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Matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) may play an important role in both inflammation with subsequent fibrosis and in repair and healing in anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). We evaluated the circulating levels of MMPs, including pregnancy-associated plasma protein A (PAPP-A), and TIMPs in patients with AAV. PAPP-A, MMP-2, MMP-3, MMP-7, MMP-9, TIMP-1, TIMP-2 and selected parameters were measured in 100 AAV patients (36 patients with active disease and 64 patients in remission) and 34 healthy subjects. The levels of MMP-2, MMP-3, MMP-7, MMP-9, TIMP-1, TIMP-2, and PAPP-A in AAV were all found to be different to those of the controls. The MMP-7 and PAPP-A concentrations were increased in active disease in comparison to the controls (MMP-7: 13 ±.7 vs. 2 ± 0.6 ng/ml, PAPP-A: 14 ± 18 vs. 6.8 ± 2.6 ng/ml, both P < 0.005). The MMP-2 and TIMP-2 levels were increased in remission when compared to the controls (MMP-2: 242 ± 50 ng/ml vs. 212 ± 26 ng /ml, TIMP-2: 82 ± 14 ng/ml vs. 68 ± 93 ng/ml) and to the active AAV (MMP-2: 242 ± 50 vs. 219 ± 54 ng/ml, TIMP-2: 82 ± 14 ng/ml vs. 73 ± 15 ng/ml, all P < 0.005). MMP-3, MMP-7, TIMP-1, and PAPP-A correlated with serum creatinine. The serum levels of MMPs, TIMPs and PAPP-A are all altered in AAV. MMP-2, MMP-7 and TIMP-2 appear to be promising markers in distinguishing active AAV from remission. MMP-3, MMP-7, TIMP-1, and PAPP-A are associated with kidney function in AAV. Further studies are needed to delineate the exact roles of circulating MMPs, TIMPs and PAPP-A in patients with AAV. [ABSTRACT FROM AUTHOR]

Background: Proteinuria may be caused by either increased glomerular basement membrane permeability, or by impairment of secretion-reabsorption tubular processes. It is often used as a surrogate marker in monitoring and predicting outcome in patients with chronic kidney disease but it is non-specific. We established a proteomics approach for identification of nephropathy-related biomarkers in urine, including Diabetic nephropathy (DN), which is a well-known complication of long-standing diabetes. The main aim of this work was to assess differences in urine proteins in patients with nephropathies and healthy controls and to identify abnormal proteins as potential biomarkers of the renal disease. Materials and Methods: In our pilot project, we have analyzed protein composition of urine in 20 patients with IgA nephropathy and an appropriate healthy control group. The proteins were separated by the isoelectric focusing method (IEF) in the first step. The second dimensional separation and protein characterization was performed using iTRAQ quantitative analysis followed by mass spectrometry LC-MS/MS. Results: We have identified 46 urinary proteins significantly up- or down regulated in the urine of IgA nephropathy patients. We have found changes in proteins of complement system, Regulation of actin cytoskeleton or retinol biosynthesis. Whilst these preliminary data require further studies that will correlate the results with clinical, laboratory and histopathological data, some of the proteins, namely Cathepsin, Retinol-binding protein, Protein AMBP were also represented in urine of patients with diabetes mellitus in previous studies made by others. Conclusion: We have optimized proteomic methodology that is able to identify potential urine biomarkers of kidney disease. Study of changes of urinary proteins could help to establish the diagnosis, assess the disease activity and/or predict the prognosis of different renal diseases, including different glomerulonephritis or DN. [ABSTRACT FROM AUTHOR]

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.)

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.)

