0-BIOPSY & KIDNEY TRANSPLANT FUNCTION OF DONOR KIDNEYS FROM ACCELERATED ORGAN ALLOCATION PROCEDURE (AOAP): REAL, RESCUE, CENTRE OFFER, COMPARED TO STANDARD EUROTRANSPLANT KIDNEY ALLOCATION SYSTEM (ETKAS) - SINGLE CENTRE ANALYSIS - Heller, K. M.; Schiffer, Mario; Opgenoorth, M. (TRANSPLANT INTERNATIONAL, 2019)
CRIS-Team WoS Importer:2019-10-29

10-YEAR CLINICAL EVENTS AVOIDED IN DIABETIC AND CHRONIC KIDNEY DISEASE HYPERTENSION PATIENTS TREATED WITH RADIOFREQUENCY RENAL DENERVATION: PROJECTIONS BASED ON 3-YEAR DATA FROM THE GLOBAL SYMPLICITY REGISTRY - Schmieder, Roland; Cao, Khoa; Esler, Murray; Kandzari, David; Lobo, Melvin; Sharp, Andrew; Mancia, Giuseppe; Boehm, Michael; Pietzch, Jan (NEPHROLOGY DIALYSIS TRANSPLANTATION, 2022)
CRIS-Team WoS Importer:2022-07-22

12-Month Results From the Unblinded Phase of the RADIANCE-HTN SOLO Trial of Ultrasound Renal Denervation - Azizi, Michel; Daemen, Joost; Lobo, Melvin D.; Mahfoud, Felix; Sharp, Andrew S.P.; Schmieder, Roland; Wang, Yale; Saxena, Manish; Lurz, Philipp; Sayer, Jeremy; Bloch, Michael J.; Basile, Jan; et al. (Jacc-Cardiovascular Interventions, 2020)
Objectives: This study reports the 12-month results of the RADIANCE-HTN (A Study of the ReCor Medical Paradise System in Clinical Hypertension) SOLO trial following unblinding of patients at 6 months. Background: The blood pressure (BP)–lowering efficacy and safety of endovascular ultrasound renal denervation (RDN) in the absence (2 months) and presence (6 months) of antihypertensive medications were previously reported. Methods: Patients with daytime ambulatory BP ≥135/85 mm Hg after 4 weeks off medication were randomized to RDN (n = 74) or sham (n = 72) and maintained off medication for 2 months. A standardized medication escalation protocol was instituted between 2 and 5 months (blinded phase). Between 6 and 12 months (unblinded phase), patients received antihypertensive medications at physicians’ discretion. Outcomes at 12 months included medication burden, change in daytime ambulatory systolic BP (dASBP) and office or home systolic BP (SBP), visit-to-visit variability in SBP, and safety. Results: Sixty-five of 74 RDN patients and 67 of 72 sham patients had 12-month dASBP measurements. The proportion of patients on ≥2 medications (27.7% vs. 44.8%; p = 0.041), the number of medications (0 vs. 1.4; p = 0.015), and defined daily dose (1.4 vs. 2.2; p = 0.007) were less with RDN versus sham. The decrease in dASBP from baseline in the RDN group (−16.5 ± 12.9 mm Hg) remained stable at 12 months. The RDN versus sham adjusted difference at 12 months was −2.3 mm Hg (95% confidence interval [CI]: −5.9 to 1.3 mm Hg; p = 0.201) for dASBP, −6.3 mm Hg (95% CI: −11.1 to −1.5 mm Hg; p = 0.010) for office SBP, and −3.4 mm Hg (95% CI: −6.9 to 0.1 mm Hg; p = 0.062) for home SBP. Visit-to-visit variability in SBP was smaller in the RDN group. No renal artery injury was detected on computed tomographic or magnetic resonance angiography. Conclusions: Despite unblinding, the BP-lowering effect of RDN was maintained at 12 months with fewer prescribed medications compared with sham.
CRIS-Team Scopus Importer:2020-12-25
Keywords: blood pressure; hypertension; renal denervation; ultrasound; variability

(1 -> 3)-beta-D-glucan and mannan guided early termination of antifungal therapy in ICU patients: a prospective randomized intervention study (REDUCE-AM) - Erb, T.; Mihai, Sidonia; Cipa, Franziska; Herbst, Larissa; Strauss, Richard; Castellanos, Ixchel; Lang, K.; Ganslmayer, Marion; Willam, Carsten; Rath, Anca; Diesch, Katharina; Held, Jürgen (MYCOSES, 2020)
CRIS-Team WoS Importer:2020-10-02

1-Year outcomes of hypertension management in 13,000 outpatients under practice conditions: Prospective 3A registry - Zeymer, Uwe; Dechend, Ralf; Riemer, Thomas; Kaiser, Edelgard; Senges, Jochen; Pittrow, David; Schmieder, Roland (International Journal of Cardiology, 2014)
Current data on characteristics and outcomes of patients with high blood pressure (BP) managed under clinical practice conditions are limited.The 3A registry is an open, prospective observational cohort study in German primary care offices, with a 4:1:1 inclusion ratio to either aliskiren (ALIS), an ACE inhibitor/angiotensin receptor blocker (ACEI/ARB), or to an antihypertensive agent not affecting the renin angiotensin system (non-RAS). A nonlinear mixed regression model was used to assess BP changes during follow-up regarding different BP values at inclusion in the various groups. ClinicalTrial.gov identifier is NCT01454583. In the total cohort of 13,433 patients with 1-year follow-up results, the mean age of patients was 64.7years, 54% were men. Mean number of antihypertensive drugs was higher in the ALIS group compared to the other groups (3.0 drugs versus 2.5 in ACEI/ARB versus 1.6 in non-RAS; p<0.0001). Statistical regression analysis revealed baseline BP as the dominant covariate. After adjustment for baseline BP and 12 other confounders, no significant differences in BP reduction between the three groups were observed. The rate of major cardiac events (death, myocardial infarction, and stroke) was 1.3% in the total cohort, and did not differ across groups.ALIS at beginning of the observation was mostly used by the physicians in patients with higher BP at entry and in higher risk populations. By study end, in all groups, stringent BP lowering measures, usually with combination therapy, led to significant improvements; more than half of these at-risk patients reached the BP targets.
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2013 ESH/ESC Practice Guidelines for the Management of Arterial Hypertension - Mancia, Giuseppe; Fagard, Robert; Narkiewicz, Krzysztof; Redon, Josep; Zanchetti, Alberto; Boehm, Michael; Christiaens, Thierry; Cifkova, Renata; De Backer, Guy; Dominiczak, Anna; Galderisi, Maurizio; Grobbee, Diederick E.; et al. (Blood Pressure, 2014)
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2018 ESC/ESH Guidelines for the management of arterial hypertension - Williams, Bryan; Mancia, Giuseppe; Spiering, Wilko; Rosei, Enrico Agabiti; Azizi, Michel; Burnier, Michel; Clement, Denis L.; Coca, Antonio; De Simone, Giovanni; Dominiczak, Anna; Kahan, Thomas; Mahfoud, Felix; et al. (Kardiologia Polska, 2019)
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2018 ESC/ESH Guidelines for the management of arterial hypertension: The Task Force for the management of arterial hypertension of the European Society of Cardiology and the European Society of Hypertension: The Task Force for the management of arterial hypertension of the European Society of Cardiology and the European Society of Hypertension - Williams, Bryan; Mancia, Giuseppe; Spiering, Wilko; Rosei, Enrico Agabiti; Azizi, Michel; Burnier, Michel; Clement, Denis L.; Coca, Antonio; De Simone, Giovanni; Dominiczak, Anna; Kahan, Thomas; Mahfoud, Felix; et al. (Journal of Hypertension, 2018)
: Document reviewers: Guy De Backer (ESC Review Co-ordinator) (Belgium), Anthony M. Heagerty (ESH Review Co-ordinator) (UK), Stefan Agewall (Norway), Murielle Bochud (Switzerland), Claudio Borghi (Italy), Pierre Boutouyrie (France), Jana Brguljan (Slovenia), Héctor Bueno (Spain), Enrico G. Caiani (Italy), Bo Carlberg (Sweden), Neil Chapman (UK), Renata Cifkova (Czech Republic), John G. F. Cleland (UK), Jean-Philippe Collet (France), Ioan Mircea Coman (Romania), Peter W. de Leeuw (The Netherlands), Victoria Delgado (The Netherlands), Paul Dendale (Belgium), Hans-Christoph Diener (Germany), Maria Dorobantu (Romania), Robert Fagard (Belgium), Csaba Farsang (Hungary), Marc Ferrini (France), Ian M. Graham (Ireland), Guido Grassi (Italy), Hermann Haller (Germany), F. D. Richard Hobbs (UK), Bojan Jelakovic (Croatia), Catriona Jennings (UK), Hugo A. Katus (Germany), Abraham A. Kroon (The Netherlands), Christophe Leclercq (France), Dragan Lovic (Serbia), Empar Lurbe (Spain), Athanasios J. Manolis (Greece), Theresa A. McDonagh (UK), Franz Messerli (Switzerland), Maria Lorenza Muiesan (Italy), Uwe Nixdorff (Germany), Michael Hecht Olsen (Denmark), Gianfranco Parati (Italy), Joep Perk (Sweden), Massimo Francesco Piepoli (Italy), Jorge Polonia (Portugal), Piotr Ponikowski (Poland), Dimitrios J. Richter (Greece), Stefano F. Rimoldi (Switzerland), Marco Roffi (Switzerland), Naveed Sattar (UK), Petar M. Seferovic (Serbia), Iain A. Simpson (UK), Miguel Sousa-Uva (Portugal), Alice V. Stanton (Ireland), Philippe van de Borne (Belgium), Panos Vardas (Greece), Massimo Volpe (Italy), Sven Wassmann (Germany), Stephan Windecker (Switzerland), Jose Luis Zamorano (Spain).The disclosure forms of all experts involved in the development of these Guidelines are available on the ESC website www.escardio.org/guidelines.
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23Na magnetic resonance imaging-determined tissue sodium in healthy subjects and hypertensive patients - Kopp, Christoph; Linz, Peter; Dahlmann, Anke; Hammon, Matthias; Jantsch, Jonathan; Mueller, Dominik N.; Schmieder, Roland; Cavallaro, Alexander Josef; Eckardt, Kai-Uwe; Uder, Michael; Luft, Friedrich C.; Titze, Jens (Hypertension, 2013)
High dietary salt intake is associated with hypertension; the prevalence of salt-sensitive hypertension increases with age. We hypothesized that tissue Na might accumulate in hypertensive patients and that aging might be accompanied by Na deposition in tissue. We implemented Na magnetic resonance imaging to measure Na content of soft tissues in vivo earlier, but had not studied essential hypertension. We report on a cohort of 56 healthy control men and women, and 57 men and women with essential hypertension. The ages ranged from 22 to 90 years. Na magnetic resonance imaging measurements were made at the level of the calf. We observed age-dependent increases in Na content in muscle in men, whereas muscle Na content did not change with age in women. We estimated water content with conventional MRI and found no age-related increases in muscle water in men, despite remarkable Na accumulation, indicating water-free Na storage in muscle. With increasing age, there was Na deposition in the skin in both women and men; however, skin Na content remained lower in women. Similarly, this sex difference was found in skin water content, which was lower in women than in men. In contrast to muscle, increasing Na content was paralleled with increasing skin water content. When controlled for age, we found that patients with refractory hypertension had increased tissue Na content, compared with normotensive controls. These observations suggest that Na magnetic resonance imaging could have utility in assessing the role of tissue Na storage for cardiovascular morbidity and mortality in longitudinal studies. © 2013 American Heart Association, Inc.
CRIS-Team Scopus Importer:2023-03-08
Keywords: aging; gender difference; hypertension; salt; sodium MRI

