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Background: Hemangioblastomas are highly vascularized tumors that may be associated with extensive architecture of the surrounding pathological vessels. The distinction between feeding arteries and draining veins is usually not obvious during microsurgical en-bloc tumor resection. The aim of this investigation is to provide recommendations in which hemangioblastomas intraoperative indocyanine green (ICG) videoangiography might be beneficial for safe en-bloc tumor resection., Methods: This is a single-center retrospective review of resected spinal hemangioblastomas over a 59-month period to identify operations in which ICG videoangiography was used. We analyzed whether intraoperative ICG videoangiography is useful for identifying possible feeding arteries and draining veins. The identified benefits and shortcomings of this technique were summarized., Results: In total, 39 patients had surgery for removal of spinal hemangioblastomas. Intraoperative ICG videoangiography was performed in 26 surgeries for resection of spinal hemangioblastomas (66.7 %). In 25 of 27 removed hemangioblastomas (92.6 %), intraoperative ICG videoangiography yielded useful insights about the vascularization of the tumor and as thus regarded as helpful. In two cases, the pathological vessels could not be clearly assigned to feeding arteries or draining vessels. Complete tumor removal was achieved in all patients., Conclusion: ICG videoangiography offers real-time intraoperative visualization of the tumor vasculature and can therefore improve surgical decision-making. Ideally, direct microscopic visualization of the structures to be assessed should be aimed for in ICG videoangiography. The information gained from ICG videoangiography may be limited in the case of tumors or vessels that lie deeper or are covered by the myelon or other structures., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Rationale & Objective: Afamin is a vitamin E-binding glycoprotein primarily expressed in liver and kidney. This study investigated whether serum afamin concentrations are associated with kidney function and incident kidney failure., Study Design: Prospective cohort study with 6.5 years follow-up., Setting & Participants: 5,041 Caucasian patients enrolled in the German Chronic Kidney Disease (GCKD) study with measured afamin concentrations and either an estimated glomerular filtration rate (eGFR) of 30-60 mL/min/1.73m 2 or an eGFR >60 mL/min/1.73m 2 with a urinary albumin to creatinine ratio (UACR) >300 mg/g at study entry., Exposure: Serum afamin concentrations (mg/L)., Outcome: Incident kidney failure (initiation of kidney replacement therapy or kidney-related death)., Analytical Approach: Generalized linear regression and quantile regression models fit to investigate the association of afamin concentrations with eGFR and UACR. Adjusted Cox regression analysis to examine the association of afamin concentrations with incident failure., Results: The mean (±SD) afamin concentration at study entry was 73.2±17.6 mg/L. Higher afamin concentrations were associated with better kidney function with a 2.60 ml/min/1.73m 2 higher eGFR (95% CI 2.30-2.89) and a 5.97 mg/g lower UACR (95% CI 3.04-8.90) for each 10 mg/L higher level of afamin concentration in adjusted analysis. During follow-up, each 10 mg/L higher level of afamin concentration was associated with a 14% lower risk of kidney failure (HR=0.86, 95%CI: 0.81 to 0.92, P<0.001)., Limitations: Residual confounding. Potential limited generalizability to non-Caucasian populations and people with mild stages of CKD or no CKD., Conclusions: Higher serum afamin concentrations appear to be associated with a higher eGFR, less albuminuria, and a lower risk for future kidney failure in patients with CKD., (Copyright © 2024. Published by Elsevier Inc.)

Background: Persons with chronic kidney disease (CKD) are at increased risk of adverse events, early mortality and multimorbidity. A detailed overview of adverse event types and rates from a large CKD cohort under regular nephrological care is missing. We generated an interactive tool to enable exploration of adverse events and their combinations in the prospective, observational German CKD (GCKD) study., Methods: The GCKD study enrolled 5217 participants under regular nephrological care with an estimated glomerular filtration rate of 30-60 or >60 mL/min/1.73 m2 and an overt proteinuria. Cardiovascular, cerebrovascular and peripheral vascular, kidney, infection, and cancer events, as well as deaths were adjudicated following a standard operation procedure. We summarized these time-to-event data points for exploration in interactive graphs within an R shiny app. Multivariable adjusted Cox models for time to first event were fitted. Cumulative incidence functions, Kaplan-Meier curves and intersection plots were used to display main adverse events and their combinations by sex and CKD etiology., Results: Over a median of 6.5 years, 10 271 events occurred in 2947 participants (56.5%), of which 680 participants (13.0%) died. The new publicly available interactive platform enables readers to scrutinize adverse events and their combinations as well as mortality trends as a gateway to better understand multimorbidity in CKD: incident rates per 1000 patient-years varied by event type, CKD etiology and baseline characteristics. Incidence rates for the most frequent events and their recurrence were 113.6 (cardiovascular), 75.0 (kidney) and 66.0 (infection). Participants with presumed diabetic kidney disease and men were more prone to experiencing events., Conclusion: This comprehensive explorative tool to visualize adverse events (https://www.gckd.org/studienhintergrund/previous-study-results/event-analysis/), their combination, mortality and multimorbidity among persons with CKD may serve as a valuable resourec for patient care, identification of high-risk groups, health services and public health policy planning., (© The Author(s) 2024. Published by Oxford University Press on behalf of the ERA.)

