SummaryBackground and objectives The principle defect in dense deposit disease and C3 glomerulonephritis is hyperactivity of the alternative complement pathway. Eculizumab, a monoclonal antibody that binds to C5 to prevent formation of the membrane attack complex, may prove beneficial. Design, setting, participants, & measurementsIn this open-label, proof of concept efficacy and safety study, six subjects with dense deposit disease or C3 glomerulonephritis were treated with eculizumab every other week for 1 year. All had proteinuria .1 g/d and/or AKI at enrollment. Subjects underwent biopsy before enrollment and repeat biopsy at the 1-year mark. ResultsThe subjects included three patients with dense deposit disease (including one patient with recurrent dense deposit disease in allograft) and three patients with C3 glomerulonephritis (including two patients with recurrent C3 glomerulonephritis in allograft). Genetic and complement function testing revealed a mutation in CFH and MCP in one subject each, C3 nephritic factor in three subjects, and elevated levels of serum membrane attack complex in three subjects. After 12 months, two subjects showed significantly reduced serum creatinine, one subject achieved marked reduction in proteinuria, and one subject had stable laboratory parameters but histopathologic improvements. Elevated serum membrane attack complex levels normalized on therapy and paralleled improvements in creatinine and proteinuria.Conclusions Clinical and histopathologic data suggest a response to eculizumab in some but not all subjects with dense deposit disease and C3 glomerulonephritis. Elevation of serum membrane attack complex before treatment may predict response. Additional research is needed to define the subgroup of dense deposit disease/C3 glomerulonephritis patients in whom eculizumab therapy can be considered.

C3 Glomerulonephritis (C3GN) is a recently described disorder that typically results from abnormalities in the alternative pathway of complement. Here, we describe the clinical features, kidney biopsy findings, alternative pathway abnormalities, glomerular proteomic profile, and follow-up in 12 cases of C3GN. This disorder equally affected all ages, both genders, and typically presented with hematuria and proteinuria. In both the short and long term, renal function remained stable in the majority of patients with native kidney disease. In two patients, C3GN recurred within one year of transplantation and resulted in a decline in allograft function. Kidney biopsy mainly showed a membranoproliferative pattern; although both mesangial proliferative and diffuse endocapillary proliferative glomerulonephritis were noted. Alternative pathway abnormalities were heterogeneous; both acquired and genetic. The most common acquired abnormality was the presence of C3 nephritic factors, while the most common genetic finding was the presence of H402 and V62 alleles of Factor H. In addition to these risk factors, other abnormalities included Factor H auto-antibodies and mutations in CFH, CFI and CFHR genes. Laser dissection and mass spectrometry of glomeruli from patients with C3GN showed accumulation of alternative pathway and terminal complement complex proteins. Thus, C3GN results from diverse abnormalities of the alternative complement pathway leading to subsequent glomerular injury.

SummaryBackground and objectives This study was designed to investigate the causes of alternative pathway dysregulation in a cohort of patients with dense deposit disease (DDD).Design, setting, participants, & measurements Thirty-two patients with biopsy-proven DDD underwent screening for C3 nephritic factors (C3Nefs), factor H autoantibodies (FHAAs), factor B autoantibodies (FBAAs), and genetic variants in CFH. C3Nefs were detected by: ELISA, C3 convertase surface assay (C3CSA), C3CSA with properdin (C3CSAP), two-dimensional immunoelectrophoresis (2DIEP), and immunofixation electrophoresis (IFE). FHAAs and FBAAs were detected by ELISA, and CFH variants were identified by Sanger sequencing.Results Twenty-five patients (78%) were positive for C3Nefs. Three C3Nef-positive patients were also positive for FBAAs and one of these patients additionally carried two novel missense variants in CFH. Of the seven C3Nef-negative patients, one patient was positive for FHAAs and two patients carried CFH variants that may be causally related to their DDD phenotype. C3CASP was the most sensitive C3Nef-detection assay. C3CASP and IFE are complementary because C3CSAP measures the stabilizing properties of C3Nefs, whereas IFE measures their expected consequence-breakdown of C3b.Conclusions A test panel that includes C3CSAP, IFE, FHAAs, FBAAs, and genetic testing for CFH variants will identify a probable cause for alternative pathway dysregulation in approximately 90% of DDD patients. Dysregulation is most frequently due to C3Nefs, although some patients test positive for FHAAs, FBAAs, and CFH mutations. Defining the pathophysiology of DDD should facilitate the development of mechanism-directed therapies.

