C4d deposits in IgA nephropathy: where does complement activation come from?

Coppo, Rosanna

doi:10.1007/s00467-016-3575-2

Cited by 19 publications

(14 citation statements)

References 30 publications

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“…In the pathogenesis of IgA nephropathy, complement activation is an important trigger of inflammation and progression, acting predominantly via the lectin and alternative pathways [7,8]. The presence of the complement cleavage product C4d has been shown to predict the progression of [19,[44][45][46][47]; however, these results did not take into account vascular lesions. In IgA nephropathy, C4d deposition is generally considered a consequence of lectin pathway activation [47].…”

Section: Discussionmentioning

confidence: 99%

Complement-mediated microangiopathy in IgA nephropathy and IgA vasculitis with nephritis

et al. 2019

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Complement factor C4d was recently observed in renal biopsies from patients who had IgA nephropathy and a poor prognosis. We previously reported that C4d is a common denominator in microangiopathies. In this retrospective cohort study, we investigated whether C4d is a marker of microangiopathy in both IgA nephropathy and IgA vasculitis with nephritis, and whether patients with C4d and microangiopathy have poor renal outcome. We examined 128 renal biopsies from adult and pediatric patients, including normotensive and hypertensive patients, who presented with IgA nephropathy or IgA vasculitis with nephritis. Biopsies were re-evaluated in accordance with the Oxford classification, scored for additional lesions, and stained for complement proteins using immunohistochemistry, including C4d and C5b-9. Clinical data were collected with a mean (±SD) follow-up period of 51 ± 39 months. Changes in estimated glomerular filtration rate over time were compared using linear mixed-effects models. Renal survival was analyzed using multivariable Cox regression. Microangiopathic lesions were present in 20% of all biopsies (23% and 9% of patients with IgA nephropathy and IgA vasculitis with nephritis, respectively). Microangiopathy was associated with C4d and C5b-9 deposits, a higher number of chronic lesions, and hypertension (all p < 0.05). Patients with C4d and microangiopathic lesions had significantly poorer renal survival than patients without these findings, corrected for hypertension (p < 0.01). In conclusion, patients with IgA nephropathy or IgA vasculitis with nephritis with a combination of C4d positivity and microangiopathy comprise a clinical subgroup with an increased number of chronic lesions, lower estimated glomerular filtration rate, and poorer renal survival, even when corrected for hypertension. These data suggest that complement activation is involved in the development of microangiopathy in patients with IgA nephropathy and IgA vasculitis with nephritis, and that complement-mediated microangiopathy contributes to disease progression.

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Section: Discussionmentioning

confidence: 99%

Complement-mediated microangiopathy in IgA nephropathy and IgA vasculitis with nephritis

et al. 2019

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“…Indeed, there is a strong association between C4d deposits and progression of IgAN in both adults and children. 14,15 It would be of interest to investigate the correlation between persistence of microscopic hematuria and C4d deposits in IgAN because the two processes might be interdependent.…”

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confidence: 99%

Persistent Microscopic Hematuria as a Risk Factor for Progression of IgA Nephropathy: New Floodlight on a Nearly Forgotten Biomarker

Coppo

Fervenza

2017

JASN

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recipient age, inferior outcomes were observed when female kidneys compared with male kidneys were transplanted into male recipients, similar to the findings of Lepeytre et al. 2 The CTS study also reported worse allograft outcomes in female recipients of female compared with male kidneys. These results are broadly consistent with the Lepeytre study.The basis for any real differences in outcomes attributable to donor or recipient sex are complex, and as these and other authors acknowledge, may be due to immunologic, hormonal, anatomic (e.g., size mismatch, nephron mass), and pharmacologic factors. 6 Additional factors not addressed in this database such as recipient pregnancy or urinary tract infection, may also be relevant and may partially explain the increased rate of graft failure in women aged 15-24 years, regardless of donor sex.The two studies published in this issue of JASN have shed new light on issues of significance to the transplantation field, and invite revisiting approaches to kidney transplantation including policy considerations. Regarding the dilemma brought to our attention by Bromberger et al. 1 that women are distinctly disadvantaged from receiving their husband's kidney, our vote is to create a national pool of spousal recipientdonor pairs, including even compatible pairs, and enable a chain of transplants by leveraging the extraordinary diverse HLA polymorphisms and overcoming pregnancy induced adverse presensitization. The investigation of Lepeytre et al. 2 raises the intriguing question of whether female kidneys should be preferentially allocated to young female recipients aged 0-14 years. Also, better strategies for adherence in the 15-24 year age group, and personalizing immunosuppression, especially in the .45 year age group, may be beneficial. Obviously, our suggestions for creating a national spousal transplant pair pool and preferential allocation of female kidneys to females aged 0-14 years need to be statistically modeled for outcomes to mitigate unintended consequences.

