scholarly journals C3 Glomerulopathy and Related Disorders in Children

2021 ◽  
pp. CJN.00320121
Author(s):  
Edwin Wong ◽  
Kevin Marchbank ◽  
Hannah Lomax-Browne ◽  
Isabel Pappworth ◽  
Harriet Denton ◽  
...  
Keyword(s):  
Risk Factor ◽  
Immune Complex ◽  
Kidney Failure ◽  
Alternative Pathway ◽  
Multivariable Analysis ◽  
Complement C3 ◽  
C3 Glomerulopathy ◽  
Prognostic Groups ◽  
Initial Biopsy

Background and objectives: Membranoproliferative Glomerulonephritis (MPGN) and C3 Glomerulopathy are rare and overlapping disorders associated with dysregulation of the alternative complement pathway. Specific aetiological data for paediatric MPGN/C3 glomerulopathy are lacking, and outcome data are based upon retrospective studies without aetiological data. Design, setting, participants, and measurements: Eighty prevalent pediatric patients with MPGN/C3 glomerulopathy underwent detailed phenotyping and long-term follow-up within the National Registry of Rare Kidney Diseases (RaDaR). Risk factors for kidney survival were determined using COX proportional hazards model. Kidney and transplant graft survival was determined using Kaplan-Meier method. Results: Central histology review determined 39 C3 glomerulopathy, 31 immune-complex MPGN and 10 immune-complex glomerulonephritis (GN) cases. Patients were aged 2-15 (median 9 (IQR 7-11) years. Median complement C3 and C4 levels were 0.31g/L and 0.14g/L respectively; acquired (anti-complement autoantibodies) or genetic alternative pathway abnormalities were detected in 46% and 9% patients respectively, across all groups including immune-complex GN. Median follow-up was 5.18 (IQR 2.13-8.08) years. Eleven patients (14%) progressed to kidney failure with 9 transplants performed in 8 patients, 2 of which failed due to recurrent disease. Presence of >50% crescents on initial biopsy was the sole variable associated with kidney failure in multivariable analysis (Hazard Ratio 6.2, p = 0.045; 95% CI 1.05 to 36.6). Three distinct C3 glomerulopathy prognostic groups were identified according to presenting eGFR and >50% crescents on initial biopsy. Conclusions: Crescentic disease was a key risk factor associated with kidney failure in a national cohort of pediatric MPGN/C3 glomerulopathy and immune-complex GN. Presenting eGFR and crescentic disease help define prognostic groups in pediatric C3 glomerulopathy. Acquired abnormalities of the alternative pathway were commonly identified but not a risk factor for kidney failure.

scholarly journals CFHR5 Genetic Variations and Serum Levels in Patients with Immune-Complex-Mediated Membranoproliferative Glomerulonephritis and C3-Glomerulopathy

2020 ◽  
Author(s):  
Nóra Garam ◽  
Marcell Cserhalmi ◽  
Zoltán Prohászka ◽  
Ágnes Szilágyi ◽  
Nóra Veszeli ◽  
...  
Keyword(s):  
Immune Complex ◽  
Membranoproliferative Glomerulonephritis ◽  
Kidney Diseases ◽  
Alternative Pathway ◽  
Serum Levels ◽  
Genetic Alterations ◽  
Factor H ◽  
Complement Factor ◽  
C3 Glomerulopathy

Abstract Background: Factor H-related-5 (FHR-5) is a member of the complement Factor H protein family. Due to the homology to Factor H, the main complement regulator of the alternative pathway, it may also be implicated in pathomechanism of kidney diseases where Factor H and alternative pathway dysregulation play a role. Here, we report the first observational study on CFHR5 variations along with serum FHR-5 levels in immune-complex-mediated membranoproliferative glomerulonephritis (IC-MPGN) and C3 glomerulopathy (C3G) patients together with the clinical, genetic, complement and follow-up data.Results: 120 patients with a histologically-proven diagnosis of IC-MPGN/C3G were enrolled in the study. FHR-5 serum levels were measured in ELISA, the CFHR5 gene was analyzed by Sanger-sequencing, and selected mutants were studied as recombinant proteins in ELISA and SPR.Eight relevant CFHR5 variations in 14 patients (11.7%) were observed, 5 of them identified as pathogenic for C3G. The FHR-5G278S and FHR-5R356H mutations altered the interaction of FHR-5 with C3b, when compared to the FHR-5WT. Serum FHR-5 levels were lower in patients compared to controls. Low serum FHR-5 concentration at presentation associated with better renal survival during the follow-up period, furthermore, it showed clear association with signs of hypocomplementemia and clinically meaningful clusters.Conclusions: Our observations support the hypothesis that FHR-5 protein and its genetic alterations play a role in the pathogenesis of IC-MPGN/C3G.

