Publications by authors named "Danilo Fliser"

255 Publications

Markers of cholesterol synthesis to cholesterol absorption across the spectrum of non-dialysis CKD: An observational study.

Pharmacol Res Perspect 2021 Aug;9(4):e00801

Department of Internal Medicine I - Cardiology, Angiology, Intensive Care Medicine, University Hospital Jena, Jena, Germany.

In dialysis patients, cholesterol-lowering therapy with statins is less effective than in other high-risk patients. This may be explained by a shift from cholesterol synthesis toward cholesterol absorption. In line, markers of cholesterol absorption-such as campesterol-better predict atherosclerotic cardiovascular events than markers of cholesterol synthesis-such as lathosterol-in dialysis patients. To test the association between markers of cholesterol absorption such as campesterol-and markers of cholesterol synthesis-such as lathosterol-against cardiovascular events in non-dialysis CKD patients. Altogether 251 patients those not on lipid-lowering agents were followed annually for the composite endpoint atherosclerotic cardiovascular disease (ASCVD) and all-cause death. During follow-up of 5.2 ± 2.1 years, 61 participants reached the primary endpoint atherosclerotic cardiovascular disease/all-cause death [ASCVD/D], 47 participants suffered from ASCVD, and 46 participants died. In univariate Cox regression analysis, campesterol/lathosterol ratio did not significantly predict ASCVD/D (HR 0.643; 0.358-1.155; 3rd vs. 1st tertile), all-cause death (HR 1.309; 0.604-2.838; 3rd vs. 1st tertile) nor ASCVD (HR 0.589; 0.311-1.118; 3rd vs. 1st tertile). We did not observe a shift from cholesterol synthesis to cholesterol absorption across the spectrum of non-dialysis CKD. Campesterol/lathosterol ratio did not predict future ASCVD or all-cause death in non-dialysis CKD.
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http://dx.doi.org/10.1002/prp2.801DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8204094PMC
August 2021

A material stress test study on occurrence of leakage and material failure of peritoneal dialysis (PD) catheters.

Sci Rep 2021 May 13;11(1):10212. Epub 2021 May 13.

Department of General, Visceral, Vascular and Pediatric Surgery, Saarland University Medical Centre, Homburg, Saar, Germany.

Peritonitis is a common complication of peritoneal dialysis (PD). Our root cause analysis allowed to attribute some cases to leakage of the PD catheter. Accordingly, a clinically based stress test study on potential material damage issues of PD catheters was performed, focusing on material damage caused by cleaning, de- and attachment procedures during dialysate changes and on the individual storage methods of PD catheters between dialysate changes. PD catheters were exposed to both chemical stress by repeating dialysate-flow and physical stress simulating de- and connecting, fixation, pressure, flexing, folding etc.-simulating standard clinical daily routine of 8-10 years PD catheter usage. Potentially by normal usage caused damages should be then detected by intraluminal pressure, light- and electron microscopy. The multi-step visual control showed no obvious damages on PD catheters nor any leakage or barrier indulgence. Our tests simulating daily routine usage of PD catheters for several years could not detect any material defects under chemical or physical stress. Hence, we presume that most PD catheter damages, as identified cause for peritonitis in some of our patients, may be due to accidental, unnoticed external damage (e.g. through scissors, while changing dressings) or neglecting PD catheter handling specifications.
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http://dx.doi.org/10.1038/s41598-021-89643-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8119981PMC
May 2021

Orphan nuclear receptor ERR-γ regulates hepatic FGF23 production in acute kidney injury.

Proc Natl Acad Sci U S A 2021 Apr;118(16)

School of Biological Sciences and Technology, Chonnam National University, 61186 Gwangju, Republic of Korea;

Fibroblast growth factor 23 (FGF23), a hormone generally derived from bone, is important in phosphate and vitamin D homeostasis. In acute kidney injury (AKI) patients, high-circulating FGF23 levels are associated with disease progression and mortality. However, the organ and cell type of FGF23 production in AKI and the molecular mechanism of its excessive production are still unidentified. For insight, we investigated folic acid (FA)-induced AKI in mice. Interestingly, simultaneous with FGF23, orphan nuclear receptor ERR-γ expression is increased in the liver of FA-treated mice, and ectopic overexpression of ERR-γ was sufficient to induce hepatic FGF23 production. In patients and in mice, AKI is accompanied by up-regulated systemic IL-6, which was previously identified as an upstream regulator of ERR-γ expression in the liver. Administration of IL-6 neutralizing antibody to FA-treated mice or of recombinant IL-6 to healthy mice confirms IL-6 as an upstream regulator of hepatic ERR-γ-mediated FGF23 production. A significant ( < 0.001) interconnection between high IL-6 and FGF23 levels as a predictor of AKI in patients that underwent cardiac surgery was also found, suggesting the clinical relevance of the finding. Finally, liver-specific depletion of ERR-γ or treatment with an inverse ERR-γ agonist decreased hepatic FGF23 expression and plasma FGF23 levels in mice with FA-induced AKI. Thus, inverse agonist of ERR-γ may represent a therapeutic strategy to reduce adverse plasma FGF23 levels in AKI.
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http://dx.doi.org/10.1073/pnas.2022841118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8072258PMC
April 2021

Genetically determined NLRP3 inflammasome activation associates with systemic inflammation and cardiovascular mortality.

Eur Heart J 2021 05;42(18):1742-1756

Emory Clinical Cardiovascular Research Institute, Division of Cardiology, Emory University School of Medicine, 1462 Clifton Road NE, Atlanta, GA 30322, USA.

