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Introduction To alleviate the burden of Heart Failure (HF), the European Society of cardiology developed guidelines (ESC-guidelines) to optimise HF-diagnosis and treatment. These guidelines state that optimal HF-care is organised in a multidisciplinary programme in which pharmacological and non-pharmacological treatment is offered. Research has proven that multidisciplinary programmes and effective self-care behaviour significantly reduce HF-mortality and (re)hospitalisation, yet little is known about implementation of these ESC-guidelines. Therefore, the INTERACT study investigated current HF-care processes and guideline adherence in three North-West European regions: Maastricht (the Netherlands), Aachen (Germany) and Noorder-Kempen (Belgium). Methods A case-study approach was adopted to study local implementation of ESC-guidelines considering non-pharmacological- and multidisciplinary care. National guidelines and local protocols were collected and studied to investigate the level of agreement with and implementation of ESC-guidelines. A matrix was developed to analyse the content of national and local guidelines and protocols in terms of non-pharmacological and multidisciplinary care. Results All national organisations promote ESC guidelines, and some developed additional national guidelines. In region A, B and C patients receive multidisciplinary care in hospital based HF-outpatient clinics. Moreover, region B and C patients benefit from either structural (region B) or project based (region C) integrated care, in which specialist- and primary care work together to provide seamless care for HF-patients. However, in region A this seamless integrated care remains to be implemented. Conclusion Although ESC-guidelines recommend clearly considering Multidisciplinary- and non-pharmacological care implementation may differ between regions.

ZUSAMMENFASSUNGBei Patienten mit Vorhofflimmern besteht ein erhöhtes Risiko für thromboembolische Komplikationen und insbesondere Schlaganfall. Patienten mit chronischer Nierenerkrankung haben gehäuft Vorhofflimmern und sowohl ein erhöhtes Blutungs- wie auch Schlaganfallrisiko. Für Patienten mit einer Kreatinin-Clearance von bis zu 25–30 ml/min sind Nicht-Vitamin-K-abhängige orale Antikoagulanzien (NOAK) evidenzbasiert zur Schlaganfallprävention den Vitamin-K-Antagonisten (VKA) vorzuziehen. Darunter bzw. bei Dialysepatienten liegen keine wissenschaftlichen Daten vor; hier muss das Konzept (keine Antikoagulation vs. NOAK vs. Vorhofohrverschluss vs. VKA) individuell entschieden werden, wobei die Gabe von VKA die schlechteste Lösung zu sein scheint.

Background Calcific uraemic arteriolopathy (CUA; calciphylaxis) is a rare disease seen predominantly in patients receiving dialysis. Calciphylaxis is characterized by poorly healing or non-healing wounds, and is associated with mortality, substantial morbidity related to infection and typically severe pain. In an open-label Phase 2 clinical trial, SNF472, a selective inhibitor of vascular calcification, was well-tolerated and associated with improvement in wound healing, reduction of wound-related pain and improvement in wound-related quality of life (QoL). Those results informed the design of the CALCIPHYX trial, an ongoing, randomized, placebo-controlled, Phase 3 trial of SNF472 for treatment of calciphylaxis. Methods In CALCIPHYX, 66 patients receiving haemodialysis who have an ulcerated calciphylaxis lesion will be randomized 1:1 to double-blind SNF472 (7 mg/kg intravenously) or placebo three times weekly for 12 weeks (Part 1), then receive open-label SNF472 for 12 weeks (Part 2). All patients will receive stable background care, which may include pain medications and sodium thiosulphate, in accordance with the clinical practices of each site. A statistically significant difference between the SNF472 and placebo groups for improvement of either primary endpoint at Week 12 will demonstrate efficacy of SNF472: change in Bates-Jensen Wound Assessment Tool-CUA (a quantitative wound assessment tool for evaluating calciphylaxis lesions) or change in pain visual analogue scale score. Additional endpoints will address wound-related QoL, qualitative changes in wounds, wound size, analgesic use and safety. Conclusions This randomized, placebo-controlled Phase 3 clinical trial will examine the efficacy and safety of SNF472 in patients who have ulcerated calciphylaxis lesions. Patient recruitment is ongoing.