23Na Magnetic Resonance Imaging of the Lower Leg of Acute Heart Failure Patients during Diuretic Treatment - Hammon, Matthias; Großmann, Susan; Linz, Peter; Kopp, Christoph; Dahlmann, Anke; Garlichs, Christoph; Janka, Rolf Matthias; Luft, Friedrich C.; Uder, Michael; Titze, Jens; Cavallaro, Alexander Josef (PLoS ONE, 2015)
Na+ can be stored in muscle and skin without commensurate water accumulation. The aim of this study was to assess Na+ and H2O in muscle and skin with MRI in acute heart failure patients before and after diuretic treatment and in a healthy cohort.Nine patients (mean age 78 years; range 58-87) and nine age and gender-matched controls were studied. They underwent 23Na/1H-MRI at the calf with a custom-made knee coil. Patients were studied before and after diuretic therapy. 23Na-MRI gray-scale measurements of Na+-phantoms served to quantify Na+-concentrations. A fat-suppressed inversion recovery sequence was used to quantify H2O content.Plasma Na+-levels did not change during therapy. Mean Na+-concentrations in muscle and skin decreased after furosemide therapy (before therapy: 30.7±6.4 and 43.5±14.5 mmol/L; after therapy: 24.2±6.1 and 32.2±12.0 mmol/L; p?0.05 and p?0.01). Water content measurements did not differ significantly before and after furosemide therapy in muscle (p = 0.17) and only tended to be reduced in skin (p = 0.06). Na+-concentrations in calf muscle and skin of patients before and after diuretic therapy were significantly higher than in healthy subjects (18.3±2.5 and 21.1±2.3 mmol/L).23Na-MRI shows accumulation of Na+ in muscle and skin in patients with acute heart failure. Diuretic treatment can mobilize this Na+-deposition; however, contrary to expectations, water and Na+-mobilization are poorly correlated.
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3D hydrogel-based microcapsules as an in vitro model to study tumorigenicity, cell migration and drug resistance. - Ertekin, Özlem; Monavari, Mahshid; Krüger, René; Fuentes Chandia, Miguel Angel; Parma, Beatrice; Letort, Gaelle; Tripal, Philipp; Boccaccini, Aldo R.; Boßerhoff, Anja Katrin; Ceppi, Paolo; Kappelmann-Fenzl, Melanie; Leal-Egaña, Aldo (Acta Biomaterialia, 2022)
In this work, we analyzed the reliability of alginate-gelatin microcapsules as artificial tumor model. These tumor-like scaffolds are characterized by their composition and stiffness (∼25 kPa), and their capability to restrict -but not hinder- cell migration, proliferation and release from confinement. Hydrogel-based microcapsules were initially utilized to detect differences in mechano-sensitivity between MCF7 and MDA-MB-231 breast cancer cells, and the endothelial cell line EA.hy926. Additionally, we used RNA-seq and transcriptomic methods to determine how the culture strategy (i.e. 2D v/s 3D) may pre-set the expression of genes involved in multidrug resistance, being then validated by performing cytotoxicological tests and assays of cell morphology. Our results show that both breast cancer cells can generate elongated multicellular spheroids inside the microcapsules, prior being released (mimicking intravasation stages), a behavior which was not observed in endothelial cells. Further, we demonstrate that cells isolated from 3D scaffolds show resistance to cisplatin, a process which seems to be strongly influenced by mechanical stress, instead of hypoxia. We finally discuss the role played by aneuploidy in malignancy and resistance to anticancer drugs, based on the increased number of polynucleated cells found within these microcapsules. Overall, our outcomes demonstrate that alginate-gelatin microcapsules represent a simple, yet very accurate tumor-like model, enabling us to mimic the most relevant malignant hints described in vivo, suggesting that confinement and mechanical stress need to be considered when studying pathogenicity and drug resistance of cancer cells in vitro. STATEMENT OF SIGNIFICANCE: In this work, we analyzed the reliability of alginate-gelatin microcapsules as an artificial tumor model. These scaffolds are characterized by their composition, elastic properties, and their ability to restrict cell migration, proliferation, and release from confinement. Our results demonstrate four novel outcomes: (i) studying cell migration and proliferation in 3D enabled discrimination between malignant and non-pathogenic cells, (ii) studying the cell morphology of cancer aggregates entrapped in alginate-gelatin microcapsules enabled determination of malignancy degree in vitro, (iii) determination that confinement and mechanical stress, instead of hypoxia, are required to generate clones resistant to anticancer drugs (i.e. cisplatin), and (iv) evidence that resistance to anticancer drugs could be due to the presence of polynucleated cells localized inside polymer-based artificial tumors.

3D-Visualization of Neurovascular Compression at the Ventrolateral Medulla in Patients with Arterial Hypertension - Manava, Panagiota; Naraghi, Ramin; Schmieder, Roland; Fahlbusch, Rudolf; Dörfler, Arnd; Lell, Michael M.; Buchfelder, Michael; Hastreiter, Peter (Clinical Neuroradiology, 2020)
Purpose: Controversy exists on the association of arterial hypertension (HTN) and neurovascular compression (NVC) at the ventrolateral medulla (VLM). No standardized and reproducible technique has been introduced yet for detection of NVC in HTN. This study aimed to generate, analyze and compare different results of exact reproducible anatomical 3D-representations of the VLM in patients with HTN, based on magnetic resonance imaging (MRI). Methods: A 3T scanner provided MRI (T2-constructive interference in steady state (CISS) high resolution imaging and three-dimensional Time-of-flight (3D-TOF) angiography) from the posterior fossa of 44 patients with clinical treatment-resistant HTN. Image processing consists of segmentation of the CISS data, registration and fusion of the CISS and TOF data and visualization. For each patient two 3D-visualizations (before and after fusion) were obtained. The reproduction quality of the vessels, flow-related signal variability and pulsation artifacts were analyzed and compared, using a ranking score. Results: Integrating vascular information from TOF into CISS data reduced artifacts in 3D-visualizations of exclusively processed CISS data. The quality of 3D-visualization of the vessels near the brain stem was significantly improved (p = 0.004). The results were reproducible and reliable. The quality of the 3D-presentations of neurovascular relationships at the VLM improved significantly (p < 0.001). Conclusion: The 3D-visualization of fused image data provides an excellent overview of the relationship between cranial nerves and vessels at the VLM and simplifies the detection of NVC in HTN. It provides a powerful tool for future clinical and scientific research. Although microvascular decompression (MVD) in treatment resistant HTN is not a standard procedure, it can be discussed in selected patients with intractable severe HTN.
CRIS-Team Scopus Importer:2020-06-05
Keywords: Cranial nerves; Image fusion; Image processing; MRI; Posterior fossa; Vascular compression disorders

