IgA nephropathy is the most common form of glomerulonephritis in many parts of the world and remains an important cause of end-stage renal disease. Current evidence suggests that IgA nephropathy is not due to a single pathogenic insult, but rather the result of multiple sequential pathogenic “hits”. An abnormally increased level of circulating poorly O-galactosylated IgA1 and the production of O-glycan-specific antibodies leads to the formation of IgA1-containing immune complexes, and their subsequent mesangial deposition results in inflammation and glomerular injury. While this general framework has formed the foundation of our current understanding of the pathogenesis of IgA nephropathy, much work is ongoing to try to precisely define the genetic, epigenetic, immunological, and molecular basis of IgA nephropathy. In particular, the precise origin of poorly O-galactosylated IgA1 and the inciting factors for the production of O-glycan-specific antibodies continue to be intensely evaluated. The mechanisms responsible for mesangial IgA1 deposition and subsequent renal injury also remain incompletely understood. In this review, we summarize the current understanding of the key steps involved in the pathogenesis of IgA nephropathy. It is hoped that further advances in our understanding of this common glomerulonephritis will lead to novel diagnostic and prognostic biomarkers, and targeted therapies to ameliorate disease progression.
<b><i>Introduction:</i></b> Acute kidney injury (AKI) in coronavirus infection disease (COVID-19) is associated with disease severity. We aimed to evaluate risk factors associated with AKI beyond COVID-19 severity. <b><i>Methods:</i></b> A retrospective observational study of COVID-19 patients admitted to a tertiary hospital in Singapore. Logistic regression was used to evaluate associations between risk factors and AKI (based on Kidney Disease Improving Global Outcomes criteria). Dominance analysis was performed to evaluate the relative importance of individual factors. <b><i>Results:</i></b> Seven hundred seven patients were included. Median age was 46 years (interquartile range [IQR]: 29–57) and 57% were male with few comorbidities (93%, Charlson Comorbidity Index [CCI] <1). AKI occurred in 57 patients (8.1%); 39 were in AKI stage 1 (68%), 9 in stage 2 (16%), and 9 in stage 3 (16%). Older age (adjusted odds ratio [aOR] 1.04; 95% confidence interval [CI]: 1.01–1.07), baseline use of angiotensin-converting enzyme inhibitor (ACE-I) or angiotensin receptor blocker (ARB) (aOR 2.86; 95% CI: 1.20–6.83), exposure to vancomycin (aOR 5.84; 95% CI: 2.10–16.19), use of nonsteroidal anti-inflammatory drugs (NSAIDs) (aOR 3.04; 95% CI: 1.15–8.05), and severe COVID-19 with hypoxia (aOR 13.94; 95% CI: 6.07–31.98) were associated with AKI in the multivariable logistic regression model. The 3 highest ranked predictors were severe COVID-19 with hypoxia, vancomycin exposure, and age, accounting for 79.6% of the predicted variance (41.6, 23.1, and 14.9%, respectively) on dominance analysis. <b><i>Conclusion:</i></b> Severe COVID-19 is independently associated with increased risk of AKI beyond premorbid conditions and age. Appropriate avoidance of vancomycin and NSAIDs are potentially modifiable means to prevent AKI in patients with COVID-19.
Immunoglobulin A nephropathy (IgAN) is one of the commonest global patterns of primary glomerulonephritis and remains a leading cause of chronic kidney disease and end‐stage renal disease. The sole diagnostic criterion of IgAN remains the presence of dominant mesangial immunoglobulin A deposits on kidney biopsy. Beyond this defining feature, there is significant heterogeneity in the epidemiology, clinical presentation, renal progression and long‐term outcomes of IgAN in different ethnic populations. Mirroring this heterogeneity in clinical phenotypes, there is also marked ethnic variation in the extent of histopathological lesions observed on kidney biopsy, which may partly explain the well‐documented differences in response to immunomodulatory agents reported in different regions of the world. In parallel, disparities have been identified in genetic association studies and key pathogenic pathways in different ethnic populations. Understanding the basis for these differences in IgAN has important implications for both clinical care and future research. In this review, we will examine the impact of ethnicity on the epidemiology, clinical presentation and outcomes, pathogenesis and genetic associations in IgAN.
With the exponential surge in patients with coronavirus disease 2019 (COVID-19) worldwide, the resources needed to provide continuous kidney replacement therapy (CKRT) for patients with acute kidney injury or kidney failure may be threatened. This article summarizes subsisting strategies that can be implemented immediately. Pre-emptive weekly multicenter projections of CKRT demand based on evolving COVID-19 epidemiology and routine workload should be made. Corresponding consumables should be quantified and acquired, with diversification of sources from multiple vendors. Supply procurement should be stepped up accordingly so that a several-week stock is amassed, with administrative oversight to prevent disproportionate hoarding by institutions. Consumption of CKRT resources can be made more efficient by optimizing circuit anticoagulation to preserve filters, extending use of each vascular access, lowering blood flows to reduce citrate consumption, moderating the CKRT intensity to conserve fluids, or running accelerated KRT at higher clearance to treat more patients per machine. If logistically feasible, earlier transition to intermittent hemodialysis with online-generated dialysate, or urgent peritoneal dialysis in selected patients, may help reduce CKRT dependency. These measures, coupled to multicenter collaboration and a corresponding increase in trained medical and nursing staffing levels, may avoid downstream rationing of care and save lives during the peak of the pandemic. Complete author and article information provided before references.
