Cocoa Flavanol Cardiovascular Effects Beyond Blood Pressure Reduction - Jumar, Agnes; Schmieder, Roland (Journal of Clinical Hypertension, 2016)
The protective cardiovascular (CV) effect of cocoa flavanol has been a target of many recent clinical prospective and retrospective investigations. Epidemiological data in different patient cohorts revealed an association between higher intake of flavanol-rich foods and decreased incidence of CV events, especially stroke and myocardial infarction. Cocoa flavanol has been shown to reduce systolic (2.8 mm Hg) and diastolic (2.2 mm Hg) office blood pressure (BP). Greater BP reduction has been found in hypertensive patients and people younger than 50 years. Cocoa flavanol intake exerts beneficial effects on pathophysiologic mechanisms of hypertension-related organ damage, such as improved endothelial function, anti-inflammatory potency, inhibition of platelet activation, and increased vasodilatory capacity. Recent clinical trials have focused on establishing a potential link between epidemiology and pathophysiology of flavanol and identified possible mechanisms for prevention of end-organ damage in patients at CV risk. This review summarizes the available data on the antihypertensive effects of cocoa flavanol beyond BP-BP lowering lowering effects, accentuates subgroup-specific protective actions of cocoa according to patients' different CV risk profile, and outlines potential cocoa flavanol-associated clinical implications.
EVALuna2:3801

Colon Cancer Microbiome Landscaping: Differences in Right- and Left-Sided Colon Cancer and a Tumor Microbiome-Ileal Microbiome Association - Kneis, Barbara; Wirtz, Stefan; Weber, Klaus; Denz, Axel; Gittler, Matthias; Geppert, Carol-Immanuel; Brunner, Maximilian; Krautz, Christian; Siebenhuener, Alexander Reinhard; Schierwagen, Robert; Tyc, Olaf; Agaimy, Abbas; et al. (International Journal of Molecular Sciences, 2023)
In the current era of precision oncology, it is widely acknowledged that CRC is a heterogeneous disease entity. Tumor location (right- or left-sided colon cancer or rectal cancer) is a crucial factor in determining disease progression as well as prognosis and influences disease management. In the last decade, numerous works have reported that the microbiome is an important element of CRC carcinogenesis, progression and therapy response. Owing to the heterogeneous nature of microbiomes, the findings of these studies were inconsistent. The majority of the studies combined colon cancer (CC) and rectal cancer (RC) samples as CRC for analysis. Furthermore, the small intestine, as the major site for immune surveillance in the gut, is understudied compared to the colon. Thus, the CRC heterogeneity puzzle is far from being solved, and more research is necessary for prospective trials that separately investigate CC and RC. Our prospective study aimed to map the colon cancer landscape using 16S rRNA amplicon sequencing in biopsy samples from the terminal ileum, healthy colon tissue, healthy rectal tissue and tumor tissue as well as in preoperative and postoperative stool samples of 41 patients. While fecal samples provide a good approximation of the average gut microbiome composition, mucosal biopsies allow for detecting subtle variations in local microbial communities. In particular, the small bowel microbiome has remained poorly characterized, mainly because of sampling difficulties. Our analysis revealed the following: (i) right- and left-sided colon cancers harbor distinct and diverse microbiomes, (ii) the tumor microbiome leads to a more consistent cancer-defined microbiome between locations and reveals a tumor microbiome-ileal microbiome association, (iii) the stool only partly reflects the microbiome landscape in patients with CC, and (iv) mechanical bowel preparation and perioperative antibiotics together with surgery result in major changes in the stool microbiome, characterized by a significant increase in the abundance of potentially pathogenic bacteria, such as Enterococcus. Collectively, our results provide new and valuable insights into the complex microbiome landscape in patients with colon cancer.
CRIS-Team Scopus Importer:2023-03-10
Keywords: colon cancer; gut microbiome; left-sided colon cancer; microbiome; right-sided colon cancer; tumor microbiome

Combination of empagliflozin and linagliptin improves blood pressure and vascular function in type 2 diabetes - Jung, Susanne; Bosch, Agnes; Kannenkeril, Dennis; Karg, Marina V.; Striepe, Kristina; Bramlage, Peter; Ott, Christian; Schmieder, Roland; Jung, Susanne (European Heart Journal - Cardiovascular Pharmacotherapy, 2020)
AIMS: Preserved vascular function represents a key prognostic factor in type 2 diabetes mellitus (T2DM), but data on vascular parameters in this patient cohort are scarce. Patients with T2DM often need more than one drug to achieve optimal glucose control. The aim of this study was to analyse the efficacy of two combination therapies on vascular function in subjects with T2DM. METHODS AND RESULTS: This prospective, randomized study included 97 subjects with T2DM. Subjects were randomized to either the combination therapy empagliflozin (E) 10 mg with linagliptin (L) 5 mg once daily or metformin (M) 850 or 1000 mg twice daily with insulin glargine (I) once daily. At baseline and after 12 weeks, subjects had peripheral office and 24-h ambulatory blood pressure (BP) measurement and underwent vascular assessment by pulse wave analysis under office and ambulatory conditions. Office, 24-h ambulatory and central BP as well as pulse pressure (PP) decreased after 12 weeks of treatment with E + L, whereas no change was observed in M + I. There were greater decreases in 24-h ambulatory peripheral systolic (between-group difference: -5.2 ± 1.5 mmHg, P = 0.004), diastolic BP (-1.9 ± 1.0 mmHg, P = 0.036), and PP (-3.3 ± 1.0 mmHg, P = 0.007) in E + L than M + I. Central office systolic BP (-5.56 ± 1.9 mmHg, P = 0.009), forward pressure height of the pulse wave (-2.0 ± 0.9 mmHg, P = 0.028), 24-h ambulatory central systolic (-3.6 ± 1.4 mmHg, P = 0.045), diastolic BP (-1.95 ± 1.1 mmHg, P = 0.041), and 24-h pulse wave velocity (-0.14 ± 0.05m/s, P = 0.043) were reduced to a greater extent with E + L. CONCLUSION: Beyond the effects on glycaemic control, the combination therapy of E + L significantly improved central BP and vascular function compared with the classic combination of M + I. CLINICALTRIALS.GOV: NCT02752113.
CRIS-Team Scopus Importer:2020-11-27
Keywords: Blood pressure; Central haemodynamics; Empagliflozin; Linagliptin; T2DM; Vascular function

Combined imaging of potassium and sodium in human skeletal muscle tissue at 7 T - Gast, Lena; Volker, Stefanie; Utzschneider, Matthias; Linz, Peter; Wilferth, Tobias; Müller, Max; Kopp, Christoph; Hensel, Bernhard; Uder, Michael; Nagel, Armin Michael (Magnetic Resonance in Medicine, 2020)
Purpose: To validate the feasibility of quantitative combined potassium (39K) and sodium (23Na) MRI in human calf muscle tissue, as well as to evaluate the reproducibility of the apparent tissue potassium concentration (aTPC) and apparent tissue sodium concentration (aTSC) determination in healthy muscle tissue. Methods: Quantitative 23Na and 39K MRI acquisition protocols were implemented on a 7 T MR system. A double-resonant 23Na/39K birdcage RF coil was used. Measurements of human lower leg were performed in a total acquisition time of TANa = 10:54 min/TAK = 8:06 min and using a nominal spatial resolution of 2.5 × 2.5 × 15 mm3/7.5 × 7.5 × 30 mm3 for 23Na/39K MRI. Two aTSC and aTPC examinations in muscle tissue were performed during the same day on 10 healthy subjects. Results: The proposed acquisition and postprocessing workflow for 23Na and 39K MRI data sets provided reproducible aTSC and aTPC measurements. In human calf muscle tissue, the coefficient of variation between scan and re-scan was 5.7% for both aTSC and aTPC determination. Overall, mean values of aTSC = (17 ± 1) mM and aTPC = (85 ± 5) mM were measured. Moreover, for 39K in calf muscle tissue, (Formula presented.) components of (Formula presented.) = (1.2 ± 0.2) ms and (Formula presented.) = (7.9 ± 0.9) ms, as well as a residual quadrupolar interaction of (Formula presented.) = (143 ± 17) Hz, were determined. The fraction of the fast component was f = (58 ± 4)%. Conclusion: Using the presented measurement and postprocessing approach, a reproducible aTSC and aTPC determination using 23Na and 39K MRI at 7 T in human skeletal muscle tissue is feasible in clinically acceptable acquisition durations.
CRIS-Team Scopus Importer:2020-09-11
Keywords: 7 T; potassium MRI; sodium MRI; tissue potassium concentration; tissue sodium concentration; ultrahigh field strengths

Combined therapy of empagliflozin and linagliptin is superior to metformin and insulin glargine in improving blood pressure and vascular function in type 2 diabetes - Jung, Susanne; Bosch, Agnes; Kannenkeril, D.; Karg, M.; Striepe, Kristina; Bramlage, P.; Ott, Christian; Schmieder, Roland (EUROPEAN HEART JOURNAL, 2019)
CRIS-Team WoS Importer:2020-02-04

Comeback of Renal Denervation As Treatment Option in Patients with Hypertension - Jung, Susan; Schmieder, Roland (Aktuelle Kardiologie, 2019)
The effectiveness of renal denervation to reduce blood pressure has been controversially discussed. After a few uncontrolled pilot studies had shown promising results with respect to the effectiveness of this method, the results of the Symplicity HTN-3 study were discouraging: no significant difference in blood pressure reduction between denervation and sham group could be observed. The results of three sham-controlled studies were finally able to prove the effectiveness of renal denervation: in comparison to sham-procedure, a significant office and 24-h ambulatory blood pressure reduction could be achieved. The findings obtained from these studies provide interesting future perspectives with respect to the application of the technique in other diseases and patients that profit most from renal denervation.
CRIS-Team WoS Importer:2019-10-29

Commentary on the KDIGO 2021 Clinical Practice Guideline for the Management of Blood Pressure in CKD - Mann, Johannes; Chang, Tara I.; Cushman, William C.; Furth, Susan L.; Ix, Joachim H.; Hou, Fan Fan; Knoll, Gregory A.; Muntner, Paul; Pecoits-Filho, Roberto; Sarnak, Mark J.; Tomson, Charles R. V.; Craig, Jonathan C.; et al. (Current Cardiology Reports, 2021)
Purpose of Review: To summarize and explain the new guideline on blood pressure (BP) management in chronic kidney disease (CKD) published by Kidney Disease: Improving Global Outcomes (KDIGO), an independent global nonprofit organization which develops and implements evidence-based clinical practice guidelines in kidney disease. KDIGO issued its first clinical practice guideline for the Management of Blood Pressure (BP) in Chronic Kidney Disease (CKD) for patients not receiving dialysis in 2012 and now updated the guideline in 2021. Recent Findings: Recommendations in this update were developed based on systematic literature reviews and appraisal of the quality of the evidence and strength of recommendation following the “Grading of Recommendations Assessment, Development and Evaluation” (GRADE) approach. The updated guideline includes five chapters covering BP measurement techniques, lifestyle interventions for lowering BP, and management of BP in three target populations, namely adults (with and without diabetes), kidney transplant recipients, and children. A dedicated chapter on BP measurement emphasizing standardized preparation and measurement protocols for office BP measurement is a new addition, following protocols used in large randomized trials of BP targets with pivotal clinical outcomes. Summary: Based on the available evidence, and in particular in the CKD subgroup of the SPRINT trial, the 2021 guideline suggests a systolic BP target of <120 mm Hg, based on standardized measurements, for most individuals with CKD not receiving dialysis, with the exception of kidney transplant recipients and children. This recommendation is strictly contingent on the measurement of BP using standardized office readings and not routine office readings.
CRIS-Team Scopus Importer:2021-08-27
Keywords: Albuminuria; Angiotensin II receptor blocker; Angiotensin-converting enzyme inhibitor; Blood pressure measurement; Blood pressure targets; Children; Chronic kidney disease; Dietary sodium; Kidney transplant recipient; Standardized office blood pressure

Comments on the consensus paper on renal denervation of the working group on hypertension of the European Society of Cardiology (ESC) and the European Association of Percutaneous Cardiovascular Interventions (EAPCI) Kommentar zum Konsensuspapier zur renalen Denervation der Arbeitsgruppe Hypertonie der European Society of Cardiology (ESC) und der European Association of Percutaneous Cardiovascular Interventions (EAPCI) - Halbach, Marcel; Boer, Jana; Böhm, Michael; Busch, Sonia; Dörr, Oliver; Elsässer, Albrecht; Erbel, Christian; Galle, Jan Christoph; Kintscher, Ulrich; Limbourg, Florian P.; Reuter, Hannes; Rump, Lars C.; et al. (Die Kardiologie, 2023)
Since the publication of the ESC/ESH guidelines on arterial hypertension in 2018, several sham-controlled, high-quality trials on renal denervation have been published, which demonstrated the safety and efficacy of renal denervation. Therefore, renal denervation is an additional therapeutic option for patients with uncontrolled resistant hypertension, whereby the latter should be confirmed by ambulatory blood pressure monitoring. Renal denervation may also be applied in selected patients with drug intolerances. Decision making should take patient preferences after comprehensive information and the individual cardiovascular risk into account. A multidisciplinary hypertension team should establish the indications for renal denervation and perform the treatment. Interventionalists must be experienced in performing renal interventions and receive a special training for renal denervation. In Germany, renal denervation should be performed by specialized centers, which fulfill personal, spatial and technical criteria as defined by the national societies [23].
CRIS-Team Scopus Importer:2023-07-14
Keywords: Interventional treatment; Nonadherence; Patient selection; Renal artery; Resistant hypertension

Comments on the guidelines (2018) of the European Society of Cardiology (ESC) and the European Society of Hypertension (ESH) on themanagement of arterial hypertension - Mahfoud, F.; Boehm, M.; Bongarth, C. M.; Bosch, R.; Schmieder, Roland; Schunkert, H.; Stellbrink, C.; Trenkwalder, P.; Vonend, O.; Weil, J.; Kreutz, R. (Der Kardiologe, 2019)
Arterial hypertension represents one of the most frequent chronic diseases that can lead to complications, such as stroke, dementia, heart attack, heart failure and renal failure. By 2025 the number of hypertensive patients will increase to approximately 1.6 billion people worldwide. The new guidelines of the European Society of Cardiology (ESC) and the European Society of Hypertension (ESH) on the management of arterial hypertension replace the guidelines of the ESC/ESH from 2013. The 2018 guidelines of the ESC/ESH were adopted by the German Cardiac Society and the German Hypertension League. In these comments national characteristics are worked out and the essential new aspects of the guidelines are critically discussed. These include, for example, the definition of hypertension, the importance of out of office blood pressure measurements, revised blood pressure targets, the modified algorithm for drug treatment and the relevance of device-based hypertension treatments. Important aspects for the management of hypertensive emergencies are also presented.
CRIS-Team WoS Importer:2019-03-08

Comments on the guidelines (2018) of the European Society of Cardiology (ESC) and the European Society of Hypertension (ESH) on the management of arterial hypertension [Kommentar zu den Leitlinien (2018) der Europäischen Gesellschaft für Kardiologie (ESC) und der Europäischen Gesellschaft für Hypertonie (ESH) für das Management der arteriellen Hypertonie] - Mahfoud, F.; Boehm, M.; Bongarth, C. M.; Bosch, R.; Schmieder, Roland; Schunkert, H.; Stellbrink, C.; Trenkwalder, P.; Vonend, O.; Weil, J.; Kreutz, R. (Internist, 2019)
Arterial hypertension represents one of the most frequent chronic diseases that can lead to complications, such as stroke, dementia, heart attack, heart failure and renal failure. By 2025 the number of hypertensive patients will increase to approximately 1.6 billion people worldwide. The new guidelines of the European Society of Cardiology (ESC) and the European Society of Hypertension (ESH) on the management of arterial hypertension replace the guidelines of the ESC/ESH from 2013. The 2018 guidelines of the ESC/ESH were adopted by the German Cardiac Society and the German Hypertension League. In these comments national characteristics are worked out and the essential new aspects of the guidelines are critically discussed. These include, for example, the definition of hypertension, the importance of out of office blood pressure measurements, revised blood pressure targets, the modified algorithm for drug treatment and the relevance of device-based hypertension treatments. Important aspects for the management of hypertensive emergencies are also presented.
CRIS-Team Scopus Importer:2019-05-07
Keywords: Device-based hypertension treatment; Fixed combination; Guidelines; Hypertension; Hypertensive emergencies; Target blood pressure

Commissural misalignment independently predicts leaflet thrombosis after transcatheter aortic valve implantation - Jung, Susanne; Ammon, Fabian; Smolka, Silvia; Moshage, Maximilian; Marwan, Mohamed; Achenbach, Stephan (Clinical Research in Cardiology, 2023)
Aims: Transcatheter aortic valve implantation (TAVI) has become a minimally invasive alternative to surgical aortic valve replacement. Hypo-attenuated leaflet thickening (HALT)—a marker of subclinical leaflet thrombosis commonly detected by cardiac computed tomography (CT) after TAVI—may influence valve durability and function. The purpose of this study was to compare commissural alignment of the native and prosthetic aortic valves in cardiac CT in subjects with and without HALT and thereby identify commissural misalignment as potential predictor for leaflet thrombosis after TAVI. Methods and results: In 170 subjects, 85 with and 85 without HALT in post-TAVI CT, commissural orientation of the prosthesis was determined comparing native and prosthetic aortic valve orientation in cardiac CT by measuring the commissural angle relative to the right coronary ostium in the aortic valve plane. For the prosthetic valve, any deviation ≤ 15° compared to the native valve was classified as “aligned”; 16–30° as “mild”, 31–45° as “moderate” and ≥ 45° as “severe” misalignment. Among subjects with HALT, median angular deviation was higher (36°, IQR 31°) than in the control group (29°, IQR 29°, p = 0.042). “Severe” misalignment was more frequent in subjects who developed HALT (n = 31, 37%) compared to the control group (n = 17, 20%, p = 0.013). In logistic regression analysis, more severe deviation (p = 0.015, OR = 1.02 per 1° deviation) and “severe” misalignment (p = 0.018, OR = 2.2) represented independent predictors for the occurrence of HALT after TAVI. Conclusion: Subclinical leaflet thrombosis after TAVI is associated with commissural misalignment. Potential clinical advantages of obtaining commissural alignment remain to be systematically assessed. Graphical abstract: [Figure not available: see fulltext.] Association of HALT with commissural misalignment after TAVI. HALT hypo-attenuated leaflet thickening, IQR interquartile range, TAVI transfemoral aortic valve replacement
CRIS-Team Scopus Importer:2023-04-21
Keywords: Commissural misalignment; HALT; Leaflet thrombosis; TAVI

Comparison of Early Retinal Microvascular Changes and Microalbuminuria as Indicators for Increased Cardioascular Risk - Huchzermeyer, Cord; Schaller, Barbara; Schmid, Kathrin; Schmieder, Roland; Michelson, Georg (Klinische Monatsblätter für Augenheilkunde, 2011)
Prevention of cardiovascular disease is an important goal in clinical medicine and public health. In the process, the diagnosis of early end-organ damage is a priority beside the treatment of classic cardiovascular risk factors. To achieve this, the ophthalmoscopic examination of the retinal vessels plays a prominent role. Alternatively, the quantification of low quantities of albumin in the urine (microalbuminuria) allows the detection of early vascular damage in the kidney. The question is addressed as to whether these two methods are interchangeable or are rather complementary.We examined 226 members of the staff of the University Hospital Erlangen who volunteered to participate in a preventive campaign. A comprehensive history was taken, and height, weight and blood pressure were measured. Analysis of serum lipids and determination of the urinary albumin/creatinine ratio were performed. Fotos of the central fundus were taken with a non-mydriatic camera and analysed by an experienced ophthalmologist in a standardised fashion. The risk for cardiovascular mortality within the next ten years was estimated from age, sex, blood pressure and serum cholesterol using the euroSCORE tables for Germany.There was no signficant correlation between the arteriovenous ratio of the retinal vessels and the urinary albumin/creatinine ratio. Neither parameter correlated with the euroSCORE Germany. Arteriovenous crossings and focal narrowing of the retinal vessels were associated signficantly with an elevated euroSCORE risk.In large population-based studies, the arteriovenous ratio and the urinary albumin/creatinine ratio have been confirmed as markers of cardiovascular risk. In our study, there was no correlation between these two parameters. Thus, they seem to present independent risk markers. The presence of arteriovenous crossings and focal narrowing seems to be linked more closely to the classic cardiovascular risk factors from which the euroSCORE is calculated. The ophathlmolscopic examination of retinal vessels and the analysis of urinary albumin/creatinine ratio seem to complement rather than replace each other.
EVALuna2:3434

Comparison of physician and artificial intelligence-based symptom checker diagnostic accuracy - Gräf, Markus; Knitza, Johannes; Leipe, Jan; Krusche, Martin; Welcker, Martin; Kuhn, Sebastian; Mucke, Johanna; Hueber, Axel; Hornig, Johannes; Klemm, Philipp; Kleinert, Stefan; Aries, Peer; et al. (Rheumatology International, 2022)
Symptom checkers are increasingly used to assess new symptoms and navigate the health care system. The aim of this study was to compare the accuracy of an artificial intelligence (AI)-based symptom checker (Ada) and physicians regarding the presence/absence of an inflammatory rheumatic disease (IRD). In this survey study, German-speaking physicians with prior rheumatology working experience were asked to determine IRD presence/absence and suggest diagnoses for 20 different real-world patient vignettes, which included only basic health and symptom-related medical history. IRD detection rate and suggested diagnoses of participants and Ada were compared to the gold standard, the final rheumatologists' diagnosis, reported on the discharge summary report. A total of 132 vignettes were completed by 33 physicians (mean rheumatology working experience 8.8 (SD 7.1) years). Ada's diagnostic accuracy (IRD) was significantly higher compared to physicians (70 vs 54%, p = 0.002) according to top diagnosis. Ada listed the correct diagnosis more often compared to physicians (54 vs 32%, p < 0.001) as top diagnosis as well as among the top 3 diagnoses (59 vs 42%, p < 0.001). Work experience was not related to suggesting the correct diagnosis or IRD status. Confined to basic health and symptom-related medical history, the diagnostic accuracy of physicians was lower compared to an AI-based symptom checker. These results highlight the potential of using symptom checkers early during the patient journey and importance of access to complete and sufficient patient information to establish a correct diagnosis.
CRIS-Team WoS Importer:2022-09-16

Comparison of Plasma and Urine Biomarker Performance in Acute Kidney Injury - Schley, Gunnar; Köberle, Carmen; Manuilova, Ekaterina; Rutz, Sandra; Forster, Christian; Weyand, Michael; Formentini, Ivan; Kientsch-Engel, Rosemarie; Eckardt, Kai-Uwe; Willam, Carsten (PLoS ONE, 2015)
New renal biomarkers measured in urine promise to increase specificity for risk stratification and early diagnosis of acute kidney injury (AKI) but concomitantly may be altered by urine concentration effects and chronic renal insufficiency. This study therefore directly compared the performance of AKI biomarkers in urine and plasma.This single-center, prospective cohort study included 110 unselected adults undergoing cardiac surgery with cardiopulmonary bypass between 2009 and 2010. Plasma and/or urine concentrations of creatinine, cystatin C, neutrophil gelatinase-associated lipocalin (NGAL), liver fatty acid-binding protein (L-FABP), kidney injury molecule 1 (KIM1), and albumin as well as 15 additional biomarkers in plasma and urine were measured during the perioperative period. The primary outcome was AKI defined by AKIN serum creatinine criteria within 72 hours after surgery.Biomarkers in plasma showed markedly better discriminative performance for preoperative risk stratification and early postoperative (within 24h after surgery) detection of AKI than urine biomarkers. Discriminative power of urine biomarkers improved when concentrations were normalized to urinary creatinine, but urine biomarkers had still lower AUC values than plasma biomarkers. Best diagnostic performance 4h after surgery had plasma NGAL (AUC 0.83), cystatin C (0.76), MIG (0.74), and L-FAPB (0.73). Combinations of multiple biomarkers did not improve their diagnostic power. Preoperative clinical scoring systems (EuroSCORE and Cleveland Clinic Foundation Score) predicted the risk for AKI (AUC 0.76 and 0.71) and were not inferior to biomarkers. Preexisting chronic kidney disease limited the diagnostic performance of both plasma and urine biomarkers.In our cohort plasma biomarkers had higher discriminative power for risk stratification and early diagnosis of AKI than urine biomarkers. For preoperative risk stratification of AKI clinical models showed similar discriminative performance to biomarkers. The discriminative performance of both plasma and urine biomarkers was reduced by preexisting chronic kidney disease.
EVALuna2:3825

Complement Factor H-Related 5-Hybrid Proteins Anchor Properdin and Activate Complement at Self-Surfaces - Chen, Qian; Manzke, Melanie; Hartmann, Andrea; Büttner, Maike; Amann, Kerstin Ute; Pauly, Diana; Wiesener, Michael; Skerka, Christine; Zipfel, Peter F. (Journal of the American Society of Nephrology, 2016)
C3 glomerulopathy (C3G) is a severe kidney disease for which no specific therapy exists. The causes of C3G are heterogeneous, and defective complement regulation is often linked to C3G pathogenesis. Copy number variations in the complement factor H-related (CFHR) gene cluster on chromosome 1q32 and CFHR5 mutant proteins associate with this disease. Here, we identified CFHR5 as a pattern recognition protein that binds to damaged human endothelial cell surfaces and to properdin, the human complement activator. We found the two N-terminal short consensus repeat domains of CFHR5 contact properdin and mediate dimer formation. These properdin-binding segments are duplicated in two mutant CFHR5 proteins, CFHR2-CFHR5Hyb from German patients with C3G and CFHR5Dup from Cypriot patients with C3G. Each of these mutated proteins assembled into large multimeric complexes and, compared to CFHR5, bound damaged human cell surfaces and properdin with greater intensity and exacerbated local complement activation. This enhanced surface binding and properdin recruitment was further evidenced in the mesangia of a transplanted and explanted kidney from a German patient with a CFHR2-CFHR5Hyb protein. Enhanced properdin staining correlated with local complement activation with C3b and C5b-9 deposition on the mesangial cell surface in vitro This gain of function in complement activation for two disease-associated CFHR5 mutants describes a new disease mechanism of C3G, which is relevant for defining appropriate treatment options for this disorder.
EVALuna2:3837

Complement factor H-related hybrid protein deregulates complement in dense deposit disease - Chen, Qian; Wiesener, Michael; Eberhardt, Hannes U.; Hartmann, Andrea; Uzonyi, Barbara; Kirschfink, Michael; Amann, Kerstin Ute; Büttner, Maike; Goodship, Tim; Hugo, Christian; Skerka, Christine; Zipfel, Peter F. (Journal of Clinical Investigation, 2014)
The renal disorder C3 glomerulopathy with dense deposit disease (C3G-DDD) pattern results from complement dysfunction and primarily affects children and young adults. There is no effective treatment, and patients often progress to end-stage renal failure. A small fraction of C3G-DDD cases linked to factor H or C3 gene mutations as well as autoantibodies have been reported. Here, we examined an index family with 2 patients with C3G-DDD and identified a chromosomal deletion in the complement factor H-related (CFHR) gene cluster. This deletion resulted in expression of a hybrid CFHR2-CFHR5 plasma protein. The recombinant hybrid protein stabilized the C3 convertase and reduced factor H-mediated convertase decay. One patient was refractory to plasma replacement and exchange therapy, as evidenced by the hybrid protein quickly returning to pretreatment plasma levels. Subsequently, complement inhibitors were tested on serum from the patient for their ability to block activity of CFHR2-CFHR5. Soluble CR1 restored defective C3 convertase regulation; however, neither eculizumab nor tagged compstatin had any effect. Our findings provide insight into the importance of CFHR proteins for C3 convertase regulation and identify a genetic variation in the CFHR gene cluster that promotes C3G-DDD. Monitoring copy number and sequence variations in the CFHR gene cluster in C3G-DDD and kidney patients with C3G-DDD variations will help guide treatment strategies.
EVALuna2:3659

Complex reinnervation pattern after unilateral renal denervation in rats - Rodionova, Kristina; Fiedler, Christian; Günther, Franziska; Grouzmann, Eric; Neuhuber, Winfried; Fischer, Michael; Ott, Christian; Linz, Peter; Freisinger, Wolfgang; Heinlein, Sonja; Schmidt, Stefan; Schmieder, Roland; et al. (American Journal of Physiology-Regulatory Integrative and Comparative Physiology, 2016)
Renal denervation (DNX) is a treatment for resistant arterial hypertension. Efferent sympathetic nerves regrow, but reinnervation by renal afferent nerves has only recently been shown in the renal pelvis of rats after unilateral DNX. We examined intrarenal perivascular afferent and sympathetic efferent nerves after unilateral surgical DNX. Tyrosine hydroxylase (TH), CGRP, and smooth muscle actin were identified in kidney sections from 12 Sprague-Dawley rats, to distinguish afferents, efferents, and vasculature. DNX kidneys and nondenervated kidneys were examined 1, 4, and 12 wk after DNX. Tissue levels of CGRP and norepinephrine (NE) were measured with ELISA and mass spectrometry, respectively. DNX decreased TH and CGRP labeling by 90% and 95%, respectively (P < 0.05) within 1 wk. After 12 wk TH and CGRP labeling returned to baseline with a shift toward afferent innervation (P < 0.05). Nondenervated kidneys showed a doubling of both labels within 12 wk (P < 0.05). CGRP content decreased by 72% [3.2 ± 0.3 vs. 0.9 ± 0.2 ng/gkidney; P < 0.05] and NA by 78% [1.1 ± 0.1 vs. 0.2 ± 0.1 pmol/mgkidney; P < 0.05] 1 wk after DNX. After 12 wk, CGRP, but not NE, content in DNX kidneys was fully recovered, with no changes in the nondenervated kidneys. The use of phenol in the DNX procedure did not influence this result. We found morphological reinnervation and transmitter recovery of afferents within 12 wk after DNX. Despite morphological evidence of sympathetic regrowth, NE content did not fully recover. These results suggest a long-term net surplus of afferent influence on the DNX kidney may be contributing to the blood pressure lowering effect of DNX.
EVALuna2:3840

Confounding Factors in Renal Denervation Trials Revisiting Old and Identifying New Challenges in Trial Design of Device Therapies for Hypertension - Kandzari, David E.; Mahfoud, Felix; Bhatt, Deepak L.; Boehm, Michael; Weber, Michael A.; Townsend, Raymond R.; Hettrick, Douglas A.; Schmieder, Roland; Tsioufis, Konstantinos; Kario, Kazuomi (Hypertension, 2020)
Recent randomized sham-controlled trials have demonstrated significant blood pressure reductions following renal denervation (RDN) in patients with hypertension, both in the presence and absence of antihypertensive therapy. These new data encouraged us to revisit previously published insights into potential clinical trial confounding factors that informed the design and conduct of forthcoming trials. Initially identified confounders related to procedural technique, medication variability, and selected patient subgroups have been addressed in contemporary trial design. Regarding procedural method and technology, blood pressure reductions may be improved by ensuring circumferential lesion creation in the distal renal arteries and branch vessels. Safety of the RDN procedure has been demonstrated in multiple independent meta-analyses including thousands of treated patients with low reported rates of renal vessel complications and maintenance of renal function. However, a newer generation of RDN trials has also introduced insights related to medication adherence, patient selection, and the definition of treatment response. Evolving evidence indicates that RDN therapy may be considered in higher risk populations of uncontrolled hypertension regardless of ethnicity and in patients expressing a strong preference for a nondrug therapy option. Despite advances in procedural technique and clinical trial conduct, inconsistent antihypertensive-drug adherence behavior remains perhaps the most critical clinical trial design issue for device-based hypertension therapies. As the balance in clinical equipoise increasingly favors RDN, justification of sham-controlled trial designs will be revisited, and novel study designs may be required to evaluate the safety and efficacy of novel devices and procedures intended to address the escalating prevalence of poorly controlled hypertension.
CRIS-Team WoS Importer:2020-10-23

Considerable international variation exists in blood pressure control and antihypertensive prescription patterns in chronic kidney disease - Alencar de Pinho, Natalia; Levin, Adeera; Fukagawa, Masafumi; Hoy, Wendy E.; Pecoits-Filho, Roberto; Reichel, Helmut; Robinson, Bruce; Kitiyakara, Chagriya; Wang, Jinwei; Eckardt, Kai-Uwe; Jha, Vivekanand; Oh, Kook Hwan; et al. (Kidney International, 2019)
Although blood pressure control is a major goal in chronic kidney disease, no worldwide overview of either its achievement or antihypertensive prescriptions is currently available. To evaluate this we compared crude prevalence of uncontrolled blood pressure among 17 cohort studies, including 34 602 individuals with estimated glomerular filtration rate under 60 ml/min/1.73 m2 and treated hypertension across four continents, and estimated observed to expected prevalence ratios, adjusted for potential confounders. Crude prevalence of blood pressure of 140/90 mm Hg or more varied from 28% to 61% and of blood pressure of 130/80 or more from 54% to 84%. Adjusted prevalence ratios indicated poorer hypertension control than expected in cohorts from European countries, India, and Uruguay, and better control in patients from North American and high-income Asian countries. Four antihypertensive drug classes or more were prescribed to more than 30% of participants in North American and some European cohorts, but this practice was less common elsewhere. Renin angiotensin-aldosterone system inhibitors were the most common antihypertensive drugs, prescribed for 54% to 91% of cohort participants. Differences for other drug classes were much stronger, ranging from 11% to 79% for diuretics, 22% to 70% for beta-blockers, and 27% to 75% for calcium-channel blockers. The confounders studied explain only a part of the international variation in blood pressure control among individuals with chronic kidney disease. Thus, considerable heterogeneity in prescription patterns worldwide calls for further investigation into the impact of different approaches on patient outcomes.
CRIS-Team Scopus Importer:2019-09-27
Keywords: antihypertensive treatment; chronic kidney disease; hypertension control; international health

Continuation of the ESH-CHL-SHOT trial after publication of the SPRINT: rationale for further study on blood pressure targets of antihypertensive treatment after stroke - Zanchetti, Alberto; Liu, Lisheng; Mancia, Giuseppe; Parati, Gianfranco; Grassi, Guido; Stramba-Badiale, Marco; Silani, Vincenzo; Bilo, Grzegorz; Corrao, Giovanni; Zambon, Antonella; Scotti, Lorenza; Zhang, Xinhua; et al. (Journal of Hypertension, 2016)
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Contrast-Enhanced µCT for Visualizing and Evaluating Murine Intestinal Inflammation - Jung, Dennis; Heiß, Rafael; Kramer, Viktoria; Thoma, Oana-Maria; Regensburger, Adrian; Rascher, Wolfgang; Uder, Michael; Neurath, Markus; Knieling, Ferdinand; Waldner, Maximilian (Theranostics, 2018)
Rationale: To develop a simple and fast protocol for the assessment of acute and chronic experimental intestinal inflammation using contrast-enhanced µCT. Methods: For the imaging studies, an acute 2% and 3% dextran sodium sulfate (n = 15, female, 8-12 weeks) and a chronic adoptive transfer colitis model (n = 10, female, 8-9 weeks) were established over 9 days or 6 weeks, respectively. Throughout the experiments, longitudinal measurement of murine intestinal wall thickness and time dependent perfusion was performed on a small animal µCT system (90 kV, 160 μA, FOV: 60 mm, scan time: 17 s, image size: 512x512, layer thickness: 118 µm) between 0.5 and 30 min after intravenous bolus injection of an iodine contrast agent. Weight development, small animal endoscopy, and histological ex vivo analysis were compared to contrast-enhanced µCT imaging findings. Results: Murine intestinal wall thickness was significantly increased in inflamed colons of acute colitis at day 9 in comparison to pre-inflamed state. Perfusion analysis revealed a late contrast enhancement in acute inflamed colons and the renal medulla at day 9 compared to control mice. An increasing intestinal wall thickness was monitored 3, 5 and 6 weeks after on-set of chronic colitis in comparison to controls. A good correlation with endoscopic (r = 0.75, p < 0.0001) and histologic degree of inflammation (r = 0.83, p = 0.04) was found. Conclusion: Contrast-enhanced µCT is a simple and fast method to assess acute intestinal inflammation and to monitor disease progression in experimental models of chronic colitis. According to our findings, one single contrast-enhanced µCT-scan is a valid non-invasive modality to quantify the degree of inflammation in the entire digestive tract in murine inflammatory models.
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Contribution of the ?8 integrin chain to the expression of extracellular matrix components - Volkert, Gudrun; Jahn, Angelika; Dinkel, Christina; Fahlbusch, Fabian; Zuern, Christina; Hilgers, Karl Friedrich; Rascher, Wolfgang; Marek, Ines; Hartner, Andrea (Cell Communication and Adhesion, 2014)
In the kidney, the ?8 integrin chain (itga8) is expressed in mesenchymal cells and is upregulated in fibrotic disease. We hypothesized that itga8 mediates a profibrotic phenotype of renal cells by promoting extracellular matrix and cytokine expression. Genetic itga8 deficiency caused complex changes in matrix expression patterns in mesangial and smooth-muscle cells, with the only concordant effect in both cell types being a reduction of collagen III expression. Silencing of itga8 with siRNA led to a decline of matrix turnover with repression of matrix metalloproteinases and reduction of matrix production. In contrast, de novo expression of itga8 in tubular epithelial cells resulted in reduced collagen synthesis. Overexpression of itga8 in fibroblasts did not change the expression of matrix molecules or regulators of matrix turnover. Thus, the influence of itga8 on the expression of matrix components was not uniform and celltype dependent. Itga8 seems unlikely to exert overall profibrotic effects in renal cells.
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Contributions of renal water loss and skin water conservation to blood pressure elevation in spontaneously hypertensive rats - Ogura, Takahiro; Kitada, Kento; Morisawa, Norihiko; Fujisawa, Yoshihide; Kidoguchi, Satoshi; Nakano, Daisuke; Kobara, Hideki; Masaki, Tsutomu; Titze, Jens; Nishiyama, Akira (Hypertension Research, 2022)
We recently reported that skin vasoconstriction to suppress transepidermal water loss (TEWL) leads to hypertension in renal injury model rats with impaired urine concentration ability. In this study, we investigated the pathogenesis of hypertension in spontaneously hypertensive rats (SHRs) from the perspective of renal water loss and skin water conservation. We compared the urinary concentration ability, body sodium and water balance, blood pressure, and TEWL in SHRs and control normotensive Wistar-Kyoto rats (WKYs). SHRs showed significantly higher urine volume and lower urinary osmolality than those of WKYs, while there were no significant differences in water intake, urinary osmolyte excretion, and plasma osmolarity between the groups. SHRs exhibited significantly higher blood pressure, skin sodium content, and lower TEWL compared with those is WKYs. Skin vasodilation, induced by elevating body temperature, increased TEWL in both SHRs and WKYs, and significantly reduced blood pressure in SHRs but not WKYs. These findings suggest that physiological adaptation can reduce dermal water loss in SHRs to compensate for renal water loss. Vasoconstriction required for successful cutaneous water conservation explains SHR hypertension. Renal concentration ability and skin barrier function for water conservation may become a novel therapeutic target for essential hypertension.
CRIS-Team WoS Importer:2022-10-28

Coordinated, Multimodal Care After Kidney Transplantation Improves Graft Survival and Cardiovascular Risks - Results of the Kidney Transplantation 360 degrees- Study (ktx360 degrees). - Pape, L.; Dezwaan, M.; Kliem, Volker; Nolting, H.; Wolff, J.; Tegtbur, U.; Schiffer, Mario (AMERICAN JOURNAL OF TRANSPLANTATION, 2022)
CRIS-Team WoS Importer:2022-10-07

