Publications by authors named "Kai Uwe Eckardt"

366 Publications

Urine Metabolite Levels, Adverse Kidney Outcomes, and Mortality in CKD Patients: A Metabolome-wide Association Study.

Am J Kidney Dis 2021 Apr 8. Epub 2021 Apr 8.

Institute of Genetic Epidemiology, Faculty of Medicine and Medical Center - University of Freiburg, Hugstetter Str. 49, 79106 Freiburg, Germany. Electronic address:

Rationale & Objective: Mechanisms underlying the variable course of disease progression in patients with chronic kidney disease (CKD) are incompletely understood. The aim of this study was to identify novel biomarkers of adverse kidney outcomes and overall mortality, which may offer insights into pathophysiological mechanisms.

Study Design: Metabolome-wide association study.

Setting & Participants: 5,087 CKD patients enrolled in the observational German Chronic Kidney Disease study.

Exposure(s): Measurements of 1,487 metabolites in urine.

Outcome(s): Endpoints of interest were time to kidney failure (KF), a combined endpoint of KF and acute kidney injury (KF+AKI), and overall mortality.

Analytical Approach: Statistical analysis was based on a discovery-replication design (ratio 2:1) and multivariable adjusted Cox regression models.

Results: After a median follow-up of 4 years, 362 patients died, 241 experienced KF, and 382 KF+AKI. Overall, we identified 55 urine metabolites whose levels were significantly associated with adverse kidney outcomes and/or mortality. Higher levels of C-glycosyltryptophan were consistently associated with all three main endpoints (KF: hazard ratio 1.43, 95% confidence interval [1.27;1.61], KF+AKI: 1.40 [1.27;1.55], death: 1.47 [1.33;1.63]). Metabolites belonging to the phosphatidylcholine pathway showed significant enrichment. Members of this pathway contributed to the improvement of the prediction performance for KF observed when multiple metabolites were added to the well-established kidney failure risk equation.

Limitations: Findings among CKD patients of European ancestry may not be generalizable to the general population.

Conclusions: Our comprehensive screen of the association between urine metabolite levels and adverse kidney outcomes and mortality identifies metabolite that predict KF and represents a valuable resource for future studies of biomarkers of CKD progression.
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http://dx.doi.org/10.1053/j.ajkd.2021.01.018DOI Listing
April 2021

Critical Illness and Systemic Inflammation Are Key Risk Factors of Severe Acute Kidney Injury in Patients With COVID-19.

Kidney Int Rep 2021 Apr 2;6(4):905-915. Epub 2021 Feb 2.

Department of Nephrology and Medical Intensive Care, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany.

Introduction: Acute kidney injury (AKI) is an important complication in COVID-19, but its precise etiology has not fully been elucidated. Insights into AKI mechanisms may be provided by analyzing the temporal associations of clinical parameters reflecting disease processes and AKI development.

Methods: We performed an observational cohort study of 223 consecutive COVID-19 patients treated at 3 sites of a tertiary care referral center to describe the evolvement of severe AKI (Kidney Disease: Improving Global Outcomes stage 3) and identify conditions promoting its development. Descriptive statistics and explanatory multivariable Cox regression modeling with clinical parameters as time-varying covariates were used to identify risk factors of severe AKI.

Results: Severe AKI developed in 70 of 223 patients (31%) with COVID-19, of which 95.7% required kidney replacement therapy. Patients with severe AKI were older, predominantly male, had more comorbidities, and displayed excess mortality. Severe AKI occurred exclusively in intensive care unit patients, and 97.3% of the patients developing severe AKI had respiratory failure. Mechanical ventilation, vasopressor therapy, and inflammatory markers (serum procalcitonin levels and leucocyte count) were independent time-varying risk factors of severe AKI. Increasing inflammatory markers displayed a close temporal association with the development of severe AKI. Sensitivity analysis on risk factors of AKI stage 2 and 3 combined confirmed these findings.

Conclusion: Severe AKI in COVID-19 was tightly coupled with critical illness and systemic inflammation and was not observed in milder disease courses. These findings suggest that traditional systemic AKI mechanisms rather than kidney-specific processes contribute to severe AKI in COVID-19.
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http://dx.doi.org/10.1016/j.ekir.2021.01.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8007085PMC
April 2021

Kinetics of Renal Function during Induction in Newly Diagnosed Multiple Myeloma: Results of Two Prospective Studies by the German Myeloma Study Group DSMM.

Cancers (Basel) 2021 Mar 16;13(6). Epub 2021 Mar 16.

Division of Hematology and Oncology, Würzburg University Hospital Medical Center, 97080 Würzburg, Germany.

Background: Preservation of kidney function in newly diagnosed (ND) multiple myeloma (MM) helps to prevent excess toxicity. Patients (pts) from two prospective trials were analyzed, provided postinduction (PInd) restaging was performed. Pts received three cycles with bortezomib (btz), cyclophosphamide, and dexamethasone (dex; VCD) or btz, lenalidomide (len), and dex (VRd) or len, adriamycin, and dex (RAD). The minimum required estimated glomerular filtration rate (eGFR) was >30 mL/min. We analyzed the percent change of the renal function using the International Myeloma Working Group (IMWG) criteria and Kidney Disease: Improving Global Outcomes (KDIGO)-defined categories.

Results: Seven hundred and seventy-two patients were eligible. Three hundred and fifty-six received VCD, 214 VRd, and 202 RAD. VCD patients had the best baseline eGFR. The proportion of pts with eGFR <45 mL/min decreased from 7.3% at baseline to 1.9% PInd ( < 0.0001). Thirty-seven point one percent of VCD versus 49% of VRd patients had a decrease of GFR ( = 0.0872). IMWG-defined "renal complete response (CRrenal)" was achieved in 17/25 (68%) pts after VCD, 12/19 (63%) after RAD, and 14/27 (52%) after VRd ( = 0.4747).

Conclusions: Analyzing a large and representative newly diagnosed myeloma (NDMM) group, we found no difference in CRrenal that occurred independently from the myeloma response across the three regimens. A trend towards deterioration of the renal function with VRd versus VCD may be explained by a better pretreatment "renal fitness" in the latter group.
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http://dx.doi.org/10.3390/cancers13061322DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7999479PMC
March 2021

NEPHRO-ZEBRA-acute troponin increase in a kidney transplant recipient-the unknown knowns?

J Nephrol 2021 Mar 24. Epub 2021 Mar 24.

Department of Nephrology and Medical Intensive Care, Charité - Universitätsmedizin Berlin, Berlin, Germany.

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http://dx.doi.org/10.1007/s40620-021-00990-7DOI Listing
March 2021

Survival on four compared with three times per week haemodialysis in high ultrafiltration patients: an observational study.

Clin Kidney J 2021 Feb 28;14(2):665-672. Epub 2020 Dec 28.

Department of Renal Medicine, University College London, UK.

