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Jana K Striefler,1,2 Phung T Binder,2 Franziska Brandes,2 Daniel Rau,3 Silvan Wittenberg,3 David Kaul,4 Siyer Roohani,4 Armin Jarosch,5 Frederik M Schäfer,6 Robert Öllinger,7 Sven Märdian,3 Lars Bullinger,2,8 Kai-Uwe Eckardt,9 Jan Kruse,9 Anne Flörcken2,8 1Department of Internal Medicine II, Oncology/Hematology/BMT/Pneumology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; 2Department of Hematology, Oncology, and Tumor Immunology, Charité–Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität Zu Berlin, and Berlin Institute of Health, Berlin, Germany; 3Centre for Musculoskeletal Surgery, Campus Virchow-Klinikum, Charité–Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany; 4Department of Radiation Oncology, Campus Virchow-Klinikum, Charité–Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität Zu Berlin, and Berlin Institute of Health, Berlin, Germany; 5Institute of Pathology, Campus Mitte, Charité–Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany; 6Department of Radiology, Charité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität Zu Berlin, Berlin, Germany; 7Department of Surgery, Campus Virchow-Klinikum, Charité–Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany; 8German Cancer Consortium (DKTK), Partner Site Berlin, and German Cancer Research Center (DKFZ), Heidelberg, Baden-Württemberg, Germany; 9Department of Nephrology and Medical Intensive Care, Campus Virchow-Klinikum, Charité - Universitätsmedizin Berlin, corporate member of Free University Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, GermanyCorrespondence: Jana K Striefler, II. Medizinische Klinik und Poliklinik, Klinik für Onkologie, Hämatologie und Knochenmarktransplantation mit Sektion Pneumologie, Universitätsklinikum Hamburg-Eppendorf, Martinistr. 52, Hamburg, D-20246, Germany, Tel +49 152 228 24370, Fax +49 40 7410-58054, Email j.striefler@uke.dePurpose: Prognosis of sarcoma patients is improving, with a better understanding of sarcomagenesis revealing novel therapeutic targets. However, aggressive chemotherapy remains an essential part of treatment, bearing the risk of severe side effects that require intensive medical treatment. Available data on the characteristics and clinical outcome of sarcoma patients admitted to intensive care units (ICU) are sparse.Patients and Methods: We performed a retrospective analysis of sarcoma patients admitted to the ICU from 2005 to 2022. Patients ≥ 18 years with histologically proven sarcoma were included in our study.Results: Sixty-six patients were eligible for analysis. The following characteristics had significant impact on overall survival: sex (p=0.046), tumour localization (p=0.02), therapeutic intention (p=0.02), line of chemotherapy (p< 0.001), SAPS II score (p=0.03) and SOFA score (p=0.02).Conclusion: Our study confirms the predictive relevance of established sepsis and performance scores in sarcoma patients. For overall survival, common clinical characteristics are also of significant value. Further investigation is needed to optimize ICU treatment of sarcoma patients.Keywords: soft tissue sarcoma, intensive care unit, sepsis and performance scores, SOFA, SAPS II, ICU-specific survival

Jennifer Scheel,1 Katharina Schieber,1 Sandra Reber,1 Sabine Jank,2 Kai-Uwe Eckardt,2 Franziska Grundmann,3 Frank Vitinius,4 Martina de Zwaan,5 Anna Bertram,6 Yesim Erim11Department of Psychosomatic Medicine and Psychotherapy, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nürnberg (FAU), Erlangen, Germany; 2Department of Nephrology and Hypertension, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nürnberg (FAU), Erlangen, Germany; 3Department II of Internal Medicine, Nephrology, Rheumatology, Diabetes and General Internal Medicine, University Hospital of Cologne, Cologne, Germany; 4Department of Psychosomatics and Psychotherapy, University Hospital of Cologne, Cologne, Germany; 5Department of Psychosomatic Medicine and Psychotherapy, Hannover Medical School, Germany; 6Department of Nephrology and Hypertension, Hannover Medical School, Hanover, GermanyIntroduction: Though psychosocial well-being and quality of life generally improve after transplantation, a relevant proportion of patients suffers from psychosocial problems. Further analysis of the psychological coping after kidney transplantation is needed to identify patients at risk. The aim of this study was to examine the psychological response after kidney transplantation and its associations with health-related quality of life and immunosuppressant medication adherence.Materials and methods: The coping process after kidney transplantation was investigated with the Transplant Effects Questionnaire (TxEQ; subscales: worry, guilt, disclosure, adherence, responsibility) in 267 adult kidney transplant recipients ≥12 