COPEPTIN AS A RESEARCH MARKER IN CARDIOVASCULAR DISEASE - Bosch, Agnes; Ott, C.; Schmid, Andrea; Kannenkeril, D.; Karg, M.; Ditting, T.; Veelken, Roland; Uder, Michael; Schmieder, Roland (2018)
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COPEPTIN LEVELS IN PATIENTS WITH TREATMENT RESISTANT HYPERTENSION BEFORE AND AFTER RENAL DENERVATION - Jumar, A.; Ott, Christian; Schmid, Axel; Kannenkeril, D.; Ditting, T.; Veelken, Roland; Uder, Michael; Schmieder, Roland (2017)
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Copeptin levels in patients with treatment resistant hypertension before and six months after renal denervation - Bosch, Agnes; Schmid, Axel; Ott, Christian; Kannenkeril, Dennis; Karg, Marina V.; Ditting, Tilmann; Veelken, Roland; Uder, Michael; Schmieder, Roland (American Journal of Hypertension, 2019)
BACKGROUND: Copeptin, the C-terminal peptide of pro-vasopressin, is released from the neurohypophysis and reflects the activity of the hormone arginine vasopressin in patients with hypertension. Elevated copeptin levels are associated with increased cardiovascular and all-cause mortality. The aim of this study is to compare copeptin levels in patients with treatment resistant hypertension (TRH) before and 6 months after renal denervation (RDN). METHODS: Copeptin was measured in 34 patients with TRH and 30 patients with primary hypertension stage 1 or 2 (HT). In addition, copeptin levels were measured in patients with TRH at 6 month follow-up visit after RDN. RDN was performed by an experienced interventionalist applying at least four ablations longitudinally and rotationally within the lengths of each renal artery to cover a full four quadrant ablation. RESULTS: In patients with TRH 24h ambulatory blood pressure (BP) decreased from 154±15/ 87±12 mmHg to 146±13/ 83±7.9 mmHg after RDN (systolic: p=0.001, diastolic: p=0.034). There was no significant change in copeptin levels in these 34 patients with TRH before versus six months after RDN (median 8.4 [interquartile range 3.6-14] vs 8.5 [4.5-13] pmol/l, p=0.334). Patients with TRH had higher copeptin levels (p=0.024) than patients with HT (24h ambulatory BP: 142±11/ 91±8.3 mmHg, copeptin: 4.2 [2.8-6.3] pmol/l). CONCLUSION: Patients with TRH showed 2 fold higher copeptin levels than patients with HT. RDN did not lead to any change of copeptin levels in patients with TRH 6 months after procedure despite significant fall in BP.
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Copeptin, Natriuretic Peptides, and Cardiovascular Outcomes in Patients With CKD: The German Chronic Kidney Disease (GCKD) Study - Schneider, Markus; Schmid, Matthias; Nadal, Jennifer; Krane, Vera; Saritas, Turgay; Busch, Martin; Schultheiss, Ulla T.; Meiselbach, Heike; Friedrich, Nele; Nauck, Matthias; Floege, Jürgen; Kronenberg, Florian; et al. (Kidney Medicine, 2023)
Rationale & Objective: Copeptin and Midrange pro-atrial natriuretic peptide (MR-pro-ANP) are associated with outcomes independently of N-terminal pro-brain natriuretic peptide (NT-pro-BNP) in patients with heart failure (HF). The value of these markers in patients with chronic kidney disease (CKD) has not been studied. Study Design: Prospective cohort study. Setting & Participants: A total of 4,417 patients enrolled in the German Chronic Kidney Disease (GCKD) study with an estimated glomerular filtration rate of 30-60 mL/min/1.73m2 or overt proteinuria (urinary albumin-creatinine ratio >300mg/g or equivalent). Exposures: Copeptin, MR-pro-ANP, and NT-pro-BNP levels were measured in baseline samples. Outcomes: Noncardiovascular death, cardiovascular (CV) death, major adverse CV event (MACE), and hospitalization for HF. Analytical Approach: HRs for associations of Copeptin, MR-pro-ANP, and NT-pro-BNP with outcomes were estimated using Cox regression analyses adjusted for established risk factors. Results: During a maximum follow-up of 6.5 years, 413 non-CV deaths, 179 CV deaths, 519 MACE, and 388 hospitalizations for HF were observed. In Cox regression analyses adjusted for established risk factors, each one of the 3 markers were associated with all the 4 outcomes, albeit the highest HRs were found for NT-pro-BNP. When models were extended to include all the 3 markers, NT-pro-BNP remained associated with all 4 outcomes. Conversely, from the 2 novel markers, associations remained only for Copeptin with non-CV death (HR, 1.62; 95% CI, 1.04-2.54 for highest vs lowest quintile) and with hospitalizations for HF (HR, 1.73; 95% CI, 1.08-2.75). Limitations: Single-point measurements of Copeptin, MR-pro-ANP, and NT-pro-BNP. Conclusions: In patients with moderately severe CKD, we confirm NT-pro-BNP to be strongly associated with all outcomes examined. As the main finding, the novel marker Copeptin demonstrated independent associations with non-CV death and hospitalizations for HF, and should therefore be evaluated further for risk assessment in CKD. Plain-Language Summary: A blood sample–based biomarker that indicates high cardiovascular risk in a patient with kidney disease would help to guide interventions and has the potential to improve outcomes. In 4,417 patients of the German Chronic Kidney Disease study, we assessed the relationship of Copeptin, pro-atrial natriuretic peptide, and N-terminal pro-brain natriuretic peptide (NT-pro-BNP) with important outcomes over a follow-up period of 6.5 years. NT-pro-BNP was strongly associated with all of the 4 outcomes, including death unrelated to cardiovascular disease, death because of cardiovascular disease, a major cardiovascular event, and hospitalization for heart failure. Copeptin was associated with death unrelated to cardiovascular disease and hospitalization for heart failure. NT-pro-BNP and Copeptin are, therefore, promising candidates for a blood sample–based strategy to identify patients with kidney disease at high cardiovascular risk.
CRIS-Team Scopus Importer:2023-10-27
Keywords: biomarkers; cardiac diseases; chronic kidney disease; Copeptin; heart failure; kidney diseases; MR-pro-ANP; NT-pro-BNP

Correction: Blood pressure control in chronic kidney disease: A cross-sectional analysis from the German Chronic Kidney Disease (GCKD) study - Schneider, Markus P.; Hilgers, Karl F.; Schmid, Matthias; Huebner, Silvia; Nadal, Jennifer; Seitz, David; Busch, Martin; Haller, Hermann; Koettgen, Anna; Kronenberg, Florian; Baid-Agrawal, Seema; Schlieper, Georg; et al. (PLoS ONE, 2018)
[This corrects the article DOI: 10.1371/journal.pone.0202604.].
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Correction to: Apolipoprotein A-IV concentrations and cancer in a large cohort of chronic kidney disease patients: results from the GCKD study (BMC Cancer, (2024), 24, 1, (320), 10.1186/s12885-024-12053-8) - Kollerits, Barbara; Gruber, Simon; Steinbrenner, Inga; Schwaiger, Johannes P.; Weissensteiner, Hansi; Schönherr, Sebastian; Forer, Lukas; Kotsis, Fruzsina; Schultheiss, Ulla T.; Meiselbach, Heike; Wanner, Christoph; Eckardt, Kai-Uwe; et al. (BMC Cancer, 2024)
Following publication of the original article [1], the author noticed an error in the affiliation of Inga Steinbrenner. Her affiliation should be 2, instead of affiliation 3. The correct affiliation for Inga Steinbrenner is: 2Institute of Genetic Epidemiology, Faculty of Medicine and Medical Center—University of Freiburg, Freiburg, Germany. The original article [1] has been corrected.
CRIS-Team Scopus Importer:2024-03-29

Correction to: Percutaneous Creation of a Central Iliac Arteriovenous Anastomosis for the Treatment of Arterial Hypertension - Bertog, Stefan C.; Sobotka, Nathan A.; Sobotka, Paul A.; Lobo, Melvin D.; Sievert, Kolja; Vaskelyte, Laura; Sievert, Horst; Schmieder, Roland (Current Hypertension Reports, 2018)
In the March 2018 issue of Current Hypertension Reports, the second author's name Nathan A. Sobotka was inadvertently left out of the byline. Also, the author names were changed from initials to spelled out. The corrected author list is given above. The original article has been corrected.
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Correction to: Rationale and design of two randomized sham‑controlled of catheter‑based renal denervation in subjects with uncontrolled hypertension in the absence (SPYRAL HTN‑OFF MED Pivotal) and presence (SPYRAL HTN‑ON MED Expansion) of antihypertensive medications: a novel approach using Bayesian design (Clinical Research in Cardiology, (2020), 109, 3, (289-302), 10.1007/s00392-020-01595-z) - Böhm, Michael; Townsend, Raymond R.; Kario, Kazuomi; Kandzari, David; Mahfoud, Felix; Weber, Michael A.; Schmieder, Roland; Tsioufis, Konstantinos; Hickey, Graeme L.; Fahy, Martin; DeBruin, Vanessa; Brar, Sandeep; et al. (Clinical Research in Cardiology, 2020)
The original version of this article unfortunately contained a mistake. The sentence within the section “Bayesian design and prespecified interim analyses” should read: Due to a Bayesian power prior approach being used, a non-standard parameterization for the ANCOVA model is used to allow for informative prior distributions to be placed separately on the RDN and control arm effects: (Formula presented.).
CRIS-Team Scopus Importer:2020-04-21

Correction to: Two adjacent phosphorylation sites in the C-terminus of the channel's α-subunit have opposing effects on epithelial sodium channel (ENaC) activity. - Diakov, Alexei; Nesterov, Viatcheslav; Dahlmann, Anke; Korbmacher, Christoph (Pflügers Archiv: European Journal of Physiology, 2022)
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Correlations Between Interleukin-11 Expression and Hypertensive Kidney Injury in a Rat Model of Renovascular Hypertension - Menendez-Castro, Carlos; Cordasic, Nada; Dambietz, Thomas; Veelken, Roland; Amann, Kerstin Ute; Hartner, Andrea; Hilgers, Karl Friedrich (American Journal of Hypertension, 2020)
BACKGROUND: Interleukin-11 (IL-11) is a pleiotropic cytokine of the interleukin-6 family. Recent studies revealed its crucial role in the development of cardiovascular fibrosis. In this study we examined IL-11 expression levels in the heart and the kidney exposed to high blood pressure in renovascular hypertensive rats and their correlations to fibrotic markers and kidney injury. METHODS: Two-kidney, one-clip renovascular hypertension (2K1C) was induced in rats. IL-11 expression was measured by real-time polymerase chain reaction in the left ventricle and the right kidney. The correlation of cardiac IL-11 expression with biomarkers of renal fibrosis was assessed. We further investigated IL-11 expression in 2K1C rats grouped into rats with malignant vs. nonmalignant hypertension (distinguishing criteria: weight loss, number of fibrinoid necrosis, and onion skin lesions). RESULTS: Thirty-five days after clipping, mean arterial pressure was significantly increased in 2K1C. Renal IL-11 expression was elevated in 2K1C. In the heart there was only a trend toward higher IL-11 expression in 2K1C. IL-11 in the kidney in 2K1C correlated with the expression of transforming growth factor (TGF)-β1/2, collagens, fibronectin, osteopontin, as well as tissue inhibitors of metalloprotease 1/2. There were also correlations of IL-11 with tissue collagen expansion, number of activated fibroblasts and serum creatinine, but no correlation with mean arterial pressure. Renal expression of IL-11 was highest in rats with malignant hypertension. CONCLUSIONS: Renal IL-11 expression of renovascular hypertensive rats is markedly increased and correlates with profibrotic markers and loss of function and might therefore serve as a biomarker for the severity of hypertensive nephrosclerosis.
CRIS-Team Scopus Importer:2020-04-14
Keywords: blood pressure; hypertension; interleukin-11 (IL-11); malignant hypertension; renal fibrosis; two-kidney one-clip renovascular hypertension (2K1C)

COST-EFFECTIVENESS ANALYSIS OF NEXT GENERATION RENAL DENERVATION THERAPY DEVICES: THRESHOLD ANALYSIS AND PROJECTIONS OF THE SPYRAL HTN-ON MED TRIAL FOR GERMANY - Pietzsch, J. B.; Geisler, B. P.; Schmieder, Roland (VALUE IN HEALTH, 2018)
CRIS-Team WoS Importer:2019-03-15

Cost Effectiveness of Endovascular Ultrasound Renal Denervation in Patients with Resistant Hypertension - Taylor, Rod S.; Bentley, Anthony; Metcalfe, Kaylie; Lobo, Melvin D.; Kirtane, Ajay J.; Azizi, Michel; Clark, Christopher; Murphy, Kieran; Boer, Jennifer H.; van Keep, Marjolijn; Ta, An Thu; Barman, Neil C.; et al. (2024)
Background: Resistant hypertension (rHTN) is defined as blood pressure (BP) of ≥ 140/90 mmHg despite treatment with at least three antihypertensive medications, including a diuretic. Endovascular ultrasound renal denervation (uRDN) aims to control BP alongside conventional BP treatment with antihypertensive medication. This analysis assesses the cost effectiveness of the addition of the Paradise uRDN System compared with standard of care alone in patients with rHTN from the perspective of the United Kingdom (UK) health care system. Methods: Using RADIANCE-HTN TRIO trial data, we developed a state-transition model. Baseline risk was calculated using Framingham and Prospective Cardiovascular Münster (PROCAM) risk equations to estimate the long-term cardiovascular risks in patients treated with the Paradise uRDN System, based on the observed systolic BP (SBP) reduction following uRDN. Relative risks sourced from a meta-analysis of randomised controlled trials were then used to project cardiovascular events in patients with baseline SBP (‘control’ patients); utility and mortality inputs and costs were derived from UK data. Costs and outcomes were discounted at 3.5% per annum. Modelled outcomes were validated against trial meta-analyses and the QRISK3 algorithm and real-world evidence of RDN effectiveness. One-way and probabilistic sensitivity analyses were conducted to assess the uncertainty surrounding the model inputs and sensitivity of the model results to changes in parameter inputs. Results were reported as incremental cost-effectiveness ratios (ICERs). Results: A mean reduction in office SBP of 8.5 mmHg with uRDN resulted in an average improvement in both absolute life-years (LYs) and quality-adjusted life-years (QALYs) gained compared with standard of care alone (0.73 LYs and 0.67 QALYs). The overall base-case ICER with uRDN was estimated at £5600 (€6500) per QALY gained (95% confidence interval £5463–£5739 [€6341–€6661]); modelling demonstrated > 99% probability that the ICER is below the £20,000–£30,000 (€23,214–€34,821) per QALYs gained willingness-to-pay threshold in the UK. Results were consistent across sensitivity analyses and validation checks. Conclusions: Endovascular ultrasound RDN with the Paradise system offers patients with rHTN, clinicians, and healthcare systems a cost-effective treatment option alongside antihypertensive medication.
CRIS-Team Scopus Importer:2024-02-09

Cost of poor adherence to anti-hypertensive therapy in five European countries - Mennini, F. S.; Marcellusi, Andrea; Von Der Schulenburg, J. M. Graf; Gray, A.; Levy, P.; Sciattella, P.; Soro, M.; Staffiero, G.; Zeidler, J.; Maggioni, A.; Schmieder, Roland (European Journal of Health Economics, 2015)
The financial burden for EU health systems associated with cardiovascular disease (CV) has been estimated to be nearly <euro>110 billion in 2006, corresponding to 10 % of total healthcare expenditure across EU or a mean <euro>223 annual cost per capita. The main purpose of this study is to estimate the costs related to hypertension and the economic impact of increasing adherence to anti-hypertensive therapy in five European countries (Italy, Germany, France, Spain and England). A probabilistic prevalence-based decision tree model was developed to estimate the direct costs of CV related to hypertension (CV defined as: stroke, heart attack, heart failure) in five European countries. Our model considered adherence to hypertension treatment as a main driver of blood pressure (BP) control (BP < 140/90 mmHg). Relative risk of CV, based on controlled or uncontrolled BP group, was estimated from the Framingham Heart Study and national review data. Prevalence and cost data were estimated from national literature reviews. A national payer (NP) perspective for 10 years was considered. Probabilistic sensitivity analysis was performed in order to evaluate uncertainty around the results (given as 95 % confidence intervals). The model estimated a total of 8.6 million (1.4 in Italy, 3.3 in Germany, 1.2 in Spain, 1.8 in France and 0.9 in England) CV events related to hypertension over the 10-year time horizon. Increasing the adherence rate to anti-hypertensive therapy to 70 % (baseline value is different for each country) would lead to 82,235 fewer CV events (24,058 in Italy, 7,870 in Germany, 18,870 in Spain, 24,855 in France and 6,553 in England). From the NP perspective, the direct cost associated with hypertension was estimated to be <euro>51.3 billion (8.1 in Italy, 17.1 in Germany, 12.2 in Spain, 8.8 in France and 5.0 in England). Increasing adherence to anti-hypertensive therapy to 70 % would save a total of <euro>332 million (CI 95 %: <euro>319-346 million) from the NPs perspective. This study is the first attempt to estimate the economic impact of non-adherence amongst patients with diagnosed hypertension in Europe, using data from five European countries (Italy, France, Germany, Spain and England).</euro></euro></euro></euro></euro>
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C-Reactive Protein and Risk of ESRD: Results From the Trial to Reduce Cardiovascular Events With Aranesp Therapy (TREAT) - Mc Causland, Finnian R.; Claggett, Brian; Burdmann, Emmanuel A.; Eckardt, Kai-Uwe; Kewalramani, Reshma; Levey, Andrew S.; Mcmurray, John J. V.; Parfrey, Patrick; Remuzzi, Giuseppe; Singh, Ajay K.; Solomon, Scott D.; Toto, Robert D.; et al. (American Journal of Kidney Diseases, 2016)
To better understand a potential association of elevated C-reactive protein (CRP) level with progression of chronic kidney disease (CKD), we examined the relationship of CRP level with the development of end-stage renal disease (ESRD) in the Trial to Reduce Cardiovascular Events With Aranesp Therapy (TREAT).Post hoc analysis of a randomized controlled trial.4,038 patients with type 2 diabetes, CKD, and anemia in TREAT.Baseline serum CRP concentrations.The primary outcome was development of ESRD; secondary outcomes included doubling of serum creatinine level, a composite of ESRD/serum creatinine doubling, and a composite of death or ESRD.We fit unadjusted and adjusted Cox regression models to test the association of baseline CRP level with time to the development of the outcomes of interest.Mean age of participants was 67 years, 43% were men, and 64% were white. Approximately half (48%) the patients had CRP levels > 3.0mg/L; 668 patients developed ESRD, and 1,270 developed the composite outcome of death or ESRD. Compared with patients with baseline CRP levels <= 3.0mg/L, those with moderately/markedly elevated CRP levels (>=6.9mg/L; 24% of patients) had a higher adjusted risk for ESRD (HR, 1.32; 95% CI, 1.07-1.63) and the composite outcome of death or ESRD (HR, 1.41; 95% CI, 1.21-1.64). Although nonsignificant, similar trends were noted in competing-risk models.Results may not be generalizable to nondiabetic CKD or diabetic CKD in the absence of anemia.Elevated baseline CRP levels are common in type 2 diabetic patients with anemia and CKD and are associated with the future development of ESRD and the composite of death or ESRD.
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Criteria of the German Cardiac Society (DGK), the German Hypertension League DHL (R)/German Society for Hypertension and Prevention and the German Society for Nephrology (DGfN) on certification of renal denervation centers (RDZ)-Update - Mahfoud, Felix; Galle, Jan; Schunkert, Heribert; Schmieder, Roland; Rump, Lars C.; Limbourg, Florian P.; Van Der Giet, Markus; Elsaesser, Albrecht; Kintscher, Ulrich; Boehm, Michael; Weil, Joachim (Der Kardiologe, 2021)
Arterial hypertension is highly prevalent and remains the most common modifiable risk factor for cardiovascular morbidity and mortality worldwide. In the development and progression of uncontrolled hypertension an increased sympathetic nerve activity has been identified as a main contributor. Catheter-based renal denervation was developed to selectively modulate renal sympathetic activity. Recently, several randomized sham-controlled trials have proven the efficacy and safety of renal denervation in patients with uncontrolled hypertension. Hence, one may expect renal denervation to be used as part of clinical practice some time soon. This paper aims to define national criteria for centers who wish to perform renal denervation procedures and to optimize care pathways for patients with uncontrolled hypertension. Centers may apply for certification once they fulfill all criteria.
CRIS-Team WoS Importer:2021-07-30

Current Conservative Treatment and Management Strategies of Skeletal Muscle Injuries - Hotfiel, Thilo; Carl, H-D.; Swoboda, Bernd; Heinrich, Marc Christopher; Heiß, Rafael; Grim, C.; Engelhardt, M. (Zeitschrift für Orthopädie und Unfallchirurgie, 2016)
Muscle injuries frequently occur during sport and are one of the commonest injuries. The diagnosis and treatment of muscle injuries impose high demands on medical treatment, in order to ensure successful regeneration and a rapid return to sport. Most of the injuries can be treated conservatively, as skeletal muscles have a high endogenous capacity for repair and regeneration. Conservative treatment includes initial on-field therapy. This is known as the "RICE" principle and is common and recommended for initial treatment for most sports injuries. The primary therapy target is to reduce pain, swelling and bleeding and thus to limit the initial inflammatory process and prevent further damage. During the first days after injury, brief immobilization helps to reduce the re-injury rate and accelerates the formation of granulation tissue. There are many possible additional treatments, including intramuscular injections, manipulation of the sacroiliac joint or rehabilitation programs, including stretching and strengthening. If the acute treatment phase is complete after 3 to 5 days, more active treatment, including trunk stabilisation, stretching and strengthening, can be started gradually. Despite their high prevalence, there have only been a few studies on the treatment and management of these injuries. The aim of this manuscript is to review the literature on the classification, pathobiology and treatment strategies for muscle injuries.
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Curriculum Internistische Intensivmedizin - John, S.; Riessen, R.; Karagiannidis, C.; Janssens, U.; Busch, H. ‑.J.; Kochanek, M.; Michels, G.; Hermes, C.; Buerke, M.; Kluge, S.; Baumgärtel, M.; Braune, S.; et al. (Medizinische Klinik - Intensivmedizin und Notfallmedizin, 2021)
Medical intensive care medicine treats patients with severe, potentially life-threatening diseases covering the complete spectrum of internal medicine. The qualification in medical intensive care medicine requires a broad spectrum of knowledge and skills in medical intensive care medicine, but also in the general field of internal medicine. Both sides of the coin must be taken into account, the treatment with life-sustaining strategies of the acute illness of the patient and also the treatment of patient’s underlying chronic diseases. The indispensable foundation of medical intensive care medicine as described in this curriculum includes basic knowledge and skills (level of competence I–III) as well as of behavior and attitudes. This curriculum is primarily dedicated to the internist in advanced training in medical intensive care medicine. However, this curriculum also intends to reach trainers in intensive care medicine and also the German physician chambers with their examiners, showing them which knowledge, skills as well as behavior and attitudes should be taught to trainees according to the education criteria of the German Society of Medical Intensive Care and Emergency Medicine (DGIIN).
CRIS-Team Scopus Importer:2021-01-22
Keywords: Advanced education in internal/medical intensive care medicine; Curriculum; German Medical Association; German Society of Medical Intensive Care and Emergency Medicine (DGIIN); Internal/medical intensive care medicine

CXCL13 elevation in early kidney allograft rejection in mice and men - Greite, R.; Kreimann, K.; Jang, M. S.; Schiffer, L.; Vijayan, V.; Braesen, J. H.; Rong, S.; Schiffer, Mario; Vondran, F. W. R.; Haller, H.; Immenschuh, S.; Gueler, F. (EUROPEAN JOURNAL OF IMMUNOLOGY, 2019)
CRIS-Team WoS Importer:2019-10-08

Cyst growth in ADPKD is prevented by pharmacological and genetic inhibition of TMEM16A in vivo - Cabrita, Ines; Kraus, Andre; Scholz, Julia Katharina; Skoczynski, Kathrin; Schreiber, Rainer; Kunzelmann, Karl; Buchholz, Björn (Nature Communications, 2020)
In autosomal dominant polycystic kidney disease (ADPKD) multiple bilateral renal cysts gradually enlarge, leading to a decline in renal function. Transepithelial chloride secretion through cystic fibrosis transmembrane conductance regulator (CFTR) and TMEM16A (anoctamin 1) are known to drive cyst enlargement. Here we demonstrate that loss of Pkd1 increased expression of TMEM16A and CFTR and Cl− secretion in murine kidneys, with TMEM16A essentially contributing to cyst growth. Upregulated TMEM16A enhanced intracellular Ca2+ signaling and proliferation of Pkd1-deficient renal epithelial cells. In contrast, increase in Ca2+ signaling, cell proliferation and CFTR expression was not observed in Pkd1/Tmem16a double knockout mice. Knockout of Tmem16a or inhibition of TMEM16A in vivo by the FDA-approved drugs niclosamide and benzbromarone, as well as the TMEM16A-specific inhibitor Ani9 largely reduced cyst enlargement and abnormal cyst cell proliferation. The present data establish a therapeutic concept for the treatment of ADPKD.
CRIS-Team Scopus Importer:2020-09-04

CytoResc - "CytoSorb" Rescue for critically ill patients undergoing the COVID-19 Cytokine Storm: A structured summary of a study protocol for a randomized controlled trial - Stockmann, Helena; Keller, Theresa; Büttner, Stefan; Jörres, Achim; Kindgen-Milles, Detlef; Kunz, Julius Valentin; Leebmann, Josef; Spies, Claudia; Träger, Karl; Treskatsch, Sascha; Uhrig, Alexander; Willam, Carsten; et al. (Trials, 2020)
OBJECTIVES: Approximately 8 - 10 % of COVID-19 patients present with a serious clinical course and need for hospitalization, 8% of hospitalized patients need ICU-treatment. Currently, no causal therapy is available and treatment is purely supportive. The main reason for death in critically ill patients is acute respiratory failure. However, in a number of patients a severe hyperinflammatory response with excessively elevated proinflammatory cytokines causes vasoplegic shock resistant to vasopressor therapy. A new polystyrene-based hemoadsorber (CytoSorb®, Cytosorbents Inc., New Jersey, USA) has been shown to adsorb effectively cytokines and other middle molecular weight toxins this way reducing their blood concentrations. This has been routinely used in clinical practice in the EU for other conditions where a cytokine storm occurs and an observational study has just been completed on COVID-19 patients. We hypothesized that the extracorporeal elimination of cytokines in critically ill COVID-19 patients with suspected hyperinflammation and shock may stabilize hemodynamics and improve outcome. The primary endpoint is time until resolution of vasoplegic shock, which is a well implemented, clinically relevant endpoint in critical care studies. TRIAL DESIGN: Phase IIb, multicenter, prospective, open-label, randomized, 1:1 parallel group pilot study comparing the additional use of "CytoSorb" to standard of care without "CytoSorb". PARTICIPANTS: Patients are recruited from the Intensive Care Units (ICUs) of 7 participating centers in Germany (approximately 10 ICUs). All patients aged 18- 80 with positive polymerase chain reaction (PCR) test for SARS-CoV-2, a C-reactive protein (CRP) ≥ 100 mg/l, a Procalcitonin (PCT) < 2 ng/l, and suspected cytokine storm defined via a vasoplegic shock (Norepinephrine > 0.2 μg/min/kg to achieve a Mean Arterial Pressure ≥ 65mmHg). Patients are included irrespective of indication for renal replacement therapy. Suspected or proven bacterial cause for vasoplegic shock is a contraindication. INTERVENTION AND COMPARATOR: Within 24 hours after meeting the inclusion criteria patients will be randomized to receive either standard of care or standard of care and additional "CytoSorb" therapy via a shaldon catheter for 3-7 days. Filter exchange is done every 24 hours. If patients receive antibiotics, an additional dose of antibiotics is administered after each change of "CytoSorb" filter in order to prevent underdosing due to "CytoSorb" treatment. MAIN OUTCOMES: Primary outcome is time to resolution of vasoplegic shock (defined as no need for vasopressors for at least 8 hours in order to sustain a MAP ≥ 65mmHg) in days. Secondary outcomes are 7 day mortality after fulfilling the inclusion criteria, mortality until hospital discharge, Interleukin-6 (IL-6) measurement on day 1 and 3, need for mechanical ventilation, duration of mechanical ventilation, duration of ICU-stay, catecholamine dose on day 1/2/3 after start of "CytoSorb" and acute kidney injury. RANDOMIZATION: An electronic randomization will be performed using the study software secuTrial® administered by the Clinical Study Center (CSC) of the Charité - Universitätsmedizin Berlin, Germany. Randomization is done in blocks by 4 stratified by including center. BLINDING (MASKING): The trial will be non-blinded for the clinicians and patients. The statistician will receive a blinded data set, so that all analyses will be conducted blinded. NUMBERS TO BE RANDOMIZED (SAMPLE SIZE): As this is a pilot study with the goal to examine the feasibility of the study design as well as the intervention effect, no formal sample size calculation was conducted. A total number of approximately 80-100 patients is planned (40-50 patients per group). Safety assessment is done after the inclusion of each 10 patients per randomization group. TRIAL STATUS: Please see the study protocol version from April 24 2020. Recruitment of patients is still pending. TRIAL REGISTRATION: The study was registered on April 27 2020 in the German Registry of Clinical Trials (DRKS) under the number DRKS00021447. FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.
CRIS-Team Scopus Importer:2020-07-10
Keywords: COVID-19; cytokine storm; extracorporeal cytokine elimination; protocol; Randomized controlled trial; vasoplegic shock

Dapagliflozin in Patients with Chronic Kidney Disease - Heerspink, Hiddo J. L.; Stefansson, Bergur V.; Correa-Rotter, Ricardo; Chertow, Glenn M.; Greene, Tom; Hou, Fan-Fan; Mann, Johannes; Mcmurray, John J. V.; Lindberg, Magnus; Rossing, Peter; Sjostrom, C. David; Toto, Roberto D.; et al. (New England Journal of Medicine, 2020)
BACKGROUND
CRIS-Team WoS Importer:2020-11-06

Darbepoetin alpha reduces oxidative stress and chronic inflammation in atherosclerotic lesions of apo e deficient mice in experimental renal failure - Arend, Nicole; Hilgers, Karl Friedrich; Campean, Valentina; Karpe, Britta; Cordasic, Nada; Klanke, Bernd; Amann, Kerstin Ute (PLoS ONE, 2014)
Cardiovascular morbidity and mortality is very important in patients with chronic renal failure. This occurs even in mild impairment of renal function and may be related to oxidative stress and chronic inflammation. The nephrectomized apo E knockout mouse is an accepted model for evaluating atherosclerosis in renal dysfunction. Erythropoietin derivates showed anti-oxidative and anti-inflammatory effects. Therefore, this study evaluates the effects of Darbepoetin on markers of oxidative stress and chronic inflammation in atherosclerotic lesions in apo E knockout mice with renal dysfunction.Apo E knockout mice underwent unilateral (Unx, n = 20) or subtotal (Snx, n = 26) nephrectomy or sham operation (Sham, n = 16). Mice of each group were either treated with Darbepoetin or saline solution, a part of Snx mice received a tenfold higher dose of Darbepoetin. The aortic plaques were measured and morphologically characterized. Additional immunhistochemical analyses were performed on tissue samples taken from the heart and the aorta.Both Unx and Snx mice showed increased expression of markers of oxidative stress and chronic inflammation. While aortic plaque size was not different, Snx mice showed advanced plaque stages when compared to Unx mice. Darbepoetin treatment elevated hematocrit and lowered Nitrotyrosin as one marker of oxidative stress, inflammation in heart and aorta, plaque stage and in the high dose even plaque cholesterol content. In contrast, there was no influence of Darbepoetin on aortic plaque size; high dose Darbepoetin treatment resulted in elevated renal serum parameters.Darbepoetin showed some protective cardiovascular effects irrespective of renal function, i.e. it improved plaque structure and reduced some signs of oxidative stress and chronic inflammation without affecting plaque size. Nevertheless, the dose dependent adverse effects must be considered as high Darbepoetin treatment elevated serum urea. Elevation of hematocrit might be a favorable effect in anemic Snx animals but a thrombogenic risk in Sham animals.
EVALuna2:3673

Daytime systolic ambulatory blood pressure with a two-step switch from candesartan to olmesartan monotherapy and the fixed-dose combination of olmesartan/amlodipine in patients with uncontrolled essential hypertension (SEVICONTROL-2) - Bramlage, Peter; Zemmrich, Claudia; Gansz, Andrea; Sturm, Claus-Dieter; Fimmers, Rolf; Nadal, Jennifer; Schmieder, Roland; Schrader, Joachim; Lueders, Stephan (Journal of Clinical Hypertension, 2014)
The objective of this study was to investigate the efficacy of the fixed-dose combination olmesartan/amlodipine 40/10 mg in patients with moderate essential hypertension not controlled on candesartan 32 mg. This was a prospective, single-arm, phase IV study. The primary endpoint was the change in mean daytime systolic blood pressure (BP). A total of 77 of 89 screened patients started candesartan 32 mg, 62 olmesartan 40 mg, and 57 olmesartan 40 mg/amlodipine 10 mg. Mean daytime systolic BP was reduced by 9.8±15.2 mm Hg (P<.001) vs candesartan monotherapy. Office BP reduction was 9.2±18.8/5.0±8.9 mm Hg (P<0.001). Treatment goals (<140/90 mm Hg for office and <135/85 mm Hg for ambulatory BP) were achieved in 58.2% and 78.4% of patients, respectively. There was one drug-related adverse event (edema) and no serious adverse events. Patients of Caucasian ethnicity with moderate essential hypertension uncontrolled on candesartan experienced a further drop in BP using olmesartan and amlodipine.
EVALuna2:3682

Deceased Donor Kidney Transplantation in the Eurotransplant Senior Program (ESP): A Single-Center Experience from 2008 to 2013 - Jacobi, Johannes; Beckmann, Sophie; Heller, Katharina; Hilgers, Karl Friedrich; Apel, Hendrik; Spriewald, Bernd; Eckardt, Kai-Uwe; Amann, Kerstin Ute (Annals of Transplantation, 2016)
BACKGROUND The aim of this study was to evaluate the outcome after transplantation of deceased allografts in donor/recipient pairs aged >=65 years enrolled in the Eurotransplant Senior Program (ESP). MATERIAL AND METHODS In this retrospective cohort study we evaluated data from 89 patients transplanted under the ESP protocol from 2008 to 2013. Outcome parameters included graft and patient survival, rate of biopsy-proven acute rejections (BPAR), peri- and post-operative complications, tumor development, development of donor-specific antibodies (DSA), and the prognostic role of preimplantation biopsies. RESULTS One-year patient and allograft survival rates were 92.1% and 84.3%, respectively. During follow-up, 23 (26%) patients died; the major cause of death was sepsis, followed by cardiovascular events and malignancies. BPAR episodes were frequent within the first year ( 33%) and overall were less common in patients treated with tacrolimus. Post-transplant malignancies were seen in 15 (17%) patients. During follow-up, 16 (18%) patients developed DSA; patients with delayed graft function (DGF) were more likely to develop DSA (p=0.029). A higher preimplantation biopsy score was associated with DGF but did not predict later graft outcome. CONCLUSIONS The results highlight increased risks in ESP transplant candidates and the importance of careful surveillance of this patient group.
EVALuna2:3834

Delayed graft function is associated with an increased rate of renal allograft rejection: A retrospective single center analysis - Weber, Susanne; Dienemann, Thomas; Jacobi, Johannes; Weidemann, Alexander; Eckardt, Kai-Uwe (PLoS ONE, 2018)
INTRODUCTION: The association of delayed graft function (DGF) and biopsy proven acute rejection (BPAR) of renal allografts is controversial. Borderline rejections comprise a major portion of biopsy results but the significance of such histologic changes is debated. The present study explores the impact of DGF on BPAR with a special emphasis on discriminating the effects of borderline rejection. METHODS: Single center analysis of 417 deceased donor kidney recipients (age>18; transplantation date 1/2008-2/2015). Patients with primary non-function were excluded. DGF was defined as the need for dialysis within the first week after transplantation. Acute rejection was defined according to Banff criteria. Cox proportional hazards models were used to examine the relationship of DGF with BPAR within the first year. RESULTS: No graft loss was observed during the first year after transplantation. DGF significantly associated with BPAR in the first year, irrespective of whether borderline rejections were included (HR 1.71, 95%CI 1.16,2.53) or excluded (HR 1.79, 95%CI 1.13,2.84). CONCLUSION: DGF is significantly associated with rejection-with or without borderline changes-within the first year.
EVALuna2:34513

Deletion of Cdh16 Ksp-cadherin leads to a developmental delay in the ability to maximally concentrate urine in mouse - Thomson, R. B.; Dynia, D. W.; Burlein, S.; Thomson, B. R.; Booth, C. J.; Knauf, F.; Wang, T.; Aronson, P. S. (American Journal of Physiology-Renal Physiology, 2021)
Ksp-cadherin (cadherin-16) is an atypical member of the cadherin superfamily of cell adhesion molecules that is ubiquitously expressed on the basolateral membrane of epithelial cells lining the nephron and the collecting system of the mammalian kidney. The principal aim of the present study was to determine if Ksp-cadherin played a critical role in the development and maintenance of the adult mammalian kidney by generating and evaluating a mouse line deficient in Ksp-cadherin. Ksp-null mutant animals were viable and fertile, and kidneys from both neonates and adults showed no evidence of structural abnormalities. Immunolocalization and Western blot analyses of Na+-K+-ATPase and E-cadherin indicated that Ksp-cadherin is not essential for either the genesis or maintenance of the polarized tubular epithelial phenotype. Moreover, E-cadherin expression was not altered to compensate for Ksp-cadherin loss. Plasma electrolytes, total CO2, blood urea nitrogen, and creatinine levels were also unaffected by Ksp-cadherin deficiency. However, a subtle but significant developmental delay in the ability to maximally concentrate urine was detected in Ksp-null mice. Expression analysis of the principal proteins involved in the generation of the corticomedullary osmotic gradient and the resultant movement of water identified misexpression of aquaporin-2 in the inner medullary collecting duct as the possible cause for the inability of young adult Ksp-cadherin-deficient animals to maximally concentrate their urine. In conclusion, Ksp-cadherin is not required for normal kidney development, but its absence leads to a developmental delay in maximal urinary concentrating ability.NEW & NOTEWORTHY Ksp-cadherin (cadherin-16) is an atypical member of the cadherin superfamily of cell adhesion molecules that is ubiquitously expressed on the basolateral membrane of epithelial cells lining the nephron and the collecting system. Using knockout mice, we found that Ksp-cadherin is in fact not required for kidney development despite its high and specific expression along the nephron. However, its absence leads to a developmental delay in maximal urinary concentrating ability.
CRIS-Team Scopus Importer:2021-06-18
Keywords: cadherin; kidney development; urinary concentrating ability

Dependency of flow-mediated vasodilatation from basal nitric oxide activity - Kannenkeril, Dennis; Bosch, Agnes; Kolwelter, Julie; Jung, Susanne; Striepe, Kristina; Ott, Christian; Delles, Christian; Schmieder, Roland (Clinical Physiology and Functional Imaging, 2021)
Background: Flow-mediated vasodilatation (FMD) has become one of the most widely assessed parameters to analyse endothelial and vascular function in cardiovascular medicine. The degree of contribution of nitric oxide (NO) to FMD is inconclusive and varies widely depending on the device used. In this study, we used a semi-automatic ultrasound device to analyse to what extent basal NO activity contributes to FMD of the brachial artery. Methods: FMD was assessed with the UNEX EF device in a cross-over single blinded randomized study at baseline and then during infusion of either a NO-synthase-inhibitor (NG-monomethyl-L-arginine (L-NMMA)) or saline. The analysis was repeated after 1 week with the alternative infusion of L-NMMA or saline. All measurements were analysed both automatically and by a technician manually. Results: In total, 25 healthy men subjects completed the study. Diastolic blood pressure and heart rate significantly changed during infusion of L-NMMA. Infusion of L-NMMA reduced FMD significantly (−37%, p = 0.002). Saline solution had no effect on FMD (+14%, p = 0.392). Change in FMD was significantly different between the groups (ΔFMDL-NMMA vs. ΔFMDsaline, p = 0.032). There was a statistically significant correlation between automatically analysed results and those obtained by an experienced technician (FMDsaline: r = 0.822, p < 0.001; FMDL-NMMA: r = 0.645, p = 0.007). Conclusion: The influence of NO on FMD is approximately 40% if assessed using the UNEX EF. Prior to use FMD as a marker of endothelial dysfunction, we should explore different methods including various duration of forearm ischaemia to increase NO dependency of FMD.
CRIS-Team Scopus Importer:2021-04-02
Keywords: basal nitric oxide activity; flow-mediated vasodilatation; UNEX EF