scholarly journals FHR-5 Serum Levels and CFHR5 Genetic Variations in Patients With Immune Complex-Mediated Membranoproliferative Glomerulonephritis and C3-Glomerulopathy

2021 ◽  
Vol 12 ◽  
Author(s):  
Nóra Garam ◽  
Marcell Cserhalmi ◽  
Zoltán Prohászka ◽  
Ágnes Szilágyi ◽  
Nóra Veszeli ◽  
...  
Keyword(s):  
Immune Complex ◽  
Membranoproliferative Glomerulonephritis ◽  
Kidney Diseases ◽  
Alternative Pathway ◽  
Serum Levels ◽  
Factor H ◽  
Fine Tuning ◽  
Complement Factor ◽  
C3 Glomerulopathy

BackgroundFactor H-related protein 5 (FHR-5) is a member of the complement Factor H protein family. Due to the homology to Factor H, the main complement regulator of the alternative pathway, it may also be implicated in the pathomechanism of kidney diseases where Factor H and alternative pathway dysregulation play a role. Here, we report the first observational study on CFHR5 variations along with serum FHR-5 levels in immune complex-mediated membranoproliferative glomerulonephritis (IC-MPGN) and C3 glomerulopathy (C3G) patients together with the clinical, genetic, complement, and follow-up data.MethodsA total of 120 patients with a histologically proven diagnosis of IC-MPGN/C3G were enrolled in the study. FHR-5 serum levels were measured in ELISA, the CFHR5 gene was analyzed by Sanger sequencing, and selected variants were studied as recombinant proteins in ELISA and surface plasmon resonance (SPR).ResultsEight exonic CFHR5 variations in 14 patients (12.6%) were observed. Serum FHR-5 levels were lower in patients compared to controls. Low serum FHR-5 concentration at presentation associated with better renal survival during the follow-up period; furthermore, it showed clear association with signs of complement overactivation and clinically meaningful clusters.ConclusionsOur observations raise the possibility that the FHR-5 protein plays a fine-tuning role in the pathogenesis of IC-MPGN/C3G.

scholarly journals CFH and CFHR Copy Number Variations in C3 Glomerulopathy and Immune Complex-Mediated Membranoproliferative Glomerulonephritis

2021 ◽  
Vol 12 ◽  
Author(s):  
Rossella Piras ◽  
Matteo Breno ◽  
Elisabetta Valoti ◽  
Marta Alberti ◽  
Paraskevas Iatropoulos ◽  
...  
Keyword(s):  
Immune Complex ◽  
Single Molecule ◽  
Copy Number ◽  
Membranoproliferative Glomerulonephritis ◽  
Alternative Pathway ◽  
Copy Number Variations ◽  
Factor H ◽  
Complement C3 ◽  
Complement Factor ◽  
C3 Glomerulopathy

C3 Glomerulopathy (C3G) and Immune Complex-Mediated Membranoproliferative glomerulonephritis (IC-MPGN) are rare diseases characterized by glomerular deposition of C3 caused by dysregulation of the alternative pathway (AP) of complement. In approximately 20% of affected patients, dysregulation is driven by pathogenic variants in the two components of the AP C3 convertase, complement C3 (C3) and Factor B (CFB), or in complement Factor H (CFH) and Factor I (CFI), two genes that encode complement regulators. Copy number variations (CNVs) involving the CFH-related genes (CFHRs) that give rise to hybrid FHR proteins also have been described in a few C3G patients but not in IC-MPGN patients. In this study, we used multiplex ligation-dependent probe amplification (MLPA) to study the genomic architecture of the CFH-CFHR region and characterize CNVs in a large cohort of patients with C3G (n = 103) and IC-MPGN (n = 96) compared to healthy controls (n = 100). We identified new/rare CNVs resulting in structural variants (SVs) in 5 C3G and 2 IC-MPGN patients. Using long-read single molecule real-time sequencing (SMRT), we detected the breakpoints of three SVs. The identified SVs included: 1) a deletion of the entire CFH in one patient with IC-MPGN; 2) an increased number of CFHR4 copies in one IC-MPGN and three C3G patients; 3) a deletion from CFHR3-intron 3 to CFHR3-3′UTR (CFHR34–6Δ) that results in a FHR3-FHR1 hybrid protein in a C3G patient; and 4) a CFHR31–5-CFHR410 hybrid gene in a C3G patient. This work highlights the contribution of CFH-CFHR CNVs to the pathogenesis of both C3G and IC-MPGN.