Early identification of patients at risk with von Hippel-Lindau (VHL) syndrome-related pheochromocytoma and paraganglioma (PPGL) is crucial to prevent morbidity. We investigated the current surveillance recommendations in VHL-related PPGL in children and adolescents. German Pediatric Oncology and Hematology-Malignant Endocrine Tumor registry (GPOH-MET) and Freiburg-VHL registry (1996-2022). In all, 75 patients (aged 0-18 years) with VHL syndrome were analyzed and 52 were in the Freiburg screening/surveillance program (median follow-up: 11.5 ± 0.94 years), including annual hormone level measurements, eye examination (starting at the age 6 years), and MRI of the abdomen and central nervous system (CNS) (starting at the age of 12 years). Retrospective analysis of clinical outcomes and descriptive statistics was performed. Of the 75 patients, 60 had a previous clinical diagnosis of PPGL with subsequent genetic testing, and 63% had a positive family history. In spite of having positive family history, large variations of timings between genetic and clinical diagnosis (range: -9 to +40 years) were observed. The mean age of first PPGL was 12.4 ± 0.41 years (range: 4-18 years). Recurrence of PPGL was common (46%; range: 2-7 per patient), and that of other tumors occurred: hemangioblastomas (73%), retinal angiomas (58%), renal cell carcinomas (21%), and pancreatic neuroendocrine tumors (12%). VHL-related PPGL appeared by the age of 12 and recurrences were observed frequently. Hemangioblastomas and retinal angiomas were common. In spite of a positive family history, VHL diagnoses were delayed. Because of high tumor proportions of affected families with children, it needs an optimization of the surveillance framework to enhance compliance and minimize anxiety and worse disease outcomes., Competing Interests: The authors reported no conflict of interest., (Copyright: Neumann-Haefelin E., et al.)

Background: Chronic kidney disease (CKD) is highly connected to inflammation and oxidative stress. Both favour the development of cancer in CKD patients. Serum apolipoprotein A-IV (apoA-IV) concentrations are influenced by kidney function and are an early marker of kidney impairment. Besides others, it has antioxidant and anti-inflammatory properties. Proteomic studies and small case-control studies identified low apoA-IV as a biomarker for various forms of cancer; however, prospective studies are lacking. We therefore investigated whether serum apoA-IV is associated with cancer in the German Chronic Kidney Disease (GCKD) study., Methods: These analyses include 5039 Caucasian patients from the prospective GCKD cohort study followed for 6.5 years. Main inclusion criteria were an eGFR of 30-60 mL/min/1.73m 2 or an eGFR > 60 mL/min/1.73m 2 in the presence of overt proteinuria., Results: Mean apoA-IV concentrations of the entire cohort were 28.9 ± 9.8 mg/dL (median 27.6 mg/dL). 615 patients had a history of cancer before the enrolment into the study. ApoA-IV concentrations above the median were associated with a lower odds for a history of cancer (OR = 0.79, p = 0.02 when adjusted age, sex, smoking, diabetes, BMI, albuminuria, statin intake, and eGFR creatinine ). During follow-up 368 patients developed an incident cancer event and those with apoA-IV above the median had a lower risk (HR = 0.72, 95%CI 0.57-0.90, P = 0.004). Finally, 62 patients died from such an incident cancer event and each 10 mg/dL higher apoA-IV concentrations were associated with a lower risk for fatal cancer (HR = 0.62, 95%CI 0.44-0.88, P = 0.007)., Conclusions: Our data indicate an association of high apoA-IV concentrations with reduced frequencies of a history of cancer as well as incident fatal and non-fatal cancer events in a large cohort of patients with CKD., (© 2024. The Author(s).)