Depression, Anxiety, Resilience and Coping Pre and Post Kidney Transplantation - Initial Findings from the Psychiatric Impairments in Kidney Transplantation (PI-KT)-Study - Mueller, Helge H.; Englbrecht, Matthias; Wiesener, Michael S.; Titze, Stephanie; Heller, Katharina; Groemer, Teja W.; Schett, Georg; Eckardt, Kai-Uwe; Kornhuber, Johannes; Maler, Juan Manuel (PLoS ONE, 2015)
Depression/anxiety, impaired Health-Related Quality of Life (HRQoL) and coping and resilience structures, are associated with increased mortality/poor outcome in chronic kidney disease (CKD) patients before (CKD/pre-KT) and after kidney (CKD-T) transplantation. Less is known about prevalence rates of psychiatric symptoms and impaired HRQoL of non-transplanted compared with transplanted patients.In a cross-sectional study comparing 101 CKD/pre-KT patients with 151 cadaveric-transplanted (CKD-T) patients, we examined prevalence of depression/anxiety (HADS questionnaire) and coping, resilience and HRQoL (SF-12, Resilience-Scale and FKV-questionnaire).The prevalence of both depressive and anxiety symptoms was not significantly different between different pre-/and CKD-T patient groups. In CKD-T no significant relations of coping strategies with kidney function were identified. Furthermore, the Resilience Scales for acceptance and competence did not suggest any differences between the CKD/pre-KT and CKD-T subgroup. In the CKD/pre-KT patients, significant correlations were identified between the acceptance subscale and partnership, as well as between the competence subscale and older age/partnership.Both the CKD/pre-KT and CKD-T patients exhibited notable impairments in the HRQoL which which showed a comparable pattern of results. KT itself does not appear to be the main risk factor for the development of mental impairments.
EVALuna2:3811

Deselection of base-learners for statistical boosting-with an application to distributional regression - Stroemer, Annika; Staerk, Christian; Klein, Nadja; Weinhold, Leonie; Titze, Stephanie; Mayr, Andreas (Statistical Methods in Medical Research, 2021)
We present a new procedure for enhanced variable selection for component-wise gradient boosting. Statistical boosting is a computational approach that emerged from machine learning, which allows to fit regression models in the presence of high-dimensional data. Furthermore, the algorithm can lead to data-driven variable selection. In practice, however, the final models typically tend to include too many variables in some situations. This occurs particularly for low-dimensional data (p < n), where we observe a slow overfitting behavior of boosting. As a result, more variables get included into the final model without altering the prediction accuracy. Many of these false positives are incorporated with a small coefficient and therefore have a small impact, but lead to a larger model. We try to overcome this issue by giving the algorithm the chance to deselect base-learners with minor importance. We analyze the impact of the new approach on variable selection and prediction performance in comparison to alternative methods including boosting with earlier stopping as well as twin boosting. We illustrate our approach with data of an ongoing cohort study for chronic kidney disease patients, where the most influential predictors for the health-related quality of life measure are selected in a distributional regression approach based on beta regression.
CRIS-Team WoS Importer:2021-12-24

Destruction of a distal hypoxia response element abolishes trans-activation of the PAG1 gene mediated by HIF-independent chromatin looping - Schoerg, Alexandra; Santambrogio, Sara; Platt, James L.; Schoedel, Johannes; Lindenmeyer, Maja T.; Cohen, Clemens D.; Schroedter, Katrin; Mole, David R.; Wenger, Roland H.; Hoogewijs, David (Nucleic Acids Research, 2015)
A crucial step in the cellular adaptation to oxygen deficiency is the binding of hypoxia-inducible factors (HIFs) to hypoxia response elements (HREs) of oxygen-regulated genes. Genome-wide HIF-1?/2?/? DNA-binding studies revealed that the majority of HREs reside distant to the promoter regions, but the function of these distal HREs has only been marginally studied in the genomic context. We used chromatin immunoprecipitation (ChIP), gene editing (TALEN) and chromosome conformation capture (3C) to localize and functionally characterize a 82 kb upstream HRE that solely drives oxygen-regulated expression of the newly identified HIF target gene PAG1. PAG1, a transmembrane adaptor protein involved in Src signalling, was hypoxically induced in various cell lines and mouse tissues. ChIP and reporter gene assays demonstrated that the -82 kb HRE regulates PAG1, but not an equally distant gene further upstream, by direct interaction with HIF. Ablation of the consensus HRE motif abolished the hypoxic induction of PAG1 but not general oxygen signalling. 3C assays revealed that the -82 kb HRE physically associates with the PAG1 promoter region, independent of HIF-DNA interaction. These results demonstrate a constitutive interaction between the -82 kb HRE and the PAG1 promoter, suggesting a physiologically important rapid response to hypoxia.
EVALuna2:3885

DETAILED ANALYSIS OF VASCULAR STIFFNESS IN PATIENTS WITH CHRONIC HEART FAILURE - Pietschner, Robert; Kolwelter, Julie; Bosch, Agnes; Striepe, Kristina; Kannenkeril, Dennis; Ott, Christan; Schiffer, Mario; Achenbach, Stephan; Schmieder, Roland (JOURNAL OF HYPERTENSION, 2022)
CRIS-Team WoS Importer:2022-07-29

DETAILED ANALYSIS OF VASCULAR STIFFNESS IN PATIENTS WITH CHRONIC HEART FAILURE - Pietschner, Robert; Kolwelter, Julie; Bosch, Agnes; Striepe, Kristina; Kannenkeril, Dennis; Ott, Christan; Schiffer, Mario; Achenbach, Stephan; Schmieder, Roland (Journal of Hypertension, 2022)
OBJECTIVE: Risk factors for chronic heart failure (CHF) lead as well to vascular stiffness of the large arteries, increasing thereby the afterload imposed on the left ventricle and deteriorating the clinical condition of CHF. The aim of this project was twofold: to compare vascular stiffness of patients with CHF (CHF+) to those without CHF (CHF-) and to analyse whether vascular stiffness is related to the severity of CHF. DESIGN AND METHOD: In this cross-sectional project a total of 223 patients were included (CHF+: n = 105, CHF-: n = 118). Patients in an euvolaemic state with a reduced left ventricular ejection fraction (LVEF) were included in the CHF+ group. The measurement of the pulse wave velocity (PWV), the most accepted vascular stiffness parameter, and the recording of the arterial pulse wave were performed using the SphygmoCor TM XCEL System under resting conditions. Under ambulatory conditions, blood pressure (BP) and vascular stiffness parameters were assessed by a validated device (Mobil-O-Graph, I.E.M.) over 24 hours. Additionally, blood and spot urine samples were used to measure laboratory markers, in particular NT-pro-BNP. RESULTS: Vascular stiffness parameters between the CHF+ and the CHF- group differed for resting central SBP (CHF+: 116.66 ± 15.18 mmHg, CHF-: 122.83 ± 15.87 mmHg, p = 0.004) and central augmentation index (CHF+: 21.24 ± 11.76 %, CHF-: 13.69 ± 11.49 %, p = <0.001) as well as for ambulatory central SBP (CHF+: 114.46 ± 15.35 mmHg, CHF-: 120.69 ± 13.97 mmHg, p = 0.007) and PWV (CHF+: 9.39 ± 1.56 m/s, CHF-: 8.19 ± 1.65 m/s, p = <0.001). In patients with CHF, greater levels of NT-pro-BNP were related to a higher central SBP (r = 0.292, p = 0.005), higher PWV (r = 0.340, p = <0.001) and a trend to higher central PP (r = 0.198, p = 0.058), after full adjustment for CHF risk factors and gender. In accordance, higher levels of NT-pro-BNP were related to a higher ambulatory peripheral PP (r = 0.322, p = 0.002) and total peripheral resistance (r = 0.227, p = 0.041). CONCLUSIONS: In patients with stable CHF we observed a worse vascular stiffness and function, compared to patients with no CHF. The extent of vascular stiffness and dysfunction was related to the severity of CHF.
CRIS-Team Scopus Importer:2022-09-09

Detecting tandem repeat variants in coding regions using code-adVNTR - Park, Jonghun; Bakhtiari, Mehrdad; Popp, Bernt; Wiesener, Michael; Bafna, Vineet (iScience, 2022)
The human genome contains more than one million tandem repeats (TRs), DNA sequences containing multiple approximate copies of a motif repeated contiguously. TRs account for significant genetic variation, with 50 + diseases attributed to changes in motif number. A few diseases have been to be caused by small indels in variable number tandem repeats (VNTRs) including poly-cystic kidney disease type 1 (MCKD1) and monogenic type 1 diabetes. However, small indels in VNTRs are largely unexplored mainly due to the long and complex structure of VNTRs with multiple motifs. We developed a method, code-adVNTR, that utilizes multi-motif hidden Markov models to detect both, motif count variation and small indels, within VNTRs. In simulated data, code-adVNTR outperformed GATK-HaplotypeCaller in calling small indels within large VNTRs. We used code-adVNTR to characterize coding VNTRs in the 1000 genomes data identifying many population-specific variants, and to reliably call MUC1 mutations for MCKD1.
CRIS-Team Scopus Importer:2022-11-18
Keywords: Genetics; Genomics; Human genetics; Molecular genetics

Detection of Changes in Renal Blood Flow Using Arterial Spin Labeling MRI - Kannenkeril, Dennis; Janka, Rolf Matthias; Bosch, Agnes; Jung, Susanne; Kolwelter, Julie; Striepe, Kristina; Ott, Christian; Martirosian, Petros; Schiffer, Mario; Uder, Michael; Schmieder, Roland (American Journal of Nephrology, 2021)
Background: Alteration in kidney perfusion is an early marker of renal damage. The purpose of this study was to evaluate if changes in renal blood flow (RBF) could be detected using MRI with arterial spin labeling (ASL) technique. Methods: RBF as assessed by cortical (CRBF), medullary, and total renal blood flow (TRBF) were measured by MRI with arterial spin labeling (ASL-MRI) using flow-sensitive alternating inversion recovery true fast imaging with steady-state precession sequence. In 11 normotensive healthy individuals (NT) and 11 hypertensive patients (HT), RBF was measured at baseline and after both feet were covered with cold ice packs (cold pressor test) that activates the sympathetic nervous system. In another experiment, RBF was measured in 10 patients with CKD before and after a pharmacological intervention. We compared RBF measurements between the 3 study populations. Results: A significant reduction in CRBF (p = 0.042) and a trend in TRBF (p = 0.053) were observed in response to the activation of the sympathetic nervous system. A trend toward reduction of CRBF (p = 0.051) and TRBF (p = 0.059) has been detected after pharmacological intervention. TRBF was significantly lower in patients with HT and CKD patients compared to NT individuals (NT vs. HT, p = 0.014; NT vs. CKD, p = 0.004). TRBF was lower in patients with CKD compared to HT (p = 0.047). Conclusion: Our data indicate that both acute and short-term changes in RBF could be detected using ASL-MRI. We were able to detect differences in RBF between healthy and diseased individuals by needing only small sample size per group. Thus, ASL-MRI offers an advantage in conducting clinical trials compared to other technologies.
CRIS-Team Scopus Importer:2021-04-02
Keywords: ASL-MRI; Cold pressor test; Renal blood flow

DETECTION OF CHANGES IN RENAL BLOOD FLOW USING ARTERIAL SPIN LABELING MRI - Kannenkeril, Dennis; Janka, Rolf Matthias; Bosch, Agnes; Jung, Susanne; Kolwelter, Julie; Striepe, Kristina; Ott, Christian; Martirosian, Petros; Schiffer, Mario; Uder, Michael; Schmieder, Roland (JOURNAL OF HYPERTENSION, 2021)
CRIS-Team WoS Importer:2021-07-30

Determinants of arterial stiffness in patients with type 2 diabetes mellitus: a cross sectional analysis - Staef, Mawadah; Ott, Christian; Kannenkeril, Dennis; Striepe, Kristina; Schiffer, Mario; Schmieder, Roland; Bosch, Agnes (Scientific Reports, 2023)
In patients with type 2 diabetes mellitus (T2DM) arterial stiffness is associated with increased cardiovascular and total mortality. Little is known about determinants of arterial stiffness in clinical routine. Identification of potential determinants of arterial stiffness will help to address treatment targets for patients in the early state of T2DM. This is a cross-sectional analysis of arterial stiffness in 266 patients in the early stage of T2DM who did not have cardiovascular or renal complications. Parameters of arterial stiffness such as central systolic blood pressure (cSBP), central pulse pressure (cPP) and pulse wave velocity (PWV) were measured with the SphygmoCor System (AtCor Medical). We investigated the influence of parameters of glucose metabolism, lipid status, body constitution, blood pressure (BP) and inflammation on the stiffness parameters using multivariate regression analysis. The study cohort consisted of male and female patients aged 61 ± 8 years with mean diabetes duration of 6.4 ± 5.1 years, mean HbA1c 7.1 ± 0.9%, mean cSBP 121 ± 12 mmHg, mean cPP 44 ± 10 mmHg and mean PWV 8.9 ± 1.8 m/s. Multiple regression analysis identified waist circumference (WC) (beta = 0.411, p = 0.026), LDL-cholesterol (beta = 0.106, p = 0.006), systolic office BP (beta = 0.936, p < 0.001) and diabetes duration (beta = 0.233, p = 0.043) as potential determinants of cSBP. cPP was determined by sex (beta = 0.330, p = 0.008), age (beta = 0.383, p < 0.001), systolic office BP (beta = 0.370, p < 0.001) and diabetes duration (beta = 0.231, p = 0.028) whereas for PWV the following determinants could be identified: age (beta = 0.405, p < 0.001), systolic office BP (beta = 0.421, p < 0.001) and diabetes duration (beta = 0.073, p = 0.038). In addition to the known parameters age, sex and systolic office BP serum LDL-cholesterol, WC and diabetes duration have been identified as determinants of arterial stiffness in patients with T2DM. Treatment of patients in the early stage of T2DM should focus on these clinical parameters to prevent progression of arterial stiffness and as a consequence reduce cardiovascular mortality. Trial registration: The patients included in the analysis participated in one of the following clinical trials NCT02752113 (registered 26.4.2016), NCT02383238 (09.03.2015), NCT02471963 (15.06.2015), NCT01319357 (21.03.2011) (http://www.clinicaltrials.gov).
CRIS-Team Scopus Importer:2023-06-30

Determinants of Successful Use of Sirolimus in Renal Transplant Patients - Naik, Marcel G.; Jürgensen, Jan Steffen; Arns, Wolfgang; Basic, Edin; Budde, Klemens; Eitner, Frank; Fischereder, Michael; Goßmann, Jan; Heller, Katharina M.; Heyne, Nils; Morath, Christian; Riester, Udo; et al. (Transplantation Proceedings, 2020)
Background: Sirolimus is an established immunosuppressant in renal transplantation with antineoplastic and antiviral features, but side effects like proteinuria limit its use. The aim of this retrospective multicenter observational study is to define predictors for determining which patients most likely benefit from a sirolimus-based therapy. Methods: All patients from 10 German centers that were switched to a sirolimus-containing maintenance immunosuppression in 2000 to 2008 after 3 months or later post-transplantation were enrolled (n = 726). Observation times after switching to sirolimus ranged from 4 days to 9 years (median: 24.3 months). With multinomial logistic regression, risk factors for the endpoints terminal graft failure and withdrawal of sirolimus therapy compared to successful therapy were identified. Results: Successful sirolimus therapy was observed in 304 patients. Forty patients died with functioning graft. Therapy failures included graft loss (n = 106) and sirolimus-discontinuation for various reasons (n = 276). Successful sirolimus-use was predicted in 83% and graft failure in 65%, whereas prediction of deliberate sirolimus-discontinuation was poor (48%). Most favorable results for sirolimus-use were observed in patients switched in 2006 to 2008. Using ROC analysis, an estimated glomerular filtration rate (eGFR) below 32 mL/min was shown to be the cut-off in patients withdrawing from therapy as a result of renal reasons, as well as in patients with graft loss. Proteinuria above 151 mg/L was shown to be predictive for patients with graft failure. Conclusions: eGFR and proteinuria are the major determinants for successful sirolimus-therapy. Our findings help stratifying patients who will benefit most from this therapy and avoid toxicities in patients without potential benefits for this therapy.
CRIS-Team Scopus Importer:2020-06-09

Development and Validation of a Prediction Model for Future Estimated Glomerular Filtration Rate in People With Type 2 Diabetes and Chronic Kidney Disease - Gregorich, Mariella; Kammer, Michael; Heinzel, Andreas; Böger, Carsten; Eckardt, Kai-Uwe; Heerspink, Hiddo Lambers; Jung, Bettina; Mayer, Gert; Meiselbach, Heike; Schmid, Matthias; Schultheiss, Ulla T.; Heinze, Georg; et al. (JAMA Network Open, 2023)
Importance: Type 2 diabetes increases the risk of progressive diabetic kidney disease, but reliable prediction tools that can be used in clinical practice and aid in patients' understanding of disease progression are currently lacking. Objective: To develop and externally validate a model to predict future trajectories in estimated glomerular filtration rate (eGFR) in adults with type 2 diabetes and chronic kidney disease using data from 3 European multinational cohorts. Design, Setting, and Participants: This prognostic study used baseline and follow-up information collected between February 2010 and December 2019 from 3 prospective multinational cohort studies: PROVALID (Prospective Cohort Study in Patients with Type 2 Diabetes Mellitus for Validation of Biomarkers), GCKD (German Chronic Kidney Disease), and DIACORE (Diabetes Cohorte). A total of 4637 adult participants (aged 18-75 years) with type 2 diabetes and mildly to moderately impaired kidney function (baseline eGFR of ≥30 mL/min/1.73 m2) were included. Data were analyzed between June 30, 2021, and January 31, 2023. Main Outcomes and Measures: Thirteen variables readily available from routine clinical care visits (age, sex, body mass index; smoking status; hemoglobin A1c[mmol/mol and percentage]; hemoglobin, and serum cholesterol levels; mean arterial pressure, urinary albumin-creatinine ratio, and intake of glucose-lowering, blood-pressure lowering, or lipid-lowering medication) were selected as predictors. Repeated eGFR measurements at baseline and follow-up visits were used as the outcome. A linear mixed-effects model for repeated eGFR measurements at study entry up to the last recorded follow-up visit (up to 5 years after baseline) was fit and externally validated. Results: Among 4637 adults with type 2 diabetes and chronic kidney disease (mean [SD] age at baseline, 63.5 [9.1] years; 2680 men [57.8%]; all of White race), 3323 participants from the PROVALID and GCKD studies (mean [SD] age at baseline, 63.2 [9.3] years; 1864 men [56.1%]) were included in the model development cohort, and 1314 participants from the DIACORE study (mean [SD] age at baseline, 64.5 [8.3] years; 816 men [62.1%]) were included in the external validation cohort, with a mean (SD) follow-up of 5.0 (0.6) years. Updating the random coefficient estimates with baseline eGFR values yielded improved predictive performance, which was particularly evident in the visual inspection of the calibration curve (calibration slope at 5 years: 1.09; 95% CI, 1.04-1.15). The prediction model had good discrimination in the validation cohort, with the lowest C statistic at 5 years after baseline (0.79; 95% CI, 0.77-0.80). The model also had predictive accuracy, with an R2ranging from 0.70 (95% CI, 0.63-0.76) at year 1 to 0.58 (95% CI, 0.53-0.63) at year 5. Conclusions and Relevance: In this prognostic study, a reliable prediction model was developed and externally validated; the robust model was well calibrated and capable of predicting kidney function decline up to 5 years after baseline. The results and prediction model are publicly available in an accompanying web-based application, which may open the way for improved prediction of individual eGFR trajectories and disease progression.
CRIS-Team Scopus Importer:2023-04-28

Development and validation of a predictive mortality risk score from a European hemodialysis cohort - Floege, Juergen; Gillespie, Iain A.; Kronenberg, Florian; Anker, Stefan D.; Gioni, Ioanna; Richards, Sharon; Pisoni, Ronald L.; Robinson, Bruce M.; Marcelli, Daniele; Froissart, Marc; Eckardt, Kai-Uwe (Kidney International, 2015)
Although mortality risk scores for chronic hemodialysis (HD) patients should have an important role in clinical decision-making, those currently available have limited applicability, robustness, and generalizability. Here we applied a modified Framingham Heart Study approach to derive 1- and 2-year all-cause mortality risk scores using a 11,508 European incident HD patient database (AROii) recruited between 2007 and 2009. This scoring model was validated externally using similar-sized Dialysis Outcomes and Practice Patterns Survey (DOPPS) data. For AROii, the observed 1- and 2-year mortality rates were 13.0 (95% confidence interval (CI; 12.3-13.8)) and 11.2 (10.4-12.1)/100 patient years, respectively. Increasing age, low body mass index, history of cardiovascular disease or cancer, and use of a vascular access catheter during baseline were consistent predictors of mortality. Among baseline laboratory markers, hemoglobin, ferritin, C-reactive protein, serum albumin, and creatinine predicted death within 1 and 2 years. When applied to the DOPPS population, the predictive risk score models were highly discriminatory, and generalizability remained high when restricted by incidence/prevalence and geographic location (C-statistics 0.68-0.79). This new model offers improved predictive power over age/comorbidity-based models and also predicted early mortality (C-statistic 0.71). Our new model delivers a robust and reproducible mortality risk score, based on readily available clinical and laboratory data.
EVALuna2:3773

Development and validation of cardiovascular risk scores for haemodialysis patients - Anker, Stefan D.; Gillespie, Iain A.; Eckardt, Kai-Uwe; Kronenberg, Florian; Richards, Sharon; Drueke, Tilman B.; Stenvinkel, Peter; Pisoni, Ronald L.; Robinson, Bruce M.; Marcelli, Daniele; Froissart, Marc; Floege, Juergen (International Journal of Cardiology, 2016)
A simple clinical tool to predict cardiovascular disease risk does not exist for haemodialysis patients. The long-term coronary risk Framingham Heart Study Risk score (FRS), although used in this population, may be inadequate. Therefore, we developed separate risk-scores for cardiovascular mortality (CVM) and cardiovascular morbidity & mortality (CVMM) in a Fresenius Medical Care-based haemodialysis patient cohort (AROii).Applying a modified FRS approach, we derived and internally validated two-year risk-scores in incident European adult patients randomly assigned to a development (N=4831) or a validation (N=4796) dataset. External validation was conducted in the third Dialysis Outcomes and Practice Patterns Study (DOPPS III) cohort. Additional discrimination comparing to the FRS was performed.The overall two-year CVM and CVMM event rates were 5.0 and 22.6 per 100 person-years respectively. Common risk predictors included increasing age, cardiovascular disease history, primary diabetic nephropathy, low blood pressure, and inflammation. The CVM score was more predictive in AROii (c-statistic 0.72) and in DOPPS III (c-statistic 0.73-0.74) than the CVMM score (c-statistic 0.66-0.67 & 0.63 respectively). The FRS was not predictive of either CVM (c-statistic 0.54) or CVMM (c-statistic 0.56) in AROii.We describe novel, easy-to-apply and interpret CV risk-scores for haemodialysis patients. Our improved cardiovascular prediction performance over traditional (FRS) scores reflected its tailored development and validation in haemodialysis populations, and the integration of non-classical cardiovascular risk factors. The lower expected versus observed CVM and CVMM risk suggests the existence of novel cardiovascular risk factors in this patient population not measured in this study.
EVALuna2:3857

Diagnosis and treatment of arterial hypertension 2021 - Ott, Christian; Schmieder, Roland (Kidney International, 2021)
In the last 4 years, several evidence-based, national, and international guidelines on the management of arterial hypertension have been published, mostly with concordant recommendations, but in some aspects with discordant opinions. This in-depth review takes these guidelines into account but also addresses several new data of interest. Although being somewhat obvious and simple, accurate blood pressure (BP) measurement with validated devices is the cornerstone of the diagnosis of hypertension, but out-of-office BP measurements are of crucial importance as well. Simplified antihypertensive drug treatment such as single-pill combinations enhances the adherence to medication and speeds up the process of getting into the BP target range, a goal not so far adequately respected. Recommended (single-pill) combination therapy includes diuretics as part of the first step of antihypertensive therapy, and updated analysis does not provide evidence to exclude diuretics from this first step because of the recently discussed potential risk of increasing cancer incidence. Target BP goals need to be individualized, according to comorbidities, hypertension-mediated organ damage, coexistence of cardiovascular risk factors (including age), frailty in older patients, and individual tolerability. There are also concordant recommendations in the guidelines that an office BP between 120 and 140 mm Hg systolic and between 70 and 80 mm Hg diastolic should be achieved. The BP target of Kidney Disease: Improving Global Outcomes for hypertensive patients with chronic kidney disease are not applicable for clinical practice because they heavily rely on 1 study that used a study-specific, nontransferable BP measurement technique and excluded the most common cause of chronic kidney disease, namely, diabetic nephropathy. Actual data even from a prospective trial on chronotherapy have to be disregarded, and antihypertensive medication should not be routinely dosed at bedtime. Rigorously conducted trials justify the revival of renal denervation for treatment of (at least, but not only) uncontrolled and treatment-resistant hypertension.
CRIS-Team Scopus Importer:2021-12-17
Keywords: ambulatory blood pressure measurement; arterial hypertension; blood pressure; guideline; renal denervation; SPRINT

Diagnosis and treatment of early renal disease in patients with type 2 diabetes mellitus: what are the clinical needs? - Mann, Johannes; Rossing, Peter; Wiecek, Andrzej; Rosivall, Laszlo; Mark, Patrick; Mayer, Gert (Nephrology Dialysis Transplantation, 2015)
Renal disease is prevalent in patients with diabetes mellitus type 2. Aggressive metabolic control and lowering of systemic and/or intraglomerular blood pressure are effective interventions but not without side effects. Thus a better, early identification of patients at risk for incidence or progression to end-stage renal failure by the use of new, validated biomarkers is highly desirable. In the majority of patients, hypertension and hyperglycaemia are pathogenetically important pathways for the progression of renal disease. Nonetheless even aggressive therapy targeting these factors does not eliminate the risk of end-stage renal failure and experimental evidence suggests that many other pathways (e.g. tubulointerstitial hypoxia or inflammation etc.) also contribute. As their individual importance might vary from patient to patient, interventions which interfere are likely not to be therapeutically effective in all subjects. In this situation, an option to preserve the statistical power of clinical trials is to rely on biomarkers that reflect individual pathophysiology. In current clinical practice, albuminuria is the biomarker that has been best evaluated to guide stratified/personalized therapy but there is a clear need to expand our diagnostic abilities.
EVALuna2:3877

Diagnosis and treatment of resistant hypertension - Waeber, Bernard; Volpe, Massimo; Ruilope, Luis M.; Schmieder, Roland (Blood Pressure, 2014)
Abstract Hypertension resistant to lifestyle interventions and antihypertensive medications is a common problem encountered by physicians in everyday practice. It is most often defined as a blood pressure remaining >= 140/90 mmHg despite the regular intake of at least three drugs lowering blood pressure by different mechanisms, one of them being a diuretic. It now appears justified to include, unless contraindicated or not tolerated, a blocker of the renin-angiotensin system and a calcium channel blocker in this drug regimen, not only to gain antihypertensive efficacy, but also to prevent or regress target organ damage and delay the development of cardiorenal complications. A non-negligible fraction of treatment-resistant hypertension have normal "out of office" blood pressures. Ambulatory blood pressure monitoring and/or home blood pressure recording should therefore be routinely performed to identify patients with true resistant hypertension, i.e. patients who are more likely to benefit from treatment intensification.
EVALuna2:3672

Diagnostik und Therapie der Nephrolithiasis - Pfau, A.; Eckardt, Kai-Uwe; Knauf, F. (Internist, 2015)
Kidney stones are a common and increasing problem worldwide. Nephrolithiasis is frequently a chronic disease given the risk of recurrence following passage of a first stone.In the present article, an update on the diagnosis and treatment of kidney stones relevant for internal medicine physicians is provided.This review is based on a selective literature search and our own work.The diagnosis of kidney stones is based on the clinical history and physical examination. Confirmatory radiologic tests include noncontrast computerized tomography or ultrasonography with both techniques having recently been shown to have equivalent overall outcomes. The therapy of kidney stones is based on the clinical presentation and diagnostic findings (e.g., fever, response to pain management, and demonstration of relevant obstruction) as well as location, size, and composition of the stone. If invasive treatment is being considered, the urology department should be consulted. Given the high risk of recurrence, stone analysis must be performed as well as the concentration of lithogenic and litholytic substances measured in a 24-h urine collection. The newly established recurrence of kidney stone nomogram (ROKS nomogram) identifies kidney stone formers at greatest risk for a second symptomatic episode who may benefit from medical intervention.
EVALuna2:3792

Dialysis and ultrafiltration therapy in patients with cardio-renal syndrome: recommendations of the working group "heart-kidney" of the German Cardiac Society and the German Society of Nephrology - Schwenger, V.; Remppis, B. A.; Westenfeld, R.; Weinreich, T.; Brunkhorst, R.; Schieren, G.; Krumme, B.; Haller, H.; Schmieder, Roland; Schlieper, G.; Frye, B.; Hoppe, U. C.; et al. (Deutsche Medizinische Wochenschrift, 2014)
Renal failure is common in patients with severe heart failure. This complex pathophysiological interaction has been classified as cardio-renal syndrome. In these patients hydropic decompensation is the main cause of hospitalization. In patients with refractory heart failure, characterized by diuretic resistance and congestion due to volume overload, ultrafiltration has to be considered. In acute decompensated heart failure with worsening of renal function, extracorporeal ultrafiltration is the preferred treatment modality. On the other hand, patients suffering from chronic decompensated heart failure, particularly patients with ascites, will profit from the treatment specific advantages of peritoneal ultrafiltration. Prerequisite for an optimized care of patients with cardio-renal syndrome is the close collaboration among intensive care doctors, cardiologists and nephrologists.
EVALuna2:3705

Diet and kidney disease in high-risk individuals with type 2 diabetes mellitus - Dunkler, Daniela; Dehghan, Mahshid; Teo, Koon K.; Heinze, Georg; Gao, Peggy; Kohl, Maria; Clase, Catherine M.; Mann, Johannes; Yusuf, Salim; Oberbauer, Rainer (JAMA Internal Medicine, 2013)
Type 2 diabetes mellitus and associated chronic kidney disease (CKD) have become major public health problems. Little is known about the influence of diet on the incidence or progression of CKD among individuals with type 2 diabetes.To examine the association between (healthy) diet, alcohol, protein, and sodium intake, and incidence or progression of CKD among individuals with type 2 diabetes.All 6213 individuals with type 2 diabetes without macroalbuminuria from the Ongoing Telmisartan Alone and in Combination With Ramipril Global Endpoint Trial (ONTARGET) were included in this observational study. Recruitment spanned from January 2002 to July 2003, with prospective follow-up through January 2008.Chronic kidney disease was defined as new microalbuminuria or macroalbuminuria or glomerular filtration rate decline of more than 5% per year at 5.5 years of follow-up. We assessed diet using the modified Alternate Healthy Eating Index (mAHEI). The analyses were adjusted for known risk factors, and competing risk of death was considered.After 5.5 years of follow-up, 31.7% of participants had developed CKD and 8.3% had died. Compared with participants in the least healthy tertile of mAHEI score, participants in the healthiest tertile had a lower risk of CKD (adjusted odds ratio [OR], 0.74; 95% CI, 0.64-0.84) and lower risk of mortality (OR, 0.61; 95% CI, 0.48-0.78). Participants consuming more than 3 servings of fruits per week had a lower risk of CKD compared with participants consuming these food items less frequently. Participants in the lowest tertile of total and animal protein intake had an increased risk of CKD compared with participants in the highest tertile (total protein OR, 1.16; 95% CI, 1.05-1.30). Sodium intake was not associated with CKD. Moderate alcohol intake reduced the risk of CKD (OR, 0.75; 95% CI, 0.65-0.87) and mortality (OR, 0.69; 95% CI, 0.53-0.89).A healthy diet and moderate intake of alcohol may decrease the incidence or progression of CKD among individuals with type 2 diabetes. Sodium intake, within a wide range, and normal protein intake are not associated with CKD.clinicaltrials.gov Identifier: NCT00153101.
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Diet and Major Renal Outcomes: A Prospective Cohort Study. The NIH-AARP Diet and Health Study - Smyth, Andrew; Griffin, Matthew; Yusuf, Salim; Mann, Johannes; Reddan, Donal; Canavan, Michelle; Newell, John; O'Donnell, Martin (Journal of Renal Nutrition, 2016)
Chronic kidney disease (CKD) is prevalent and associated with significant morbidity and mortality. Dietary modification may be an approach to reducing CKD.In this prospective cohort study, we evaluated the association between diet quality, sodium and potassium intakes, and major renal outcomes. A total of 544,635 community-dwelling adults, aged 51 to 70 years, living in 6 states and 2 urban areas in the United States, from the National Institutes of Health-American Association of Retired Persons Diet and Health Study. Using a food frequency questionnaire completed at baseline, we assessed diet quality using the Alternate Healthy Eating Index (AHEI), Healthy Eating Index (HEI), Mediterranean Diet Score (MDS), Recommended Food Score, and Dietary Approaches to Stop Hypertension (DASH) scores. This was also used to estimate daily sodium and potassium intakes.Multivariable adjusted competing risks regression calculated sub-hazard ratios (sHRs) for a composite of death due to a renal cause and dialysis, with death due to a nonrenal cause as the competing event.During a mean of 14.3-year follow-up, a total of 4,848 participants died from a renal cause or initiated dialysis. Four diet quality scores (AHEI, HEI, MDS, and DASH) were significantly associated with the composite renal outcome; the Recommended Food Score was not. Compared to the lowest score quintile, the highest quintiles of AHEI (sHR 0.71; 95% confidence interval [CI] 0.65-0.79), HEI (sHR 0.82; 95% CI 0.74-0.91), MDS (sHR 0.84; 95% CI 0.74-0.95), and DASH (sHR 0.85; 95% CI 0.77-0.94) were associated with a reduced hazard of the composite. The highest sodium quintile (sHR 1.17; 95% CI 1.02-1.33 for sodium intake > 3.6 g/day) was associated with an increased hazard, whereas the highest potassium quintile (sHR 0.83 [0.73-0.95]) with a reduced hazard.Our findings support an association between healthy dietary patterns and reduced risk of major renal outcomes and provide observational evidence to inform dietary guideline recommendations for CKD prevention.
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Dietary risk factors for incidence or progression of chronic kidney disease in individuals with type 2 diabetes in the European Union - Dunkler, Daniela; Kohl, Maria; Teo, Koon K.; Heinze, Georg; Dehghan, Mahshid; Clase, Catherine M.; Gao, Peggy; Yusuf, Salim; Mann, Johannes; Oberbauer, Rainer (Nephrology Dialysis Transplantation, 2015)
Although the prevalence of chronic kidney disease (CKD) is 30% in the group of people with diabetes, data on interventions in the very early stage of the disease are still missing. Furthermore, the effects of modifiable lifestyle factors such as nutrition on incidence and progression of CKD in patients with diabetes in Europe remain elusive.We analyzed whether diet quality and adherence to dietary guidelines using the modified Alternate Healthy Eating Index (mAHEI) score was associated with CKD incidence or progression after 5.5 years in 3088 European participants of the ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial (ONTARGET) with type 2 diabetes and baseline normo- or micro-albuminuria. Death was considered as a competing risk in the multinomial logit regression models, which were adjusted for age, gender, duration of diabetes, ONTARGET randomization, baseline albuminuria and glomerular filtration rate (GFR). We also estimated the potential impact on population health of improvement in diet quality.At study end, 450 (14.6%) participants had died and 926 (30%) had experienced the renal endpoint of incidence or progression of CKD, of which 422 (13.7%) participants had progressed to micro- or macro-albuminuria, 596 (19.3%) had a GFR-decline of >5% per year and 18 (0.6%) had developed end-stage renal disease. Participants in the healthiest tertile of the mAHEI score had a decreased risk of incidence or progression of CKD (odds ratio 0.8, 95% confidence interval 0.68-0.94) and death (0.65, 0.52-0.81) compared with participants in the least healthy tertile. If individuals with a suboptimal dietary quality (e.g. mAHEI < 28) were able to improve their diet to an mAHEI of 28, 3.2% of CKD incidence or progression and 10.0% of deaths might be avoided in 5.5 years.If the association between diet and these endpoints is causal, then optimizing diet quality in individuals with diabetes who have no CKD or very early CKD would have substantial population benefits in terms of prevention of CKD incidence or progression and mortality in this high-risk population.
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Difference in renal parenchymal perfusion after renal denervation comparing treated vs. non-treated arteries - Schmieder, R. S.; Schmid, Axel; Janka, Rolf Matthias; Schmieder, Roland; Ott, Christian; Uder, Michael (EUROPEAN HEART JOURNAL, 2018)
CRIS-Team WoS Importer:2019-03-15

Differences in patient and physician perspectives on pharmaceutical therapy and renal denervation for the management of hypertension - Schmieder, Roland; Kandzari, David E.; Wang, Tzung Dau; Lee, Ying Hsiang; Lazarus, Gabriel; Pathak, Atul (Journal of Hypertension, 2021)
OBJECTIVE: To study patient and physician attitudes to pharmaceutical therapy and renal denervation for the management of hypertension. METHODS: Data were analyzed from 19 market research studies in Western Europe and the United States conducted between 2010 and 2019 to obtain quantitative and qualitative perspectives. The analysis incorporated insights from 2768 patients and the experiences of 1902 physicians either actively performing or interested to perform device procedures, or hypertension specialists who would refer patients for a device-based intervention. RESULTS: Referring cardiologists and proceduralists were more likely to recommend the renal denervation procedure to patients with higher BP levels and a greater number of antihypertensive medications. Physicians perceived patient reluctance towards a procedure as an important obstacle to recommending renal denervation as a treatment option for uncontrolled hypertension. Patient interest in the renal denervation procedure did not correlate with BP severity (P = NS), and the highest preference for the procedure was in patients diagnosed with hypertension but not receiving treatment (P < 0.001). Patients who perceived high BP as a major problem (P = 0.029) and those who experienced side effects attributed to their BP medications (P = 0.006) had a higher preference for renal denervation. CONCLUSION: Patients with hypertension often regard the choice of renal denervation to lower BP differently from physicians. A considerable proportion of hypertensive patients, especially those not taking medications, may prefer a device-based approach to reduce their BP.
CRIS-Team Scopus Importer:2020-12-11

DIFFERENT FORMS OF AFFERENT NERVE INPUT IN CARDIAC AND RENAL DISEASE IN RATS? - Rodionova, Kristina; Ditting, Tilmann; Pickny, Lisa; Ott, Christian; Schmieder, Roland; Schiffer, Mario; Amann, Kerstin Ute; Veelken, Roland (JOURNAL OF HYPERTENSION, 2021)
CRIS-Team WoS Importer:2021-07-30