MO265LONGITUDINAL CHANGE IN PROTEINURIA AND KIDNEY OUTCOMES IN C3 GLOMERULOPATHY

2021 ◽  
Vol 36 (Supplement_1) ◽  
Author(s):  
Fernando Caravaca-Fontán ◽  
Elena Goicoechea de Jorge ◽  
Manuel Praga
Keyword(s):  
Kidney Failure ◽  
Cox Model ◽  
Strong Association ◽  
Fold Increase ◽  
Joint Modeling ◽  
Longitudinal Change ◽  
C3 Glomerulopathy ◽  
Dynamic Prediction ◽  
Over Time

Abstract Background and Aims The association between a change in proteinuria over time and its impact in kidney prognosis has not been analyzed in C3 glomerulopathy. This study aims to investigate the association between the longitudinal change in proteinuria and the risk of kidney failure. Method Retrospective, multicenter observational cohort study in 35 nephrology departments belonging to the GLOSEN group. Patients diagnosed with C3 glomerulopathy between 1995 and 2020 were enrolled. A joint modeling of linear mixed-effects models was applied to assess the underlying trajectory of a repeatedly measured proteinuria, and a Cox model to evaluate the association of this trajectory with the risk of kidney failure. Results The study group consisted of 85 patients, 70 C3 glomerulonephritis and 15 dense deposit disease, with a median age of 26 years (range 13–41). During a median follow-up of 42 months, 25 patients reached kidney failure. The longitudinal change in proteinuria showed a strong association with the risk of this outcome, with a doubling of proteinuria levels resulting in a 2.5-fold increase of the risk. A second model showed that a ≥50% proteinuria reduction over time was significantly associated with a lower risk of kidney failure (HR: 0.79; 95%CI:0.56–0.97; p<0.001). This association was also found when the ≥50% proteinuria reduction was observed within the first 6 and 12 months of follow-up. Conclusion The longitudinal change in proteinuria is strongly associated with the risk of kidney failure. The change in proteinuria over time can provide clinicians a dynamic prediction of kidney outcomes.

African American race to predict for earlier failure of active surveillance: Results from the Duke Prostate Center.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 4670-4670
Author(s):  
Mitchell Bassett ◽  
Michael Abern ◽  
Lionel Lloyds Banez ◽  
Michael Ferrandino ◽  
Cary N. Robertson ◽  
...  
Keyword(s):  
African American ◽  
Active Surveillance ◽  
Clinical Stage ◽  
Multivariable Analysis ◽  
Adverse Outcomes ◽  
Patient Choice ◽  
Gleason Grade ◽  
Volume Number ◽  
Initial Biopsy

4670 Background: As concerns mount regarding overtreatment and over-diagnosis of prostate cancer (CaP), active surveillance (AS) is increasingly utilized in low risk patients. While African-American (AA) race is associated with adverse outcomes after prostatectomy, its effect on patients managed with AS is not known. Methods: A retrospective review identified 222 patients managed with AS at the Duke Prostate Center from January 2005 to September 2011. All men had CaP diagnosed on biopsy performed at our center, and elected AS over treatment. Failure was defined as progression to treatment. In men who failed AS, the reasons for failure, follow-up PSA and biopsy characteristics were analyzed. The primary outcome - time from diagnosis to failure of AS for a reason other than patient choice - was analyzed with univariable and multivariable Cox proportional hazards models. Results: In our AS cohort, 73% are Caucasian and 23% AA. Median follow-up is 25.4 months. Age, household income, BMI, PSA, clinical stage, family history, prostate volume, number of cores with cancer, and Gleason grade on initial biopsy did not differ by race. The number of biopsies and PSA tests performed on AS did not differ by race. A higher proportion of AA men tended to fail from biopsy progression (72.7% vs. 63.8%) while a lower proportion failed by choice (9.1% vs. 14.9%) compared to Caucasians (p = 0.114). AA men had a significantly shorter time to failure (HR 1.74, p = 0.045) compared to Caucasians. There was a trend toward increased Gleason grade 8 or higher cancer on follow-up biopsy in AA compared to Caucasian men (10% vs. 2.5%, p = 0.08). AA race remained a predictor (HR 1.76, p = 0.058) of failure on multivariable analysis, as did initial PSA (HR 1.90, p = 0.031) and number of cores with cancer on initial biopsy (HR 1.29, p = 0.013). Conclusions: AA race was associated with higher risk for failure of AS. There was a trend toward AA men failing due to biopsy progression and with higher grade cancer. Additional follow-up is necessary to determine how this affects the long term outcomes of these men.