months post-transplantation. Furthermore, perceived health-related quality of life, self-reported immunosuppressant medication adherence, and sub-therapeutic immunosuppressant trough levels as biological markers of adherence were assessed.Results: Patients showed moderate scores concerning the subscales “worry”, “guilt”, and “responsibility” as well as high scores concerning “disclosure”. Except for “adherence”, all TxEQ subscales were associated with mental, but not with physical health-related quality of life and self-reported adherence. Sub-therapeutic immunosuppressant trough levels were significantly associated only with the TxEQ subscale “worry”.Conclusions: The present results suggest a conditional structure in which mental health-related quality of life is negatively associated with worries, guilt, and responsibility and positively with disclosure. Adherence seems to be a complex behavior, which is not necessarily directly associated with the psychological processing of organ transplantations. As mental health-related quality of life is related to this psychological processing, the TxEQ could be used as a screening tool for problematic psychological processing after kidney transplantation.Keywords: kidney transplantation, psychological processing, Transplant Effects Questionnaire, health-related quality of life, adherence, immunosuppressant trough levels

Hypertension is linked to disturbed total-body sodium (Na(+)) regulation; however, measuring Na(+) disposition in the body is difficult. We implemented (23)Na magnetic resonance spectroscopy ((23)Na-MR) and imaging technique ((23)Na-MRI) at 9.4T for animals and 3T for humans to quantify Na(+) content in skeletal muscle and skin. We compared (23)Na-MRI data with actual tissue Na(+) content measured by chemical analysis in animal and human tissue. We then quantified tissue Na(+) content in normal humans and in patients with primary aldosteronism. We found a 29% increase in muscle Na(+) content in patients with aldosteronism compared with normal women and men. This tissue Na(+) was mobilized after successful treatment without accompanying weight loss. We suggest that, after further refinements, this tool could facilitate understanding the relationships between Na(+) accumulation and hypertension. Furthermore, with additional technical advances, a future clinical use may be possible. [ABSTRACT FROM AUTHOR]

BACKGROUND: Anemia augments the already high rates of fatal and major nonfatal cardiovascular and renal events in individuals with type 2 diabetes. In 2004, we initiated the Trial to Reduce Cardiovascular Events With Aranesp Therapy (TREAT). This report presents the baseline characteristics and therapies of TREAT participants and subgroups defined by the presence or absence of overt proteinuria and history of cardiovascular disease. The design of TREAT and baseline characteristics also are compared with 2 recent trials of nondialysis patients with chronic kidney disease (CKD) in which treatment with another erythropoiesis-stimulating agent targeting greater hemoglobin levels had either a neutral or adverse effect on clinical outcomes. STUDY DESIGN: Randomized trial. SETTING & PARTICIPANTS: 4,044 participants with type 2 diabetes, CKD (defined as estimated glomerular filtration rate of 20 to 60 mL/min/1.73 m(2)), and anemia (hemoglobin < or = 11 g/dL) from 24 countries. INTERVENTION: Darbepoetin alfa to attempt to increase hemoglobin levels to 13 g/dL compared with placebo. OUTCOMES: TREAT is an event-driven design to continue until approximately 1,203 patients experience a primary event: the composite end point of death or cardiovascular morbidity (nonfatal myocardial infarction, congestive heart failure, stroke, or hospitalization for myocardial ischemia). The composite end point of death or need for long-term renal replacement therapy also is a primary end point. CONCLUSIONS: With several-fold more patient-years and a placebo arm, TREAT will provide a robust estimate of the safety and efficacy of darbepoetin alfa and generate prospective data regarding the risks of major cardiovascular and renal events in a contemporarily managed cohort of patients with type 2 diabetes, CKD, and anemia. Copyright © 2009 National Kidney Foundation, Inc. [ABSTRACT FROM AUTHOR]