INTRODUCTION: Vitamin K antagonists (VKA) and non-vitamin K oral antagonist anticoagulants (NOAC) are used in the clinic to reduce risk of thrombosis. However, they also exhibit vascular off-target effects. The aim of this study is to compare VKA and NOAC on atherosclerosis progression and calcification in an experimental setup.MATERIAL AND METHODS: Female Apoe-/- mice (age 12 weeks) were fed Western-type diet as control or supplemented with dabigatran etexilate or warfarin for 6 or 18 weeks. Vascular calcification was measured in whole aortic arches using µCT and [18 F]-NaF. Atherosclerotic burden was assessed by (immuno)histochemistry. Additionally, in vitro effects of warfarin, thrombin, and dabigatran on primary vascular smooth muscle cells (VSMC) were assessed.RESULTS: Short-term treatment with warfarin promoted formation of atherosclerotic lesions with a pro-inflammatory phenotype, and more rapid plaque progression compared with control and dabigatran. In contrast, dabigatran significantly reduced plaque progression compared with control. Long-term warfarin treatment significantly increased both presence and activity of plaque calcification compared with control and dabigatran. Calcification induced by warfarin treatment was accompanied by increased presence of uncarboxylated matrix Gla protein. In vitro, both warfarin and thrombin significantly increased VSMC oxidative stress and extracellular vesicle release, which was prevented by dabigatran.CONCLUSION: Warfarin aggravates atherosclerotic disease activity, increasing plaque inflammation, active calcification, and plaque progression. Dabigatran lacks undesired vascular side effects and reveals beneficial effects on atherosclerosis progression and calcification. The choice of anticoagulation impacts atherosclerotic disease by differential off target effect. Future clinical studies should test whether this beneficial effect also applies to patients.

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.Bei Patienten mit Herzinsuffizienz und reduzierter Ejektionsfraktion wird durch eine optimierte medikamentöse Therapie sowohl die Symptomkontrolle verbessert als auch die Mortalität gesenkt. Eckpfeiler der Herzinsuffizienztherapie sind dabei Medikamente mit Einfluss auf das Renin-Angiotensin-Aldosteron-System, sogenannte RAAS-Inhibitoren. Dieser Artikel stellt einen kardiologisch-nephrologischen Konsens zur praxisorientierten Hilfestellung bei abnehmender glomerulärer Filtrationsrate oder Anstieg des Serum-Kaliumspiegels vor. Dies sind die 2 häufigsten Gründe für eine Dosisreduktion oder das Absetzen von prognoseverbessernden Medikamenten bei Herzinsuffizienzpatienten.

Was ist neu? Phosphathaushalt Nach wie vor ist unklar, wann, mit welchem Zielspiegel und mittels welcher Art von phosphatsenkenden Maßnahmen und Medikamenten die Hyperphosphatämie behandelt werden sollte. Aus Erfahrung ist eine Kombination aus phosphatarmer Diät und Phosphatbindern sinnvoll. Hyperparathyreoidismus Bei chronischer Nierenerkrankung (CKD) ist eine stärkere PTH-Stimulation nötig als bei Nierengesunden, um nicht eine adyname Osteopathie zu entwickeln. Deutlich erhöhte PTH-Werte wiederum gehen jedoch mit einer gesteigerten Morbidität und Mortalität einher. Für Dialysepatienten liegt der Zielbereich im Serum-PTH gemäß den KDIGO-Leitlinien zwischen dem 2- und 9-Fachen der oberen Norm. Für Patienten mit CKD ohne Dialyse ist der optimale PTH-Bereich nicht klar. Vitamin D Vitamin D kann weiterhin begleitend zur Therapie der CKD-MBD und insbesondere des Hyperparathyreoidismus eingesetzt werden. Außerhalb des Skelettsystems dürften einer nativen Vitamin-D-Supplementierung jedoch kaum messbare Effekte zuzuschreiben sein. Arteriosklerose Der Verzicht auf eine Therapie mit Vitamin-K-Antagonisten und der Ersatz durch Rivaroxaban kann wahrscheinlich das Fortschreiten der Koronarkalzifikation verlangsamen. Biomarker In der Routinediagnostik von CKD-MBD und deren Therapie spielen auch weiterhin die klassischen Biomarkern wie PTH, Phosphat, Kalzium oder alkalische Phosphatase die größte Rolle. Renale Osteodystrophie und Osteoporose Es ist noch nicht ausreichend belegt, wie bei CKD das Frakturrisiko zu senken ist. SGLT2-Inhibitoren Aktuell ist der breite Einsatz von SGLT2-Inhibitoren für Patienten mit CKD G3 oder G4 noch keine Option. Zu erwarten ist eine Indikationserweiterung auf einen GFR-Grenzwert von zumindest 30 ml/min für die Indikation CKD und/oder Herzinsuffizienz (auch jeweils ohne Diabetes mellitus).