Detailed analytical ultracentrifugation and X-ray/neutron scattering data and a new atomistic modelling approach revealed asymmetric extended solution structures for human IgA1 that account for its receptor-binding function. IgA1 with different hinge O-galactosylation patterns showed similar structures.
The International Diabetes Federation (IDF) estimated that 425 million people were living with diabetes mellitus (DM) in 2017 (1), which had far exceeded what was originally predicted in 2003 (333 million people by 2025). Consequently, the IDF provided a new projection of a near doubling of 629 million people with DM in 2045, with 4 out of 5 people with DM living in low-and middle-income countries (LMICs), majority from South East Asia (82 million) and the Western Pacific (159 million) regions. The increasing prevalence of DM has contributed to the growing burden of ESKD, and it is estimated that DKD is responsible for about 50% of ESKD in the developed world (2). The global burden of DKD and ESKD has a major impact on healthcare costs and resources; making screening, early detection and preventive treatment important strategies to mitigate this worldwide pandemic.
examines a number of current and recently commenced studies in immunoglobulin A nephropathy, emphasizing newer therapies and therapeutic targets. ABSTRACT:Despite advances in our understanding of immunoglobulin A nephropathy (IgAN) over the past decade, there are currently no specific therapies capable of targeting key pathways involved in the pathogenesis of the disease. Recent studies have, however, provided new insights into important molecular pathways that are likely to be amenable to therapeutic manipulation in the future. Specifically, a deeper understanding of the role of mucosal immunity, B-cell activation and mesangial cell activation in IgAN has provided the impetus for a number of exciting phase II/III clinical trials in IgAN. In this review, we examine some of these on-going studies, first examining studies that clarify the role of traditional immunosuppression in IgAN, then focusing on novel therapies in early clinical studies, looking closely at the rationale for these agents in relation to our current understanding of the pathogenesis of IgAN. Finally, we examine emerging pathways and therapeutic agents that have the potential to be developed as novel therapies in the coming years. It is hoped that as we continue to develop a greater understanding of IgAN, emerging therapies will soon become a reality in the day-to-day treatment of patients with IgAN.
Background Coronavirus Disease 2019 (COVID-19) infection has been associated with a hypercoagulable state with increased reports of thrombotic events. Acute kidney injury requiring dialysis is common in critically ill patients and circuit clotting compromises efficacy of treatment. This study aims to analyze the circuit life and circuit clotting during continuous kidney replacement therapy (CKRT) and intermittent hemodialysis in patients with and without COVID-19. Methods This is a single-center, retrospective cohort study in critically ill patients undergoing CKRT or intermittent hemodialysis between 1 February 2020 to 22 May 2020. Patients in the intensive care unit (ICU) with COVID-19 infection and contemporary controls who tested negative were included. Co-primary outcomes were functional circuit life for patients on CKRT and all circuit clotting events for patients on CKRT and/or intermittent hemodialysis. Results Seventy CKRT circuits and 32 intermittent hemodialysis sessions for 12 COVID-19 cases and 22 CKRT circuits and 18 intermittent hemodialysis sessions for 15 controls were analyzed. CKRT circuit clotting was more common in the COVID-19 group compared to the control group (64% vs 36%, p = 0.02), despite higher anticoagulation use in the COVID-19 group (41% vs 14%, p = 0.02). Functional CKRT circuit life was similar in COVID-19 patients and controls (median 11 vs 12 h, p = 0.69). On Cox regression analysis, circuit clotting was similar with hazard ratio (HR) 1.90 [95% confidence interval (CI): 0.89–4.04]; however, clotting was increased in COVID-19 patients after adjustment for anticoagulation use (HR: 3.31 [95% CI 1.49–7.33]). In patients with COVID-19, CKRT circuits with anticoagulation had a longer circuit life compared to CKRT circuits without anticoagulation (median 22 versus 7 h respectively, p < 0.001). Circuit clotting was similar in both groups undergoing intermittent hemodialysis. Conclusion Dialysis clotting amongst COVID-19 patients is increased despite more anticoagulation use and the hazard for clotting is greater especially after adjusting for anticoagulation use. Circuit life was suboptimal in COVID-19 patients on circuits without anticoagulation and therefore routine use of anticoagulation amongst COVID-19 patients should be considered whenever possible.
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