Single-cell RNA sequencing of pediatric renal tissues revealed the potential relationship between immunoglobulin A nephropathy and immunoglobulin A vasculitis with nephritis.
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SUBMITTER: Ye Q
PROVIDER: S-EPMC11002991 | biostudies-literature | 2024 Apr
REPOSITORIES: biostudies-literature
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Single-cell RNA sequencing of pediatric renal tissues revealed the potential relationship between immunoglobulin A nephropathy and immunoglobulin A vasculitis with nephritis.
Ye Qing Q Meng Hanyan H Ye Fang F Fu Haidong H Wang Jingjing J Liu Fei F Shen Huijun H Bao Yu Y Feng Chunyue C Zhang Xiaojing X Huang Guoping G Xie Yi Y Zhu Xiujuan X Zhao Manli M Guo Guoji G Mao Jianhua J
Clinical and translational medicine 20240401 4
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Project description:BackgroundApproximately 30% of adult patients with immunoglobulin A (IgA) nephropathy (IgAN) or IgA vasculitis with nephritis (IgAVN) develop end-stage renal disease during long-term follow-up. In particular, patients with nephritic-nephrotic syndrome have an increased risk of rapid progression. Conventional immunosuppressive therapy with corticosteroids (CSs) may be insufficient for disease control and is associated with a number of side effects. Rituximab (RTX) has been shown to be well tolerated and effective in a range of glomerular diseases, but there is little information on its therapeutic potential in IgAN. The humanized anti-CD20 monoclonal antibody ofatumumab (OFAB) may be an alternative drug for patients intolerant or unresponsive to RTX, but so far there is no report on its use in IgAVN or IgAN.MethodsWe describe clinical outcomes after 17-22 months in four adult patients with biopsy-confirmed IgAVN or IgAN treated with RTX or OFAB as well as CS soon after diagnosis. All presented with nephritic-nephrotic syndrome and one had crescentic IgAN. Rebiopsy was performed in two cases.ResultsRTX and OFAB were well tolerated. Albuminuria was <250 mg/day in three patients at last evaluation and two regained normal renal function. In all cases, renal function improved after therapy. In one patient with severe IgA vasculitis, rebiopsy showed disappearance of subendothelial but not mesangial immune complexes. In the case with crescentic IgAN, rebiopsy after 9 months showed no active necrotic lesions.ConclusionsB cell-depleting therapy may be an alternative treatment for patients with IgAN or IgAVN and nephritic-nephrotic syndrome. A possible CS-sparing effect should be further evaluated in randomized controlled clinical trials.
| S-EPMC5469569 | biostudies-literature
Project description:BackgroundThe objective of this study is to investigate the clinical and pathological differences between patients with IgA nephropathy (IgAN) and IgA vasculitis associated nephritis (IgAVN).MethodsA total of 253 patients with IgAN and 71 patients with IgAVN were retrospectively included in the study, and clinical and laboratory data were collected and analysed.ResultsCompared with IgAVN group, months from onset to kidney biopsy were significantly prolonged in IgAN patients because of the lack of obvious symptoms such as rash, abdominal symptoms, and joint pain (13.5 ± 26.6 vs. 10.2 ± 31.6 months, P = 0.007), and the levels of serum creatinine (92.3 ± 94.7 vs. 68.9 ± 69.2 µmol/L, P = 0.015) was higher and eGFR (99.1 ± 35.2 vs. 123.4 ± 41.8 mL/min/1.73m2, P < 0.001) was lower in IgAN group. The pathological results revealed that patients with IgAN have a greater degree of chronic kidney injury compared to patients with IgAVN. In addition, the levels of plasma D-Dimers (1415.92 ± 1774.69 vs. 496.78 ± 711.91 ng/mL, P < 0.001) and fibrinogen degradation products (FDP) (3.92 ± 4.73 vs. 1.63 ± 2.46 µg/mL, P = 0.001) were significantly higher in IgAVN patients than in IgAN patients. The deposition of fibrinogen in the renal tissues was more severe and the cumulative partial remission rate was higher in patients with IgAVN as compared to those with IgAN (P = 0.001).ConclusionsIn comparison, IgAN patients had poorer renal function, whereas IgAVN patients had more severe coagulation abnormalities. These findings provide a basis for the differentiation of the two diseases at an early stage.