3 Tesla (23)Na magnetic resonance imaging during aerobic and anaerobic exercise - Hammon, Matthias; Großmann, Susan; Linz, Peter; Kopp, Christoph; Dahlmann, Anke; Janka, Rolf Matthias; Uder, Michael; Titze, Jens; Cavallaro, Alexander Josef (Academic Radiology, 2015)
The aim of the work described here was to determine the feasibility of monitoring Na(+) concentration and distribution in muscle/skin during aerobic/anaerobic exercise with (23)Na magnetic resonance imaging (MRI).The Na(+) concentration and water content of muscle/skin of the left lower leg of six healthy subjects (mean age, 26 years; range, 22-30 years; three men and three women) were assessed before and after aerobic/anaerobic cycle ergometry and during recovery with 3-T (23)Na/(1)H MRI. (23)Na MRI was performed with a custom-made knee coil. A gradient echo sequence with an acquisition time of 3.25 minutes, echo time of 2.07 ms, repetition time of 100 ms, and spatial resolution of 3 × 3 × 30 mm(3) was applied. Phantoms with increasing sodium concentration served for quantification via linear extrapolation. Blood values were determined by blood gas analysis.The concentration of Na(+) significantly increased during anaerobic exercise in all muscle compartments except the medial gastrocnemius muscle, whereas no significant change was observed in most muscle compartments during aerobic exercise (only the soleus muscle exhibited a significant increase in Na(+) concentration during aerobic exercise: 1.6 ± 1.5 mmol/kg, 4.5%, P = .046). During anaerobic exercise, the mean Na(+) concentration of the triceps surae and the whole leg increased by 9.0% (3.1 ± 2.1 mmol/kg, P = .016) and 6.5% (2.2 ± 1.3 mmol/kg, P < .01). MRI revealed a water-independent increase in Na(+) concentration in most muscle compartments during anaerobic exercise. Na(+) concentration significantly decreased during recovery after anaerobic and aerobic exercise in all muscle compartments except the soleus. The Na(+) concentration of the skin did not significantly change during anaerobic/aerobic exercise.Sodium(23) MRI allows reliable and noninvasive visualization and quantification of Na(+) concentration and distribution in muscle and skin during exercise. (23)Na MRI can be used to gain new insights into Na(+) homeostasis, presumably leading to better comprehension of pathophysiology.
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4-Azidobenzyl ferrocenylcarbamate as an anticancer prodrug activated under reductive conditions - Kinski, Elisa; Marzenell, Paul; Hofer, Walter; Hagen, Helen; Raskatov, Jevgenij A.; Knaup, Karl; Zolnhofer, Eva; Meyer, Karsten; Mokhir, Andriy (Journal of Inorganic Biochemistry, 2016)
Aminoferrocene-based prodrugs are activated in the presence of cancer-specific amounts of reactive oxygen species, e.g. H2O2, with the formation of products of two types: Fe-containing complexes, which catalyze generation of HO and O2-, and quinone methides, which alkylate glutathione and inhibit the antioxidative system of the cell. Both processes act synergistically by increasing the oxidative stress in cancer cells thereby leading to their death. However, in the activation step including the cleavage of a B-C bond one molecule of H2O2 is consumed that counteracts the desired effect of the products released from aminoferrocenes. We replaced an H2O2-sensitive trigger in original prodrugs with an azide group. This trigger is slowly reduced in the presence of glutathione with the formation of an unstable arylamine intermediate, which decomposes with the release of iron ions and iminoquinone methides. These products induce strong oxidative stress in cells as we confirmed using 2′,7′-dichlorodihydrofluorescin diacetate reagent in combination with flow cytometry. In this case the activation process does not consume H2O2. Correspondingly, we observed that the azide-containing prodrug is substantially more toxic towards human promyelocytic leukemia cell line HL-60 (IC50 = 27 ± 4 μM) than its H2O2-responsive analogue (IC50 > 50 μM).
CRIS-Team Scopus Importer:2020-09-14
Keywords: Azide; Cancer; Ferrocene; Prodrug; Reduction

A 3D In Vivo Model for Studying Human Renal Cystic Tissue and Mouse Kidney Slices - Bichlmayer, Eva Marie; Mahl, Lina; Hesse, Leo; Pion, Eric; Haller, Victoria; Moehwald, Andreas; Hackl, Christina; Werner, Jens M.; Schlitt, Hans J.; Schwarz, Siegfried; Kainz, Philipp; Brochhausen, Christoph; et al. (Cells, 2022)
(1) Background: Autosomal dominant polycystic kidney disease (ADPKD) is a frequent monogenic disorder that leads to progressive renal cyst growth and renal failure. Strategies to inhibit cyst growth in non-human cyst models have often failed in clinical trials. There is a significant need for models that enable studies of human cyst growth and drug trials. (2) Methods: Renal tissue from ADPKD patients who received a nephrectomy as well as adult mouse kidney slices were cultured on a chorioallantoic membrane (CAM) for one week. The cyst volume was monitored by microscopic and CT-based applications. The weight and angiogenesis were quantified. Morphometric and histological analyses were performed after the removal of the tissues from the CAM. (3) Results: The mouse and human renal tissue mostly remained vital for about one week on the CAM. The growth of cystic tissue was evaluated using microscopic and CT-based volume measurements, which correlated with weight and an increase in angiogenesis, and was accompanied by cyst cell proliferation. (4) Conclusions: The CAM model might bridge the gap between animal studies and clinical trials of human cyst growth, and provide a drug-testing platform for the inhibition of cyst enlargement. Real-time analyses of mouse kidney tissue may provide insights into renal physiology and reduce the need for animal experiments.
CRIS-Team Scopus Importer:2022-08-12
Keywords: 3D in vivo model; ADPKD; chorioallantoic membrane (CAM) model; human renal cystic tissue; mouse kidney slices; polycystic kidney disease

Abdominal Panniculectomy Can Simplify Kidney Transplantation in Obese Patients - Promny, Dominik; Hauck, Theresa; Cai, Aijia; Arkudas, Andreas; Heller, Katharina M.; Wullich, Bernd; Apel, Hendrik; Horch, Raymund E.; Ludolph, Ingo (Urologia Internationalis, 2021)
Background: Obesity is frequently present in patients suffering from end-stage renal disease (ESRD). However, overweight kidney transplant candidates are a challenge for the transplant surgeon. Obese patients tend to develop a large abdominal panniculus after weight loss creating an area predisposed to wound-healing disorders. Due to concerns about graft survival and postoperative complications after kidney transplantation, obese patients are often refused in this selective patient cohort. The study aimed to analyze the effect of panniculectomies on postoperative complications and transplant candidacy in an interdisciplinary setting. Methods: A retrospective database review of 10 cases of abdominal panniculectomies performed in patients with ESRD prior to kidney transplantation was conducted. Results: The median body mass index was 35.2 kg/m(2) (range 28.5-53.0 kg/m(2)) at first transplant-assessment versus 31.0 kg/m(2) (range 28.0-34.4 kg/m(2)) at panniculectomy, and 31.6 kg/m(2) (range 30.3-32.4 kg/m(2)) at kidney transplantation. We observed no major postoperative complications following panniculectomy and minor wound-healing complications in 2 patients. All aside from 1 patient became active transplant candidates 6 weeks after panniculectomy. No posttransplant wound complications occurred in the transplanted patients. Conclusion: Abdominal panniculectomy is feasible in patients suffering ESRD with no major postoperative complications, thus converting previously ineligible patients into kidney transplant candidates. An interdisciplinary approach is advisable in this selective patient cohort.
CRIS-Team WoS Importer:2021-07-02

Aberrant Ca2+signals in ADPKD activate TMEM16A and Cyst Growth - Cabrita, I.; Buchholz, Björn; Schreiber, R.; Kunzelmann, K. (Acta Physiologica, 2019)

Aberrant Ca2+signals in ADPKD activate TMEM16A and Cyst Growth - Cabrita, I.; Buchholz, B.; Schreiber, R.; Kunzelmann, K. (ACTA PHYSIOLOGICA, 2019)
CRIS-Team WoS Importer:2019-11-12

A catalog of genetic loci associated with kidney function from analyses of a million individuals - Wuttke, Matthias; Li, Yong; Li, Man; Sieber, Karsten B.; Feitosa, Mary F.; Gorski, Mathias; Tin, Adrienne; Wang, Lihua; Chu, Audrey Y.; Hoppmann, Anselm; Kirsten, Holger; Giri, Ayush; et al. (Nature Genetics, 2019)
Chronic kidney disease (CKD) is responsible for a public health burden with multi-systemic complications. Through trans-ancestry meta-analysis of genome-wide association studies of estimated glomerular filtration rate (eGFR) and independent replication (n = 1,046,070), we identified 264 associated loci (166 new). Of these, 147 were likely to be relevant for kidney function on the basis of associations with the alternative kidney function marker blood urea nitrogen (n = 416,178). Pathway and enrichment analyses, including mouse models with renal phenotypes, support the kidney as the main target organ. A genetic risk score for lower eGFR was associated with clinically diagnosed CKD in 452,264 independent individuals. Colocalization analyses of associations with eGFR among 783,978 European-ancestry individuals and gene expression across 46 human tissues, including tubulo-interstitial and glomerular kidney compartments, identified 17 genes differentially expressed in kidney. Fine-mapping highlighted missense driver variants in 11 genes and kidney-specific regulatory variants. These results provide a comprehensive priority list of molecular targets for translational research.
CRIS-Team Scopus Importer:2019-06-18

ACCELERATED ORGAN ALLOCATION PROCEDURE (AOAP) FOR KIDNEY DONATION (REAL, RESCUE, CENTRE OFFER) IN THE EUROTRANSPLANT KIDNEY ALLOCATION SYSTEM (ETKAS), IS IT WORTH?-5 YEAR SINGLE CENTER EXPERIENCES - Heller, K. M.; Schiffer, Mario; Opgenoorth, M. (TRANSPLANT INTERNATIONAL, 2019)
CRIS-Team WoS Importer:2019-10-29

Accuracy and concordance of measurement methods to assess non-adherence after renal transplantation - A prospective study - Lieb, Marietta; Hepp, Tobias; Schiffer, Mario; Opgenoorth, Mirian; Erim, Yesim (BMC Nephrology, 2020)
Background: Non-adherence (NA) to immunosuppressants (IS) among renal transplant recipients (RTRs) is associated with higher risk of allograft rejection, graft loss, and mortality. A precise measurement of NA is indispensable, although its prevalence differs greatly depending on the respective measurement methods. The objective of this study was to assess the accuracy and concordance of different measurement methods of NA in patients after renal transplantation. Design and methods: This was a single-center prospective observational study. At baseline (T0), NA was measured via physicians' estimates (PE), self-reports (SR), and tacrolimus trough level variability (CV%) in 78 RTRs. A Visual Analogue Scale (VAS, 0-100%) was applied both for SR and PE. In addition, we used BAASIS© for SR and a 5-point Likert scale for PE. NA was measured prospectively via electronic monitoring (EM, VAICA©) during a three month period. Meanwhile, all participants received phone calls in a two week interval (T1-T6) during which SRs were given. Results: Seventy-eight RTRs participated in our study. At t0, NA rates of 6.4%, 28.6%, and 15.4% were found for PE, SR, and CV%, respectively. No correlation was found between these methods. During the study, the percentages of self-reported and electronically monitored adherence remained high, with a minimum mean of 91.2% for the strictest adherence measure (Timing Adherence ±30 min). Our results revealed a moderate to high association between SR and EM. In contrast to PE and CV%, SR significantly predicted electronically monitored adherence. Overall, a decreasing effect of electronically monitored adherence was found for both taking and timing adherence (±2 h, ±30 min) over the course of the study. Discussion: The moderate to high concordance of SR and EM suggests that both methods measure NA equally accurately. SR seems to be a method that can adequately depict electronically monitored NA and may represent a good and economical instrument to assess NA in clinical practice. The increased adherence at the beginning of the study and its subsequent decrease suggests an intervention effect. Surveillance of IS intake via EM with intermittent phone calls could improve adherence on a short-term basis. To establish long-term effects, further research is necessary.
CRIS-Team Scopus Importer:2020-04-14
Keywords: Accuracy; Adherence; Electronic monitoring; IS trough level variability; Measurement methods; Physicians' estimates; Prospective study; Renal transplant recipients; Self-report

