Glomerular angiotensinogen protein is enhanced in pediatric IgA nephropathy.
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ABSTRACT:
SUBMITTER: Takamatsu M
PROVIDER: S-EPMC2441593 | biostudies-other | 2008 Aug
REPOSITORIES: biostudies-other
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Project description:Anti-glomerular basement membrane (GBM) nephritis is characterized by circulating anti-GBM antibodies and crescentic glomerulonephritis (GN) with deposition of IgG along the GBM. In a limited number of cases, glomerular immune complexes have been identified in anti-GBM nephritis. A 38-year-old female presented azotemia, hematuria, and proteinuria without any pulmonary symptoms. A renal biopsy showed crescentic GN with linear IgG deposition along the GBM and mesangial IgA deposition. The patient was diagnosed as concurrent anti-GBM nephritis and IgA nephropathy. Therapies with pulse methylprednisolone and cyclophosphamide administration were effective. Concurrent cases of both anti-GBM nephritis and IgA nephropathy are rare among cases of anti-GBM diseases with deposition of immune complexes. This rare case of concurrent anti-GBM nephritis and IgA nephropathy with literature review is noteworthy.
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Project description:BackgroundIgA nephropathy (IgAN) and IgA vasculitis with nephritis (IgAVN) are related glomerular diseases characterized by marked similarities in immunological and histological findings. We herein performed a comparative proteomic analysis of glomerular proteins in IgAN and IgAVN.MethodsWe used renal biopsy specimens from 6 IgAN patients without nephrotic syndrome (NS) (IgAN-I subgroup), 6 IgAN patients with NS (IgAN-II subgroup), 6 IgAVN patients with 0-8.0% of glomeruli with crescent formation (IgAVN-I subgroup), 6 IgAVN patients with 21.2-44.8% of glomeruli with crescent formation (IgAVN-II subgroup), 9 IgAVN patients without NS (IgAVN-III subgroup), 3 IgAVN patients with NS (IgAN-IV subgroup), and 5 control cases. Proteins were extracted from laser microdissected glomeruli and analyzed using mass spectrometry. The relative abundance of proteins was compared between groups. An immunohistochemical validation study was also performed.ResultsMore than 850 proteins with high confidence were identified. A principal component analysis revealed a clear separation between IgAN and IgAVN patients and control cases. In further analyses, 546 proteins that were matched with ≥ 2 peptides were selected. The levels of immunoglobulins (IgA, IgG, and IgM), complements (C3, C4A, C5, and C9), complement factor H-related proteins (CFHR) 1 and 5, vitronectin, fibrinogen chains, and transforming growth factor-β inducible gene-h3 were higher (> 2.6 fold) in the IgAN and IgAVN subgroups than in the control group, whereas hornerin levels were lower (< 0.3 fold). Furthermore, C9 and CFHR1 levels were significantly higher in the IgAN group than in the IgAVN group. The abundance of some podocyte-associated proteins and glomerular basement membrane (GBM) proteins was significantly less in the IgAN-II subgroup than in the IgAN-I subgroup as well as in the IgAVN-IV subgroup than in the IgAVN-III subgroup. Among the IgAN and IgAVN subgroups, talin 1 was not detected in the IgAN-II subgroup. This result was supported by immunohistochemical findings.ConclusionsThe present results suggest shared molecular mechanisms for glomerular injury in IgAN and IgAVN, except for enhanced glomerular complement activation in IgAN. Differences in the protein abundance of podocyte-associated and GBM proteins between IgAN and IgAVN patients with and without NS may be associated with the severity of proteinuria.