| S-EPMC10811929 | biostudies-literature
Project description:BackgroundGlomerular disease, including immunoglobulin A nephropathy (IgAN) and Henoch-Schönlein purpura nephritis, is one of the most common kidney diseases in children. The diagnosis of these diseases depends on pathological biopsy, although this procedure is seriously limited by its invasive and high-risk nature.ObjectiveTo investigate the potential of contrast-enhanced ultrasonography (CEUS) for evaluating the histopathological severity of IgAN and Henoch-Schönlein purpura nephritis (HSPN).Materials and methodsWe investigated a total of 13 children with IgAN and 12 children with HSPN confirmed by renal histopathology. We reevaluated the pathological lesions of the children according to the Oxford classification and the Lee grading system and then all the children underwent CEUS. Using SonoLiver software, we constructed time-intensity curves of CEUS for regions of interest in the renal cortex. We analyzed CEUS quantitative parameters for IgAN and HSPN and used Spearman correlation analysis to examine the correlation between CEUS parameters and clinicopathological indexes in the study cohort.ResultsThe CEUS parameters rise time (RT) and time to peak (TTP) were significantly higher in children with Lee grade IV than in those with Lee grades II or III. Spearman correlation analysis revealed a positive correlation between rise time and time to peak with Lee grade in the overall cohort of children, and a positive correlation between rise time and time to peak and severity of crescents in the Oxford classification scoring system.ConclusionContrast-enhanced US may be used as a noninvasive imaging technique to evaluate the severity of renal pathology and formation of crescents in children with IgAN and HSPN.
| S-EPMC9701653 | biostudies-literature
Project description:IgA nephropathy (IgAN) and IgA vasculitis-associated nephritis (IgAVN) are among the most frequent childhood glomerular diseases and are characterized by significant variability in clinical manifestations, pathological presentation and long-term outcomes. IgAVN, alternatively called purpura nephritis, is pathologically indistinguishable from kidney-limited IgAN. In Chinese children, the clinical presentations and pathological manifestations of IgAN and IgAVN are variable. The severity of proteinuria and abnormalities in kidney function and blood pressure of children in China are comparable to those of children in Europe, the USA, and Japan. Compared to Caucasian children and Japanese children, crescents were more common in Chinese children with IgAN or IgAVN. Approximately 10-20% of childhood IgAN or IgAVN progresses to impaired kidney function in China. Since 2007, a series of guidelines on the diagnosis and treatment of pediatric kidney diseases has been published following the principles of evidence-based medicine. However, a large difference exists between the Chinese evidence-based guidelines and the guidelines developed by Kidney Disease: Improving Global Outcomes (KDIGO) in 2021. Chinese children with IgAN or IgAVN were more likely to be treated with steroids or immunosuppressive agents. Further studies exploring the optimal treatment regimen for childhood IgAN or IgAVN are needed in the future.
| S-EPMC10154255 | biostudies-literature
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.
| S-EPMC10182656 | biostudies-literature
Project description:A nomogram for assessing the risk of IgA vasculitis nephritis (originally termed Henoch-Schönlein purpura nephritis, HSPN) in IgA vasculitis (originally termed Henoch-Schönlein purpura, HSP) pediatric patients can effectively improve early diagnosis and prognosis of IgA vasculitis nephritis. However, currently, no nomogram is available. 246 IgA vasculitis and 142 IgA vasculitis nephritis Asian pediatric patients confirmed by renal biopsy were enrolled. Univariate and multivariate logistic regressions were performed to identify the independent risk factors and construct a series of predictive models. The receiver operating characteristic curve, calibration plot, decision curve analysis, net reclassification index and integrated discrimination index were used to screen the best model. Stratification analysis was applied to optimize model's clinical utility. An external validation set was introduced to verify the predictive efficiency. The final predictive model was converted to nomogram for visual use. We identified age, duration of rash (Dor), D-dimer and IgG as independent risk factors and constructed four models as follows: AIDD (Age + IgG + Dor + D-dimer), AIDi (Age + IgG + D-dimer), AIDo (Age + IgG + Dor) and ADD (Age + Dor + D-dimer), which achieved the receiver operator characteristic curve (AUROC) of 0.931, 0.920, 0.856 and 0.907, respectively. Finally, AIDi model with an AUROC of 0.956 and 0.897 in internal and external validating sets was proposed as a novel predictive model. In stratification analysis by gender and histological grade, the AUROC of AIDi was 0.949 in female, 0.926 in male, 0.933 in mild histological grades and 0.939 in severe histological grades, respectively. AIDi nomogram is an effective and visual tool for assessing the risk of nephritis in IgA vasculitis Asian pediatric patients, regardless of IgA vasculitis nephritis histological grades and gender.