Differential Prognostic Utility of Adiposity Measures in Chronic Kidney Disease - Cejka, Vladimir; Störk, Stefan; Nadal, Jennifer; Schmid, Matthias; Sommerer, Claudia; Sitter, Thomas; Meiselbach, Heike; Busch, Martin; Schneider, Markus; Saritas, Turgay; Schultheiss, Ulla T.; Kotsis, Fruzsina; et al. (Journal of Renal Nutrition, 2023)
Objective: Adipose tissue contributes to adverse outcomes in chronic kidney disease (CKD), but there is uncertainty regarding the prognostic relevance of different adiposity measures. We analyzed the associations of neck circumference (NC), waist circumference (WC), and body mass index (BMI) with clinical outcomes in patients with mild to severe CKD. Methods: The German Chronic Kidney Disease study is a prospective cohort study, which enrolled Caucasian adults with mild to severe CKD, defined as estimated glomerular filtration rate : 30-60 mL/min/1.73 m2, or >60 mL/min/1.73 m2 in the presence of overt proteinuria. Associations of NC, WC, and BMI with all-cause death, major adverse cardiovascular events (MACE: a composite of nonfatal stroke, nonfatal myocardial infarction, peripheral artery disease intervention, and cardiovascular death), and kidney failure (a composite of dialysis or transplantation) were analyzed using multivariable Cox proportional hazards regression models adjusted for confounders and the Akaike information criteria were calculated. Models included sex interactions with adiposity measures. Results: A total of 4537 participants (59% male) were included in the analysis. During a 6.5-year follow-up, 339 participants died, 510 experienced MACE, and 341 developed kidney failure. In fully adjusted models, NC was associated with all-cause death in women (hazard ratio 1.080 per cm; 95% CI 1.009-1.155) but not in men. Irrespective of sex, WC was associated with all-cause death (hazard ratio 1.014 per cm; 95% CI 1.005-1.038). NC and WC showed no association with MACE or kidney failure. BMI was not associated with any of the analyzed outcomes. Models of all-cause death, including WC offered the best (lowest) Akaike information criteria. Conclusion: In Caucasian patients with mild to severe CKD, higher NC (in women) and WC were significantly associated with increased risk of death from any cause but BMI was not.
CRIS-Team Scopus Importer:2023-09-29
Keywords: adiposity; body Mass Index; chronic kidney disease; mortality; neck circumference; waist circumference

Different Murine Models of Kidney Injury Reveal a Common Pattern of Dysregulation within the Polyamine System in Favour of its Catabolic Pathways - Sieckmann, Tobias; Ögel, Neslihan; Kelterborn, Simon; Boivin, Felix J.; Schley, Gunnar; Fähling, Michael; Ashraf, Muhammad Imtiaz; Reichel, Martin; Vigolo, Emilia; Hartner, Andrea; Knauf, Felix; Rosenberger, Christian; et al. (The FASEB Journal, 2022)
The polyamines putrescine, spermidine and spermine are organic polycations that regulate many cell functions including proliferation and differentiation. It is known that certain genes of the polyamine system are dysregulated after kidney ischemia reperfusion injury. Here we examined the hypothesis that different forms of acute and chronic kidney injury lead to similar changes in the expression patterns of the polyamine system. In different models of acute and chronic kidney injury expression of genes involved in polyamine homeostasis were analyzed by RT-qPCR and RNAScope. In these models, expression of catabolic enzymes (Aoc1 and Sat1) was upregulated, and the anabolic enzymes (Odc1, Sms) were downregulated. The putrescine-degrading enzyme AOC1 exhibits the most striking changes. Interestingly, it can act together with ODC1 as gatekeepers of the polyamine system. The detected increase of Aoc1 takes place in the injured but regenerating proximal tubules. As a screening for stimuli of increased Aoc1 expression, we used mouse embryonic kidney explants. Here we observed changes of Aoc1expression under hypoxia and hyperosmotic conditions. These changes were further examined in mouse models of hypoxia. However, in vivo, hypoxia did not lead to changes of Aoc1 expression. Hyperosmolarity was confirmed as a stimulus by using the kidney cell lines M15 and 209/MDCT as well as cultured primary proximal tubules. Using reporter gene and RNA-stability assays, we could show that the increase in Aoc1 expression is based on mRNA-stabilization and transcriptional activation of one certain isoform. The activated isoform contains an additional set of 22 amino acids N-terminally that lead to an altered subcellular localization. In conclusion, different models of kidney injury exhibit a similar pattern of dysregulation of the polyamine system with the most striking change being the upregulation of Aoc1 in proximal tubules. Using hyperosmolarity as a stimulus, we provide first insights into the regulation of Aoc1 under harmful conditions.
CRIS-Team Scopus Importer:2022-05-27

DIFFERENT RESPONSE PATTERN TO AIRCRAFT NOISE EXPOSURE IN RENAL VERSUS SYSTEMIC HEMODYNAMIC - Bosch, Agnes; Ott, C.; Kannenkeril, D.; Harazny, J. M.; Striepe, Kristina; Karg, M.; Dienemann, T.; Jung, Susan; Schmieder, Roland (2018)
EVALuna2:202964

Different roles of protein biomarkers predicting eGFR trajectories in people with chronic kidney disease and diabetes mellitus: a nationwide retrospective cohort study - Kammer, Michael; Heinzel, Andreas; Hu, Karin; Meiselbach, Heike; Gregorich, Mariella; Busch, Martin; Duffin, Kevin L.; Gomez, Maria F.; Eckardt, Kai-Uwe; Oberbauer, Rainer (Cardiovascular Diabetology, 2023)
BACKGROUND: Chronic kidney disease (CKD) is a common comorbidity in people with diabetes mellitus, and a key risk factor for further life-threatening conditions such as cardiovascular disease. The early prediction of progression of CKD therefore is an important clinical goal, but remains difficult due to the multifaceted nature of the condition. We validated a set of established protein biomarkers for the prediction of trajectories of estimated glomerular filtration rate (eGFR) in people with moderately advanced chronic kidney disease and diabetes mellitus. Our aim was to discern which biomarkers associate with baseline eGFR or are important for the prediction of the future eGFR trajectory. METHODS: We used Bayesian linear mixed models with weakly informative and shrinkage priors for clinical predictors (n = 12) and protein biomarkers (n = 19) to model eGFR trajectories in a retrospective cohort study of people with diabetes mellitus (n = 838) from the nationwide German Chronic Kidney Disease study. We used baseline eGFR to update the models' predictions, thereby assessing the importance of the predictors and improving predictive accuracy computed using repeated cross-validation. RESULTS: The model combining clinical and protein predictors had higher predictive performance than a clinical only model, with an [Formula: see text] of 0.44 (95% credible interval 0.37-0.50) before, and 0.59 (95% credible interval 0.51-0.65) after updating by baseline eGFR, respectively. Only few predictors were sufficient to obtain comparable performance to the main model, with markers such as Tumor Necrosis Factor Receptor 1 and Receptor for Advanced Glycation Endproducts being associated with baseline eGFR, while Kidney Injury Molecule 1 and urine albumin-creatinine-ratio were predictive for future eGFR decline. CONCLUSIONS: Protein biomarkers only modestly improve predictive accuracy compared to clinical predictors alone. The different protein markers serve different roles for the prediction of longitudinal eGFR trajectories potentially reflecting their role in the disease pathway.
CRIS-Team Scopus Importer:2023-04-07
Keywords: Chronic kidney disease; Diabetes mellitus; Prognosis; Proteomics

Discordant Clinical Course of Vitamin-D-Hydroxylase (CYP24A1) Associated Hypercalcemia in Two Adult Brothers With Nephrocalcinosis - Jobst-Schwan, Tilman; Pannes, Andrea; Schlingmann, Karl Peter; Eckardt, Kai-Uwe; Beck, Bodo B.; Wiesener, Michael (Kidney & Blood Pressure Research, 2015)
Hypercalcemia can result in nephrocalcinosis/nephrolithiasis and may lead to renal failure. Idiopathic infantile hypercalcemia is caused by mutations of the CYP24A1 gene, which regulates vitamin D activity. Classically infants present with hypercalcemia. Recently, a number of individuals have been reported with late onset clinical manifestation or late diagnosis in adulthood. All these patients are believed to show hypercalciuria.We report a 24 year old patient of healthy consanguine parents. Genetic analysis was performed by Sanger sequencing of the CYP24A1 gene in the index patient and targeted exon 2 analysis of all other family members.The patient was hospitalized with severe malaise during an acute EBV-infection. He showed hypercalcemia > 3mmol/l and acute, hypovolemic renal failure with profound nephrocalcinosis, but no hypercalciuria. Genetic workup revealed a homozygous loss-of-function mutation p.E143del in the CYP24A1 gene. His clinically asymptomatic brother showed nephrocalcinosis of lesser degree. Repeatedly, low parathyroid hormone levels were detected in both brothers.This family displays the highly variable phenotype of CYP24A1 biallelic mutation carriers. CYP24A1 associated disease is an important differential diagnosis for the workup and counseling of infants as well as adults with hypercalcemia since a proper genetic diagnosis may result in therapeutic consequence
EVALuna2:3793

Disease burden and risk profile in referred patients with moderate chronic kidney disease: composition of the German Chronic Kidney Disease (GCKD) cohort - Titze, Stephanie; Schmid, Matthias; Köttgen, Anna; Busch, Martin; Flöge, Jürgen; Wanner, Christoph; Kronenberg, Florian; Eckardt, Kai-Uwe (Nephrology Dialysis Transplantation, 2015)
A main challenge for targeting chronic kidney disease (CKD) is the heterogeneity of its causes, co-morbidities and outcomes. Patients under nephrological care represent an important reference population, but knowledge about their characteristics is limited.We enrolled 5217 carefully phenotyped patients with moderate CKD [estimated glomerular filtration rate (eGFR) 30-60 mL/min per 1.73 m(2) or overt proteinuria at higher eGFR] under routine care of nephrologists into the German Chronic Kidney Disease (GCKD) study, thereby establishing the currently worldwide largest CKD cohort.The cohort has 60% men, a mean age (±SD) of 60 ± 12 years, a mean eGFR of 47 ± 17 mL/min per 1.73 m(2) and a median (IQR) urinary albumin/creatinine ratio of 51 (9-392) mg/g. Assessment of causes of CKD revealed a high degree of uncertainty, with the leading cause unknown in 20% and frequent suspicion of multifactorial pathogenesis. Thirty-five per cent of patients had diabetes, but only 15% were considered to have diabetic nephropathy. Cardiovascular disease prevalence was high (32%, excluding hypertension); prevalent risk factors included smoking (59% current or former smokers) and obesity (43% with BMI >30). Despite widespread use of anti-hypertensive medication, only 52% of the cohort had an office blood pressure <140/90 mmHg. Family histories for cardiovascular events (39%) and renal disease (28%) suggest familial aggregation.Patients with moderate CKD under specialist care have a high disease burden. Improved diagnostic accuracy, rigorous management of risk factors and unravelling of the genetic predisposition may represent strategies for improving prognosis.
EVALuna2:3732

Disparate effects of the combined therapy of empagliflozin and linagliptin versus metformin and insulin glargine on renal haemodynamics in type 2 diabetes - Ott, Christian; Jung, Susan; Kannenkeril, D.; Striepe, Kristina; Bosch, Agnes; Korn, M.; Bramlage, P.; Schmieder, Roland (DIABETOLOGIA, 2019)
CRIS-Team WoS Importer:2019-10-11

DISPARATE NITRIC OXIDE ACTIVITY OF THE RETINAL CIRCULATION IN HYPERTENSIVE VS TYPE 2 DIABETES-PATIENTS - Kannenkeril, D.; Jung, Susan; Harazny, J. M.; Bosch, Agnes; Ott, Christian; Schmieder, Roland (JOURNAL OF HYPERTENSION, 2019)
CRIS-Team WoS Importer:2019-09-20

Disproportional decrease in office blood pressure compared with 24-hour ambulatory blood pressure with antihypertensive treatment: dependency on pretreatment blood pressure levels - Schmieder, Roland; Schmidt, Stefan; Riemer, Thomas; Dechend, Ralf; Hagedorn, Ina; Senges, Jochen; Messerli, Franz H.; Zeymer, Uwe (Hypertension, 2014)
The long-term relationship between 24-hour ambulatory blood pressure (ABP) and office BP in patients on therapy is not well documented. From a registry we included all patients in whom antihypertensive therapy needed to be uptitrated. Drug treatment included the direct renin inhibitor aliskiren or an angiotensin-converting enzyme inhibitor/angiotensin receptor blocker or drugs not blocking the renin-angiotensin system, alone or on top of an existing drug regimen. In all patients, office BP and 24-hour ABP were obtained at baseline and after 1 year with validated devices. In the study population of 2722 patients, there was a good correlation between the change in office BP and 24-hour ABP (systolic: r=0.39; P<0.001; diastolic: r=0.34; P<0.001). However, the numeric decrease in office BP did not correspond to the decrease in ABP in a 1:1 fashion, for example, a decrease of 10, 20, and 30 mm Hg corresponded to a decrease of ?7.2, 10.5, and 13.9 mm Hg in systolic ABP, respectively. The disproportionally greater decrease in systolic office BP compared with ABP was dependent on the level of the pretreatment BP, which was consistently higher for office BP than ABP. The white coat effect (difference between office BP and ABP) was on average 10/5 mm Hg lower 1 year after intensifying treatment and the magnitude of that was also dependent on pretreatment BP. There was a disproportionally greater decrease in systolic office BP than in ABP, which for both office BP and ABP seemed to depend on the pretreatment BP level.
EVALuna2:3733

Dissecting TSC2-mutated renal and hepatic angiomyolipomas in an individual with ARID1B-associated intellectual disability - Popp, Bernt; Agaimy, Abbas; Kraus, Cornelia; Knaup, Karl; Ekici, Arif Bülent; Uebe, Steffen; Reis, André; Wiesener, Michael; Zweier, Christiane (BMC Cancer, 2019)
Background: Several subunits of the SWI/SNF chromatin remodeling complex are implicated in both cancer and neurodevelopmental disorders (NDD). Though there is no clinical evidence for an increased tumor risk in individuals with NDDs due to germline mutations in most of these genes so far, this has been repeatedly proposed and discussed. A young woman with NDD due to a de novo mutation in ARID1B now presented with a large renal (> 19 cm in diameter) and multiple hepatic angiomyolipomas (AMLs) but no other signs of tuberous sclerosis complex. Methods: We analyzed tumor and healthy tissue samples with exome and panel sequencing. Results: Additionally to the previously known, germline ARID1B variant we identified a post-zygotic truncating TSC2 variant in both renal and hepatic AMLs but not in any of the healthy tissues. We did not detect any further, obvious tumor driver events. The identification of a passenger variant in SIPA1L3 in both AMLs points to a common clonal origin. Metastasis of the renal AML into the liver is unlikely on the basis of discordant histopathological features. Our findings therefore point to very low-grade mosaicism for the TSC2 variant, possibly in a yet unknown mesenchymal precursor cell that expanded clonally during tumor development. A possible contribution of the germline ARID1B variant to the tumorigenesis remains unclear but cannot be excluded given the absence of any other evident tumor drivers in the AMLs. Conclusion: This unique case highlights the blurred line between tumor genetics and post-zygotic events that can complicate exact molecular diagnoses in patients with rare manifestations. It also demonstrates the relevance of multiple disorders in a single individual, the challenges of detecting low-grade mosaicisms, and the importance of proper diagnosis for treatment and surveillance.
CRIS-Team Scopus Importer:2019-05-21
Keywords: Angiomyolipoma; ARID1B; Mosaic; Neurodevelopmental disorders; TSC2; Tuberous sclerosis complex

Disseminated Multifocal Intracerebral Bleeding Events in Three Coronavirus Disease 2019 Patients on Extracorporeal Membrane Oxygenation As Rescue Therapy. - Bihlmaier, Karl; Coras, Roland; Willam, Carsten; Grampp, Steffen; Jabari, Samir; Eichhorn, Philip; Haller, Florian; Kuramatsu, Joji; Schwab, Stefan; Castellanos, Ixchel; Birkholz, Torsten; Schüttler, Jürgen; et al. (Critical Care Explorations, 2020)
Objectives: To describe three coronavirus disease 2019 patients suffering from acute respiratory distress syndrome under venovenous extracorporeal membrane oxygenation therapy and tight anticoagulation monitoring presenting a novel pattern of multifocal brain hemorrhage in various degrees in all cerebral and cerebellar lobes. Design: Clinical observation of three patients. Post mortem examinations. Setting: Two ICUs at the University Hospital Erlangen. Patients: Three patients (medium age 56.6 yr, two male with hypertension and diabetes, one female with no medical history) developed severe acute respiratory distress syndrome on the basis of a severe acute respiratory syndrome coronavirus 2 infection. All required mechanical ventilation and venovenous extracorporeal membrane oxygenation support. Interventions: Clinical observation, CT, data extraction from electronic medical records, and post mortem examinations. Main Results: We report on an unusual multifocal bleeding pattern in the white matter in three cases with severe acute respiratory distress syndrome due to coronavirus disease 2019 undergoing venovenous extracorporeal membrane oxygenation therapy. Bleeding pattern with consecutive herniation was found in CT scans as well as in neuropathologic post mortem examinations. Frequency for this unusual brain hemorrhage in coronavirus disease 2019 patients with extracorporeal membrane oxygenation therapy at our hospital is currently 50%, whereas bleeding events in extracorporeal membrane oxygenation patients generally occur at 10-15%. Conclusions: Multifocality and high frequency of the unusual white matter hemorrhage pattern suggest a coherence to coronavirus disease 2019. Neuropathological analyses showed circumscribed thrombotic cerebrovascular occlusions, which eventually led to microvascular and later on macrovascular disseminated bleeding events. However, signs of cerebrovascular inflammation could not be detected. Polymerase chain reaction analyses of brain tissue or cerebrospinal fluid remained negative. Increased susceptibility for fatal bleeding events should be taken into consideration in terms of systemic anticoagulation strategies in coronavirus disease 2019.
EVALuna2:313697
Keywords: acute respiratory distress syndrome; cerebral microhemorrhage; coronavirus disease 2019; extracorporeal membrane oxygenation; intracerebral bleeding

Distal and proximal hypoxia response elements co-operate to regulate organ-specific erythropoietin gene expression - Orlando, Ilaria M. C.; Lafleur, Veronique N.; Storti, Federica; Spielmann, Patrick; Crowther, Lisa; Santambrogio, Sara; Schödel, Johannes; Hoogewijs, David; Mole, David R.; Wenger, Roland H. (Haematologica, 2020)
While it has been well-established that distal hypoxia response elements (HRE) regulate hypoxia-inducible factor (HIF) target genes such as erythropoietin (Epo), an interplay between multiple distal and proximal (promoter) HRE has not yet been described. Hepatic Epo expression is regulated by an HRE located downstream of the EPO gene, but this 3' HRE is not essential for renal EPO gene expression. We previously identified a 5' HRE and could show that both HRE direct exogenous reporter gene expression. Here, we show that, whereas in hepatic cells the 3' but not the 5' HRE is required, in neuronal cells both the 5' and 3' HRE contribute to endogenous Epo induction. Moreover, two novel putative HRE were identified in the EPO promoter. In hepatoma cells, HIF interacted mainly with the distal 3' HRE, but in neuronal cells, HIF most strongly bound the promoter, bound to a lesser extent the 3' HRE, and did not bind the 5' HRE. Interestingly, mutation of either of the two distal HRE abrogated HIF binding to the 3' and promoter HRE. These results suggest that a canonical functional HRE can recruit multiple transcription factors (not necessarily HIF) to mediate HIF binding to different distant HRE in an organ-specific manner.
CRIS-Team Scopus Importer:2020-12-25

Distinct mircobiomes in right- and left-sided colon cancer - Langheinrich, Melanie C.; Wirtz, Stefan; Kneis, Barbara; Weber, Klaus; Brunner, Maximilian; Krautz, Christian; Trebicka, Jonel; Agaimy, Abbas; Grützmann, Robert; Kersting, Stephan (ONCOLOGY RESEARCH AND TREATMENT, 2022)
CRIS-Team WoS Importer:2022-12-16

Diverse molecular causes of unsolved autosomal dominant tubulointerstitial kidney diseases - Wopperer, Florian; Knaup, Karl; Stanzick, Kira J.; Schneider, Karen; Jobst-Schwan, Tilman; Ekici, Arif Bülent; Uebe, Steffen; Wenzel, Andrea; Schliep, Stefan; Schürfeld, Carsten; Seitz, Randolf; Bernhardt, Wanja; et al. (Kidney International, 2022)
Autosomal Dominant Tubulointerstitial Kidney Disease (ADTKD) is caused by mutations in one of at least five genes and leads to kidney failure usually in mid adulthood. Throughout the literature, variable numbers of families have been reported, where no mutation can be found and therefore termed ADTKD-not otherwise specified. Here, we aim to clarify the genetic cause of their diseases in our ADTKD registry. Sequencing for all known ADTKD genes was performed, followed by SNaPshot minisequencing for the dupC (an additional cytosine within a stretch of seven cytosines) mutation of MUC1. A virtual panel containing 560 genes reported in the context of kidney disease (nephrome) and exome sequencing were then analyzed sequentially. Variants were validated and tested for segregation. In 29 of the 45 registry families, mutations in known ADTKD genes were found, mostly in MUC1. Sixteen families could then be termed ADTKD-not otherwise specified, of which nine showed diagnostic variants in the nephrome (four in COL4A5, two in INF2 and one each in COL4A4, PAX2, SALL1 and PKD2). In the other seven families, exome sequencing analysis yielded potential disease associated variants in novel candidate genes for ADTKD; evaluated by database analyses and genome-wide association studies. For the great majority of our ADTKD registry we were able to reach a molecular genetic diagnosis. However, a small number of families are indeed affected by diseases classically described as a glomerular entity. Thus, incomplete clinical phenotyping and atypical clinical presentation may have led to the classification of ADTKD. The identified novel candidate genes by exome sequencing will require further functional validation.
CRIS-Team Scopus Importer:2022-07-15
Keywords: ADTKD; Alport syndrome; exome; MITKD; MUC1; UMOD

Does renal artery supply indicate treatment success of renal denervation? - Schmid, Axel; Ditting, Tilmann; Sobotka, Paul A.; Veelken, Roland; Schmieder, Roland; Uder, Michael; Ott, Christian (Cardiovascular and Interventional Radiology, 2013)
Purpose: Renal denervation (RDN) emerged as an innovative interventional antihypertensive therapy. With the exception of pretreatment blood pressure (BP) level, no other clear predictor for treatment efficacy is yet known. We analyzed whether the presence of multiple renal arteries has an impact on BP reduction after RDN. Methods: Fifty-three patients with treatment-resistant hypertension (office BP ≥ 140/90 mmHg and 24-h ambulatory BP monitoring (≥130/80 mmHg) underwent bilateral catheter-based RDN. Patients were stratified into one-vessel (OV) (both sides) and at least multivessel (MV) supply at one side. Both groups were treated on one vessel at each side; in case of multiple arteries, only the dominant artery was treated on each side. Results: Baseline clinical characteristics (including BP, age, and estimated glomerular filtration rate) did not differ between patients with OV (n = 32) and MV (n = 21). Office BP was significantly reduced in both groups at 3 months (systolic: OV -15 ± 23 vs. MV -16 ± 20 mmHg; diastolic: OV -10 ± 12 vs. MV -8 ± 11 mmHg, both p = NS) as well as 6 months (systolic: OV -18 ± 18 vs. MV -17 ± 22 mmHg; diastolic: OV -10 ± 10 vs. -10 ± 12 mmHg, both p = NS) after RDN. There was no difference in responder rate (rate of patients with office systolic BP reduction of at least 10 mmHg after 6 months) between the groups. Conclusion: In patients with multiple renal arteries, RDN of one renal artery - namely, the dominant one - is sufficient to induce BP reduction in treatment-resistant hypertension. © 2013 Springer Science+Business Media New York and the Cardiovascular and Interventional Radiological Society of Europe (CIRSE).
CRIS-Team Scopus Importer:2023-03-08
Keywords: Ablation; Artery; Endovascular treatment; Hypertension; Kidney/renal; Radiofrequency ablation

Dominant PAX2 mutations may cause steroid-resistant nephrotic syndrome and FSGS in children - Vivante, Asaf; Chacham, Orna Staretz; Shril, Shirlee; Schreiber, Ruth; Mane, Shrikant M.; Pode-Shakked, Ben; Soliman, Neveen A.; Koneth, Irene; Schiffer, Mario; Anikster, Yair; Hildebrandt, Friedhelm (Pediatric Nephrology, 2019)
BACKGROUND: Heterozygous PAX2 mutations cause renal coloboma syndrome (RCS) [OMIM no. 120330]. RCS is a renal syndromic disease encompassing retinal coloboma and sensorineural hearing loss. Recently, a causative role for PAX2 was reported in adult-onset nephrotic syndrome secondary to focal segmental glomerulosclerosis (FSGS). However, the prevalence of PAX2 mutations among large cohort of children with steroid-resistant nephrotic syndrome (SRNS) and FSGS has not been systematically studied. METHODS: We employed whole-exome sequencing (WES) to identify the percentage of SRNS cases explained by monogenic mutations in known genes of SRNS/FSGS. As PAX2 mutations are not an established cause of childhood FSGS, we evaluated a cohort of 215 unrelated families with SRNS, in whom no underlying genetic etiology had been previously established. RESULTS: Using WES, we identified 3 novel causative heterozygous PAX2 mutations in 3 out of the 215 unrelated index cases studied (1.3%). All three cases were detected in individuals from families with more than one affected and compatible with an autosomal dominant mode of inheritance (3/57 familial cases studied (5.2%)). The clinical diagnosis in three out of four pediatric index patients was done during routine medical evaluation. CONCLUSIONS: Our findings demonstrate high frequency of PAX2 mutations in familial form of SRNS (5.2%) and further expand the phenotypic spectrum of PAX2 heterozygous mutations to include autosomal dominant childhood-onset FSGS. These results highlight the importance of including PAX2 in the list of genes known to cause FSGS in children.
EVALuna2:118625

Donor acute kidney injury and short-term graft outcome in renal transplantation - Jacobi, Johannes; Rebhan, Dirk; Heller, Katharina; Velden, Joachim; Hilgers, Karl Friedrich; Wullich, Bernd; Eckardt, Kai-Uwe; Amann, Kerstin Ute (Clinical Transplantation, 2014)
With increased waiting times for kidney transplantation, marginal organs from expanded criteria donors (ECD) are increasingly offered for allocation. In addition to ECD status, donors may have suffered from acute kidney injury (AKI) prior to organ procurement.In this retrospective cohort study, we studied short-term allograft function in 517 kidney transplants performed between the years 2008-2014. Recipients of allografts from deceased organ donors were categorized as standard criteria donors (SCD) or ECD with or without AKI defined by RIFLE criteria.Of 382 deceased donations, 174 (45.5%) were classified as ECD and 63 (16.5%) fulfilled AKI criteria. Donor creatinine on hospital admission was similar, whereas creatinine before organ procurement differed (p < 0.001). Despite these differences, serum creatinine and eGFR at discharge and after one yr showed only minor differences between kidneys with or without AKI. In multivariate linear regression analyses, donor AKI was not a predictor of one-yr allograft function.Given the poor prognosis of dialysis patients and the increase in waiting time, kidneys from SCD and ECD donors with AKI should be allocated for transplantation. In case of ECD donors with AKI, recipients should be informed about the possibility of permanent non-function or early graft loss.
EVALuna2:3714

Donor treatment with a PHD-inhibitor activating HIFs prevents graft injury and prolongs survival in an allogenic kidney transplant model - Bernhardt, W. M.; Gottmann, U.; Doyon, F.; Buchholz, Björn; Campean, Valentina; Schödel, Johannes; Reisenbuechler, A.; Klaus, S.; Arend, M.; Flippin, L.; Willam, Carsten; Yard, B.; et al. (Proceedings of the National Academy of Sciences of the United States of America, 2009)
Long-term survival of renal allografts depends on the chronic immune response and is probably influenced by the initial injury caused by ischemia and reperfusion. Hypoxia-inducible transcription factors (HIFs) are essential for adaptation to low oxygen. Normoxic inactivation of HIFs is regulated by oxygen-dependent hydroxylation of specific prolyl-residues by prolyl-hydroxylases (PHDs). Pharmacological inhibition of PHDs results in HIF accumulation with subsequent activation of tissue-protective genes. We examined the effect of donor treatment with a specific PHD inhibitor (FG-4497) on graft function in the Fisher-Lewis rat model of allogenic kidney transplantation (KTx). Orthotopic transplantation of the left donor kidney was performed after 24 h of cold storage. The right kidney was removed at the time of KTx (acute model) or at day 10 (chronic model). Donor animals received a single dose of FG-4497 (40 mg/kg i.v.) or vehicle 6 h before donor nephrectomy. Recipients were followed up for 10 days (acute model) or 24 weeks (chronic model). Donor preconditioning with FG-4497 resulted in HIF accumulation and induction of HIF target genes, which persisted beyond cold storage. It reduced acute renal injury (serum creatinine at day 10: 0.66 +/- 0.20 vs. 1.49 +/- 1.36 mg/dL; P < 0.05) and early mortality in the acute model and improved long-term survival of recipient animals in the chronic model (mortality at 24 weeks: 3 of 16 vs. 7 of 13 vehicle-treated animals; P < 0.05). In conclusion, pretreatment of organ donors with FG-4497 improves short-and long-term outcomes after allogenic KTx. Inhibition of PHDs appears to be an attractive strategy for organ preservation that deserves clinical evaluation.
Keywords: hypoxia-inducible transcription factors; kidney injury; protection; transplantation

Dose adjustment of anti-infective drugs in patients with renal failure and renal replacement therapy in intensive care medicine : Recommendations from the renal section of the DGIIN, ÖGIAIN and DIVI - Czock, D.; Schwenger, V.; Kindgen-Milles, D.; Joannidis, M.; John, S.; Schmitz, M.; Joerres, A.; Zarbock, A.; Oppert, M.; Kielstein, J. T.; Willam, Carsten (Medizinische Klinik - Intensivmedizin und Notfallmedizin, 2018)
BACKGROUND: Many anti-infective drugs require dose adjustments in critically ill patients with acute kidney injury (AKI) and renal replacement therapy, in order to achieve adequate therapeutic drug concentrations. OBJECTIVES: The fundamental pharmacokinetic and pharmacodynamic principles of drug dose adjustment are presented. Recommendations on anti-infective drug dosage in intensive care are provided. MATERIALS AND METHODS: We established dose recommendations of selected anti-infective drugs based on information in the summary of product characteristics, published studies and recommendations, pharmacokinetic and pharmacodynamic considerations, and the experience and expert opinion of the authors. RESULTS: Out of a total of 37 anti-infective drugs (31 antibiotics, 2 antivirals, 4 antifungals) 8 can be administered independent of renal function. For 29 anti-infective drugs, a specific recommendation on drug dosage could be made in case of intermittent hemodialysis and for 24 anti-infective drugs in case of continuous hemo(dia)filtration. CONCLUSIONS: Recommendations on dosing of important anti-infective drugs in critically ill patients with AKI and renal replacement therapy are provided.
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Dosing of indocyanine-green for intraoperative laser fluorescence angiography in kidney transplantation - Rother, Ulrich; Gerken, Andreas L. H.; Karampinis, Ioannis; Klumpp, Madeline; Regus, Susanne; Meyer, Alexander; Apel, Hendrik; Kraemer, Bernhard K.; Hilgers, Karl Friedrich; Lang, Werner; Nowak, Kai (Microcirculation, 2017)
Sufficient blood supply is a crucial factor determining postoperative allograft function in kidney transplantation. Therefore, besides the surgeon's individual impression a method for evaluating the quality of the organ's microperfusion is required. Laser fluorescence angiography with indocyanine-green (ICG) is an emerging tool for this purpose. However, no reproducible quantification of ICG fluorescence has been performed in transplantation so far.This retrospective two-center study was designed to evaluate the dosing of ICG for intraoperative laser fluorescence angiography in kidney transplantation. The Spy Elite(®) system (NOVADAQ, Canada) was employed for quantitative assessment of allograft microperfusion. ICG was administered systemically 5 min after reperfusion applying doses between 0.25 and 0.01 mg ICG per kg body weight. Quantitative assessment was performed with the implemented SPY-Q Software.57 kidney recipients were included in two centers. The generated curves showing ICG ingress and egress rates were not evaluable due to oversensing when doses exceeded 0.02 mg per kg body weight.Fluorescence angiography with ICG is an emerging tool for the intraoperative quality control and evaluation of microperfusion in kidney transplantation. A dose of 0.02 mg ICG per kg body weight is recommended in order to ensure the quantitative assessment with SPY-Q. This article is protected by copyright. All rights reserved.
EVALuna2:3964

Do telomeres have a higher plasticity than thought? Results from the German Chronic Kidney Disease (GCKD) study as a high-risk population - Raschenberger, Julia; Kollerits, Barbara; Titze, Stephanie; Koettgen, Anna; Bärthlein, Barbara; Ekici, Arif Bülent; Forer, Lukas; Schoenherr, Sebastian; Weissensteiner, Hansi; Haun, Margot; Wanner, Christoph; Eckardt, Kai-Uwe; et al. (Experimental Gerontology, 2015)
Telomere length is considered as a biological marker for aging. It is expected that telomeres shorten with age and with conditions associated with oxidative stress and inflammation. Both are present in patients with chronic kidney disease (CKD) who have a very high cardiovascular risk. We investigated whether CKD duration is associated with relative telomere length (RTL) in 4802 patients from the German Chronic Kidney Disease (GCKD) study. We measured RTL in each sample in quadruplicates using a quantitative polymerase chain reaction (qPCR). We observed a U-shaped association of RTL with CKD duration: the longest RTL was found in those 339 patients who reported the shortest disease duration (<6months) and shorter RTL in 2108 patients with duration between 6months and less than 5years. Most importantly, those 2331 patients who reported a CKD duration of 5years and more had significantly longer RTL compared to those with intermediate CKD duration (6months to less than 5years): mean 0.954, 95%CI 0.946-0.961 versus 0.937, 95%CI 0.929-0.944, p=0.002). Due to the cross-sectional nature of the study these surprising results have to be considered with caution and as hypothesis-generating. Whether the longer RTL in patients with long-lasting disease is caused by an activation of telomerase to counteract the shortening of RTL due to oxidative stress and inflammation or whether they are caused by a survival bias needs to be investigated in longitudinal studies. Our data are in support of a higher plasticity of shortening and elongations of RTL as until recently anticipated.
EVALuna2:138

Dual inhibition of Src family kinases and Aurora kinases by SU6656 modulates CTGF (connective tissue growth factor) expression in an ERK-dependent manner - Cicha, Iwona; Zitzmann, Rita; Goppelt-Strübe, Margarete (International Journal of Biochemistry & Cell Biology, 2014)
Src kinases are regulators of the expression of connective tissue growth factor (CTGF/CCN2), which plays a role in fibrotic injuries. The aim of the present study was to evaluate the potential of SU6656, a dual inhibitor of Src family and Aurora kinases, to interfere with the synthesis of this pro-fibrotic factor. SU6656 impaired TGF-?-mediated upregulation of CTGF mRNA and protein in proximal epithelial HKC-8 cells, and also reduced CTGF expression in cells exposed to autocrine growth factors. In association with the inhibition of Src family kinases and diminished focal adhesion kinase activity, adherence of the cells was reduced. Furthermore, SU6656 interfered with Aurora kinase activity resulting in inhibition of cell division and formation multilobular nuclei after 24h. Comparable alterations were observed in primary tubular cells. When cell division was inhibited by SU6656 or ZM447439, a specific inhibitor of Aurora kinases, CTGF levels were back to control or even increased after 48h. The activity of RhoA-Rho kinase and ERK signaling was analyzed to delineate the signaling pathways responsible for the biphasic regulation of CTGF. While Rho kinase was not significantly altered by SU6656, ERK activity was inhibited in the early phase and increased after 24-48h. ERK activity correlated with secreted CTGF. As ZM447439 increased ERK activity only after 48h, cellular reorganization is likely responsible for triggering the ERK-dependent upregulation of CTGF. Taken together, in non-transformed epithelial cells, SU6656 modulates the expression of the pro-fibrotic factor CTGF in a time-dependent manner by inhibition of Src kinases and Aurora kinases.
EVALuna2:3674

Dual renin-angiotensin system blockade and outcome benefits in hypertension: a narrative review - Mann, Johannes; Boehm, Michael (Current Opinion in Cardiology, 2015)
Inhibition of the renin-angiotensin system (RASi) lowers blood pressure, reduces cardiovascular outcomes and blunts the progressive course of heart failure and of chronic kidney disease. This narrative article summarizes why the hypothesis came up that more complete RASi with two different agents should be more beneficial compared with one agent and how this hypothesis was deflated in randomized clinical trials (RCTs).The hypothesis was based on experimental findings and surrogate endpoints in patients, namely lowering of blood pressure and reduction of proteinuria. Three large RCTs in patients with atherosclerotic vascular disease or in diabetic kidney disease randomized almost 40, 000 patients. RASi with one agent was compared with RASi with two agents. All three RCTs ruled out benefits of dual RASi on major cardiovascular outcomes and reported substantial adverse effects of dual RASi. The latter included hyperkalemia, acute kidney injury, symptomatic hypotension and syncope. There was also no substantial advantage of dual over monotherapy on decline in kidney function. In one RCT, there was a hint of nonsustained, early benefit on kidney outcomes with dual therapy.Outside heart failure, RASi with two agents is not indicated to treat hypertension because of substantial safety concerns and lack of benefit on major cardiovascular and kidney outcomes.
EVALuna2:3878

Durability of blood pressure reduction after ultrasound renal denervation: three-year follow-up of the treatment arm of the randomised RADIANCE-HTN SOLO trial - Rader, Florian; Kirtane, Ajay J.; Wang, Yale; Daemen, Joost; Lurz, Philipp; Sayer, Jeremy; Saxena, Manish; Levy, Terry; Scicli, Andrea P.; Thackeray, Lisa; Azizi, Michel; Weber, Michael A.; et al. (EuroIntervention, 2022)
Background: While the blood pressure (BP)-lowering effect of renal denervation (RDN) has been established, long-term durability is a key prerequisite for a broader clinical implementation. Aims: Our aims were to assess the long-term durability of the office BP (OBP)-lowering efficacy, antihypertensive medication (AHM) use, and safety of ultrasound RDN (uRDN). Methods: Four weeks after withdrawal of AHM, patients with untreated daytime ambulatory BP ≥135/85 mmHg and <170/105 mmHg were randomised to uRDN (n=74) or sham (n=72) in the RADIANCE-HTN SOLO trial. Initiation of AHM was encouraged for home BP >135/85 mmHg following primary endpoint ascertainment at 2 months. Patients and physicians were unblinded at 6 months. Results: Fifty-one of 74 patients (age: 53.9±11 years; 67% men) originally randomised to uRDN completed the 36-month follow-up. Initial screening OBP upon study entry was 145/92±14/10 mmHg on a mean of 1.2 AHM (range: 0-2.0). Baseline OBP after AHM washout was 154/99±13/8 mmHg. At 36 months, patients were on an average of 1.3 AHM (range: 0-3.0) with 8 patients on no AHM. OBP decreased by 18/11±15/9 mmHg from baseline to 36 months (p<0.001 for both). Overall, OBP control (<140/90 mmHg) improved from 29.4% at screening to 45.1% at 36 months (p=0.059). For patients uncontrolled at screening (n=36), systolic OBP decreased by 10.8 mmHg (p<0.001) at 36 months on similar AHM (p=0.158). Conclusions: The safety and effectiveness of uRDN was durable to 36 months, with reduced OBP and improved OBP control despite a similar starting medication burden. No new uRDN-related long-term safety concerns were identified.
CRIS-Team Scopus Importer:2022-11-25
Keywords: clinical research; clinical trials; renal sympathetic denervation