Longitudinal change in proteinuria and kidney outcomes in C3 glomerulopathy

2021 ◽  
Author(s):  
Fernando Caravaca-Fontán ◽  
Montserrat Díaz-Encarnación ◽  
Virginia Cabello ◽  
Gema Ariceta ◽  
Luis F Quintana ◽  
...  
Keyword(s):  
Kidney Failure ◽  
Cox Model ◽  
Strong Association ◽  
Fold Increase ◽  
Longitudinal Change ◽  
C3 Glomerulopathy ◽  
Dynamic Prediction ◽  
Glomerular Diseases ◽  
Over Time

Abstract Introduction The association between a change in proteinuria over time and its impact on kidney prognosis has not been analysed in complement component 3 (C3) glomerulopathy. This study aims to investigate the association between the longitudinal change in proteinuria and the risk of kidney failure. Methods This was a retrospective, multicentre observational cohort study in 35 nephrology departments belonging to the Spanish Group for the Study of Glomerular Diseases. Patients diagnosed with C3 glomerulopathy between 1995 and 2020 were enrolled. A joint modelling of linear mixed-effects models was applied to assess the underlying trajectory of a repeatedly measured proteinuria, and a Cox model to evaluate the association of this trajectory with the risk of kidney failure. Results The study group consisted of 85 patients, 70 C3 glomerulonephritis and 15 dense deposit disease, with a median age of 26 years (range 13–41). During a median follow-up of 42 months, 25 patients reached kidney failure. The longitudinal change in proteinuria showed a strong association with the risk of this outcome, with a doubling of proteinuria levels resulting in a 2.5-fold increase of the risk. A second model showed that a ≥50% proteinuria reduction over time was significantly associated with a lower risk of kidney failure (hazard ratio 0.79; 95% confidence interval 0.56–0.97; P < 0.001). This association was also found when the ≥50% proteinuria reduction was observed within the first 6 and 12 months of follow-up. Conclusions The longitudinal change in proteinuria is strongly associated with the risk of kidney failure. The change in proteinuria over time can provide clinicians a dynamic prediction of kidney outcomes.

scholarly journals Long-term follow-up including extensive complement analysis of a pediatric C3 glomerulopathy cohort

2021 ◽  
Author(s):  
Marloes A. H. M. Michels ◽  
Kioa L. Wijnsma ◽  
Roel A. J. Kurvers ◽  
Dineke Westra ◽  
Michiel F. Schreuder ◽  
...  
Keyword(s):  
Mixed Model ◽  
Linear Mixed Model ◽  
Immunosuppressive Treatment ◽  
Complement C3 ◽  
C3 Glomerulopathy ◽  
Laboratory Findings ◽  
Mixed Model Analysis ◽  
Long Term Follow Up

Abstract Background C3 glomerulopathy (C3G) is a rare kidney disorder characterized by predominant glomerular depositions of complement C3. C3G can be subdivided into dense deposit disease (DDD) and C3 glomerulonephritis (C3GN). This study describes the long-term follow-up with extensive complement analysis of 29 Dutch children with C3G. Methods Twenty-nine C3G patients (19 DDD, 10 C3GN) diagnosed between 1992 and 2014 were included. Clinical and laboratory findings were collected at presentation and during follow-up. Specialized assays were used to detect rare variants in complement genes and measure complement-directed autoantibodies and biomarkers in blood. Results DDD patients presented with lower estimated glomerular filtration rate (eGFR). C3 nephritic factors (C3NeFs) were detected in 20 patients and remained detectable over time despite immunosuppressive treatment. At presentation, low serum C3 levels were detected in 84% of all patients. During follow-up, in about 50% of patients, all of them C3NeF-positive, C3 levels remained low. Linear mixed model analysis showed that C3GN patients had higher soluble C5b-9 (sC5b-9) and lower properdin levels compared to DDD patients. With a median follow-up of 52 months, an overall benign outcome was observed with only six patients with eGFR below 90 ml/min/1.73 m2 at last follow-up. Conclusions We extensively described clinical and laboratory findings including complement features of an exclusively pediatric C3G cohort. Outcome was relatively benign, persistent low C3 correlated with C3NeF presence, and C3GN was associated with higher sC5b-9 and lower properdin levels. Prospective studies are needed to further elucidate the pathogenic mechanisms underlying C3G and guide personalized medicine with complement therapeutics. Graphical abstract

scholarly journals Different Aspects of Classical Pathway Overactivation in Patients With C3 Glomerulopathy and Immune Complex-Mediated Membranoproliferative Glomerulonephritis

