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Science Advances Oct 2022The underlying pathology of immunoglobulin A (IgA) nephropathy (IgAN), the most common glomerulonephritis worldwide, is driven by the deposition of immune complexes...
The underlying pathology of immunoglobulin A (IgA) nephropathy (IgAN), the most common glomerulonephritis worldwide, is driven by the deposition of immune complexes containing galactose-deficient IgA1 [Tn(+)IgA1] in the glomerular mesangium. Here, we report that novel anti-Tn circulating immune complexes (anti-Tn CICs) contain predominantly IgM, representing large macromolecular complexes of ~1.2 megadaltons to several megadalton sizes together with Tn(+)IgA1 and some IgG. These complexes are significantly elevated in sera of patients with IgAN, which contains higher levels of complement C3, compared to healthy individuals. Anti-Tn CICs are bioactive and induce specific proliferation of human renal mesangial cells. We found that these anti-Tn CICs can be dissociated with small glycomimetic compounds, which mimic the Tn antigen of Tn(+)IgA1, releasing IgA1 from anti-Tn CICs. This glycomimetic compound can also significantly inhibit the proliferative activity of anti-Tn CICs of patients with IgAN. These findings could enhance both the diagnosis of IgAN and its treatment, as specific drug treatments are now unavailable.
Topics: Humans; Glomerulonephritis, IGA; Antigen-Antibody Complex; Glomerular Mesangium; Immunoglobulin A; Mesangial Cells
PubMed: 36306365
DOI: 10.1126/sciadv.abm8783 -
BMC Nephrology Oct 2022Immunoglobulin A dominant postinfectious glomerulonephritis (IgA PIGN) is a unique medical entity that is rare in the paediatric population. It usually presents with...
BACKGROUND
Immunoglobulin A dominant postinfectious glomerulonephritis (IgA PIGN) is a unique medical entity that is rare in the paediatric population. It usually presents with severe renal failure, heavy proteinuria, hypertension, and hypocomplementemia and frequently has an unfavourable prognosis. IgA PIGN generally occurs in association with staphylococcal infections and diabetes mellitus in adult patients. Other pathogens include Escherichia coli and Streptococcus sp. Immunofluorescence studies of kidney biopsy samples show IgA as dominant or codominant antibody.
CASE PRESENTATION
We encountered a 3-year-old girl with IgA PIGN presenting with acute renal failure, oedema, hypertension, and heavy proteinuria of 7955 mg/g creatinine. Renal biopsy specimens showed diffuse glomerular endocapillary hypercellularity with prominent neutrophil and monocyte infiltration on light microscopy. Strong deposits of IgA and C were observed along the glomerular basement membranes and the mesangium by immunofluorescence microscopy, and electron microscopy revealed the presence of subepithelial humps. The patient was managed with steroid (and probatory antibiotic) therapy and is now undergoing follow-up, with a significant improvement 6 months after the initial presentation (glomerular filtration rate (GFR) and cystatin C clearance rate of 165 ml/min/1.73m and 106 ml/min/1.73m, respectively). No signs of bacterial infection were detectable.
CONCLUSION
This variant of IgA PIGN must be distinguished from other clinical entities, especially IgA nephropathy (mesangial IgA deposits) and postinfectious glomerulonephritis (C3, IgG and occasional IgM capillary loop deposits with or without mesangial distribution), since patients with IgA PIGN may require steroid treatment in addition to antibiotic therapy. Differential diagnosis should also include C glomerulopathy. IgA PIGN is a recently identified disease entity that generally manifests in adult patients with both IgA and C3 mesangial and glomerular capillary wall deposits. We present a biopsy-proven case of IgA PIGN that manifested in a patient at an exceptionally young age and that has had a good clinical outcome. To the best of our knowledge, this is the youngest IgA PIGN patient reported thus far.