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Project description:ObjectiveWe aimed to explore the relationship between the presence and intensity of glomerular IgG deposition and the occurrence of kidney progression events in IgA nephropathy (IgAN).MethodsThis retrospective study encompassed a total of 1207 patients with IgAN spanning the period from 2010 to 2022, and complete follow-up data were accessible for 736 patients. The IgG intensity was categorized as follows: low-level, defined as IgG (±) and IgG (+), and high-level, defined as IgG (++) and IgG (+++).ResultsWe found that the IgG-positive deposited group (N = 113, 9.36%) had significantly higher levels of ESR, TC, LDL, uric acid, proteinuria, and blood glucose, and lower serum albumin level compared to the IgG-negative deposited group (N = 1094, 90.64%). In terms of pathology, the IgG-positive deposited group had a significantly higher percentage of T2 score compared to the IgG-negative deposited group (p = 0.002). At the end of the follow-up period, the IgG-positive deposited group had a higher eGFR decline (-5.7 ± 4.37 ml/year) compared to the IgG-negative deposited group (-4 ± 2.52 ml/year), however, there was not a statistically significant difference between the two groups (p = 0.096). We observed that the high-IgG group had significantly higher level of TG compared to the low-IgG group (p = 0.042). Further analysis revealed that the group of patients with high level of IgG deposition in the kidney experienced a higher incidence of composite kidney outcomes compared to the group with low level of IgG deposition (p = 0.009). Logistic regression analyses showed that high level IgG deposition was an independent risk factor for kidney progression of IgAN (HR 13.419; 95% CI 2.690-66.943, P = 0.029). Further analyses for a solid conclusion using Cox regression that we found high level IgG deposition (HR 115.277; 95% CI 2.299-5.779E3, P = 0.017), eGFR (HR 0.932; 95% CI 0.870-0.999, P = 0.047), and urine protein excretion (HR 1.001; 95% CI 1.000-1.002, P = 0.015) were independent risk factor for kidney progression of IgAN.ConclusionsThe intensity of IgG deposition has been found to be associated with the progression of IgAN. Future prospective studies should provide more robust evidence on the impact of IgG deposition on kidney outcomes in patients with IgAN.
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Project description:We applied scRNAseq analysis to investigate the mouse kidney glomerular injury in IgA nephropathy
2022-02-01 | GSE166793 | GEO
Project description:We demonstrated previously that the blood pressure of patients with IgA nephropathy becomes salt sensitive as renal damage progresses. We also showed that increased urinary angiotensinogen levels in such patients closely correlate with augmented renal tissue angiotensinogen gene expression and angiotensin II levels. Here, we investigated the relationship between urinary angiotensinogen and salt sensitivity of blood pressure in patients with IgA nephropathy. Forty-one patients with IgA nephropathy consumed an ordinary salt diet (12 g/d of NaCl) for 1 week and a low-salt diet (5 g/d of NaCl) for 1 week in random order. The salt-sensitivity index was calculated as the reciprocal of the slope of the pressure-natriuresis curve drawn by linking 2 data points obtained during consumption of each diet. The urinary angiotensinogen:creatinine ratio was significantly higher in patients who consumed the ordinary salt diet compared with the low-salt diet (17.5 ?g/g [range: 7.3 to 35.6 ?g/g] versus 7.9 ?g/g [range: 3.1 to 14.2 ?g/g] of creatinine, respectively; P<0.001). The sodium sensitivity index in our patients positively correlated with the glomerulosclerosis score (r=0.43; P=0.008) and changes in logarithmic urinary angiotensinogen:creatinine ratio (r=0.37; P=0.017) but not with changes in urinary protein excretion (r=0.18; P=0.49). In contrast, changes in sodium intake did not alter the urinary angiotensinogen:creatinine ratio in patients with Ménière disease and normal renal function (n=9). These data suggest that the inappropriate augmentation of intrarenal angiotensinogen induced by salt and associated renal damage contribute to the development of salt-sensitive hypertension in patients with IgA nephropathy.