BackgroundThe impacts of social restrictions for COVID-19 on children’s vision and lifestyle remain unknown.AimsTo investigate myopia incidence, spherical equivalent refraction (SER) and lifestyle changes among schoolchildren during the COVID-19 pandemic.MethodsTwo separate longitudinal cohorts of children aged 6–8 years in Hong Kong were included. The COVID-19 cohort was recruited at the beginning of the COVID-19 outbreak, whereas the pre-COVID-19 cohort was recruited before the COVID-19 pandemic. All children received ocular examinations, and answered a standardised questionnaire relating to their lifestyle, including time spent on outdoor activities and near work, both at baseline and at follow-up visits.ResultsA total of 1793 subjects were recruited, of whom 709 children comprised the COVID-19 cohort with 7.89±2.30 months of follow-up, and 1084 children comprised the pre-COVID-19 cohort with 37.54±3.12 months of follow-up. The overall incidence was 19.44% in the COVID-19 cohort, and 36.57% in pre-COVID-19 cohort. During the COVID-19 pandemic, the change in SER and axial length was –0.50±0.51 D and 0.29±0.35 mm, respectively; the time spent on outdoor activities decreased from 1.27±1.12 to 0.41±0.90 hours/day (p<0.001), while screen time increased from 2.45±2.32 to 6.89±4.42 hours/day (p<0.001).ConclusionsWe showed a potential increase in myopia incidence, significant decrease in outdoor time and increase in screen time among schoolchildren in Hong Kong during the COVID-19 pandemic. Our results serve to warn eye care professionals, and also policy makers, educators and parents, that collective efforts are needed to prevent childhood myopia—a potential public health crisis as a result of COVID-19.

Background C3 Glomerulonephritis (C3GN) is a proliferative glomerulonephritis resulting from glomerular deposition of complement factors due to dysregulation of the alternative pathway of complement. The dysregulation of the alternative pathway of complement may occur as a result of mutations or functional inhibition of complement regulating proteins. Functional inhibition of the complement regulating proteins may result from a monoclonal gammopathy. Study Design Case series Setting and Participants 32 Mayo Clinic patients of C3GN, of which 10 patients (31.25%) had evidence of a monoclonal immunoglobulin in the serum. Outcomes Clinical features, hematological and bone marrow biopsy findings, kidney biopsy findings, renal outcomes, complement pathway abnormalities, treatment and follow-up of patients with C3GN that was associated with a monoclonal gammopathy. Results The mean age of patients with C3GN associated with monoclonal gammopathy was 54.5 years. Bone marrow biopsy done in 9 patients revealed monoclonal gammopathy of undetermined significance (MGUS) in 5 patients, small lymphocytic lymphoma/chronic lymphocytic leukemia (CLL) in one patient ,and no abnormal clones in the remaining 3 patients. Kidney biopsy showed a membranoproliferative glomerulonephritis with bright capillary wall C3 staining in all 10 patients. Evaluation of the alternative pathway of complement showed abnormalities in 7 of the 9 patients tested. None of the patients had a mutation in the complement regulating proteins. As an index case, one patient with C3GN and CLL was treated with Rituximab, cyclophosphamide, vincristine and prednisone and one patient with C3GN and MGUS was treated with dexamethasone and bortezomib. Both patients showed significant decrease in hematuria and proteinuria, and stabilization of renal function. Limitations Studies to show evidence of direct activation of the alternative pathway by the monoclonal immunoglobulin were not done. Conclusions The study highlights the association of C3GN and monoclonal gammopathy, in particular in the older population, and the importance of targeting the underlying hematologic malignancy as an approach to treating C3GN.