The development of clinical practice guidelines for the treatment of anemia in chronic kidney disease has been instrumental in identifying and reducing variations in the use of erythropoiesis-stimulating agents and iron replacement. Challenges to the effectiveness and safety of recommendations made in these guidelines were magnified when recent clinical trials showed no benefit or harm with respect to cardiovascular outcomes in subjects randomized to higher target hemoglobin levels. To address these concerns, Kidney Disease: Improving Global Outcomes (KDIGO) convened an international conference to examine the problems and shortcomings of existing anemia guidelines, which are a prime example of duplication of efforts to derive recommendations from a limited evidence base. The meeting was attended by representatives of the major guideline developing organizations, who agreed to avoid future duplicative efforts and to save resources in generating a common evidence report, whose recommendations could then be prioritized and implemented locally. This is a report to the international nephrology community of the recommendations for and timeline of the next anemia guidelines. It has been reviewed by the conference participants and approved as a position statement by the KDIGO Board of Directors.Kidney International (2008) 74, 1237-1240; doi:10.1038/ki.2008.299; published online 2 July 2008. [ABSTRACT FROM AUTHOR]

'Low-dose' dopamine is frequently used in intensive care units (ICU) for its presumed renoprotective effects, but prospective and retrospective studies have so far not proven prevention or amelioration of renal injury. Data on renal perfusion following dopamine infusion are limited. In order to circumvent the problem of patient heterogeneity in the ICU setting, we used a crossover design in a prospective, double-blind randomized controlled study to investigate the effect of 'low-dose' dopamine on renal resistance indices, as determined by Doppler ultrasound. Forty patients, 10 without and 30 with acute renal failure (ARF, defined as doubling of baseline creatinine or an increase above 2 mg/dl), were included. Dopamine (2 mug/kg min) or placebo was given intravenously in alternating sequence for four subsequent periods of 60 min, starting randomly with either dopamine or placebo. Resistive (RI) and pulsatility index (PI) were closely correlated, positively related to serum creatinine values at baseline and highly reproducible during the two paired infusion periods. Dopamine reduced renal vascular resistance in patients without ARF (median RI/PI from 0.70 to 0.65/1.20 to 1.07, P<0.01) but increased resistance indices in patients with ARF (median RI/PI from 0.77 to 0.81/1.64 to 1.79, P<0.01) in the absence of effects on systemic hemodynamics. Subgroup analysis of patients with ARF revealed that dopamine induced renal vasoconstriction above 55 years (n=22) and in patients not receiving norepinephrine (n=20). In conclusion 'low-dose' dopamine can worsen renal perfusion in patients with ARF, which adds to the rationale for abandoning the routine use of 'low-dose' dopamine in critically ill patients. [ABSTRACT FROM AUTHOR]

Background: Hypernatremia presents a common complication in intensive care unit (ICU) patients, associated with increased mortality and length of stay. This study investigates the effect of sodium chloride 0.9% compared with glucose 5% solution as the standard intravenous drug diluent on the prevalence of hypernatremia in a medical ICU., Methods: This is a retrospective before-and-after study comparing two consecutive patient groups before and after the standard drug solvent was changed from sodium chloride 0.9% to glucose 5% solution for compatible medications. A total of 265 adult COVID-19 patients admitted between October 2020 and March 2021 to the study ICU were included, with 161 patients in the timeframe when sodium chloride 0.9% was employed as the standard drug solvent and 104 patients when glucose 5% was used. Routine sodium measurements from arterial and venous blood gases, along with heparinized lithium plasma, were analyzed. The daily sodium concentrations and the prevalence of severe hypernatremia (>150 mmol/l) were assessed during the first 8 days after ICU admission., Results: Baseline characteristics were similar between the two groups. The cumulative volume of intravenous drug diluents was comparable. In the glucose 5% group, about half of the total drug diluent volume was glucose 5% [mean (SD): 2251.6 (2355.4) ml], compared to 135.0 (746.9) ml ( P  < .001) in the control group. Average sodium concentrations diverged after day two, with the glucose 5% group consistently showing lower sodium levels (mean difference of ∼2.5 mmol/l). Severe hypernatremia occurred less frequently in the glucose 5% group (6.6% vs. 20%)., Conclusion: Glucose 5% solution as the standard intravenous drug solvent significantly reduced sodium concentrations and the occurrence of severe hypernatremia. This simple modification in solvent choice may serve as a preventive strategy against hypernatremia in the ICU. Further prospective research is necessary to determine associated clinical outcomes., Trial Registration: The trial was registered in the German Clinical Trials Register (DRKS00031877)., Competing Interests: None declared., (© The Author(s) 2024. Published by Oxford University Press on behalf of the ERA.)

