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Background: Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis is a heterogenous autoimmune disease. While traditionally stratified into two conditions, granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA), the subclassification of ANCA-associated vasculitis is subject to continued debate. Here we aim to identify phenotypically distinct subgroups and develop a data-driven subclassification of ANCA-associated vasculitis, using a large real-world dataset., Methods: In the collaborative data reuse project FAIRVASC (Findable, Accessible, Interoperable, Reusable, Vasculitis), registry records of patients with ANCA-associated vasculitis were retrieved from six European vasculitis registries: the Czech Registry of ANCA-associated vasculitis (Czech Republic), the French Vasculitis Study Group Registry (FVSG; France), the Joint Vasculitis Registry in German-speaking Countries (GeVas; Germany), the Polish Vasculitis Registry (POLVAS; Poland), the Irish Rare Kidney Disease Registry (RKD; Ireland), and the Skåne Vasculitis Cohort (Sweden). We performed model-based clustering of 17 mixed-type clinical variables using a parsimonious mixture of two latent Gaussian variable models. Clinical validation of the optimal cluster solution was made through summary statistics of the clusters' demography, phenotypic and serological characteristics, and outcome. The predictive value of models featuring the cluster affiliations were compared with classifications based on clinical diagnosis and ANCA specificity. People with lived experience were involved throughout the FAIRVASVC project., Findings: A total of 3868 patients diagnosed with ANCA-associated vasculitis between Nov 1, 1966, and March 1, 2023, were included in the study across the six registries (Czech Registry n=371, FVSG n=1780, GeVas n=135, POLVAS n=792, RKD n=439, and Skåne Vasculitis Cohort n=351). There were 2434 (62·9%) patients with GPA and 1434 (37·1%) with MPA. Mean age at diagnosis was 57·2 years (SD 16·4); 2006 (51·9%) of 3867 patients were men and 1861 (48·1%) were women. We identified five clusters, with distinct phenotype, biochemical presentation, and disease outcome. Three clusters were characterised by kidney involvement: one severe kidney cluster (555 [14·3%] of 3868 patients) with high C-reactive protein (CRP) and serum creatinine concentrations, and variable ANCA specificity (SK cluster); one myeloperoxidase (MPO)-ANCA-positive kidney involvement cluster (782 [20·2%]) with limited extrarenal disease (MPO-K cluster); and one proteinase 3 (PR3)-ANCA-positive kidney involvement cluster (683 [17·7%]) with widespread extrarenal disease (PR3-K cluster). Two clusters were characterised by relative absence of kidney involvement: one was a predominantly PR3-ANCA-positive cluster (1202 [31·1%]) with inflammatory multisystem disease (IMS cluster), and one was a cluster (646 [16·7%]) with predominantly ear-nose-throat involvement and low CRP, with mainly younger patients (YR cluster). Compared with models fitted with clinical diagnosis or ANCA status, cluster-assigned models demonstrated improved predictive power with respect to both patient and kidney survival., Interpretation: Our study reinforces the view that ANCA-associated vasculitis is not merely a binary construct. Data-driven subclassification of ANCA-associated vasculitis exhibits higher predictive value than current approaches for key outcomes., Funding: European Union's Horizon 2020 research and innovation programme under the European Joint Programme on Rare Diseases., Competing Interests: Declaration of interests PL has received grants or contracts from the German Research Society, Federal Ministry of Education and Research, German Society for Rheumatology, John Grube Foundation, and Vifor Pharma; consulting fees from AbbVie, AstraZeneca, GSK, Novartis, UCB, and Vifor Pharma; payment or honoraria for lectures, presentations, speakers, bureaus, manuscript writing, or educational events from AstraZeneca, Boehringer Ingelheim, GSK, Janssen, Novartis, Rheumaakademie, UCB, and Vifor Pharma; support for attending meetings or travel from Vifor Pharma; and has participated on Data Safety Monitoring Boards or Advisory Boards of AbbVie, AstraZeneca, GSK, and Vifor Pharma. XP has received grants as an investigator of academic studies of ANCA-associated vasculitis for which rituximab was provided by Roche Pharma. MS has received consulting fees from Vifor Pharma, Otsuka, and Hansa Biopharma. BT has received consulting fees from Novartis, AstraZeneca, CSL Vifor, GSK, and Boehringer Ingelheim; payment or honoraria for lectures, presentations, speakers, bureaus, manuscript writing, or educational events from Novartis, AstraZeneca, CSL Vifor, GSK, and Boehringer Ingelheim; support for attending meetings or travel from GSK, AstraZeneca, and Novartis; and participates on the Advisory Board for Amgen. KW is a member of the Advisory Board at CSL Vifor. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Objectives: Rituximab is being increasingly prescribed for the treatment of autoimmune glomerular diseases. While it is highly effective for some diseases, the response is less predictable for others, which may be due to differing requirements in terms of the dosing according to the disease type and variations concerning exposure to the drug., Methods: We compiled novel rituximab dosing schedules according to pharmacokinetic analysis of data gathered from rituximab treated patients in a tertiary referral nephrology centre between May 2020 and June 2023. The population-pharmacokinetic analysis was based on the rituximab dosing, the patients' characteristics, rituximab levels and anti-rituximab antibodies., Results: The analysis, which was based on data from 185 patients, clearly highlighted differing rituximab dosing requirements for patients with ANCA associated vasculitis and minimal change disease compared to those with membranous nephropathy, focal-segmental glomerulosclerosis and lupus nephritis. This corresponded to the good treatment response of the first two diseases and the unreliable efficacy for the others. The model predicts the rituximab pharmacokinetics with high degree of accuracy when body weight, proteinuria, type of glomerulonephritis, treatment length and anti-rituximab antibodies formation are used as covariates. We proposed a dosing schedule with shortened dosing intervals for difficult-to-treat diagnoses with high proteinuria., Conclusion: In order to ensure reliable and comparable exposure of rituximab with respect to the full range of glomerular diseases, the dosing schedule should be adjusted for membranous nephropathy, focal-segmental glomerulosclerosis and lupus nephritis. This is largely, but not solely, due to the enhanced level of unselective proteinuria in these diseases., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in the paper “Population pharmacokinetics of rituximab in patients with glomerular diseases” of authors Jan Miroslav Hartinger, Martin Šíma, Zdenka Hrušková, Alena Pilková, Vojtěch Krátký, Romana Ryšavá, Eva Jančová, Daniel Bobek, Ivana Francová, Vladimír Tesař and Ondřej Slanař., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Delivery of care for kidney failure (KF) globally has a significant disparity; even in some countries, it means end of life for the person. The International Society of Nephrology Global Kidney Health Atlas (ISN-GKHA) tries to address gaps in KF care and standardize global nephrology care. From the third iteration of the ISN-GKHA, we present data for countries in the ISN Eastern and Central Europe region. The median prevalences of chronic kidney disease (12.8%) and treated KF (873.5 pmp) were higher than the global rates, respectively. Hemodialysis was the most preferred modality for KF in adults, whereas kidney replacement therapy was more balanced in children. Although most of the countries in the region had lower-middle-income and upper-middle-income levels, health expenditures for kidney health care were almost generally covered publicly. Nephrologists were responsible for the medical kidney care of people with KF in all countries. There was adequate infrastructure to provide all kinds of treatment for kidney care in the region. Regional characteristics such as high levels of obesity, smoking, and Balkan nephropathy as an endemic disease coupled with a shortage of workforce and finance continued to affect kidney care in the region negatively. By making organizational and legislative arrangements, partnerships with national authorities and societies may accelerate the improvement of kidney health care in the region., (© 2024 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