Background: The harm caused by the long interdialytic interval in three-times-per-week haemodialysis regimens (3×WHD) may relate to fluid accumulation and associated high ultrafiltration rate (UFR). Four-times-per-week haemodialysis (4×WHD) may offer a solution, but its impact on mortality, hospitalization and vascular access complications is unknown.

Methods: From the AROii cohort of incident in-centre haemodialysis patients, 3×WHD patients with a UFR >10 mL/kg/h were identified. The hazard for the outcomes of mortality, hospitalization and vascular access complications in those who switched to 4×WHD compared with staying on 3×WHD was estimated using a marginal structural Cox proportional hazards model. Adjustment included baseline patient and treatment characteristics with inverse probability weighting used to adjust for time-varying UFR and cardiovascular comorbidities.

Results: From 10 637 European 3×WHD patients, 3842 (36%) exceeded a UFR >10 mL/kg/h. Of these, 288 (7.5%) started 4×WHD and at baseline were more comorbid. Event rates while receiving 4×WHD compared with 3×WHD were 12.6 compared with 10.8 per 100 patient years for mortality, 0.96 compared with 0.65 per year for hospitalization and 14.7 compared with 8.0 per 100 patient years for vascular access complications. Compared with 3×WHD, the unadjusted hazard ratio (HR) for mortality on 4×WHD was 1.05 [95% confidence interval (CI) 0.78-1.42]. Following adjustment for baseline demographics, time-varying treatment probability and censoring risks, this HR was 0.73 (95% CI 0.50-1.05; P = 0.095). Despite these adjustments on 4×WHD, the HR for hospitalization remained elevated and vascular access complications were similar to 3×WHD.

Conclusions: This observational study was not able to demonstrate a mortality benefit in patients switched to 4×WHD. To demonstrate the true benefits of 4×WHD requires a large, well-designed clinical trial. Our data may help in the design of such a study.
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http://dx.doi.org/10.1093/ckj/sfaa250DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7886573PMC
February 2021

Use of Hemoadsorption in Patients With Severe Intoxication Requiring Extracorporeal Cardiopulmonary Support-A Case Series.

ASAIO J 2021 Feb 9. Epub 2021 Feb 9.

From the Charité-Universitätsmedizin Berlin, Freie Universität Berlin, Berlin Institute of Health, Clinic for Nephrology and Intensive Care Medicine, Humboldt-Universität zu Berlin, Berlin, Germany.

Drugs intoxications often lead to severe vasoplegia and cardiogenic shock, and VA-ECMO represents a viable therapy option. However, as cardiopulmonary support is not contributing to the removal of the causal agent from the blood, detoxification by a new hemoadsorption device (CytoSorb) could represent a potential therapeutic tool due to its highly efficient elimination capacity of endogenous but also exogenous hydrophobic substances for which otherwise no effective antidote exist. In this case series, four anecdotal cases of acute intoxications requiring VA-ECMO support used as extracorporeal cardiopulmonary resuscitation after intoxication-induced out-of-hospital cardiac arrest (OHCA) are presented, who were additionally treated with CytoSorb hemoadsorption in combination with renal replacement therapy. Combined treatment was associated with a considerable decrease in plasma levels of the overdosed drugs. Additionally, the combination of applied techniques was safe, practical, and technically feasible with no adverse or any device-related side effects documented during or after the treatment sessions. Based on the reported dramatic decline in drug levels during treatment, that fits in the device's characteristics, we strongly suggest to further investigate the potentially lifesaving role of CytoSorb therapy in patients with acute intoxications requiring multiple organ support techniques.
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http://dx.doi.org/10.1097/MAT.0000000000001362DOI Listing
February 2021

Rare genetic variants affecting urine metabolite levels link population variation to inborn errors of metabolism.

Nat Commun 2021 02 11;12(1):964. Epub 2021 Feb 11.

Institute of Genetic Epidemiology, Faculty of Medicine and Medical Center - University of Freiburg, Freiburg, Germany.

Metabolite levels in urine may provide insights into genetic mechanisms shaping their related pathways. We therefore investigate the cumulative contribution of rare, exonic genetic variants on urine levels of 1487 metabolites and 53,714 metabolite ratios among 4864 GCKD study participants. Here we report the detection of 128 significant associations involving 30 unique genes, 16 of which are known to underlie inborn errors of metabolism. The 30 genes are strongly enriched for shared expression in liver and kidney (odds ratio = 65, p-FDR = 3e-7), with hepatocytes and proximal tubule cells as driving cell types. Use of UK Biobank whole-exome sequencing data links genes to diseases connected to the identified metabolites. In silico constraint-based modeling of gene knockouts in a virtual whole-body, organ-resolved metabolic human correctly predicts the observed direction of metabolite changes, highlighting the potential of linking population genetics to modeling. Our study implicates candidate variants and genes for inborn errors of metabolism.
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http://dx.doi.org/10.1038/s41467-020-20877-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7878905PMC
February 2021

Kidney physiology and susceptibility to acute kidney injury: implications for renoprotection.

Nat Rev Nephrol 2021 Feb 5. Epub 2021 Feb 5.

Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany.

Kidney damage varies according to the primary insult. Different aetiologies of acute kidney injury (AKI), including kidney ischaemia, exposure to nephrotoxins, dehydration or sepsis, are associated with characteristic patterns of damage and changes in gene expression, which can provide insight into the mechanisms that lead to persistent structural and functional damage. Early morphological alterations are driven by a delicate balance between energy demand and oxygen supply, which varies considerably in different regions of the kidney. The functional heterogeneity of the various nephron segments is reflected in their use of different metabolic pathways. AKI is often linked to defects in kidney oxygen supply, and some nephron segments might not be able to shift to anaerobic metabolism under low oxygen conditions or might have remarkably low basal oxygen levels, which enhances their vulnerability to damage. Here, we discuss why specific kidney regions are at particular risk of injury and how this information might help to delineate novel routes for mitigating injury and avoiding permanent damage. We suggest that the physiological heterogeneity of the kidney should be taken into account when exploring novel renoprotective strategies, such as improvement of kidney tissue oxygenation, stimulation of hypoxia signalling pathways and modulation of cellular energy metabolism.
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http://dx.doi.org/10.1038/s41581-021-00394-7DOI Listing
February 2021

Low adherence to CKD-specific dietary recommendations associates with impaired kidney function, dyslipidemia, and inflammation.

Eur J Clin Nutr 2021 Feb 2. Epub 2021 Feb 2.

Division of Nephrology and Clinical Immunology, University Hospital RWTH Aachen, Aachen, Germany.

Background/objectives: A diet following chronic kidney disease (CKD)-specific recommendations is considered essential for optimal management of patients with CKD. However, data on the adherence to these recommendations and its implications for health-relevant biomarkers are lacking. The objectives were to estimate adherence to CKD-specific dietary recommendations, to identify characteristics and lifestyle variables associated with poor adherence, and to investigate the relationship of adherence with biomarkers.