Aim: 2,3-bisphosphoglycerate mutase (BPGM) is traditionally recognized for its role in modulating oxygen affinity to hemoglobin in erythrocytes. Recent transcriptomic analyses, however, have indicated a significant upregulation of BPGM in acutely injured murine and human kidneys, suggesting a potential renal function for this enzyme. Here we aim to explore the physiological role of BPGM in the kidney., Methods: A tubular-specific, doxycycline-inducible Bpgm-knockout mouse model was generated. Histological, immunofluorescence, and proteomic analyses were conducted to examine the localization of BPGM expression and the impact of its knockout on kidney structure and function. In vitro studies were performed to investigate the metabolic consequences of Bpgm knockdown under osmotic stress., Results: BPGM expression was localized to the distal nephron and was absent in proximal tubules. Inducible knockout of Bpgm resulted in rapid kidney injury within 4 days, characterized by proximal tubular damage and tubulointerstitial fibrosis. Proteomic analyses revealed involvement of BPGM in key metabolic pathways, including glycolysis, oxidative stress response, and inflammation. In vitro, Bpgm knockdown led to enhanced glycolysis, decreased reactive oxygen species elimination capacity under osmotic stress, and increased apoptosis. Furthermore, interactions between nephron segments and immune cells in the kidney suggested a mechanism for propagating stress signals from distal to proximal tubules., Conclusion: BPGM fulfills critical functions beyond the erythrocyte in maintaining glucose metabolism in the distal nephron. Its absence leads to metabolic imbalances, increased oxidative stress, inflammation, and ultimately kidney injury., (© 2024 The Author(s). Acta Physiologica published by John Wiley & Sons Ltd on behalf of Scandinavian Physiological Society.)

During inflammation, human neutrophils engage β 2 -integrins to migrate from the blood circulation to inflammatory sites with high cytokine but low oxygen concentrations. We tested the hypothesis that the inhibition of prolyl hydroxylase domain-containing enzymes (PHDs), cytokines, and β 2 -integrins cooperates in HIF pathway activation in neutrophils. Using either the PHD inhibitor roxadustat (ROX) (pseudohypoxia) or normobaric hypoxia to stabilize HIF, we observed HIF1α protein accumulation in adherent neutrophils. Several inflammatory mediators did not induce HIF1α protein but provided additive or even synergistic signals (e.g., GM-CSF) under pseudohypoxic and hypoxic conditions. Importantly, and in contrast to adherent neutrophils, HIF1α protein expression was not detected in strictly suspended neutrophils despite PHD enzyme inhibition and the presence of inflammatory mediators. Blocking β 2 -integrins in adherent and activating β 2 -integrins in suspension neutrophils established the indispensability of β 2 -integrins for increasing HIF1α protein. Using GM-CSF as an example, increased HIF1α mRNA transcription via JAK2-STAT3 was necessary but not sufficient for HIF1α protein upregulation. Importantly, we found that β 2 -integrins led to HIF1α mRNA translation through the phosphorylation of the essential translation initiation factors eIF4E and 4EBP1. Finally, pseudohypoxic and hypoxic conditions inducing HIF1α consistently delayed apoptosis in adherent neutrophils on fibronectin under low serum concentrations. Pharmacological HIF1α inhibition reversed delayed apoptosis, supporting the importance of this pathway for neutrophil survival under conditions mimicking extravascular sites. We describe a novel β 2 -integrin-controlled mechanism of HIF1α stabilization in human neutrophils. Conceivably, this mechanism restricts HIF1α activation in response to hypoxia and pharmacological PHD enzyme inhibitors to neutrophils migrating toward inflammatory sites., Competing Interests: K-UE has been involved in the clinical trial program of the PHD inhibitor vadadustat. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Kling, Eulenberg-Gustavus, Jerke, Rousselle, Eckardt, Schreiber and Kettritz.)