Background: Amikacin monotherapy is recommended for urinary tract infection (UTI) treatment with multi-resistant pathogens. Even though amikacin efficacy in the treatment of UTIs is dependent on its urinary concentration, there are no robust data proving that sufficiently high urinary concentration is reached in patients with reduced glomerular filtration rate (GFR)., Methods: A prospective study to monitor amikacin penetration into urine of 70 patients [40 males, median (interquartile range) age 70 (65-79) years] with different levels of glomerular filtration decline, including patients treated by dialysis, was conducted. The bactericidal efficacy of amikacin in urine samples has been evaluated., Results: Patients with estimated GFR (eGFR) <30 mL/min had significantly lower median amikacin urinary concentration than patients with eGFR >30 mL/min (89.75 vs 186.0 mg/L, P  < .0001; 200.5 vs 830.0 mg/L, P  < .0001; and 126.0 vs 408.0 mg/L, P  < .0001 for minimal, maximal and minimal together with maximal concentrations, respectively). The amount of amikacin eliminated in the first 10-13 h after dose administration was dependent on eGFR (r 2  = 0.6144, P  < .0001). The urinary concentration of amikacin in patients treated by dialysis was indirectly proportional to pH of urine. The plasma concentrations of amikacin did not correlate with urinary levels in patients in either of the GFR categories. Microbiological evaluation showed that the critical urinary concentration for efficacy of amikacin during UTI monotherapy in patients treated by dialysis is 100 mg/L. We found that 4 out of 11 patients treated by dialysis did not reach this level during the treatment., Conclusion: Systemic administration of amikacin monotherapy in patients treated by dialysis is questionable as the concentrations of amikacin in their urine are often below the threshold of effectivity. Amikacin plasma concentrations are not a major determinant of amikacin concentration in urine, therefore pulse dosing is neither necessary nor safe in patients treated by dialysis, and may cause undesirable toxicity., Competing Interests: The authors declare they do not have any conflict of interest regarding this article., (© The Author(s) 2024. Published by Oxford University Press on behalf of the ERA.)

ANCA-associated vasculitides (AAV) are small-vessel necrotizing vasculitides, with no or few immune deposits. They are usually associated with the presence of ANCA antibodies (AntiNeutrophil Cytoplasmic Antibody), targeted either against proteinase 3 (PR3-ANCA) or myeloperoxidase (MPO-ANCA). ANCA-associated vasculitides include granulomatosis with polyangiitis (formerly Wegener's), microscopic polyangiitis and eosinophilic granulomatosis with polyangiitis (formerly Churg-Strauss syndrome). The most commonly afflicted organs involve the lungs and the respiratory tract, ENT area, and the kidneys. Renal involvement typically manifests as pauci-immune necrotizing crescentic rapidly progressive glomerulonpehritis. Pulmo-renal syndrome with lung haemorrhage and deteriorating kidney function may be acutely life-threatening. Diagnostic methods include ANCA measurement, imaging methods and biopsy. Early recognition of the diagnosis and an early start of adequate treatment are necessary for a good outcome. The current treatment typically consists of corticosteroids and either cyclophoshapmide or rituximab (a monoclonal antibody directed against CD20 antigen). The addition of plasma exchange may be considered in severe cases. Rituximab is preferred for the treatment of all relapsing forms of this vasculitis.

Objective: To investigate the occurrence of cardiovascular events (CVEs) in a large cohort of patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) across the European Union, China, Turkey, Russia, the United Kingdom, and the USA., Methods: Patients with a definite diagnosis of AAV who were followed for ≥ 3 months and had sufficient documentation were included. Data on myocardial infarction (MI) and stroke were collected retrospectively from tertiary vasculitis centers. Univariate and multivariate Cox regression models were used to estimate hazard ratios (HRs) and 95% CIs., Results: Over a median follow-up of 62.0 months (IQR 22.6-100.0), CVEs (mostly MIs) occurred in 245 (10.7%) of 2286 patients with AAV, with a higher frequency in China and the UK. On multivariate regression analysis, older age (55-64.9 yrs, HR 2.93, 95% CI 1.99-4.31), smoking (HR 1.98, 95% CI 1.48-2.64), Chinese origin (HR 4.24, 95% CI 3.07-5.85), and pulmonary (HR 1.50, 95% CI 1.09-2.06) and kidney (HR 3.02, 95% CI 2.08-4.37) involvement were independent variables associated with a higher occurrence of CVEs., Conclusion: We showed that geographic region and both traditional and disease-specific (kidney involvement in particular) factors were independently associated with CVEs. Proper assessment and management of modifiable cardiovascular (CV) risk factors are essential for prevention of CV morbidity in patients with AAV., (Copyright © 2023 by the Journal of Rheumatology.)