Methods: In this cross-sectional analysis, average dietary intake was estimated in 3193 participants with moderately severe CKD enrolled into the observational multicenter German CKD study using a food frequency questionnaire. A CKD diet score was developed to assess adherence to CKD-specific dietary recommendations based on intake of sodium, potassium, fiber, protein, sugar, and cholesterol. The associations of dietary adherence with characteristics, lifestyle variables, and biomarker levels were determined.

Results: Logistic regression analysis revealed younger age, higher body mass index, male gender, lower educational attainment, various lifestyle variables (cigarette smoking, infrequent alcohol consumption, low physical activity), and lower estimated glomerular filtrate rate associated with lower adherence to dietary recommendations. Low adherence to dietary recommendations was further associated with dyslipidemia, higher uric acid, and C-reactive protein levels. Associations between low dietary adherence and biomarkers were mostly driven by low intake of fiber and potassium, and high intake of sugar and cholesterol.

Conclusions: This study revealed differential characteristics and biomarkers associated with lower adherence to CKD-specific dietary recommendations. Promotion of CKD-specific dietary recommendations may help to mitigate the adverse prognosis in CKD patients.
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http://dx.doi.org/10.1038/s41430-020-00849-3DOI Listing
February 2021

High rates of long-term renal recovery in survivors of coronavirus disease 2019-associated acute kidney injury requiring kidney replacement therapy.

Kidney Int 2021 04 27;99(4):1021-1022. Epub 2021 Jan 27.

Department of Nephrology and Medical Intensive Care, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany. Electronic address:

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http://dx.doi.org/10.1016/j.kint.2021.01.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7839389PMC
April 2021

Nomenclature for Kidney Function and Disease: Executive Summary and Glossary from a Kidney Disease: Improving Global Outcomes (KDIGO) Consensus Conference.

Kidney Dis (Basel) 2020 Sep 19;6(5):309-317. Epub 2020 Jun 19.

Selzman Institute for Kidney Health, Section of Nephrology, Department of Medicine, Baylor College of Medicine, Houston, Texas, USA.

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http://dx.doi.org/10.1159/000509359DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7745658PMC
September 2020

Acid sphingomyelinase promotes SGK1-dependent vascular calcification.

Clin Sci (Lond) 2021 Feb;135(3):515-534

Institute for Physiology and Pathophysiology, Johannes Kepler University Linz, Linz, Austria.

In chronic kidney disease (CKD), hyperphosphatemia is a key factor promoting medial vascular calcification, a common complication associated with cardiovascular events and high mortality. Vascular calcification involves osteo-/chondrogenic transdifferentiation of vascular smooth muscle cells (VSMCs), but the complex signaling events inducing pro-calcific pathways are incompletely understood. The present study investigated the role of acid sphingomyelinase (ASM)/ceramide as regulator of VSMC calcification. In vitro, both, bacterial sphingomyelinase and phosphate increased ceramide levels in VSMCs. Bacterial sphingomyelinase as well as ceramide supplementation stimulated osteo-/chondrogenic transdifferentiation during control and high phosphate conditions and augmented phosphate-induced calcification of VSMCs. Silencing of serum- and glucocorticoid-inducible kinase 1 (SGK1) blunted the pro-calcific effects of bacterial sphingomyelinase or ceramide. Asm deficiency blunted vascular calcification in a cholecalciferol-overload mouse model and ex vivo isolated-perfused arteries. In addition, Asm deficiency suppressed phosphate-induced osteo-/chondrogenic signaling and calcification of cultured VSMCs. Treatment with the functional ASM inhibitors amitriptyline or fendiline strongly blunted pro-calcific signaling pathways in vitro and in vivo. In conclusion, ASM/ceramide is a critical upstream regulator of vascular calcification, at least partly, through SGK1-dependent signaling. Thus, ASM inhibition by repurposing functional ASM inhibitors to reduce the progression of vascular calcification during CKD warrants further study.
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http://dx.doi.org/10.1042/CS20201122DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7859357PMC
February 2021

[COVID-19 and acute kidney injury in the intensive care unit].

Nephrologe 2020 Dec 22:1-5. Epub 2020 Dec 22.

Medizinische Klinik m. S. Nephrologie und Internistische Intensivmedizin, Charité - Unversitätsmedizin Berlin, Charitéplatz 1, 10117 Berlin, Deutschland.

Acute kidney injury (AKI) is a frequent and severe complication in coronavirus disease 2019 (COVID-19) patients in the intensive care unit. The development of COVID-19 associated AKI is closely linked to the severity of the disease course. The main risk factor for kidney failure requiring kidney replacement therapy is the necessity for invasive ventilation, whereby the onset of renal failure is often closely associated with the timing of intubation. Additionally, the risk factors for a severe course of COVID-19 have been shown to also be risk factors for renal failure. AKI in COVID-19 shows a high mortality and in some patients leads to chronic kidney disease; however, full recovery of kidney function in survivors who need dialysis is not uncommon. With respect to prevention and treatment of renal failure associated with COVID-19, the same recommendations as for AKI from other causes are valid (Kidney Disease: Improving Global Outcomes, KDIGO bundles). Due to the large numbers of patients in the setting of overwhelmed resources, the availability of extracorporeal renal replacement procedures can become critical, especially since hypercoagulation is frequent in COVID‑19. In order to avoid triage situations, in some centers acute peritoneal dialysis was used as an alternative to extracorporeal procedures.
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http://dx.doi.org/10.1007/s11560-020-00471-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7754700PMC
December 2020

High frequency of cerebrospinal fluid autoantibodies in COVID-19 patients with neurological symptoms.

Brain Behav Immun 2021 03 24;93:415-419. Epub 2020 Dec 24.

Department of Neurology and Experimental Neurology, Charité - Universitätsmedizin Berlin, Berlin, Germany; German Center for Neurodegenerative Diseases (DZNE), Berlin, Germany.

Background: COVID-19 intensive care patients can present with neurological syndromes, usually in the absence of SARS-CoV-2 in cerebrospinal fluid (CSF). The recent finding of some virus-neutralizing antibodies cross-reacting with brain tissue suggests the possible involvement of specific autoimmunity.

Design: Blood and CSF samples from eleven critically ill COVID-19 patients presenting with unexplained neurological symptoms including myoclonus, oculomotor disturbance, delirium, dystonia and epileptic seizures, were analyzed for anti-neuronal and anti-glial autoantibodies.

Results: Using cell-based assays and indirect immunofluorescence on unfixed murine brain sections, all patients showed anti-neuronal autoantibodies in serum or CSF. Antigens included intracellular and neuronal surface proteins, such as Yo or NMDA receptor, but also various specific undetermined epitopes, reminiscent of the brain tissue binding observed with certain human monoclonal SARS-CoV-2 antibodies. These included vessel endothelium, astrocytic proteins and neuropil of basal ganglia, hippocampus or olfactory bulb.