Topics: Adult; Anti-Bacterial Agents; Biopsy; Child; Child, Preschool; Creatinine; Cystatin C; Female; Glomerulonephritis; Glomerulonephritis, IGA; Humans; Hypertension; Immunoglobulin A; Immunoglobulin G; Immunoglobulin M; Proteinuria; Staphylococcal Infections
PubMed: 36253737
DOI: 10.1186/s12882-022-02965-7 -
Kidney360 Sep 2022Immunoglobulin A nephropathy(IgAN) is the most common primary glomerulonephritis worldwide. The working model for the pathogenesis of IgAN involves a multistep process... (Review)
Review
Immunoglobulin A nephropathy(IgAN) is the most common primary glomerulonephritis worldwide. The working model for the pathogenesis of IgAN involves a multistep process starting from the production of galactose-deficient and polymeric immunoglobulin A-1 (gd-IgA1) that enters systemic circulation from gut-associated lymphoid tissue (GALT). Galactose-deficient IgA are targeted by endogenous IgG, leading to the formation of circulating immune complexes that deposit in the mesangium and resulting in glomerular inflammation. Disease onset and relapses are often associated with gut infections, supporting the hypothesis that the gut plays an important pathogenic role. In the presence of microbial pathogens or food antigens, activated dendritic cells in the gut mucosa induce T cell dependent and independent B cell differentiation into IgA secreting plasma cells. In IgAN patients, this promotes the systemic release of mucosal gd-IgA1. Not all bacterial strains have the same capacity to elicit IgA production, and little is known about the antigen specificity of the pathogenic gd-IgA1. However, efficacy of treatments targeting gut inflammation support a pathogenic link between the bowel immune system and IgAN. Herein, we review the evidence supporting the role of gut inflammation in IgAN pathogenesis.
Topics: Antigen-Antibody Complex; Galactose; Glomerulonephritis, IGA; Humans; Immunoglobulin A; Immunoglobulin G; Inflammation; Kidney
PubMed: 36245664
DOI: 10.34067/KID.0002382022 -
The American Journal of Pathology Dec 2022The development of focal and segmental glomerulosclerosis (FSGS) as a consequence of glomerular hypertension resulting from arterial hypertension is widely considered a...
The development of focal and segmental glomerulosclerosis (FSGS) as a consequence of glomerular hypertension resulting from arterial hypertension is widely considered a podocyte disease. However, the primary damage is encountered in the mesangium. In acute settings, mesangial cells disconnect from their insertions to the glomerular basement membrane, causing a ballooning of capillaries and severe changes of the folding pattern of the glomerular basement membrane, of the arrangement of the capillaries, and thereby of the architecture of the tuft. The displacement of capillaries led to contact of podocytes and parietal epithelial cells, initiating the formation of tuft adhesions to Bowman's capsule, the committed lesion to progress to FSGS. In addition, the displacement of capillaries also caused an abnormal stretching of podocytes, resulting in podocyte damage. Thus, the podocyte damage that starts the sequence to FSGS is predicted to develop secondary to the mesangial damage. This sequence was found in two hypertensive rat models of FSGS and in human hypertensive nephrosclerosis.
Topics: Rats; Humans; Animals; Podocytes; Glomerulosclerosis, Focal Segmental; Nephrosclerosis; Capillaries; Glomerular Basement Membrane; Hypertension, Renal
PubMed: 36150506
DOI: 10.1016/j.ajpath.2022.08.007 -
Evidence-based Complementary and... 2022Diabetes in children and its complications are on the rise globally, which is accompanied by increasing in diabetes-related complications. Oxidative stress and...
Diabetes in children and its complications are on the rise globally, which is accompanied by increasing in diabetes-related complications. Oxidative stress and inflammation induced by elevated blood sugar in diabetic patients are considered risk factors associated with the development of diabetes complications, including chronic kidney disease and its later development to end-stage renal disease. Microvascular changes within the kidneys of DM patients often lead to chronic kidney disease, which aggravates the illness. extract (SOE), reported to have strong antioxidative and excellent anti-inflammatory activities, is used in the modern practice of traditional Chinese medicine. Kidneys from three groups of control mice (CTR), mice with streptozotocin (STZ)-induced diabetes (DM), and mice with STZ-induced DM treated with SOE (DMRx) were excised for morphological analyses and immunohistochemical assessments. Only mice in the DM group exhibited significantly lower body weight, but higher blood sugar was present. The results revealed more obvious renal injury in the DM group than in the other groups, which appeared as greater glomerular damage and tubular injury, sores, and plenty of connective tissues within the mesangium. Not only did the DM group have a higher level of cytokine, tumor necrosis factor, and the oxidative stress marker, 8-hydroxyguanosine expression, but also factors of the nuclear factor pathway and biomarkers of microvascular status had changed. Disturbances to the kidneys in DMRx mice were attenuated compared to the DM group. We concluded that SOE is an effective medicine, with antioxidative and anti-inflammatory abilities, to protect against or attenuate diabetic nephropathy from inflammatory disturbances by oxidative stress and to cure vessel damage in a hyperglycemic situation.