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Project description: Not available
| S-EPMC8977377 | biostudies-literature
Project description:IntroductionThe activation of the complement system plays an important role in the pathogenesis of IgA nephropathy (IgAN). Our primary aim was to evaluate a range of complement-related proteins, including pentraxin-3 (PTX-3), in blood and urine at diagnosis and their association with disease activity in the kidney biopsy, eGFR, albuminuria, and outcome. Our secondary aim was to compare the same biomarkers between patients with IgAN and IgA vasculitis with renal involvement (IgAVN).MethodsIn a longitudinal Swedish cohort of 96 patients with IgAN (n = 65) or IgAVN (n = 31), with a median follow-up time of 10.8 years, we analysed mainly lectin-pathway-related proteins and PTX-3 in plasma and urine (u) samples stored at the time of kidney biopsy. Outcome was defined by the GFR slope or by the combined outcome of 50% loss of eGFR or end-stage kidney disease (ESKD).ResultsPatients with detectable vs undetectable u-PTX-3 and u-mannose-binding lectin (MBL) more frequently had mesangial hypercellularity, endocapillary proliferation, and crescents in their kidney biopsy. u-C4c levels were higher in patients with advanced tubulointerstitial fibrosis, and u-C4c was also an independent predictor of a more severe eGFR slope. There were no differences in the levels of biomarkers between patients with IgAN and IgAVN.Conclusionu-PTX-3 and u-MBL might be biomarkers of an active proliferative stage of the disease, while higher u-C4c levels indicate more chronic lesions in both IgAN and IgAVN. These results must, however, be confirmed in larger and multiethnic cohorts.
| S-EPMC11852328 | biostudies-literature
Project description:BackgroundSimilarities in clinicopathological presentations in immunoglobulin A (IgA) nephropathy and IgA vasculitis with nephritis (IgAVN) raise the question of the utility of the Oxford classification in the latter. The aim of this study was to evaluate the Oxford classification in IgAVN.MethodsWe conducted a retrospective cohort study and meta-analysis following systematic searching of the MEDLINE and Excerpta Medica Database (EMBASE) databases between January 2009 and September 2019. We modeled the association of 30 and 50% decline in estimated glomerular filtration rate or end-stage renal disease with pathologic lesions of the Oxford classification including mesangial hypercellularity (M), endocapillary hypercellularity (E), segmental glomerulosclerosis (S), interstitial fibrosis/tubular atrophy (T) and crescents (C). Results were pooled using random-effects meta-analysis.ResultsThe cohort study included 132 patients, and only T lesion was an independently risk factor in IgAVN. The meta-analysis yielded six retrospective studies with 721 patients and 139 endpoints. In multivariate model, T lesion was significantly associated with renal outcome (hazard ratio = 2.45, P = 0.007). M and C lesions could not predict renal outcome without evidence of heterogeneity. E and S lesions could not predict renal outcome with evidence of heterogeneity (I 2 = 66.6%; P = 0.01, and I 2 = 65.8%; P = 0.03, respectively). Subgroup analysis showed that the possible reasons to the heterogeneity were from usage of immunosuppressant, sample size and follow-up time.ConclusionsThe study suggests that the Oxford classification could not be fully validated in IgAVN. Higher portion of immunosuppressant especially before renal biopsy might be the main confounder for the predictive value of Oxford classification in IgAVN.
| S-EPMC7886544 | biostudies-literature
Project description:IgA nephropathy and IgA vasculitis with nephritis, albeit rare, represent two relatively frequent glomerular conditions in childhood. Compared to adults, pediatric IgA nephropathy has a more acute presentation, most frequently with synpharyngitic macrohematuria and histologically with more intense inflammation and less intense chronic damage. Management of these conditions is controversial and supported by little high-quality evidence. The paucity of evidence is due to the disease heterogeneity, its inter-ethnic variability, and the difficulty of extrapolating data from adult studies due to the peculiarities of the condition in children. IgA vasculitis with nephritis is a kidney manifestation of a systemic disorder, typical of the pediatric age, in which both the diagnosis of kidney involvement and its management are poorly defined, and an interdisciplinary approach is crucial. Both conditions can have a profound and long-lasting impact on kidney function and the global health of affected children. The International Pediatric Nephrology Association has therefore convened a diverse international group of experts from different disciplines to provide guidance on the recommended management of these conditions in children and to establish common definitions and define priorities for future high-quality, evidence-based collaborative studies for the benefit of children.
| S-EPMC11666671 | biostudies-literature