Medial vascular calcification in chronic kidney disease (CKD) involves pro-inflammatory pathways induced by hyperphosphatemia. Several interleukin 6 family members have been associated with pro-calcific effects in vascular smooth muscle cells (VSMCs) and are considered as therapeutic targets. Therefore, we investigated the role of leukemia inhibitory factor (LIF) during VSMC calcification. LIF expression was found to be increased following phosphate exposure of VSMCs. LIF supplementation aggravated, while silencing of endogenous LIF or LIF receptor (LIFR) ameliorated the pro-calcific effects of phosphate in VSMCs. The soluble LIFR mediated antagonistic effects towards LIF and reduced VSMC calcification. Mechanistically, LIF induced phosphorylation of the non-receptor tyrosine-protein kinase 2 (TYK2) and signal transducer and activator of transcription-3 (STAT3) in VSMCs. TYK2 inhibition by deucravacitinib, a selective, allosteric oral immunosuppressant used in psoriasis treatment, not only blunted the effects of LIF, but also interfered with the pro-calcific effects induced by phosphate. Conversely, TYK2 overexpression aggravated VSMC calcification. Ex vivo calcification of mouse aortic rings was ameliorated by Tyk2 pharmacological inhibition and genetic deficiency. Cholecalciferol-induced vascular calcification in mice was improved by Tyk2 inhibition and in the Tyk2-deficient mice. Similarly, calcification was ameliorated in Abcc6/Tyk2-deficient mice after adenine/high phosphorus-induced CKD. Thus, our observations indicate a role for LIF in CKD-associated vascular calcification. Hence, the effects of LIF identify a central pro-calcific role of TYK2 signaling, which may be a future target to reduce the burden of vascular calcification in CKD., (Copyright © 2024 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

Rationale & Objective: Biomarkers that enable better identification of persons with chronic kidney disease (CKD) who are at higher risk for disease progression and adverse events are needed. This study sought to identify urine and plasma metabolites associated with progression of kidney disease., Study Design: Prospective metabolome-wide association study., Setting & Participants: Persons with CKD enrolled in the GCKD (German CKD) study with metabolite measurements, with external validation within the ARIC (Atherosclerosis Risk in Communities) Study., Exposures: 1,513 urine and 1,416 plasma metabolites (Metabolon Inc) measured at study entry using untargeted mass spectrometry., Outcomes: Main end points were kidney failure (KF) and a composite kidney end point (CKE) of KF, estimated glomerular filtration rate<15mL/min/1.73m 2 , or a 40% decrease in estimated glomerular filtration rate. Death from any cause was a secondary end point. After a median of 6.5 years of follow-up, 500 persons had experienced KF, 1,083 had experienced the CKE, and 680 had died., Analytical Approach: Time-to-event analyses using multivariable proportional hazard regression models in a discovery-replication design with external validation., Results: 5,088 GCKD study participants were included in analyses of urine metabolites, and 5,144 were included in analyses of plasma metabolites. Among 182 unique metabolites, 30 were significantly associated with KF, 49 with the CKE, and 163 with death. The strongest association with KF was observed for plasma hydroxyasparagine (HR, 1.95; 95% CI, 1.68-2.25). An unnamed metabolite measured in plasma and urine was significantly associated with KF, the CKE, and death. External validation of the identified associations of metabolites with KF or the CKE revealed directional consistency for 88% of observed associations. Selected associations of 18 metabolites with study outcomes have not been previously reported., Limitations: Use of observational data and semiquantitative metabolite measurements at a single time point., Conclusions: The observed associations between metabolites and KF, the CKE, or death in persons with CKD confirmed previously reported findings and also revealed several associations not previously described. These findings warrant confirmatory research in other study cohorts., Plain-Language Summary: Incomplete understanding of the variability of chronic kidney disease (CKD) progression motivated the search for new biomarkers that would help identify people at