Dyadic Coping of Kidney Transplant Recipients and Their Partners: Sex and Role Differences - Tkachenko, Daria; Franke, Laura; Peters, Luisa; Schiffer, Mario; Zimmermann, Tanja (Frontiers in Psychology, 2019)
Background: Coping with stressful health issues - e.g., organ transplantation - can affect interpersonal relationships. Objective: The study examines individual and dyadic coping (DC) in kidney transplant recipients and their partners under consideration of sex and role differences. The Dyadic Coping Inventory allows analyzing partners' perception of their own DC and also of their partner's behavior and investigating different perspectives with three discrepancy indexes (similarity, perceived similarity, congruence). Methods: Fifty-six kidney transplant recipients and their partners completed self-report questionnaires (N = 112) on DC, depression, anxiety, and relationship satisfaction. The average age of the patients was 58.1 years and of the partners 57.2 years; 64.3% of the patients were male; time since transplantation was on average 9.7 years. Results: (1) Individual and dyadic functioning: In couples with male patients female caregivers showed higher own supportive DC than the males. In couples with female patients, women reported higher own stress communication, supportive DC, total positive DC and total DC as well as depression compared to men. (2) Regarding the discrepancy indexes, in couples with male patients lower levels of similarity in DC reactions of the couple was associated with higher depression of the males as well as higher anxiety of the females. Moreover, lower comparability of the own DC with partner-perception was correlated with higher depression in males. In couples with female patients, higher comparability was associated with higher DC. Higher DC of the males was associated with lower own anxiety and better similarity in DC reactions. Lower levels of similarity of the male spouse showed correlations with higher depression and anxiety of the females. (3) Sex and role differences occurred. No significant differences between male patients and male partners occurred whereas female patients showed higher own stress communication, supportive DC, common DC, total positive DC, total DC and relationship satisfaction compared to female caregivers (role differences). The same differences were found comparing female with male patients. No differences occurred between male and female caregivers (sex differences). (4) Regarding male's relationship quality, male's DC total score and similarity index seem to be important predictors in couples with male patients. Discussion: The results demonstrate the relevance of DC in couples with kidney transplantation and show differences between males and females as well as between patients and partners.
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Dysregulation of the polyamine system in favour of its catabolism is a common mechanism after kidney injury - Sieckmann, T.; Ogel, N.; Kelterborn, S.; Boivin, F.; Schley, Gunnar; Fahling, M.; Ashraf, M. I.; Reichel, M.; Vigolo, E.; Knauf, F.; Rosenberger, C.; Aigner, F.; et al. (ACTA PHYSIOLOGICA, 2022)
CRIS-Team WoS Importer:2022-10-07

Early conversion to a CNI-free immunosuppression with SRL after renal transplantation-Long-term follow-up of a multicenter trial - Andrassy, Joachim; Guba, Markus; Habicht, Antje; Fischereder, Michael; Pratschke, Johann; Pascher, Andreas; Heller, Katharina M.; Banas, Bernhard; Hakenberg, Oliver; Vogel, Thomas; Meiser, Bruno; Dick, Andrea; et al. (PLoS ONE, 2020)
INTRODUCTION: Early conversion to a CNI-free immunosuppression with SRL was associated with an improved 1- and 3- yr renal function as compared with a CsA-based regimen in the SMART-Trial. Mixed results were reported on the occurrence of donor specific antibodies under mTOR-Is. Here, we present long-term results of the SMART-Trial. METHODS AND MATERIALS: N = 71 from 6 centers (n = 38 SRL and n = 33 CsA) of the original SMART-Trial (ITT n = 140) were enrolled in this observational, non-interventional extension study to collect retrospectively and prospectively follow-up data for the interval since baseline. Primary objective was the development of dnDSA. Blood samples were collected on average 8.7 years after transplantation. RESULTS: Development of dnDSA was not different (SRL 5/38, 13.2% vs. CsA 9/33, 27.3%; P = 0.097). GFR remained improved under SRL with 64.37 ml/min/1.73m2 vs. 53.19 ml/min/1.73m2 (p = 0.044). Patient survival did not differ between groups at 10 years. There was a trend towards a reduced graft failure rate (11.6% SRL vs. 23.9% CsA, p = 0.064) and less tumors under SRL (2.6% SRL vs. 15.2% CsA, p = 0.09). CONCLUSIONS: An early conversion to SRL did not result in an increased incidence of dnDSA nor increased long-term risk for the recipient. Transplant function remains improved with benefits for the graft survival.
CRIS-Team Scopus Importer:2020-08-14

Early Signs of End-Organ Damage in Retinal Arterioles in Patients with Type 2 Diabetes Compared to Hypertensive Patients - Jumar, Agnes; Ott, Christian; Kistner, Iris; Friedrich, Stefanie; Michelson, Georg; Harazny, Joanna M.; Schmieder, Roland (Microcirculation, 2016)
Eutrophic and hypertrophic remodeling are major vascular hallmarks for hypertension and diabetes-associated microvascular end-organ damage in peripheral arterioles. The aim of this study is to compare retinal arterioles of diabetic, hypertensive, and healthy individuals.Retinal parameters were assessed in 99 patients with T2DM, 158 hypertensive, and 149 healthy individuals. WT and CA of retinal arterioles (80-140 ?m) were measured noninvasively and in vivo by scanning laser Doppler flowmetry (Heidelberg Engineering, Germany).After adjustment for values differing between the groups (age, BMI, gender, HDL cholesterol and serum creatinine, systolic office BP), patients with T2DM showed no significant difference in WT (14.2 ± 3), and CA (4199 ± 1107) in comparison with hypertensive patients (WT = 13.3 ± 4, p = 0.18, CA = 3862 ± 1546, p = 0.10) and healthy individuals (WT = 13.1 ± 3, p = 0.55, CA = 3864 ± 1216, p = 0.86). However, the subgroup of patients with diabetes duration of more than 60 months showed greater WT (14.9 ± 4, p = 0.04) and CA (4557 ± 1137, p = 0.02) than the hypertensive group and greater WT (p = 0.04) and CA (p = 0.03) than the healthy group, which is consistent with hypertrophic remodeling.In the early stage of T2DM no hypertrophic remodeling was seen in retinal arterioles. However, hypertrophic remodeling was found in diabetic patients with more than 60 months duration of disease.
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Early vascular damage in retinal microcirculation in arterial hypertension: the Czech post-MONICA study - Cífková, Renata; Harazny, Joanna; Bruthans, Jan; Wohlfahrt, Peter; Krajčoviechová, Alena Hrubeš; Lánská, Věra; Gelžinský, Július; Mateřánková, Markéta; Mareš, Štěpán; Filipovský, Jan; Mayer, Otto; Schmieder, Roland (Journal of Hypertension, 2024)
Retinal microcirculation reflects retinal perfusion abnormalities and retinal arterial structural changes at relatively early stages of various cardiovascular diseases. Wall-to-lumen ratio (WLR) may represent the earliest step in hypertension-mediated organ damage.Our objective was to compare functional and structural parameters of retinal microcirculation in a randomly selected urban population sample, in hypertensive and normotensive individuals. DESIGN AND METHOD: A total of 398 randomly selected individuals from an urban population aged 25-65 years, residing in Pilsen, Czech Republic, were screened for major cardiovascular risk factors. Retinal microcirculation was assessed using scanning laser Doppler flowmetry, with data evaluable in 343 patients. Complete data were available for 342 individuals divided into four groups based on blood pressure and control status of hypertension: normotensive individuals ( n = 213), treated controlled hypertensive individuals ( n = 30), treated uncontrolled hypertensive individuals ( n = 26), and newly detected/untreated hypertensive individuals ( n = 73). RESULTS: There was a tendency to higher wall thickness in treated but uncontrolled hypertensive patients (compared to normotensive and treated controlled hypertensive individuals). WLR was significantly increased in treated but uncontrolled hypertensive patients as well as in individuals with newly detected thus untreated hypertension or in patients with known but untreated hypertension. There was no difference in WLR in treated, controlled hypertensive patients compared with normotensive individuals. CONCLUSION: Our results show that an increased WLR, reflecting early vascular damage, was found in newly detected individuals with hypertension and in untreated hypertensive patients, reflecting early hypertension-mediated vascular damage. Early initiation of hypertension treatment may be warranted.
CRIS-Team Scopus Importer:2024-02-16

Early vascular parameters in the micro- and macrocirculation in type 2 diabetes - Kannenkeril, Dennis; Bosch, Agnes; Harazny, Joanna; Karg, Marina; Jung, Susan; Ott, Christian; Schmieder, Roland (Cardiovascular Diabetology, 2018)
BACKGROUND: Diabetes converts from a metabolic disorder into a predominantly vascular disease, once its duration extends over several years or/and when additional cardiovascular risk factors such as hypertension coexist. In a cross-sectional analysis we analyzed various vascular parameters in the renal, retinal and systemic circulation, with the goal to identify which vascular parameter of early organ damage is the earliest that can be clinically detected. METHODS: In 111 patients with type 2 diabetes (T2DM) (off any anti-diabetic medication for at least 4 weeks) and 54 subjects without T2DM we compared various parameters of early vascular remodeling in the same patient: urinary albumin creatinine ratio ([UACR], early morning spot urine) and estimated glomerular filtration rate (eGFR), retinal capillary flow (RCF) and intercapillary distance (ICD) as parameters of capillary rarefaction, wall-to-lumen ratio (WLR) of the retinal arterioles [all assessed by Scanning Laser Doppler Flowmetry], and central systolic pressure (cSBP) and central pulse pressure (cPP) [measured by pulse wave analysis, Syphygmocor] both reflecting vascular stiffness of large arteries. RESULTS: Compared to subjects without T2DM, patients with T2DM (diabetes duration: median 48 months, interquartile range 24-88 months) were older (59.8 ± 7.3 vs 43.4 ± 12.9 years, p < 0.001), more females (33.3 vs 20.4%, p < 0.001), but 24-h systolic and diastolic blood pressure did not differ between the two groups. The analysis adjusted for age, gender and cardiovascular risk factors revealed that ICD (23.9 ± 5.1 vs 20.8 ± 3.5 µm, p value = 0.001) and cPP (41.8 ± 11.7 vs 34.8 ± 10.6 mmHg, p value < 0.001) were significantly higher and eGFR (91.7 ± 9.9 vs 95.9 ± 17.3 ml/min/1.73 m2, p value < 0.001) was significantly lower in patients with T2DM than in subjects without T2DM. CONCLUSION: These data suggest that at similar blood pressure capillary rarefaction in the retinal circulation (ICD), decreased eGFR in the renal circulation and increased central pulse pressure (cPP) of large arteries are earlier detectable than other vascular remodeling parameters of the micro- (WLR, RCF, UACR) and macrocirculation (cSBP) in patients with T2DM. Trial registration Trial registration number: NCT02471963, Date of registration: June 15, 2015, retrospectively registered; Trial registration number: NCT01319357, Date of registration: March 21, 2011, retrospectively registered; Trial registration number: NCT02383238, Date of registration: March 9, 2015, retrospectively registered; Trial registration number: NCT00152698, Date of registration: September 9, 2005, prospectively registered; Trial registration number: NCT00136188, Date of registration: August 26, 2005, prospectively registered.
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Editorial comment: Renal denervation COMMENT - Schmieder, Roland; Bosch, Agnes (Hypertension Research, 2021)
CRIS-Team WoS Importer:2021-12-24

Educational Attainment Is Associated With Kidney and Cardiovascular Outcomes in the German CKD (GCKD) Cohort - Winitzki, Doris; Zacharias, Helena U.; Nadal, Jennifer; Baid-Agrawal, Seema; Schaeffner, Elke; Schmid, Matthias; Busch, Martin; Bergmann, Manuela M.; Schultheiss, Ulla; Kotsis, Fruzsina; Stockmann, Helena; Meiselbach, Heike; et al. (Kidney International Reports, 2022)
Introduction: Prospective data on impact of educational attainment on prognosis in patients with chronic kidney disease (CKD) are scarce. We investigated the association between educational attainment and all-cause mortality, major adverse cardiovascular (CV) events (MACEs), kidney failure requiring dialysis, and CKD etiology. Methods: Participants (N = 5095, aged 18–74 years) of the ongoing multicenter German Chronic Kidney Disease (GCKD) cohort, enrolled on the basis of an estimated glomerular filtration rate (eGFR) of 30 to 60 ml/min (stages G3, A1–A3) or overt proteinuria (stages G1–G2, A3), were divided into 3 categories according to their educational attainment and were followed for 6.5 years. Results: Participants with low educational attainment (vs. high) had a higher risk for mortality (hazard ratio [HR] 1.48, 95% CI: 1.16–1.90), MACE (HR 1.37, 95% CI: 1.02–1.83), and kidney failure (HR 1.54, 95% CI: 1.15–2.05). Mediators between low educational attainment and mortality were smoking, CV disease (CVD) at baseline, low income, higher body mass index, and higher serum levels of CRP, high-density lipoprotein cholesterol, uric acid, NGAL, BAP, NT-proBNP, OPN, H-FABP, and urea. Low educational attainment was positively associated with diabetic nephropathy (odds ratio [OR] 1.65, 95% CI: 1.36–2.0) and CKD subsequent to acute kidney injury (OR 1.56, 95% CI: 1.03–2.35), but negatively associated with IgA nephropathy (OR 0.68, 95% CI: 0.52–0.90). Conclusion: Low educational attainment is associated with adverse outcomes and CKD etiology. Lifestyle habits and biomarkers mediate associations between low educational attainment and mortality. Recognition of the role of educational attainment and the associated health-relevant risk factors is important to optimize the care of patients with CKD and improve prognosis.
CRIS-Team Scopus Importer:2022-03-11
Keywords: biomarker; CASMIN; chronic kidney disease; CKD; educational attainment; socioeconomic status

Effective CKD care in European countries: challenges and opportunities for health policy - Bello, Aminu K.; Levin, Adeera; Manns, Braden J.; Feehally, John; Drueke, Tilman; Faruque, Labib; Hemmelgarn, Brenda R.; Kernahan, Charles; Mann, Johannes; Klarenbach, Scott; Remuzzi, Giuseppe; Tonelli, Marcello (American Journal of Kidney Diseases, 2015)
Chronic kidney disease (CKD) is an important global public health problem that is associated with adverse health outcomes and high health care costs. Effective and cost-effective treatments are available for slowing the progression of CKD and preventing its complications, including cardiovascular disease. Although wealthy nations have highly structured schemes in place to support the care of people with kidney failure, less consideration has been given to health systems and policy for the much larger population of people with non-dialysis-dependent CKD. Further, how to integrate such strategies with national and international initiatives for control of other chronic noncommunicable diseases (NCDs) merits attention. We synthesized the various approaches to CKD control across 17 European countries and present our findings according to the key domains suggested by the World Health Organization framework for NCD control. This report identifies opportunities to strengthen CKD-relevant health systems and explores potential mechanisms to capitalize on these opportunities. Across the 17 countries studied, we found a number of common barriers to the care of people with non-dialysis-dependent CKD: limited work force capacity, the nearly complete absence of mechanisms for disease surveillance, lack of a coordinated CKD care strategy, poor integration of CKD care with other NCD control initiatives, and low awareness of the significance of CKD. These common challenges faced by diverse health systems reflect the need for international cooperation to strengthen health systems and policies for CKD care.
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Effect of aliskiren on vascular remodelling in small retinal circulation - Jumar, Agnes; Ott, Christian; Kistner, Iris; Friedrich, Stefanie; Schmidt, Stefan; Harazny, Joanna M.; Schmieder, Roland (Journal of Hypertension, 2015)
In hypertension, changes in small arterial structure are characterized by an increased wall-to-lumen ratio (WLR). These adaptive processes are modulated by the rennin-angiotensin system. It is unclear whether direct renin inhibitors exert protective effects on small arteries in hypertensive patients.In this double-blind, randomized, placebo-controlled study (http://www.clinicaltrials.gov: NCT01318395), 114 patients with primary hypertension were randomized to additional therapy with either placebo or aliskiren 300 mg for 8 weeks after 4 weeks of standardized open-label treatment with valsartan 320 mg (run-in phase). Parameter of arteriolar remodelling was WLR of retinal arterioles (80 - 140 ?m) assessed noninvasively and in vivo by scanning laser Doppler flowmetry (Heidelberg Engineering, Germany). In addition, pulse wave analysis (SphygmoCor, AtCor Medical, Australia) and pulse pressure (PP) amplification were determined.In the whole study population, no clear effect of additional therapy with aliskiren on vascular parameters was documented. When analyses were restricted to patients with vascular remodelling, defined by a median of WLR more than 0.3326 (n = 57), WLR was reduced after 8 weeks by the treatment with aliskiren compared with placebo (-0.044 ± 0.07 versus 0.0043 ± 0.07, P = 0.015). Consistently, after 8 weeks of on-top treatment with aliskiren, there was an improvement of PP amplification compared with placebo (0.025 ± 0.07 versus -0.034 ± 0.08, P = 0.013), indicative of less stiff arteries in the peripheral circulation.Thus, our data indicate that treatment with aliskiren, given on top of valsartan therapy, improves altered vascular remodelling in hypertensive patients.
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Effect of Arteriovenous Anastomosis on Blood Pressure Reduction in Patients With Isolated Systolic Hypertension Compared With Combined Hypertension - Ott, Christian; Lobo, Melvin D.; Sobotka, Paul A.; Mahfoud, Felix; Stanton, Alice; Cockcroft, John; Sulke, Neil; Dolan, Eamon; Van Der Giet, Markus; Hoyer, Joachim; Furniss, Stephen S.; Foran, John P.; et al. (Journal of the American Heart Association, 2016)
Options for interventional therapy to lower blood pressure (BP) in patients with treatment-resistant hypertension include renal denervation and the creation of an arteriovenous anastomosis using the ROX coupler. It has been shown that BP response after renal denervation is greater in patients with combined hypertension (CH) than in patients with isolated systolic hypertension (ISH). We analyzed the effect of ROX coupler implantation in patients with CH as compared with ISH.The randomized, controlled, prospective ROX Control Hypertension Study included patients with true treatment-resistant hypertension (office systolic BP >=140 mm Hg, average daytime ambulatory BP >=135/85 mm Hg, and treatment with >=3 antihypertensive drugs including a diuretic). In a post hoc analysis, we stratified patients with CH (n=31) and ISH (n=11). Baseline office systolic BP (177±18 mm Hg versus 169±17 mm Hg, P=0.163) and 24-hour ambulatory systolic BP (159±16 mm Hg versus 154±11 mm Hg, P=0.463) did not differ between patients with CH and those with ISH. ROX coupler implementation resulted in a significant reduction in office systolic BP (CH: -29±21 mm Hg versus ISH: -22±31 mm Hg, P=0.445) and 24-hour ambulatory systolic BP (CH: -14±20 mm Hg versus ISH: -13±15 mm Hg, P=0.672), without significant differences between the two groups. The responder rate (office systolic BP reduction >=10 mm Hg) after 6 months was not different (CH: 81% versus ISH: 82%, P=0.932).Our data suggest that creation of an arteriovenous anastomosis using the ROX coupler system leads to a similar reduction of office and 24-hour ambulatory systolic BP in patients with combined and isolated systolic hypertension.URL: http://www.clinicaltrials.gov. Unique identifier: NCT01642498.
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Effect of Compression Garments on the Development of Delayed-Onset Muscle Soreness: A Multimodal Approach Using Contrast-Enhanced Ultrasound and Acoustic Radiation Force Impulse Elastography - Heiß, Rafael; Kellermann, Marion; Swoboda, Bernd; Grim, Casper; Lutter, Christoph; May, Matthias; Wüst, Wolfgang; Uder, Michael; Nagel, Armin Michael; Hotfiel, Thilo (Journal of Orthopaedic & Sports Physical Therapy, 2018)
BACKGROUND: Delayed-onset muscle soreness (DOMS) is one of the most common reasons for impaired muscle performance in sports. However, little consensus exists regarding which treatments may be most effective, and the underlying mechanisms are poorly understood. OBJECTIVES: To investigate the influence of compression garments on the development of DOMS, focusing on changes in muscle perfusion and muscle stiffness. METHODS: In this controlled laboratory study with repeated measures, muscle perfusion and stiffness, calf circumference, muscle soreness, passive ankle dorsiflexion, and creatine kinase levels were assessed in participants before (baseline) a DOMS-inducing eccentric calf exercise intervention and 60 hours later (follow-up). After DOMS induction, a sports compression garment (18-21 mmHg) was worn on 1 randomly selected calf until follow-up, while the contralateral calf served as an internal control. Muscle perfusion was assessed using contrast-enhanced ultrasound (peak enhancement and wash-in area under the curve), while muscle stiffness was assessed using acoustic radiation force impulse (shear-wave velocities). A magnetic resonance imaging scan of both lower legs was also performed during the follow-up testing session to characterize the extent of exercise-induced muscle damage. Comparisons were made between limbs and over time. RESULTS: Shear-wave velocity values of the medial gastrocnemius showed a significant interaction between time and treatment (P = .006), with the noncompressed muscle demonstrating lower muscle stiffness values at follow-up compared to baseline or to the compressed muscle. No significant differences in soleus muscle stiffness were noted between limbs or over time, as was the case for muscle perfusion metrics (peak enhancement and wash-in area under the curve) for the medial gastrocnemius and soleus muscles. Further, compression had no significant effect on passive ankle dorsiflexion, muscle soreness, calf circumference, or injury severity, per magnetic resonance imaging. CONCLUSION: Continuous wearing of compression garments during the inflammation phase of DOMS may play an important role in regulating muscle stiffness; however, compression garments have no significant effects on intramuscular perfusion or other common clinical assessments. J Orthop Sports Phys Ther 2018;48(11):887-894. Epub12 Jun 2018. doi:10.2519/jospt.2018.8038.
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Effect of Compression Garments on the Development of Edema and Soreness in Delayed-Onset Muscle Soreness (DOMS) - Heiß, Rafael; Hotfiel, Thilo; Kellermann, Marion; May, Matthias; Wüst, Wolfgang; Janka, Rolf Matthias; Nagel, Armin M.; Uder, Michael; Hammon, Matthias (Journal of Sports Science and Medicine, 2018)
Delayed-onset muscle soreness (DOMS), an ultrastructural muscle injury, is one of the most common reasons for impaired muscle performance. The purpose of this study was to investigate the influence of sport compression garments on the development of exercise-induced intramuscular edema in the context of DOMS. DOMS was induced in 15 healthy participants. The participants performed a standardized eccentric exercise of the calf muscles. Magnetic resonance imaging (MRI) was performed at baseline and 60h after exercise (T2-weighted signal intensity and T2 relaxation time was evaluated in each compartment and the intramuscular edema in the medial head of the gastrocnemius muscle was segmented). After the exercise, a conventional compression garment (18-21 mmHg) was placed on one randomized calf for 60h. The level of muscle soreness was evaluated using a visual analogue pain scale. T2-weighted signal intensity, T2 relaxation time and intramuscular edema showed a significant interaction for time with increased signal intensities/intramuscular edema in the medial head of the gastrocnemius muscle at follow-up compared to baseline. No significant main effect for compression or interaction between time and limb occurred. Further, no significant differences in the soleus muscle and the lateral head of the gastrocnemius muscle were noted between limbs or over time. After exercise, there was significantly increased muscle soreness in both lower legs in resting condition and when going downstairs and a decreased range of motion in the ankle joint. No significant difference was observed between the compressed and the non-compressed calf. Our results indicate that wearing conventional compression garments after DOMS has been induced has no significant effect on the development of muscle edema, muscle soreness, range of motion and calf circumference.
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Effect of Dapagliflozin on Clinical Outcomes in Patients With Chronic Kidney Disease, With and Without Cardiovascular Disease - McMurray, John J.V.; Wheeler, David C.; Stefánsson, Bergur V.; Jongs, Niels; Postmus, Douwe; Correa-Rotter, Ricardo; Chertow, Glenn M.; Greene, Tom; Held, Claes; Hou, Fan Fan; Mann, Johannes; Rossing, Peter; et al. (Circulation, 2021)
BACKGROUND: Dapagliflozin reduces the risk of end-stage renal disease in patients with chronic kidney disease. We examined the relative risk of cardiovascular and renal events in these patients and the effect of dapagliflozin on either type of event, taking account of history of cardiovascular disease. METHODS: In the DAPA-CKD trial (Dapagliflozin and Prevention of Adverse Outcomes in Chronic Kidney Disease), 4304 participants with chronic kidney disease were randomly assigned to dapagliflozin 10 mg once daily or placebo. The primary end point was a composite of sustained decline in estimated glomerular filtration rate ≥50%, end-stage kidney disease, or kidney or cardiovascular death. The secondary end points were a kidney composite outcome (primary end point, minus cardiovascular death), the composite of hospitalization for heart failure or cardiovascular death, and all-cause death. In a prespecified subgroup analysis, we divided patients into primary and secondary prevention subgroups according to history of cardiovascular disease. RESULTS: Secondary prevention patients (n=1610; 37.4%) were older, were more often male, had a higher blood pressure and body mass index, and were more likely to have diabetes. Mean estimated glomerular filtration rate and median urinary albumin-to-creatinine ratio were similar in the primary and secondary prevention groups. The rates of adverse cardiovascular outcomes were higher in the secondary prevention group, but kidney failure occurred at the same rate in the primary and secondary prevention groups. Dapagliflozin reduced the risk of the primary composite outcome to a similar extent in both the primary (hazard ratio, 0.61 [95% CI, 0.48-0.78]) and secondary (0.61 [0.47-0.79]) prevention groups (P-interaction=0.90). This was also true for the composite of heart failure hospitalization or cardiovascular death (0.67 [0.40-1.13] versus 0.70 [0.52-0.94], respectively; P-interaction=0.88), and all-cause mortality (0.63 [0.41-0.98] versus 0.70 [0.51-0.95], respectively; P-interaction=0.71). Rates of adverse events were low overall and did not differ between patients with and without cardiovascular disease. CONCLUSIONS: Dapagliflozin reduced the risk of kidney failure, death from cardiovascular causes or hospitalization for heart failure, and prolonged survival in people with chronic kidney disease, with or without type 2 diabetes, independently of the presence of concomitant cardiovascular disease. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03036150.
CRIS-Team Scopus Importer:2021-04-19
Keywords: cardiovascular diseases; heart failure; renal insufficiency; chronic; sodium-glucose transporter 2 inhibitors

Effect of empagliflozin on ketone bodies in patients with stable chronic heart failure - Pietschner, Robert; Kolwelter, Julie; Bosch, Agnes; Striepe, Kristina; Jung, Susan; Kannenkeril, Dennis; Ott, C.; Schiffer, Mario; Achenbach, Stephan; Schmieder, Roland (Cardiovascular Diabetology, 2021)
Background: Recent studies indicated that sodium glucose cotransporter (SGLT)2 inhibition increases levels of ketone bodies in the blood in patients with type 1 and 2 diabetes. Other studies suggested that in patients with chronic heart failure (CHF), increased myocardial oxygen demand can be provided by ketone bodies as a fuel substrate. Experimental studies reported that ketone bodies, specifically beta-hydroxybutyrate (β-OHB) may increase blood pressure (BP) by impairing endothelium-dependant relaxation, thereby leading to increased vascular stiffness. In our study we assessed whether the SGLT 2 inhibition with empagliflozin increases ketone bodies in patients with stable CHF and whether such an increase impairs BP and vascular function. Methods: In a prospective, double blind, placebo controlled, parallel-group single centre study 75 patients with CHF (left ventricular ejection fraction 39.0 ± 8.2%) were randomised (2:1) to the SGLT-2 inhibitor empagliflozin 10 mg orally once daily or to placebo, 72 patients completed the study. After a run-in phase we evaluated at baseline BP by 24 h ambulatory blood pressure (ABP) monitoring, vascular stiffness parameters by the SphygmoCor system (AtCor Medical, Sydney, NSW, Australia) and fasting metabolic parameters, including β-OHB by an enzymatic assay (Beckman Coulter DxC 700 AU). The same measurements were repeated 12 weeks after treatment. In 19 of the 72 patients serum levels of β-OHB were beneath the lower border of our assay (< 0.05 mmol/l) therefore being excluded from the subsequent analysis. Results: In patients with stable CHF, treatment with empagliflozin (n = 36) was followed by an increase of β-OHB by 33.39% (p = 0.017), reduction in 24 h systolic (p = 0.038) and diastolic (p = 0.085) ABP, weight loss (p = 0.003) and decrease of central systolic BP (p = 0.008) and central pulse pressure (p = 0.008). The increase in β-OHB was related to an attenuated decrease of empagliflozin-induced 24 h systolic (r = 0.321, p = 0.069) and diastolic (r = 0.516, p = 0.002) ABP and less reduction of central systolic BP (r = 0.470, p = 0.009) and central pulse pressure (r = 0.391, p = 0.033). No significant changes were seen in any of these parameters after 12 weeks of treatment in the placebo group (n = 17). Conclusion: In patients with stable CHF ketone bodies as assessed by β-OHB increased after treatment with empagliflozin. This increase led to an attenuation of the beneficial effects of empagliflozin on BP and vascular parameters. Trial registration The study was registered at http://www.clinicaltrials.gov (NCT03128528).
CRIS-Team Scopus Importer:2021-11-19

Effect of Finerenone on Albuminuria in Patients With Diabetic Nephropathy: A Randomized Clinical Trial - Bakris, George L.; Agarwal, Rajiv; Chan, Juliana C.; Cooper, Mark E.; Gansevoort, Ron T.; Haller, Hermann; Remuzzi, Giuseppe; Rossing, Peter; Schmieder, Roland; Nowack, Christina; Kolkhof, Peter; Joseph, Amer; et al. (Journal of the American Medical Association, 2015)
Steroidal mineralocorticoid receptor antagonists, when added to a renin-angiotensin system blocker, further reduce proteinuria in patients with chronic kidney disease but may be underused because of a high risk of adverse events.To evaluate the safety and efficacy of different oral doses of the nonsteroidal mineralocorticoid receptor antagonist finerenone, given for 90 days to patients with diabetes and high or very high albuminuria who are receiving an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker.Randomized, double-blind, placebo-controlled, parallel-group study conducted at 148 sites in 23 countries. Patients were recruited from June 2013 to February 2014 and the study was completed in August 2014. Of 1501 screened patients, 823 were randomized and 821 received study drug.Participants were randomly assigned to receive oral, once-daily finerenone (1.25 mg/d, n = 96; 2.5 mg/d, n = 92; 5 mg/d, n = 100; 7.5 mg/d, n = 97; 10 mg/d, n = 98; 15 mg/d, n = 125; and 25 mg/d, n = 119) or matching placebo (n = 94) for 90 days.The primary outcome was the ratio of the urinary albumin-creatinine ratio (UACR) at day 90 vs at baseline. Safety end points were changes from baseline in serum potassium and estimated glomerular filtration rate.The mean age of the participants was 64.2 years; 78% were male. At baseline, 36.7% of patients treated had very high albuminuria (UACR >=300 mg/g) and 40.0% had an estimated glomerular filtration rate of 60 mL/min/1.73 m2 or lower. Finerenone demonstrated a dose-dependent reduction in UACR. The primary outcome, the placebo-corrected mean ratio of the UACR at day 90 relative to baseline, was reduced in the finerenone 7.5-, 10-, 15-, and 20-mg/d groups (for 7.5 mg/d, 0.79 [90% CI, 0.68-0.91; P = .004]; for 10 mg/d, 0.76 [90% CI, 0.65-0.88; P = .001]; for 15 mg/d, 0.67 [90% CI, 0.58-0.77; P<.001]; for 20 mg/d, 0.62 [90% CI, 0.54-0.72; P < .001]). The prespecified secondary outcome of hyperkalemia leading to discontinuation was not observed in the placebo and finerenone 10-mg/d groups; incidences in the finerenone 7.5-, 15-, and 20-mg/d groups were 2.1%, 3.2%, and 1.7%, respectively. There were no differences in the incidence of the prespecified secondary outcome of an estimated glomerular filtration rate decrease of 30% or more or in incidences of adverse events and serious adverse events between the placebo and finerenone groups.Among patients with diabetic nephropathy, most receiving an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker, the addition of finerenone compared with placebo resulted in improvement in the urinary albumin-creatinine ratio. Further trials are needed to compare finerenone with other active medications.clinicaltrials.gov Identifier: NCT1874431.
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Effect of finerenone on ambulatory blood pressure in chronic kidney disease in type 2 diabetes - Agarwal, Rajiv; Ruilope, Luis M.; Ruiz-Hurtado, Gema; Haller, Hermann; Schmieder, Roland; Anker, Stefan D.; Filippatos, Gerasimos; Pitt, Bertram; Rossing, Peter; Lambelet, Marc; Nowack, Christina; Kolkhof, Peter; et al. (Journal of Hypertension, 2023)
OBJECTIVE: Finerenone is a selective nonsteroidal mineralocorticoid receptor antagonist with a short half-life. Its effects on cardiorenal outcomes were thought to be mediated primarily via nonhemodynamic pathways, but office blood pressure (BP) measurements were insufficient to fully assess hemodynamic effects. This analysis assessed the effects of finerenone on 24-h ambulatory BP in patients with chronic kidney disease and type 2 diabetes. METHODS: ARTS-DN (NCT01874431) was a phase 2b trial that randomized 823 patients with type 2 diabetes and chronic kidney disease, with urine albumin-to-creatinine ratio ≥30 mg/g and estimated glomerular filtration rate of 30-90 ml/min per 1.73 m2 to placebo or finerenone (1.25-20 mg once daily in the morning) administered over 90 days. Ambulatory BP monitoring (ABPM) over 24 h was performed in a subset of 240 patients at screening, Day 60, and Day 90. RESULTS: Placebo-adjusted change in 24-h ABPM systolic BP (SBP) at Day 90 was -8.3 mmHg (95% confidence interval [CI], -16.6 to 0.1) for finerenone 10 mg (n = 27), -11.2 mmHg (95% CI, -18.8 to -3.6) for finerenone 15 mg (n = 34), and -9.9 mmHg (95% CI, -17.7 to -2.0) for finerenone 20 mg (n = 31). Mean daytime and night-time SBP recordings were similarly reduced and finerenone did not increase the incidence of SBP dipping. Finerenone produced a persistent reduction in SBP over the entire 24-h interval. CONCLUSIONS: Finerenone reduced 24-h, daytime, and night-time SBP. Despite a short half-life, changes in BP were persistent over 24 h with once-daily dosing in the morning.
CRIS-Team Scopus Importer:2023-01-06

Effect of Heart Rate on the Outcome of Renal Denervation in Patients With Uncontrolled Hypertension - Böhm, Michael; Tsioufis, Konstantinos; Kandzari, David E.; Kario, Kazuomi; Weber, Michael A.; Schmieder, Roland; Townsend, Raymond R.; Kulenthiran, Saarraaken; Ukena, Christian; Pocock, Stuart; Ewen, Sebastian; Weil, Joachim; et al. (Journal of the American College of Cardiology, 2021)
Background: Sham-controlled trials demonstrated safety and efficacy of renal denervation (RDN) to lower blood pressure (BP). Association of baseline heart rate with BP reduction after RDN is incompletely understood. Objectives: The purpose of this analysis was to evaluate the impact of baseline heart rate on BP reduction without antihypertensive medications in the SPYRAL HTN-OFF MED (Global Clinical Study of Renal Denervation With the Symplicity Spyral Multi-electrode Renal Denervation System in Patients With Uncontrolled Hypertension in the Absence of Antihypertensive Medications) Pivotal trial. Methods: Patients removed from any antihypertensive medications were enrolled with office systolic blood pressure (SBP) ≥150 and <180 mm Hg and randomized 1:1 to RDN or sham control. Patients were separated according to baseline office heart rate <70 or ≥70 beats/min. BP changes from baseline to 3 months between treatment arms were adjusted for baseline SBP using analysis of covariance. Results: Scatter plots of 3-month changes in 24-hour and office SBP illustrate a wide range of changes in SBP for different baseline heart rates. Treatment difference at 3 months between RDN and sham control with baseline office heart rate ≥70 beats/min for 24-hour SBP was −6.2 mm Hg (95% CI: −9.0 to −3.5 mm Hg) (P < 0.001) and for baseline office heart rate <70 beats/min it was −0.1 mm Hg (−3.8 to 3.6 mm Hg) (P = 0.97) with an interaction P value of 0.008. Results were similar for changes in office, daytime, and nighttime SBP at 3 months, with a greater reduction in SBP with baseline office heart rate ≥70 beats/min. Conclusions: Reduction in mean office, 24-hour, daytime, and nighttime SBP for RDN at 3 months was greater with baseline office heart rate ≥70 than <70 beats/min, suggesting an association between baseline heart rate and BP reduction after RDN. (SPYRAL PIVOTAL—SPYRAL HTN-OFF MED Study; NCT02439749)
CRIS-Team Scopus Importer:2021-09-03
Keywords: blood pressure; heart rate; hypertension; renal denervation; sympathetic activation

Effect of High-Flux Dialysis on Circulating FGF-23 Levels in End-Stage Renal Disease Patients: Results from a Randomized Trial - Schneider, Andreas; Schneider, Markus P.; Krieter, Detlef H.; Genser, Bernd; Scharnagl, Hubert; Stojakovic, Tatjana; Wanner, Christoph; Drechsler, Christiane (PLoS ONE, 2015)
In patients undergoing maintenance hemodialysis (HD), increased levels of circulating fibroblast growth factor-23 (FGF-23) are independently associated with cardiovascular events and mortality. Interventional strategies aiming to reduce levels of FGF-23 in HD patients are of particular interest. The purpose of the current study was to compare the impact of high-flux versus low-flux HD on circulating FGF-23 levels.We conducted a post-hoc analysis of the MINOXIS study, including 127 dialysis patients randomized to low-flux (n = 62) and high-flux (n = 65) HD for 52 weeks. Patients with valid measures for FGF-23 investigated baseline and after 52 weeks were included.Compared to baseline, a significant increase in FGF-23 levels after one year of low-flux HD was observed (Delta plasma FGF-23: +4026 RU/ml; p < 0.001). In contrast, FGF-23 levels remained stable in the high flux group (Delta plasma FGF-23: +373 RU/ml, p = 0.70). The adjusted difference of the absolute change in FGF-23 levels between the two treatment groups was statistically significant (p < 0.01).Over a period of 12 months, high-flux HD was associated with stable FGF-23 levels, whereas the low-flux HD group showed an increase of FGF-23. However, the implications of the different FGF 23 time-trends in patients on high flux dialysis, as compared to the control group, remain to be explored in specifically designed clinical trials.German Clinical Trials Register (DRKS) DRKS00007612.
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Effect of lowering asymmetric dimethylarginine (ADMA) on vascular pathology in atherosclerotic ApoE-deficient mice with reduced renal mass - Jacobi, Johannes; Maas, Renke; Arend, Michaela; Cordasic, Nada; Hilgers, Karl Friedrich (International Journal of Molecular Sciences, 2014)
The purpose of the work was to study the impact of the endogenous nitric oxide synthase (NOS) inhibitor asymmetric dimethylarginine (ADMA) and its degrading enzyme, dimethylarginine dimethylaminohydrolase (DDAH1), on atherosclerosis in subtotally nephrectomized (SNX) ApoE-deficient mice. Male DDAH1 transgenic mice (TG, n=39) and C57Bl/6J wild-type littermates (WT, n=27) with or without the deletion of the ApoE gene underwent SNX at the age of eight weeks. Animals were sacrificed at 12 months of age, and blood chemistry, as well as the extent of atherosclerosis within the entire aorta were analyzed. Sham treated (no renal mass reduction) ApoE-competent DDAH1 transgenic and wild-type littermates (n=11) served as a control group. Overexpression of DDAH1 was associated with significantly lower ADMA levels in all treatment groups. Surprisingly, SNX mice did not exhibit higher ADMA levels compared to sham treated control mice. Furthermore, the degree of atherosclerosis in ApoE-deficient mice with SNX was similar in mice with or without overexpression of DDAH1. Overexpression of the ADMA degrading enzyme, DDAH1, did not ameliorate atherosclerosis in ApoE-deficient SNX mice. Furthermore, SNX in mice had no impact on ADMA levels, suggesting a minor role of this molecule in chronic kidney disease (CKD) in this mouse model.
EVALuna2:3703