Background: Chronic kidney disease (CKD), a major public health problem with differing disease etiologies, leads to complications, comorbidities, polypharmacy, and mortality. Monitoring disease progression and personalized treatment efforts are crucial for long-term patient outcomes. Physicians need to integrate different data levels, e.g., clinical parameters, biomarkers, and drug information, with medical knowledge. Clinical decision support systems (CDSS) can tackle these issues and improve patient management. Knowledge about the awareness and implementation of CDSS in Germany within the field of nephrology is scarce., Purpose: Nephrologists' attitude towards any CDSS and potential CDSS features of interest, like adverse event prediction algorithms, is important for a successful implementation. This survey investigates nephrologists' experiences with and expectations towards a useful CDSS for daily medical routine in the outpatient setting., Methods: The 38-item questionnaire survey was conducted either by telephone or as a do-it-yourself online interview amongst nephrologists across all of Germany. Answers were collected and analysed using the Electronic Data Capture System REDCap, as well as Stata SE 15.1, and Excel. The survey consisted of four modules: experiences with CDSS (M1), expectations towards a helpful CDSS (M2), evaluation of adverse event prediction algorithms (M3), and ethical aspects of CDSS (M4). Descriptive statistical analyses of all questions were conducted., Results: The study population comprised 54 physicians, with a response rate of about 80-100% per question. Most participants were aged between 51-60 years (45.1%), 64% were male, and most participants had been working in nephrology out-patient clinics for a median of 10.5 years. Overall, CDSS use was poor (81.2%), often due to lack of knowledge about existing CDSS. Most participants (79%) believed CDSS to be helpful in the management of CKD patients with a high willingness to try out a CDSS. Of all adverse event prediction algorithms, prediction of CKD progression (97.8%) and in-silico simulations of disease progression when changing, e. g., lifestyle or medication (97.7%) were rated most important. The spectrum of answers on ethical aspects of CDSS was diverse., Conclusion: This survey provides insights into experience with and expectations of out-patient nephrologists on CDSS. Despite the current lack of knowledge on CDSS, the willingness to integrate CDSS into daily patient care, and the need for adverse event prediction algorithms was high., (© 2023. The Author(s).)

Mineral and bone disorder (MBD) in chronic kidney disease (CKD) is tightly linked to cardiovascular disease (CVD). In this study, we aimed to compare the prognostic value of nine MBD biomarkers to determine those associated best with adverse cardiovascular (CV) outcomes and mortality. In 5 217 participants of the German CKD (GCKD) study enrolled with an estimated glomerular filtration rate (eGFR) between 30-60 mL·min -1 per 1.73 m 2 or overt proteinuria, serum osteoprotegerin (OPG), C-terminal fibroblast growth factor-23 (FGF23), intact parathyroid hormone (iPTH), bone alkaline phosphatase (BAP), cross-linked C-telopeptide of type 1 collagen (CTX1), procollagen 1 intact N-terminal propeptide (P1NP), phosphate, calcium, and 25-OH vitamin D were measured at baseline. Participants with missing values among these parameters (n = 971) were excluded, leaving a total of 4 246 participants for analysis. During a median follow-up of 6.5 years, 387 non-CV deaths, 173 CV deaths, 645 nonfatal major adverse CV events (MACEs) and 368 hospitalizations for congestive heart failure (CHF) were observed. OPG and FGF23 were associated with all outcomes, with the highest hazard ratios (HRs) for OPG. In the final Cox regression model, adjusted for CV risk factors, including kidney function and all other investigated biomarkers, each standard deviation increase in OPG was associated with non-CV death (HR 1.76, 95% CI: 1.35-2.30), CV death (HR 2.18, 95% CI: 1.50-3.16), MACE (HR 1.38, 95% CI: 1.12-1.71) and hospitalization for CHF (HR 2.05, 95% CI: 1.56-2.69). Out of the nine biomarkers examined, stratification based on serum OPG best identified the CKD patients who were at the highest risk for any adverse CV outcome and mortality., (© 2023. West China School of Stomatology Sichuan University.)