Objective: To investigate the occurrence of venous thromboembolic events (VTE) in a large cohort of patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) across the European Union, Turkey, Russia, UK and North America., Methods: Patients with a definite diagnosis of AAV who were followed for at least 3 months and had sufficient documentation were included. Data on VTE, including either deep vein thrombosis or pulmonary embolism, were collected retrospectively from tertiary vasculitis centres. Univariate and multivariate regression models were used to estimate odds ratios (ORs) and 95% CIs., Results: Over a median follow-up of 63 (interquartile range: 29, 101) months, VTE occurred in 278 (9.7%) of 2869 AAV patients with a similar frequency across different countries (from 6.3% to 13.7%), and AAV subtype [granulomatosis with polyangiitis: 9.8% (95% CI: 8.3, 11.6%); microscopic polyangiitis: 9.6% (95% CI: 7.9, 11.4%); and eosinophilic granulomatosis with polyangiitis: 9.8% (95% CI: 7.0, 13.3%)]. Most VTE (65.6%) were reported in the first-year post-diagnosis. Multiple factor logistic regression analysis adjusted for sex and age showed that skin (OR 1.71, 95% CI: 1.01, 2.92), pulmonary (OR 1.78, 95% CI: 1.04, 3.14) and kidney [eGFR 15-60 ml/min/1.73 m2, OR 2.86 (95% CI: 1.27, 6.47); eGFR <15 ml/min/1.73 m2, OR 6.71 (95% CI: 2.94, 15.33)] involvement were independent variables associated with a higher occurrence of VTE., Conclusion: Two-thirds of VTE occurred during the initial phase of active disease. We confirmed previous findings from smaller studies that a decrease in kidney function, skin involvement and pulmonary disease are independently associated with VTE., (© The Author(s) 2021. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Membranous nephropathy (MN) is the most common cause of primary nephrotic syndrome among adults. The identification of phospholipase A2 receptor (PLA2R) as target antigen in most patients changed the management of MN dramatically, and provided a rationale for B-cell depleting agents such as rituximab. The efficacy of rituximab in inducing remission has been investigated in several studies, including 3 randomized controlled trials, in which complete and partial remission of proteinuria was achieved in approximately two-thirds of treated patients. Due to its favorable safety profile, rituximab is now considered a first-line treatment option for MN, especially in patients at moderate and high risk of deterioration in kidney function. However, questions remain about how to best use rituximab, including the optimal dosing regimen, a potential need for maintenance therapy, and assessment of long-term safety and efficacy outcomes. In this review, we provide an overview of the current literature and discuss both strengths and limitations of "the new standard.", (© 2021 Published by Elsevier, Inc., on behalf of the International Society of Nephrology.)

Objective: According to the manufacturer's documentation, rituximab (RTX) should be administered with slow infusion rates to prevent infusion-related adverse events (AEs). Nevertheless, slow infusions are time-consuming and uncomfortable for patients and medical staff. Therefore, faster infusion rates have been studied and proven safe and well tolerated in lymphomas and rheumatoid arthritis (RA). A small amount of data is available for rapid RTX infusions in non-RA autoimmune diseases., Methods: Beginning in September 2015, all RTX-reated patients in our centre and willing to participate, were switched from slow RTX infusions (4.25 hours, given at least once to all patients) to fast infusions (2 hours). A total of 85 RTX 2-hour infusions was administered to 53 patients with autoimmune diseases with renal involvement and selected primary glomerulonephritides (26 ANCA-associated vasculitis, nine systemic lupus erythematodes, seven membranous nephropathy, five IgM nephropathy and six other autoimmune disease). Most of the patients received chronic corticosteroid therapy. The prednisone equivalent dose median (IQR) was 0.1 (0.0-0.2) mg/kg/day., Results: Rapid RTX infusions were generally well tolerated. Only two infusion-related AEs were recorded: one Common Terminology Criteria for Adverse Events, grade 3, (lower back pain and hypotension followed by chills necessitating methylprednisolone and dipyrone administration) and one grade 1 (subjective intolerance). The AEs frequency does not differ from other studies with rapid RTX infusions in patients with lymphomas and RA., Conclusions: Our experience supported other published data and provides evidence concerning the safety of non-initial RTX 2-hour infusion which can be administered without raising the infusion-related AEs rate in patients with kidney-affecting autoimmune diseases and glomerulonephritides., Competing Interests: Competing interests: None declared.

