressive effect, panobinostat induced differentiation of an immature hyperplastic parietal epithelial cell subset into podocytes, thereby restoring the glomerular filtration barrier. Single-cell RNA sequencing of human renal progenitor cells in vitro identified an immature stratifin-positive cell subset and revealed that expansion of this stratifin-expressing progenitor cell subset was associated with a poor outcome in human crescentic glomerulonephritis. Treatment of human parietal epithelial cells in vitro with panobinostat attenuated stratifin expression in renal progenitor cells, reduced their proliferation, and promoted their differentiation into podocytes. These results offer mechanistic insights into the formation of glomerular crescents and demonstrate that selective targeting of renal progenitor cells can attenuate crescent formation and the deterioration of kidney function in crescentic glomerulonephritis in mice.
Topics: Animals; Disease Models, Animal; Glomerulonephritis; Humans; Kidney; Mice; Panobinostat; Podocytes; Stem Cells
PubMed: 35947676
DOI: 10.1126/scitranslmed.abg3277 -
Pediatric Nephrology (Berlin, Germany) May 2020To date, there is insufficient knowledge about crescentic glomerulonephritis (cGN), the most frequent immunologic cause of acute kidney injury in children.
BACKGROUND
To date, there is insufficient knowledge about crescentic glomerulonephritis (cGN), the most frequent immunologic cause of acute kidney injury in children.
METHODS
Over a period of 16 years, we retrospectively analyzed kidney biopsy results, the clinical course, and laboratory data in 60 pediatric patients diagnosed with cGN.
RESULTS
The underlying diseases were immune complex GN (n = 45/60, 75%), including IgA nephropathy (n = 19/45, 42%), lupus nephritis (n = 10/45, 22%), Henoch-Schoenlein purpura nephritis (n = 7/45, 16%) and post-infectious GN (n = 7/45, 16%), ANCA-associated pauci-immune GN (n = 10/60, 17%), and anti-glomerular basement-membrane GN (n = 1/60, 2%). Patient CKD stages at time of diagnosis and at a median of 362 days (range 237-425) were CKD I: n = 13/n = 29, CKD II: n = 15/n = 9, CKD III: n = 16/n = 7, CKD IV: n = 3/n = 3, CKD V: n = 13/n = 5. Course of cGN was different according to class of cGN, duration of disease from first clinical signs to diagnosis of cGN by biopsy, percentage of crescentic glomeruli, amount of tubular atrophy/interstitial fibrosis and necrosis on renal biopsy, gender, age, nephrotic syndrome, arterial hypertension, dialysis at presentation, and relapse. Forty-eight/60 children were treated with ≥ 5 (methyl-) prednisolone pulses and 53 patients received oral prednis(ol)one in combination with mycophenolate mofetil (n = 20), cyclosporine A (n = 20), and/or cyclophosphamide (n = 6), rituximab (n = 5), azathioprine (n = 2), tacrolimus (n = 1), and plasmapheresis/immunoadsorption (n = 5).
CONCLUSIONS
The treatment success of cGN is dependent on early diagnosis and aggressive therapy, as well as on the percentage of crescentic glomeruli on renal biopsy and on the underlying type of cGN. CsA and MMF seem to be effective alternatives to cyclophosphamide.