Accuracy of Cuff-Measured Blood Pressure: Systematic Reviews and Meta-Analyses - Picone, Dean S.; Schultz, Martin G.; Otahal, Petr; Aakhus, Svend; Al-Jumaily, Ahmed M.; Black, J. Andrew; Bos, Willem J.; Chambers, John B.; Chen, Chen-Huan; Cheng, Hao-Min; Cremer, Antoine; Davies, Justin E.; et al. (Journal of the American College of Cardiology, 2017)
Hypertension (HTN) is the single greatest cardiovascular risk factor worldwide. HTN management is usually guided by brachial cuff blood pressure (BP), but questions have been raised regarding accuracy.This comprehensive analysis determined the accuracy of cuff BP and the consequent effect on BP classification compared with intra-arterial BP reference standards.Three individual participant data meta-analyses were conducted among studies (from the 1950s to 2016) that measured intra-arterial aortic BP, intra-arterial brachial BP, and cuff BP.A total of 74 studies with 3,073 participants were included. Intra-arterial brachial systolic blood pressure (SBP) was higher than aortic values (8.0 mm Hg; 95% confidence interval [CI]: 5.9 to 10.1 mm Hg; p < 0.0001) and intra-arterial brachial diastolic BP was lower than aortic values (-1.0 mm Hg; 95% CI: -2.0 to -0.1 mm Hg; p = 0.038). Cuff BP underestimated intra-arterial brachial SBP (-5.7 mm Hg; 95% CI: -8.0 to -3.5 mm Hg; p < 0.0001) but overestimated intra-arterial diastolic BP (5.5 mm Hg; 95% CI: 3.5 to 7.5 mm Hg; p < 0.0001). Cuff and intra-arterial aortic SBP showed a small mean difference (0.3 mm Hg; 95% CI: -1.5 to 2.1 mm Hg; p = 0.77) but poor agreement (mean absolute difference 8.0 mm Hg; 95% CI: 7.1 to 8.9 mm Hg). Concordance between BP classification using the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure cuff BP (normal, pre-HTN, and HTN stages 1 and 2) compared with intra-arterial brachial BP was 60%, 50%, 53%, and 80%, and using intra-arterial aortic BP was 79%, 57%, 52%, and 76%, respectively. Using revised intra-arterial thresholds based on cuff BP percentile rank, concordance between BP classification using cuff BP compared with intra-arterial brachial BP was 71%, 66%, 52%, and 76%, and using intra-arterial aortic BP was 74%, 61%, 56%, and 65%, respectively.Cuff BP has variable accuracy for measuring either brachial or aortic intra-arterial BP, and this adversely influences correct BP classification. These findings indicate that stronger accuracy standards for BP devices may improve cardiovascular risk management.
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Achieved blood pressure and cardiovascular outcomes in high-risk patients: results from ONTARGET and TRANSCEND trials - Boehm, Michael; Schumacher, Helmut; Teo, Koon K.; Lonn, Eva M.; Mahfoud, Felix; Mann, Johannes F. E.; Mancia, Giuseppe; Redon, Josep; Schmieder, Roland; Sliwa, Karen; Weber, Michael A.; Williams, Bryan; et al. (Lancet, 2017)
Studies have challenged the appropriateness of accepted blood pressure targets. We hypothesised that different levels of low blood pressure are associated with benefit for some, but harm for other outcomes.In this analysis, we assessed the previously reported outcome data from high-risk patients aged 55 years or older with a history of cardiovascular disease, 70% of whom had hypertension, from the ONTARGET and TRANSCEND trials investigating ramipril, telmisartan, and their combination, with a median follow-up of 56 months. Detailed descriptions of randomisation and intervention have already been reported. We analysed the associations between mean blood pressure achieved on treatment; prerandomisation baseline blood pressure; or time-updated blood pressure (last on treatment value before an event) on the composite outcome of cardiovascular death, myocardial infarction, stroke, and hospital admission for heart failure; the components of the composite outcome; and all-cause death. Analysis was done by Cox regression analysis, ANOVA, and ?(2). These trials were registered with ClinicalTrials.gov, number NCT00153101.Recruitment for ONTARGET took place between Dec 1, 2001, and July 31, 2008. TRANSCEND took place between Nov 1, 2001, and May 30, 2004. 30 937 patients were recruited from 733 centres in 40 countries and followed up for a median of 56 months. In ONTARGET, 25 127 patients known to be tolerant to angiotensin-converting-enzyme (ACE)-inhibitors were randomly assigned after a run-in period to oral ramipril 10 mg/day (n=8407), telmisartan 80 mg/day (n=8386), or the combination of both (n=8334). In TRANSCEND, 5810 patients who were intolerant to ACE-inhibitors were randomly assigned to oral telmisartan 80 mg/day (n=2903) or placebo (n=2907). Baseline systolic blood pressure (SBP) 140 mm Hg or higher was associated with greater incidence of all outcomes compared with 120 mm Hg to less than 140 mm Hg. By contrast, a baseline diastolic blood pressure (DBP) less than 70 mm Hg was associated with the highest risk for most outcomes compared with all DBP categories 70 mm Hg or more. In 4052 patients with SBP less than 120 mm Hg on treatment, the risk of the composite cardiovascular outcome (adjusted hazard ratio [HR] 1·14, 95% CI 1·03-1·26), cardiovascular death (1·29, 1·12-1·49), and all deaths (1·28, 1·15-1·42) were increased compared with those in whom SBP was 120-140 mm Hg during treatment (HR 1 for all outcomes, n=16099). No harm or benefit was observed for myocardial infarction, stroke, or hospital admission for heart failure. Mean achieved SBP more accurately predicted outcomes than baseline or time-updated SBP, and was associated with the lowest risk at approximately 130 mm Hg, and at 110-120 mm Hg risk increased for the combined outcome, cardiovascular death, and all-cause death except stroke. A mean DBP less than 70 mm Hg (n=5352) during treatment was associated with greater risk of the composite primary outcome (HR 1·31, 95% CI 1·20-1·42), myocardial infarction (1·55, 1·33-1·80), hospital admission for heart failure (1·59, 1·36-1·86) and all-cause death (1·16, 1·06-1·28) than a DBP 70-80 mm Hg (14 305). A pretreatment and mean on-treatment DBP of about 75 mm Hg was associated with the lowest risk.Mean achieved SBP less than 120 mm Hg during treatment was associated with increased risk of cardiovascular outcomes except for myocardial infarction and stroke. Similar patterns were observed for DBP less than 70 mm Hg, plus increased risk for myocardial infarction and hospital admission for heart failure. Very low blood pressure achieved on treatment was associated with increased risks of several cardiovascular disease events. These data suggest that the lowest blood pressure possible is not necessarily the optimal target for high-risk patients, although it is not possible to rule out some effect of reverse causality.Boehringer Ingelheim.
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Achieved diastolic blood pressure and pulse pressure at target systolic blood pressure (120-140 mmHg) and cardiovascular outcomes in high-risk patients: results from ONTARGET and TRANSCEND trials - Boehm, Michael; Schumacher, Helmut; Teo, Koon K.; Lonn, Eva; Mahfoud, Felix; Mann, Johannes F. E.; Mancia, Giuseppe; Redon, Josep; Schmieder, Roland; Weber, Michael; Sliwa, Karen; Williams, Bryan; et al. (European Heart Journal, 2018)
Aims: Current guidelines of hypertensive management recommend upper limits for systolic (SBP) and diastolic blood pressure (DBP). J-curve associations of BP with risk exist for some outcomes suggesting that lower limits of DBP goals may also apply. We examined the association between mean attained DBP and cardiovascular (CV) outcomes in patients who achieved an on-treatment SBP in the range of 120 to <140 mmHg in the Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial (ONTARGET) and Telmisartan Randomized AssessmeNt Study in ACE iNtolerant participants with cardiovascular Disease (TRANSCEND) trials on patients with high CV risk. This SBP range was associated with the lowest CV risk. Methods: We analysed the outcome data from patients age 55 years or older with CV disease from the ONTARGET and TRANSCEND trials that randomized high-risk patients to ramipril, telmisartan, and the combination. In patients with controlled SBP (on-treatment 120 to <140 mmHg), the composite outcome of CV death, myocardial infarction, stroke and hospital admission for heart failure, the components thereof, and all-cause mortality were analysed according to mean on-treatment DBP as categorical (<70, 70 to <80, 80 to <90, and ≥90 mmHg) and continuous variable as well as the change of DBP according to baseline DBP. Pulse pressure (PP) was related to outcomes as a continuous variable. Results: In 16 099 of 31 546 patients, mean achieved SBP was 120 to <140 mmHg. The nominally lowest risk for all outcomes was observed at an achieved DBP of 70 to <80 mmHg. A higher achieved DBP was associated with a higher risk for the outcomes of stroke and of hospitalization for heart failure (≥80 mmHg) and myocardial infarction (≥90 mmHg). A lower achieved DBP (<70 mmHg) was associated with a higher risk for the primary outcome [hazard ratio (HR) 1.29, 95% confidence interval (95% CI) 1.15-1.45; P < 0.0001], myocardial infarction HR 1.54 (95% CI 1.26-1.88, P < 0.0001) and hospitalization for heart failure HR 1.81 (95% CI 1.47-2.24, P < 0.0001) and all-cause death (HR 1.19, 95% CI 1.04-1.35; P < 0.0001) while there was no signal for stroke and CV death compared to DBP 70 to <80 mmHg. A decrease of DBP was associated with lower risk when baseline DBP was >80 mmHg. The associations to outcomes were similar when patients were divided to SBP 120 to <130 mmHg or 130 to <140 mmHg for DBP or PP. Conclusion: Compared to a DBP of 70 to <80 mmHg, lower and higher DBP was associated with a higher risk in patients achieving a SBP of 120 to <140 mmHg. Associations of DBP and PP to risk were similar notably at controlled SBP. These data suggest at optimal achieved SBP, risk is still defined by low or high DBP. These findings support guidelines which take DBP at optimal SBP control into consideration.
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Achievement of individualized treatment targets in patients with comorbid type-2 diabetes and hypertension: 6 months results of the DIALOGUE registry - Schmieder, Roland; Gitt, Anselm K.; Koch, Cornelia; Bramlage, Peter; Ouarrak, Taoufik; Tschoepe, Diethelm (BMC Endocrine Disorders, 2015)
Patients with type-2 diabetes mellitus (T2DM) and hypertension have increased risk of cardiovascular disease (CVD). We studied individualized treatment targets and their achievement in clinical practice.DIALOGUE is a prospective, multi-center registry in patients with both T2DM and hypertension.Patients (n = 6,586) had a baseline fasting glucose (8.5 ± 2.8 mmol/l), postprandial glucose (10.9 ± 3.4 mmol/l), and HbA1c (7.8 ± 2.1%) levels indicated poor glycemic control. Baseline systolic and diastolic BP were 140.3 ± 15.7 and 82.6 ± 9.5, respectively. Patients were categorized by HbA1c treatment goals: <=6.5% (strict), >6.5 to <=7.0% (medium), and >7.0 to <=7.5% (loose). When considering systolic BP (SBP) targets (<=130 mmHg [strict], >130 to <=135 mmHg [medium], and >135 to <=140 mmHg [loose]), patients with strict SBP treatment goals displayed similar characteristics to those with strict HbA1c targets. Although approximately 70% of patients received both strict HbA1c and SBP targeting, overall treatment goals remained unmet in all HbA1c target groups at the 6-month follow-up. SBP targets were not reached in the strict and medium groups, but were achieved in the loose treatment group. Specific predictors for choosing loose SBP or HbA1c treatment goals were identified, including SBP/HbA1c levels and various comorbidities.Individualized glucose and BP targets were selected by treating physicians based on patient characteristics and overall comorbidity. While treatment goals were not consistently met using various antidiabetic and antihypertensive therapies, our analyses indicated that the strictly targeted patient populations maintained lower overall HbA1c and SBP levels at 6 months.
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Acid sphingomyelinase-ceramide system mediates effects of antidepressant drugs - Gulbins, Erich; Palmada, Monica; Reichel, Martin; Lueth, Anja; Boehmer, Christoph; Amato, Davide; Müller, Christian P.; Tischbirek, Carsten H.; Groemer, Teja W.; Tabatabai, Ghazaleh; Becker, Katrin A.; Tripal, Philipp; et al. (Nature Medicine, 2013)
Major depression is a highly prevalent severe mood disorder that is treated with antidepressants. The molecular targets of antidepressants require definition. We investigated the role of the acid sphingomyelinase (Asm)-ceramide system as a target for antidepressants. Therapeutic concentrations of the antidepressants amitriptyline and fluoxetine reduced Asm activity and ceramide concentrations in the hippocampus, increased neuronal proliferation, maturation and survival and improved behavior in mouse models of stress-induced depression. Genetic Asm deficiency abrogated these effects. Mice overexpressing Asm, heterozygous for acid ceramidase, treated with blockers of ceramide metabolism or directly injected with C16 ceramide in the hippocampus had higher ceramide concentrations and lower rates of neuronal proliferation, maturation and survival compared with controls and showed depression-like behavior even in the absence of stress. The decrease of ceramide abundance achieved by antidepressant-mediated inhibition of Asm normalized these effects. Lowering ceramide abundance may thus be a central goal for the future development of antidepressants.
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Acoustic radiation force impulse tissue characterization of the anterior talofibular ligament: a promising noninvasive approach in ankle imaging - Hotfiel, Thilo; Heiß, Rafael; Janka, Rolf Matthias; Forst, Raimund; Raithel, Martin; Lutter, Christoph; Gelse, Kolja; Pachowsky, Milena; Golditz, Tobias (The physician and sportsmedicine, 2018)
OBJECTIVES: The anterior talofibular ligament (ATFL) is the most frequently injured ligament during inversion strains of the ankle. The purpose of this study was to evaluate the feasibility of acoustic radiation force impulse (ARFI) elastography and to determine the in vivo mechanical properties of the ATFL in healthy athletes. METHODS: Sixty healthy athletes (32 female, 28 male; 28.9 ± 2.1 years) were recruited from the medical and sports faculty. ARFI values, represented as shear wave velocities (SWVs) as well as conventional ultrasound were obtained for the ATFL in neutral ankle position. A clinical assessment was performed in which the American Orthopaedic Foot & Ankle Society (AOFAS) Ankle-Hindfoot Score and the functional ankle ability measure (FAAM) were collected. Interobserver and intraobserver reliability (repeated sessions and repeated days) were assessed using an intra class correlation coefficient (ICC) and typical error (TE) calculation in absolute (TE) and relative units as coefficient of the variation (CV). RESULTS: SWV values of the ATFL had an average velocity of 1.79 ± 0.20 m/s for all participants, with an average of 1.72 ± 0.36 m/s for females and 1.85 ± 0.31 m/s for males. The interobserver and intraobserver reliability revealed an ICC of 0.902 and 0.933 (TE of 0.67 (CV: 5.2%) and 0.52 (CV: 3.84%)), respectively. FAAM and AOFAS revealed the best possible scores. CONCLUSION: ARFI seems to be a valuable diagnostic modality and represents a promising imaging marker for the assessment and monitoring of ankle ligaments in the context of acute and chronic ankle instabilities; ARFI could also be used to investigate loading or sport dependent adaptions.
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Actin-mediated gene expression depends on RhoA and Rac1 signaling in proximal tubular epithelial cells - Giehl, Klaudia; Keller, Christof; Muehlich, Susanne; Goppelt-Strübe, Margarete (PLoS ONE, 2015)
Morphological alterations of cells can lead to modulation of gene expression. An essential link is the MKL1-dependent activation of serum response factor (SRF), which translates changes in the ratio of G- and F-actin into mRNA transcription. SRF activation is only partially characterized in non-transformed epithelial cells. Therefore, the impact of GTPases of the Rho family and changes in F-actin structures were analyzed in renal proximal tubular epithelial cells. Activation of SRF signaling was compared to the regulation of a known MKL1/SRF target gene, connective tissue growth factor (CTGF). In the human proximal tubular cell line HKC-8 overexpression of two actin mutants either favoring or preventing the formation of F-actin fibers regulated SRF-mediated transcription as well as CTGF expression. Only overexpression of constitutively active RhoA activated SRF-dependent gene expression whereas no effect was detected upon overexpression of Rac1 mutants. To elucidate the functional role of Rho kinases as downstream mediators of RhoA, pharmacological inhibition and genetic inhibition by transient siRNA knock down were compared. Upon stimulation with lysophosphatidic acid (LPA) Rho kinase inhibitors partially suppressed SRF-mediated transcription, whereas interference with Rho kinase expression by siRNA reduced activation of SRF, but barely affected CTGF expression. Together with the partial inhibition of CTGF expression by the pharmacological inhibitors Y27432 and H1154, Rho kinases seem to be less important in mediating RhoA signaling related to CTGF expression in HKC-8 epithelial cells. Short term pharmacological inhibition of Rac1 activity by EHT1864 reduced SRF-dependent CTGF expression in HKC-8 cells, but was overcome by a stimulatory effect after prolonged incubation after 4-6 h. Similarly, human primary cells of proximal but not of distal tubular origin showed inhibitory as well as stimulatory effects of Rac1 inhibition. Thus, RhoA signaling activates MKL1-SRF-mediated CTGF expression in proximal tubular cells, whereas Rac1 signaling is more complex with adaptive cellular responses.
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Activation of Hypoxia Signaling in Stromal Progenitors Impairs Kidney Development - Gerl, Katharina; Steppan, Dominik; Fuchs, Michaela; Wagner, Charlotte; Willam, Carsten; Kurtz, Armin; Kurt, Birguel (American Journal of Pathology, 2017)
Intrauterine hypoxia is a reason for impaired kidney development. The cellular and molecular pathways along which hypoxia exerts effects on nephrogenesis are not well understood. They are likely triggered by hypoxia-inducible transcription factors (HIFs), and their effects appear to be dependent on the cell compartment contributing to kidney formation. In this study, we investigated the effects of HIF activation in the developing renal stroma, which also essentially modulates nephron development from the metanephric mesenchyme. HIF activation was achieved by conditional deletion of the von Hippel-Lindau tumor suppressor (VHL) protein in the forkhead box FOXD1 cell lineage, from which stromal progenitors arise. The resulting kidneys showed maturation defects associated with early postnatal death. In particular, nephron formation, tubular maturation, and the differentiation of smooth muscle, renin, and mesangial cells were impaired. Erythropoietin expression was strongly enhanced. Codeletion of VHL together with HIF2A but not with HIF1A led to apparently normal kidneys, and the animals reached normal age but were anemic because of low erythropoietin levels. Stromal deletion of HIF2A or HIF1A alone did not affect kidney development. These findings emphasize the relevance of sufficient intrauterine oxygenation for normal renal stroma differentiation, suggesting that chronic activity of HIF2 in stromal progenitors impairs kidney development. Finally, these data confirm the concept that normal stroma function is essential for normal tubular differentiation.
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Acute change in glomerular filtration rate with inhibition of the renin-angiotensin system does not predict subsequent renal and cardiovascular outcomes - Clase, Catherine M.; Barzilay, Joshua; Gao, Peggy; Smyth, Andrew; Schmieder, Roland; Tobe, Sheldon; Teo, Koon K.; Yusuf, Salim; Mann, Johannes (Kidney International, 2017)
Initiation of blockade of the renin-angiotensin system may cause an acute decrease in glomerular filtration rate (GFR): the prognostic significance of this is unknown. We did a post hoc analysis of patients with, or at risk for, vascular disease, in two randomized controlled trials: Ongoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial (ONTARGET) and the Telmisartan Randomized AssessmeNt Study in ACE iNtolerant participants with cardiovascular Disease (TRANSCEND), whose median follow-up was 56 months. In 9340 patients new to renin-angiotensin system blockade, who were then randomized to renin-angiotensin system blockade, a fall in GFR of 15% or more at 2 weeks after starting renin-angiotensin system blockade was seen in 1480 participants (16%), with persistence at 8 weeks in 700 (7%). Both acute increases and decreases in GFR after initiation of renin-angiotensin system blockade were associated with tendencies, mostly not statistically significant, to increased risk of cardiovascular outcomes, which occurred in 1280 participants, and of microalbuminuria, which occurred in 864. Analyses of creatinine-based outcomes were suggestive of regression to the mean. In more than 3000 patients randomized in TRANSCEND to telmisartan or placebo, there was no interaction between acute change in GFR and renal or cardiovascular benefit from telmisartan. Thus, both increases and decreases in GFR on initiation of renin-angiotensin system blockade are common, and may be weakly associated with increased risk of cardiovascular and renal outcomes. Changes do not predict increased benefit from therapy.
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Acute Effects of Lateral Thigh Foam Rolling on Arterial Tissue Perfusion Determined by Spectral Doppler and Power Doppler Ultrasound - Hotfiel, Thilo; Swoboda, Bernd; Krinner, Sebastian; Grim, Casper; Engelhardt, Martin; Uder, Michael; Heiß, Rafael (Journal of strength and conditioning research, 2017)
Hotfiel, T, Swoboda, B, Krinner, S, Grim, C, Engelhardt, M, Uder, M, and Heiss, R. Acute effects of lateral thigh foam rolling on arterial tissue perfusion determined by spectral Doppler and power Doppler ultrasound. J Strength Cond Res 31(4): 893-900, 2017-Foam rolling has been developed as a popular intervention in training and rehabilitation. However, evidence on its effects on the cellular and physiological level is lacking. The aim of this study was to assess the effect of foam rolling on arterial blood flow of the lateral thigh. Twenty-one healthy participants (age, 25 ± 2 years; height, 177 ± 9 cm; body weight, 74 ± 9 kg) were recruited from the medical and sports faculty. Arterial tissue perfusion was determined by spectral Doppler and power Doppler ultrasound, represented as peak flow (Vmax), time average velocity maximum (TAMx), time average velocity mean (TAMn), and resistive index (RI), and with semiquantitative grading that was assessed by 4 blindfolded investigators. Measurement values were assessed under resting conditions and twice after foam rolling exercises of the lateral thigh (0 and 30 minutes after intervention). The trochanteric region, mid portion, and distal tibial insertion of the lateral thigh were representative for data analysis. Arterial blood flow of the lateral thigh increased significantly after foam rolling exercises compared with baseline (p <= 0.05). We detected a relative increase in Vmax of 73.6% (0 minutes) and 52.7% (30 minutes) (p < 0.001), in TAMx of 53.2% (p < 0.001) and 38.3% (p = 0.002), and in TAMn of 84.4% (p < 0.001) and 68.2% (p < 0.001). Semiquantitative power Doppler scores at all portions revealed increased average grading of 1.96 after intervention and 2.04 after 30 minutes compared with 0.75 at baseline. Our results may contribute to the understanding of local physiological reactions to self-myofascial release.
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Adaptive physiological water conservation explains hypertension and muscle catabolism in experimental chronic renal failure - Kovarik, Johannes; Morisawa, Norihiko; Wild, Johannes; Marton, Adriana; Takase-Minegishi, Kaoru; Minegishi, Shintaro; Daub, Steffen; Sands, Jeff M.; Klein, Janet D.; Bailey, James L.; Kovalik, Jean Paul; Rauh, Manfred; et al. (Acta Physiologica, 2021)
Aim: We have reported earlier that a high salt intake triggered an aestivation-like natriuretic-ureotelic body water conservation response that lowered muscle mass and increased blood pressure. Here, we tested the hypothesis that a similar adaptive water conservation response occurs in experimental chronic renal failure. Methods: In four subsequent experiments in Sprague Dawley rats, we used surgical 5/6 renal mass reduction (5/6 Nx) to induce chronic renal failure. We studied solute and water excretion in 24-hour metabolic cage experiments, chronic blood pressure by radiotelemetry, chronic metabolic adjustment in liver and skeletal muscle by metabolomics and selected enzyme activity measurements, body Na+, K+ and water by dry ashing, and acute transepidermal water loss in conjunction with skin blood flow and intra-arterial blood pressure. Results: 5/6 Nx rats were polyuric, because their kidneys could not sufficiently concentrate the urine. Physiological adaptation to this renal water loss included mobilization of nitrogen and energy from muscle for organic osmolyte production, elevated norepinephrine and copeptin levels with reduced skin blood flow, which by means of compensation reduced their transepidermal water loss. This complex physiologic-metabolic adjustment across multiple organs allowed the rats to stabilize their body water content despite persisting renal water loss, albeit at the expense of hypertension and catabolic mobilization of muscle protein. Conclusion: Physiological adaptation to body water loss, termed aestivation, is an evolutionary conserved survival strategy and an under-studied research area in medical physiology, which besides hypertension and muscle mass loss in chronic renal failure may explain many otherwise unexplainable phenomena in medicine.
CRIS-Team Scopus Importer:2021-03-19
Keywords: aestivation; body sodium; body water; dehydration; double-barrier concept; glucose-alanine-shuttle; glycine methylation; hepato-renal; hypertension; kidney; liver; muscle mass loss; organic osmolytes; purine metabolism; skin; transamination; transepidermal water loss; urea cycle; urine concentration