European journal of heart failure (2020). doi:10.1002/ejhf.1749, Published by Wiley, Oxford

Abstract. Background: Physical activity (PA) is recommended by heart failure treatment guidelines. Adherence to exercise prescriptions is low and not much is known about everyday PA in this patient group. Aims: This study describes objectively assessed everyday PA/sedentary behavior in men and women with chronic heart failure and examines associations of potential barriers for engaging in PA, namely fear of physical activity (FoPA), general anxiety, and depression, with indicators of PA and sedentary behavior. Method: In 61 outpatients with heart failure (67.5 ± 10.7 years of age) the impact of FoPA, trait anxiety, and depression on 6-day accelerometer measures was evaluated using linear regression models. Results: Sedentary behavior was prevalent in men and women alike, with lying down and sitting/standing as predominant activity classes during daytime. Men had higher PA energy expenditure (726 vs. 585 kcal/d, Cohen’s effect size d = 0.74) and walked up/down more often (0.21% vs. 0.12% of total PA, d = 0.56) than women. FoPA did not differ between sexes. FoPA, but not anxiety and depression, significantly and consistently predicted less walking up/down independent of covariates (β-values between −0.26 and −0.44, p-values

BACKGROUND: In order to manage Heart Failure (HF) properly, both pharmacological and non-pharmacological interventions including patient education and self-care (SC) support are important. Appropriate health care (HC) professional support is necessary to improve patient SC-skills. However, little is known which HC-professionals deliver specific education and support in daily HF-care.OBJECTIVES: To describe patient-education and SC-support as perceived by different HC-professionals in three neighboring North-West European regions: Maastricht(the Netherlands), Noorder-Kempen(Belgium), Aachen (Germany).METHODS: Semi-structured interviews with cardiologists, HF-nurses and general practitioners (GPs) were performed, followed by qualitative content analysis with a five-step approach: 1) familiarization with data, 2) initial coding with an a-priori code manual, 3) structuring of data in main themes, 4) revision and recoding of initial codes and 5) synthesizing codes in main themes.RESULTS: The sample consisted of 15 cardiologists, 35 GPs and 8 HF-nurses. All interviewed HC-professionals provide HF patient-education, yet, the extent differs between them. Whereas HF-nurses identify patient-education and SC-support as one of their main tasks, physicians report that they provide little education. Moreover, little patient education takes place in primary care; with almost none of the GPs reporting to educate patients about SC. GPs in region 2 refer HF-patients to their practice nurse for education and SC-support. None of the HC-professionals reported to provide patients with all key-topics for patient education and SC-support as defined by the ESC.CONCLUSION: HF nurses consider patient-education and SC-support as one of their main tasks, whereas physicians pay limited attention to education. In none of the three regions, all recommended topics are addressed.

Clinical cardiology 45(4), 352-358 (2022). doi:10.1002/clc.23819, Published by Wiley, Weinheim [u.a.]

Cells : open access journal 10(8), 2097 (2021). doi:10.3390/cells10082097 special issue: "Special Issue "Research on Vascular Calcification in Cardiovascular Disease" / Special Issue Editors: Prof. Dr. Leon Schurgers, Guest Editor; Dr. Peter Stenvinkel, Guest Editor", Published by MDPI, Basel

Elevated fibroblast growth factor 23 (FGF23) levels are associated with adverse outcome in populations with cardiovascular disease and chronic kidney failure. It is unclear if FGF23 has significance in prognosis estimation in patients with acute heart failure (HF) when compared to traditional risk estimation tools. Serum levels of intact FGF23 were assessed in 139 patients admitted to the Intermediate Care Unit of a tertiary hospital for acute HF. Patients were followed-up for one year. After exclusion of patients who were lost to follow-up, data outliers, and patients with sampling errors, the final study cohort comprised 133 patients. The Seattle Heart Failure (SHF) Model was used to estimate one-year survival. FGF23 levels correlated with HF severity and were strongly associated with one-year mortality. Associations between one-year outcome and FGF23, assessed on day 1 after admission, were still evident after multivariable adjustment (OR 15.07; 95%CI 1.75–129.79; p = 0.014). FGF23 levels predicted the one-year outcome with similar accuracy as the SHF Model, both if assessed on day 1 and on day 2 after admission (FGF23d1: AUC 0.784; 95%CI 0.669–0.899; FGF23d2: AUC 0.766; 95%CI 0.631–0.901; SHF: AUC 0.771; 95%CI 0.651–0.891). The assessment of FGF23 in patients with acute HF might help identify high-risk patients that are more prone to complications, need a closer follow-up and more aggressive treatment.

In patients with intact kidney function and in patients with mild to moderate chronic kidney disease (CKD), strong evidence suggests the use of non-vitamin K dependent oral anticoagulants (NOAC) for preventing ischemic strokes and systemic thromboembolic events in patients with non-valvular atrial fibrillation (nvAF) and elevated thromboembolic risk. In contrast, less evidence is available on the risk-benefit ratio of oral anticoagulation (OAC) in patients with nvAF and severe CKD, particularly in dialysis patients. No large randomised study has tested whether OAC will reduce the risk of thromboembolic events in nvAF without prohibitively high bleeding risk, and whether NOACs or vitamin K antagonists are the superior strategy for OAC. Considering absence of strong evidence, the authors suggest that in dialysis patients with nvAF, in whom the treatment team sees the clear need to prevent thromboembolic events, the use of NOACs or left atrial appendage occlusion should be preferred over treatment with vitamin K antagonists. Any OAC treatment for dialysis patients with nvAF is not in-label in most European countries.