Aims: Inflammation plays an important role in cardiovascular disease (CVD) development. The NOD-like receptor protein-3 (NLRP3) inflammasome contributes to the development of atherosclerosis in animal models. Components of the NLRP3 inflammasome pathway such as interleukin-1β can therapeutically be targeted. Associations of genetically determined inflammasome-mediated systemic inflammation with CVD and mortality in humans are unknown.

Methods And Results: We explored the association of genetic NLRP3 variants with prevalent CVD and cardiovascular mortality in 538 167 subjects on the individual participant level in an explorative gene-centric approach without performing multiple testing. Functional relevance of single-nucleotide polymorphisms on NLRP3 inflammasome activation has been evaluated in monocyte-enriched peripheral blood mononuclear cells (PBMCs). Genetic analyses identified the highly prevalent (minor allele frequency 39.9%) intronic NLRP3 variant rs10754555 to affect NLRP3 gene expression. rs10754555 carriers showed significantly higher C-reactive protein and serum amyloid A plasma levels. Carriers of the G allele showed higher NLRP3 inflammasome activation in isolated human PBMCs. In carriers of the rs10754555 variant, the prevalence of coronary artery disease was significantly higher as compared to non-carriers with a significant interaction between rs10754555 and age. Importantly, rs10754555 carriers had significantly higher risk for cardiovascular mortality during follow-up. Inflammasome inducers (e.g. urate, triglycerides, apolipoprotein C3) modulated the association between rs10754555 and mortality.

Conclusion: The NLRP3 intronic variant rs10754555 is associated with increased systemic inflammation, inflammasome activation, prevalent coronary artery disease, and mortality. This study provides evidence for a substantial role of genetically driven systemic inflammation in CVD and highlights the NLRP3 inflammasome as a therapeutic target.
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http://dx.doi.org/10.1093/eurheartj/ehab107DOI Listing
May 2021

Cardiovascular Disease in Chronic Kidney Disease: Pathophysiological Insights and Therapeutic Options.

Circulation 2021 Mar 15;143(11):1157-1172. Epub 2021 Mar 15.

Department of Internal Medicine I (Cardiology) (N.M.), University Hospital, Rheinisch-Westfälische Technische Hochschule Aachen (RWTH), Aachen, Germany.

Patients with chronic kidney disease (CKD) exhibit an elevated cardiovascular risk manifesting as coronary artery disease, heart failure, arrhythmias, and sudden cardiac death. Although the incidence and prevalence of cardiovascular events is already significantly higher in patients with early CKD stages (CKD stages 1-3) compared with the general population, patients with advanced CKD stages (CKD stages 4-5) exhibit a markedly elevated risk. Cardiovascular rather than end-stage kidney disease (CKD stage 5) is the leading cause of death in this high-risk population. CKD causes a systemic, chronic proinflammatory state contributing to vascular and myocardial remodeling processes resulting in atherosclerotic lesions, vascular calcification, and vascular senescence as well as myocardial fibrosis and calcification of cardiac valves. In this respect, CKD mimics an accelerated aging of the cardiovascular system. This overview article summarizes the current understanding and clinical consequences of cardiovascular disease in CKD.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.120.050686DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7969169PMC
March 2021

Adherence to the Kidney Disease: Improving Global Outcomes CKD Guideline in Nephrology Practice Across Countries.

Kidney Int Rep 2021 Feb 17;6(2):437-448. Epub 2020 Dec 17.

Arbor Research Collaborative for Health, Ann Arbor, Michigan, USA.

Introduction: The uptake of the Kidney Disease: Improving Global Outcomes (KDIGO) 2012 chronic kidney disease (CKD) Guideline is not fully described in real-world nephrology practice across the world.

Methods: We used baseline data from the CKD Outcomes and Practice Patterns Study (2013-2017), a 4-country cohort of patients with estimated glomerular filtration rate <60 ml/min per 1.73 m recruited from national samples of nephrology clinics, to describe adherence to measures for monitoring and delaying CKD progression. Data were collected as in clinical practice, except laboratory measures per protocol in France.

Results: The mean age ranged from 65 years in Brazil to 72 years in Germany. Albuminuria (mostly proteinuria) was measured routinely in 36% to 43% of patients in Brazil, Germany, and the United States. Blood pressure control (≤140/90 mm Hg) ranged from 49% in France to 76% in Brazil; <40% of patients had blood pressure ≤130/80 mm Hg everywhere but Brazil (52%). More than 40% of nephrologists in Brazil reported a systolic blood pressure target ≤130 mm Hg for nondiabetic patients without proteinuria, but only 19% to 24% elsewhere. Prescription of renin-angiotensin aldosterone system inhibitors ranged from 52% in the United States to 81% in Germany. Dietary advice was more frequent for salt than protein intake; dietitian visits were uncommon. In nondiabetic patients, achievement of all 3 targets including blood pressure ≤130/80 mm Hg, renin-angiotensin aldosterone system inhibition, and dietary advice, ranged from 10% in the United States to 32% in Brazil; in treated diabetic patients, this ranged from 6% to 11% after including hemoglobin A1c target.

Conclusion: Adherence to recommendations to slow CKD progression is low in typical practice settings, and substantial variation among countries for some indicates opportunities for improvement.
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http://dx.doi.org/10.1016/j.ekir.2020.11.039DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7879121PMC
February 2021

EDTAKI: A Nephrology and Public Policy Committee (NPPC) Platform Call for More European Involvement in AKI.

Nephrol Dial Transplant 2021 Feb 2. Epub 2021 Feb 2.

Department of Nephrology, Ambroise Paré University Hospital, APHP, Boulogne-Billancourt/Paris, and Centre for Research in Epidemiology and Population Health (CESP), Paris-Saclay University, Versailles Saint Quentin University, INSERM UMRS 1018, Team5 Villejuif, France.