Effect of Radiofrequency Renal Denervation on Blood Pressure in the Presence of Antihypertensive Drugs: 6-Month Primary Results From the SPYRAL HTN-ON Med Expansion Randomized Trial - Kandzari, David E.; Townsend, Raymond R.; Kario, Kazuomi; Mahfoud, Felix; Weber, Michael A.; Schmieder, Roland; Pocock, Stuart; Tsioufis, Konstantinos; Brar, Sandeep; Debruin, Vanessa; Fahy, Martin; Boehm, Michael (CIRCULATION, 2022)
CRIS-Team WoS Importer:2023-03-17

EFFECT OF RENAL DENERVATION IN ATTENUATING THE MORNING SURGE IN BLOOD PRESSURE: FINDINGS FROM THE SPYRAL HTN-ON MED TRIAL - Kario, K.; Boehm, M.; Townsend, R.; Mahfoud, F.; Weber, M.; Pocock, S.; Tsioufi, C.; Schmieder, Roland; Fahy, M.; Kandzari, D. (JOURNAL OF HYPERTENSION, 2019)
CRIS-Team WoS Importer:2019-09-10

Effect of renal denervation in attenuating the stress of morning surge in blood pressure: post-hoc analysis from the SPYRAL HTN-ON MED trial - Kario, Kazuomi; Weber, Michael A.; Böhm, Michael; Townsend, Raymond R.; Mahfoud, Felix; Schmieder, Roland; Tsioufis, Konstantinos; Cohen, Sidney A.; Fahy, Martin; Kandzari, David E. (Clinical Research in Cardiology, 2020)
Background: Catheter-based renal denervation (RDN) reduces blood pressure (BP) throughout the 24-h period, as reported in several randomized sham-controlled trials. Reduction of BP in the early morning hours is especially important due to increased cardiovascular risks during that time. Objective: In this report, we examine the impact of RDN on systolic BP (SBP) and diastolic BP (DBP) during the critical morning surge period in a post-hoc analysis of patients in the SPYRAL HTN-ON MED trial. Methods and results: Ambulatory BP measurements were collected at baseline and 6 months for treatment and control patient groups over 24-h periods. Average morning BP surge is the difference between average morning BP and average nighttime BP, and the morning surge slope reflects the rate of change of BP from nighttime to morning. Mean morning DBP surge slopes were significantly lower for RDN vs. control groups at 6 months (1.1 vs. 3.6 mmHg/h; p = 0.029). In the RDN group, morning DBP surge slopes were significantly lower at 6 months compared to baseline (1.1 vs. 4.1 mmHg/h; p = 0.006). Similar patterns were observed for mean morning SBP surge slope but did not reach statistical significance. Conclusions: This decrease in the morning DBP surge slope, an index of the sympathetically-mediated morning BP surge, thus indicates a drop in late morning BP relative to early morning/nocturnal BP in the RDN group. Thus, RDN appears effective in attenuating the slope of morning surge in DBP that might indicate possible benefits in a high-risk hypertensive population. Clinical trial registration: https://www.clinicaltrials.gov (NCT02439775), registered May 12, 2015.
CRIS-Team Scopus Importer:2020-08-07
Keywords: Blood pressure; Hypertension; Morning surge; Renal denervation

Effect of SGLT2 inhibition on ketone bodies in patients with stable chronic heart failure - Pietschner, Robert; Kolwelter, Julie; Bosch, Agnes; Kannenkeril, Dennis; Ott, C.; Schiffer, Mario; Achenbach, Stephan; Schmieder, Roland (DIABETOLOGIA, 2021)
CRIS-Team WoS Importer:2021-10-01

Effects of ACE inhibitors and angiotensin receptor blockers: protocol for a UK cohort study using routinely collected electronic health records with validation against the ONTARGET trial - Baptiste, Paris J.; Wong, Angel Y.S.; Schultze, Anna; Cunnington, Marianne; Mann, Johannes; Clase, Catherine; Leyrat, Clémence; Tomlinson, Laurie A.; Wing, Kevin (BMJ Open, 2022)
INTRODUCTION: Cardiovascular disease is a leading cause of death globally, responsible for nearly 18 million deaths worldwide in 2017. Medications to reduce the risk of cardiovascular events are prescribed based on evidence from clinical trials which explore treatment effects in an indicated sample of the general population. However, these results may not be fully generalisable because of trial eligibility criteria that generally restrict to younger patients with fewer comorbidities. Therefore, evidence of effectiveness of medications for groups underrepresented in clinical trials such as those aged ≥75 years, from ethnic minority backgrounds or with low kidney function may be limited.Using individual anonymised data from the Ongoing Telmisartan Alone and the Ramipril Global Endpoint Trial (ONTARGET) trial, in collaboration with the original trial investigators, we aim to investigate clinical trial replicability within a real-world setting in the area of cardiovascular disease. If the original trial results are replicable, we will estimate treatment effects and risk in groups underrepresented and excluded from the original clinical trial. METHODS AND ANALYSIS: We will develop a cohort analogous to the ONTARGET trial within the Clinical Practice Research Datalink between 1 January 2001 and 31 July 2019 using the trial eligibility criteria and propensity score matching. The primary outcome is a composite of cardiovascular death, non-fatal myocardial infarction, non-fatal stroke and hospitalisation for congestive heart failure. If results from the cohort study fall within pre-specified limits, we will expand the cohort to include under represented and excluded groups. ETHICS AND DISSEMINATION: Ethical approval has been granted by the London School of Hygiene & Tropical Medicine Ethics Committee (Ref: 22658). The study has been approved by the Independent Scientific Advisory Committee of the UK Medicines and Healthcare Products Regulatory Agency (protocol no. 20_012). Access to the individual patient data from the ONTARGET trial was obtained by the trial investigators. Findings will be submitted to peer-reviewed journals and presented at conferences.
CRIS-Team Scopus Importer:2022-03-18
Keywords: clinical trials; epidemiology; statistics & research methods; vascular medicine

Effects of cardiovascular single pill combinations compared with identical multi-pill therapies on healthcare cost and utilization in Germany - Wilke, Thomas; Weisser, Burkhard; Predel, Hans-Georg; Schmieder, Roland; Wassmann, Sven; Gillessen, Anton; Blettenberg, Joerg; Maywald, Ulf; Randerath, Olaf; Mueller, Sabrina; Boehm, Michael (Journal of Comparative Effectiveness Research, 2022)
Aim: This study assessed whether a single pill combination (SPC) is associated with lower direct healthcare costs. Materials & methods: Anonymized claims data of patients >= 18 years treated with drugs for cardiovascular (CV)-related diseases either as a single pill combination or multi-pill combination (follow-up to 1 year) were evaluated. After propensity score matching, 59,336 out of 1,369,840 patients were analyzed. Results: In all cohorts, patients receiving a single pill combination had a lower frequency of general practitioner and specialist visits. The patients also had a significantly lower ratio of all-cause hospitalization days and number of CV-related prescriptions as well as all-cause prescriptions (with one exception) compared with those receiving a multi-pill combination. Conclusion: Direct CV-related costs were significantly lower in four out of seven comparisons, with a trend toward lower costs in the other three comparisons.
CRIS-Team WoS Importer:2022-04-08

EFFECTS OF FINERENONE ON CARDIORENAL OUTCOMES IN BLOOD PRESSURE SUBGROUPS IN PATIENTS WITH CKD AND T2D - Ruilope, Luis; Agarwal, Rajiv; Anker, Stefan D.; Filippatos, Gerasimos; Pitt, Bertram; Rossing, Peter; Sarafidis, Pantelis; Schmieder, Roland; Joseph, Amer; Mentenich, Nicole; Nowack, Christina; Bakris, George (NEPHROLOGY DIALYSIS TRANSPLANTATION, 2021)
CRIS-Team WoS Importer:2021-12-03

Effects of folic acid on renal endothelial function in patients with diabetic nephropathy: results from a randomized trial - Schneider, Markus P.; Schneidert, Andreas; Jumar, Agnes; Kistner, Iris; Ott, Christian; Schmieder, Roland (Clinical Science, 2014)
Endothelial dysfunction has been shown to promote podocyte injury and albuminuria in diabetes, highlighting the importance of the interaction between renal endothelial cells and podocytes. Folic acid (FA) improves nitric oxide synthase (NOS) function and reduces progression of diabetic nephropathy in animal models. We tested whether high-dose FA treatment improves renal endothelial function and albuminuria in human subjects with incipient diabetic nephropathy. Following a double-blind, randomized, cross-over design, 28 patients with Type 2 diabetes and albuminuria were allocated to 4 weeks' treatment with placebo and high-dose FA (5 mg/day). Renal nitric oxide (NO) production determined as the response of renal plasma flow (RPF) to NOS inhibition with NG-monomethyl-L-arginine (L-NMMA) (4.25 mg/kg intravenously), renal oxidant stress as response of RPF to vitamin C infusion (3 mg/kg) and albuminuria were determined after each treatment phase. Neither the reduction in RPF to L-NMMA nor the increase in RPF to vitamin C infusion differed between treatment phases (?RPF to L-NMMA: -74±71 ml/min per m2 during placebo compared with -63±56 ml/min per m2 during FA, P=0.57; ?RPF to vitamin C: +93±118 ml/min per m2 compared with +94±108 ml/min per m2; P=0.70). In line with the lack of effect on the renal endothelium, albuminuria was not affected by FA treatment (110±179 mg/day during placebo compared with 87±146 mg/day during FA; P=0.12). High-dose FA treatment does not improve renal endothelial function and fails to reduce albuminuria in human subjects with diabetic nephropathy. Novel treatment options for oxidant stress and endothelial dysfunction in patients with diabetes are urgently needed.
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Effects of Linagliptin on Cardiovascular and Kidney Outcomes in People With Normal and Reduced Kidney Function: Secondary Analysis of the CARMELINA Randomized Trial - Perkovic, Vlado; Toto, Robert; Cooper, Mark E.; Mann, Johannes; Rosenstock, Julio; Mcguire, Darren K.; Kahn, Steven E.; Marx, Nikolaus; Alexander, John H.; Zinman, Bernard; Pfarr, Egon; Schnaidt, Sven; et al. (Diabetes Care, 2020)
OBJECTIVE: Type 2 diabetes is a leading cause of kidney failure, but few outcome trials proactively enrolled individuals with chronic kidney disease (CKD). We performed secondary analyses of cardiovascular (CV) and kidney outcomes across baseline estimated glomerular filtration rate (eGFR) categories (≥60, 45 to <60, 30 to <45, and <30 mL/min/1.73 m2) in Cardiovascular and Renal Microvascular Outcome Study With Linagliptin (CARMELINA), a cardiorenal placebo-controlled outcome trial of the dipeptidyl peptidase 4 inhibitor linagliptin (NCT01897532). RESEARCH DESIGN AND METHODS: Participants with CV disease and/or CKD were included. The primary outcome was time to first occurrence of CV death, nonfatal myocardial infarction, or nonfatal stroke (three-point major adverse CV event [3P-MACE]), with a secondary outcome of renal death, end-stage kidney disease, or sustained ≥40% decrease in eGFR from baseline. Other end points included progression of albuminuria, change in HbA1c, and adverse events (AEs) including hypoglycemia. RESULTS: A total of 6,979 subjects (mean age 65.9 years; eGFR 54.6 mL/min/1.73 m2; 80.1% albuminuria) were followed for 2.2 years. Across eGFR categories, linagliptin as compared with placebo did not affect the risk for 3P-MACE (hazard ratio 1.02 [95% CI 0.89, 1.17]) or the secondary kidney outcome (1.04 [0.89, 1.22]) (interaction P values >0.05). Regardless of eGFR, albuminuria progression was reduced with linagliptin, as was HbA1c, without increasing risk for hypoglycemia. AEs were balanced among groups overall and across eGFR categories. CONCLUSIONS: Across all GFR categories, in participants with type 2 diabetes and CKD and/or CV disease, there was no difference in risk for linagliptin versus placebo on CV and kidney events. Significant reductions in risk for albuminuria progression and HbA1c and no difference in AEs were observed.
CRIS-Team Scopus Importer:2020-07-31

Effects of linagliptin on renal endothelial function in patients with type 2 diabetes: a randomised clinical trial - Ott, Christian; Kistner, Iris; Keller, Mirjam; Friedrich, Stefanie; Willam, Carsten; Bramlage, Peter; Schmieder, Roland (Diabetologia, 2016)
Endothelial dysfunction predicts cardiovascular damage and renal involvement. Animal experiments and human studies indicate an increased nitric oxide (NO) activity and endothelial NO synthase (NOS) expression in the early stage of type 2 diabetes. The aim of the study was to assess the effect of linagliptin on the endothelial function of the renal vasculature.In this randomised, double-blind, parallel-group, investigator-initiated trial, 62 patients with type 2 diabetes were randomly assigned (by computer-generated random code) to receive linagliptin 5 mg (n = 30) or placebo (n = 32) for 4 weeks. The primary objective was to assess endothelial function of the renal vasculature, by constant-infusion input-clearance and urinary albumin/creatinine ratio (UACR), both before and after blockade of NOS with N (G)-monomethyl-L-arginine (L-NMMA).Treatment with linagliptin for 4 weeks reduced fasting, postprandial blood glucose and HbA1c, although not significantly; no change occurred with placebo. Renal plasma flow (RPF) did not change after linagliptin or placebo. After 4 weeks the absolute change in RPF due to L-NMMA was smaller in the linagliptin group than in the placebo group (-46.8 ± 34 vs -65.1 ± 36 ml/min, p = 0.045), indicating a lower basal NO activity after treatment with linagliptin. Consistently, the response of UACR to L-NMMA increased in the placebo group (p = 0.059) but not in the linagliptin group (p = 0.276), pointing to an upregulation of NO activity in the placebo group. No clinically meaningful safety concerns were evident.Our data suggest that treatment with the dipeptidyl peptidase-4 inhibitor linagliptin for 4 weeks prevented the impairment of renal endothelial function due to hyperglycaemia in type 2 diabetes.ClinicalTrials.gov NCT01835678 FUNDING: : This study was funded by Boehringer Ingelheim.
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EFFECTS OF NEUROGENIC CGRP ON RENAL AFFERENT PEPTIDERGIC NEURONS - Veelken, Roland; Raschke, Giulia; Ditting, Tilmann; Ott, Christian; Schmieder, Roland; Amann, Kerstin Ute; Rodionova, Kristina (2018)
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Effects of once-weekly subcutaneous semaglutide on kidney function and safety in patients with type 2 diabetes: a post-hoc analysis of the SUSTAIN 1–7 randomised controlled trials - Mann, Johannes; Hansen, Thomas; Idorn, Thomas; Leiter, Lawrence A.; Marso, Steven P.; Rossing, Peter; Seufert, Jochen; Tadayon, Sayeh; Vilsbøll, Tina (Lancet Diabetes and Endocrinology, 2020)
Background: Patients with type 2 diabetes have a high risk of developing chronic kidney disease. We examined the effects of semaglutide on kidney function and safety in a large, broad type 2 diabetes population. Methods: We did a post-hoc analysis of 8416 patients with type 2 diabetes enrolled in the SUSTAIN 1–5 and SUSTAIN 7 randomised controlled trials, and the SUSTAIN 6 cardiovascular outcomes trial, to examine the effects of once-weekly subcutaneous semaglutide 0·5 mg and 1·0 mg versus comparators (active treatments or placebo) on estimated glomerular filtration rate (eGFR), urinary albumin-to-creatinine ratio (UACR), and kidney adverse events. Data from SUSTAIN 1–5 and SUSTAIN 7 were pooled. eGFR and UACR were also analysed by kidney function and albuminuria status. Findings: In SUSTAIN 1–5 and SUSTAIN 7, eGFR decreased from baseline to week 12 with all active treatments; estimated treatment differences (ETDs) versus placebo were −2·15 (95% CI −3·47 to −0·83) mL/min per 1·73 m2 with semaglutide 0·5 mg and −3·00 (−4·31 to −1·68) mL/min per 1·73 m2 with semaglutide 1·0 mg; after week 12, eGFR plateaued. In SUSTAIN 1–5 and SUSTAIN 7, from baseline to end of treatment the decline in eGFR was greater with semaglutide than with placebo (ETD −1·58 [95% CI −2·92 to −0·25] mL/min per 1·73 m2 with semaglutide 0·5 mg and −2·02 [–3·35 to −0·68] mL/min per 1·73 m2 with semaglutide 1·0 mg). In SUSTAIN 6, the decline in eGFR was greater with semaglutide than with placebo from baseline to week 16 (ETD −1·29 [95% CI −2·07 to −0·51] mL/min per 1·73 m2 with semaglutide 0·5 mg and −1·56 [–2·33 to −0·78] mL/min per 1·73 m2 with semaglutide 1·0 mg), but not from week 16 to week 104 (1·29 [0·30 to 2·28] mL/min per 1·73 m2 with semaglutide 0·5 mg and 2·44 [1·45 to 3·44] mL/min per 1·73 m2 with semaglutide 1·0 mg). Overall (ie, from baseline to week 104), the eGFR decline in SUSTAIN 6 was similar between semaglutide and placebo (ETD 0·07 [95% CI −0·92 to 1·07] mL/min per 1·73 m2 with semaglutide 0·5 mg and 0·97 [–0·03 to 1·97] mL/min per 1·73 m2 with semaglutide 1·0 mg). In SUSTAIN 1–5, UACR ratios at end of treatment to baseline were 0·917 with semaglutide 0·5 mg, 0·836 with semaglutide 1·0 mg, and 1·239 with placebo; at end of treatment, greater reductions in UACR were observed with semaglutide versus placebo (estimated treatment ratios 0·74 [95% CI 0·64 to 0·85] for semaglutide 0·5 mg and 0·68 [0·59 to 0·78] for semaglutide 1·0 mg). In SUSTAIN 6, UACR ratios at end of treatment (week 104) to baseline were 0·973 with semaglutide 0·5 mg, 0·858 with semaglutide 1·0 mg, and 1·302 with placebo; at week 104, greater reductions in UACR were observed with semaglutide versus placebo (estimated treatment ratios 0·75 [95% CI 0·66 to 0·85] for semaglutide 0·5 mg and 0·66 [0·58 to 0·75] for semaglutide 1·0 mg). In SUSTAIN 1–7, eGFR initially declined in patients with normal kidney function (and in those with mild kidney impairment with semaglutide 1·0 mg in SUSTAIN 6), but overall (ie, by week 30 for SUSTAIN 1–5 and SUSTAIN 7, and week 104 for SUSTAIN 6), eGFR did not differ between semaglutide and placebo. In SUSTAIN 1–6, UACR decreased in patients with pre-existing microalbuminuria or macroalbuminuria at baseline; it did not change or increased in those with normoalbuminuria at baseline. Kidney adverse events were balanced between treatment groups. Interpretation: Across the SUSTAIN 1–7 trials, semaglutide was associated with initial reductions in eGFR that plateaued, and marked reductions in UACR. This post-hoc analysis suggests no increase in the risk of kidney adverse events with semaglutide versus the active comparators used across SUSTAIN 1–7. Funding: Novo Nordisk.
CRIS-Team Scopus Importer:2020-10-16

EFFECTS OF RENAL DENERVATION IN PATIENTS WITH VERSUS WITHOUT CHRONIC KIDNEY DISEASE: UPDATED DATA FROM THE GLOBAL SYMPLICITY REGISTRY WITH FOLLOW-UP OF 3 YEARS - Ott, Christian; Mahfoud, F.; Mancia, G.; Narkiewicz, K.; Ruilope, L. M.; Schlaich, M. P.; Williams, B.; Boehm, M.; Schmieder, Roland (JOURNAL OF HYPERTENSION, 2019)
CRIS-Team WoS Importer:2019-09-20

Effects of renal denervation on blood pressure in hypertensive patients with end-stage renal disease: a single centre experience - Ott, Christian; Schmid, Axel; Ditting, Tilmann; Veelken, Roland; Uder, Michael; Schmieder, Roland (Clinical and Experimental Nephrology, 2019)
Background: Sympathetic nerve activity is a hallmark of hypertension in end-stage renal disease (ESRD). An initial proof-of-concept study implies that renal denervation (RDN) is feasible and safe in RDN, but overall data are limited. Methods: In this single-centre prospective pilot study six patients with ESRD and treatment resistant hypertension were consecutively included. Ambulatory blood pressure (ABP) was measured before and 6 months after RDN (Symplictiy Flex™, Medtronic Inc., Santa Rosa, CA). Moreover, haemodialysis parameters which may affect BP reduction were monitored closely. Results: In all patients bilateral RDN was successful done, without documentation of peri- or postprocedural complications. There was a significant reduction in 24-h ABP by 20 ± 17/15 ± 12 mmHg 6 months after RDN (systolic: 163 ± 16 versus 143 ± 9 mmHg, p = 0.043; diastolic: 96 ± 9 versus 81 ± 15 mmHg, p = 0.043), with similar results for day-, and nighttime values, respectively. Antihypertensive medication was kept stable as well as there was no change in haemodialysis parameters during follow-up. In addition, ultrafiltration/week (1.4 ± 1.4 versus 2.2 ± 1.4 l, p = 0.08) as well as hematocrit (measured at baseline and 6 months after RDN) (33.7 ± 4.3 versus 33.1 ± 3.9%, p = 0.715) revealed no change in volume status. Conclusion: Our single-centre pilot study not only supports current data on renal safety of RDN even in small arteries of patients with ESRD, but also enhances the knowledge towards an effective ABP reduction in this type of hypertensive patients.
CRIS-Team Scopus Importer:2019-05-07
Keywords: End-stage renal disease; Renal denervation; Treatment resistant hypertension

EFFECTS OF RENAL DENERVATION ON BLOOD PRESSURE IN PATIENTS WITH END-STAGE RENAL DISEASE: A SINGLE CENTER EXPERIENCE - Ott, C.; Schmid, Axel; Ditting, T.; Veelken, Roland; Uder, Michael; Schmieder, Roland (2018)
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Effects of renal denervation on kidney function and long-term outcomes: 3-year follow-up from the Global SYMPLICITY Registry - Mahfoud, Felix; Böhm, Michael; Schmieder, Roland; Narkiewicz, Krzysztof; Ewen, Sebastian; Ruilope, Luis; Schlaich, Markus; Williams, Bryan; Fahy, Martin; Mancia, Giuseppe (European Heart Journal, 2019)
AIMS: Several studies and registries have demonstrated sustained reductions in blood pressure (BP) after renal denervation (RDN). The long-term safety and efficacy after RDN in real-world patients with uncontrolled hypertension, however, remains unknown. The objective of this study was to assess the long-term safety and efficacy of RDN, including its effects on renal function. METHODS AND RESULTS: The Global SYMPLICITY Registry is a prospective, open-label registry conducted at 196 active sites worldwide in hypertensive patients receiving RDN treatment. Among 2237 patients enrolled and treated with the SYMPLICITY Flex catheter, 1742 were eligible for follow-up at 3 years. Baseline office and 24-h ambulatory systolic BP (SBP) were 166 ± 25 and 154 ± 18 mmHg, respectively. SBP reduction after RDN was sustained over 3 years, including decreases in both office (-16.5 ± 28.6 mmHg, P < 0.001) and 24-h ambulatory SBP (-8.0 ± 20.0 mmHg; P < 0.001). Twenty-one percent of patients had a baseline estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2. Between baseline and 3 years, renal function declined by 7.1 mL/min/1.73 m2 in patients without chronic kidney disease (CKD; eGFR ≥60 mL/min/1.73 m2; baseline eGFR 87 ± 17 mL/min/1.73 m2) and by 3.7 mL/min/1.73 m2 in patients with CKD (eGFR <60 mL/min/1.73 m2; baseline eGFR 47 ± 11 mL/min/1.73 m2). No long-term safety concerns were observed following the RDN procedure. CONCLUSION: Long-term data from the Global SYMPLICITY Registry representing the largest available cohort of hypertensive patients receiving RDN in a real-world clinical setting demonstrate both the safety and efficacy of the procedure with significant and sustained office and ambulatory BP reductions out to 3 years.
CRIS-Team Scopus Importer:2019-11-15
Keywords: Ambulatory blood pressure monitoring; Denervation; Hypertension; Renal function; SYMPLICITY

Effects of Renal Denervation vs Sham in Resistant Hypertension After Medication Escalation Prespecified Analysis at 6 Months of the RADIANCE-HTN TRIO Randomized Clinical Trial - Azizi, Michel; Mahfoud, Felix; Weber, Michael A.; Sharp, Andrew S. P.; Schmieder, Roland; Lurz, Philipp; Lobo, Melvin D.; Fisher, Naomi D. L.; Daemen, Joost; Bloch, Michael J.; Basile, Jan; Sanghvi, Kintur; et al. (JAMA Cardiology, 2022)
IMPORTANCE Although early trials of endovascular renal denervation (RDN) for patients with resistant hypertension (RHTN) reported inconsistent results, ultrasound RDN (uRDN) was found to decrease blood pressure (BP) vs sham at 2 months in patients with RHTN taking stable background medications in the Study of the ReCor Medical Paradise System in Clinical Hypertension (RADIANCE-HTN TRIO) trial.
CRIS-Team WoS Importer:2022-12-02

Effects of renal sympathetic denervation on urinary sodium excretion in patients with resistant hypertension - Poss, Janine; Ewen, Sebastian; Schmieder, Roland; Muhler, Sonja; Vonend, Oliver; Ott, Christian; Linz, Dominik; Geisel, Juergen; Rump, Lars C.; Schlaich, Markus; Boehm, Michael; Mahfoud, Felix (Clinical Research in Cardiology, 2015)
Sympathetic overactivity increases sodium retention and contributes to the pathophysiology of hypertension. Renal sympathetic denervation lowers blood pressure and reduces sympathetic activity in certain patients with resistant hypertension.This study aimed to assess the effect of renal denervation on urinary sodium excretion. 24-h urinary sodium excretion was estimated at baseline and after 6 months using the Kawasaki formula in 137 patients with resistant hypertension undergoing renal denervation. Sodium excretion was adjusted for cystatin C GFR and fractional sodium excretion was assessed. Mean office systolic blood pressure at baseline was 171 ± 2 mmHg despite an intake of 5.2 ± 0.1 antihypertensive drugs. Six months after renal denervation, systolic and diastolic BP decreased by 18 ± 2 mmHg (p < 0.0001) and 10 ± 1 mmHg (p < 0.001). 90 patients (65.7 %) had SBP reductions >=10 mmHg (responders). After 6 months, 24-h UNa increased by 13 % compared to baseline (236 ± 9 vs. 268 ± 9 mmol/day, p < 0.003). This increase was most pronounced in patients with less response in BP. These findings were paralleled by a significant increase in fractional sodium excretion (1.19 ± 0.11 vs. 1.64 ± 0.14 %, p < 0.0001) and were observed independently of the intake of antihypertensive drugs affecting sodium balance, such as mineralocorticoid receptor antagonists or diuretics.RDN lowered BP and increased estimated UNa and fractional sodium excretion in patients with resistant hypertension independently of renal function and antihypertensive therapy.
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Effects of saxagliptin on early microvascular changes in patients with type 2 diabetes - Ott, Christian; Raff, Ulrike; Schmidt, Stefan; Kistner, Iris; Friedrich, Stefanie; Bramlage, Peter; Harazny, Joanna M.; Schmieder, Roland (Cardiovascular Diabetology, 2014)
Patients with diabetes mellitus are at increased risk for microvascular complications. Early changes in microcirculation are characterized by hyperperfusion (e.g. in the retina and kidney) and increased pulse wave reflection leading to increased aortic pressure. We investigated the effects of the DPP-4-inhibitor saxagliptin on early retinal microvascular changes.In this double-blind, controlled, cross-over trial 50 patients (without clinical signs of microvascular alterations) with type-2 diabetes (mean duration of 4 years) were randomized to receive placebo or 5 mg saxagliptin for 6 weeks. Retinal arteriolar structure and retinal capillary flow (RCF) at baseline and during flicker-light exposure was assessed by scanning laser Doppler flowmetry. Central hemodynamics were assessed by pulse wave analysis.Postprandial blood glucose (9.27 ± 0.4 versus 10.1 ± 0.4 mmol/L; p = 0.001) and HbA1c (6.84 ± 0.15 (51 ± 1.6) versus 7.10 ± 0.17% (54 ± 1.9 mmol/mol); p < 0.001) were significantly reduced with saxagliptin treatment compared to placebo. RCF was significantly reduced after treatment with saxagliptin (288 ± 13.2 versus 314 ± 14.1 AU; p = 0.033). This was most pronounced in a subgroup of patients (n = 32) with a fall in postprandial blood glucose (280 ± 12.1 versus 314 ± 16.6 AU; p = 0.011). No significant changes in RCF were seen during flicker-light exposure between placebo and saxagliptin, but the vasodilatory capacity increased two-fold with saxagliptin treatment. Central augmentation pressure tended to be lower after treatment with saxagliptin (p = 0.094), and central systolic blood pressure was significantly reduced (119 ± 2.3 versus 124 ± 2.3 mmHg; p = 0.038).Our data suggest that treatment with saxagliptin for 6 weeks normalizes retinal capillary flow and improves central hemodynamics in type-2 diabetes.The study was registered at (ID: NCT01319357).
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EFFECTS OF SEMAGLUTIDE AND LIRAGLUTIDE ON URINARY ALBUMIN-TO-CREATININE RATIO (UACR) - A POOLED ANALYSIS OF SUSTAIN 6 AND LEADER - Perkovic, Vlado; Bain, Stephen; Bakris, George; Buse, John; Idorn, Thomas; Mahaffey, Kenneth; Marso, Steven; Nauck, Michael; Pratley, Richard; Rasmussen, Soren; Rossing, Peter; Tornoe, Karen; et al. (NEPHROLOGY DIALYSIS TRANSPLANTATION, 2019)
CRIS-Team WoS Importer:2019-11-26

Effects of Single Pill Combinations Compared to Identical Multi Pill Therapy on Outcomes in Hypertension, Dyslipidemia and Secondary Cardiovascular Prevention: The START-Study - Wilke, Thomas; Weisser, Burkhard; Predel, Hans Georg; Schmieder, Roland; Wassmann, Sven; Gillessen, Anton; Blettenberg, Jörg; Maywald, Ulf; Randerath, Olaf; Mueller, Sabrina; Böhm, Michael (Integrated Blood Pressure Control, 2022)
Aim: Current guidelines for the treatment of arterial hypertension (AH) or cardiovascular (CV) prevention recommend combination drug treatments with single pill combinations (SPC) to improve adherence to treatment. We aimed to assess whether the SPC concept is clinically superior to multi pill combination (MPC) with identical drugs. Methods and Results: In an explorative study, we analyzed anonymized claims data sets of patients treated with CV drugs for hypertension and/or CV disorders who were insured by the German AOK PLUS statutory health fund covering 01/07/2012-30/06/2018. Patients at age ≥18 years who received either a SPC or MPC with identical drugs were followed for up to one year. A one to one propensity score matching (PSM) was applied within patient groups who started identical drug combinations, and results were reported as incidence rate ratios (IRRs) as well as hazard ratios (HRs). After PSM, data from 59,336 patients were analyzed. In 30 out of 56 IRR analyses, superiority of SPC over MPC was shown. In 5 out of 7 comparisons, the HR for the composite outcome of all-cause death and all-cause hospitalizations was in favor of the SPC regimen (SPC versus MPC): valsartan/amlodipine: HR=0.87 (95% CI: 0.84–0.91, p ≤ 0.001); candesartan/amlodipine: 0.77 (95% CI: 0.65– 0.90, p = 0.001); valsartan/amlodipine/hydrochlorothiazide: HR=0.68 (95% CI: 0.61–0.74, p ≤ 0.001); ramipril/amlodipine: HR=0.80 (95% CI: 0.77–0.83, p ≤ 0.001); acetylsalicylic acid (ASA)/atorvastatin/ramipril: HR=0.64 (95% CI: 0.47–0.88, p = 0.005). Conclusion: SPC regimens are associated with a lower incidence of CV events and lower all-cause mortality in clinical practice. SPC regimens should generally be preferred to improve patient’s prognosis.
CRIS-Team Scopus Importer:2022-03-11
Keywords: Adherence; Cardiovascular outcomes; Clinical practice; Mortality; Prognosis; Single pill

EFFECTS OF THE GLUCAGON-LIKE PEPTIDE-1 (GLP-1) ANALOGUES SEMAGLUTIDE AND LIRAGLUTIDE ON RENAL OUTCOMES - A POOLED ANALYSIS OF THE SUSTAIN 6 AND LEADER TRIALS - Perkovic, Vlado; Bain, Stephen; Bakris, George; Buse, John; Idorn, Thomas; Mahaffey, Kenneth; Marso, Steven; Nauck, Michael; Pratley, Richard; Rasmussen, Soren; Rossing, Peter; Tornoe, Karen; et al. (NEPHROLOGY DIALYSIS TRANSPLANTATION, 2019)
CRIS-Team WoS Importer:2019-11-26

Effects of the nitric oxide synthase inhibitor ronopterin (VAS203) on renal function in healthy volunteers - Ott, Christian; Bosch, Agnes; Winzer, Nicole; Friedrich, Stephanie; Schinzel, Reinhard; Tegtmeier, Frank; Schmieder, Roland (British Journal of Clinical Pharmacology, 2019)
Aims: Reduced nitric oxide (NO) availability may adversely affect renal perfusion and glomerular filtration. The aim of the present study was to characterize in detail the pharmacological effects of VAS203, an inhibitor of NO synthase, on renal haemodynamics in humans. Methods: This double-blind, randomized, placebo-controlled, cross-over phase-I-study comprised 18 healthy men. Renal haemodynamics were assessed with constant-infusion input-clearance technique with p-aminohippurate and inulin for renal plasma flow (RPF) and glomerular filtration rate (GFR), respectively. After baseline measurement, a constant infusion of the tetrahydrobiopterin analogue ronopterin (VAS203, total 10 mg/kg body weight) or placebo was administered at random order for 6 hours additionally. After a wash-out phase of 28 days, the second course was applied. In parallel, markers of early kidney injury and renal function were assessed repeatedly up to 48 hours after starting VAS203/placebo-infusion. Results: VAS203-infusion resulted in a significant decrease of RPF (P <.0001) and GFR (P <.001) compared to placebo, but magnitude was within the physiological range. RPF and GFR recovered partly 2 hours after end of VAS203-infusion and was normal at beginning of the second infusion period. Compared to placebo, preglomerular resistance (P <.0001), and to lesser extent postglomerular resistance (P <.0001) increased, resulting in a decrease of intraglomerular pressure (P <.01). No treatment related effect on markers of early kidney injury, and on renal function (P for all >.20) have been observed. Conclusions: Our phase-I-study in healthy humans indicates that VAS203 (10 mg/kg body weight) reduces renal perfusion and glomerular function within the physiological range mainly due to vasoconstriction at the preglomerular site.
CRIS-Team Scopus Importer:2019-05-03
Keywords: glomerular filtration rate; nitric oxide synthase; renal haemodynamics; renal plasma flow; VAS203

EFFECTS OF THE NO SYNTHASE INHIBITOR RONOPTERIN (VAS203) ON MICRO- AND MACROCIRCULATION IN HEALTHY VOLUNTEERS - Ott, Christian; Bosch, Agnes; Jung, Susan; Kannenkeril, D.; Schinzel, R.; Tegtmeier, F.; Schmieder, Roland (JOURNAL OF HYPERTENSION, 2019)
CRIS-Team WoS Importer:2019-09-20

Effects of the Selective Sodium-Glucose Cotransporter 2 Inhibitor Empagliflozin on Vascular Function and Central Hemodynamics in Patients With Type 2 Diabetes Mellitus - Striepe, Kristina; Jumar, Agnes; Ott, Christian; Karg, Margarete; Schneider, Markus; Kannenkeril, Dennis; Schmieder, Roland (Circulation, 2017)
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EFFECTS OF THE SGLT2 INHIBITOR EMPAGLIFLOZIN ON VASCULAR FUNCTION IN PATIENTS WITH CHRONIC HEART FAILURE - Kolwelter, Julie; Bosch, Agnes; Jung, Susanne; Linz, Peter; Kannenkeril, Dennis; Nagel, Armin Michael; Ott, Christian; Bramlage, Peter; Uder, Michael; Achenbach, Stephan; Schmieder, Roland (JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY, 2021)
CRIS-Team WoS Importer:2021-06-04

Effects of the sodium-glucose cotransporter 2 inhibitor empagliflozin on vascular function in patients with chronic heart failure - Kolwelter, Julie; Bosch, Agnes; Jung, Susanne; Stabel, Lena; Kannenkeril, Dennis; Ott, Christian; Bramlage, Peter; Schiffer, Mario; Achenbach, Stephan; Schmieder, Roland (ESC Heart Failure, 2021)
Aims Impairment of vascular function contributes to the progression of chronic heart failure (HF) by increasing the afterload. Treatment with selective sodium-glucose cotransporter 2 (SGLT2) inhibitors improves the prognosis of HF, but the precise mechanisms remain unclear. The aim of this study was to analyse the effect of empagliflozin on vascular function in patients with HF.
CRIS-Team WoS Importer:2021-10-01

Effects of treatment with SGLT-2 inhibitors on arginine-related cardiovascular and renal biomarkers - Geßner, Arne; Gemeinhardt, Anna; Bosch, Agnes; Kannenkeril, Dennis; Staerk, Christian; Mayr, Andreas; Fromm, Martin; Schmieder, Roland; Maas, Renke (Cardiovascular Diabetology, 2022)
Background: In patients with type 2 diabetes (T2D) sodium-glucose cotransporter 2 (SGLT-2) inhibitors improve glycaemic control as well as cardiovascular and renal outcomes. Their effects on L-arginine (Arg) related risk markers asymmetric and symmetric dimethylarginine (ADMA and SDMA) and the protective biomarker L-homoarginine (hArg) linking T2D to cardiovascular and renal disease have not yet been reported.
CRIS-Team WoS Importer:2022-01-14

EGFR LOSS WITH GLUCAGON-LIKE PEPTIDE-1 (GLP-1) ANALOGUE TREATMENT: DATA FROM SUSTAIN 6 AND LEADER - Perkovic, Vlado; Bain, Stephen; Bakris, George; Buse, John; Gondolf, Theis; Idorn, Thomas; Lausvig, Nanna; Mahaffey, Kenneth; Marso, Steven; Nauck, Michael; Pratley, Richard; Rossing, Peter; et al. (NEPHROLOGY DIALYSIS TRANSPLANTATION, 2019)
CRIS-Team WoS Importer:2019-11-26

Einfluss neuer Techniken in der Bildgebung der Niere - Uder, Michael; Heinrich, Marc Christopher; Jäger, Florian; Hornegger, Joachim; Schmieder, Roland; Janka, Rolf Matthias (Nephrologe, 2009)
Computed tomography and magnetic resonance imaging have developed very rapidly in recent years. Today these methods are capable not only of morphological assessment of the kidneys but also provide data of a functional nature. Urography by MRI and CT have long been established in clinical routine. Other techniques such as blood level oxygenation-dependent (BOLD), diffusion-weighted, and renal perfusion imaging using MRI or CT are used almost exclusively for research purposes, but they also have many possibilities for renal applications under study conditions in diagnostics and for monitoring vascular and parenchymatous disorders. © 2009 Springer-Verlag.