Background: In anti-neutrophil cytoplasmic antibody (ANCA)-associated glomerulonephritis, antigen specificity varies between myeloperoxidase (MPO) and proteinase 3 (PR3). This has been reported to vary in relation to age, gender, geography and extrarenal manifestations. However, studies are difficult to compare as criteria for inclusion vary. The aim of this study was to investigate the relationship between ANCA serotype, latitude, ultraviolet (UV) radiation levels, age, gender and renal function at diagnosis in a large study with uniform inclusion criteria., Methods: Patients with biopsy-proven ANCA-associated glomerulonephritis were identified from regional or nationwide registries in 14 centres in Norway, Sweden, the UK, the Czech Republic, Croatia, Italy and the USA during the period 2000-13. UV radiation levels for 2000-13 in Europe were obtained from the Swedish Meteorological and Hydrological Institute., Results: A total of 1408 patients (45.2% PR3-ANCA) were included in the study. In univariable analysis, PR3-ANCA was significantly associated with male gender {odds ratio [OR] 2.12 [95% confidence interval (CI) 1.71-2.62]}, younger age [OR per year 0.97 (95% CI 0.96-0.98)] and higher glomerular filtration rate [OR per mL/min 1.01 (95% CI 1.01-1.02); P < 0.001] at diagnosis but not with latitude or UV radiation. In multivariable logistic regression analysis, latitude and UV radiation also became significant, with higher odds for PR3-ANCA positivity at northern latitudes/lower UV radiation levels. However, the latitudinal difference in MPO:PR3 ratio is smaller than differences previously reported concerning microscopic polyangiitis and granulomatosis with polyangiitis., Conclusions: The ratio between PR3-ANCA and MPO-ANCA varies in glomerulonephritis with respect to age, gender, renal function and geographic latitude/UV radiation levels.

Co-presentation with both ANCA and anti-GBM antibodies is thought to be relatively rare. Current studies of such 'double-positive' cases report small numbers and variable outcomes. To study this further we retrospectively analyzed clinical features and long-term outcomes of a large cohort of 568 contemporary patients with ANCA-associated vasculitis, 41 patients with anti-GBM disease, and 37 double-positive patients with ANCA and anti-GBM disease from four European centers. Double-positive patients shared characteristics of ANCA-associated vasculitis (AAV), such as older age distribution and longer symptom duration before diagnosis, and features of anti-GBM disease, such as severe renal disease and high frequency of lung hemorrhage at presentation. Despite having more evidence of chronic injury on renal biopsy compared to patients with anti-GBM disease, double-positive patients had a greater tendency to recover from being dialysis-dependent after treatment and had intermediate long-term renal survival compared to the single-positive patients. However, overall patient survival was similar in all three groups. Predictors of poor patient survival included advanced age, severe renal failure, and lung hemorrhage at presentation. No single-positive anti-GBM patients experienced disease relapse, whereas approximately half of surviving patients with AAV and double-positive patients had recurrent disease during a median follow-up of 4.8 years. Thus, double-positive patients have a truly hybrid disease phenotype, requiring aggressive early treatment for anti-GBM disease, and careful long-term follow-up and consideration for maintenance immunosuppression for AAV. Since double-positivity appears common, further work is required to define the underlying mechanisms of this association and define optimum treatment strategies., (Copyright © 2017 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

Background: Clinically isolated syndrome (CIS) represents first neurological symptoms suggestive of demyelinating lesion in the central nervous system (CNS). Currently, there are no sufficient immunological or genetic markers predicting relapse and disability progression, nor there is evidence of the efficacy of registered disease modifying treatments (DMTs), such as intramuscular interferon beta1a. The aim of the study is to evaluate immunological predictors of a relapse or disability progression., Methods: One hundred and eighty one patients with CIS were treated with interferon beta1a and followed over the period of 4 years. Lymphocyte subsets were analyzed by flow cytometry. A Kaplan-Meier estimator of survival probability was used to analyze prognosis. For statistical assessment only individual differences between baseline values and values at the time of relapse or confirmed disability progression were analysed., Results: Higher levels of B lymphocytes predicted relapse-free status. On the other hand, a decrease of the naïve subset of cells (CD45RA+ in CD4+) after 12, 24, and 36 months of follow-up were associated with an increased risk of confirmed disability progression., Conclusion: Our data suggest that the quantification of lymphocyte subsets in patients after the first demyelinating event suggestive of MS may be an important biomarker.