ZUSAMMENFASSUNGMaßnahmen zur Blutverdünnung (orale Antikoagulation (OAK) und/oder Anti-Plättchen-Therapie (APT)) tragen in erheblichem Maße zur Anämie bei unseren Patienten mit chronischer Niereninsuffizienz (CKD) bei. Erkrankungen mit einer Indikation zur OAK (z. B. VHF: Vorhofflimmern) oder APT (z. B. KHK: koronare Herzerkrankung) steigen in Inzidenz und Prävalenz mit Verschlechterung der CKD an. Gleichzeitig sind CKD und Dialysepatienten besonders blutungsgefährdet. Die nicht-Vitamin-K-abhängigen oralen Antikoagulanzien (NOAK) zeigen generell eine geringere Neigung zu schweren, lebensbedrohlichen Blutungen als die Vitamin-K-Antagonisten (VKA). Allerdings wurden in den NOAK-Zulassungsstudien Patienten mit einer Kreatinin-Clearance (Krea-Cl) von weniger als 30 ml/min meist nicht inkludiert. Noch unübersichtlicher ist die Datenlage zum Einsatz einer OAK gegen VHF bei dialysepflichtigen Patienten. Es ist in diesem Kollektiv unklar, ob Patienten überhaupt von einer OAK profitieren und welches hierfür eine sichere und effektive Substanz ist. Weder die NOAKs noch der VKA Marcumar® (Phenprocoumon) sind für Dialysepatienten in Deutschland überhaupt zugelassen. Etwas anders ist die Situation hinsichtlich einer APT: Generell sollten Patienten auch mit schwerer CKD oder Dialysepflichtigkeit die APT nach allgemeiner kardiologischer Empfehlung erhalten. Auf dem Boden des erhöhten Blutungsrisikos in diesem Kollektiv erscheinen moderne Kombinationen aus NOAK und einer einzelnen APT-Substanz als Ersatz für das alte Triple-Regime besonders interessant.

Accelerated and premature cardiovascular calcification is a hallmark of patients with chronic kidney disease (CKD) or end-stage renal disease (ESRD). The presence and the amount of cardiovascular calcification are among the driving forces of increased morbidity and mortality in renal patients. Cardiovascular calcification occurs at different sites, including the cardiac valves-a location that is of particular importance for both the patient and the treating physician. The correlation between degree of calcification and functional impairment is particularly close at the aortic valve, that is, the amount of calcification predicts the degree of stenosis. Calcific aortic stenosis (CAS) is the most prevalent valvular heart disease in Western societies. CAS is particularly prevalent in patients with underlying CKD or ESRD. CAS increases afterload and hence contributes to the widespread finding of left ventricular hypertrophy in CKD/ESRD patients. Medical treatment options to prevent the development and progression of CAS are limited. Hence, close surveillance and timely referral of patients for heart valve replacement therapy is a mainstay of current therapy. Novel treatment approaches, such as transcatheter aortic valve implantation, offer promising yet challenging options for elderly, comorbid, and often frail patients with CAS in combination with advanced CKD/ESRD.

Was ist neu? Orale Antikoagulation bei nicht dialysepflichtiger chronischer Nierenkrankheit In großen Zulassungsstudien haben sich die Nicht-Vitamin-K-abhängigen oralen Antikoagulanzien (NOAK) bei Patienten mit nicht valvulärem Vorhofflimmern als mindestens so effektiv in der Verhinderung thromboembolischer Ereignisse gezeigt wie Vitamin-K-Antagonisten (VKA). Die NOAK zeigen generell eine geringere Neigung zu schweren, lebensbedrohlichen Blutungen als die VKA. In den Zulassungsstudien wurden Patienten mit einer Kreatinin-Clearance von kleiner 30 ml/min meist nicht inkludiert, sodass für Patienten mit einer Kreatinin-Clearance von 15–30 ml/min zwar für Rivaroxaban, Apixaban und Edoxaban eine Zulassung besteht, die Datenlage zur Effektivität und Sicherheit jedoch nicht so fundiert ist wie bei Patienten mit einer Kreatinin-Clearance von > 30 ml/min. Antikoagulation bei terminaler Niereninsuffizienz Die Indikation zur Antikoagulation muss bei chronischen Dialysepatienten mit Vorhofflimmern derzeit weiterhin individualisiert gestellt werden. Es ist in diesem Kollektiv unklar, ob dialysepflichtige VHF-Patienten überhaupt von einer oralen Antikoagulation profitieren und welches hierfür eine sichere und effektive Substanz ist: Randomisiert-kontrollierte Studien zu Apixaban versus VKA werden klären, ob NOAK eine sichere und effiziente Therapiestrategie bei diesem Patientenkollektiv sind (RENAL-AF, AXADIA). Thrombozytenaggregationshemmung bei chronischer Nierenkrankheit Generell sollten Patienten auch mit schwerer CKD oder Dialysepflichtigkeit die Thrombozytenaggregationshemmung nach kardiologischer Leitlinienempfehlung erhalten. Auf dem Boden des erhöhten Blutungsrisikos in diesem Kollektiv erscheinen moderne Kombinationen aus NOAK und einer einzelnen TAH-Substanz, die das alte „Triple-Regime“, bestehend aus doppelter TAH plus VKA ersetzen, besonders interessant.