Acute Kidney Injury (AKI) is an often neglected but crucial element of clinical nephrology. The aim of the Nephrology Public Policy Committee (NPPC) of the European Renal Association - European Dialysis and Transplant Association (ERA-EDTA) is to promote several key aspects of European nephrology. One of the targets proposed by NPPC was to advance European nephrology involvement in AKI. We undertook literature analyses to define the current position of European nephrology in the field of AKI compared to other regions, and about how different European countries compare to each other. It appeared that vis-à-vis countries with a comparable socio-economic status (the US, Australia, New Zealand, Canada), the European contribution was almost 50% lower. Within Europe, Central/Eastern Europe and countries with a lower gross domestic product (GDP) showed lower scientific output. Nephrologists contributed to less than half of the output. There was no trend for a change over the last decade. It is concluded that there is room to improve the contribution of European nephrology in the field of AKI. We propose a model on how to promote clinical collaboration on AKI across Europe, the creation of a pan-European nephrology network of interested units is proposed, to improve clinical outcomes, increase nephrologist involvement and awareness outside nephrology, and stimulate research on AKI in Europe. Accordingly, we also propose a list of research priorities and stress the need for more European funding of AKI research.
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http://dx.doi.org/10.1093/ndt/gfab018DOI Listing
February 2021

[Symptom control in heart failure patients - how to handle GFR decrease and hyperkalaemia].

Dtsch Med Wochenschr 2021 Mar 22;146(6):e47-e55. Epub 2021 Jan 22.

Klinik für Nephrologie, Blutreinigung und Rheumatologie, Klinikum Braunschweig.

For heart failure patients with reduced ejection fraction, optimised medication improves symptom control and reduces mortality. Substances influencing the renin-angiotensin-aldosteron-system, so-called RAAS-inhibitors, are the cornerstone of heart failure treatment. This article summarises a consensus between experts in cardiology and in nephrology on a pragmatic approach to manage a drop in glomerular filtration rate and incident hyperkalaemia - the two most common reasons for reducing or discontinuing heart failure medication.
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http://dx.doi.org/10.1055/a-1307-8652DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7972821PMC
March 2021

Lipoproteins in chronic kidney disease: from bench to bedside.

Eur Heart J 2021 Jun;42(22):2170-2185

Translational Cardio-Renal Medicine, Saarland University, Kirrberger Strasse, Building 41, D-66421 Homburg/Saar, Germany.

Chronic kidney disease (CKD) is associated with high cardiovascular risk. CKD patients exhibit a specific lipoprotein pattern termed 'uraemic dyslipidaemia', which is characterized by rather normal low-density lipoprotein cholesterol, low high-density lipoprotein cholesterol, and high triglyceride plasma levels. All three lipoprotein classes are involved in the pathogenesis of CKD-associated cardiovascular diseases (CVDs). Uraemia leads to several modifications of the structure of lipoproteins such as changes of the proteome and the lipidome, post-translational protein modifications (e.g. carbamylation) and accumulation of small-molecular substances within the lipoprotein moieties, which affect their functionality. Lipoproteins from CKD patients interfere with lipid transport and promote inflammation, oxidative stress, endothelial dysfunction as well as other features of atherogenesis, thus contributing to the development of CKD-associated CVD. While, lipid-modifying therapies play an important role in the management of CKD patients, their efficacy is modulated by kidney function. Novel therapeutic agents to prevent the adverse remodelling of lipoproteins in CKD and to improve their functional properties are highly desirable and partially under development.
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http://dx.doi.org/10.1093/eurheartj/ehaa1050DOI Listing
June 2021

Heart and kidney disease: a cardiovascular high-risk constellation.

Herz 2021 Jun 30;46(3):206-211. Epub 2020 Dec 30.

Klinik für Innere Medizin IV, Universitätsklinikum des Saarlandes, Homburg/Saar, Germany.

Chronic kidney disease (CKD) is associated with substantial cardiovascular morbidity and mortality. This is mediated by highly prevalent traditional cardiovascular risk factors such as arterial hypertension and diabetes mellitus in patients with CKD, but also by the presence of CKD-specific so-called nontraditional cardiovascular risk factors such as vascular calcification, uremic toxins, uremic dyslipidemia, inflammation, and oxidative stress. Therefore, the primary and secondary prevention of cardiovascular disease represents an important part of the care of patients with CKD. This entails optimal control of blood pressure and diabetes, treatment of the uremic dyslipidemia, as well as life-style modifying factors such as weight reduction and smoking cessation.
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http://dx.doi.org/10.1007/s00059-020-05012-zDOI Listing
June 2021

Kinetic Changes of Plasma Renin Concentrations Predict Acute Kidney Injury in Cardiac Surgery Patients.

Am J Respir Crit Care Med 2021 May;203(9):1119-1126

Department of Anesthesiology, Intensive Care Medicine and Pain Therapy, University Hospital Muenster, Muenster, Germany.