Adherence to Antihypertensive Medication in Treatment-Resistant Hypertension Undergoing Renal Denervation - Schmieder, Roland; Ott, Christian; Schmid, Andrea; Friedrich, Stefanie; Kistner, Iris; Ditting, Tilmann; Veelken, Roland; Uder, Michael; Toennes, Stefan W. (Journal of the American Heart Association, 2016)
Adherence to medication has been repeatedly proposed to represent a major cause of treatment-resistant hypertension (TRH); however, treatment decisions such as treating TRH with renal denervation depend on accurate judgment of adherence. We carefully analyzed adherence rates to medication before and after renal denervation and its effect on blood pressure (BP) control.Eighty patients with TRH were included in 2 prospective observational studies that assessed the difference of potential antihypertensive and nephroprotective effects of renal denervation. To compare prescribed with actual medication intake (representing a measure of adherence), we analyzed urine samples collected at baseline and at 6 months after renal denervation for antihypertensive compounds or metabolites (by liquid chromatography-mass spectrometry). In addition to office BP, 24-hour ambulatory BP and central hemodynamics (central systolic pressure, central pulse pressure) were assessed. Informed consent for analyses of urine metabolites was obtained from 79 of 80 patients. Actual intake of all antihypertensive drugs was detected at baseline and at 6 months after renal denervation in 44 (56%) and 52 (66%) patients, respectively; 1 drug was missing in 22 (28%) and 17 (22%) patients, respectively, and >=2 drugs were missing in 13 (16%) and 10 (13%) patients, respectively. At baseline, 24-hour ambulatory BP (P=0.049) and central systolic BP (P=0.012) were higher in nonadherent patients. Adherence did not significantly change overall (McNemar-Bowker test, P=0.362). An increase in adherence was observed in 21 patients, and a decrease was observed in 11 patients. The decrease in 24-hour ambulatory BP was not different in those with stable adherence 6 months after renal denervation (n=41, -7±13 mm Hg) compared with those with increased adherence (n=21, -10±13 mm Hg) and decreased adherence (n=11, -7±14 mm Hg) (P>0.20). Our study is limited by the relatively small sample size and potentially by the specific health environment of our university center (Northern Bavaria, Germany).Nonadherence to medication among patients with TRH was relatively low: ?1 of 6 patients with TRH did not take >=2 of the prescribed drugs. Adherence pattern did not change significantly after renal denervation and had no impact on the overall observed BP changes, supporting the concept that renal denervation is an effective treatment in patients with TRH.URL: https://www.clinicaltrials.gov. Unique identifiers: NCT00888433, NCT01442883 and NCT01687725.
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Adhesion GPCR Gpr126 (Adgrg6) Expression Profiling in Zebrafish, Mouse, and Human Kidney. - Cazorla-Vázquez, Salvador; Kösters, Peter; Bertz, Simone; Pfister, Frederick; Daniel, Christoph; Dedden, Mark; Zundler, Sebastian; Jobst-Schwan, Tilman; Amann, Kerstin Ute; Engel, Felix (Cells, 2023)
Adhesion G protein-coupled receptors (aGPCRs) comprise the second-largest class of GPCRs, the most common target for approved pharmacological therapies. aGPCRs play an important role in development and disease and have recently been associated with the kidney. Several aGPCRs are expressed in the kidney and some aGPCRs are either required for kidney development or their expression level is altered in diseased kidneys. Yet, general aGPCR function and their physiological role in the kidney are poorly understood. Here, we characterize in detail Gpr126 (Adgrg6) expression based on RNAscope® technology in zebrafish, mice, and humans during kidney development in adults. Gpr126 expression is enriched in the epithelial linage during nephrogenesis and persists in the adult kidney in parietal epithelial cells, collecting ducts, and urothelium. Single-cell RNAseq analysis shows that gpr126 expression is detected in zebrafish in a distinct ionocyte sub-population. It is co-detected selectively with slc9a3.2, slc4a4a, and trpv6, known to be involved in apical acid secretion, buffering blood or intracellular pH, and to maintain high cytoplasmic Ca2+ concentration, respectively. Furthermore, gpr126-expressing cells were enriched in the expression of potassium transporter kcnj1a.1 and gcm2, which regulate the expression of a calcium sensor receptor. Notably, the expression patterns of Trpv6, Kcnj1a.1, and Gpr126 in mouse kidneys are highly similar. Collectively, our approach permits a detailed insight into the spatio-temporal expression of Gpr126 and provides a basis to elucidate a possible role of Gpr126 in kidney physiology.
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Keywords: adhesion GPCR; kidney development; Gpr126; parietal epithelial cell; collecting duct; urothelium; ionocytes; zebrafish; RNAscope

