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Introduction: Maintaining renin-angiotensin-aldosterone system inhibition (RAASi) in advanced chronic kidney disease (CKD) to delay CKD progression is still controversial. This is due to potential side effects associated with RAASi, such as a decline in glomerular filtration rate (GFR) and hyperkalemia. This study aims to examine the effect of RAASi on progression of advanced CKD to kidney failure (eGFR <15 ml/min/1.73 m2, CKD stage 5) in a real-life outpatient cohort., Methods: This single-center retrospective observational study presents data from 954 individuals with advanced CKD (estimated glomerular filtration rate [eGFR] 15-30 ml/min/1.73 m2), comparing 806 RAASi with 511 control intervals over a median follow-up period of 19 months. The endpoint was defined as time to manifestation of kidney failure. Univariate and multivariate time-to-event analysis were performed to assess effects of RAASi on endpoint probabilities., Results: Univariate time-to-event analysis did not show a significant difference in the median time to kidney failure between RAASi and control intervals (7.6 vs. 7.0 years, p=0.74). Covariate-adjusted multivariate regression models also demonstrated no association between RAASi treatment and progression to kidney failure in patients with advanced CKD (hazard ratio 0.92 [95% CI: 0.67 - 1.23], p=0.63)., Conclusion: RAASi has no significant impact on the time to kidney failure in patients with advanced CKD. Hence, this study supports maintenance of RAASi in advanced CKD, if used for extrarenal indications such as cardiovascular protection., (S. Karger AG, Basel.)

Background: Small extracellular vesicles (sEV) released by tumor cells (tumor-derived sEV; TEX) mediate intercellular communication between tumor and non-malignant cells and were shown to impact disease progression. This study investigates the relationship between the expression levels of the vesiculation-related genes linked to sEV production and the tumor microenvironment (TME)., Methods: Two independent gene sets were analyzed, both previously linked to sEV production in various non-malignant or malignant cells. Expression profiles were compared among 28 tumor types listed in the Cancer Genome Atlas (TCGA). Gene expression and survival analysis (GEPIA2), immunogenomic analysis (TISIDB), and genomic analysis (GSCA) were performed., Results: Vesiculation-related genes were overexpressed in tissues of most tumor types compared to healthy tissues, and high expression levels were associated with worse overall survival in cervical squamous cell carcinoma, kidney chromophobe, lower grade glioma, hepatocellular carcinoma, lung squamous cell carcinoma, and pancreatic adenocarcinoma but with improved overall survival in kidney renal clear cell carcinoma. Expression of these signatures correlated with an increased abundance of infiltrating CD4( +) T cells and dendritic cells, a decreased abundance of B cells and eosinophils, and activation of tumor cell apoptosis and epithelial-mesenchymal transition pathways in all tumor types. 17-AAG was identified as a potential drug candidate to target tumors with elevated expression of vesiculation-related genes., Conclusions: Vesiculation-related genes were associated with distinct immunological and genomic landscapes further emphasizing the important role of TEX in cancer progression., Competing Interests: Declarations. Conflict of interest: S.H. is an employee of and holds equity interest in Roche/Genentech Inc. The other authors declare that they have no conflict of interest., (© 2024. The Author(s), under exclusive licence to Federación de Sociedades Españolas de Oncología (FESEO).)

Autosomal dominant polycystic kidney disease (ADPKD) is caused by mutations in PKD1 and PKD2, encoding polycystin-1 (PC1) and polycystin-2 (PC2), which are required for the regulation of the renal tubular diameter. Loss of polycystin function results in cyst formation. Atypical forms of ADPKD are caused by mutations in genes encoding endoplasmic reticulum (ER)-resident proteins through mechanisms that are not well understood. Here, we investigate the function of DNAJB11, an ER co-chaperone associated with atypical ADPKD. We generated mouse models with constitutive and conditional Dnajb11 inactivation and Dnajb11-deficient renal epithelial cells to investigate the mechanism underlying autosomal dominant inheritance, the specific cell types driving cyst formation, and molecular mechanisms underlying DNAJB11-dependent polycystic kidney disease. We show that biallelic loss of Dnajb11 causes cystic kidney disease and fibrosis, mirroring human disease characteristics. In contrast to classical ADPKD, cysts predominantly originate from proximal tubules. Cyst formation begins in utero and the timing of Dnajb11 inactivation strongly influences disease severity. Furthermore, we identify impaired PC1 cleavage as a potential mechanism underlying DNAJB11-dependent cyst formation. Proteomic analysis of Dnajb11- and Pkd1-deficient cells reveals common and distinct pathways and dysregulated proteins, providing a foundation to better understand phenotypic differences between different forms of ADPKD., (© 2024 The Author(s). The FASEB Journal published by Wiley Periodicals LLC on behalf of Federation of American Societies for Experimental Biology.)