The renin-angiotensin-aldosterone system is a major pathway in regulating blood pressure, glomerular filtration, and fluid homeostasis. During inflammatory diseases, generation of angiotensin II might be disturbed, leading to increased renin concentrations. Cardiac surgery and the use of cardiopulmonary bypass both induce inflammatory response and cardiovascular instability, which can contribute to acute kidney injury (AKI). To investigate whether renin concentrations are associated with hypotension and AKI. This is a single-center, prospective, observational study among patients undergoing cardiac surgery. The primary endpoint was the occurrence of AKI within 72 hours after cardiac surgery. A total of 197 patients were available for the primary analysis. The median renin serum concentration was 40.2 μU/ml (quartile 1 [Q1]-Q3, 9.3-144.4) at baseline and 51.3 μU/ml (Q1-Q3, 19.1-167.0) 4 hours after cardiac surgery, whereas the difference between postoperation and preoperation concentrations (Δ-renin) was 3.7 μU/ml (Q1-Q3, -22.7 to 50.9). Patients with an elevated Δ-renin developed an AKI significantly more often (43% vs. 12.2%;  < 0.001). High Δ-renin after cardiac surgery was associated with a significantly lower mean arterial pressure, longer time on vasopressors, and longer length of ICU and hospital stay. The area under the curve (AUC) of Δ-renin for the prediction of AKI (AUC, 0.817; 95% confidence interval, 0.747-0.887) was significantly greater compared with the AUC of the postoperative renin concentrations (AUC, 0.702; 95% CI, 0.610-0.793;  = 0.007). Elevated renin concentrations were associated with cardiovascular instability and increased AKI after cardiac surgery. Elevated renin concentrations could be used to identify high-risk patients for cardiovascular instability and AKI who would benefit from timely intervention that could improve their outcomes.
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http://dx.doi.org/10.1164/rccm.202005-2050OCDOI Listing
May 2021

WNT-β-catenin signalling - a versatile player in kidney injury and repair.

Nat Rev Nephrol 2021 03 28;17(3):172-184. Epub 2020 Sep 28.

Department of Nephrology and Clinical Immunology, University Hospital, Rheinisch Westfälische Technische Hochschule (RWTH), Aachen, Germany.

The WNT-β-catenin system is an evolutionary conserved signalling pathway that is of particular importance for morphogenesis and cell organization during embryogenesis. The system is usually suppressed in adulthood; however, it can be re-activated in organ injury and regeneration. WNT-deficient mice display severe kidney defects at birth. Transient WNT-β-catenin activation stimulates tissue regeneration after acute kidney injury, whereas sustained (uncontrolled) WNT-β-catenin signalling promotes kidney fibrosis in chronic kidney disease (CKD), podocyte injury and proteinuria, persistent tissue damage during acute kidney injury and cystic kidney diseases. Additionally, WNT-β-catenin signalling is involved in CKD-associated vascular calcification and mineral bone disease. The WNT-β-catenin pathway is tightly regulated, for example, by proteins of the Dickkopf (DKK) family. In particular, DKK3 is released by 'stressed' tubular epithelial cells; DKK3 drives kidney fibrosis and is associated with short-term risk of CKD progression and acute kidney injury. Thus, targeting the WNT-β-catenin pathway might represent a promising therapeutic strategy in kidney injury and associated complications.
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http://dx.doi.org/10.1038/s41581-020-00343-wDOI Listing
March 2021

Funding kidney research as a public health priority: challenges and opportunities.

Nephrol Dial Transplant 2020 Sep 4. Epub 2020 Sep 4.

Division of Nephrology, University of Würzburg, Würzburg, Germany.

Medical societies have a social responsibility to disseminate knowledge and inform health authorities on threats to public health posed by various diseases. Advocacy for health protection programmes and for medical research funding is now embedded into the missions of most scientific societies. To promote kidney research funding in Europe, the European Renal Association - European Dialysis and Transplant Association (ERA-EDTA), rather than acting as an individual society advocating for the fight against kidney disease, has actively helped to create an alliance of national associations centred on kidney diseases, the European Kidney Health Alliance (EKHA), and joined the Biomedical Alliance (BMA). The ERA-EDTA is fully committed to supporting its working groups (WGs) and consortia of its members to allow them to produce valuable kidney research. The framing and formalization of projects, and the regulatory issues related to submission to the European Commission, are complex. To help WGs to gain expert advice from agencies with specific know-how, the ERA-EDTA has adopted a competitive approach. The best research projects proposed by WGs and consortia of other European investigators will receive seed funding to cover the costs of consultancy by expert agencies. Via its broader platforms, the EKHA and the BMA, the ERA-EDTA will strive towards broader recognition of kidney disease and related clusters of non-communicable diseases, by European and national agencies, as major threats to the qualities of life of their populations and their economies.
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http://dx.doi.org/10.1093/ndt/gfaa163DOI Listing
September 2020

Therapeutic apheresis within immune-mediated neurological disorders: dosing and its effectiveness.

Sci Rep 2020 05 13;10(1):7925. Epub 2020 May 13.

Department of Internal Medicine, Nephrology and Hypertension, Homburg, Germany.

Plasma exchange (PE) and immunoadsorption (IA) are standard therapeutic options of immune-mediated neurological disorders. This study evaluates the relation of the relative quantity of applied dose of PE and/ or IA and its achieved therapeutic effectiveness within the treated underlying neurological disorders. In a retrospective study, we evaluated data from PE and IA carried out 09/2009-06/2014 in neurological patients at the University-Hospital of Saarland, Germany. Apheresis dose was defined as the ratio of the extracorporeal treated plasma volume to the patient's plasma volume. Effectiveness was assessed through disease-specific tests and scores by the attending neurologist(s); results were classified into response or no response. 1101 apheresis (PE:238, IA:863), in 153 hospital-stays were carried out, averaged, 7.0 treatments per patients, 82% responded, 18% not. Mean applied apheresis dose per treatment was 0.91 with mean doses of 1.16 for PE and 0.81 for IA. The totally applied mean dose per stay was 5.6 (PE:5.01, IA:5.81). No correlation was seen between apheresis dosing and treatment effectiveness (PE:R2 = 0.074, IA:R2 = 0.0023). PE and IA in therapy-refractory immune-mediated neurological disorders majorly achieved a measurable severity improvement - without correlation to the applied dose. Moreover, our data rather suggest, that effectiveness may be given with volumes below currently recommended volumes.
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http://dx.doi.org/10.1038/s41598-020-64744-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7220931PMC
May 2020

Dickkopf 3-a novel biomarker of the 'kidney injury continuum'.