Adhesive blood microsampling systems for steroid measurement via LC-MS/MS in the rat - Heussner, Kirsten; Rauh, Manfred; Cordasic, Nada; Menendez-Castro, Carlos; Hübner, Hanna; Rübner, Matthias; Schmidt, Marius; Hartner, Andrea; Rascher, Wolfgang; Fahlbusch, Fabian B. (Steroids, 2017)
INTRODUCTION: Liquid Chromatography Tandem Mass Spectrometry (LC-MS/MS) allows for the direct analysis of multiple hormones in a single probe with minimal sample volume. Rodent-based animal studies strongly rely on microsampling, such as the dry blood spot (DBS) method. However, DBS suffers the drawback of hematocrit-dependence (non-volumetric). Hence, novel volumetric microsampling techniques were introduced recently, allowing sampling of fixed accurate volumes. We compared these methods for steroid analysis in the rat to improve inter-system comparability. EXPERIMENTAL: We analyzed steroid levels in blood using the absorptive microsampling devices Whatman® 903 Protein Saver Cards, Noviplex™ Plasma Prep Cards and the Mitra™ Microsampling device and compared the obtained results to the respective EDTA plasma levels. Quantitative steroid analysis was performed via LC-MS/MS. For the determination of the plasma volume factor for each steroid, their levels in pooled blood samples from each human adults and rats (18weeks) were compared and the transferability of these factors was evaluated in a new set of juvenile (21days) and adult (18weeks) rats. Hematocrit was determined concomitantly. RESULTS: Using these approaches, we were unable to apply one single volume factor for each steroid. Instead, plasma volume factors had to be adjusted for the recovery rate of each steroid and device individually. The tested microsampling systems did not allow the use of one single volume factor for adult and juvenile rats based on an unexpectedly strong hematocrit-dependency and other steroid specific (pre-analytic) factors. DISCUSSION: Our study provides correction factors for LC-MS/MS steroid analysis of volumetric and non-volumetric microsampling systems in comparison to plasma. It argues for thorough analysis of chromatographic effects before the use of novel volumetric systems for steroid analysis.
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A different view on sodium balance - Titze, Jens (Current Opinion in Nephrology and Hypertension, 2015)
Textbook theory holds that extracellular fluids readily equilibrate, electrolyte concentrations in the extracellular fluid compartments are constant, and the kidney is solely responsible for controlling the body sodium content.Investigation of salt and water balance traditionally relies on short-term studies of bodily responses to extremes in salt intake. Ultra-long-term sodium balance studies instead studied the kidney's response to constant salt intake. The studies suggest that steady-state sodium balance in humans is characterized by storage and release of sodium from the body. The absence of accompanying changes in the body fluid matrix indicates the presence of metabolically relevant sodium reservoir sites in the body. In rats and mice, sodium is stored in skeletal muscle and skin. Homeostatic immune cells control reservoir electrolyte metabolism via the lymphatics. Failure of this extrarenal clearance process results in skin electrolyte accumulation and arterial hypertension. Noninvasive detection of sodium reservoir metabolism in patients by NaMRi methodology allows rapid transfer into the clinical arena.Body sodium content in humans and animals is not constant, does not always readily equilibrate with water, and is not exclusively controlled by the kidneys. This different view provides with new research avenues for basic and clinical investigators.
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Adsorber und ihre Evidenzen - Willam, Carsten (Die Anaesthesiologie, 2023)
CRIS-Team Scopus Importer:2023-10-13