Topics: Acute Kidney Injury; Adolescent; Antibodies, Antineutrophil Cytoplasmic; Biopsy; Child; Child, Preschool; Combined Modality Therapy; Drug Therapy, Combination; Female; Fibrosis; Glomerular Basement Membrane; Glomerular Filtration Rate; Glomerulonephritis; Humans; Immunosuppressive Agents; Male; Necrosis; Plasmapheresis; Prednisolone; Prognosis; Pulse Therapy, Drug; Retrospective Studies; Severity of Illness Index; Treatment Outcome
PubMed: 32052153
DOI: 10.1007/s00467-019-04436-y -
Seminars in Respiratory and Critical... Aug 2018Antiglomerular basement membrane (anti-GBM) disease is a rare but life-threatening autoimmune vasculitis that is characterized by the development of pathogenic... (Review)
Review
Antiglomerular basement membrane (anti-GBM) disease is a rare but life-threatening autoimmune vasculitis that is characterized by the development of pathogenic autoantibodies to type IV collagen antigens expressed in the glomerular and alveolar basement membranes. Once deposited in tissue, these autoantibodies incite a local capillaritis which manifests as rapidly progressive glomerulonephritis (GN) in 80 to 90% of patients, and with concurrent alveolar hemorrhage in ∼50%. A small proportion of cases may present with pulmonary disease in isolation. Serological testing for anti-GBM antibodies may facilitate rapid diagnosis, though renal biopsy is often required to confirm the presence of necrotizing or crescentic GN and linear deposition of autoantibody on the glomerular basement membrane. Alveolar hemorrhage may be evident clinically, or detected on imaging, pulmonary function testing, or bronchoscopy. Prompt treatment with plasmapheresis, cyclophosphamide, and steroids is usually indicated to remove pathogenic autoantibodies, to prevent their ongoing production, and to ameliorate end-organ inflammation. Alveolar hemorrhage is usually responsive to this treatment, and long-term respiratory sequelae are uncommon. Renal prognosis is more variable, though with aggressive treatment, independent renal function is maintained at 1 year in more than 80% of patients not requiring renal replacement therapy at presentation. Relapse in uncommon in anti-GBM disease, unless there is a concomitant antineutrophil cytoplasm antibody (present in 30-40%), in which case maintenance immunosuppression is recommended.
Topics: Adrenal Cortex Hormones; Anti-Glomerular Basement Membrane Disease; Antibodies, Antineutrophil Cytoplasmic; Autoantibodies; Cyclophosphamide; Disease Progression; Glomerulonephritis; Hemorrhage; Humans; Immunosuppressive Agents; Plasma Exchange; Pulmonary Alveoli
PubMed: 30404116
DOI: 10.1055/s-0038-1669413 -
Frontiers in Immunology 2023The Monocyte chemoattractant protein-1 (MCP-1), also referred to as chemokine ligand 2 (CCL2), belongs to the extensive chemokine family and serves as a crucial mediator... (Review)
Review
The Monocyte chemoattractant protein-1 (MCP-1), also referred to as chemokine ligand 2 (CCL2), belongs to the extensive chemokine family and serves as a crucial mediator of innate immunity and tissue inflammation. It has a notable impact on inflammatory conditions affecting the kidneys. Upon binding to its receptor, MCP-1 can induce lymphocytes and NK cells' homing, migration, activation, differentiation, and development while promoting monocytes' and macrophages' infiltration, thereby facilitating kidney disease-related inflammation. As a biomarker for kidney disease, MCP-1 has made notable advancements in primary kidney diseases such as crescentic glomerulonephritis, chronic glomerulonephritis, primary glomerulopathy, idiopathic proteinuria glomerulopathy, acute kidney injury; secondary kidney diseases like diabetic nephropathy and lupus nephritis; hereditary kidney diseases including autosomal dominant polycystic kidney disease and sickle cell kidney disease. MCP-1 not only predicts the occurrence, progression, prognosis of the disease but is also closely associated with the severity and stage of nephropathy. When renal tissue is stimulated or experiences significant damage, the expression of MCP-1 increases, demonstrating a direct correlation with the severity of renal injury.
Topics: Humans; Chemokine CCL2; Glomerulonephritis; Lupus Nephritis; Diabetic Nephropathies; Biomarkers; Inflammation
PubMed: 38239353
DOI: 10.3389/fimmu.2023.1303076 -
Cell and Tissue Research Aug 2021Crescentic glomerulonephritis represents a group of kidney diseases characterized by rapid loss of kidney function and the formation of glomerular crescents. While the... (Review)
Review
Crescentic glomerulonephritis represents a group of kidney diseases characterized by rapid loss of kidney function and the formation of glomerular crescents. While the role of the immune system has been extensively studied in relation to the development of crescents, recent findings show that parietal epithelial cells play a key role in the pathophysiology of crescent formation, even in the absence of immune modulation. This review highlights our current understanding of parietal epithelial cell biology and the reported physiological and pathological roles that these cells play in glomerular lesion formation, especially in the context of crescentic glomerulonephritis.