Nephrol Dial Transplant 2021 Apr;36(5):761-767

Department of Internal Medicine IV - Nephrology and Hypertension, Saarland University Medical Center, Homburg/Saar, Germany.

Chronic kidney disease (CKD) is a global public health problem accompanied by substantial comorbidities and reduced life expectancy. In this respect, progressive CKD leading to uraemia can be seen as a systemic disease with a critical impact on virtually all organ systems. Therefore, it is of particular importance to identify patients with ongoing CKD progression, which is challenging, because the individual course of CKD is difficult to predict. Patterns of progression in CKD patients include linear and non-linear trajectories of GFR loss, but kidney function can also remain stable for years. Moreover, a substantial GFR decline may occur in the absence of higher-grade albuminuria (non-proteinuric CKD), rendering the measurement of albuminuria less reliable for progression prediction in such individuals. In the present review, we focus on the recently identified glycoprotein Dickkopf-3 (DKK3) as a stress-induced, renal tubular epithelial cell-derived, pro-fibrotic molecule. In experimental CKD models, DKK3 promoted renal tubulointerstitial fibrosis through modulation of the canonical Wnt/β-catenin signalling pathway. In clinical studies, increased urinary DKK3 levels identified patients at high risk for short-term CKD progression, regardless of the cause of kidney disease, baseline kidney function and albuminuria. Moreover, increased urinary DKK3 levels are associated with a high risk for acute kidney injury and the subsequent loss of kidney function after cardiac surgery. These findings highlight DKK3 as a mediator of renal tubular cell damage in kidney injury and short-term progression of kidney disease, with potential therapeutic implications.
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http://dx.doi.org/10.1093/ndt/gfaa003DOI Listing
April 2021

Chronic kidney disease progression and mortality risk profiles in Germany: results from the Chronic Kidney Disease Outcomes and Practice Patterns Study.

Nephrol Dial Transplant 2020 05;35(5):803-810

Internal Medicine - Nephrology and Hypertension, University Hospital of the Saarland, Homburg, Germany.

Background: Chronic kidney disease (CKD) progression among German patients in a representative setting has not been described previously. The Verband Deutsche Nierenzentren and Chronic Kidney Disease Outcomes and Practice Patterns Study established a longitudinal observational cohort among German CKD patients to research variations in patient care and outcomes in real-world nephrology practices.

Methods: A cohort of CKD Stages 3 (25%) and 4 (75%) patients was established from German nephrologist-run CKD clinics in 2013-16. Linear models were used to determine the estimated glomerular filtration rate (eGFR) slope during follow-up and Cox models were used to assess outcomes of end-stage kidney disease (ESKD) and death.

Results: A total of 1834 patients (median age 75 years, 58% male, 42% diabetics, median baseline eGFR 25 mL/min/1.73 m2) were followed for a median of 29 months. More than 50% had slow or no decline and 17% declined ≥5 mL/min/1.73 m2/year. After 4.5 years, the incidence of ESKD was 8% and of deaths without ESKD 16% among patients with eGFR ≥30 mL/min/1.73 m2 and 37% and 19% for eGFR <30 mL/min/1.73 m2. Adjusted models showed higher risks of ESKD or death for patients with worse kidney function at baseline, male sex, diabetes and higher blood pressure; a higher risk of ESKD with higher albuminuria; and a higher risk of death with older age or cardiovascular comorbidity.

Conclusions: Routine nephrology care of patients in Germany comprises mostly elderly patients, many with slow CKD progression. Identification of risk factors for CKD progression and mortality may help guide resources by closer follow-up of high-risk patients.
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http://dx.doi.org/10.1093/ndt/gfz260DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7203560PMC
May 2020

Inflammation is an amplifier of lung congestion by high lv filling pressure in hemodialysis patients: a longitudinal study.

J Nephrol 2020 Jun 8;33(3):583-590. Epub 2020 Jan 8.

Aristotle University, Thessaloniki, Greece.

Introduction: Since inflammation alters vascular permeability, including vascular permeability in the lung, we hypothesized that it can be an amplifier of lung congestion in a category of patients at high risk for pulmonary oedema like end stage kidney disease (ESKD) patients.

Objective And Methods: We investigated the effect modification by systemic inflammation (serum CRP) on the relationship between a surrogate of the filling pressure of the LV [left atrial volume indexed to the body surface area (LAVI)] and lung water in a series of 220 ESKD patients. Lung water was quantified by the number of ultrasound B lines (US-B) on lung US. Six-hundred and three recordings were performed during a 2-year follow up. Longitudinal data analysis was made by the Mixed Linear Model.

Results: At baseline, 88 had absent, 101 had mild to moderate lung congestion and 31 severe congestion. The number of US B lines associated with LAVI (r = 0.23, P < 0.001) and serum CRP was a robust modifier of this relationship (P < 0.001). Similarly, in fully adjusted longitudinal analyses US-B lines associated with simultaneous estimates of LAVI (P = 0.002) and again CRP was a strong modifier of this relationship in adjusted analyses (P ≤ 0.01). Overall, at comparable LAVI levels, lung congestion was more pronounced in inflamed than in non-inflamed patients.

Conclusion: In ESKD systemic inflammation is a modifier of the relationship between LAVI, an integrate measure of LV filling pressure, and lung water. For any given pressure, lung water is increased with higher CRP levels, likely reflecting a higher permeability of the alveolar-capillary barrier.
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http://dx.doi.org/10.1007/s40620-019-00696-xDOI Listing
June 2020

Apolipoprotein C3 induces inflammation and organ damage by alternative inflammasome activation.