2021 ◽  
Vol 12 ◽  
Author(s):  
Marloes A. H. M. Michels ◽  
Nicole C. A. J. van de Kar ◽  
Sanne A. W. van Kraaij ◽  
Sebastian A. Sarlea ◽  
Valentina Gracchi ◽  
...  
Keyword(s):  
Immune Complex ◽  
Membranoproliferative Glomerulonephritis ◽  
Alternative Pathway ◽  
Classical Pathway ◽  
Healthy Controls ◽  
C3 Glomerulopathy ◽  
Hemolytic Assay ◽  
The Stability ◽  
The Complement System

The rare and heterogeneous kidney disorder C3 glomerulopathy (C3G) is characterized by dysregulation of the alternative pathway (AP) of the complement system. C3G is often associated with autoantibodies stabilizing the AP C3 convertase named C3 nephritic factors (C3NeF). The role of classical pathway (CP) convertase stabilization in C3G and related diseases such as immune complex-mediated membranoproliferative glomerulonephritis (IC-MPGN) remains largely unknown. Here, we investigated the CP convertase activity in patients with C3G and IC-MPGN. Using a refined two-step hemolytic assay, we measured the stability of CP convertases directly in the serum of 52 patients and 17 healthy controls. In four patients, CP convertase activity was prolonged compared to healthy controls, i.e. the enzymatic complex was stabilized. In three patients (2 C3G, 1 IC-MPGN) the convertase stabilization was caused by immunoglobulins, indicating the presence of autoantibodies named C4 nephritic factors (C4NeFs). Importantly, the assay also enabled detection of non-immunoglobulin-mediated stabilization of the CP convertase in one patient with C3G. Prolonged CP convertase activity coincided with C3NeF activity in all patients and for up to 70 months of observation. Crucially, experiments with C3-depleted serum showed that C4NeFs stabilized the CP C3 convertase (C4bC2a), that does not contain C3NeF epitopes. All patients with prolonged CP convertase activity showed clear signs of complement activation, i.e. lowered C3 and C5 levels and elevated levels of C3d, C3bc, C3bBbP, and C5b-9. In conclusion, this work provides new insights into the diverse aspects and (non-)immunoglobulin nature of factors causing CP convertase overactivity in C3G/IC-MPGN.

scholarly journals Complement C3 identified as a unique risk factor for disease severity among young COVID-19 patients in Wuhan, China

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Weiting Cheng ◽  
Roman Hornung ◽  
Kai Xu ◽  
Cai hong Yang ◽  
Jian Li
Keyword(s):  
Risk Factors ◽  
Risk Factor ◽  
Elderly Patients ◽  
Disease Severity ◽  
Severe Disease ◽  
Multivariable Analysis ◽  
Young Patients ◽  
Complement C3 ◽  
Disease Course ◽  
Non Linear

AbstractGiven that a substantial proportion of the subgroup of COVID-19 patients that face a severe disease course are younger than 60 years, it is critical to understand the disease-specific characteristics of young COVID-19 patients. Risk factors for a severe disease course for young COVID-19 patients and possible non-linear influences remain unknown. Data were analyzed from COVID-19 patients with clinical outcome in a single hospital in Wuhan, China, collected retrospectively from Jan 24th to Mar 27th. Clinical, demographic, treatment and laboratory data were collected from patients' medical records. Uni- and multivariable analysis using logistic regression and random forest, with the latter allowing the study of non-linear influences, were performed to investigate the clinical characteristics of a severe disease course. A total of 762 young patients (median age 47 years, interquartile range [IQR] 38–55, range 18–60; 55.9% female) were included, as well as 714 elderly patients as a comparison group. Among the young patients, 362 (47.5%) had a severe/critical disease course and the mean age was statistically significantly higher in the severe subgroup than in the mild subgroup (59.3 vs. 56.0, Student's t-test: p < 0.001). The uni- and multivariable analysis suggested that several covariates such as elevated levels of serum amyloid A (SAA), C-reactive protein (CRP) and lactate dehydrogenase (LDH), and decreased lymphocyte counts influence disease severity independently of age. Elevated levels of complement C3 (odds ratio [OR] 15.6, 95% CI 2.41–122.3; p = 0.039) are particularly associated with the risk of developing severe COVID-19 specifically in young patients, whereas no such influence seems to exist for elderly patients. Additional analysis suggests that the influence of complement C3 in young patients is independent of age, gender, and comorbidities. Variable importance values and partial dependence plots obtained using random forests delivered additional insights, in particular indicating non-linear influences of risk factors on disease severity. This study identified increased levels of complement C3 as a unique risk factor for adverse outcomes specific to young COVID-19 patients.

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