Background: Diabetes mellitus (DM) and chronic kidney disease (CKD) are well-known cardiovascular and mortality risk factors. To what extent they act in an additive manner and whether the etiology of CKD modifies the risk is uncertain., Methods: The multicenter, prospective, observational German Chronic Kidney Disease study comprises 5217 participants (1868 with DM) with a baseline mean estimated glomerular filtration rate of 30-60 mL/min/1.73 m 2 and/or proteinuria >0.5 g/day. We categorized patients whose CKD was caused by cardiovascular or metabolic diseases (CKDcvm) with and without DM, as opposed to genuine CKD (CKDgen) with and without DM. Recorded outcomes were first events of non-cardiovascular and cardiovascular death, 4-point major adverse cardiovascular events (4-point MACE) and hospitalization for heart failure (HHF)., Results: During the 6.5-year follow-up 603 (12%) non-cardiovascular and 209 (4%) cardiovascular deaths, 645 (12%) 4-point MACE, and 398 (8%) HHF were observed, most frequently in patients with DM having CKDcvm. DM increased the risk of non-cardiovascular [hazard ratio (HR) 1.92; 95% confidence interval (CI) 1.59-2.32] and cardiovascular (HR 2.25; 95% CI 1.62-3.12) deaths, 4-point MACE (HR 1.93; 95% CI 1.62-2.31) and HHF (HR 1.87; 95% CI 1.48-2.36). Mortality risks were elevated by DM to a similar extent in CKDcvm and CKDgen, but for HHF in CKDcvm only (HR 2.07; 95% CI 1.55-2.77). In patients with DM, CKDcvm (versus CKDgen) only increased the risk for HHF (HR 1.93; 95% CI 1.15-3.22)., Conclusions: DM contributes to cardiovascular and mortality excess risk in patients with moderate to severe CKD in both, CKDcvm and CKDgen. Patients with DM and CKDcvm are particularly susceptible to HHF., Competing Interests: The authors J.N., F.K., H.S., V.K., C.S., I.L., T.Saritas, T.Sitter, M.P.S., M.S. and G.W. have no competing conflict of interest to declare. J.R. reports receiving support for attending meetings including travel support by Vifor and Alexion, and receiving lecture honoraria from Novartis. B.B. and H.M. report receiving study grants by the BEAt DKD Consortium. U.T.S. reports receiving travel support grant from German Ministry of Education and Research (BMBF, grant number 01ZX1912B) within the framework of the e:Med junior consortium CKDNapp entailed travel support. J.T.K. reports receiving honoraria from Vifor, FMC, ExThera Medical, AstraZeneca and Takeda, and stock from BAYER, Quanteryx and Synlab. C.W. reports receiving institutional grants from Idorsia, Sanofi and Boehringer Ingelheim; consulting fees from AstraZeneca, Boehringer Ingelheim, Idorsia, Bayer, GILEAD, GSK and MSD; and honoraria from Boehringer Ingelheim, AstraZeneca, FMC, Chiesi, Lilly and Vifor; and participation on a data safety monitoring board of Sanofi and Australasian Kidney Trials Network and on a leadership of the European Renal Association. K.-U.E. reports receiving grants, fees from consultancy and/or lecture fees from Akebia, Amgen, AstraZeneca, Bayer, Evotec, Otsuka, Retrophin and Vifor; and participation on data safety monitoring boards of Akebia, Bayer and Travere. M.B. reports receiving consulting fees from Boehringer Ingelheim, GSK, Novartis and Oksuka thereby participating in the (local) advisory boards; honoraria from Boehringer Ingelheim, AstraZeneca, Vifor, Pfizer, Bristol Myers Squibb and Novartis; support for attending meetings from Lilly, AstraZeneca and Hexal; and being an unpaid board member in the Thuringian Society of Internal Medicine., (© The Author(s) 2023. Published by Oxford University Press on behalf of the ERA.)

Objective: Adipose tissue contributes to adverse outcomes in chronic kidney disease (CKD), but there is uncertainty regarding the prognostic relevance of different adiposity measures. We analyzed the associations of neck circumference (NC), waist circumference (WC), and body mass index (BMI) with clinical outcomes in patients with mild to severe CKD., Methods: The German Chronic Kidney Disease study is a prospective cohort study, which enrolled Caucasian adults with mild to severe CKD, defined as estimated glomerular filtration rate : 30-60 mL/min/1.73 m 2 , or >60 mL/min/1.73 m 2 in the presence of overt proteinuria. Associations of NC, WC, and BMI with all-cause death, major adverse cardiovascular events (MACE: a composite of nonfatal stroke, nonfatal myocardial infarction, peripheral artery disease intervention, and cardiovascular death), and kidney failure (a composite of dialysis or transplantation) were analyzed using multivariable Cox proportional hazards regression models adjusted for confounders and the Akaike information criteria were calculated. Models included sex interactions with adiposity measures., Results: A total of 4537 participants (59% male) were included in the analysis. During a 6.5-year follow-up, 339 participants died, 510 experienced MACE, and 341 developed kidney failure. In fully adjusted models, NC was associated with all-cause death in women (hazard ratio 1.080 per cm; 95% CI 1.009-1.155) but not in men. Irrespective of sex, WC was associated with all-cause death (hazard ratio 1.014 per cm; 95% CI 1.005-1.038). NC and WC showed no association with MACE or kidney failure. BMI was not associated with any of the analyzed outcomes. Models of all-cause death, including WC offered the best (lowest) Akaike information criteria., Conclusion: In Caucasian patients with mild to severe CKD, higher NC (in women) and WC were significantly associated with increased risk of death from any cause but BMI was not., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