Nat Immunol 2020 01 9;21(1):30-41. Epub 2019 Dec 9.

Institute of Molecular Health Science, ETH, Zurich, Switzerland.

NLRP3-inflammasome-driven inflammation is involved in the pathogenesis of a variety of diseases. Identification of endogenous inflammasome activators is essential for the development of new anti-inflammatory treatment strategies. Here, we identified that apolipoprotein C3 (ApoC3) activates the NLRP3 inflammasome in human monocytes by inducing an alternative NLRP3 inflammasome via caspase-8 and dimerization of Toll-like receptors 2 and 4. Alternative inflammasome activation in human monocytes is mediated by the Toll-like receptor adapter protein SCIMP. This triggers Lyn/Syk-dependent calcium entry and the production of reactive oxygen species, leading to activation of caspase-8. In humanized mouse models, ApoC3 activated human monocytes in vivo to impede endothelial regeneration and promote kidney injury in an NLRP3- and caspase-8-dependent manner. These data provide new insights into the regulation of the NLRP3 inflammasome and the pathophysiological role of triglyceride-rich lipoproteins containing ApoC3. Targeting ApoC3 might prevent organ damage and provide an anti-inflammatory treatment for vascular and kidney diseases.
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http://dx.doi.org/10.1038/s41590-019-0548-1DOI Listing
January 2020

Does a rise in plasma erythropoietin after high-altitude exposure affect FGF23 in healthy volunteers on a normal or low-phosphorus diet?

Nutr Metab Cardiovasc Dis 2019 12 9;29(12):1361-1367. Epub 2019 Sep 9.

Saarland University Medical Center, Internal Medicine IV - Nephrology and Hypertension, Homburg, Germany; Agaplesion Markus Krankenhaus, Frankfurt (Main), Germany.

Background And Aims: Data of experimental rodent models suggest that hypoxia with subsequent increase in erythropoietin stimulates the expression of the phosphaturic hormone fibroblast growth factor 23 (FGF23).

Methods And Results: To translate the findings of animal studies into human physiology, herein we exposed eight healthy volunteers to high altitude (2656 m above sea level) for four days. The volunteers were randomized on a low-phosphorous diet (n = 4) or a normal phosphorus diet (n = 4). Although high-altitude exposure caused a significant increase in plasma erythropoietin (EPO) (before high-altitude exposure: low phosphorus: median EPO 6.6 mIU/ml [interquartile range (IQR) 6.0; 8.2], normal phosphorus: median EPO 9.0 mIU/ml [IQR 7.9; 11.5]; at day 2: low phosphorus: median EPO 21.3 mIU/ml [IQR 19.5; 23.8], normal phosphorus: median EPO 19.4 mIU/ml [IQR 18.0; 20.8]), there was no consistent increase in plasma c-terminal FGF23 or plasma intact FGF23. We observed only a single, intermittent peak in c-terminal FGF23 levels after 5 h of maximal aerobic exercise.

Conclusion: These data do not support a substantial effect of moderate hypoxia alone on the expression of FGF23, but they suggest that combined exercise and high-altitude exposure may temporarily induce FGF23 expression.
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http://dx.doi.org/10.1016/j.numecd.2019.09.002DOI Listing
December 2019

The nephrology crystal ball: the medium-term future.

Nephrol Dial Transplant 2020 02;35(2):222-226

Division of Nephrology, University of Würzburg, Würzburg, Germany.

In January 2019, the ERA-EDTA surveyed nephrologists with questions on kidney care and kidney research designed to explore comprehension of the impact of alterations to organization of renal care and of advancements in technology and knowledge of kidney disease. Eight hundred and twenty-five ERA-EDTA members, ∼13% of the whole ERA-EDTA membership, replied to an ad hoc questionnaire. More than half of the respondents argued that kidney centres will be increasingly owned by large dialysis providers, nearly a quarter of respondents felt that many medical aspects of dialysis will be increasingly overseen by non-nephrologists and a quarter (24%) also believed that the care and long-term follow-up of kidney transplant patients will be increasingly under the responsibility of transplant physicians caring for patients with any organ transplant. Nearly half of the participants (45%, n = 367) use fully electronic clinical files integrating the clinical ward, the outpatient clinics, the haemodialysis and peritoneal dialysis units, as well as transplantation. Smartphone-based self-management programmes for the care of chronic kidney disease (CKD) patients are scarcely applied (only 11% of surveyed nephrologists), but a substantial proportion of respondents (74%) are eager to know more about the potential usefulness of these apps. Finally, European nephrologists expressed a cautious optimism about the application of omic sciences to nephrology and on wearable and implantable kidneys, but their expectations for the medium term are limited.
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http://dx.doi.org/10.1093/ndt/gfz199DOI Listing
February 2020

Consequences of chronic kidney disease in chronic obstructive pulmonary disease.

Respir Res 2019 Jul 12;20(1):151. Epub 2019 Jul 12.

Department of Internal Medicine V - Pulmonology, Allergology Critical Care Care Medicine, Saarland University Hospital, Homburg, Germany.

Background: The combination of chronic obstructive pulmonary disease (COPD) and chronic kidney disease (CKD) is associated with a higher prevalence of comorbidities and increased mortality. The impact of kidney function on patient-centered outcomes in COPD has not been evaluated.

Methods: Patients from the German COPD and Systemic Consequences - Comorbidities Network (COSYCONET) cohort COPD were analysed. CKD was diagnosed if the estimated glomerular filtration rate (eGFR) measurements were < 60 mL/min/1.73m at study inclusion and six month later. The effect of CKD, on comorbidities, symptoms [modified British Medical Research Council dyspnoea scale], physical capacity [six-minute walk test, and timed up and go] and St George's Respiratory Questionnaire were analysed. Restricted cubic spline models were used to evaluate a nonlinear relationship between eGFR with patient-centered outcomes, cox survival analysis was applied to evaluate mortality.