Ischaemic heart disease, sudden cardiac death and arrhythmias, heart failure, stroke and peripheral arterial disease make up >50% of the causes of death in advanced chronic kidney disease (CKD). Calcification of the vascular tree and heart valves is partially related to these complications and has received growing attention in the literature. However, the main focus of research has been on the pathophysiology and consequences of vascular calcification, with less attention being paid to valvular calcification (VC) and its impact on the survival of CKD patients. Although VC has long been seen as an age-related degenerative disorder with minimal functional impact, several studies proved that it carries an increased risk of death and clinical consequences different from those of vascular calcification. In dialysis patients, the annual incidence of aortic valve calcification is nearly 3.3% and the reported prevalence of aortic and mitral VC varies between 25% and 59%. Moreover, calcification of both valves occurs 10–20 years earlier in CKD patients compared with the general population. Therefore, the purpose of this review is to summarize the current knowledge on the pathophysiology and relevance of VC in CKD patients, and to highlight specific clinical consequences and potential therapeutic implications.

ZUSAMMENFASSUNGPatienten mit chronischer Nierenerkrankung (CKD) weisen eine massiv erhöhte kardiovaskuläre Morbidität und Mortalität auf. Insbesondere myokardiale Erkrankungen – linksventrikuläre Hypertrophie mit konsekutiver linksventrikulärer Insuffizienz und maligner Arrhythmie – haben bei CKD-Patienten eine zentrale prognostische Bedeutung. Dennoch werden bisher zu selten kardioprotektive Therapiestrategien bei CKD-Patienten eingesetzt. Ein mögliches Argument ist, dass positive Studienergebnisse für die Therapie der Herzinsuffizienz mit reduzierter Ejektionsfraktion (HFREF: Heart Failure with Reduced Ejection Fraction) nicht unkritisch auf Patienten mit fortgeschrittener CKD übertragen werden dürfen. So hatten die großen Landmark-Trials der vergangenen Jahre Patienten mit höhergradiger Nierenfunktionsstörung zumeist ausgeschlossen, und Nebenwirkungen wie Elektrolytstörungen unter medikamentöser Herzinsuffizienztherapie sind bei CKD-Patienten deutlich häufiger. Unumstritten jedoch ist, dass für Patienten mit moderater CKD und HFREF Subgruppenanalysen der gleichen Landmark-Trials einen prognostischen Benefit einer Therapie mit Inhibitoren des Renin-Aldosteron-Systems und von Betablockern aufzeigen, der zumindest genauso groß ist wie der Benefit bei nierengesunden Patienten mit HFREF. Die Interventionsmöglichkeiten bei HFREF werden sich in den nächsten Jahren erweitern, falls neue Therapiestrategien – insbesondere eine intravenöse Eisensubstitution und SGLT-Inhibitoren – in aktuell laufenden klinischen Studien bei herzinsuffizienten Patienten eine Reduktion kardialer Ereignisse erreichen.

Objective: We aimed to elucidate the local role of FGF23 after myocardial infarction in a mouse model induced by left anterior descending artery (LAD) ligation.Approach and results: (C57BL/6N) mice underwent MI via LAD ligation and were sacrificed at different time-points post MI. The expression and influence of FGF23 on fibroblast and macrophages was also analyzed using isolated murine cells.We identified enhanced cardiac FGF23 mRNA expression in a time-dependent manner with an early increase, already on the first day after MI. FGF23 protein expression was abundantly detected in the infarcted area during the inflammatory phase. While described to be primarily produced in bone or macrophages, we identified cardiac fibroblasts as the only source of local FGF23 production after MI. Inflammatory mediators, such as IL-1 beta, IL-6 and TNF-alpha, were able to induce FGF23 expression in these cardiac fibroblasts. Interestingly, we were not able to detect FGF23 at later time points after MI in mature scar tissue or remote myocardium, most likely due to TGF-beta 1, which we have shown to inhibit the expression of FGF23. We identified FGFR1c to be the most abundant receptor for FGF23 in infarcted myocardium and cardiac macrophages and fibroblasts. FGF23 increased migration of cardiac fibroblast, as well as expression of Collagen 1, Periostin, Fibronectin and MMP8. FGF23 also increased expression of TGF-beta 1 in M2 polarized macrophages.Conclusion: In conclusion, cardiac fibroblasts in the infarcted myocardium produce and express FGF23 as well as its respective receptors in a time-dependent manner, thus potentially influencing resident cell migration. The transitory local expression of FGF23 after MI points towards a complex role of FGF23 in myocardial ischemia and warrants further exploration, considering its role in ventricular remodeling. (C) 2019 Elsevier Inc. All rights reserved.