Advances in Delayed-Onset Muscle Soreness (DOMS) Part II: Treatment and Prevention - Heiß, Rafael; Lutter, Christoph; Freiwald, Juergen; Hoppe, Matthiasw.; Grim, Casper; Poettgen, Klaus; Forst, Raimund; Bloch, Wilhelm; Huettel, Moritz; Hotfiel, Thilo (Sportverletzung-Sportschaden, 2019)
Delayed-onset muscle soreness (DOMS) describes an entity of ultrastructural muscle damage. The manifestation of DOMS is caused by eccentric muscle contractions or unaccustomed forms of exercise. Clinical signs include impaired muscular force capacities, painful restriction of movement, stiffness, swelling, and altered biomechanics in adjacent joints. Although DOMS is categorised as a mild type of muscle damage, it is one of the most common reasons for compromised sportive performance. In the last decade, many hypotheses have been developed to explain the aetiology of DOMS, and there are a wide range of different interventions aiming to prevent or alleviate the symptoms. Many studies have evaluated various types of cold or heat therapy, compression, massage, physical therapy or nutritional interventions. Treatment considerations focus on the primary prevention of ultrastructural lesions during exercise, the treatment of the inflammatory response that leads to DOMS, and recovery strategies for manifest DOMS. This narrative review aims to present an overview of the current treatment and preventive strategies in the field of DOMS.
CRIS-Team WoS Importer:2019-03-29

Aestivation motifs explain hypertension and muscle mass loss in mice with psoriatic skin barrier defect - Wild, Johannes; Jung, Rebecca; Knopp, Tanja; Efentakis, Panagiotis; Benaki, Dimitra; Grill, Alexandra; Wegner, Joanna; Molitor, Michael; Garlapati, Venkata; Rakova, Natalia; Markó, Lajos; Marton, Adriana; et al. (Acta Physiologica, 2021)
Aim: Recent evidence suggests that arterial hypertension could be alternatively explained as a physiological adaptation response to water shortage, termed aestivation, which relies on complex multi-organ metabolic adjustments to prevent dehydration. Here, we tested the hypothesis that chronic water loss across diseased skin leads to similar adaptive water conservation responses as observed in experimental renal failure or high salt diet. Methods: We studied mice with keratinocyte-specific overexpression of IL-17A which develop severe psoriasis-like skin disease. We measured transepidermal water loss and solute and water excretion in the urine. We quantified glomerular filtration rate (GFR) by intravital microscopy, and energy and nitrogen pathways by metabolomics. We measured skin blood flow and transepidermal water loss (TEWL) in conjunction with renal resistive indices and arterial blood pressure. Results: Psoriatic animals lost large amounts of water across their defective cutaneous epithelial barrier. Metabolic adaptive water conservation included mobilization of nitrogen and energy from muscle to increase organic osmolyte production, solute-driven maximal anti-diuresis at normal GFR, increased metanephrine and angiotensin 2 levels, and cutaneous vasoconstriction to limit TEWL. Heat exposure led to cutaneous vasodilation and blood pressure normalization without parallel changes in renal resistive index, albeit at the expense of further increased TEWL. Conclusion: Severe cutaneous water loss predisposes psoriatic mice to lethal dehydration. In response to this dehydration stress, the mice activate aestivation-like water conservation motifs to maintain their body hydration status. The circulatory water conservation response explains their arterial hypertension. The nitrogen-dependency of the metabolic water conservation response explains their catabolic muscle wasting.
CRIS-Team Scopus Importer:2021-03-05
Keywords: aestivation; catabolism; dehydration; double barrier concept; hypertension; transepidermal water loss

Afferent Nerve Fibers of the Skin - Influence of salt intake - Ditting, Tilmann; Rodionova, Kristina; Reeh, Peter; Eberhardt, Miriam; Veelken, Roland (FASEB JOURNAL, 2020)
CRIS-Team WoS Importer:2020-10-16

Afferent neurons of the kidney with impaired firing pattern in inflammation – role of sodium currents? - Lale, Nena; Ditting, Tilmann; Hilgers, Karl Friedrich; Linz, Peter; Ott, Christian; Schmieder, Roland; Schiffer, Mario; Amann, Kerstin Ute; Veelken, Roland; Rodionova, Kristina (Pflügers Archiv: European Journal of Physiology, 2023)
Peripheral neurons with renal afferents exhibit a predominantly tonic firing pattern of higher frequency that is reduced to low frequencies (phasic firing pattern) in renal inflammation. We wanted to test the hypothesis that the reduction in firing activity during inflammation is due to high-activity tonic neurons switching from higher to low frequencies depending on altered sodium currents. We identified and cultivated afferent sensory neurons with renal projections from the dorsal root ganglia (Th11-L2). Cultivated neurons were incubated with the chemokine CXCL1 (1,5 nmol/ml) for 12 h. We characterized neurons as “tonic,” i.e., sustained action potential (AP) firing, or “phasic,” i.e., < 5 APs upon stimulation in the current clamp. Their membrane currents were investigated in a voltage clamp. Data analyzed: renal vs. non-renal and tonic vs. phasic neurons. Renal afferent neurons exposed to CXCL1 showed a decrease in tonic firing pattern (CXCL1: 35,6% vs. control: 57%, P < 0.05). Na+ and K+ currents were not different between control renal and non-renal DRG neurons. Phasic neurons exhibited higher Na+ and K+ currents than tonic resulting in shorter APs (3.7 ± 0.3 vs. 6.1 ± 0.6 ms, P < 0.01). In neurons incubated with CXCL1, Na+ and K+ peak current density increased in phasic (Na+: − 969 ± 47 vs. − 758 ± 47 nA/pF, P < 0.01; K+: 707 ± 22 vs. 558 ± 31 nA/pF, P < 0.01), but were unchanged in tonic neurons. Phasic neurons exposed to CXCL1 showed a broader range of Na+ currents ([− 365– − 1429 nA] vs. [− 412– − 4273 nA]; P < 0.05) similar to tonic neurons. After CXCL1 exposure, significant changes in phasic neurons were observed in sodium activation/inactivation as well as a wider distribution of Na+ currents characteristic of tonic neurons. These findings indicate a subgroup of tonic neurons besides mere tonic or phasic neurons exists able to exhibit a phasic activity pattern under pathological conditions.
CRIS-Team Scopus Importer:2023-09-15
Keywords: Chemokine; Firing pattern; Phasic; Renal afferent nerve; Sodium currents; Tonic; Voltage-gated sodium channels