Conclusion: The high frequency of autoantibodies targeting the brain in the absence of other explanations suggests a causal relationship to clinical symptoms, in particular to hyperexcitability (myoclonus, seizures). Several underlying autoantigens and their potential molecular mimicry with SARS-CoV-2 still await identification. However, autoantibodies may already now explain some aspects of multi-organ disease in COVID-19 and can guide immunotherapy in selected cases.
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http://dx.doi.org/10.1016/j.bbi.2020.12.022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7834471PMC
March 2021

Novichok nerve agent poisoning.

Lancet 2021 01 23;397(10270):249-252. Epub 2020 Dec 23.

Department of Nephrology and Medical Intensive Care, Charité-Universitätsmedizin Berlin, Berlin, Germany. Electronic address:

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http://dx.doi.org/10.1016/S0140-6736(20)32644-1DOI Listing
January 2021

Thromboembolic complications in critically ill COVID-19 patients are associated with impaired fibrinolysis.

Crit Care 2020 12 7;24(1):676. Epub 2020 Dec 7.

Department of Nephrology and Medical Intensive Care, Charité - Universitätsmedizin Berlin, Augustenburger Platz 1, 13353, Berlin, Germany.

Background: There is emerging evidence for enhanced blood coagulation in coronavirus 2019 (COVID-19) patients, with thromboembolic complications contributing to morbidity and mortality. The mechanisms underlying this prothrombotic state remain enigmatic. Further data to guide anticoagulation strategies are urgently required.

Methods: We used viscoelastic rotational thromboelastometry (ROTEM) in a single-center cohort of 40 critically ill COVID-19 patients.

Results: Clear signs of a hypercoagulable state due to severe hypofibrinolysis were found. Maximum lysis, especially following stimulation of the extrinsic coagulation system, was inversely associated with an enhanced risk of thromboembolic complications. Combining values for maximum lysis with D-dimer concentrations revealed high sensitivity and specificity of thromboembolic risk prediction.

Conclusions: The study identifies a reduction in fibrinolysis as an important mechanism in COVID-19-associated coagulopathy. The combination of ROTEM and D-dimer concentrations may prove valuable in identifying patients requiring higher intensity anticoagulation.
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http://dx.doi.org/10.1186/s13054-020-03401-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7719734PMC
December 2020

Kidney Single-cell Transcriptomes Predict Spatial Corticomedullary Gene Expression and Tissue Osmolality Gradients.

J Am Soc Nephrol 2021 Feb 25;32(2):291-306. Epub 2020 Nov 25.

Department of Nephrology and Medical Intensive Care, Charité - Universitätsmedizin, Berlin, Germany

Background: Single-cell transcriptomes from dissociated tissues provide insights into cell types and their gene expression and may harbor additional information on spatial position and the local microenvironment. The kidney's cells are embedded into a gradient of increasing tissue osmolality from the cortex to the medulla, which may alter their transcriptomes and provide cues for spatial reconstruction.

Methods: Single-cell or single-nuclei mRNA sequencing of dissociated mouse kidneys and of dissected cortex, outer, and inner medulla, to represent the corticomedullary axis, was performed. Computational approaches predicted the spatial ordering of cells along the corticomedullary axis and quantitated expression levels of osmo-responsive genes. hybridization validated computational predictions of spatial gene-expression patterns. The strategy was used to compare single-cell transcriptomes from wild-type mice to those of mice with a collecting duct-specific knockout of the transcription factor grainyhead-like 2 (Grhl2), which display reduced renal medullary osmolality.

Results: Single-cell transcriptomics from dissociated kidneys provided sufficient information to approximately reconstruct the spatial position of kidney tubule cells and to predict corticomedullary gene expression. Spatial gene expression in the kidney changes gradually and osmo-responsive genes follow the physiologic corticomedullary gradient of tissue osmolality. Single-nuclei transcriptomes from Grhl2 mice indicated a flattened expression gradient of osmo-responsive genes compared with control mice, consistent with their physiologic phenotype.

Conclusions: Single-cell transcriptomics from dissociated kidneys facilitated the prediction of spatial gene expression along the corticomedullary axis and quantitation of osmotically regulated genes, allowing the prediction of a physiologic phenotype.
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http://dx.doi.org/10.1681/ASN.2020070930DOI Listing
February 2021

Global Phase 3 programme of vadadustat for treatment of anaemia of chronic kidney disease: rationale, study design and baseline characteristics of dialysis-dependent patients in the INNO2VATE trials.

Nephrol Dial Transplant 2020 Nov 14. Epub 2020 Nov 14.

Department of Medicine, Stanford University School of Medicine, Palo Alto, CA, USA.

Background: Erythropoiesis-stimulating agents (ESAs) are currently the mainstay of treatment for anaemia of chronic kidney disease (CKD). Vadadustat is an investigational oral hypoxia-inducible factor prolyl-hydroxylase inhibitor that stimulates endogenous erythropoietin formation. The INNO2VATE programme comprises two studies designed to evaluate the safety and efficacy of vadadustat versus the ESA darbepoetin alfa in ameliorating anaemia in patients with dialysis-dependent CKD (DD-CKD). Here we describe the trial design along with patient demographics and baseline characteristics.

Methods: Two Phase 3, open-label, sponsor-blind, active-controlled trials enrolled adults with anaemia of CKD who recently initiated dialysis and had limited ESA exposure (incident DD-CKD trial) or were receiving maintenance dialysis with ESA treatment (prevalent DD-CKD trial). Study periods include correction/conversion (Weeks 0-23), maintenance (Weeks 24-52), long-term treatment (Weeks 53 to end of treatment) and safety follow-up. The primary safety endpoint is the time to the first major adverse cardiovascular event and the primary efficacy endpoint is the change in haemoglobin (baseline to Weeks 24-36).

Results: A total of 369 and 3554 patients were randomized in the incident DD-CKD and prevalent DD-CKD trials, respectively. Demographics and baseline characteristics were similar among patients in both trials and comparable to those typically observed in DD-CKD.

Conclusions: The two INNO2VATE trials will provide important information on the safety and efficacy of a novel approach for anaemia management in a diverse DD-CKD population. Demographics and baseline characteristics of enrolled patients suggest that study results will be representative for a large proportion of the DD-CKD population.
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http://dx.doi.org/10.1093/ndt/gfaa204DOI Listing
November 2020

Assessment of Plasma Oxalate Concentration in Patients With CKD.

Kidney Int Rep 2020 Nov 2;5(11):2013-2020. Epub 2020 Sep 2.

Department of Nephrology and Medical Intensive Care, Charité - Universitätsmedizin Berlin, Berlin, Germany.