The association between vitamin D deficiency and especially critical shortage of active vitamin D (1,25-dihydroxyvitamin D, calcitriol) with the development of secondary hyperparathyroidism (sHPT) is a well-known fact in patients with chronic kidney disease (CKD). The association between sHPT and important clinical outcomes, such as kidney disease progression, fractures, cardiovascular events, and mortality, has turned the prevention and the control of HPT into a core issue of patients with CKD and on dialysis. However, vitamin D therapy entails the risk of unwanted side effects, such as hypercalcemia and hyperphosphatemia. This review summarizes the developments of vitamin D therapies in CKD patients of the last decades, from calcitriol substitution to extended-release calcifediol. In view of the study situation for vitamin D insufficiency and sHPT in CKD patients, we conclude that the nephrology community has to solve three core issues: (1) What is the optimal parathyroid hormone (PTH) target level for CKD and dialysis patients? (2) What is the optimal vitamin D level to support optimal PTH titration? (3) How can sHPT treatment support reduction in the occurrence of hard renal and cardiovascular events in CKD and dialysis patients?

The protein α-Klotho acts as transmembrane co-receptor for fibroblast growth factor 23 (FGF23) and is a key regulator of phosphate homeostasis. However, α-Klotho also exists in a circulating form, with pleiotropic, but incompletely understood functions and regulation. Therefore, we undertook a genome-wide association study (GWAS) meta-analysis followed by Mendelian randomization (MR) of circulating α-Klotho levels. Plasma α-Klotho levels were measured by enzyme-linked immunosorbent assay (ELISA) in the Ludwigshafen Risk and Cardiovascular Health and Avon Longitudinal Study of Parents and Children (mothers) cohorts, followed by a GWAS meta-analysis in 4376 individuals across the two cohorts. Six signals at five loci were associated with circulating α-Klotho levels at genome-wide significance (P 9% of the variation in circulating α-Klotho levels. MR analyses revealed no causal relationships between α-Klotho and renal function, FGF23-dependent factors such as vitamin D and phosphate levels, or bone mineral density. The screening for genetic correlations with other phenotypes followed by targeted MR suggested causal effects of liability of Crohn’s disease risk [Inverse variance weighted (IVW) beta = 0.059 (95% confidence interval 0.026, 0.093)] and low-density lipoprotein cholesterol levels [−0.198 (−0.332, −0.063)] on α-Klotho. Our GWAS findings suggest that two enzymes involved in post-translational modification, B4GALNT3 and CHST9, contribute to genetic influences on α-Klotho levels, presumably by affecting protein turnover and stability. Subsequent evidence from MR analyses on α-Klotho levels suggest regulation by mechanisms besides phosphate-homeostasis and raise the possibility of cross-talk with FGF19- and FGF21-dependent pathways, respectively. Significance statement: α-Klotho as a transmembrane protein is well investigated along the endocrine FGF23-α-Klotho pathway. However, the role of the circulating form of α-Klotho, which is generated by cleavage of transmembrane α-Klotho, remains incompletely understood. Genetic analyses might help to elucidate novel regulatory and functional mechanisms. The identification of genetic factors related to circulating α-Klotho further enables MR to examine causal relationships with other factors. The findings from the first GWAS meta-analysis of circulating α-Klotho levels identified six genome-wide significant signals across five genes. Given the function of two of the genes identified, B4GALNT3 and CHST9, it is tempting to speculate that post-translational modification significantly contributes to genetic influences on α-Klotho levels, presumably by affecting protein turnover and stability.

FGF23 measurements have entered clinical medicine several years ago, and FGF23 has become a treatment target in endocrinology with the introduction of burosumab in 2018. A detailed understanding of FGF23 is needed to properly differentiate various causes of hypophosphatemia with renal phosphorus losses. A variety of different genetic disorders that directly or indirectly affect FGF23 regulation cause inherited phosphate wasting, among which X-linked hypophosphatemia (XLH)—caused by a loss of function of the cell surface–bound protein-cleavage enzyme PHEX (phosphate-regulating neutral endopeptidase)—is by far the most frequent disease. Acquired causes of renal phosphorus wasting with high plasma FGF23 comprise hypophosphatemia after certain iron compounds for intravenous iron repletion and tumor-induced osteomalacia (“oncogenic osteomalacia”), in which so-called “phosphaturic mesenchymal tumors” excessively produce FGF23. Standard of care patients with XLH has been revolutionized when regulatory authorities both in the United States and Europe have approved burosumab, which is a fully human monoclonal antibody that neutralizes FGF23 and thus ameliorates hypophosphatemia. Beyond the field of phosphorus regulation, clinical implications of elevated FGF23 are less certain. Even though experimental and epidemiologic work suggests FGF23 to induce left ventricular hypertrophy and to affect cardiovascular outcome, it is premature to consider plasma FGF23 a clinical target for cardiovascular prevention in today's clinical practice.