PubMed: 35966750
DOI: 10.1155/2022/3323745 -
Journal of Biological Engineering Aug 2022Diabetic nephropathy, a kidney complication arising from diabetes, is the leading cause of death in diabetic patients. Unabated, the growing epidemic of diabetes is... (Review)
Review
Diabetic nephropathy, a kidney complication arising from diabetes, is the leading cause of death in diabetic patients. Unabated, the growing epidemic of diabetes is increasing instances of diabetic nephropathy. Although the main causes of diabetic nephropathy have been determined, the mechanisms of their combined effects on cellular and tissue function are not fully established. One of many damages of diabetic nephropathy is the development of fibrosis within the kidneys, termed mesangial expansion. Mesangial expansion is an important structural lesion that is characterized by the aberrant proliferation of mesangial cells and excess production of matrix proteins. Mesangial expansion is involved in the progression of kidney failure in diabetic nephropathy, yet its causes and mechanism of impact on kidney function are not well defined. Here, we review the literature on the causes of mesangial expansion and its impacts on cell and tissue function. We highlight the gaps that still remain and the potential areas where bioengineering studies can bring insight to mesangial expansion in diabetic nephropathy.
PubMed: 35918708
DOI: 10.1186/s13036-022-00299-4 -
Medicine Jul 2022Amyloidogenic leukocyte chemotactic factor 2 (ALECT2) was recently considered as a new clinicopathologic type of amyloid, which frequently affects kidney in adults and...
RATIONALE
Amyloidogenic leukocyte chemotactic factor 2 (ALECT2) was recently considered as a new clinicopathologic type of amyloid, which frequently affects kidney in adults and results in different degrees of renal insufficiency and failure with or without proteinuria. Here, we present a case of combining LECT2-associated renal amyloidosis with immunoglobulin (Ig)A nephropathy.
PATIENT CONCERNS
A 71-year-old Chinese man presented with edema of both lower extremities.
DIAGNOSES
There was pale eosinophilic material strongly positive for the Congo red stain in interstitium with demonstrated apple green birefringence under polarized light. Immunofluorescent stain was positive for IgA deposits (4+), IgG deposits (2+), C3 deposits (3+) within the mesangium and capillary wall. Immunohistochemistry was positive for κ (+), λ (2+) in mesangial area, and LECT2 (2+) in the interstitium. On electron microscopy, there were electron-dense deposits within mesangial area and subendothelial and randomly orientated and nonbranching fibrils 10 nm in size found in the interstitium areas. Liquid chromatography tandem mass spectrometry was performed on peptides extracted from Congo red-positive, microdissected areas of the paraffin-embedded kidney specimen. LECT 2-associated renal amyloidosis with IgA nephropathy was pathologically confirmed by renal biopsy.
INTERVENTIONS
Steroids (60 mg/d) were used to treat IgA nephropathy daily. Antihypertensive treatment was switched to an angiotensin-converting enzyme inhibitor.
OUTCOMES
One year after diagnosis, creatine remained stable in the normal range, and 24-hour proteinuria decreased to 2.9 g.
LESSONS
To date, ALECT2 has still not been comprehensively investigated. The findings of this research provide insights for concurrent IgA nephropathy with ALECT2.
Topics: Adult; Aged; Amyloidosis; CD8 Antigens; Chemotactic Factors; Congo Red; Glomerulonephritis, IGA; Humans; Intercellular Signaling Peptides and Proteins; Kidney; Leukocytes; Male; Proteinuria
PubMed: 35866785
DOI: 10.1097/MD.0000000000029638 -
Cureus Jun 2022Fibrillary glomerulonephritis (FGN) is a rare but severe kidney disease found to have non-amyloid fibrillary deposits in the mesangium and/or glomerular capillary wall....