Background: Diabetes mellitus is a major risk factor for the development of chronic kidney disease (CKD). There is limited data addressing the value of glycated hemoglobin (HbA1c) to predict renal outcomes independent of diabetes status., Methods: This single-center retrospective observational study presents data of 19,285 subjects, irrespective of initial CKD or diabetes status. The primary endpoint was defined as the time to manifestation of moderate CKD (estimated glomerular filtration rate [eGFR] <60 mL/min/1.73 m 2 ) in subjects with eGFR ≥60 mL/min/1.73 m 2 at baseline. The secondary endpoint was defined as time to progression of CKD (eGFR <30 mL/min/1.73 m 2 ) in subjects with eGFR 30-60 mL/min/1.73 m 2 . Multivariate time-to-event and logistic regression models were applied to estimate the influences of HbA1c, sex, age, eGFR, triglycerides, and cholesterol on both endpoints., Results: Lowest baseline HbA1c levels were associated with the slowest decline of kidney function (median time to manifestation of moderate CKD for HbA1c <5.7%: 15.9 years [95% confidence interval (CI): 15.2-16.7]; for HbA1c 5.7%-6.5%: 14.5 years [95% CI: 14.0-15.1]; for HbA1c 6.5%-8.5%: 11.1 years [95% CI: 10.4-11.7]; for HbA1c >8.5%: 8.3 years [95% CI: 7.8-9.2]; p < 0.001). Similar results were observed for the secondary endpoint. Covariate-adjusted time-to-event analysis demonstrated an almost linear correlation between continuous baseline HbA1c levels and the probabilities of reaching both endpoints., Conclusions: HbA1c levels are a strong predictor for eGFR decline, irrespective of diabetes status or CKD stage, demonstrating a tight concentration-dependent relationship. This association becomes apparent in the prediabetic HbA1c range and remains constant over the entire HbA1c spectrum., (© 2023 The Authors. Journal of Internal Medicine published by John Wiley & Sons Ltd on behalf of Association for Publication of The Journal of Internal Medicine.)

Objective: B-cell depletion using the anti-CD20 monoclonal antibody rituximab is a cornerstone in the therapeutic concept of multiple autoimmune diseases. B-cell depletion is associated with a higher risk for severe infections, and the time span of B-cell repopulation differs greatly between individuals. Data on factors influencing B-cell repopulation kinetics are limited. This study aims to identify patient-specific and therapy-associated covariates that modulate B-cell repopulation., Methods: This single-center retrospective observational study presents data of 839 subjects receiving 2,017 courses of rituximab for autoimmune diseases. Assessed covariates are patient-specific factors (sex, age, kidney function, and underlying disease) and co-immunosuppression with common agents (azathioprine, cyclosporine A, cyclophosphamide, hydroxychloroquine, methotrexate, mycophenolate mofetil, tacrolimus, and corticosteroids). The primary end point is the time to B-cell repopulation (≥5/μl). The secondary end point is the time to B-cell reconstitution (≥50/μl). Multivariate time-to-event analysis and logistic regression models were applied to estimate the influence of covariates., Results: Age over 60 years (hazard ratio [HR] 0.71 for repopulation, P = 0.008), impaired kidney function (HR 0.72, P = 0.001), antineutrophil cytoplasmic antibody-associated vasculitis (HR 0.61, P < 0.001), solid organ transplantation (HR 0.4, P < 0.001), and co-immunosuppression with corticosteroids (HR 0.64, P < 0.001) or azathioprine (HR 0.49, P < 0.001) were associated with impaired B-cell repopulation and reconstitution. Effects of corticosteroids (P = 0.043) and azathioprine (P = 0.025) were dose dependent., Conclusion: Prolonged rituximab dosing intervals may be effective to achieve B-cell depletion and reduce risk of infection in advanced age or patients with impaired kidney function. Co-medication with corticosteroids or azathioprine prolongs B-cell recovery, which may increase therapeutic effects but also the rate of adverse events., (© 2023 The Authors. Arthritis & Rheumatology published by Wiley Periodicals LLC on behalf of American College of Rheumatology.)