Introduction: Alterations in oxalate homeostasis are associated with kidney stone disease and progression of chronic kidney disease (CKD). However, accurate measurement of plasma oxalate (P) concentrations in large patient cohorts is challenging as prompt acidification of samples has been deemed necessary. In the present study, we investigated the effects of variations in sample handling on P results and examined an alternative strategy to the established preanalytical procedures.

Methods: The effect of storage time at room temperature (RT) and maintenance of samples at -80°C was tested. P was measured in 1826 patients enrolled in the German Chronic Kidney Disease (GCKD) study, an ongoing multicenter, prospective, observational cohort study.

Results: We demonstrate that P concentrations increased rapidly when samples were maintained at RT. This was most relevant for P <10 μM, as concentrations more than doubled within a few hours. Immediate freezing on dry ice and storage at -80°C provided stable results and allowed postponement of acidification for >1 year. In the patients of the lowest estimated glomerular filtration rate (eGFR) quartile, median P was 2.7 μM (interquartile range [IQR] <2.0-4.2) with a median eGFR of 25.1 ml/min per 1.73 m (IQR 20.3-28.1).

Conclusion: We conclude that immediate freezing and maintenance of plasma samples at -80°C facilitates the sample collection process and allows accurate P assessment in large cohorts. The present study may serve as a reference for sample handling to assess P in clinical trials and to determine its role in CKD progression.
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http://dx.doi.org/10.1016/j.ekir.2020.08.029DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7609998PMC
November 2020

Incorporating kidney disease measures into cardiovascular risk prediction: Development and validation in 9 million adults from 72 datasets.

EClinicalMedicine 2020 Oct 14;27:100552. Epub 2020 Oct 14.

Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, United States.

Background: Chronic kidney disease (CKD) measures (estimated glomerular filtration rate [eGFR] and albuminuria) are frequently assessed in clinical practice and improve the prediction of incident cardiovascular disease (CVD), yet most major clinical guidelines do not have a standardized approach for incorporating these measures into CVD risk prediction. "CKD Patch" is a validated method to calibrate and improve the predicted risk from established equations according to CKD measures.

Methods: Utilizing data from 4,143,535 adults from 35 datasets, we developed several "CKD Patches" incorporating eGFR and albuminuria, to enhance prediction of risk of atherosclerotic CVD (ASCVD) by the Pooled Cohort Equation (PCE) and CVD mortality by Systematic COronary Risk Evaluation (SCORE). The risk enhancement by CKD Patch was determined by the deviation between individual CKD measures and the values expected from their traditional CVD risk factors and the hazard ratios for eGFR and albuminuria. We then validated this approach among 4,932,824 adults from 37 independent datasets, comparing the original PCE and SCORE equations (recalibrated in each dataset) to those with addition of CKD Patch.

Findings: We confirmed the prediction improvement with the CKD Patch for CVD mortality beyond SCORE and ASCVD beyond PCE in validation datasets (Δc-statistic 0.027 [95% CI 0.018-0.036] and 0.010 [0.007-0.013] and categorical net reclassification improvement 0.080 [0.032-0.127] and 0.056 [0.044-0.067], respectively). The median (IQI) of the ratio of predicted risk for CVD mortality with CKD Patch vs. the original prediction with SCORE was 2.64 (1.89-3.40) in very high-risk CKD (e.g., eGFR 30-44 ml/min/1.73m with albuminuria ≥30 mg/g), 1.86 (1.48-2.44) in high-risk CKD (e.g., eGFR 45-59 ml/min/1.73m with albuminuria 30-299 mg/g), and 1.37 (1.14-1.69) in moderate risk CKD (e.g., eGFR 60-89 ml/min/1.73m with albuminuria 30-299 mg/g), indicating considerable risk underestimation in CKD with SCORE. The corresponding estimates for ASCVD with PCE were 1.55 (1.37-1.81), 1.24 (1.10-1.54), and 1.21 (0.98-1.46).

Interpretation: The "CKD Patch" can be used to quantitatively enhance ASCVD and CVD mortality risk prediction equations recommended in major US and European guidelines according to CKD measures, when available.

Funding: US National Kidney Foundation and the NIDDK.
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http://dx.doi.org/10.1016/j.eclinm.2020.100552DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7599294PMC
October 2020

Nomenclature for kidney function and disease-executive summary and glossary from a Kidney Disease: Improving Global Outcomes (KDIGO) consensus conference.

Eur Heart J 2020 12;41(48):4592-4598

Selzman Institute for Kidney Health, Section of Nephrology, Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA.

The worldwide burden of kidney disease is rising, but public awareness remains limited, underscoring the need for more effective communication by stakeholders in the kidney health community. Despite this need for clarity, the nomenclature for describing kidney function and disease lacks uniformity. In June 2019, Kidney Disease: Improving Global Outcomes (KDIGO) convened a consensus conference with the goal of standardizing and refining the nomenclature used in the English language to describe kidney function and disease, and of developing a glossary that could be used by journals in scientific publications. Guiding principles of the conference were that the revised nomenclature should be patient-centred, precise, and consistent with nomenclature used in the KDIGO guidelines. Conference attendees reached general consensus on the following recommendations: (i) to use 'kidney' rather than 'renal' or 'nephro' when referring to kidney disease and kidney function; (ii) to use 'kidney failure' with appropriate descriptions of the presence or absence of symptoms, signs, and treatment rather than 'end-stage' kidney disease; (iii) to use the KDIGO definition and classification of acute kidney diseases and disorders (AKD) and acute kidney injury (AKI) rather than alternative descriptions to define and classify the severity of AKD and AKI; (iv) to use the KDIGO definition and classification of chronic kidney disease (CKD) rather than alternative descriptions to define and classify the severity of CKD; and (v) to use specific kidney measures, such as albuminuria or decreased glomerular filtration rate, rather than 'abnormal or reduced kidney function' to describe alterations in kidney structure and function. A proposed five-part glossary contains specific items for which there was general agreement. Conference attendees acknowledged limitations of the recommendations and glossary but considered that standardizing scientific nomenclature is essential for improving communication.
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http://dx.doi.org/10.1093/eurheartj/ehaa650DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7774468PMC
December 2020

Meta-analysis uncovers genome-wide significant variants for rapid kidney function decline.

