Background: Acquired or genetic abnormalities of the complement alternative pathway are the primary cause of C3glomerulopathy(C3G) but may occur in immune-complex-mediated membranoproliferative glomerulonephritis (IC-MPGN) as well. Less is known about the presence and role of C4nephritic factor(C4NeF) which may stabilize the classical pathway C3-convertase. Our aim was to examine the presence of C4NeF and its connection with clinical features and with other pathogenic factors. Results: One hunfe IC-MPGN/C3G patients were enrolled in the study. C4NeF activity was determined by hemolytic assay utilizing sensitized sheep erythrocytes. Seventeen patients were positive for C4NeF with lower prevalence of renal impairment and lower C4d level, and higher C3 nephritic factor (C3NeF) prevalence at time of diagnosis compared to C4NeF negative patients. Patients positive for both C3NeF and C4NeF had the lowest C3 levels and highest terminal pathway activation. End-stage renal disease did not develop in any of the C4NeF positive patients during follow-up period. Positivity to other complement autoantibodies (anti-C1q, anti-C3) was also linked to the presence of nephritic factors. Unsupervised, data-driven cluster analysis identified a group of patients with high prevalence of multiple complement autoantibodies, including C4NeF.
Background A novel data-driven cluster analysis identified distinct pathogenic patterns in C3-glomerulopathies and immune complex-mediated membranoproliferative glomerulonephritis. Our aim was to replicate these observations in an independent cohort and elucidate disease pathophysiology with detailed analysis of functional complement markers. Methods A total of 92 patients with clinical, histological, complement and genetic data were involved in the study, and hierarchical cluster analysis was done by Ward method, where four clusters were generated. Results High levels of sC5b-9 (soluble membrane attack complex), low serum C3 levels and young age at onset (13 years) were characteristic for Cluster 1 with a high prevalence of likely pathogenic variations (LPVs) and C3 nephritic factor, whereas for Cluster 2—which is not reliable because of the small number of cases—strong immunoglobulin G staining, low C3 levels and high prevalence of nephritic syndrome at disease onset were observed. Low plasma sC5b-9 levels, decreased C3 levels and high prevalence of LPV and sclerotic glomeruli were present in Cluster 3, and patients with late onset of the disease (median: 39.5 years) and near-normal C3 levels in Cluster 4. A significant difference was observed in the incidence of end-stage renal disease during follow-up between the different clusters. Patients in Clusters 3–4 had worse renal survival than patients in Clusters 1–2. Conclusions Our results confirm the main findings of the original cluster analysis and indicate that the observed, distinct pathogenic patterns are replicated in our cohort. Further investigations are necessary to analyse the distinct biological and pathogenic processes in these patient groups.
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.
The outbreak of COVID-19 can be associated with cardiac and pulmonary involvement and is emerging as one of the most significant and life-threatening complications in patients with kidney failure receiving hemodialysis. Here, we report a critically ill case of a 13-year-old female patient with acute pericarditis and bilateral pleurisy, screened positive for SARS-CoV-2 RT-PCR, presented with high fever, frequent dry cough, and dyspnea with tachypnea. COVID-19-induced myopericarditis has been noted to be a complication in patients with concomitant kidney failure with replacement therapy (KFRT). This article brings information in the light of our case experience, suggesting that the direct effect of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection on cardiac tissue was a significant contributor to myopericarditis in our patient. Further studies in this direction are required, as such associations have thus far been reported.
STUDY QUESTION What is the prevalence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibodies in triage-negative patients undergoing ART and fertility care providers after lockdown release and throughout 2020? SUMMARY ANSWER Out of the triage-negative patients whose blood samples were assessed for SARS-CoV-2 antibodies over 6 months, 5.2% yielded positive results with a significantly higher rate in health care workers (HCWs) and a significant month-by-month increase in those with evidence of antibodies. WHAT IS KNOWN ALREADY Patients of reproductive age are more prone to asymptomatic or minimal forms of coronavirus disease 2019 (COVID-19) as compared to older age groups, and the identification of those with active infection and those already exposed (and probably immunized) is important for safety and cost-effective use of testing resources in the fertility setting. Data on the prevalence of SARS-CoV-2 in ART patients are limited and encompass short time frames; current rates are unknown. There is also no consensus on the optimal way of screening triage-negative ART patients in moderate/high-risk areas. STUDY DESIGN, SIZE, DURATION A prospective longitudinal unicentric study on triage negative ART patients (n = 516) and clinical staff (n = 30) was carried out. We analyzed 705 serological tests for SARS-CoV-2 sampled between 17 May 2020 (the first working day after lockdown release) up to 1 December 2020, to assess the positivity rates for SARS-CoV-2 antibodies. PARTICIPANTS/MATERIALS, SETTING, METHODS We collected data on the serological status for IgM and IgG antibodies against SARS-CoV-2 in 516 triage-negative men (n = 123) and women (n = 393) undergoing ART at a private fertility center and 30 HCWs that were at work during the study period. Antibodies were detected with a capture chemiluminescence assay (CLIA) targeting the highly Immunogenic S1 and S2 domains on the virus spike protein. We also analyzed the molecular test results of the cases exhibiting a positive serology. MAIN RESULTS AND THE ROLE OF CHANCE The data showed that 5.2% of the triage-negative ART patients had a positive serological result for SARS-CoV-2, with an overall conversion rate of 2.1% for IgG and 4.6% for IgM. There was no significant difference in seroprevalence between sexes. The small cohort (n = 30) of HCWs had a markedly increased seroprevalence (12.9% for Ig M and 22.6% for IgG). The highest seropositivity in our cohort was recorded in November (16.2%). The IgM positivity rates revealed significant monthly increments, paralleling official prevalence rates based on nasopharyngeal swabs. No positive molecular tests were identified in cases exhibiting a solitary positive IgG result. We show that despite a 6-fold increase in the number of ART patients with a positive serology between May and December 2020, most of our patients remain unexposed to the virus. The study was undertaken in a high-risk area for COVID-19, with a 20-times increase in the active cases across the study period. LIMITATIONS, REASONS FOR CAUTION The geographical restriction, alongside the lack of running a second, differently-targeted immunoassay (orthogonal testing), could limit the generalizability and translation of our results to other fertility settings or other immunoassays. WIDER IMPLICATIONS OF THE FINDINGS The low positivity rates for IgG against the SARS-CoV-2 spike protein seen at the end of 2020 imply that most of the fertility patients are still at risk for SARS-CoV-2 infection. Until mass vaccination and other measures effectively diminish the pandemic, risk mitigation strategies must be maintained in the fertility units in the foreseeable future. Patients with a solitary IgG+ status are most likely ‘non-infectious’ and can elude further testing without giving up the strict use of universal protective measures. With increasing seroprevalences owing to infection or vaccination, and with the consecutive increase in test performance, it is possible that serological screening of ART patients might be more cost-effective than PCR testing, especially for the many patients with repeat treatments/procedures in a time-frame of months. STUDY FUNDING/COMPETING INTERESTS This research received no external funding. All authors declare having no conflict of interest with regard to this trial.
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