Results: 2274 patients were analysed, with CKD diagnosed in 161 (7.1%). Spline models adjusted for age, gender, BMI, FEV and cardiovascular comorbidities revealed independent associations between eGFR with modified British Medical Research Council dyspnoea scale, St George's Respiratory Questionnaire, (p < 0.001 and p = 0.011), six-minute walk test (p = 0.015) and timed up and go (p < 0.001). CKD was associated with increased mortality, independently from for other cardiovascular comorbidities (hazard ratio 2.3; p < 0.001).

Conclusion: These data show that CKD is a relevant comorbidity in COPD patients which impacts on patient-centered outcomes and mortality.

Trial Registration: NCT01245933.
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http://dx.doi.org/10.1186/s12931-019-1107-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6626422PMC
July 2019

Association between urinary dickkopf-3, acute kidney injury, and subsequent loss of kidney function in patients undergoing cardiac surgery: an observational cohort study.

Lancet 2019 08 12;394(10197):488-496. Epub 2019 Jun 12.

Department of Internal Medicine 4, Nephrology and Hypertension, Saarland University Medical Centre, Homburg, Germany; Department of Nephrology, Hôpitaux Robert Schuman, Hôpital Kirchberg, Luxembourg, Luxembourg.

Background: Cardiac surgery is associated with a high risk of postoperative acute kidney injury (AKI) and subsequent loss of kidney function. We explored the clinical utility of urinary dickkopf-3 (DKK3), a renal tubular stress marker, for preoperative identification of patients at risk for AKI and subsequent kidney function loss.

Methods: This observational cohort study included patients who had cardiac surgery in a derivation cohort and those who had cardiac surgery in a validation cohort (RenalRIP trial). The study comprised consecutive patients who had elective cardiac surgery at the Saarland University Medical Centre (Homburg, Germany; derivation cohort) and those undergoing elective cardiac surgery (selected on the basis of a Cleveland Clinical Foundation score of 6 or higher) who were enrolled in the prospective RenalRIP multicentre trial (validation cohort) and who were randomly assigned to remote ischaemic preconditioning or a sham procedure. The association between the ratio of preoperative urinary concentrations of DKK3 to creatinine (DKK3:creatinine) and postoperative AKI, defined according to the Kidney Disease Improving Global Outcomes criteria, and subsequent kidney function loss, as determined by estimated glomerular filtration rate, was assessed.

Findings: In the 733 patient in the derivation cohort, urinary concentrations of DKK3 to creatinine that were higher than 471 pg/mg were associated with significantly increased risk for AKI (odds ratio [OR] 1·65, 95% CI 1·10-2·47, p=0·015), independent of baseline kidney function. Compared with clinical and other laboratory measurements, urinary concentrations of DKK3:creatinine significantly improved AKI prediction (net reclassification improvement 0·32, 95% CI 0·23-0·42, p<0·0001). High urinary DKK3:creatinine concentrations were independently associated with significantly lower kidney function at hospital discharge and after a median follow-up of 820 days (IQR 733-910). In the RenalRIP trial, preoperative urinary DKK3:creatinine concentrations higher than 471 pg/mg were associated with a significantly higher risk for AKI (OR 1·94, 95% CI 1·08-3·47, p=0·026), persistent renal dysfunction (OR 6·67, 1·67-26·61, p=0·0072), and dialysis dependency (OR 13·57, 1·50-122·77, p=0·020) after 90 days compared with DKK3:creatinine concentrations of 471 pg/mg or less. Urinary DKK3:creatinine concentrations higher than 471 pg/mg were associated with significantly higher risk for AKI (OR 2·79, 95% CI 1·45-5·37) and persistent renal dysfunction (OR 3·82, 1·32-11·05) only in patients having a sham procedure, but not remote ischaemic preconditioning (AKI OR 1·35, 0·76-2·39 and persistent renal dysfunction OR 1·05, 0·12-9·45).

Interpretation: Preoperative urinary DKK3 is an independent predictor for postoperative AKI and for subsequent loss of kidney function. Urinary DKK3 might aid in the identification of patients in whom preventive treatment strategies are effective.

Funding: No study funding.
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http://dx.doi.org/10.1016/S0140-6736(19)30769-XDOI Listing
August 2019

Nephrology and Public Policy Committee propositions to stimulate research collaboration in adults and children in Europe.

Nephrol Dial Transplant 2019 09;34(9):1469-1480

CNR-IFC, Ospedali Riuniti, Reggio Calabria, Italy.

The strengths and the limitations of research activities currently present in Europe are explored in order to outline how to proceed in the near future. Epidemiological and clinical research and public policy in Europe are generally considered to be comprehensive and successful, and the European Renal Association - European Dialysis and Transplant Association (ERA-EDTA) is playing a key role in the field of nephrology research. The Nephrology and Public Policy Committee (NPPC) aims to improve the current situation and translation into public policy by planning eight research topics to be supported in the coming 5 years by ERA-EDTA.
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http://dx.doi.org/10.1093/ndt/gfz089DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6736134PMC
September 2019

Proprotein convertase subtilisin/kexin type 9 in kidney disease.

Nephrol Dial Transplant 2019 08;34(8):1266-1271

Department of Internal Medicine IV, Nephrology and Hypertension, Saarland University Medical Centre, Homburg/Saar, Germany.