Authors:
Mathias Gorski Bettina Jung Yong Li Pamela R Matias-Garcia Matthias Wuttke Stefan Coassin Chris H L Thio Marcus E Kleber Thomas W Winkler Veronika Wanner Jin-Fang Chai Audrey Y Chu Massimiliano Cocca Mary F Feitosa Sahar Ghasemi Anselm Hoppmann Katrin Horn Man Li Teresa Nutile Markus Scholz Karsten B Sieber Alexander Teumer Adrienne Tin Judy Wang Bamidele O Tayo Tarunveer S Ahluwalia Peter Almgren Stephan J L Bakker Bernhard Banas Nisha Bansal Mary L Biggs Eric Boerwinkle Erwin P Bottinger Hermann Brenner Robert J Carroll John Chalmers Miao-Li Chee Miao-Ling Chee Ching-Yu Cheng Josef Coresh Martin H de Borst Frauke Degenhardt Kai-Uwe Eckardt Karlhans Endlich Andre Franke Sandra Freitag-Wolf Piyush Gampawar Ron T Gansevoort Mohsen Ghanbari Christian Gieger Pavel Hamet Kevin Ho Edith Hofer Bernd Holleczek Valencia Hui Xian Foo Nina Hutri-Kähönen Shih-Jen Hwang M Arfan Ikram Navya Shilpa Josyula Mika Kähönen Chiea-Chuen Khor Wolfgang Koenig Holly Kramer Bernhard K Krämer Brigitte Kühnel Leslie A Lange Terho Lehtimäki Wolfgang Lieb Ruth J F Loos Mary Ann Lukas Leo-Pekka Lyytikäinen Christa Meisinger Thomas Meitinger Olle Melander Yuri Milaneschi Pashupati P Mishra Nina Mononen Josyf C Mychaleckyj Girish N Nadkarni Matthias Nauck Kjell Nikus Boting Ning Ilja M Nolte Michelle L O'Donoghue Marju Orho-Melander Sarah A Pendergrass Brenda W J H Penninx Michael H Preuss Bruce M Psaty Laura M Raffield Olli T Raitakari Rainer Rettig Myriam Rheinberger Kenneth M Rice Alexander R Rosenkranz Peter Rossing Jerome I Rotter Charumathi Sabanayagam Helena Schmidt Reinhold Schmidt Ben Schöttker Christina-Alexandra Schulz Sanaz Sedaghat Christian M Shaffer Konstantin Strauch Silke Szymczak Kent D Taylor Johanne Tremblay Layal Chaker Pim van der Harst Peter J van der Most Niek Verweij Uwe Völker Melanie Waldenberger Lars Wallentin Dawn M Waterworth Harvey D White James G Wilson Tien-Yin Wong Mark Woodward Qiong Yang Masayuki Yasuda Laura M Yerges-Armstrong Yan Zhang Harold Snieder Christoph Wanner Carsten A Böger Anna Köttgen Florian Kronenberg Cristian Pattaro Iris M Heid

Kidney Int 2021 04 31;99(4):926-939. Epub 2020 Oct 31.

Department of Genetic Epidemiology, University of Regensburg, Regensburg, Germany. Electronic address:

Rapid decline of glomerular filtration rate estimated from creatinine (eGFRcrea) is associated with severe clinical endpoints. In contrast to cross-sectionally assessed eGFRcrea, the genetic basis for rapid eGFRcrea decline is largely unknown. To help define this, we meta-analyzed 42 genome-wide association studies from the Chronic Kidney Diseases Genetics Consortium and United Kingdom Biobank to identify genetic loci for rapid eGFRcrea decline. Two definitions of eGFRcrea decline were used: 3 mL/min/1.73m/year or more ("Rapid3"; encompassing 34,874 cases, 107,090 controls) and eGFRcrea decline 25% or more and eGFRcrea under 60 mL/min/1.73m at follow-up among those with eGFRcrea 60 mL/min/1.73m or more at baseline ("CKDi25"; encompassing 19,901 cases, 175,244 controls). Seven independent variants were identified across six loci for Rapid3 and/or CKDi25: consisting of five variants at four loci with genome-wide significance (near UMOD-PDILT (2), PRKAG2, WDR72, OR2S2) and two variants among 265 known eGFRcrea variants (near GATM, LARP4B). All these loci were novel for Rapid3 and/or CKDi25 and our bioinformatic follow-up prioritized variants and genes underneath these loci. The OR2S2 locus is novel for any eGFRcrea trait including interesting candidates. For the five genome-wide significant lead variants, we found supporting effects for annual change in blood urea nitrogen or cystatin-based eGFR, but not for GATM or LARP4B. Individuals at high compared to those at low genetic risk (8-14 vs. 0-5 adverse alleles) had a 1.20-fold increased risk of acute kidney injury (95% confidence interval 1.08-1.33). Thus, our identified loci for rapid kidney function decline may help prioritize therapeutic targets and identify mechanisms and individuals at risk for sustained deterioration of kidney function.
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http://dx.doi.org/10.1016/j.kint.2020.09.030DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8010357PMC
April 2021

Would Oscillometry be Able to Solve the Dilemma of Blood Pressure Independent Pulse Wave Velocity - A Novel Approach Based on Long-Term Pulse Wave Analysis?

Front Physiol 2020 8;11:579852. Epub 2020 Oct 8.

Department of Nephrology and Intensive Care Medicine, Campus Benjamin Franklin, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany.

The utility of pulse wave velocity (PWV) as a surrogate parameter of arterial vessel damage (AVD) beyond the traditional brachial blood pressure (BP) measurement may be questioned as changes in BP are often accompanied by the corresponding changes in PWV. We sought to establish a new way for BP-independent estimation of AVD with PWV. We retrospectively analyzed data from 507 subjects with at least one available 24 h ambulatory BP- and pulse wave analysis, performed with Mobil-O-Graph (I.E.M., Stolberg, Germany). Individual relationship between eaPWV and central systolic BP (cSBP) was analyzed for every 24 h recording. The analysis revealed linear relation between eaPWV and cSBP in all subjects, which is described by equation eaPWV = acSBP + b. We termed "a" as PWVslope and "b" as PWVbaseline. All available demographic parameters and clinical data were correlated with eaPWV, PWVslope and PWVbaseline. 108 subjects had repeated 24 h recordings. Mean age was 60.7 years and 48.7% were female. 92.5% had hypertension, 22.9% were smoker, 20.5% had diabetes mellitus and 29.6% eGFR < 60 ml/min/1,73 m. Direct correlation was observed between age, SBP and eaPWV, while diastolic BP (DBP) and eGFR correlated inversely with eaPWV. PWVbaseline correlated directly with age and inversely with DBP, while PWVslope didn't correlate with any inputted parameter. Using simple mathematical approach by plotting eaPWV and cSBP values obtained during ABPM, it is possible to visualize unique course of individual PWV related to BP. Using PWVslope and PWVbaseline as novel parameters could be a feasible way to approach BP-independent PWV, though their clinical relevance should be tested in future studies. Our data underline the importance of BP-independent expression of PWV, when we use it as a clinical surrogate parameter for the vascular damage.
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http://dx.doi.org/10.3389/fphys.2020.579852DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7579143PMC
October 2020

Cardiovascular safety and efficacy of vadadustat for the treatment of anemia in non-dialysis-dependent CKD: Design and baseline characteristics.

Am Heart J 2020 Oct 30;235:1-11. Epub 2020 Oct 30.

Department of Nephrology and Medical Intensive Care, Charité - Universitätsmedizin Berlin, Berlin, Germany.