The kidneys operate at the interface of plasma and urine by clearing molecular waste products while retaining valuable solutes. Genetic studies of paired plasma and urine metabolomes may identify underlying processes. We conducted genome-wide studies of 1,916 plasma and urine metabolites and detected 1,299 significant associations. Associations with 40% of implicated metabolites would have been missed by studying plasma alone. We detected urine-specific findings that provide information about metabolite reabsorption in the kidney, such as aquaporin (AQP)-7-mediated glycerol transport, and different metabolomic footprints of kidney-expressed proteins in plasma and urine that are consistent with their localization and function, including the transporters NaDC3 (SLC13A3) and ASBT (SLC10A2). Shared genetic determinants of 7,073 metabolite-disease combinations represent a resource to better understand metabolic diseases and revealed connections of dipeptidase 1 with circulating digestive enzymes and with hypertension. Extending genetic studies of the metabolome beyond plasma yields unique insights into processes at the interface of body compartments., (© 2023. The Author(s).)

Background: Osteopontin (OPN), synthesized in the thick ascending limb of Henle's loop and in the distal tubule, is involved in the pathogenesis of kidney fibrosis, a hallmark of kidney failure (KF). In a cohort of chronic kidney disease (CKD) patients, we evaluated OPN's association with kidney markers and KF., Methods: OPN was measured from baseline serum samples of German Chronic Kidney Disease study participants. Cross-sectional regression models for estimated glomerular filtration rate (eGFR) and urinary albumin-to-creatinine ratio (UACR) as well as Cox regression models for all-cause mortality and KF were evaluated to estimate the OPN effect. Additionally, the predictive ability of OPN and time-dependent population-attributable fraction were evaluated., Results: Over a median follow-up of 6.5 years, 471 KF events and 629 deaths occurred among 4950 CKD patients. One-unit higher log(OPN) was associated with 5.5 mL/min/1.73 m2 lower eGFR [95% confidence interval (95% CI) -6.4 to -4.6] and 1% change in OPN with 0.7% higher UACR (estimated effect 0.7, 95% CI 0.6-0.8). Moreover, higher OPN levels were associated with a higher risk of KF [hazard ratio (HR) 1.4, 95% CI 1.2-1.7] and all-cause mortality (HR 1.5, 95% CI 1.3-1.8). After 6 years, 31% of the KF events could be attributed to higher OPN levels (95% CI 3%-56%)., Conclusions: In this study, higher OPN levels were associated with kidney function markers worsening and a higher risk for adverse outcomes. A larger proportion of KF could be attributed to higher OPN levels, warranting further research on OPN with regards to its role in CKD progression and possible treatment options., (© The Author(s) 2022. Published by Oxford University Press on behalf of the ERA.)

Treatment resistant hypertension (TRH) appears of particular relevance in patients with chronic kidney disease (CKD). However, causes and consequences of TRH in CKD patients remain incompletely understood. Therefore, we analyzed the prevalence of apparent TRH (aTRH), and phenotypic characteristics and prognosis associated with aTRH among participants of the German Chronic Kidney Disease (GCKD) study. As insufficient medication adherence has been shown to be a frequent cause of pseudoresistance, we also assessed treatment adherence. Study participants were classified as having aTRH, controlled hypertension and uncontrolled hypertension based on study visit blood pressure and self-reported medication intake. Drug adherence was assessed by comparing self-reported antihypertensive medication with detectable urinary drug metabolites measured by mass spectroscopy. Out of 4901 individuals included in this study, 38% were classified as having aTRH. Male sex, older age, lower estimated glomerular filtration rate (eGFR), higher body mass index (BMI), higher urine albumin-to-creatinine ratio (UACR) and presence of diabetes mellitus were independently associated with higher prevalence of aTRH in a multivariable adjusted regression model. Patients classified as aTRH had higher risk for major adverse cardiovascular events and worsening of kidney disease compared to patients with no aTRH after multivariate adjustment for potential confounders. There was a high agreement between self-reported medication and detectable urinary drug metabolites. In conclusion, in a cohort of Caucasian patients with moderately severe CKD, aTRH was highly prevalent and, in most cases, likely not caused by low medication adherence. Furthermore, aTRH was linked to cardio-renal endpoints, emphasizing the need for improved management., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