Background: Primary membranous nephropathy (PMN) frequently causes nephrotic syndrome and declining kidney function. Disease progression is likely modulated by patient-specific and therapy-associated factors awaiting characterization. These cofactors may facilitate identification of risk groups and could result in more individualized therapy recommendations., Methods: In this single-center retrospective observational study, we analyze the effect of patient-specific and therapy-associated covariates on proteinuria, hypoalbuminemia, and estimated glomerular filtration rate (eGFR) in 74 patients diagnosed with antibody positive PMN and nephrotic-range proteinuria (urine-protein-creatinine-ratio [UPCR] ≥ 3.5 g/g), treated at the University of Freiburg Medical Center between January 2000 - November 2022. The primary endpoint was defined as time to proteinuria / serum-albumin response (UPCR ≤ 0.5 g/g or serum-albumin ≥ 3.5 g/dl), the secondary endpoint as time to permanent eGFR decline (≥ 40% relative to baseline)., Results: The primary endpoint was reached after 167 days. The secondary endpoint was reached after 2413 days. Multivariate time-to-event analyses showed significantly faster proteinuria / serum-albumin response for higher serum-albumin levels (HR 2.7 [95% CI: 1.5 - 4.8]) and cyclophosphamide treatment (HR 3.6 [95% CI: 1.3 - 10.3]). eGFR decline was significantly faster in subjects with old age at baseline (HR 1.04 [95% CI: 1 - 1.1])., Conclusion: High serum-albumin levels, and treatment with cyclophosphamide are associated with faster proteinuria reduction and/or serum-albumin normalization. Old age constitutes a risk factor for eGFR decline in subjects with PMN., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Introduction: Experience of pain during screening mammography is shown to affect further attendance negatively. We aimed to explore the experience of pain during screening mammography using three different breast compression paddles., Methods: Using a self-report questionnaire, we collected information on pain experienced during mammography from 938 women screened in Bodø at Nordland Hospital County in 2018, as a part of BreastScreen Norway. Pain was assessed by a numeric rating scale (NRS, 0-10). A fixed paddle, a flexible paddle or a fixed paddle standardizing pressure (study paddle) were used during screening. Compression force (kg) was recorded by the radiographers for each screening examination. Log-binomial regression was used to determine the relative risk (RR) of severe (≥7 on NRS) versus mild/moderate (<7 on NRS) experience of pain associated with type of compression paddle, adjusting for breast tenderness, shoulder(s) and/or neck pain prior to screening, compression force, age, body mass index and screening history., Results: Mean score of self-reported experienced pain was 2.8 for the fixed, 2.3 for the flexible and 2.8 for the study paddle (p < 0.03 for fixed versus flexible and for flexible versus study paddle). Adjusted RR of severe pain was higher for the fixed (RR Adj 2.01, 95%CI 1.13-3.59) and the study paddle (RR Adj 2.52, 95%CI 1.44-4.42) compared to the flexible paddle. Breast tenderness was associated with a higher risk (RR Adj 1.93, 95%CI 1.04-3.58) of severe pain compared to no breast tenderness., Conclusion: Women screened with the flexible paddle reported lower experience of pain than those screened with the fixed or study paddle., Implication for Practice: The flexible compression paddle might be the best choice regarding experience of pain in screening mammography. Breast tenderness should be considered by the radiographers in a practical screening setting., (Copyright © 2023 The College of Radiographers. Published by Elsevier Ltd. All rights reserved.)

