Background Failure of the glomerular filtration barrier, primarily by loss of slit diaphragm architecture, underlies nephrotic syndrome in minimal change disease. The etiology remains unknown. The efficacy of B cell-targeted therapies in some patients, together with the known proteinuric effect of antinephrin antibodies in rodent models, prompted us to hypothesize that nephrin autoantibodies may be present in patients with minimal change disease. Methods We evaluated sera from patients with minimal change disease enrolled in the Nephrotic Syndrome Study Network (NEPTUNE) cohort and from our own institutions for circulating nephrin autoantibodies by indirect ELISA and by immunoprecipitation of full-length nephrin from human glomerular extract or a recombinant purified extracellular domain of human nephrin. We also evaluated renal biopsies from our institutions for podocyte-associated punctate IgG colocalizing with nephrin by immunofluorescence Results In two independent patient cohorts, we identified in a subset of patients with minimal change disease circulating nephrin autoantibodies during active disease that were significantly reduced or absent during treatment response. We correlated the presence of these autoantibodies with podocyte-associated punctate IgG in renal biopsies from our institutions. We also identified a patient with steroid-dependent childhood minimal change disease that progressed to end-stage kidney disease; she developed a massive posttransplant recurrence of proteinuria that was associated with high pretransplant circulating nephrin autoantibodies. Conclusions Our discovery of nephrin autoantibodies in a subset of adults and children with minimal change disease aligns with published animal studies and provides further support for an autoimmune etiology. We propose a new molecular classification of nephrin autoantibody minimal change disease to serve as framework for instigation of precision therapeutics for these patients.
Background. Solid organ transplant (SOT) recipients are considered to be "vulnerable" to COVID-19 infection due to immunosuppression. To date, there are no studies that compared the disease severity of COVID-19 in SOT recipients with nontransplant patients. Methods. In this case-control study, we compared the outcomes of COVID-19 between SOT recipients and their matched nontransplant controls. The cases were all adult SOT recipients (N = 41) from our academic health center who were diagnosed with COVID-19 between March 10, 2020 and May 15, 2020 using positive reverse transcriptase polymerase chain reaction for SARS-CoV2. The controls (N = 121) were matched on age (±5 y), race, and admission status (hospital or outpatient). The primary outcome was death and secondary outcomes were severe disease, intubation and renal replacement therapy (RRT). Results. Median age of SOT recipients (9 heart, 3 lung, 16 kidney, 8 liver, and 5 dual organ) was 60 y, 80% were male and 67% were Black. Severe disease adjusted risk of death was similar in both the groups (hazard ratio = 0.84 [0.32-2.20]). Severity of COVID-19 and intubation were similar, but the RRT use was higher in SOT (odds ratio = 5.32 [1.26, 22.42]) compared to non-SOT COVID-19 patients. Among SOT recipients, COVID-19-related treatment with hydroxychloroquine (HCQ) was associated with 10-fold higher hazard of death compared to without HCQ (hazard ratio = 10.62 [1.24-91.09]). Conclusions. Although African Americans constituted one-tenth of all SOT in our center, they represented two-thirds of COVID-19 cases. Despite high RRT use in SOT recipients, the severe disease and short-term death were similar in both groups. HCQ for the treatment of COVID-19 among SOT recipients was associated with high mortality and therefore, its role as a treatment modality requires further scrutiny.
Each author contributed important intellectual content during manuscript drafting or revision and accepts accountability for the overall work by ensuring that questions pertaining to the accuracy or integrity of any portion of the work are appropriate investigated and resolved. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Background The ISARIC prospective multinational observational study is the largest cohort of hospitalized patients with COVID-19. We present relationships of age, sex, and nationality to presenting symptoms. Methods International, prospective observational study of 60 109 hospitalized symptomatic patients with laboratory-confirmed COVID-19 recruited from 43 countries between 30 January and 3 August 2020. Logistic regression was performed to evaluate relationships of age and sex to published COVID-19 case definitions and the most commonly reported symptoms. Results ‘Typical’ symptoms of fever (69%), cough (68%) and shortness of breath (66%) were the most commonly reported. 92% of patients experienced at least one of these. Prevalence of typical symptoms was greatest in 30- to 60-year-olds (respectively 80, 79, 69%; at least one 95%). They were reported less frequently in children (≤ 18 years: 69, 48, 23; 85%), older adults (≥ 70 years: 61, 62, 65; 90%), and women (66, 66, 64; 90%; vs. men 71, 70, 67; 93%, each P < 0.001). The most common atypical presentations under 60 years of age were nausea and vomiting and abdominal pain, and over 60 years was confusion. Regression models showed significant differences in symptoms with sex, age and country. Interpretation This international collaboration has allowed us to report reliable symptom data from the largest cohort of patients admitted to hospital with COVID-19. Adults over 60 and children admitted to hospital with COVID-19 are less likely to present with typical symptoms. Nausea and vomiting are common atypical presentations under 30 years. Confusion is a frequent atypical presentation of COVID-19 in adults over 60 years. Women are less likely to experience typical symptoms than men.
doi: medRxiv preprint NOTE: This preprint reports new research that has not been certified by peer review and should not be used to guide clinical practice.
The time course of the concentration of active thrombin in clotting plasma (the thrombogram) was measured by subsampling from platelet-rich plasma (PRP) and continuous chromogenic measurement of platelet-poor plasma (PPP) in 41 stroke patients under the age of 50, in whom stroke could not be attributed to cardioembolic disease, arterial dissection or vasculitis. A significant increase in the area under the thrombogram (endogenous thrombin potential, ETP) was seen in 23 patients. In 9 of them, ETP was increased in PRP but normal in PPP. High ETP in PRP was significantly associated with stroke, both in the middle and in the highest tercile of the ETP (odds ratio 5.1, range 1.8–15.1, and 3.7, range 1.3–10.3, respectively). A decreased sensitivity to the inhibitory action of thrombomodulin (TM) on thrombin generation was observed in 5 of 37 cases. No further definition of the cause of increased thrombin generation or TM resistance was attempted, except for the role of von Willebrand factor (vWF). ETP in PRP, platelet-derived procoagulant activity and vWF were correlated and higher in patients than in controls (p = 0.002, p = 0.045 and p = 0.0006, respectively). This confirms the correlation between vWF level and stroke at young age found in epidemiological studies. It suggests that the role of vWF in thrombin generation, which has been demonstrated in vitro, may be the underlying mechanism of this correlation. In summary, hypercoagulability, defined as an increased capacity of the platelet plasma system to form thrombin, is found in over half of the patients under 50 years with an otherwise unexplained stroke. Sometimes it is due to increased plasma factor activity, sometimes to an increased procoagulant activity of the platelets.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.