Background: Plasma exchange (PLEX) has been used routinely for treatment of severe renal vasculitis and/or alveolar haemorrhage (AH) in anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), but the long-term benefit of PLEX in AAV remains unclear. We aimed to describe the characteristics and outcomes of patients treated with PLEX in a single centre., Methods: Patients with AAV were identified by performing a case review of medical records of 705 patients who received PLEX in a single tertiary referral centre between 2000 and 2010. Patient characteristics and outcomes were recorded. The Kaplan-Meier method, log-rank tests and Cox regression analysis were used for survival analyses., Results: A total of 94 patients with AAV were identified (44 men, 50 women; median age 60 years, range 21-90 years; 52 proteinase 3-ANCA, 41 myeloperoxidase-ANCA and 1 ANCA-negative; 8 double-positive for ANCA and anti-glomerular basement membrane; 93 newly diagnosed/1 relapse; 55 [58.5 %] required dialysis). The reasons for initiating PLEX therapy were severe renal involvement alone in 52 %, AH in 10 %, both renal involvement and AH in 35 %, and "other" in 3 %. The patients had 3-27 (median 7) PLEX sessions. At 3 months, 81 (86 %) of 94 were alive and 62 (66 %) of 94 were alive and dialysis-independent. The median follow-up was 41 months (minimum-maximum 0.5-137 months), when 56 (59.6 %) of 94 patients were alive and 47 (50 %) were dialysis-independent. The estimated overall survival rates were 75.3 % at 1 year and 61.1 % at 5 years. Patient survival decreased with increasing age at presentation (5-year survival 85 % for age <50 years, 64.4 % for ages 50-65 years, and 41 % for >65 years; p < 0.01 for comparison between all groups). Estimated renal survival rates were 65.5 % at 1 year and 43 % at 5 years. Renal survival was worse in patients aged >65 years than in the younger patients (5-year survival 25.1 % in patients >65 years vs. 50.8 % for those ≤65 years, p < 0.01). The estimated renal survival was better in patients with higher Disease Extent Index (DEI) >6 than in patients with DEI ≤6 (5-year survival 52.1 % vs. 39.4 %, p = 0.04), even though this was not confirmed in multivariate analysis., Conclusions: The mortality of patients presenting with severe manifestations of AAV remains high despite the use of PLEX. Older age at presentation is associated with worse overall and renal prognosis.

Glomerulonephritides together create a heterogenic group of supposedly immunologically mediated diseases of glomeruli. They still belong among the most frequent causes of chronic renal failure. Detection of podocytes in urine might serve as an important marker of glomerulonephritides activity. The aim of this study was to develop a novel flow cytometric method for the detection of podocyte fragments and podocytes in urine and assess its possible use in clinical practice. We placed emphasis on the improvement of pre-analytic phase. To suppress the autofluorescence of the background, blocking solutions and magnetic separation were used. An additional surface marker CD10 (nephrilysin) was used together with routinely used podocalyxin (PCX) in order to achieve better identification of podocytes. Based on the surface marker expression, three different element types were identified in the urine samples: PCX+/CD10+ elements (EL) (supposedly podocytes), PCX-/CD10+ EL (supposedly parietal epithelial cells) and PCX+ EL. We examined a total of 36 patients who underwent renal biopsy (non-glomerular nephropathy, MGN, FSGS, IgAN, AAV and MPGN) and 27 healthy controls. Negative results were found in non-glomerular nephropathy and in MGN. In patients with FSGS and IgAN, the levels of urine elements were slightly increased. The highest levels of all elements were found in AAV and MPGN. Our first results suggest that flow cytometric detection may distinguish between glomerular and nonglomerular diseases and that the levels of urine elements might correlate with the degree of glomerular destruction.

Background and Aims. Deoxyribonuclease I (DNaseI) is an endonuclease that facilitates chromatin breakdown and promotes susceptibility to autoimmune disorders. The aim of current study was to investigate serum DNase I activity in patients with inflammatory bowel diseases (IBD). Patients and Methods. A cohort of 110 IBD patients was evaluated, aged 35 ± 12 years, 77 with Crohn's disease (CD) and 33 with ulcerative colitis (UC). 50 SLE patients and 50 healthy blood donors were examined as control groups. Results. DNase I activity in IBD patients was significantly lower than in healthy individuals, but higher than in SLE patients (P < .0001). Patients with UC showed higher DNase I activity than CD patients, P = .21. DNase I activity in female patients with IBD was significantly lower than in males, P = .024; however, no differences in DNase I activity were found in relation to gender in healthy individuals. DNase I activity has shown a strong negative correlation with the serum concentration of anti-nucleosomal antibodies in the autoimmune (SLE + IBD) cohort, as well as in the separate IBD cohort. Conclusions. Reduced serum DNase I activity probably has pathogenetic consequences in IBD. Induction of autoantibodies towards nucleosomes could be a reflection of impaired DNase I activity.