Background: The progression of chronic kidney disease (CKD), a global public health burden, is accompanied by a declining number of functional nephrons. Estimation of remaining nephron mass may improve assessment of CKD progression. Uromodulin has been suggested as a marker of tubular mass. We aimed to identify metabolites associated with uromodulin concentrations in urine and serum to characterize pathophysiologic alterations of metabolic pathways to generate new hypotheses regarding CKD pathophysiology., Methods: We measured urinary and serum uromodulin levels (uUMOD, sUMOD) and 607 urinary metabolites and performed cross-sectional analyses within the German Chronic Kidney Disease study (N = 4628), a prospective observational study. Urinary metabolites significantly associated with uUMOD and sUMOD were used to build weighted metabolite scores for urine (uMS) and serum uromodulin (sMS) and evaluated for time to adverse kidney events over 6.5 years., Results: Metabolites cross-sectionally associated with uromodulin included amino acids of the tryptophan metabolism, lipids and nucleotides. Higher levels of the sMS [hazard ratio (HR) = 0.73 (95% confidence interval 0.64; 0.82), P = 7.45e-07] and sUMOD [HR = 0.74 (95% confidence interval 0.63; 0.87), P = 2.32e-04] were associated with a lower risk of adverse kidney events over time, whereas uUMOD and uMS showed the same direction of association but were not significant., Conclusions: We identified urinary metabolites associated with urinary and serum uromodulin. The sUMOD and the sMS were associated with lower risk of adverse kidney events among CKD patients. Higher levels of sUMOD and sMS may reflect a higher number of functional nephrons and therefore a reduced risk of adverse kidney outcomes., (© The Author(s) 2022. Published by Oxford University Press on behalf of the ERA.)

The opportunistic bacterium Pseudomonas aeruginosa can infect mucosal tissues of the human body. To persist at the mucosal barrier, this highly adaptable pathogen has evolved many strategies, including invasion of host cells. Here, we show that the P. aeruginosa lectin LecB binds and cross-links fucosylated receptors at the apical plasma membrane of epithelial cells. This triggers a signaling cascade via Src kinases and phosphoinositide 3-kinase (PI3K), leading to the formation of patches enriched with the basolateral marker phosphatidylinositol (3,4,5)-trisphosphate (PIP 3 ) at the apical plasma membrane. This identifies LecB as a causative bacterial factor for activating this well-known host cell response that is elicited upon apical binding of P. aeruginosa. Downstream from PI3K, Rac1 is activated to cause actin rearrangement and the outgrowth of protrusions at the apical plasma membrane. LecB-triggered PI3K activation also results in aberrant recruitment of caveolin-1 to the apical domain. In addition, we reveal a positive feedback loop between PI3K activation and apical caveolin-1 recruitment, which provides a mechanistic explanation for the previously observed implication of caveolin-1 in P. aeruginosa host cell invasion. Interestingly, LecB treatment also reversibly removes primary cilia. To directly prove the role of LecB for bacterial uptake, we coated bacterium-sized beads with LecB, which drastically enhanced their endocytosis. Furthermore, LecB deletion and LecB inhibition with l-fucose diminished the invasion efficiency of P. aeruginosa bacteria. Taken together, the results of our study identify LecB as a missing link that can explain how PI3K signaling and caveolin-1 recruitment are triggered to facilitate invasion of epithelial cells from the apical side by P. aeruginosa. IMPORTANCE An intriguing feature of the bacterium P. aeruginosa is its ability to colonize highly diverse niches. P. aeruginosa can, besides forming biofilms, also enter and proliferate within epithelial host cells. Moreover, research during recent years has shown that P. aeruginosa possesses many different mechanisms to invade host cells. In this study, we identify LecB as a novel invasion factor. In particular, we show that LecB activates PI3K signaling, which is connected via a positive feedback loop to apical caveolin-1 recruitment and leads to actin rearrangement at the apical plasma membrane. This provides a unifying explanation for the previously reported implication of PI3K and caveolin-1 in host cell invasion by P. aeruginosa. In addition, our study adds a further function to the remarkable repertoire of the lectin LecB, which is all brought about by the capability of LecB to recognize fucosylated glycans on many different niche-specific host cell receptors.