BACKGROUND: Chronic heart failure is one of the most common medical conditions, affecting more than 23 million people worldwide. Despite established guideline‐based, multidrug pharmacotherapy, chronic heart failure is still the cause of frequent hospitalisation, and about 50% die within five years of diagnosis. OBJECTIVES: To assess the effectiveness and safety of ivabradine in individuals with chronic heart failure. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, and CPCI‐S Web of Science in March 2020. We also searched ClinicalTrials.gov and the WHO ICTRP. We checked reference lists of included studies. We did not apply any time or language restrictions. SELECTION CRITERIA: We included randomised controlled trials in which adult participants diagnosed with chronic heart failure were randomly assigned to receive either ivabradine or placebo/usual care/no treatment. We distinguished between type of heart failure (heart failure with a reduced ejection fraction or heart failure with a preserved ejection fraction) as well as between duration of ivabradine treatment (short term (< 6 months) or long term (≥ 6 months)). DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trials for inclusion, extracted data, and checked data for accuracy. We calculated risk ratios (RR) using a random‐effects model. We completed a comprehensive ’Risk of bias’ assessment for all studies. We contacted authors for missing data. Our primary endpoints were: mortality from cardiovascular causes; quality of life; time to first hospitalisation for heart failure during follow‐up; and number of days spent in hospital due to heart failure during follow‐up. Our secondary endpoints were: rate of serious adverse events; exercise capacity; and economic costs (narrative report). We assessed the certainty of the evidence applying the GRADE methodology. MAIN RESULTS: We included 19 studies (76 reports) involving a total of 19,628 participants (mean age 60.76 years, 69% male). However, few studies contributed data to meta‐analyses due to inconsistency in trial design (type of heart failure) and outcome reporting and measurement. In general, risk of bias varied from low to high across the included studies, with insufficient detail provided to inform judgement in several cases. We were able to perform two meta‐analyses focusing on participants with heart failure with a reduced ejection fraction (HFrEF) and long‐term ivabradine treatment. There was evidence of no difference between ivabradine and placebo/usual care/no treatment for mortality from cardiovascular causes (RR 0.99, 95% confidence interval (CI) 0.88 to 1.11; 3 studies; 17,676 participants; I(2) = 33%; moderate‐certainty evidence). Furthermore, we found evidence of no difference in rate of serious adverse events amongst HFrEF participants randomised to receive long‐term ivabradine compared with those randomised to placebo, usual care, or no treatment (RR 0.96, 95% CI 0.92 to 1.00; 2 studies; 17,399 participants; I(2) = 12%; moderate‐certainty evidence). We were not able to perform meta‐analysis for all other outcomes, and have low confidence in the findings based on the individual studies. AUTHORS' CONCLUSIONS: We found evidence of no difference in cardiovascular mortality and serious adverse events between long‐term treatment with ivabradine and placebo/usual care/no treatment in participants with heart failure with HFrEF. Nevertheless, due to indirectness (male predominance), the certainty of the available evidence is rated as moderate.

In patients with intact kidney function and in patients with mild to moderate chronic kidney disease (CKD), strong evidence suggests the use of non-vitamin K dependent oral anticoagulants (NOAC) for preventing ischemic strokes and systemic thromboembolic events in patients with non-valvular atrial fibrillation (nvAF) and elevated thromboembolic risk. In contrast, less evidence is available on the risk-benefit ratio of oral anticoagulation (OAC) in patients with nvAF and severe CKD, particularly in dialysis patients. No large randomised study has tested whether OAC will reduce the risk of thromboembolic events in nvAF without prohibitively high bleeding risk, and whether NOACs or vitamin K antagonists are the superior strategy for OAC. Considering absence of strong evidence, the authors suggest that in dialysis patients with nvAF, in whom the treatment team sees the clear need to prevent thromboembolic events, the use of NOACs or left atrial appendage occlusion should be preferred over treatment with vitamin K antagonists. Any OAC treatment for dialysis patients with nvAF is not in-label in most European countries.