Topics: Animals; Epithelial Cells; Glomerulonephritis; Humans; Kidney Glomerulus
PubMed: 34453566
DOI: 10.1007/s00441-021-03513-9 -
Seminars in Nephrology Nov 2013Antineutrophil cytoplasmic autoantibodies (ANCA) are the likely cause for necrotizing small-vessel vasculitis and crescentic glomerulonephritis. Unlike other forms of... (Review)
Review
Antineutrophil cytoplasmic autoantibodies (ANCA) are the likely cause for necrotizing small-vessel vasculitis and crescentic glomerulonephritis. Unlike other forms of crescentic glomerulonephritis induced by immune complexes or anti-glomerular basement membrane antibodies that have conspicuous vessel wall immunoglobulin and complement, there is a paucity, although usually not an absence, of vessel wall immunoglobulin and complement in ANCA-associated glomerulonephritis. Despite this comparatively lower level and more localized distribution of vessel wall complement, experimental and clinical observations strongly incriminate alternative complement pathway activation as critically important in the pathogenesis of ANCA disease. Experimental data in animal models and in vitro experiments has shown that primed neutrophils are activated by ANCA, which generates C5a, which engages C5a receptors on neutrophils. This attracts and in turn primes more neutrophils for activation by ANCA. In patients with ANCA disease, plasma levels of C3a, C5a, soluble C5b-9, and Bb have been reported to be higher in active disease than in remission, whereas no difference was reported in plasma C4d in active versus ANCA disease remission. Thus, experimental and clinical data support the hypothesis that ANCA-induced neutrophil activation activates the alternative complement pathway and generates C5a. C5a not only recruits additional neutrophils through chemotaxis but also primes neutrophils for activation by ANCA. This creates a self-fueling inflammatory amplification loop that results in the extremely destructive necrotizing vascular injury.
Topics: Animals; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Complement Pathway, Alternative; Complement System Proteins; Disease Models, Animal; Glomerulonephritis; Humans; Immunoglobulins; Mice
PubMed: 24161040
DOI: 10.1016/j.semnephrol.2013.08.006 -
BMC Nephrology May 2022Bartonella endocarditis is often a diagnostic challenge due to its variable clinical manifestations, especially when it is first presented with involvement of...
BACKGROUND
Bartonella endocarditis is often a diagnostic challenge due to its variable clinical manifestations, especially when it is first presented with involvement of organs other than skin and lymph nodes, such as the kidney.
CASE PRESENTATION
This was a 13-year-old girl presenting with fever, chest and abdominal pain, acute kidney injury, nephrotic-range proteinuria and low complement levels. Her kidney biopsy showed diffuse crescentic proliferative glomerulonephritis with a full-house pattern of immune complex deposition shown by immunofluorescence, which was initially considered consistent with systemic lupus erythematous-associated glomerulonephritis (lupus nephritis). After extensive workup, Bartonella endocarditis was diagnosed. Antibiotic treatment and valvular replacement surgery were undertaken with subsequent return of kidney function to normal range.
CONCLUSION
This case demonstrates the importance of considering the full clinical picture when interpreting clinical, laboratory and biopsy findings, because the treatment strategy for infective endocarditis versus lupus nephritis is drastically different.
Topics: Adolescent; Antigen-Antibody Complex; Bartonella; Endocarditis; Female; Glomerulonephritis; Glomerulonephritis, Membranoproliferative; Humans; Lupus Nephritis; Male
PubMed: 35549887
DOI: 10.1186/s12882-022-02811-w