Background and Objectives: Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a key regulator of lipid homeostasis. Studies investigating the association between PCSK9 and cardiovascular disease in large cohorts of patients with CKD are limited., Design, Setting, Participants, & Measurements: The association of PCSK9 concentrations with prevalent and incident cardiovascular disease was investigated in 5138 White participants of the German Chronic Kidney Disease study with a median follow-up of 6.5 years. Inclusion criteria were eGFR of 30-60 or >60 ml/min per 1.73 m 2 in the presence of overt proteinuria (urine albumin-creatinine ratio >300 mg/g or equivalent). Prevalent cardiovascular disease was defined as a history of nonfatal myocardial infarction, coronary artery bypass grafting, percutaneous transluminal coronary angioplasty, carotid arteries interventions, and stroke. Incident major adverse cardiovascular disease events included death from cardiovascular causes, acute nonfatal myocardial infarction, and nonfatal stroke., Results: Median PCSK9 concentration in the cohort was 285 ng/ml (interquartile range, 231-346 ng/ml). There was no association between PCSK9 concentrations and baseline eGFR and albuminuria. With each 100-ng/ml increment of PCSK9, the odds for prevalent cardiovascular disease ( n =1284) were 1.22-fold (95% confidence interval, 1.12 to 1.34; P <0.001) higher in a model with extended adjustment for major confounders. This association was stronger in nonstatin than statin users ( P value for interaction =0.009). During follow-up, 474 individuals experienced a major adverse cardiovascular disease event, and participants in PCSK9 quartiles 2-4 had a 32%-47% higher risk compared with those in quartile 1 ( P <0.05). Subgroup analysis revealed that this association was restricted to those participants who already had cardiovascular disease at baseline (all hazard ratios >1.75; P =0.01). In addition, PCSK9 showed a valuable gain in classification accuracy for both prevalent cardiovascular disease (net reclassification index =0.27; 95% confidence interval, 0.20 to 0.33) and incident major adverse cardiovascular disease events during follow-up (net reclassification index =0.10; 95% confidence interval, 0.01 to 0.21) when added to an extended adjustment model., Conclusions: Our findings reveal no relation of PCSK9 with baseline eGFR and albuminuria but a significant association between higher PCSK9 concentrations and risk of cardiovascular disease independent of traditional risk factors, including LDL cholesterol levels. Clinical Trial registry name and registration number: German Chronic Kidney Disease Study (GCKD), DRKS 00003971., (Copyright © 2022 by the American Society of Nephrology.)

Background: Chronic kidney disease (CKD) represents a chronic proinflammatory state and is associated with very high cardiovascular risk. Apolipoprotein A-IV (apoA-IV) has antiatherogenic, antioxidative, anti-inflammatory and antithrombotic properties and levels increase significantly during the course of CKD., Objectives: We aimed to investigate the association between apoA-IV and all-cause mortality and cardiovascular outcomes in the German Chronic Kidney Disease study., Methods: This was a prospective cohort study including 5141 Caucasian patients with available apoA-IV measurements and CKD. The majority of the patients had an estimated glomerular filtration rate (eGFR) of 30-60 ml/min/1.73m 2 or an eGFR >60 ml/min/1.73m 2 in the presence of overt proteinuria. Median follow-up was 6.5 years. The association of apoA-IV with comorbidities at baseline and endpoints during follow-up was modelled adjusting for major confounders., Results: Mean apoA-IV concentrations of the entire cohort were 28.9 ± 9.8 mg/dl. Patients in the highest apoA-IV quartile had the lowest high-sensitivity C-reactive protein values despite the highest prevalence of diabetes, albuminuria and the lowest eGFR. Each 10 mg/dl higher apoA-IV translated into lower odds of prevalent cardiovascular disease (1289 cases, odds ratio = 0.80, 95% confidence interval [CI] 0.72-0.86, p = 0.0000003). During follow-up, each 10 mg/dl higher apoA-IV was significantly associated with a lower risk for all-cause mortality (600 cases, hazard ratio [HR] = 0.81, 95% CI 0.73-0.89, p = 0.00004), incident major adverse cardiovascular events (506 cases, HR = 0.88, 95% CI 0.79-0.99, p = 0.03) and death or hospitalizations due to heart failure (346 cases, HR = 0.84, 95% CI 0.73-0.96, p = 0.01)., Conclusions: These data support a link between elevated apoA-IV concentrations and reduced inflammation in moderate CKD. ApoA-IV appears to be an independent risk marker for reduced all-cause mortality, cardiovascular events and heart failure in a large cohort of patients with CKD., (© 2021 The Authors. Journal of Internal Medicine published by John Wiley & Sons Ltd on behalf of Association for Publication of The Journal of Internal Medicine.)