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“…IgA nephropathy, is a kidney disease with high incidence [1]. Although complement system activation leading to the production of terminal C5b-9 complex has been found in the renal mesangium of MsPGN patients [4,37,38], the relationship between C5b-9 and GMC lesion as well as the role and mechanism of C5b-9-mediated GMC injury remains unclear. Rat Thy-1N is a well-accepted animal model for studying MsPGN [7].…”

Section: Discussionmentioning

confidence: 99%

Sublytic C5b-9 Induces Glomerular Mesangial Cell Apoptosis Through miR-3546/SOX4/Survivin Axis in Rat Thy-1 Nephritis

Yao

Liu

et al. 2018

Cell Physiol Biochem

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Background/Aims: The activation of complement system and the formation of C5b-9 complex have been confirmed in the glomeruli of patients with mesangioproliferative glomerulonephritis (MsPGN). However, the role and mechanism of C5b-9-induced injury in glomerular mesangial cell (GMC) are poorly understood. Rat Thy-1N is an animal model for studying MsPGN. It has been revealed that the attack of C5b-9 to the GMC in rat Thy-1N is sublytic, and sublytic C5b-9 can cause GMC apoptosis, but the underlying mechanism is not fully elucidated. To explore the role and regulatory mechanism of C5b-9 in MsPGN lesion, we used rat Thy-1N model and first detected the change of microRNA (miRNA) profiles both in Thy-1N rat renal tissues (in vivo) and in the cultured GMCs with sublytic C5b-9 stimulation (in vitro). Then we determined the effect of miR-3546, which increased both in vivo and in vitro, on GMC apoptosis upon sublytic C5b-9 as well as the involved mechanism. Methods: Rat Thy-1N model was established and GMCs were treated with sublytic C5b-9. The rat renal cortex and the stimulated GMCs were obtained for miRNA microarray detection. Subsequently, the increased miRNAs were verified by real-time PCR. Meanwhile, to ascertain the ability of some miRNAs to upregulate cleaved caspase 3 and induce GMC apoptosis, the corresponding miRNA mimics were transfected into GMCs, followed by western blotting (WB) and flow cytometry mesurement. Thereafter, the miR-3546-targeted gene (SOX4) was predicted using bioinformatics approaches, and SOX4 expression in Thy-1N tissues and in the GMCs upon sublytic C5b-9 stimulation or miR-3546 mimic/inhibitor transfection were detected using real-time PCR and WB. To prove that miR-3546 can affect SOX4 gene transcription and SOX4 can regulate survivin expression, dual luciferase reporter assay, real-time PCR, WB and chromatin immunoprecipitation (ChIP) assays were performed. Furthermore, the role of miR-3546/SOX4/survivin axis in the GMC apoptosis induced by sublytic C5b-9 was examined using WB and flow cytometry. Results: Compared with normal renal tissues and untreated GMCs, there were 43 and 62 upregulated miRNAs (> 2-fold) in Thy-1N tissues and sublytic C5b-9-stimulated GMCs respectively. A total of 17 miRNAs were increased both in vivo and in vitro, 11 of which were validated by real-time PCR. Among them, miR-3546 could markedly promote GMC apoptosis and inhibit SOX4 or survivin expression in response to sublytic C5b-9, and either SOX4 or survivin overexpression markedly rescued the GMC apoptosis mediated by miR-3546 mimic. Additionally, SOX4 overexpression could reverse the survivin suppression by miR-3546 mimic, and SOX4 could bind to survivin promoter (-1,278 to -853 nt) and activate survivin gene transcription. Conclusion: MiR-3546/ SOX4/survivin axis has a promoting role in the GMC apoptosis triggered by sublytic C5b-9, and our findings may provide a new insight into the pathogenesis of rat Thy-1N and human MsPGN.

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C4d deposits in IgA nephropathy: where does complement activation come from?

Cited by 19 publications

References 30 publications

Complement-mediated microangiopathy in IgA nephropathy and IgA vasculitis with nephritis

Complement-mediated microangiopathy in IgA nephropathy and IgA vasculitis with nephritis

Persistent Microscopic Hematuria as a Risk Factor for Progression of IgA Nephropathy: New Floodlight on a Nearly Forgotten Biomarker

Sublytic C5b-9 Induces Glomerular Mesangial Cell Apoptosis Through miR-3546/SOX4/Survivin Axis in Rat Thy-1 Nephritis

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