Electrocardiographic parameters of left ventricular hypertrophy and prediction of mortality in hemodialysis patients - Braunisch, Matthias C.; Gundel, Peter; Werfel, Stanislas; Mayer, Christopher C.; Bauer, Axel; Haller, Bernhard; Guenthner, Roman; Lorenz, Georg; Angermann, Susanne; Matschkal, Julia; Schaller, Carolin; Holzmann-Littig, Christopher; et al. (Journal of Nephrology, 2021)
Background In hemodialysis patients, left ventricular hypertrophy (LVH) contributes to high cardiovascular mortality. We examined cardiovascular mortality prediction by the recently proposed Peguero-Lo Presti voltage since it identifies more patients with electrocardiographic (ECG) LVH than Cornell or Sokolow-Lyon voltages.
CRIS-Team WoS Importer:2021-05-28

Elementary immunology: Na(+) as a regulator of immunity - Schatz, Valentin; Neubert, Patrick; Schröder, Agnes; Binger, Katrina; Gebhard, Matthias; Mueller, Dominik N.; Luft, Friedrich C.; Titze, Jens; Jantsch, Jonathan (Pediatric Nephrology, 2017)
The skin can serve as an interstitial Na(+) reservoir. Local tissue Na(+) accumulation increases with age, inflammation and infection. This increased local Na(+) availability favors pro-inflammatory immune cell function and dampens their anti-inflammatory capacity. In this review, we summarize available data on how NaCl affects various immune cells. We particularly focus on how salt promotes pro-inflammatory macrophage and T cell function and simultaneously curtails their regulatory and anti-inflammatory potential. Overall, these findings demonstrate that local Na(+) availability is a promising novel regulator of immunity. Hence, the modulation of tissue Na(+) levels bears broad therapeutic potential: increasing local Na(+) availability may help in treating infections, while lowering tissue Na(+) levels may be used to treat, for example, autoimmune and cardiovascular diseases.
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Elevated tissue sodium deposition in patients with type 2 diabetes on hemodialysis detected by 23Na magnetic resonance imaging - Kopp, Christoph; Linz, Peter; Maier, Carolin; Wabel, Peter; Hammon, Matthias; Nagel, Armin Michael; Rosenhauer, Daniela; Horn, Stephan; Uder, Michael; Luft, Friedrich C.; Titze, Jens; Dahlmann, Anke (Kidney International, 2018)
Long-term elevated blood sugar levels result in tissue matrix compositional changes in patients with diabetes mellitus type 2 (T2DM). We hypothesized that hemodialysis patients with T2DM might accumulate more tissue sodium than control hemodialysis patients. To test this, 23Na magnetic resonance imaging (23Na MRI) was used to estimate sodium in skin and muscle tissue in hemodialysis patients with or without T2DM. Muscle fat content was estimated by 1H MRI and tissue sodium content by 23Na MRI pre- and post-hemodialysis in ten hemodialysis patients with T2DM and in 30 matched control hemodialysis patients. We also assessed body fluid distribution with the Body Composition Monitor. 1H MRI indicated a tendency to higher muscle fat content in hemodialysis patients with T2DM compared to non-diabetic hemodialysis patients. 23Na MRI indicated increased sodium content in muscle and skin tissue of hemodialysis patients with T2DM compared to control hemodialysis patients. Multi-frequency bioimpedance was used to estimate extracellular water (ECW), and excess ECW in T2DM hemodialysis patients correlated with HbA1c levels. Sodium mobilization during hemodialysis lowered muscle sodium content post-dialysis to a greater degree in T2DM hemodialysis patients than in control hemodialysis patients. Thus, our findings provide evidence that increased sodium accumulation occurs in hemodialysis patients with T2DM and that impaired serum glucose metabolism is associated with disturbances in tissue sodium and water content.
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Endogenous De Novo Synthesis of Isopropanol Following Severe Non-Diabetic Ketoacidosis in a Patient With Duchenne Muscular Dystrophy - Bihlmaier, Karl; Grampp, Steffen; Willam, Carsten; Schiffer, Mario; Herbst, Larissa (Journal of Endocrinology and Metabolism, 2022)
In Duchenne muscular dystrophy (DMD), patients seem prone to severe metabolic acidosis following excessive bicarbonate loss due to laxative use or gastrointestinal disorders. In addition, hypoalimentation and fasting can cause life-threatening non-diabetic ketoacidoses with acetonemia in these patients. Isopropanolemia instead is predominantly found following intoxication. Only few reports exist describing isopropanolemia in diabetic or alcoholic ketoacidosis. Here, we report on a patient suffering from DMD who developed lifethreatening non-diabetic ketoacidosis, acetonemia, and endogenous de novo synthesis of isopropanol following glucose fasting. We hypothesize isopropanolemia being a byproduct of acetone metabolism, possibly in association with a metabolic predisposition in patients with DMD such as an altered NADH/NAD(+) ratio leading to a reduction from acetone to isopropyl alcohol whilst in severe ketoacidosis.
CRIS-Team WoS Importer:2022-07-01
Keywords: Isopropanolemia; Acetonemia; Ketoacidosis; Refeeding syndrome; Duchenne muscular dystrophy

Endothelin-1 as a master regulator of whole-body Na+ homeostasis - Speed, Joshua S.; Heimlich, J. Brett; Hyndman, Kelly A.; Fox, Brandon M.; Patel, Vivek; Yanagisawa, Masashi; Pollock, Jennifer S.; Titze, Jens; Pollock, David M. (The FASEB Journal, 2015)
The current study was designed to determine whether vascular endothelial-derived endothelin-1 (ET-1) is important for skin Na(+) buffering. In control mice (C57BL/6J), plasma Na(+) and osmolarity were significantly elevated in animals on high- vs. low-salt (HS and LS, respectively) intake. The increased plasma Na(+) and osmolarity were associated with increased ET-1 mRNA in vascular tissue. There was no detectable difference in skin Na(+):H2O in HS fed mice (0.119 ± 0.005 mM vs. 0.127 ± 0.007 mM; LS vs. HS); however, skin Na(+):H2O was significantly increased by blockade of the endothelin type A receptor with ABT-627 (0.116 ± 0.006 mM vs. 0.137 ± 0.007 mM; LS vs. HS; half-maximal inhibitory concentration, 0.055 nM). ET-1 peptide content in skin tissue was increased in floxed control animals on HS (85.9 ± 0.9 pg/mg vs. 106.4 ± 6.8 pg/mg; P < 0.05), but not in vascular endothelial cell endothelin-1 knockout (VEET KO) mice (76.4 ± 5.7 pg/mg vs. 65.7 ± 7.9 pg/mg; LS vs. HS). VEET KO mice also had a significantly elevated skin Na(+):H2O (0.113 ± 0.007 mM vs. 0.137 ± 0.005 mM; LS vs. HS; P < 0.05). Finally, ET-1 production was elevated in response to increasing extracellular osmolarity in cultured human endothelial cells. These data support the hypothesis that increased extrarenal vascular ET-1 production in response to HS intake is mediated by increased extracellular osmolarity and plays a critical role in regulating skin storage of Na(+).
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Endothelin antagonism for patients with chronic kidney disease: still a hope for the future - Schneider, Markus P.; Mann, Johannes (Nephrology Dialysis Transplantation, 2014)
Endothelin is tightly involved in the regulation of vascular and renal function in health and in disease. In a variety of animal models of kidney disease, endothelin promotes renal injury through effects on inflammation and fibrosis. Furthermore, experimental data strongly suggest that blocking the actions of endothelin should be beneficial in patients with chronic kidney disease. However, despite encouraging pre-clinical and clinical evidence, endothelin antagonists are not yet an established treatment option in patients with chronic kidney disease. This article reviews key physiological and pathophysiological aspects of the endothelin system in the vasculature and the kidney, as well as results of pre-clinical and clinical studies on the use of endothelin antagonists in chronic kidney disease. We will also provide an outlook on the future of endothelin antagonism in this area, and issues to be resolved before endothelin antagonists are to become a reality for patients with chronic kidney disease.
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Endovascular ultrasound renal denervation to treat hypertension (RADIANCE-HTN SOLO): a multicentre, international, single-blind, randomised, sham-controlled trial - Azizi, Michel; Schmieder, Roland; Mahfoud, Felix; Weber, Michael A.; Daemen, Joost; Davies, Justin; Basile, Jan; Kirtane, Ajay J.; Wang, Yale; Lobo, Melvin D.; Saxena, Manish; Feyz, Lida; et al. (Lancet, 2018)
BACKGROUND: Early studies suggest that radiofrequency-based renal denervation reduces blood pressure in patients with moderate hypertension. We investigated whether an alternative technology using endovascular ultrasound renal denervation reduces ambulatory blood pressure in patients with hypertension in the absence of antihypertensive medications. METHODS: RADIANCE-HTN SOLO was a multicentre, international, single-blind, randomised, sham-controlled trial done at 21 centres in the USA and 18 in Europe. Patients with combined systolic-diastolic hypertension aged 18-75 years were eligible if they had ambulatory blood pressure greater than or equal to 135/85 mm Hg and less than 170/105 mm Hg after a 4-week discontinuation of up to two antihypertensive medications and had suitable renal artery anatomy. Patients were randomised (1:1) to undergo renal denervation with the Paradise system (ReCor Medical, Palo Alto, CA, USA) or a sham procedure consisting of renal angiography only. The randomisation sequence was computer generated and stratified by centres with randomised blocks of four or six and permutation of treatments within each block. Patients and outcome assessors were blinded to randomisation. The primary effectiveness endpoint was the change in daytime ambulatory systolic blood pressure at 2 months in the intention-to-treat population. Patients were to remain off antihypertensive medications throughout the 2 months of follow-up unless specified blood pressure criteria were exceeded. Major adverse events included all-cause mortality, renal failure, an embolic event with end-organ damage, renal artery or other major vascular complications requiring intervention, or admission to hospital for hypertensive crisis within 30 days and new renal artery stenosis within 6 months. This study is registered with ClinicalTrials.gov, number NCT02649426. FINDINGS: Between March 28, 2016, and Dec 28, 2017, 803 patients were screened for eligibility and 146 were randomised to undergo renal denervation (n=74) or a sham procedure (n=72). The reduction in daytime ambulatory systolic blood pressure was greater with renal denervation (-8·5 mm Hg, SD 9·3) than with the sham procedure (-2·2 mm Hg, SD 10·0; baseline-adjusted difference between groups: -6·3 mm Hg, 95% CI -9·4 to -3·1, p=0·0001). No major adverse events were reported in either group. INTERPRETATION: Compared with a sham procedure, endovascular ultrasound renal denervation reduced ambulatory blood pressure at 2 months in patients with combined systolic-diastolic hypertension in the absence of medications. FUNDING: ReCor Medical.
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Endovascular Ultrasound Renal Denervation to Treat Hypertension: The RADIANCE II Randomized Clinical Trial - Azizi, Michel; Saxena, Manish; Wang, Yale; Jenkins, J. Stephen; Devireddy, Chandan; Rader, Florian; Fisher, Naomi D.L.; Schmieder, Roland; Mahfoud, Felix; Lindsey, Jason; Sanghvi, Kintur; Todoran, Thomas M.; et al. (Journal of the American Medical Association, 2023)
Importance: Two initial sham-controlled trials demonstrated that ultrasound renal denervation decreases blood pressure (BP) in patients with mild to moderate hypertension and hypertension that is resistant to treatment. Objective: To study the efficacy and safety of ultrasound renal denervation without the confounding influence of antihypertensive medications in patients with hypertension. Design, Setting, and Participants: Sham-controlled, randomized clinical trial with patients and outcome assessors blinded to treatment assignment that was conducted between January 14, 2019, and March 25, 2022, at 37 centers in the US and 24 centers in Europe, with randomization stratified by center. Patients aged 18 years to 75 years with hypertension (seated office systolic BP [SBP] ≥140 mm Hg and diastolic BP [DBP] ≥90 mm Hg despite taking up to 2 antihypertensive medications) were eligible if they had an ambulatory SBP/DBP of 135/85 mm Hg or greater and an SBP/DBP less than 170/105 mm Hg after a 4-week washout of their medications. Patients with an estimated glomerular filtration rate of 40 mL/min/1.73 m2or greater and with suitable renal artery anatomy were randomized 2:1 to undergo ultrasound renal denervation or a sham procedure. Patients were to abstain from antihypertensive medications until the 2-month follow-up unless prespecified BP criteria were exceeded and were associated with clinical symptoms. Interventions: Ultrasound renal denervation vs a sham procedure. Main Outcomes and Measures: The primary efficacy outcome was the mean change in daytime ambulatory SBP at 2 months. The primary safety composite outcome of major adverse events included death, kidney failure, and major embolic, vascular, cardiovascular, cerebrovascular, and hypertensive events at 30 days and renal artery stenosis greater than 70% detected at 6 months. The secondary outcomes included mean change in 24-hour ambulatory SBP, home SBP, office SBP, and all DBP parameters at 2 months. Results: Among 1038 eligible patients, 150 were randomized to ultrasound renal denervation and 74 to a sham procedure (mean age, 55 years [SD, 9.3 years]; 28.6% female; and 16.1% self-identified as Black or African American). The reduction in daytime ambulatory SBP was greater with ultrasound renal denervation (mean, -7.9 mm Hg [SD, 11.6 mm Hg]) vs the sham procedure (mean, -1.8 mm Hg [SD, 9.5 mm Hg]) (baseline-adjusted between-group difference, -6.3 mm Hg [95% CI, -9.3 to -3.2 mm Hg], P <.001), with a consistent effect of ultrasound renal denervation throughout the 24-hour circadian cycle. Among 7 secondary BP outcomes, 6 were significantly improved with ultrasound renal denervation vs the sham procedure. No major adverse events were reported in either group. Conclusions and Relevance: In patients with hypertension, ultrasound renal denervation reduced daytime ambulatory SBP at 2 months in the absence of antihypertensive medications vs a sham procedure without postprocedural major adverse events. Trial Registration: ClinicalTrials.gov Identifier: NCT03614260.
CRIS-Team Scopus Importer:2023-03-10

Enhanced Acid Sphingomyelinase Activity Drives Immune Evasion and Tumor Growth in Non-Small Cell Lung Carcinoma - Kachler, Katerina; Bailer, Maximilian; Heim, Lisanne; Schumacher, Fabian; Reichel, Martin; Holzinger, Corinna D.; Trump, Sonja; Mittler, Susanne; Monti, Juliana; Trufa, Denis; Rieker, Ralf; Hartmann, Arndt; et al. (Cancer Research, 2017)
The lipid hydrolase enzyme acid sphingomyelinase (ASM) is required for the conversion of the lipid cell membrane component sphingomyelin into ceramide. In cancer cells, ASM-mediated ceramide production is important for apoptosis, cell proliferation, and immune modulation, highlighting ASM as a potential multimodal therapeutic target. In this study, we demonstrate elevated ASM activity in the lung tumor environment and blood serum of patients with non-small cell lung cancer (NSCLC). RNAi-mediated attenuation of SMPD1 in human NSCLC cells rendered them resistant to serum starvation-induced apoptosis. In a murine model of lung adenocarcinoma, ASM deficiency reduced tumor development in a manner associated with significant enhancement of Th1-mediated and cytotoxic T-cell-mediated antitumor immunity. Our findings indicate that targeting ASM in NSCLC can act by tumor cell-intrinsic and -extrinsic mechanisms to suppress tumor cell growth, most notably by enabling an effective antitumor immune response by the host. Cancer Res; 77(21); 5963-76. ©2017 AACR.
EVALuna2:4034

Enteric Oxalate Secretion Mediated by Slc26a6 Defends against Hyperoxalemia in Murine Models of Chronic Kidney Disease - Neumeier, Laura; Thomson, Robert B.; Reichel, Martin; Eckardt, Kai-Uwe; Aronson, Peter S.; Knauf, Felix (Journal of the American Society of Nephrology, 2020)
Background A state of oxalate homeostasis is maintained in patients with healthy kidney function. However, as GFR declines, plasma oxalate (Pox) concentrations start to rise. Several groups of researchers have described augmentation of oxalate secretion in the colon in models of CKD, but the oxalate transporters remain unidentified. The oxalate transporter Slc26a6 is a candidate for contributing to the extrarenal clearance of oxalate via the gut in CKD. Methods Feeding a diet high in soluble oxalate or weekly injections of aristolochic acid induced CKD in age- and sex-matched wild-type and Slc26a62/2 mice. qPCR, immunohistochemistry, and western blot analysis assessed intestinal Slc26a6 expression. An oxalate oxidase assay measured fecal and Pox concentrations. Results Fecal oxalate excretion was enhanced in wild-type mice with CKD. This increase was abrogated in Slc26a62/2 mice associated with a significant elevation in plasma oxalate concentration. Slc26a6 mRNA and protein expression were greatly increased in the intestine of mice with CKD. Raising Pox without inducing kidney injury did not alter intestinal Slc26a6 expression, suggesting that changes associated with CKD regulate transporter expression rather than elevations in Pox. Conclusions Slc26a6-mediated enteric oxalate secretion is critical in decreasing the body burden of oxalate in murine CKD models. Future studies are needed to address whether similar mechanisms contribute to intestinal oxalate elimination in humans to enhance extrarenal oxalate clearance.
CRIS-Team Scopus Importer:2020-09-11

Epigenome-wide association study of serum urate reveals insights into urate co-regulation and the SLC2A9 locus - Tin, Adrienne; Schlosser, Pascal; Matias-Garcia, Pamela R.; Thio, Chris H. L.; Joehanes, Roby; Liu, Hongbo; Yu, Zhi; Weihs, Antoine; Hoppmann, Anselm; Grundner-Culemann, Franziska; Min, Josine L.; Kuhns, Victoria L. Halperin; et al. (Nature Communications, 2021)
Serum urate concentration can be studied in large datasets to find genetic and epigenetic loci that may be related to cardiometabolic traits. Here the authors identify and replicate 100 urate-associated CpGs, which provide insights into urate GWAS loci and shared CpGs of urate and cardiometabolic traits.
CRIS-Team WoS Importer:2021-12-17

Erythropoietic response to oral iron in patients with nondialysis-dependent chronic kidney disease in the FIND-CKD trial? - Macdougall, Iain C.; Bock, Andreas H.; Carrera, Fernando; Eckardt, Kai-Uwe; Gaillard, Carlo; Van Wyck, David; Meier, Yvonne; Larroque, Sylvain; Perrin, Amandine; Roger, Simon D. (Clinical Nephrology, 2017)
To evaluate erythropoietic response rates to oral iron over time in iron-deficient anemic patients with nondialysis-dependent chronic kidney disease (ND-CKD).FIND-CKD was a 1-year, randomized, multicenter trial of iron therapy in patients with ND-CKD, anemia, and iron deficiency, without erythropoiesis-stimulating agent (ESA) therapy. Patients with active infection or C-reactive protein > 20 mg/L were excluded. In this post-hoc analysis, response was defined as >= 1 g/dL increase in hemoglobin (Hb) from baseline, before initiation of alternative anemia therapy (i.e., ESA, transfusion, or intravenous iron).308 patients received oral iron (200 mg elemental iron/day). Mean (SD) Hb at baseline was 10.4 (0.7) g/dL. At week 4, Hb data were available from 292 patients without alternative anemia therapy: 63/292 (21.6%) showed a response. Among the 229 nonresponders at week 4, 48.8% showed a cumulative response on >= 1 occasion by week 52 (11.1%, 19.9%, 25.9%, and 28.7% had a response at weeks 8, 12, 24, and 52, respectively), and 27.9% had received alternative iron therapy by week 52. Baseline levels of Hb, ferritin, and transferrin saturation were lower in responders than in nonresponders. Neither concomitant medication nor adherence (as assessed by medication count) was substantially different between early responders and nonresponders.Four weeks after starting oral iron therapy, only 21.6% of anemic patients with ND-CKD and iron deficiency showed an Hb increase of at least 1 g/dL. Among early nonresponders, < 30% responded at any subsequent time point. Earlier consideration of alternative therapy could improve anemia management in this population.?.
EVALuna:34854

Erythropoietin production by PDGFR-?(+) cells - Gerl, Katharina; Nolan, Karen A.; Karger, Christian; Fuchs, Michaela; Wenger, Roland H.; Stolt, Claus; Willam, Carsten; Kurtz, Armin; Kurt, Birguel (Pflügers Archiv: European Journal of Physiology, 2016)
PDGFR-?-expressing cells of the kidneys are considered as a relevant site of erythropoietin (EPO) production. The origin of these cells, their contribution to renal EPO production, and if PDGFR-?-positive cells in other organs are also capable to express EPO are less clear. We addressed these questions in mice, in which hypoxia-inducible transcription factors were stabilized in PDGFR-?(+) cells by inducible deletion of the von Hippel-Lindau (Vhl) protein. Vhl deletion led to a 600-fold increase of plasma EPO concentration, 170-fold increase of renal EPO messenger RNA (mRNA) levels, and an increase of hematocrit values up to 70 %. Intrarenal localization of EPO-expressing cells coincided with the zonal heterogeneity and distribution of cells expressing PDGFR-?. Amongst a variety of extrarenal organs only adrenal glands showed significant EPO mRNA expression after Vhl deletion in PDGFR-?(+) cells. EPO mRNA, plasma EPO, and hematocrit fell to subnormal values if HIF-2?, but not HIF-1?, was deleted either alone or in combination with Vhl in PDGFR-?(+) cells. Treatment of mice with a prolyl-hydroxylase inhibitor caused an increase of EPO mRNA abundance and plasma EPO concentrations in wild-type mice and in mice lacking HIF-1? in PDGFR-?(+) cells but exerted no effect in mice lacking HIF-2? in PDGFR-?(+) cells. These findings suggest that PDGFR-?(+) cells are the only relevant site of EPO expression in the kidney and that HIF-2 is the essential transcription factor triggering EPO expression therein. Moreover, our findings suggest that PDGFR-?(+) cells elaborating EPO might arise from the metanephric mesenchyme, rather than from the neural crest.
EVALuna2:3861

ESRD After Heart Failure, Myocardial Infarction, or Stroke in Type 2 Diabetic Patients With CKD - Charytan, David M.; Solomon, Scott D.; Ivanovich, Peter; Remuzzi, Giuseppe; Cooper, Mark E.; McGill, Janet B.; Parving, Hans Henrik; Parfrey, Patrick; Singh, Ajay K.; Burdmann, Emmanuel A.; Levey, Andrew S.; de Zeeuw, Dick; et al. (American Journal of Kidney Diseases, 2017)
How cardiovascular (CV) events affect progression to end-stage renal disease (ESRD), particularly in the setting of type 2 diabetes, remains uncertain.Observational study.4,022 patients with type 2 diabetes, anemia, and chronic kidney disease from the Trial to Reduce Cardiovascular Events With Aranesp Therapy (TREAT).Postrandomization CV events.ESRD (defined as initiation of dialysis for >30 days, kidney transplantation, or refusal or nonavailability of renal replacement therapy) and post-ESRD mortality within 30 days and during overall follow-up after an intercurrent CV event.Population limited to clinical trial participants with diabetes and anemia.155 of 652 (23.8%) ESRD cases occurred after an intercurrent CV event; 110 (16.9%) cases followed heart failure, 28 (4.3%) followed myocardial infarction, 12 (1.84%) followed stroke, and 5 (0.77%) followed multiple CV events. ESRD rate was higher within 30 days in individuals with an intercurrent CV event compared with those without an intercurrent event (HR, 22.2; 95% CI, 17.0-29.0). Compared to no intercurrent CV events, relative risks for ESRD were higher after the occurrence of heart failure overall (HR, 3.4; 95% CI, 2.7-4.2) and at 30 days (HR, 20.1; 95% CI, 14.5-27.9) than after myocardial infarction or stroke (P<0.001). Compared with individuals without pre-ESRD events, those with ESRD following intercurrent CV events were older, were more likely to have prior CV disease, and had higher (24.4 vs 23.1mL/min/1.73m(2); P=0.01) baseline estimated glomerular filtration rates (eGFRs) and higher eGFRs at last measurement before ESRD (18.6 vs 15.2mL/min/1.73m(2); P<0.001), whereas race, sex, and medication use were similar. Post-ESRD mortality was similar (P=0.3) with and without preceding CV events.Most ESRD cases occurred in individuals without intercurrent CV events who had lower eGFRs than individuals with intercurrent CV events, but similar post-ESRD mortality. Nevertheless, intercurrent CV events, particularly heart failure, are strongly associated with risk for ESRD. These findings underscore the need for kidney-specific therapies in addition to treatment of CV risk factors to lower ESRD incidence in diabetes.
EVALuna2:3957

Estimated GFR (eGFR) loss with glucagon-like peptide-1 (GLP-1) analogue treatment: data from SUSTAIN 6 and LEADER - Perkovic, V.; Bain, S. C.; Bakris, G.; Buse, J. B.; Gondolf, T.; Idorn, T.; Lausvig, N.; Mahaffey, K.; Marso, S. P.; Nauck, M. A.; Pratley, R.; Rossing, P.; et al. (DIABETOLOGIA, 2019)
CRIS-Team WoS Importer:2019-10-11

Estimating salt intake in humans: not so easy! - Titze, Jens (American Journal of Clinical Nutrition, 2017)
EVALuna2:35436

Estrogen-mediated downregulation of HIF-1 alpha signaling in B lymphocytes influences postmenopausal bone loss - Meng, Xianyi; Lin, Zhen; Cao, Shan; Janowska, Iga; Sonomoto, Koshiro; Andreev, Darja; Knab, Katharina; Wen, Jinming; Knaup, Karl; Krönke, Gerhard; Rizzi, Marta; Schett, Georg; et al. (Bone Research, 2022)
In the bone marrow, B cells and bone-resorbing osteoclasts colocalize and form a specific microenvironment. How B cells functionally influence osteoclasts and bone architecture is poorly understood. Using genetically modified mice and high-throughput analyses, we demonstrate that prolonged HIF-1 alpha signaling in B cells leads to enhanced RANKL production and osteoclast formation. In addition, deletion of HIF-1 alpha in B cells prevents estrogen deficiency-induced bone loss in mice. Mechanistically, estrogen controls HIF-1 alpha protein stabilization through HSP70-mediated degradation in bone marrow B cells. The stabilization of HIF-1 alpha protein in HSP70-deficient bone marrow B cells promotes RANKL production and osteoclastogenesis. Induction of HSP70 expression by geranylgeranylacetone (GGA) administration alleviates ovariectomy-induced osteoporosis. Moreover, RANKL gene expression has a positive correlation with HIF1A expression in human B cells. In conclusion, HIF-1 alpha signaling in B cells is crucial for the control of osteoclastogenesis, and the HSP70/HIF-1 alpha axis may serve as a new therapeutic target for osteoporosis.
CRIS-Team WoS Importer:2022-03-04

European guidelines for the management of arterial hypertension 2018-what has changed? - Jung, Susan; Schmieder, Roland (Internist, 2019)
BackgroundIn November 2017, the latest American guidelines for the management of arterial hypertension were published. With these guidelines lowering the threshold for hypertension to 130/80mmHg, the latest European guidelines were expected with excitement.ObjectivesThis article gives an overview on the European Society of Cardiology (ESC) and European Society of Hypertension (ESH) 2018 guidelines for the management of arterial hypertension, thereby identifying the most relevant changes in comparison to previous guidelines.Current dataThe latest 2018 ESC/ESH guidelines adhere to the previous definition of hypertension, in which ablood pressure of 140/90mmHg is considered as threshold for diagnosis. In contrast, there was achange in blood pressure treatment target from below 140/90 to between 120-129/70-79mmHg in patients<65years if well tolerated. Among patients65years, asystolic blood pressure between 130 and 139mmHg is recommended, whereas adiastolic blood pressure between 70 and 79mmHg should be targeted. Additionally the guidelines recommend the use of fixed dose combinations as first choice instead of monotherapy to improve adherence. Interventional treatment strategies should only be applied in carefully selected patients at experienced centers and are not recommended outside of clinical studies and registers. Furthermore, the chapters regarding initiation of blood pressure-lowering therapy and clinical evaluation as well as management of hypertension emergencies have been outlined.ConclusionsThe latest European guidelines for the management of hypertension include several changes. One of the most important aspects is thatin contrast to the American guidelinesthe threshold for diagnosis remains at 140/90mmHg, whereas treatment target range has been lowered by roughly 10mmHg and single pill fixed dose combinations are recommended.
CRIS-Team WoS Importer:2019-02-21

European Society of Hypertension position paper on renal denervation 2018 - Schmieder, Roland; Mahfoud, Felix; Azizi, Michel; Pathak, Atul; Dimitriadis, Kyriakos; Kroon, Abraham A.; Ott, Christian; Scalise, Filippo; Mancia, Giuseppe; Tsioufis, Costas (Journal of Hypertension, 2018)
: This ESH update was deemed necessary with the publication of new results of sham-controlled randomized blinded prospective trials with renal denervation (RDN). Proof of concept studies and first randomized trials (some were sham-controlled) displayed discrepant results about the efficacy of RDN. Three sham-controlled randomized trials of the 2.0 generation yielded now similarity in the average blood pressure decrease following RDN. Reduction of ambulatory blood pressure was approximately 5 to 7 mmHg and of office blood pressure 10 mmHg. Such a decrease in blood pressure by pharmacologic therapy has been found to be associated with lower incidence of cardiovascular events in particular with respect to heart failure and stroke by roughly 25%. Nevertheless, some questions about renal denervation are unanswered. The heterogeneity of the blood pressure-lowering response point to the clinical need to identify predictors for efficacy, and questions on long-term safety could not have been answered due to the short duration of the sham-controlled randomized clinical trials.
EVALuna2:34507

European Society of Hypertension position paper on renal denervation 2021 - Schmieder, Roland; Mahfoud, Felix; Mancia, Giuseppe; Azizi, Michael; Boehm, Michael; Dimitriadis, Kyriakos; Kario, Kazuomi; Kroon, Abraham A.; Lobo, Melvin D.; Ott, Christian; Pathak, Atul; Persu, Alexandre; et al. (Journal of Hypertension, 2021)
This ESH Position Paper 2021 with updated proposed recommendations was deemed necessary after the publication of a set of new pivotal sham-controlled randomized clinical trials (RCTs), which provided important information about the efficacy and safety of endovascular device-based renal denervation (RDN) for hypertension treatment. RDN is effective in reducing or interrupting the sympathetic signals to the kidneys and decreasing whole body sympathetic activity. Five independent, fully completed, sham-controlled RCTs provide conclusive evidence that RDN lowers ambulatory and office blood pressure (BP) to a significantly greater extent than sham treatment. BP-lowering efficacy is evident both in patients with and without concomitant antihypertensive medication. The average decrease of 10mmHg in office BP is estimated to lower the incidence of cardiovascular events by 25-30%, based on meta-analyses of RCTs using pharmacological treatment. Neither peri-procedural, nor short-term or long-term adverse events or safety signals (available up to 3 years) have been observed. Implementing RDN as an innovative third option in the armamentarium of antihypertensive treatment requires a structured process that ensures the appropriate performance of the endovascular RDN procedure and adequate selection of hypertensive patients. The latter should also incorporate patients' perspective and preference that needs to be respected in a shared decision-making process.
CRIS-Team WoS Importer:2021-08-20

Evaluation of dilution and normalization strategies to correct for urinary output in HPLC-HRTOFMS metabolomics - Vogl, Franziska C.; Mehrl, Sebastian; Heizinger, Leonhard; Schlecht, Inga; Zacharias, Helena U.; Ellmann, Lisa; Nuernberger, Nadine; Gronwald, Wolfram; Leitzmann, Michael F.; Rossert, Jerome; Eckardt, Kai-Uwe; Dettmer, Katja; et al. (Analytical and Bioanalytical Chemistry, 2016)
Reliable identification of features distinguishing biological groups of interest in urinary metabolite fingerprints requires the control of total metabolite abundance, which may vary significantly as the kidneys adjust the excretion of water and solutes to meet the homeostatic needs of the body. Failure to account for such variation may lead to misclassification and accumulation of missing data in case of less concentrated urine specimens. Here, different pre- and post-acquisition methods of normalization were compared systematically for their ability to recover features from liquid chromatography-mass spectrometry metabolite fingerprints of urine that allow distinction between patients with chronic kidney disease and healthy controls. Methods of normalization that were employed prior to analysis included dilution of urine specimens to either a fixed creatinine concentration or osmolality value. Post-acquisition normalization methods applied to chromatograms of 1:4 diluted urine specimens comprised normalization to creatinine, osmolality, and sum of all integrals. Dilution of urine specimens to a fixed creatinine concentration resulted not only in the least number of missing values, but it was also the only method allowing the unambiguous classification of urine specimens from healthy and diseased individuals. The robustness of classification could be confirmed for two independent patient cohorts of chronic kidney disease patients and yielded a shared set of 49 discriminant metabolite features. Graphical Abstract Dilution to a uniform creatinine concentration across urine specimens yields more comparable urinary metabolite fingerprints.
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Evaluation of Morphological Changes in Retinal Vessels in Type 1 Diabetes Mellitus Patients with the Use of Adaptive Optics - Matuszewski, Wojciech; Gontarz-Nowak, Katarzyna; Harazny, Joanna; Bandurska-Stankiewicz, Elzbieta (Biomedicines, 2022)
Introduction. Diabetes mellitus contributes to the development of microvascular complications in the eye. Moreover, it affects multiple end organs, including brain damage, leading to premature death. The use of adaptive optics technique allows to perform non-invasive in vivo assessment of retinal vessels and to identify changes in arterioles about 100 μm in diameter. The retinal vasculature may be a model of the cerebral vessels both morphologically and functionally. Aim. To evaluate morphological parameters of retinal arterioles in patients with type 1 diabetes mellitus (DM1). Material and methods. The study included 22 DM1 patients (13 females) aged 43.00 ± 9.45 years with a mean diabetes duration of 22.55 ± 10.05 years, and 23 healthy volunteers (10 females) aged 41.09 ± 10.99 years. Blood pressure, BMI, waist circumference, and metabolic control markers of diabetes were measured in both groups. Vascular examinations were performed using an rtx1 adaptive optics retinal camera (Imagine Eyes, Orsay, France); the vessel wall thickness (WT), lumen diameter (LD), wall-to-lumen ratio (WLR), and vascular wall cross-sectional area (WCSA) were assessed. Statistical analysis was performed with the application of IMB SPSS version 23 software. Results. The DM1 group did not differ significantly in age, BMI, waist circumference, blood pressure, or axial length of the eye compared to the control group. Intraocular pressure (IOP) in both groups was normal, but in the DM1 group it was significantly higher. The DM1 group had significantly higher WT, WLR, and WCSA. These parameters correlated significantly with the duration of diabetes, but not with IOP. Conclusions. The presented study demonstrates the presence of significant morphological changes in retinal vessels in DM1 patients without previously diagnosed diabetic retinopathy. Similar changes may occur in the brain and may be early indicators of cardiovascular risk, but further investigation is required to confirm that.
CRIS-Team Scopus Importer:2022-09-16
Keywords: adaptive optics; diabetes mellitus; diabetic retinopathy

Evaluation of the safety and immunogenicity of subcutaneous HX575 epoetin alfa in the treatment of anemia associated with chronic kidney disease in predialysis and dialysis patients? - Casadevall, Nicole; Dobronravov, Vladimir; Eckardt, Kai-Uwe; Ertürk, Sehsuvar; Martynyuk, Liliya; Schmitt, Susanne; Schaffar, Gregor; Rudy, Anita; Krendyukov, Andriy; Ode, Marité (Clinical Nephrology, 2017)
To assess the safety and immunogenicity of subcutaneous (SC) HX575 (epoetin-?) in dialysis- and nondialysis-dependent adult patients with chronic kidney disease (CKD).Open-label, single-arm, multicenter study in patients (n = 416) from Germany, Italy, Poland, Romania, Russia, Turkey, and Ukraine.Mean (standard deviation (SD)) age was 52.3 (15.8) years, all patients were Caucasian, and similar proportions were male/female. 250 patients (60.1%) were erythropoiesis-stimulating agent (ESA)-naïve, and 166 (39.9%) were receiving ESA maintenance therapy at study start; mean (SD) on-study treatment duration with HX575 was 43.4 (15.8) weeks and 45.3 (13.7) weeks, respectively. Binding antierythropoietin (EPO) antibodies were detected by radioimmunoprecipitation (RIP) assay in 7 patients (1.7%; incidence 0.019); 5 of these were ESA-naïve at study entry. No patient developed neutralizing antibodies as determined in a cell-based epoetin neutralizing assay. Of the 7 patients with a positive binding anti-EPO RIP assay, 4 tested negative at later time points while continuing HX575 treatment. Three patients had low titers of anti-EPO antibodies at the last study assessment. There were no clinical signs of immunogenicity or hypersensitivity.SC HX575 was effective for correcting and maintaining correction of anemia, and the mean weekly dose remained stable over time.?.
EVALuna2:4017

Evidence of neurodegeneration in individuals with only mildly elevated blood pressure - Jung, Susanne; Bosch, Agnes; Kohler, Nikolas; Ott, Christian; Kannenkeril, Dennis; Dienemann, Thomas; Harazny, Joanna M.; Michelson, Georg; Schmieder, Roland (Journal of Hypertension, 2019)
OBJECTIVE: Initiation of antihypertensive drug treatment in low-risk individuals with grade 1 hypertension is under debate. The aim of this study was to examine the impact of mildly elevated blood pressure (BP) on early neurodegenerative processes independent of ageing. METHODS: Sixty-two individuals were included in this study: 25 young (aged <40 years) and 37 older (aged ≥40 years) individuals at low cardiovascular risk and grade 1 hypertension at most. Macular retinal layer volumes of both eyes were determined by SD-OCT. Total retinal volume but also each inner retinal layer volume separately including retinal nerve fiber layer (RNFL), ganglion cell layer (GCL), inner plexiform layer (IPL), and GCL-IPL were measured in each individual. RESULTS: Retinal layer volumes were lower among older individuals compared with young individuals (RNFL right eye: P = 0.037/left eye: P = 0.021; GCL and GCL-IPL: both eyes P < 0.001; IPL right eye: P = 0.005/left eye: P = 0.002; total retinal volume: both eyes P = 0.002) and there was an inverse correlation between retinal layer volumes and age. Partial correlation analysis, excluding age as a cofactor, revealed an inverse association between retinal layer volumes and DBP. In multiple regression analysis, DBP was identified as a determinant of retinal neurodegenerative processes. CONCLUSION: In the current study, we observed an inverse association between retinal neurodegenerative processes and DBP, suggesting that BP-lowering therapy by early antihypertensive drug-treatment might be beneficial to avoid early neurodegeneration.
EVALuna2:203883

Excellent efficacy and beneficial safety during observational 5-year follow-up of rapid steroid withdrawal after renal transplantation (Harmony FU study) - Stumpf, Julian; Thomusch, Oliver; Opgenoorth, Mirian; Wiesener, Michael; Pascher, Andreas; Woitas, Rainer Peter; Suwelack, Barbara; Rentsch, Markus; Witzke, Oliver; Rath, Thomas; Banas, Bernhard; Benck, Urs; et al. (Nephrology Dialysis Transplantation, 2024)
Background: We previously reported excellent efficacy and improved safety aspects of rapid steroid withdrawal (RSWD) in the randomized controlled 1-year "Harmony"trial with 587 predominantly deceased-donor kidney transplant recipients randomized either to basiliximab or rabbit antithymocyte globulin induction therapy and compared with standard immunosuppressive therapy consisting of basiliximab, low tacrolimus once daily, mycophenolate mofetil and corticosteroids. Methods: The 5-year post-trial follow-up (FU) data were obtained in an observational manner at a 3- and a 5-year visit only for those Harmony patients who consented to participate and covered clinical events that occurred from the second year onwards. Results: Biopsy-proven acute rejection and death-censored graft loss rates remained low and independent of RSWD. Rapid steroid withdrawal was an independent positive factor for patient survival (adjusted hazard ratio 0.554, 95% confidence interval 0.314-0.976; P =. 041). The reduced incidence of post-transplantation diabetes mellitus in RSWD patients during the original 1-year study period was not compensated by later incidences during FU. Incidences of other important outcome parameters such as opportunistic infections, malignancies, cardiovascular morbidity/risk factors, donor-specific antibody formation or kidney function did not differ during FU period. Conclusions: With all the limitations of a post-trial FU study, the Harmony FU data confirm excellent efficacy and beneficial safety aspects of RSWD under modern immunosuppressive therapy over the course of 5 years after kidney transplantation in an immunologically low-risk, elderly population of Caucasian kidney transplant recipients.
CRIS-Team Scopus Importer:2024-01-12
Keywords: Harmony study; long-term follow-up; mortality; rapid steroid withdrawal; renal transplantation

