Defective gene expression of the membrane complement inhibitor CD46 in patients with progressive immunoglobulin A nephropathy

Coppo, Rosanna; Peruzzi, Licia; Loiacono, Elisa; Bergallo, Massimilano; Krutova, Alexandra; Russo, María Luisa; Cocchi, Enrico; Amore, Alessandro; Lundberg, Sigrid; Maixnerová, Dita; Tesař, Vladimı́r; Perkowska‐Ptasińska, Agnieszka; Durlik, Magdalena; Goumenos, Dimitris; Gerolymos, Miltiadis; Gales̃ić, Kres̆imir; Toric, Luka; Papagianni, Αikaterini; Stangou, Μaria; Membek, Malgorzata Mizerska-Wasia; Gesualdo, Loreto; Montemurno, Eustacchio; Benozzi, Luisa; Cusinato, Stefano; Hryszko, Tomasz; Klinger, Marian; Kamińska, Dorota; Krajewska, Magdalena

doi:10.1093/ndt/gfy064

Cited by 19 publications

(12 citation statements)

References 33 publications

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“…They recently described a cohort of patients with biopsy-proven microangiopathy that was attributed clinically to severe hypertension; however, they found that 67% of patients had a mutation in the genes that encode complement factor C3 or the complement regulators CFH, CFI, or CD46, with concomitant evidence of complement activation in vivo, and poor renal outcome [39]. It would therefore be interesting to investigate whether IgA nephropathy patients with hypertension-associated microangiopathy share a similar genetic predisposition with the patients reported by Timmermans et al [39], particularly given the evidence that disease progression is more rapid in patients who have IgA nephropathy and a deficiency in complement regulation, as well as case reports describing atypical hemolytic uremic syndrome as a comorbidity in IgA nephropathy [18,[40][41][42][43].…”

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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“…Interestingly, very recently, expression pattern of CD46 and CD55 , both complement protein regulators were studied in the peripheral blood in patients with progressive IgAN nephropathy ( 27 ). The study showed that defective peripheral CD46 gene expression did not correlate with eGFR at sampling but with a faster annual loss of GFR.…”

Section: Discussionmentioning

confidence: 99%

Intrarenal Complement System Transcripts in Chronic Antibody-Mediated Rejection and Recurrent IgA Nephropathy in Kidney Transplantation

et al. 2018

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Background: The complement system activation and regulation have been linked to post-transplant pathologies including chronic antibody mediated rejection (cAMR) and the recurrence of IgA nephropathy (ReIgAN) but distinct mechanisms remain to be elucidated.Methods: In this retrospective single center study, the outcome of kidney transplantation was studied in 150 patients with late histological diagnosis to be either cAMR or ReIgAN, 14 stable kidney grafts at 3 months and finally 11 patients with native kidney IgAN nephropathy. To study a role of complement cascade and regulation in cAMR and ReIgAN, the RNA was extracted from available frozen kidney biopsy samples and using RT-qPCR transcripts of 11 target genes along with clinical data were determined and compared with stable grafts at 3 months protocol biopsies or IgAN native kidney nephropathy. Immunohistologically, CD46 (MCP), and C5 proteins were stained in biopsies.Results: Interestingly, there were no differences in kidney graft survival between cAMR and ReIgAN since transplantation. cAMR was associated with significantly higher intragraft transcripts of C3, CD59, and C1-INH as compared to ReIgAN (p < 0.05). When compared to normal stable grafts, cAMR grafts exhibited higher C3, CD55, CD59, CFH, CFI, and C1-INH (p < 0.01). Moreover, ReIgAN was associated with the increase of CD46, CD55, CD59 (p < 0.01), and CFI (p < 0.05) transcripts compared with native kidney IgAN. Rapid progression of cAMR (failure at 2 years after biopsy) was observed in patients with lower intrarenal CD55 expression (AUC 0.77, 78.6% sensitivity, and 72.7 specificity). There was highly significant association of several complement intrarenal transcripts and the degree of CKD regardless the diagnosis; C3, CD55, CFH, CFI, and C1-INH expressions positively correlated with eGFR (for all p < 0.001). Neither the low mRNA transcripts nor the high mRNA transcripts biopsies were associated with distinct trend in MCP or C5 proteins staining.Conclusions: The intrarenal complement system transcripts are upregulated in progressively deteriorated kidney allografts.

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Section: Mechanism Of Diseasementioning

confidence: 99%

“…Interestingly, the expression patterns of CD46 and CD55, both complement protein regulators, were studied in the peripheral blood in patients with progressive IgAN [ 65 ]. The study showed that defective peripheral CD46 gene expression did not correlate with eGFR at sampling, but with a faster annual loss of GFR [ 65 ]. Similarly, Cernoch et al [ 66 ], in a retrospective study of kidney-transplanted patients with IgAN recurrence, showed that there were no associations of eGFR with intrarenal CD46 complement transcripts, however they did describe the association of several intrarenal gene transcripts, including CD55, with CKD stage.…”

Section: Mechanism Of Diseasementioning

confidence: 99%

Recurrence of immunoglobulin A nephropathy after kidney transplantation: a narrative review of the incidence, risk factors, pathophysiology and management of immunosuppressive therapy

Infante

Rossini

Lorenzo

et al. 2020

Clinical Kidney Journal

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Glomerulonephritis (GN) is the underlying cause of end-stage renal failure in 30–50% of kidney transplant recipients. It represents the primary cause of end-stage renal disease for 25% of the dialysis population and 45% of the transplant population. For patients with GN requiring renal replacement therapy, kidney transplantation is associated with superior outcomes compared with dialysis. Recurrent GN was previously considered to be a minor contributor to graft loss, but with the prolongation of graft survival, the effect of recurrent disease on graft outcome assumes increasing importance. Thus the extent of recurrence of original kidney disease after kidney transplantation has been underestimated for several reasons. This review aims to provide updated knowledge on one particular recurrent renal disease after kidney transplantation, immunoglobulin A nephropathy (IgAN). IgAN is one of the most common GNs worldwide. The pathogenesis of IgAN is complex and remains incompletely understood. Evidence to date is most supportive of a several hit hypothesis. Biopsy is mandatory not only to diagnose the disease in the native kidney, but also to identify and characterize graft recurrence of IgAN in the kidney graft. The optimal therapy for IgAN recurrence in the renal graft is unknown. Supportive therapy aiming to reduce proteinuria and control hypertension is the mainstream, with corticosteroids and immunosuppressive treatment tailored for certain subgroups of patients experiencing a rapidly progressive course of the disease with active lesions on renal biopsy and considering safety issues related to infectious complications.

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Defective gene expression of the membrane complement inhibitor CD46 in patients with progressive immunoglobulin A nephropathy

Abstract: Patients with progressive IgAN showed lower expression of mRNA encoding for the complement inhibitory protein CD46, which may implicate a defective regulation of C3 convertase with uncontrolled complement activation.

Cited by 19 publications

References 33 publications

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

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

Intrarenal Complement System Transcripts in Chronic Antibody-Mediated Rejection and Recurrent IgA Nephropathy in Kidney Transplantation

Recurrence of immunoglobulin A nephropathy after kidney transplantation: a narrative review of the incidence, risk factors, pathophysiology and management of immunosuppressive therapy

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