Current clinical practice guidelines for anemia management in non-dialysis-dependent chronic kidney disease (NDD-CKD) recommend the use of erythropoiesis-stimulating agents (ESAs) as standard of care. Vadadustat, an investigational oral hypoxia-inducible factor prolyl-hydroxylase inhibitor, stimulates endogenous erythropoietin production. The PROTECT program comprises 2 global, Phase 3, randomized, open-label, active-controlled, sponsor-blind clinical trials to evaluate safety and efficacy of vadadustat vs darbepoetin alfa in adult patients with anemia associated with NDD-CKD. Patients recruited into the ESA-untreated NDD-CKD trial (N = 1751) had hemoglobin <10 g/dL and had not received an ESA within 8 weeks prior to inclusion in the study. Patients recruited into the ESA-treated NDD-CKD trial (N = 1725) had hemoglobin between 8 and 11 g/dL (US) or 9 and 12 g/dL (non-US) and were actively treated with an ESA for anemia associated with CKD. Trial periods in both trials include (1) correction/conversion (weeks 0-23); (2) maintenance (weeks 24-52); (3) long-term treatment (week 53 to end of treatment); and (4) safety follow-up (end-of-treatment to 4 weeks later). The primary safety endpoint is time to first adjudicated major adverse cardiovascular event, defined as all-cause mortality, nonfatal myocardial infarction, or nonfatal stroke, pooled across both trials. The primary efficacy endpoint in each trial is change in hemoglobin from baseline to primary evaluation period (weeks 24-36), comparing vadadustat vs darbepoetin alfa treatment groups. Demographics and baseline characteristics are similar among patients in both trials and broadly representative of the NDD-CKD population. These trials will help to evaluate the safety and efficacy of vadadustat for management of anemia associated with NDD-CKD.
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http://dx.doi.org/10.1016/j.ahj.2020.10.068DOI Listing
October 2020

Hypoxia-inducible factors not only regulate but also are myeloid-cell treatment targets.

J Leukoc Biol 2020 Oct 18. Epub 2020 Oct 18.

Department of Nephrology and Medical Intensive Care, Charité-Universitätsmedizin Berlin, Berlin, Germany.

Hypoxia describes limited oxygen availability at the cellular level. Myeloid cells are exposed to hypoxia at various bodily sites and even contribute to hypoxia by consuming large amounts of oxygen during respiratory burst. Hypoxia-inducible factors (HIFs) are ubiquitously expressed heterodimeric transcription factors, composed of an oxygen-dependent α and a constitutive β subunit. The stability of HIF-1α and HIF-2α is regulated by oxygen-sensing prolyl-hydroxylases (PHD). HIF-1α and HIF-2α modify the innate immune response and are context dependent. We provide a historic perspective of HIF discovery, discuss the molecular components of the HIF pathway, and how HIF-dependent mechanisms modify myeloid cell functions. HIFs enable myeloid-cell adaptation to hypoxia by up-regulating anaerobic glycolysis. In addition to effects on metabolism, HIFs control chemotaxis, phagocytosis, degranulation, oxidative burst, and apoptosis. HIF-1α enables efficient infection defense by myeloid cells. HIF-2α delays inflammation resolution and decreases antitumor effects by promoting tumor-associated myeloid-cell hibernation. PHDs not only control HIF degradation, but also regulate the crosstalk between innate and adaptive immune cells thereby suppressing autoimmunity. HIF-modifying pharmacologic compounds are entering clinical practice. Current indications include renal anemia and certain cancers. Beneficial and adverse effects on myeloid cells should be considered and could possibly lead to drug repurposing for inflammatory disorders.
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http://dx.doi.org/10.1002/JLB.4RI0820-535RDOI Listing
October 2020

Role of SGK1 in the Osteogenic Transdifferentiation and Calcification of Vascular Smooth Muscle Cells Promoted by Hyperglycemic Conditions.

Int J Mol Sci 2020 Sep 29;21(19). Epub 2020 Sep 29.

Institute for Physiology and Pathophysiology, Johannes Kepler University Linz, Altenberger Strasse 69, 4040 Linz, Austria.

In diabetes mellitus, hyperglycemia promotes the osteogenic transdifferentiation of vascular smooth muscle cells (VSMCs) to enhance medial vascular calcification, a common complication strongly associated with cardiovascular disease and mortality. The mechanisms involved are, however, still poorly understood. Therefore, the present study explored the potential role of serum- and glucocorticoid-inducible kinase 1 (SGK1) during vascular calcification promoted by hyperglycemic conditions. Exposure to high-glucose conditions up-regulated the SGK1 expression in primary human aortic VSMCs. High glucose increased osteogenic marker expression and activity and, thus, promoted the osteogenic transdifferentiation of VSMCs, effects significantly suppressed by additional treatment with the SGK1 inhibitor EMD638683. Moreover, high glucose augmented the mineralization of VSMCs in the presence of calcification medium, effects again significantly reduced by SGK1 inhibition. Similarly, SGK1 knockdown blunted the high glucose-induced osteogenic transdifferentiation of VSMCs. The osteoinductive signaling promoted by high glucose required SGK1-dependent NF-kB activation. In addition, advanced glycation end products (AGEs) increased the SGK1 expression in VSMCs, and SGK1 inhibition was able to interfere with AGEs-induced osteogenic signaling. In conclusion, SGK1 is up-regulated and mediates, at least partly, the osteogenic transdifferentiation and calcification of VSMCs during hyperglycemic conditions. Thus, SGK1 inhibition may reduce the development of vascular calcification promoted by hyperglycemia in diabetes.
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http://dx.doi.org/10.3390/ijms21197207DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7583813PMC
September 2020

Establishment of an extracorporeal cardio-pulmonary resuscitation program in Berlin - outcomes of 254 patients with refractory circulatory arrest.

Scand J Trauma Resusc Emerg Med 2020 Sep 23;28(1):96. Epub 2020 Sep 23.

Department of Nephrology and Medical Intensive Care, Charité-Universitätsmedizin Berlin, Augustenburger Platz 1, 13353, Berlin, Germany.

Objective: Optimal management of out of hospital circulatory arrest (OHCA) remains challenging, in particular in patients who do not develop rapid return of spontaneous circulation (ROSC). Extracorporeal cardiopulmonary resuscitation (eCPR) can be a life-saving bridging procedure. However its requirements and feasibility of implementation in patients with OHCA, appropriate inclusion criteria and achievable outcomes remain poorly defined.

Design: Prospective cohort study.

Setting: Tertiary referral university hospital center.

Patients: Here we report on characteristics, course and outcomes on the first consecutive 254 patients admitted between August 2014 and December 2017.

Intervention: eCPR program for OHCA.