Fibrillary glomerulonephritis (FGN) is a rare but severe kidney disease found to have non-amyloid fibrillary deposits in the mesangium and/or glomerular capillary wall. It was initially thought to be idiopathic, but recent studies show an association with autoimmune disease, malignancy, and hepatitis C infection. We report a case of a non-diabetic patient presenting with long-standing microscopic hematuria, progressive proteinuria, hypertension, and worsening kidney function. The kidney biopsy demonstrated subepithelial fibrillar deposits of size 17 mm randomly oriented with one partial cellular crescent on electron microscopy. Direct immunofluorescence showed no staining for IgG or light chains. It was weakly positive for Congo red staining with a slightly higher serum free kappa/lambda light chain ratio, but serum immunofixation showed no monoclonal protein detection. We empirically treated with rituximab but with no clear benefit or no renal recovery and eventually started on hemodialysis. FGN has an extremely poor prognosis with very few treatment options available. We report this case to emphasize the need for larger, multi-center studies for treatment approaches with collaborating and consolidating data from case reports and case series due to the rarity of the disease.
PubMed: 35865414
DOI: 10.7759/cureus.26001 -
Journal of the American Society of... Sep 2022The glomerular vascular pole is the gate for the afferent and efferent arterioles and mesangial cells and a frequent location of peripolar cells with an unclear...
The glomerular vascular pole is the gate for the afferent and efferent arterioles and mesangial cells and a frequent location of peripolar cells with an unclear function. It has been studied in definitive detail for >30 years, and functionally interrogated in the context of signal transduction from the macula densa to the mesangial cells and afferent arteriolar smooth muscle cells from 10 to 20 years ago. Two recent discoveries shed additional light on the vascular pole, with possibly far-reaching implications. One, which uses novel serial section electron microscopy, reveals a shorter capillary pathway between the basins of the afferent and efferent arterioles. Such a pathway, when patent, may short-circuit the multitude of capillaries in the glomerular tuft. Notably, this shorter capillary route is enclosed within the glomerular mesangium. The second study used anti-Thy1.1-induced mesangiolysis and intravital microscopy to unequivocally establish the long-suspected contractile function of mesangial cells, which have the ability to change the geometry and curvature of glomerular capillaries. These studies led me to hypothesize the existence of a glomerular perfusion rheostat, in which the shorter path periodically fluctuates between being more and less patent. This action reduces or increases blood flow through the entire glomerular capillary tuft. A corollary is that the GFR is a net product of balance between the states of capillary perfusion, and that deviations from the balanced state would increase or decrease GFR. Taken together, these studies may pave the way to a more profound understanding of glomerular microcirculation under basal conditions and in progression of glomerulopathies.
Topics: Microcirculation; Kidney Glomerulus; Glomerular Mesangium; Arterioles; Kidney Tubules
PubMed: 35853715
DOI: 10.1681/ASN.2022030354 -
International Journal of Molecular... Jul 2022Since 1995, when we reported the case of a patient with glomerulonephritis with IgA deposition that occurred after a methicillin-resistant (MRSA) infection, many... (Review)
Review
Since 1995, when we reported the case of a patient with glomerulonephritis with IgA deposition that occurred after a methicillin-resistant (MRSA) infection, many reports of MRSA infection-associated glomerulonephritis have accumulated. This disease is being systematized as Staphylococcus infection-associated glomerulonephritis (SAGN) in light of the apparent cause of infection, and as immunoglobulin A-dominant deposition infection-related glomerulonephritis (IgA-IRGN) in light of its histopathology. This glomerulonephritis usually presents as rapidly progressive glomerulonephritis or acute kidney injury with various degrees of proteinuria and microscopic hematuria along with an ongoing infection. Its renal pathology has shown several types of mesangial and/or endocapillary proliferative glomerulonephritis with various degrees of crescent formation and tubulointerstitial nephritis. IgA, IgG, and C staining in the mesangium and along the glomerular capillary walls have been observed on immunofluorescence examinations. A marked activation of T cells, an increase in specific variable regions of the T-cell receptor β-chain-positive cells, hypercytokinemia, and increased polyclonal immune complexes have also been observed in this glomerulonephritis. In the development of this disease, staphylococcal enterotoxin may be involved as a superantigen, but further investigations are needed to clarify the mechanisms underlying this disease. Here, we review 336 cases of IgA-IRGN and 218 cases of SAGN.
Topics: Glomerulonephritis; Glomerulonephritis, IGA; Humans; Immunoglobulin A; Methicillin-Resistant Staphylococcus aureus; Staphylococcal Infections; Staphylococcus aureus
PubMed: 35806487
DOI: 10.3390/ijms23137482