Background: C3 Glomerulopathy (C3G) is a rare glomerular disease caused by dysregulation of the complement pathway. Based on its pathophysiology, treatment with the monoclonal antibody eculizumab targeting complement C5 may be a therapeutic option. Due to the rarity of the disease, observational data on the clinical response to eculizumab treatment is scarce., Methods: Fourteen patients (8 female, 57%) treated for C3 glomerulopathy at the medical center of the University of Freiburg between 2013 and 2022 were included. Subjects underwent biopsy before enrollment. Histopathology, clinical data, and response to eculizumab treatment were analyzed. Key parameters to determine the primary outcome were changes of estimated glomerular filtration rate (eGFR) over time. Positive outcome was defined as > 30% increase, stable outcome as ±30%, negative outcome as decrease > 30% of eGFR., Results: Eleven patients (78.8%) were treated with eculizumab, three received standard of care (SoC, 27.2%). Median follow-up time was 68 months (IQR: 45-98 months). Median eculizumab treatment duration was 10 months (IQR 5-46 months). After eculizumab treatment, five patients showed a stable outcome, six patients showed a negative outcome. Among patients receiving SoC, one patient showed a stable outcome, two patients showed a negative outcome., Conclusions: The benefit of eculizumab in chronic progressive C3 glomerulopathy is limited., (© 2023. The Author(s).)

Genome editing tools such as CRISPR/Cas9 enable the rapid and precise manipulation of genomes. CRISPR-based genome editing has greatly simplified the study of gene function in cell lines, but its widespread use has also highlighted challenges of reproducibility. Phenotypic variability among different knockout clones of the same gene is a common problem confounding the establishment of robust genotype-phenotype correlations. Optimized genome editing protocols to enhance reproducibility include measures to reduce off-target effects. However, even if current state-of-the-art protocols are applied phenotypic variability is frequently observed. Here we identify heterogeneity of wild-type cells as an important and often neglected confounding factor in genome-editing experiments. We demonstrate that isolation of individual wild-type clones from an apparently homogenous stable cell line uncovers significant phenotypic differences between clones. Strikingly, we observe hundreds of differentially regulated transcripts (477 up- and 306 downregulated) when comparing two populations of wild-type cells. Furthermore, we show a variety of cellular and biochemical alterations in different wild-type clones in a range that is commonly interpreted as biologically relevant in genome-edited cells. Heterogeneity of wild-type cells thus contributes to variability in genome-edited cells when these are generated through isolation of clones. We show that the generation of monoclonal isogenic wild-type cells prior to genomic manipulation reduces phenotypic variability. We therefore propose to generate matched isogenic control cells prior to genome editing to increase reproducibility., (© 2022. The Author(s).)

Background: Severe COVID-19 can necessitate multiple organ support including veno-venous extracorporeal membrane oxygenation (vvECMO) and renal replacement therapy. The therapy can be complicated by venous thromboembolism due to COVID-19-related hypercoagulability, thus restricting vascular access beyond the vvECMO cannula. Although continuous renal replacement therapy can be performed via a vvECMO circuit, studies addressing sustained low-efficiency dialysis (SLED) integration into vvECMO circuits are scarce. Here we address the lack of evidence by evaluating feasibility of SLED integration into vvECMO circuits., Methods: Retrospective cohort study on nine critically ill COVID-19 patients, treated with integrated ECMO-SLED on a single intensive care unit at a tertiary healthcare facility between December 2020 and November 2021. The SLED circuits were established between the accessory arterial oxygenator outlets of a double-oxygenator vvECMO setup. Data on filter survival, quality of dialysis, and volume management were collected and compared with an internal control group receiving single SLED., Results: This study demonstrates general feasibility of SLED integration into existing vvECMO circuits. Filter lifespans of ECMO-SLED compared with single SLED are significantly prolonged (median 18.3 h vs. 10.3 h, p < 0.01). ECMO-SLED treatment is furthermore able to sufficiently normalize creatinine, blood urea nitrogen, and serum sodium, and allows for adequate ultrafiltration rates., Conclusions: We can show that ECMO-SLED is practical, safe, results in adequate dialysis quality and enables sufficient electrolyte and volume management. Our data indicate that SLED devices can serve as potential alternative to continuous-veno-venous-hemodialysis for integration in vvECMO circuits., (© 2022 The Authors. Artificial Organs published by International Center for Artificial Organ and Transplantation (ICAOT) and Wiley Periodicals LLC.)