increased risk. We explored metabolites in plasma and urine for their association with unfavorable kidney outcomes or death in persons with CKD. Metabolomic analyses revealed 182 metabolites significantly associated with CKD progression or death. Many of these associations confirmed previously reported findings or were validated by analysis in an external study population. Our comprehensive screen of the metabolome serves as a valuable foundation for future investigations into biomarkers associated with CKD progression., (Copyright © 2024 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Background: Identifying candidates for extracorporeal cardiopulmonary resuscitation (eCPR) is challenging, and novel predictive markers are urgently needed. Hyperfibrinolysis is linked to tissue hypoxia and is associated with poor outcomes in out-of-hospital cardiac arrest (OHCA). Rotational thromboelastometry (ROTEM) can detect or rule out hyperfibrinolysis, and could, therefore, provide decision support for initiation of eCPR. We explored early detection of hyperfibrinolysis in patients with refractory OHCA referred for eCPR., Methods: We analysed ROTEM results and resuscitation parameters of 57 adult patients with ongoing OHCA who presented to our ICU for eCPR evaluation., Results: Hyperfibrinolysis, defined as maximum lysis ≥15%, was present in 36 patients (63%) and was associated with higher serum lactate, lower arterial blood pH, and increased low-flow intervals. Of 42 patients who achieved return of circulation, 28 had a poor 30-day outcome. The incidence of hyperfibrinolysis was higher in the poor outcome group compared with patients with good outcomes (75% [21 of 28] vs 7.1% [1 of 14]; P<0.001). The ratio of EXTEM A5 to lactate concentration showed good predictive value in detecting hyperfibrinolysis (AUC of 0.89 [95% confidence interval 0.8-1])., Conclusions: Hyperfibrinolysis was common in patients with refractory cardiac arrest, and was associated with poor prognosis. The combination of high lactate with early clot firmness values, such as EXTEM A5, appears promising for early detection of hyperfibrinolysis. This finding could facilitate decisions to perform eCPR, particularly for patients with prolonged low-flow duration but lacking hyperfibrinolysis., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Lipoprotein(a) (Lp(a)) is a causal, genetically determined risk factor for cardiovascular disease (CVD) in the general population. Patients with chronic kidney disease (CKD) have an increased CVD risk and elevated Lp(a) concentrations. Only a few studies on Lp(a) were performed in persons with mild-to-moderate CKD; none of them used genetic variants to explore potential causal associations., Objectives: This study aims to investigate the association of measured and genetically predicted Lp(a) concentrations on prevalent and incident CVD events in the German Chronic Kidney Disease (GCKD) study., Methods: The study included 5043 participants of European ancestry with an estimated glomerular filtration rate (eGFR) between 30 and 60 mL/min/1.73 m 2 or an eGFR >60 mL/min/1.73 m 2 in the presence of overt albuminuria with a follow-up of 6.5 years., Results: With each 10 mg/dL higher Lp(a) concentration, odds for prevalent CVD (1290 events) increased 1.065-fold (95%CI: 1.042-1.088, p < 0.001). The risk was significantly higher in patients with Lp(a) ≥50 mg/dL but most pronounced in Lp(a) ≥70 mg/dL (odds ratio = 1.775 [1.409-2.231], p < 0.001) compared to Lp(a) <30 mg/dL. Each 10 mg/dL higher Lp(a) concentration and Lp(a) ≥70 mg/dL increased the risk for incident 3-point major adverse cardiovascular events (MACEs) (474 events): hazard ratio [HR] = 1.037 [1.009-1.067], p = 0.009 and HR = 1.335 [1.001-1.781], p = 0.050), respectively. Similar results were obtained for 4-point MACE (653 events). Analyses based on apo(a) isoforms and genetically predicted Lp(a) concentrations led to even stronger associations., Conclusions: In patients with mild-to-severe CKD, elevated Lp(a) concentrations and genetic determinants of Lp(a) concentrations are significantly associated with CVD at baseline and during follow-up, independent of traditional risk factors., (© 2024 The Author(s). Journal of Internal Medicine published by John Wiley & Sons Ltd on behalf of Association for Publication of The Journal of Internal Medicine.)