Introduction: Prospective data on impact of educational attainment on prognosis in patients with chronic kidney disease (CKD) are scarce. We investigated the association between educational attainment and all-cause mortality, major adverse cardiovascular (CV) events (MACEs), kidney failure requiring dialysis, and CKD etiology., Methods: Participants ( N  = 5095, aged 18-74 years) of the ongoing multicenter German Chronic Kidney Disease (GCKD) cohort, enrolled on the basis of an estimated glomerular filtration rate (eGFR) of 30 to 60 ml/min (stages G3, A1-A3) or overt proteinuria (stages G1-G2, A3), were divided into 3 categories according to their educational attainment and were followed for 6.5 years., Results: Participants with low educational attainment (vs. high) had a higher risk for mortality (hazard ratio [HR] 1.48, 95% CI: 1.16-1.90), MACE (HR 1.37, 95% CI: 1.02-1.83), and kidney failure (HR 1.54, 95% CI: 1.15-2.05). Mediators between low educational attainment and mortality were smoking, CV disease (CVD) at baseline, low income, higher body mass index, and higher serum levels of CRP, high-density lipoprotein cholesterol, uric acid, NGAL, BAP, NT-proBNP, OPN, H-FABP, and urea. Low educational attainment was positively associated with diabetic nephropathy (odds ratio [OR] 1.65, 95% CI: 1.36-2.0) and CKD subsequent to acute kidney injury (OR 1.56, 95% CI: 1.03-2.35), but negatively associated with IgA nephropathy (OR 0.68, 95% CI: 0.52-0.90)., Conclusion: Low educational attainment is associated with adverse outcomes and CKD etiology. Lifestyle habits and biomarkers mediate associations between low educational attainment and mortality. Recognition of the role of educational attainment and the associated health-relevant risk factors is important to optimize the care of patients with CKD and improve prognosis., (© 2022 International Society of Nephrology. Published by Elsevier Inc.)

Rationale & Objective: Stratification of chronic kidney disease (CKD) patients at risk for progressing to kidney failure requiring kidney replacement therapy (KFRT) is important for clinical decision-making and trial enrollment., Study Design: Four independent prospective observational cohort studies., Setting & Participants: The development cohort comprised 4,915 CKD patients, and 3 independent validation cohorts comprised a total of 3,063. Patients were observed for approximately 5 years., Exposure: 22 demographic, anthropometric, and laboratory variables commonly assessed in CKD patients., Outcome: Progression to KFRT., Analytical Approach: A least absolute shrinkage and selection operator (LASSO) Cox proportional hazards model was fit to select laboratory variables that best identified patients at high risk for KFRT. Model discrimination and calibration were assessed and compared against the 4-variable Tangri (T4) risk equation both in a resampling approach within the development cohort and in the validation cohorts using cause-specific concordance (C) statistics, net reclassification improvement, and calibration graphs., Results: The newly derived 6-variable risk score (Z6) included serum creatinine, albumin, cystatin C, and urea, as well as hemoglobin and the urinary albumin-creatinine ratio. In the the resampling approach, Z6 achieved a median C statistic of 0.909 (95% CI, 0.868-0.937) at 2 years after the baseline visit, whereas the T4 achieved a median C statistic of 0.855 (95% CI, 0.799-0.915). In the 3 independent validation cohorts, the Z6C statistics were 0.894, 0.921, and 0.891, whereas the T4C statistics were 0.882, 0.913, and 0.862., Limitations: The Z6 was both derived and tested only in White European cohorts., Conclusions: A new risk equation based on 6 routinely available laboratory tests facilitates identification of patients with CKD who are at high risk of progressing to KFRT., (Copyright © 2021 National Kidney Foundation, Inc. All rights reserved.)