Chronic kidney disease (CKD) is associated with a substantially increased risk for the development of atherosclerotic cardiovascular (CV) disease. Accordingly, CV mortality is increased even in the earliest stages of CKD. In the general population and in CKD patients, high plasma levels of low-density lipoprotein cholesterol (LDL-C) are crucially involved in the initiation and progression of atherosclerotic vascular lesions. Lowering LDL-C by use of statins and/or ezetimibe represents the gold standard of lipid-lowering therapy, with a great body of evidence from several large clinical trials. Statin therapy reduces CV events in patients with normal and impaired kidney function alike, while the evidence for patients on maintenance haemodialysis is weaker. The inhibition of proprotein convertase subtilisin/kexin type 9 (PCSK9) serine protease represents a novel lipid-lowering tool. Currently the monoclonal antibodies evolocumab and alirocumab are the approved PCSK9 inhibitors. Despite maximum-tolerated statin therapy, they efficiently further reduce LDL-C plasma levels without any major adverse effects. Moreover, in large clinical outcome trials, both antibodies have been proven to lower CV events. Notably, the LDL-lowering capacity was independent of baseline kidney function and also efficient in patients with moderate CKD. However, patients with severely impaired kidney function, that is, the population at the highest CV risk, have been excluded from those trials. The relevance of the LDL-independent effects of PCSK9 inhibitors, such as lowering lipoprotein(a) or ameliorating dyslipidaemia in patients with nephrotic syndrome, has to be determined. Therefore further specific studies assessing the effects and outcomes of PCSK9-inhibiting treatment in CKD patients are warranted.
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http://dx.doi.org/10.1093/ndt/gfz122DOI Listing
August 2019

Prescription of renin-angiotensin-aldosterone system inhibitors (RAASi) and its determinants in patients with advanced CKD under nephrologist care.

J Clin Hypertens (Greenwich) 2019 07 6;21(7):991-1001. Epub 2019 Jun 6.

CESP, Center for Research in Epidemiology and Population Health, University Paris-Saclay, University Paris-Sud, UVSQ, Villejuif, France.

Renin-angiotensin-aldosterone system inhibitors (RAASi) are recommended for chronic kidney disease (CKD) patients. In this study, we describe RAASi prescription patterns in the Chronic Kidney Disease Outcomes and Practice Patterns Study (CKDopps) in Brazil, Germany, France, and the United States (US). 5870 patients (mean age 66-72 years; congestive heart failure [CHF] in 11%-19%; diabetes in 43%-54%; serum potassium ≥5 in 20%-35%) were included. RAASi prescription was more common in Germany (80%) and France (77%) than Brazil (66%) and the United States (52%), where the prevalence of prescription decreases particularly in patients with CKD stage 5. In the multivariable regression model, RAASi prescription was least common in the United States and more common in patients who were younger, had diabetes, hypertension, or less advanced CKD. In conclusion, RAASi prescription patterns vary by country, and by demographic and clinical characteristics. RAASi appear to be underused, even among patients with strong class-specific recommendations. Although the reasons for this variation could not be fully identified in this cross-sectional observation, our data indicate that the risk of hyperkalemia may contribute to the underuse of this class of agents in moderate to advanced CKD.
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http://dx.doi.org/10.1111/jch.13563DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6771881PMC
July 2019

Low serum lathosterol levels associate with fatal cardiovascular disease and excess all-cause mortality: a prospective cohort study.

Clin Res Cardiol 2019 Dec 4;108(12):1381-1385. Epub 2019 Apr 4.

Klinik für Innere Medizin IV, Abteilung für Nieren-und Hochdruckkrankheiten, Universitätsklinikum des Saarlandes, Homburg, Saar, Germany.

Importance: A more precise identification of patients at "high cardiovascular risk" is preeminent in cardiovascular risk stratification.

Objective: To investigate the relationships between markers of cholesterol homeostasis, cardiovascular events and all-cause mortality.

Design, Setting And Participants: We quantified markers of cholesterol homeostasis by gas chromatography-mass spectrometry in 377 subjects with suspected coronary artery disease, who were not on lipid-lowering drugs at baseline. All patients were followed for occurrence of cardiovascular events and mortality over a period of 4.9 +/- 1.7 years. The standardized mortality ratio (SMR) was calculated as the ratio of the observed and the expected deaths based on the death rates of the Regional Databases Germany, and Poisson regression (rate ratio, RR) was used to compare subgroups. The SMR and RR were standardized for sex, age category and calendar period. In addition, Cox regression (Hazard ratio, HR) was used to determine the effect of co-variables on (cardiovascular) mortality within the cohort.

Main Outcomes: Cardiovascular events, cardiovascular mortality and all-cause mortality.

Results: A total of 42 deaths were observed in 1818 person-years corresponding with an SMR of 0.99 (95% CI 0.71-1.33; p = 0.556). A fatal cardiovascular event occurred in 26 patients. Lower levels of lathosterol were associated with increased cardiovascular mortality (HR 1.59; 95% CI: 1.16-2.17; p = 0.004) and excess all-cause mortality (HR 1.41; 95% CI: 1.09-1.85; p = 0.011). Lower lathosterol tertile compared to the adjacent higher tertile was associated with 1.6 times higher all-cause mortality risk (RR 1.60; 95% CI 1.07-2.40; p for trend = 0.022). This corresponded with a 2.3 times higher mortality risk of a lathosterol-LDL ratio equal to or below the median (RR 2.29; 95% CI 1.19-4.43; p = 0.013). None of the other cholesterol homeostasis markers were associated with cardiovascular and all-cause mortality.

Conclusions: In patients not on lipid-lowering agents, low serum lathosterol correlated with increased risk of cardiovascular events and excess all-cause mortality.
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http://dx.doi.org/10.1007/s00392-019-01474-2DOI Listing
December 2019