Mesurements And Main Results: A structured clinical pathway was designed and implemented as 24/7 eCPR service at the Charité in Berlin. In total, 254 patients were transferred with ongoing CPR, including automated chest compression, of which 30 showed or developed ROSC after admission. Following hospital admission predefined in- and exclusion criteria for eCPR were checked; in the remaining 224, 126 were considered as eligible for eCPR. State of the art postresuscitation therapy was applied and prognostication of neurological outcome was performed according to a standardized protocol. Eighteen patients survived, with a good neurological outcome (cerebral performance category (CPC) 1 or 2) in 15 patients. Compared to non-survivors survivors had significantly shorter time between collaps and start of eCPR (58 min (IQR 12-85) vs. 90 min (IQR 74-114), p = 0.01), lower lactate levels on admission (95 mg/dL (IQR 44-130) vs. 143 mg/dL (IQR 111-178), p <  0.05), and less severe acidosis on admission (pH 7.2 (IQR 7.15-7.4) vs. 7.0 (IQR6.9-7.2), p <  0.05). Binary logistic regression analysis identified latency to eCPR and low pH as independent predictors for mortality.

Conclusion: An eCPR program can be life-saving for a subset of individuals with refractory circulatory arrest, with time to initiation of eCPR being a main determinant of survival.
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http://dx.doi.org/10.1186/s13049-020-00787-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7513459PMC
September 2020

Nomenclature for kidney function and disease: executive summary and glossary from a Kidney Disease: Improving Global Outcomes consensus conference.

Clin Kidney J 2020 Aug 18;13(4):485-493. Epub 2020 Aug 18.

Selzman Institute for Kidney Health, Section of Nephrology, Department of Medicine, Baylor College of Medicine, Houston, TX, USA.

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http://dx.doi.org/10.1093/ckj/sfaa123DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7467601PMC
August 2020

Investigation of a nonsense mutation located in the complex KIV-2 copy number variation region of apolipoprotein(a) in 10,910 individuals.

Genome Med 2020 08 21;12(1):74. Epub 2020 Aug 21.

Institute of Genetic Epidemiology, Department of Genetics and Pharmacology, Medical University of Innsbruck, Schöpfstrasse 41, A-6020, Innsbruck, Austria.

Background: The concentrations of the highly atherogenic lipoprotein(a) [Lp(a)] are mainly genetically determined by the LPA gene locus. However, up to 70% of the coding sequence is located in the complex so-called kringle IV type 2 (KIV-2) copy number variation, a region hardly accessible by common genotyping and sequencing technologies. Despite its size, little is known about genetic variants in this complex region. The R21X variant is a functional variant located in this region, but it has never been analyzed in large cohorts.

Methods: We typed R21X in 10,910 individuals from three European populations using a newly developed high-throughput allele-specific qPCR assay. R21X allelic location was determined by separating the LPA alleles using pulsed-field gel electrophoresis (PFGE) and typing them separately. Using GWAS data, we identified a proxy SNP located outside of the KIV-2. Linkage disequilibrium was determined both statistically and by long-range haplotyping using PFGE. Worldwide frequencies were determined by reanalyzing the sequencing data of the 1000 Genomes Project with a dedicated pipeline.

Results: R21X carriers (frequency 0.016-0.021) showed significantly lower mean Lp(a) concentrations (- 11.7 mg/dL [- 15.5; - 7.82], p = 3.39e-32). The variant is located mostly on medium-sized LPA alleles. In the 1000 Genome data, R21X mostly occurs in Europeans and South Asians, is absent in Africans, and shows varying frequencies in South American populations (0 to 0.022). Of note, the best proxy SNP was another LPA null mutation (rs41272114, D' = 0.958, R = 0.281). D' was very high in all 1000G populations (0.986-0.996), although rs41272114 frequency varies considerably (0-0.182). Co-localization of both null mutations on the same allele was confirmed by PFGE-based long-range haplotyping.

Conclusions: We performed the largest epidemiological study on an LPA KIV-2 variant so far, showing that it is possible to assess LPA KIV-2 mutations on a large scale. Surprisingly, in all analyzed populations, R21X was located on the same haplotype as the splice mutation rs41272114, creating "double-null" LPA alleles. Despite being a nonsense variant, the R21X status does not provide additional information beyond the rs41272114 genotype. This has important implications for studies using LPA loss-of-function mutations as genetic instruments and emphasizes the complexity of LPA genetics.
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http://dx.doi.org/10.1186/s13073-020-00771-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7442989PMC
August 2020

Microvascular inflammation is a risk factor in kidney transplant recipients with very late conversion from calcineurin inhibitor-based regimens to belatacept.

BMC Nephrol 2020 08 20;21(1):354. Epub 2020 Aug 20.

Department of Nephrology and Medical Intensive Care, Charité Universitätsmedizin Berlin, Augustenburger Platz 1, 13353, Berlin, Germany.

Background: In de novo kidney transplant recipients (KTR) treatment with belatacept has been established as a comparable option as maintenance immunosuppression, preferably as a strategy to convert from calcineurin inhibitor (CNI)- to belatacept-based immunosuppression. Switch to belatacept demonstrated improved renal function in patients with CNI-induced nephrotoxicity, but risk of transplant rejection and the development of donor-specific antibodies (DSA) are still a matter of debate. Only few data are available in patients at increased immunological risk and late after transplantation.

Methods: We analyzed 30 long-term KTR (including 2 combined pancreas-KTR) converted from CNI to belatacept > 60 months after transplantation with moderate to severe graft dysfunction (GFR ≤ 45 mL/min). Biopsies were classified according to the Banff 2015 criteria. Group differences were assessed in a univariate analysis using Mann Whitney U or Chi square test, respectively. Multivariate analysis of risk factors for treatment failure was performed using a binary logistic regression model including significant predictors from univariate analysis. Fifty-six KTR matched for donor and recipient characteristics were used as a control cohort remaining under CNI-treatment.

Results: Patient survival in belatacept cohort at 12/24 months was 96.7%/90%, overall graft survival was 76.7 and 60.0%, while graft survival censored for death was 79.3%/66.7%. In patients with functioning grafts, median GFR improved from 22.5 mL/min to 24.5 mL/min at 24 months. Positivity for DSA at conversion was 46.7%. From univariate analysis of risk factors for graft loss, GFR < 25 mL/min (p = 0.042) and Banff microvascular inflammation (MVI) sum score ≥ 2 (p = 0.023) at conversion were significant at 24 months. In the analysis of risk factors for treatment failure, a MVI sum score ≥ 2 was significant univariately (p = 0.023) and in a bivariate (p = 0.037) logistic regression at 12 months. DSA-positivity was neither associated with graft loss nor treatment failure. The control cohort had comparable graft survival outcomes at 24 months, albeit without increase of mean GFR in patients with functioning grafts (ΔGFR of - 3.6 ± 8.5 mL/min).

Conclusion: Rescue therapy with conversion to belatacept is feasible in patients with worsening renal function, even many years after transplantation. The benefit in patients with MVI and severe GFR impairment remains to be investigated.
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http://dx.doi.org/10.1186/s12882-020-01992-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7439694PMC
August 2020