Posttransplant diabetes mellitus (PTDM) and prediabetes represent serious complications after kidney transplantation and are associated with increased cardiovascular morbidity and mortality. We assessed the predictive performance of continuous glucose monitoring (CGM) compared with plasma glucose and hemoglobin A1c in 46 kidney transplant recipients (KTRs) without known preexisting diabetes mellitus. CGM (14-day recording duration) was performed on days 8, 30, 45, 60, 90, and 180 posttransplant. Eight patients (17%) developed PTDM and nine (20%) impaired glucose tolerance (IGT), as diagnosed by oral glucose tolerance test (oGTT)-derived 2-hour plasma glucose (2hPG) or glucose-lowering therapy on day 90. CGM-readouts percent of time >140 mg/dL (%TAR (140 mg/dL)) and percent of time >180 mg/dL (%TAR (180 mg/dL)) showed excellent in-sample test characteristics regarding PTDM from day 8 onward (days 8-90 receiver operating characteristic area under the curve: 0.88-0.99) and regarding PTDM/IGT with the commencement of maintenance immunosuppression from day 30 onward (days 30-90 receiver operating characteristic area under the curve: 0.88-0.91). Exploratory CGM-%TAR (140 mg/dL)-screening thresholds of 31.8% on day 8 and 13.2% on day 30 yielded sensitivities/specificities of 88%/83% for PTDM and 94%/78% for PTDM/IGT on day 90, respectively. Although our findings need to be replicated in studies with larger sample sizes, CGM bears promising potential to facilitate clinical practice and research regarding PTDM., Competing Interests: Declaration of competing interests The authors of this manuscript have conflicts of interest to disclose as described by the American Journal of Transplantation. G. Eleftheriadis reports travel support from Chiesi. M.G. Naik reports research funding from Berlin Institute of Health; travel support from Deutsche Gesellschaft für Nephrologie; and lecture honoraria from Novartis, Thermo Fisher Scientific, and Deutsche Gesellschaft für Nephrologie. B. Osmanodja reports travel support from Oncocyte. L. Liefeldt reports lecture honoraria from Universität Heidelberg and travel support from Deutsche Transplantationsgesellschaft. F. Halleck reports consulting fees from Orifarm; honoraria from Hansa, Chiesi, Novartis, and MSD; and travel support from Hansa Pharma; and is a member of the Advisory Board of TolerogenixX TOL-2 Study. E. Schrezenmeier reports grants from DFG, BMBF, and EKFS Exzellenzstipendium and honoraria from AstraZeneca, Medupdate Europe, and Berliner Dialyseseminar. K.-U. Eckardt reports grants from Amgen, Astra Zeneca, Bayer, Evotec, and Vifor and consulting fees from Akebia, Astra Zeneca, Bayer, Otsuka, and Retrophin and is a member of the Advisory Board of Astra Zeneca. K. Budde reports grants/contracts from Alexion, Astellas, AstraZeneca, Chiesi, CSL Behring, MSD, Otsuka, Stada, and Takeda; consulting fees from Alcuris, Alexion, Astellas, AstraZeneca, Bayer, Bristol-Myers Squibb, Carealytics, CareDx, Chiesi, CSL Behring, Fresenius, Hansa, HiBio, MSD, Natera, Neovii, Paladin, Pfizer, Pirche, Sanofi, Stada, Takeda, Veloxis, Vifor, and Xenothera; honoraria from Astellas, AstraZeneca, Chiesi, Fresenius, MSD, Paladin, Sanofi, and Takeda; and travel support from AstraZeneca, Chiesi, HiBio, MSD, Neovii, Paladin, Stada, Takeda, and Veloxis; is a member of the Advisory Board of Alcuris, Alexion, Astellas, AstraZeneca, Bristol-Myers Squibb, Carealytics, CareDx, Chiesi, CSL Behring, HiBio, MSD, Natera, Neovii, Paladin, Pfizer, Stada, Takeda, Veloxis, and Vifor; and reports leadership or fiduciary role in Deutsche Transplantationsgesellschaft and Eurotransplant. The other authors report no conflicts on interest., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Health-related quality of life (HRQL) has become an important outcome parameter in cardiology. The MOS 36-ltem Short-Form Health Survey (SF-36) and the PROMIS-29 are two widely used generic measures providing composite HRQL scores. The domains of the SF-36, a well-established instrument utilized for several decades, can be aggregated to physical (PCS) and mental (MCS) component summary scores. Alternative scoring algorithms for correlated component scores (PCS c and MCS c ) have also been suggested. The PROMIS-29 is a newer but increasingly used HRQL measure. Analogous to the SF-36, physical and mental health summary scores can be derived from PROMIS-29 domain scores, based on a correlated factor solution. So far, scores from the PROMIS-29 are not directly comparable to SF-36 results, complicating the aggregation of research findings. Thus, our aim was to provide algorithms to convert PROMIS-29 data to well-established SF-36 component summary scores., Methods: Data from n = 662 participants of the Berlin Long-term Observation of Vascular Events (BeLOVE) study were used to estimate linear regression models with either PROMIS-29 domain scores or aggregated PROMIS-29 physical/mental health summary scores as predictors and SF-36 physical/mental component summary scores as outcomes. Data from a subsequent assessment point (n = 259) were used to evaluate the agreement between empirical and predicted SF-36 scores., Results: PROMIS-29 domain scores as well as PROMIS-29 health summary scores showed high predictive value for PCS, PCS c , and MCS c (R 2  ≥ 70%), and moderate predictive value for MCS (R 2  = 57% and R 2  = 40%, respectively). After applying the regression coefficients to new data, empirical and predicted SF-36 component summary scores were highly correlated (r > 0.8) for most models. Mean differences between empirical and predicted scores were negligible (|SMD|<0.1)., Conclusions: This study provides easy-to-apply algorithms to convert PROMIS-29 data to well-established SF-36 physical and mental component summary scores in a cardiovascular population. Applied to new data, the agreement between empirical and predicted SF-36 scores was high. However, for SF-36 mental component summary scores, considerably better predictions were found under the correlated (MCS c ) than under the original factor model (MCS). Additionally, as a pertinent byproduct, our study confirmed construct validity of the relatively new PROMIS-29 health summary scores in cardiology patients., (© 2024. The Author(s).)