| S-EPMC3161117 | biostudies-literature
Project description:Immunoglobulin A nephropathy (IgAN) is a major cause of secondary hypertension (HT) of renal origin - a significant prognostic factor of IgAN. In children, similar to HT, prehypertension (pre-HT) is becoming a significant health issue. However, the role of secondary HT and pre-HT (HT/pre-HT) in the progression of pediatric IgAN remains unclear. We investigated the effects of HT/pre-HT on prognosis and its determinants as well as their correlation with clinicopathological parameters to identify more effective therapeutic targets.This single-center retrospective study compared clinicopathological features and treatment outcomes between patients with and without HT/pre-HT in 108 children with IgAN. Independent risk factors for HT/pre-HT were evaluated; segmental glomerulosclerosis was a significant variable, whose relationship with clinicopathological parameters was analyzed.Clinical outcomes of patients with and without HT/pre-HT differed considerably (P = .006) on ≥6 months follow-up. Patients with HT/pre-HT reached complete remission less frequently than those without HT/pre-HT (P = .014). Age, serum creatinine, prothrombin time, and segmental glomerulosclerosis or adhesion were independent risk factors for HT/pre-HT in pediatric IgAN (P = .012, P = .017, P = .002, and P = .016, respectively). Segmental glomerulosclerosis or adhesion was most closely associated with glomerular crescents (r = 0.456, P < .01), followed by Lees grades (r = 0.454, P < .01), renal arteriolar wall thickening (r = 0.337, P < .01), and endocapillary hypercellularity (r = 0.306, P = .001). The intensity of IgA deposits, an important marker of pathogenetic activity in IgAN, was significantly associated with the intensity and location of fibrinogen deposits (intensity: r = 0.291, P = .002; location: r = 0.275, P = .004).HT/pre-HT in pediatric IgAN patients is an important modifiable factor. A relationship is observed between HT/pre-HT and its determinants, especially segmental glomerulosclerosis. Potential therapeutic approaches for IgAN with HT/pre-HT might be directed toward the management of coagulation status, active lesions, and hemodynamics for slowing disease progression.
| S-EPMC7535649 | biostudies-literature
Project description:BackgroundIn a recent study we demonstrated that low birth weight (LBW) was associated with increased risk of progressive IgA nephropathy (IgAN). In the present study we investigate whether this could be explained by differences in glomerular morphological parameters.MethodsThe Medical Birth Registry of Norway has registered all births since 1967 and the Norwegian Kidney Biopsy Registry has registered all kidney biopsies since 1988. Patients diagnosed with IgAN, registered birth weight and estimated glomerular filtration rate above 60 ml/min/1.73m2 at time of diagnosis were eligible for inclusion. Patients were included in a case-control manner based on whether or not they had LBW or were small for gestational age (SGA). Glomerular area, volume and density were measured using high resolution digital images and differences were compared between groups.ResultsWe included 51 IgAN patients with a mean age of 23.6 years, 47.1% male. Compared to IgAN patients without LBW or SGA, IgAN patients with LBW and/or SGA had larger glomerular area (16,235?±?3744 vs 14,036?±?3502 ?m2, p-value 0.04). This was significant for total cohort and male but not female. On separate analysis by gender, glomerular area was significantly larger only in males (17,636?±?3285 vs 13,346?±?2835 ?m2, p-value 0.004). Glomerular density was not different between groups. In adjusted linear regression analysis, glomerular area was negatively associated with birth weight.ConclusionAmong young adult IgAN patients, low birth weight is associated with having larger glomerular area, especially in males. Larger glomeruli may be a sign of congenital nephron deficit that may explain the increased risk of progressive IgAN.