Executive Summary of the Joint Position Paper on Renal Denervation of the Cardiovascular and Interventional Radiological Society of Europe (CIRSE) and the European Society of Hypertension (ESH) - Moss, Jonathan G.; Belli, Anna-Maria; Coca, Antonio; Lee, Michael; Mancia, Giuseppe; Peregrin, Jan H.; Redon, Josep; Reekers, Jim A.; Tsioufis, Costas; Vorwerk, Dierk; Schmieder, Roland (Cardiovascular and Interventional Radiology, 2016)
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Executive summary of the KDIGO 2021 Clinical Practice Guideline for the Management of Blood Pressure in Chronic Kidney Disease - Cheung, Alfred K.; Chang, Tara I.; Cushman, William C.; Furth, Susan L.; Hou, Fan Fan; Ix, Joachim H.; Knoll, Gregory A.; Muntner, Paul; Pecoits-Filho, Roberto; Sarnak, Mark J.; Tobe, Sheldon W.; Tomson, Charles R.V.; et al. (Kidney International, 2021)
The Kidney Disease: Improving Global Outcomes (KDIGO) 2021 Clinical Practice Guideline for the Management of Blood Pressure in Chronic Kidney Disease for patients not receiving dialysis represents an update to the KDIGO 2012 guideline on this topic. Development of this guideline update followed a rigorous process of evidence review and appraisal. Guideline recommendations are based on systematic reviews of relevant studies and appraisal of the quality of the evidence. The strength of recommendations is based on the “Grading of Recommendations Assessment, Development and Evaluation” (GRADE) approach. The scope includes topics covered in the original guideline, such as optimal blood pressure targets, lifestyle interventions, antihypertensive medications, and specific management in kidney transplant recipients and children. Some aspects of general and cardiovascular health, such as lipid and smoking management, are excluded. This guideline also introduces a chapter dedicated to proper blood pressure measurement since all large randomized trials targeting blood pressure with pivotal outcomes used standardized preparation and measurement protocols adhered to by patients and clinicians. Based on previous and new evidence, in particular the Systolic Blood Pressure Intervention Trial (SPRINT) results, we propose a systolic blood pressure target of less than 120 mm Hg using standardized office reading for most people with chronic kidney disease (CKD) not receiving dialysis, the exception being children and kidney transplant recipients. The goal of this guideline is to provide clinicians and patients a useful resource with actionable recommendations supplemented with practice points. The burden of the recommendations on patients and resources, public policy implications, and limitations of the evidence are taken into consideration. Lastly, knowledge gaps and recommendations for future research are provided.
CRIS-Team Scopus Importer:2021-03-05
Keywords: albuminuria; ambulatory blood pressure monitoring; angiotensin II receptor blocker; angiotensin-converting enzyme inhibitor; antihypertensive agents; automated office blood pressure; blood pressure measurement; blood pressure targets; children; chronic kidney disease; creatinine; diabetes; dietary sodium; evidence-based; guideline; home blood pressure monitoring; hyperkalemia; KDIGO; kidney transplant recipient; lifestyle; mineralocorticoid receptor antagonist; office blood pressure; physical activity; potassium; proteinuria; renin-angiotensin system; standardized office blood pressure; systematic review; weight loss

EXPECTATION AND ACCEPTANCE OF A CLINICAL DECISION SUPPORT SOFTWARE BY NEPHROLOGIST END-USERS: THE CKDNAPP SURVEY - Kotsis, Fruzsina Kinga; Beachle, Helena; Altenbuchinger, Michael; Meiselbach, Heike; Kosch, Robin; Sabine, Schalloch; Tanja, Bratan; Schultheiss, Ulla T. (NEPHROLOGY DIALYSIS TRANSPLANTATION, 2022)
CRIS-Team WoS Importer:2022-07-22

Expectation of clinical decision support systems: a survey study among nephrologist end-users - Kotsis, Fruzsina; Bächle, Helena; Altenbuchinger, Michael; Dönitz, Jürgen; Njipouombe Nsangou, Yacoub Abelard; Meiselbach, Heike; Kosch, Robin; Salloch, Sabine; Bratan, Tanja; Zacharias, Helena U.; Schultheiss, Ulla T. (BMC Medical Informatics and Decision Making, 2023)
Background: Chronic kidney disease (CKD), a major public health problem with differing disease etiologies, leads to complications, comorbidities, polypharmacy, and mortality. Monitoring disease progression and personalized treatment efforts are crucial for long-term patient outcomes. Physicians need to integrate different data levels, e.g., clinical parameters, biomarkers, and drug information, with medical knowledge. Clinical decision support systems (CDSS) can tackle these issues and improve patient management. Knowledge about the awareness and implementation of CDSS in Germany within the field of nephrology is scarce. Purpose: Nephrologists’ attitude towards any CDSS and potential CDSS features of interest, like adverse event prediction algorithms, is important for a successful implementation. This survey investigates nephrologists’ experiences with and expectations towards a useful CDSS for daily medical routine in the outpatient setting. Methods: The 38-item questionnaire survey was conducted either by telephone or as a do-it-yourself online interview amongst nephrologists across all of Germany. Answers were collected and analysed using the Electronic Data Capture System REDCap, as well as Stata SE 15.1, and Excel. The survey consisted of four modules: experiences with CDSS (M1), expectations towards a helpful CDSS (M2), evaluation of adverse event prediction algorithms (M3), and ethical aspects of CDSS (M4). Descriptive statistical analyses of all questions were conducted. Results: The study population comprised 54 physicians, with a response rate of about 80–100% per question. Most participants were aged between 51–60 years (45.1%), 64% were male, and most participants had been working in nephrology out-patient clinics for a median of 10.5 years. Overall, CDSS use was poor (81.2%), often due to lack of knowledge about existing CDSS. Most participants (79%) believed CDSS to be helpful in the management of CKD patients with a high willingness to try out a CDSS. Of all adverse event prediction algorithms, prediction of CKD progression (97.8%) and in-silico simulations of disease progression when changing, e. g., lifestyle or medication (97.7%) were rated most important. The spectrum of answers on ethical aspects of CDSS was diverse. Conclusion: This survey provides insights into experience with and expectations of out-patient nephrologists on CDSS. Despite the current lack of knowledge on CDSS, the willingness to integrate CDSS into daily patient care, and the need for adverse event prediction algorithms was high.
CRIS-Team Scopus Importer:2023-11-03
Keywords: CDSS; Clinical Decision Support Systems; Nephrology; Survey

Experience with belatacept rescue therapy in kidney transplant recipients - Brakemeier, Susanne; Kannenkeril, Dennis; Duerr, Michael; Braun, Timm; Bachmann, Friederike; Schmidt, Danilo; Wiesener, Michael; Budde, Klemens (Transplant International, 2016)
In kidney transplant recipients with chronic graft dysfunction, long-term immunosuppression with calcineurin inhibitors (CNIs) or mTOR inhibitors (mTORi) can be challenging due to adverse effects, such as nephrotoxicity and proteinuria. Seventy-nine kidney transplant recipients treated with CNI-based or mTORi-based maintenance immunosuppression who had CNI-induced nephrotoxicity or severe adverse events were switched to belatacept. Mean time from transplantation to belatacept conversion was 69.0 months. Mean estimated glomerular filtration rate (eGFR) ± standard deviation at baseline was 26.1 ± 15.0 ml/min/1.73 m(2) , increasing to 34.0 ± 15.2 ml/min/1.73 m(2) at 12 months postconversion (P < 0.0005). Renal function improvements were also seen in patients with low eGFR (<25 ml/min/1.73 m(2) ) or high proteinuria (>500 mg/l) at conversion. The Kaplan-Meier estimates for patient and graft survival at 12 months were 95.0% and 85.6%, respectively. The discontinuation rate due to adverse events was 7.9%. One case of post-transplant lymphoproliferative disorder occurred at 17 months postconversion. For comparison, a historical control group of 41 patients converted to mTORi-based immunosuppression because of biopsy-confirmed CNI-induced toxicity was examined; eGFR increased from 27.6 ± 7.2 ml/min/1.73 m(2) at baseline to 31.1 ± 11.9 ml/min/1.73 m(2) at 12 months (P = 0.018). Belatacept-based immunosuppression may be an alternative regimen for kidney transplant recipients with CNI- or mTORi-induced toxicity.
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Expertise: no longer a sine qua non for guideline authors? - Messerli, Franz H.; Hofstetter, Louis; Agabiti-Rosei, Enrico; Burnier, Michel; Elliott, William J.; Franklin, Stanley S.; Grodzicki, Tomasz; Kario, Kazuomi; Kjeldsen, Sverre E.; Kostis, John B.; Laurent, Stephane; Leenen, Frans H.; et al. (Journal of Hypertension, 2017)
: Several sets of guidelines have been published recently and more are in the works. The very recent American College of Physicians/American Academy of Family Practitioners guidelines were put together by a set of authors and consultants without any expertise in the topic under discussion, that is, hypertension. Although we are not maintaining that all guidelines should be written exclusively by experts, complete lack of expertise among guideline authors is not acceptable.
EVALuna2:3962

Expression of Retinoid Acid Receptor-Responsive Genes in Rodent Models of Placental Pathology - Mocker, Alexander; Schmidt, Marius; Hübner, Hanna; Wachtveitl, Rainer; Cordasic, Nada; Menendez-Castro, Carlos; Hartner, Andrea; Fahlbusch, Fabian (International Journal of Molecular Sciences, 2019)
In humans, retinoic acid receptor responders (RARRES) have been shown to be altered in third trimester placentas complicated by the pathologies preeclampsia (PE) and PE with intrauterine growth restriction (IUGR). Currently, little is known about the role of placental Rarres in rodents. Therefore, we examined the localization and expression of Rarres1 and 2 in placentas obtained from a Wistar rat model of isocaloric maternal protein restriction (E18.5, IUGR-like features) and from an eNOS-knockout mouse model (E15 and E18.5, PE-like features). In both rodent models, Rarres1 and 2 were mainly localized in the placental spongiotrophoblast and giant cells. Their placental expression, as well as the expression of the Rarres2 receptor chemokine-like receptor 1 (CmklR1), was largely unaltered at the examined gestational ages in both animal models. Our results have shown that RARRES1 and 2 may have different expression and roles in human and rodent placentas, thereby underlining immanent limitations of comparative interspecies placentology. Further functional studies are required to elucidate the potential involvement of these proteins in early placentogenesis.
EVALuna2:209516

Extensive regulation of the non-coding transcriptome by hypoxia: role of HIF in releasing paused RNApol2 - Choudhry, Hani; Schoedel, Johannes; Oikonomopoulos, Spyros; Camps, Carme; Grampp, Steffen; Harris, Adrian L.; Ratcliffe, Peter J.; Ragoussis, Jiannis; Mole, David R. (EMBO Reports, 2014)
Hypoxia is central to both ischaemic and neoplastic diseases. However, the non-coding transcriptional response to hypoxia is largely uncharacterized. We undertook integrated genomic analyses of both non-coding and coding transcripts using massively parallel sequencing and interfaced this data with pan-genomic analyses of hypoxia-inducible factor (HIF) and RNApol2 binding in hypoxic cells. These analyses revealed that all classes of RNA are profoundly regulated by hypoxia and implicated HIF as a major direct regulator of both the non-coding and coding transcriptome, acting predominantly through release of pre-bound promoter-paused RNApol2. These findings indicate that the transcriptional response to hypoxia is substantially more extensive than previously considered.
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Externally Delivered Focused Ultrasound for Renal Denervation - Neuzil, Petr; Ormiston, John; Brinton, Todd J.; Starek, Zdenek; Esler, Murray; Dawood, Omar; Anderson, Thomas L.; Gertner, Michael; Whitbourne, Rob; Schmieder, Roland (Jacc-Cardiovascular Interventions, 2016)
The aim of this study was to assess clinical safety and efficacy outcomes of renal denervation executed by an externally delivered, completely noninvasive focused therapeutic ultrasound device.Renal denervation has emerged as a potential treatment approach for resistant hypertension.Sixty-nine subjects received renal denervation with externally delivered focused ultrasound via the Kona Medical Surround Sound System. This approach was investigated across 3 consecutive studies to optimize targeting, tracking, and dosing. In the third study, treatments were performed in a completely noninvasive way using duplex ultrasound image guidance to target the therapy. Short- and long-term safety and efficacy were evaluated through use of clinical assessments, magnetic resonance imaging scans prior to and 3 and 24 weeks after renal denervation, and, in cases in which a targeting catheter was used to facilitate targeting, fluoroscopic angiography with contrast.All patients tolerated renal denervation using externally delivered focused ultrasound. Office blood pressure (BP) decreased by 24.6 ± 27.6/9.0 ± 15.0 mm Hg (from baseline BP of 180.0 ± 18.5/97.7 ± 13.7 mm Hg) in 69 patients after 6 months and 23.8 ± 24.1/10.3 ± 13.1 mm Hg in 64 patients with complete 1-year follow-up. The response rate (BP decrease >10 mm Hg) was 75% after 6 months and 77% after 1 year. The most common adverse event was post-treatment back pain, which was reported in 32 of 69 patients and resolved within 72 h in most cases. No intervention-related adverse events involving motor or sensory deficits were reported. Renal function was not altered, and vascular safety was established by magnetic resonance imaging (all patients), fluoroscopic angiography (n = 48), and optical coherence tomography (n = 5).Using externally delivered focused ultrasound and noninvasive duplex ultrasound, image-guided targeting was associated with substantial BP reduction without any major safety signals. Further randomized, sham-controlled trials will be needed to validate this unique approach.
EVALuna2:3868

Extracellular DNA traps in inflammation, injury and healing - Daniel, Christoph; Leppkes, Moritz; Munoz, Luis Enrique; Muñoz, Luis E.; Schley, Gunnar; Schett, Georg; Herrmann, Martin (Nature Reviews Nephrology, 2019)
Following strong activation signals, several types of immune cells reportedly release chromatin and granular proteins into the extracellular space, forming DNA traps. This process is especially prominent in neutrophils but also occurs in other innate immune cells such as macrophages, eosinophils, basophils and mast cells. Initial reports demonstrated that extracellular traps belong to the bactericidal and anti-fungal armamentarium of leukocytes, but subsequent studies also linked trap formation to a variety of human diseases. These pathological roles of extracellular DNA traps are now the focus of intensive biomedical research. The type of pathology associated with the release of extracellular DNA traps is mainly determined by the site of trap formation and the way in which these traps are further processed. Targeting the formation of aberrant extracellular DNA traps or promoting their efficient clearance are attractive goals for future therapeutic interventions, but the manifold actions of extracellular DNA traps complicate these approaches.
CRIS-Team Scopus Importer:2019-07-09

Extracorporeal renal replacement therapy in acute kidney injury : Recommendations from the renal section of the DGIIN, ÖGIAIN and DIVI - Schwenger, V.; Kindgen-Milles, D.; Willam, Carsten; Joerres, A.; Druml, W.; Czock, D.; Klein, S. J.; Oppert, M.; Schmitz, M.; Kielstein, J. T.; Zarbock, A.; Joannidis, M.; et al. (Medizinische Klinik - Intensivmedizin und Notfallmedizin, 2018)
BACKGROUND: Acute kidney injury (AKI) is a common complication in intensive care unit (ICU) patients. The incidence of AKI in ICU patients exceeds 50% and the associated morbidity and mortality rates increase with severity of AKI. In addition, long-term consequences of AKI are underestimated and several studies show impaired long-term outcome after AKI. In about 5-25% of ICU patients with AKI renal replacement therapy (RRT) is required. OBJECTIVES: To assist in indication, timing, modality and application of renal replacement therapy of adult patients, current recommendations from the renal sections of the DGIIN (Deutschen Gesellschaft für Internistische Intensivmedizin und Notfallmedizin), ÖGIAIN (Österreichischen Gesellschaft für Internistische und Allgemeine Intensivmedizin und Notfallmedizin) and DIVI (Deutschen Interdisziplinären Vereinigung für Intensiv- und Notfallmedizin) are stated. MATERIALS AND METHODS: The recommendations stated in this paper are based on the current KDIGO (Kidney Disease: Improving Global Outcomes) guidelines, recommendations from the 17th Acute Disease Quality Initiative (ADQI) Consensus Group, the French Intensive Care Society (SRLF) with the French Society of Anesthesia Intensive Care (SFAR) and the expert knowledge and clinical experience of the authors. RESULTS: Today, different treatment modalities for RRT are available. Although continuous RRT and intermittent dialysis therapy as well as continuous dialysis therapy have comparable outcomes, differences exist with respect to practical application as well as health-economic aspects. Individualized risk stratification might be helpful to choose the right time to start and the right treatment modality for patients.
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Facing the Challenge of Lowering Blood Pressure and Cholesterol in the Same Patient: Report of a Symposium at the European Society of Hypertension - Williams, Bryan; Masi, Stefano; Wolf, Jacek; Schmieder, Roland (Cardiology and Therapy, 2020)
A symposium held at the 29th European Meeting on Hypertension and Cardiovascular Protection in Milan, Italy, discussed the potential impact and long-term benefits of early active management of cardiovascular disease (CVD) risk in patients with hypertension, and potential barriers to this strategy. Hypertension often aggregates with other cardiovascular risk factors, exponentially increasing morbidity and mortality. While effective therapies to treat hypertension exist, a substantial number of patients still experience major cardiovascular events. Two major issues account for these disappointing results: interventions initiated too late in the disease trajectory and lack of effective translation of the research findings into daily clinical practice. Results from genetic studies suggest that lifetime exposure to lower blood pressure (BP) and cholesterol levels due to protective gene mutations, can provide greater cardiovascular benefits than middle-/late-age interventions. Clinical guidelines suggest adding statins to BP-lowering therapies for further cardiovascular benefits in most hypertensive patients; however, real-world data show that physicians' compliance with these recommendations and patients' adherence to BP- and lipid-lowering treatments remain poor, resulting in poor risk factor control and an increased risk of adverse outcomes. The use of single-pill combinations (SPC) can partially mitigate these issues, as they are associated with increased patient adherence and improved BP control. Treatment with SPC has been recommended in the European Hypertension Guidelines, but optimization of the total CVD risk may need adoption of more ambitious treatment strategies aimed to deliver single pills that control multiple CVD risk factors. Amlodipine, perindopril and atorvastatin have been shown to improve BP and lipid levels to a great extent when given separately, and this combination has also been shown to improve cardiovascular outcomes. Overall, early intervention in patients with hypertension with use of an effective, high-intensity cardiovascular risk reduction regimen and attention to medication adherence through reducing pill burden are likely to result in optimal outcomes.
CRIS-Team WoS Importer:2020-05-29

Factors precipitating erythropoiesis-stimulating agent responsiveness in a European haemodialysis cohort: case-crossover study - Gillespie, Iain A.; Macdougall, Iain C.; Richards, Sharon; Jones, Vincent; Marcelli, Daniele; Froissart, Marc; Eckardt, Kai-Uwe (Pharmacoepidemiology and Drug Safety, 2015)
Hyporesponsiveness to erythropoiesis-stimulating agents (ESAs) is clinically and economically important in the treatment of anaemia in chronic kidney disease (CKD) patients. Previous studies focused on baseline predictors of ESA hyporesponsiveness, rather than factors associated with the transition to this state. Reversibility of ESA hyporesponsiveness has also not been studied previously.Case-crossover methodology was applied to a cohort of 6645 European CKD patients undergoing haemodialysis and prescribed ESAs. Ninety-day ESA exposure periods were defined, haemoglobin (Hb) response was calculated using the last 30 days of one period and the first 30 days of the next, and periods were classified based on a median ESA dose (80.8 IU/kg/week) and a 10 g/dL Hb threshold. Clinical, dialysis and laboratory data from patients' first hyporesponsive 'case' period was compared with the preceding responsive 'control' period using conditional logistic regression. A similar approach was applied to hyporesponsiveness reversal.Of the patients, 672 experienced hyporesponsiveness periods with preceding responsive periods; 711 reversed to normality from hyporesponsiveness periods. Transition to hyporesponsiveness was associated with hospitalization, vascular access changes or worsening inflammation, with these factors accounting for over two-thirds of transitions. Findings were largely insensitive to alternative ESA doses and Hb thresholds. Continued hospitalization, catheter insertion and uncontrolled secondary hyperparathyroidism were associated with a lack of regain of responsiveness.Transition to hyporesponsiveness is linked to the development of conditions such as hospitalization events, vascular access issues or episodes of systemic inflammation. However, a third of hyporesponsive episodes remain unexplained.
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Fatal Puumala Hantavirus Infection in a Patient with Common Variable Immunodeficiency (CVID) - Steininger, Philipp; Herbst, Larissa; Bihlmaier, Karl; Willam, Carsten; Koerper, Sixten; Schrezenmeier, Hubert; Klueter, Harald; Pfister, Frederick; Amann, Kerstin Ute; Weiss, Sabrina; Krueger, Detlev H.; Zimmermann, Robert; et al. (Microorganisms, 2023)
Puumala hantavirus (PUUV) infections usually show a mild or moderate clinical course, but may sometimes also lead to life-threatening disease. Here, we report on a 60-year-old female patient with common variable immunodeficiency (CVID) who developed a fatal PUUV infection with persistent renal failure, thrombocytopenia, and CNS infection with impaired consciousness and tetraparesis. Hantavirus-specific antibodies could not be detected due to the humoral immunodeficiency. Diagnosis and virological monitoring were based on the quantitative detection of PUUV RNA in blood, cerebrospinal fluid, bronchial lavage, and urine, where viral RNA was found over an unusually extended period of one month. Due to clinical deterioration and virus persistence, treatment with ribavirin was initiated. Additionally, fresh frozen plasma (FFP) from convalescent donors with a history of PUUV infection was administered. Despite viral clearance, the clinical condition of the patient did not improve and the patient died on day 81 of hospitalization. This case underlines the importance of the humoral immune response for the course of PUUV disease and illustrates the need for PCR-based virus diagnostics in those patients. Due to its potential antiviral activity, convalescent plasma should be considered in the therapy of severe hantavirus diseases.
CRIS-Team Scopus Importer:2023-03-10
Keywords: common variable immunodeficiency; convalescent plasma; encephalitis; Puumala hantavirus; ribavirin

Ferritin-Mediated Iron Sequestration Stabilizes Hypoxia-Inducible Factor-1α upon LPS Activation in the Presence of Ample Oxygen. - Siegert, Isabel; Schoedel, Johannes; Nairz, Manfred; Schatz, Valentin; Dettmer, Katja; Dick, Christopher; Kalucka, Joanna; Franke, Kristin; Ehrenschwender, Martin; Schley, Gunnar; Beneke, Angelika; Sutter, Jörg; et al. (Cell Reports, 2015)
Both hypoxic and inflammatory conditions activate transcription factors such as hypoxia-inducible factor (HIF)-1α and nuclear factor (NF)-κB, which play a crucial role in adaptive responses to these challenges. In dendritic cells (DC), lipopolysaccharide (LPS)-induced HIF1α accumulation requires NF-κB signaling and promotes inflammatory DC function. The mechanisms that drive LPS-induced HIF1α accumulation under normoxia are unclear. Here, we demonstrate that LPS inhibits prolyl hydroxylase domain enzyme (PHD) activity and thereby blocks HIF1α degradation. Of note, LPS-induced PHD inhibition was neither due to cosubstrate depletion (oxygen or α-ketoglutarate) nor due to increased levels of reactive oxygen species, fumarate, and succinate. Instead, LPS inhibited PHD activity through NF-κB-mediated induction of the iron storage protein ferritin and subsequent decrease of intracellular available iron, a critical cofactor of PHD. Thus, hypoxia and LPS both induce HIF1α accumulation via PHD inhibition but deploy distinct molecular mechanisms (lack of cosubstrate oxygen versus deprivation of co-factor iron).

FHR5 Binds to Laminins, Uses Separate C3b and Surface-Binding Sites, and Activates Complement on Malondialdehyde-Acetaldehyde Surfaces - Rudnick, Ramona B.; Chen, Qian; Stea, Emma Diletta; Hartmann, Andrea; Papac-Milicevic, Nikolina; Person, Fermin; Wiesener, Michael; Binder, Christoph J.; Wiech, Thorsten; Skerka, Christine; Zipfel, Peter F. (Journal of Immunology, 2018)
Factor H related-protein 5 (CFHR5) is a surface-acting complement activator and variations in the CFHR5 gene are linked to CFHR glomerulonephritis. In this study, we show that FHR5 binds to laminin-521, the major constituent of the glomerular basement membrane, and to mesangial laminin-211. Furthermore, we identify malondialdehyde-acetaldehyde (MAA) epitopes, which are exposed on the surface of human necrotic cells (Homo sapiens), as new FHR5 ligands. Using a set of novel deletion fragments, we show that FHR5 binds to laminin-521, MAA epitopes, heparin, and human necrotic cells (HUVECs) via the middle region [short consensus repeats (SCRs) 5-7]. In contrast, surface-bound FHR5 contacts C3b via the C-terminal region (SCRs8-9). Thus, FHR5 uses separate domains for C3b binding and cell surface interaction. MAA epitopes serve as a complement-activating surface by recruiting FHR5. The complement activator FHR5 and the complement inhibitor factor H both bind to oxidation-specific MAA epitopes and FHR5 competes with factor H for binding. The C3 glomerulopathy-associated FHR21-2-FHR5 hybrid protein is more potent in MAA epitope binding and activation compared with wild-type FHR5. The implications of these results for pathology of CFHR glomerulonephritis are discussed. In conclusion, we identify laminins and oxidation-specific MAA epitopes as novel FHR5 ligands and show that the surface-binding site of FHR5 (SCRs5-7) is separated from the C3b binding site (SCRs8-9). Furthermore, FHR5 competes with factor H for binding to MAA epitopes and activates complement on these modified structures.
EVALuna2:34259

Fibrillin-1 and alpha8 integrin are co-expressed in the glomerulus and interact to convey adhesion of mesangial cells - Marek, Ines; Volkert, Gudrun; Hilgers, Karl Friedrich; Bieritz, Beate; Rascher, Wolfgang; Reinhardt, Dieter P.; Hartner, Andrea (Cell Adhesion and Migration, 2014)
Fibrillin-1 is a microfibrillar extracellular matrix protein that was described to be a ligand for ?8 integrin. ?8 integrin is a matrix receptor specifically expressed in mesangial and smooth muscle cells of the kidney. In previous studies we detected glomerular expression of fibrillin-1. Moreover, fibrillin-1 promoted adhesion, migration, and proliferation of mesangial cells. We hypothesized that fibrillin-1 and ?8 integrin might interact in the glomerulus, and thus, regulate mesangial cell properties. Our studies showed that fibrillin-1 and ?8 integrin colocalize in the glomerular mesangium. Induction of experimental glomerulonephritis led to an increase of both fibrillin-1 and ?8 integrin expression. In vitro studies revealed that mesangial cells deficient for ?8 integrin adhere weaker to fibrillin-1 and migrate more easily on fibrillin-1 than wild-type mesangial cells. Baseline proliferation on fibrillin-1 is higher in ?8 integrin-deficient mesangial cells, but the induction of proliferation is not different in ?8 integrin-deficient and wild-type mesangial cells. We conclude that fibrillin-1 and ?8 integrin interact, and thus, regulate mesangial cell adhesion and migration. The concomitant induction of both fibrillin-1 and ?8 integrin in a self-limited model of glomerular injury points to a protective role of the interaction of fibrillin-1 with ?8 integrin in the glomerulus resulting in reduced damage of the glomerular tuft as a consequence of firm adhesion of mesangial cells.
EVALuna2:3751

FIND-CKD: a randomized trial of intravenous ferric carboxymaltose versus oral iron in patients with chronic kidney disease and iron deficiency anaemia - Macdougall, Iain C.; Bock, Andreas H.; Carrera, Fernando; Eckardt, Kai-Uwe; Gaillard, Carlo; Van Wyck, David; Roubert, Bernard; Nolen, Jacqueline G.; Roger, Simon D. (Nephrology Dialysis Transplantation, 2014)
The optimal iron therapy regimen in patients with non-dialysis-dependent chronic kidney disease (CKD) is unknown.Ferinject® assessment in patients with Iron deficiency anaemia and Non-Dialysis-dependent Chronic Kidney Disease (FIND-CKD) was a 56-week, open-label, multicentre, prospective and randomized study of 626 patients with non-dialysis-dependent CKD, anaemia and iron deficiency not receiving erythropoiesis-stimulating agents (ESAs). Patients were randomized (1:1:2) to intravenous (IV) ferric carboxymaltose (FCM), targeting a higher (400-600 µg/L) or lower (100-200 µg/L) ferritin or oral iron therapy. The primary end point was time to initiation of other anaemia management (ESA, other iron therapy or blood transfusion) or haemoglobin (Hb) trigger of two consecutive values <10 g/dL during Weeks 8-52.The primary end point occurred in 36 patients (23.5%), 49 patients (32.2%) and 98 patients (31.8%) in the high-ferritin FCM, low-ferritin FCM and oral iron groups, respectively [hazard ratio (HR): 0.65; 95% confidence interval (CI): 0.44-0.95; P = 0.026 for high-ferritin FCM versus oral iron]. The increase in Hb was greater with high-ferritin FCM versus oral iron (P = 0.014) and a greater proportion of patients achieved an Hb increase >=1 g/dL with high-ferritin FCM versus oral iron (HR: 2.04; 95% CI: 1.52-2.72; P < 0.001). Rates of adverse events and serious adverse events were similar in all groups.Compared with oral iron, IV FCM targeting a ferritin of 400-600 µg/L quickly reached and maintained Hb level, and delayed and/or reduced the need for other anaemia management including ESAs. Within the limitations of this trial, no renal toxicity was observed, with no difference in cardiovascular or infectious events.NCT00994318.
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First experience in analysing pulsatile retinal capillary flow and arteriolar structural parameters measured noninvasively in hypertensive patients - Harazny, Joanna M.; Ott, Christian; Raff, Ulrike; Welzenbach, Juergen; Kwella, Norbert; Michelson, Georg; Schmieder, Roland (Journal of Hypertension, 2014)
Increased pulsatile pressure induces as well as aggravates microvascular damage. Scanning laser Doppler flowmetry allows the noninvasive assessment of both retinal capillary flow (RCF) and arteriolar structural parameters of the retinal circulation. Moreover, pulsatile characteristics of the retinal arterioles can be assessed.In study 1, reliability of pulsatile RCF and structural parameters were examined in randomly selected patients. In study 2, pulsatile RCF as well as the structural parameters of retinal arterioles were assessed in hypertension grade 1-2 (HT1-2; n = 20) and treatment-resistant hypertension (TRH; n = 19).In study 1, test-retest, interobserver and intraobserver reliability of all parameters showed coefficients of variation of less than 10%. In study 2, it was shown that patients with TRH had higher pulse pressure (P = 0.003) and pulsed RCF values (P < 0.001) as patients with HT1-2. Patients with HT1-2 had no change in the vessel diameter, but a significant difference in lumen diameter, resulting in an altered wall thickness (P = 0.001) between systole and diastole. In contrast, patients with TRH showed differences in vessel diameter (P = 0.005) as well as lumen diameter (P = 0.001), resulting in an unaltered wall thickness between systole and diastole. Hence, wall thickness change as a result of pulsed flow regulation observed in HT1-2 was missing in TRH.We suggest a new reliable tool for evaluating the pulsatility in the retinal circulation in humans, and found significant differences in pulsatile RCF and structural parameters between patients with HT1-2 and those with TRH.
EVALuna2:3718

First report of the Global SYMPLICITY Registry on the effect of renal artery denervation in patients with uncontrolled hypertension - Boehm, Michael; Mahfoud, Felix; Ukena, Christian; Hoppe, Uta C.; Narkiewicz, Krzysztof; Negoita, Manuela; Ruilope, Luis; Schlaich, Markus P.; Schmieder, Roland; Whitbourn, Robert; Williams, Bryan; Zeymer, Uwe; et al. (Hypertension, 2015)
This study aimed to assess the safety and effectiveness of renal denervation using the Symplicity system in real-world patients with uncontrolled hypertension (NCT01534299). The Global SYMPLICITY Registry is a prospective, open-label, multicenter registry. Office and 24-hour ambulatory blood pressures (BPs) were measured. Change from baseline to 6 months was analyzed for all patients and for subgroups based on baseline office systolic BP, diabetic status, and renal function; a cohort with severe hypertension (office systolic pressure, >=160 mm Hg; 24-hour systolic pressure, >=135 mm Hg; and >=3 antihypertensive medication classes) was also included. The analysis included protocol-defined safety events. Six-month outcomes for 998 patients, including 323 in the severe hypertension cohort, are reported. Mean baseline office systolic BP was 163.5±24.0 mm Hg for all patients and 179.3±16.5 mm Hg for the severe cohort; the corresponding baseline 24-hour mean systolic BPs were 151.5±17.0 and 159.0±15.6 mm Hg. At 6 months, the changes in office and 24-hour systolic BPs were -11.6±25.3 and -6.6±18.0 mm Hg for all patients (P<0.001 for both) and -20.3±22.8 and -8.9±16.9 mm Hg for those with severe hypertension (P<0.001 for both). Renal denervation was associated with low rates of adverse events. After the procedure through 6 months, there was 1 new renal artery stenosis >70% and 5 cases of hospitalization for a hypertensive emergency. In clinical practice, renal denervation resulted in significant reductions in office and 24-hour BPs with a favorable safety profile. Greater BP-lowering effects occurred in patients with higher baseline pressures.URL: www.clinicaltrials.gov. Unique identifier: NCT01534299.
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FIRST RESULTS OF THE COVID-19 PATIENTS TREATED WITH THE SERAPH (R) 100 MICROBIND (R) AFFINITY FILTER (COSA) REGISTRY - Schmidt, Julius J.; Van'T Klooster, Mariet; Borchina, Dan N.; Buettner, Stefan; Bader, Birgit; Herbst, Larissa; Fuehner, Thomas; Kielstein, Jan T. (NEPHROLOGY DIALYSIS TRANSPLANTATION, 2021)
CRIS-Team WoS Importer:2021-12-03

Fixed low dose versus concentration-controlled initial tacrolimus dosing with reduced target levels in the course after kidney transplantation: results from a prospective randomized controlled non-inferiority trial (Slow & Low study) - Stumpf, Julian; Budde, Klemens; Witzke, Oliver; Sommerer, Claudia; Vogel, Thomas; Schenker, Peter; Woitas, Rainer Peter; Opgenoorth, Mirian; Trips, Evelyn; Schrezenmeier, Eva; Hugo, Christian; Girndt, Matthias; et al. (EClinicalMedicine, 2024)
Background: Optimal initial tacrolimus dosing and early exposure of tacrolimus after renal transplantation is not well studied. Methods: In this open-label, 6 months, multicenter, randomized controlled, non-inferiority study, we randomly assigned 432 renal allograft recipients to receive basiliximab induction, mycophenolate and steroids and either standard prolonged-release tacrolimus (trough levels: 7–9 ng/ml; Standard Care arm), or an initial 7-day fixed 5 mg/day dose of prolonged-release tacrolimus followed by lower tacrolimus predose levels (trough levels: 5–7 ng/ml; Slow & Low arm). The primary end point was the combined incidence rate of biopsy-proven acute rejections (BPAR; including borderline), graft failure, or death at 6 months with a non-inferiority margin of 12.5%. (EudraCT-Nr: 2013-001770-19. Findings: The combined primary endpoint in the Slow & Low arm was non-inferior compared to the Standard Care arm (22.1% versus 20.7%; difference: 1.4%, 90% CI −5.5% to 8.3%). The overall rate of BPAR including borderlines was similar (Slow & Low 17.4% versus Standard Care 16.6%). Safety parameters such as delayed graft function, kidney function, donor specific HLA-antibodies, infections, or post-transplantation diabetes mellitus did not differ. Interpretation: This is the first study to show that an initial fixed dose of 5 mg per day followed by lower tacrolimus exposure is non-inferior compared to standard tacrolimus therapy and equally efficient and safe within 6 months after renal transplantation. These data suggest that therapeutic drug monitoring for prolonged release tacrolimus can be abandoned until start of the second week after transplantation. Funding: Investigator-initiated trial, financial support by Astellas Pharma GmbH.
CRIS-Team Scopus Importer:2024-01-05
Keywords: Fixed low dose; Immunosuppression; Renal transplantation; Tacrolimus monitoring

FLOW MEDIATED VASODILATION/VASOCONSTRICTION IN DIFFERENT DISEASE POPULATIONS - Kannenkeril, D.; Dienemann, T.; Jung, Susan; Striepe, Kristina; Kopp, C.; Schneider, M.; Ott, Christian; Schmieder, Roland (JOURNAL OF HYPERTENSION, 2019)
CRIS-Team WoS Importer:2019-09-20

Fluid management in emergency and intensive care medicine - Kluge, Stefan; Willam, Carsten (Medizinische Klinik - Intensivmedizin und Notfallmedizin, 2021)
CRIS-Team WoS Importer:2021-11-12

Flüssigkeitsmanagement in der Intensivmedizin: Eine Aufgabe von unterschätzter Relevanz - Willam, Carsten; Herbst, L.; Kribben, A. (Nephrologe, 2019)
In critically ill patients with shock fluid replacement is crucial to stabilize the circulation and organ perfusion. Initially, a hemodynamically controlled, aggressive fluid therapy aims to restore circulation, whereas the second, later phase of therapy is characterized by fluid overload, which then needs to be reverted. Both, an adequate initial shock therapy as well as the subsequent normalization of fluid balance have an important impact on morbidity and mortality and therefore profound proficiencies of fluid management are of need. Here we give a summary of hemodynamic aspects of fluid therapy, the type of fluid replacement and the evaluation of fluid balance in respect to fluid management of the critically ill.
CRIS-Team Scopus Importer:2019-11-01
Keywords: Acute kidney injury; Critical illness; Fluid therapy; Sepsis; Shock

Forgotten Technology in the COVID-19 Pandemic: Filtration Properties of Cloth and Cloth Masks—A Narrative Review - Clase, Catherine M.; Fu, Edouard L.; Ashur, Aurneen; Beale, Rupert C.L.; Clase, Imogen A.; Dolovich, Myrna B.; Jardine, Meg J.; Joseph, Meera; Kansiime, Grace; Mann, Johannes; Pecoits-Filho, Roberto; Winkelmayer, Wolfgang C.; et al. (Mayo Clinic Proceedings, 2020)
Management of the global crisis of the coronavirus disease 2019 pandemic requires detailed appraisal of evidence to support clear, actionable, and consistent public health messaging. The use of cloth masks for general public use is being debated, and is in flux. We searched the MEDLINE and EMBASE databases and Google for articles reporting the filtration properties of flat cloth or cloth masks. We reviewed the reference lists of relevant articles to identify further articles and identified articles through social and conventional news media. We found 25 articles. Study of protection for the wearer used healthy volunteers, or used a manikin wearing a mask, with airflow to simulate different breathing rates. Studies of protection of the environment, also known as source control, used convenience samples of healthy volunteers. The design and execution of the studies was generally rigorously described. Many descriptions of cloth lacked the detail required for reproducibility; no study provided all the expected details of material, thread count, weave, and weight. Some of the homemade mask designs were reproducible. Successful masks were made of muslin at 100 threads per inch (TPI) in 3 to 4 layers (4-layer muslin or a muslin-flannel-muslin sandwich), tea towels (also known as dish towels), made using 1 layer (2 layers would be expected to be better), and good-quality cotton T-shirts in 2 layers (with a stitched edge to prevent stretching). In flat-cloth experiments, linen tea towels, 600-TPI cotton in 2 layers, and 600-TPI cotton with 90-TPI flannel performed well but 80-TPI cotton in 2 layers did not. We therefore recommend cotton or flannel at least 100 TPI, at least 2 layers. More layers, 3 or 4, will provide increased filtration but there is a trade-off in that more layers increases the resistance to breathing. Although this is not a systematic review, we included all the articles that we identified in an unbiased way. We did not include gray literature or preprints. A plain language summary of these data and recommendations, as well as information on making, wearing and cleaning cloth masks is available at www.clothmasks.ca.
CRIS-Team Scopus Importer:2020-10-16