Choline has important physiological functions as a precursor for essential cell components, signaling molecules, phospholipids, and the neurotransmitter acetylcholine. Choline is a water-soluble charged molecule requiring transport proteins to cross biological membranes. Although transporters continue to be identified, membrane transport of choline is incompletely understood and knowledge about choline transport into intracellular organelles such as mitochondria remains limited. Here we show that SLC25A48 imports choline into human mitochondria. Human loss-of-function mutations in SLC25A48 show impaired choline transport into mitochondria and are associated with elevated urine and plasma choline levels. Thus, our studies may have implications for understanding and treating conditions related to choline metabolism., (Copyright © 2024 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

Background: The importance of albuminuria as opposed to proteinuria in predicting kidney outcomes in primary immunoglobulin A nephropathy (IgAN) is not well established., Methods: From 2010 to 2012, 421 patients with biopsy-proven IgAN have been enrolled into the German Chronic Kidney Disease (GCKD) cohort, a prospective observational cohort study ( N  = 5217). Adjudicated endpoints include a composite kidney endpoint (CKE) consisting of eGFR decline >40%, eGFR <15 ml/min/1.73 m 2 and initiation of kidney replacement therapy; the individual components of the CKE; and combined major adverse cardiac events (MACE), including non-fatal myocardial infarction, non-fatal stroke and all-cause mortality. The associations between the incidence of CKE and baseline factors, including demographics, laboratory values and comorbidities were analysed using the Cox proportional hazards regression model., Results: The mean age of IgAN patients at baseline was 51.6 years (± 13.6) and 67% were male. The patient-reported duration of disease at baseline was 5.9 ± 8.1 years. Baseline median urine albumin:creatinine ratio (UACR) was 0.4 g/g [interquartile range (IQR) 0.1-0.8] and mean eGFR was 52.5 ± 22.4 ml/min/1.73 m 2 . Over a follow-up of 6.5 years, 64 (15.2%) patients experienced a >40% eGFR decline, 3 (0.7%) reached eGFR <15 ml/min/1.73 m 2 , 53 (12.6%) initiated kidney replacement therapy and 28% of the patients experienced the CKE. Albuminuria, with reference to <0.1 g/g, was most associated with CKE. Hazard ratios (HRs) at UACRs of 0.1-0.6 g/g, 0.6-1.4 g/g, 1.4-2.2 g/g and >2.2 g/g were 2.03 [95% confidence interval (CI) 1.02-4.05], 3.8 (95% CI 1.92-7.5), 5.64 (95% CI 2.58-12.33) and 5.02 (95% CI 2.29-11-03), respectively. Regarding MACE, the presence of diabetes [HR 2.53 (95% CI 1.11-5.78)] was the most strongly associated factor, whereas UACR and eGFR did not show significant associations., Conclusion: In the GCKD IgAN subcohort, more than every fourth patient experienced a CKE event within 6.5 years. Our findings support the use of albuminuria as a surrogate to assess the risk of poor kidney outcomes., Competing Interests: J.F. is the Editor-in-Chief of CKJ., (© The Author(s) 2024. Published by Oxford University Press on behalf of the ERA.)

Oxalate kidney stones are common and exert a huge burden of morbidity worldwide. However, circulating or excreted concentrations of oxalate are rarely measured. We argue that oxalate and its metabolism are important above and beyond kidney stone formation. There is emerging evidence that increased concentrations of oxalate could be a driver of chronic kidney disease progression. Furthermore, oxalate has been implicated in cardiovascular disease. Thus, the reduction of elevated plasma oxalate concentrations may represent a novel cardioprotective and nephroprotective strategy., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)