Background In patients with iron deficiency anemia, ferric carboxymaltose (FCM) and ferric derisomaltose (FDI) allow high-dose iron repletion. While FCM is reported to induce hypophosphatemia, the frequency of hypophosphatemia after an equivalent dosage of FDI had not been assessed prospectively. Methods In the prospective, single-center, double-blind HOMe aFers study, 26 women with iron deficiency anemia (hemoglobin Results Hypophosphatemia occurred more frequently in women treated with FCM (9 out of 12 [75%]) than in those treated with FDI (1 out of 13 [8%]; p = 0.001). Within 24 h after iron supplementation, women in the FCM group had significant higher plasma intact FGF23 (p p p = 0.021 at day 7 ± 2 after iron supplementation). We did not observe differences in skeletal and cardiovascular markers, potentially because of the limited number of participants. Conclusions While both FCM and FDI provide efficient iron repletion in participants with iron deficiency anemia, FCM induced hypophosphatemia more often than FDI. Trial registration Clinical Trials.gov NCT02905539. Registered on 8 September 2016. 2015-004808-36 (EudraCT Number) U1111-1176-4563 (WHO Universal Trial Number) DRKS00010766 (Deutsches Register Klinischer Studien)

PLOS ONE 15(3), e0229636 (2020). doi:10.1371/journal.pone.0229636, Published by PLOS, San Francisco, California, US

Journal of Clinical Medicine 11(3), 601 (2022). doi:10.3390/jcm11030601, Published by MDPI, Basel

ZusammenfassungDie Kalziphylaxie (kalzifizierende urämische Arteriolopathie) ist eine seltene, aber dramatische Spielart der Weichteilverkalkung bei Patienten mit terminaler Niereninsuffizienz. Noch seltener ist sie auch bei Patienten ohne nennenswerte Nierenerkrankung 1. Die Kalziphylaxie ist eine diagnostische und vor allem therapeutische Herausforderung. Sie trifft die Patienten mit heftigen Einschränkungen der Lebensqualität und ist trotz aller Fortschritte immer noch mit einem hohen Mortalitätsrisiko behaftet. Die Ätiologie der Kalziphylaxie ist nur teilweise verstanden und in der Therapie sind große Lücken hinsichtlich evidenzbasierter Standards zu beklagen. Betroffene Patienten sollten in einem interdisziplinären Team und gegebenenfalls in einem spezialisierten Zentrum betreut werden. Allerdings spricht unsere Erfahrung aus solchen überregionalen Behandlungszentren für einen Rückgang der Erkrankungsziffern und ein besseres Ansprechen der Therapie. Die Kooperation mit überregionalen Registern und Netzwerken, Aufklärungskampagnen sowie eine verbesserte Sensibilität im Umgang mit ausschaltbaren Risikofaktoren könnten daher in den letzten Jahren doch Früchte getragen haben.

Dyspnea is one of the most disturbing symptoms for patients with chronic obstructive pulmonary disease (COPD) or heart failure (HF). This study investigated dyspnea triggers and factors associated with worsening dyspnea in patients with COPD or HF. COPD support group members and HF patients with reduced ejection fraction (HFrEF) and no airway obstruction answered a questionnaire describing different weather conditions (rising/falling air pressure, sunny, foggy, rainy, windy, snowy, hazy, high ozone levels, and airborne pollen) and environmental circumstances (cooking, grilling, perfumes, cigarette smoke, gasoline odor, and flower scents) and were asked to estimate the occurrence and severity of dyspnea under these conditions using predefined scales. 230 patients with COPD and 90 with HFrEF (left ventricular ejection fraction 34 ± 10%, Tiffeneau index > 70%) were analyzed. COPD patients reported dyspnea more often than HF patients in almost all weather and environmental conditions (p = 0.004 to p

Background: Chronic obstructive pulmonary disease (COPD) and coronary heart disease (CHD) often occur together. However, COPD is underdiagnosed among CHD patients. Objectives: This study investigated the prevalence of COPD and relevant pulmonary function test (PFT) impairments in patients with acute myocardial infarction (AMI). Methods: Patients undergoing coronary angiography for AMI were prospectively included. Body plethysmography, lung diffusing capacity, blood gas analysis, and echocardiography were performed. The following patient subgroups were compared: with versus without COPD, ST elevation myocardial infarction (STEMI) versus non-STEMI (NSTEMI). The prevalence of PFT impairments was also recorded. Results: A total of 100 patients (51 with NSTEMI, 49 with STEMI) were included. Twenty patients had diagnosed COPD, of whom 15 were diagnosed for the first time; 80% of all COPD patients were not receiving COPD therapy. Patients with COPD had higher maximum creatine kinase (p = 0.008) and troponin T (p = 0.054) levels than those without COPD. Hypoxaemia was more common in COPD patients (lower oxygen saturation [p = 0.008] and partial pressure of oxygen [PaO2] [p = 0.005]). PaO2 was significantly lower in STEMI compared with NSTEMI (p = 0.017). Independent of a COPD diagnosis, 65 patients had relevant PFT impairments. Conclusions: The high prevalence of undiagnosed COPD and relevant pulmonary function impairments in this cohort of patients with AMI, and the fact that pulmonary disease was untreated in the majority of COPD patients, highlight the importance of a general pulmonary workup of patients with AMI. Furthermore, patients with CHD should undergo screening for COPD, given the fact that COPD patients had larger infarction size.