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Project description:BackgroundGlomerulonephritis (GN), including post-transplant IgAN (post-Tx IgAN) is an important contributor to decreased long-term allograft survival. The immunopathological detection of the complement degradation product C4d in glomeruli (C4dG) has been recently described as a risk factor in native kidney IgAN, however little is known about C4dG deposition in post-Tx IgAN. We hypothesized that glomerular C4d may indicate a more aggressive disease course and worse allograft survival in patients with post-Tx IgAN.MethodsIn this retrospective study we assessed the presence and clinical relevance of C4dG in patients with post-transplant IgAN. We analyzed 885 renal allograft recipients, including 84 patients with post-transplant GN. All patients were transplanted between January 1999 and April 2006 and underwent at least one biopsy for differnt causes. The primary endpoint was death-censored graft survival, with a median follow-up of 9.6 (IQR 3.8-13.2) years.ResultsThe prevalence of post-Tx GN was 9.5%. Twenty-seven patients with post-Tx IgAN were included. C4dG positive patients (N = 18, 66.7%) had significantly worse allograft survival compared to C4dG negative post-Tx IgAN patients and patients without post-Tx IgAN [C4dG positive: 27.8% vs. 55.6% and 66.0%; log-rank: p = 0.01]. C4dG remained a significant risk factor (HR 2.22, 95% CI 1.27-3.87) for allograft loss even after adjustment for T cell mediated rejection (TCMR) and antibody mediated rejection.ConclusionGlomerular C4d deposition is an independent risk factor for worse graft-survival in patients with post-Tx IgAN, even after adjusting for other risk factors such as antibody mediated rejection. Assessment of glomerular C4d deposition may provide a valuable prognostic risk assessment tool to identify high risk patients in post-Tx IgAN.
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Project description:Mesangial proliferation is a diagnostic feature and a prognostic predictor of immunoglobulin A nephropathy (IgAN). We aimed to investigate the gene expression profiles of IgAN glomerulus according to the presence of mesangial proliferation. We performed spatial-specific transcriptomic profiling on kidney biopsy tissues using the GeoMx Digital Spatial Profiler. Twelve cases with three glomeruli for each case were profiled using direct pathologic classification (4 M1-IgAN, 4 M0-IgAN, and 4 donor controls). The results of enriched glom-specific genes demonstrated that M1-IgAN could be distinguished from controls (77 upregulated and 55 downregulated DEGs), while some DEGs were identified between M1-IgAN and M0-IgAN cases (24 upregulated and 8 downregulated DEGs) or between M0 and controls (1 upregulated and 16 downregulated DEGs). TCF21, an early podocyte damage marker, was the only differentially expressed gene (DEG) consistently upregulated in both M1-IgAN and M0-IgAN patients, whereas ATF3, EGR1, DUSP1, FOS, JUNB, KLF2, NR4A1, RHOB, and ZFP36 were consistently downregulated in IgAN cases. Glomeruli from M1-IgAN cases were significantly enriched for cell surface/adhesion molecules and gene expressions associated with vascular development or the extracellular matrix. Spatial transcriptomic analysis may contribute to dissecting structure-specific pathophysiology and molecular changes in IgAN.
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Project description:Immunoglobulin A nephropathy (IgAN) involves repeated events of gross haematuria with concurrent upper airway infections. The mucosal immune system, especially the tonsil, is considered the initial site of inflammation, although the role of the tonsillar microbiota has not been established in IgAN. In this study, we compared the tonsillar microbiota of patients with IgAN (n = 21) and other glomerular diseases (n = 36) as well as, healthy controls (n = 23) from three medical centres in Korea. The microbiota was analysed from tonsil swabs using the Illumina MiSeq system based on 16S rRNA gene. Tonsillar bacterial diversity was higher in IgAN than in other glomerular diseases, although it did not differ from that of healthy controls. Principal coordinates analysis revealed differences between the tonsillar microbiota of IgAN and both healthy and disease controls. The proportions of Rahnella, Ruminococcus_g2, and Clostridium_g21 were significantly higher in patients with IgAN than in healthy controls (corrected p < 0.05). The relative abundances of several taxa were correlated with the estimated glomerular filtration rate, blood urea nitrogen, haemoglobin, and serum albumin levels. Based on our findings, tonsillar microbiota may be associated with clinical features and possible immunologic pathogenesis of IgAN.
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