Study Design: This single-center retrospective study analyzed patients with an implant-associated infection of spinal instrumentation (four or more segments) treated between 2010 and 2018., Purpose: This study aimed to investigate the treatment of implant-associated infections of long-segment spinal instrumentation and to define risk factors for implant removal., Overview of Literature: Implant-associated infection occurs in 0.7%-20% of spinal instrumentation. Significant blood loss, delayed reoperation, and use of effective antibiotics are reported risk factors for implant removal., Methods: Patients with superficial infections not involving the implant were excluded. All patients received surgical and antibiotic treatments according to our interdisciplinary osteomyelitis board protocol. An infection was considered healed if a patient showed no signs of infection 1 year after termination of treatment. The patients were divided into an implant retention group and implant removal group, and their clinical and microbiological data were compared., Results: Forty-six patients (27 women, 19 men) with an implant-associated infection of long-segment spinal instrumentation and mean age of 65.3±14.3 years (range, 22-89 years) were included. The mean length of the infected instrumentation was 6.5±2.4 segments (range, 4-13 segments). Implant retention was possible in 21 patients (45.7%); in the other 25 patients (54.3%), a part of or the entire implant required removal. Late infections were associated with implant removal, which correlated with longer hospitalization. Both groups showed high postoperative complication rates (50%) and high mortality rates (8.7%). In 39 patients (84.8%), infection was eradicated at a mean follow-up of 18.9±11.1 months (range, 12-60 months). Three patients (6.5%) were lost to follow-up., Conclusions: Implant-associated infections of long-segment spinal instrumentations are associated with high complication and mortality rates. Late infections are associated with implant removal. Treatment should be interdisciplinary including orthopedic surgeons and clinical infectiologists.

Background: There is debate regarding criteria to select patients for lumbar fusion surgery who have chronic low back pain (CLBP) and corresponding degenerative changes, but without nerve root compression or neurogenic claudication. The aim of this study was to compare patterns in current practice., Method: A total of 143 printed questionnaires containing 51 questions were distributed at the German Spine Societies' (DWG) annual congress, 6-8 December 2018., Results: We received 127 (89%) surveys (64 orthopedic surgeons and 63 neurosurgeons). Excluding the 22% who do not perform lumbar fusion for CLBP, 41.4% reported performing 1-10 lumbar fusion procedures for patients with CLBP per year, 20.2% reported 11-20, 10.1% reported 21-30 and 17.2% reported performing more than 50. A total of 44.9% of surgeons reported treating patients for at least 6-12 months conservatively before considering surgery; 65.6% considered postoperative pain reduction of 50-70% a treatment success; 32.6% of respondents believe that <50% of patients showed good outcomes after fusion in CLBP and only 15.5% believed that 70% or more showed good outcomes. Orthopedic surgeons perform more lumbar fusion surgeries than neurosurgeons (p = 0.05), fuse more lumbar segments than neurosurgeons (p = 0.02) and are more likely to suggest that their patients with CLBP cease smoking preoperatively (p = 0.02)., Conclusions: Despite discouraging evidence in the literature, the majority of respondents still perform fusion surgery in patients with CLBP. The use of preoperative diagnostics and tests vary widely among spine surgeons.

Purpose The lack of culturally and linguistically appropriate interventions contributes to unsatisfactory hearing health care service delivery and outcomes for Spanish-speaking persons from Hispanic/Latino background. To address this issue, our objective was to cross-culturally adapt a "Hearing Loss Toolkit for Self-Management" for use with Spanish-speaking adults seen in a clinical setting. In this clinical focus article, we describe a process for translation and cross-cultural adaptation of patient education materials based on current best practices guidelines. Method We utilized guidelines from the International Society for Pharmoeconomics Outcomes Research Task Force for Translation and Cultural Adaptation, the World Health Organization, and the International Collegium of Rehabilitative Audiology to complete a comprehensive, systematic, cross-cultural adaptation process of the source materials. The adaptation stages included forward translation and reconciliation, back translation and review, field testing with representative end users from the target population, and finalization. Results We successfully cross-culturally adapted the source materials following best practice guidelines. The Spanish-language adaptation was deemed understandable, actionable, aesthetically pleasing, and culturally appropriate by a group of native Spanish speakers. Conclusions There is an unmet need for the development of hearing loss self-management materials that incorporate cultural and linguistic competence with best health literacy practices. High-quality cross-cultural adaptations that consider the intersection of culture, language, and health literacy are a positive step toward reducing barriers to hearing health care related to language access for U.S. Hispanic/Latino adults with hearing loss.