AFFERENT PEPTIDERGIC NERVE FIBERS - IMPORTANCE FOR THE SALT METABOLISM BEYOND THE KIDNEYS? - Ditting, Tilmann; Rodionova, Kristina; Reeh, Peter; Schmieder, Roland; Schiffer, Mario; Amann, Kerstin Ute; Ott, Christianroland; Veelken, Roland (JOURNAL OF HYPERTENSION, 2021)
CRIS-Team WoS Importer:2021-07-30

Afferent renal innervation in anti-Thy1.1 nephritis in rats - Rodionova, Kristina; Veelken, Roland; Hilgers, Karl Friedrich; Paulus, Eva Maria; Linz, Peter; Fischer, Michael J.M.; Schenker, Martina; Reeh, Peter; Tiegs, Gisa; Ott, Christian; Schmieder, Roland; Schiffer, Mario; et al. (American Journal of Physiology-Renal Physiology, 2020)
Afferent renal nerves exhibit a dual function controlling central sympathetic outflow via afferent electrical activity and influencing intrarenal immunological processes by releasing peptides such as calcitonin gene-related peptide (CGRP). We tested the hypothesis that increased afferent and efferent renal nerve activity occur with augmented release of CGRP in anti-Thy1.1 nephritis, in which enhanced CGRP release exacerbates inflammation. Nephritis was induced in Sprague-Dawley rats by intravenous injection of OX-7 antibody (1.75 mg/kg), and animals were investigated neurophysiologically, electrophysiologically, and pathomorphologically 6 days later. Nephritic rats exhibited proteinuria (169.3 ± 10.2 mg/24 h) with increased efferent renal nerve activity (14.7 ± 0.9 bursts/s vs. control 11.5 ± 0.9 bursts/s, n = 11, P < 0.05). However, afferent renal nerve activity (in spikes/s) decreased in nephritis (8.0 ± 1.8 Hz vs. control 27.4 ± 4.1 Hz, n = 11, P < 0.05). In patch-clamp recordings, neurons with renal afferents from nephritic rats showed a lower frequency of high activity following electrical stimulation (43.4% vs. 66.4% in controls, P < 0.05). In vitro assays showed that renal tissue from nephritic rats exhibited increased CGRP release via spontaneous (14 ± 3 pg/mL vs. 6.8 ± 2.8 pg/ml in controls, n = 7, P < 0.05) and stimulated mechanisms. In nephritic animals, marked infiltration of macrophages in the interstitium (26 ± 4 cells/mm2) and glomeruli (3.7 ± 0.6 cells/glomerular cross-section) occurred. Pretreatment with the CGRP receptor antagonist CGRP8-37 reduced proteinuria, infiltration, and proliferation. In nephritic rats, it can be speculated that afferent renal nerves lose their ability to properly control efferent sympathetic nerve activity while influencing renal inflammation through increased CGRP release.
CRIS-Team Scopus Importer:2020-11-13
Keywords: afferent renal neerves; calcitonin gene-related peptide; renal inflammation; renal innervation; sympathetic innervation

AFFERENT RENAL NERVE PATHWAYS IN RATS - RESPONSIVENESS TO HIGH SALT INTAKE - Rodionova, Kristina; Ditting, Tilmann; Fahrmeier, Franziska; Ott, Chirstian; Schmieder, Roland; Schiffer, Mario; Amann, Kerstin Ute; Veelken, Roland (JOURNAL OF HYPERTENSION, 2021)
CRIS-Team WoS Importer:2021-07-30

A Fluorescent Benzo[g]isoquinoline-based HIF Prolyl Hydroxylase Inhibitor for Cellular Imaging. - Mayer, Marleen; Fey, Kerstin; Heinze, Eva; Wick, Christian; Abboud, Martine I.; Yeh, Tzu Lan; Tumber, Anthony; Orth, Nicole; Schley, Gunnar; Buchholz, Björn; Clark, Timothy; Schofield, Christopher J.; et al. (ChemMedChem, 2018)
Prolyl hydroxylation domain enzymes (PHD) catalyze the hydroxylation of the transcription factor Hypoxia Inducible Factor (HIF) and serve as cellular oxygen sensors. HIF and the PHD enzymes regulate numerous potentially tissue protective target genes which can adapt cells to metabolic and ischemic stress. We describe a fluorescent PHD inhibitor (1-chloro-4-hydroxybenzo[g]isoquinoline-3-carbonyl)-glycine which is suited to fluorescent based detection assays and for monitoring PHD inhibitors in biological systems. In cell based assays, application of the fluorescent PHD inhibitor allowed co-localization with a cellular PHD enzyme and led to live cell imaging of processes involved in cellular oxygen sensing.
Keywords: fluorescence microscopy; HIF system; hypoxia; oxygen sensing; PHD inhibitors

After ten years of follow-up, no difference between supportive care plus immunosuppression and supportive care alone in IgA nephropathy - Rauen, Thomas; Wied, Stephanie; Fitzner, Christina; Eitner, Frank; Sommerer, Claudia; Zeier, Martin; Otte, Britta; Panzer, Ulf; Budde, Klemens; Benck, Urs; Mertens, Peter R.; Kuhlmann, Uwe; et al. (Kidney International, 2020)
The randomized, controlled STOP-IgAN trial in patients with IgA nephropathy (IgAN) and substantial proteinuria showed no benefit of immunosuppression added on top of supportive care on renal function over three years. As a follow-up we evaluated renal outcomes in patients over a follow-up of up to ten years in terms of serum creatinine, proteinuria, end-stage kidney disease (ESKD), and death. The adapted primary endpoint was the time to first occurrence of a composite of death, ESKD, or a decline of over 40% in the estimated glomerular filtration rate (eGFR) compared to baseline at randomization into STOP-IgAN. Data were analyzed by Cox-regression models. Follow-up data were available for 149 participants, representing 92% of the patients originally randomized. Median follow-up was 7.4 years (inter quartile range 5.7 to 8.3 years). The primary endpoint was reached in 36 of 72 patients randomized to supportive care and 35 of 77 patients randomized to additional immunosuppression (hazard ratio 1.20; 95% confidence interval 0.75 to 1.92). ESKD occurred in 17 of the patients with supportive care and in 20 of the patients with additional immunosuppression. Additionally, the rates of eGFR loss over 40% and annual eGFR loss did not differ between groups. Two patients died with supportive care and three with additional immunosuppression. Thus, within the limitations of a retrospective study, over a follow-up of up to ten years, and using an adapted primary endpoint, we failed to detect differences in key clinical outcomes in IgAN patients randomized to receive added immunosuppression on top of supportive care versus supportive care alone.
CRIS-Team Scopus Importer:2020-09-11
Keywords: IgA nephropathy; IgAN; immunosuppression; long term; STOP-IgAN

A gene variant in CERS2 is associated with rate of increase in albuminuria in patients with diabetes from ONTARGET and TRANSCEND - Shiffman, Dov; Pare, Guillaume; Oberbauer, Rainer; Louie, Judy Z.; Rowland, Charles M.; Devlin, James J.; Mann, Johannes; Mcqueen, Matthew J. (PLoS ONE, 2014)
Although albuminuria and subsequent advanced stage chronic kidney disease are common among patients with diabetes, the rate of increase in albuminuria varies among patients. Since genetic variants associated with estimated glomerular filtration rate (eGFR) were identified in cross sectional studies, we asked whether these variants were also associated with rate of increase in albuminuria among patients with diabetes from ONTARGET and TRANSCEND-randomized controlled trials of ramipril, telmisartan, both, or placebo. For 16 genetic variants associated with eGFR at a genome-wide level, we evaluated the association with annual rate of increase in albuminuria estimated from urine albumin:creatinine ratio (uACR). One of the variants (rs267734) was associated with rate of increase in albuminuria. The annual rate of increase in albuminuria among risk homozygotes (69% of the study population) was 11.3% (95%CI; 7.5% to 15.3%), compared with 5.0% (95%CI; 3.3% to 6.8%) for heterozygotes (27% of the population), and 1.7% (95%CI; -1.7% to 5.3%) for non-risk homozygotes (4% of the population); P = 0.0015 for the difference between annual rates in the three genotype groups. These estimates were adjusted for age, sex, ethnicity, and principal component of genetic heterogeneity. Among patients without albuminuria at baseline (uACR<30 mg/g), each risk allele was associated with 50% increased risk of incident albuminuria (OR = 1.50; 95%CI 1.15 to 1.95; P = 0.003) after further adjustment for traditional risk factors including baseline uACR and eGFR. The rs267734 variant is in almost perfect linkage-disequilibrium (r2 = 0.94) with rs267738, a single nucleotide polymorphism encoding a glutamic acid to alanine change at position 115 of the ceramide synthase 2 (CERS2) encoded protein. However, it is unknown whether CERS2 function influences albuminuria. In conclusion, we found that rs267734 in CERS2 is associated with rate of increase in albuminuria among patients with diabetes and elevated risk of cardiovascular disease.
EVALuna2:3809

Agreement Between 24-Hour Salt Ingestion and Sodium Excretion in a Controlled Environment - Lerchl, Kathrin; Rakova, Natalia; Dahlmann, Anke; Rauh, Manfred; Goller, Ulrike; Basner, Mathias; Dinges, David F.; Beck, Luis; Agureev, Alexander; Larina, Irina; Baranov, Victor; Morukov, Boris; et al. (Hypertension, 2015)
Accurately collected 24-hour urine collections are presumed to be valid for estimating salt intake in individuals. We performed 2 independent ultralong-term salt balance studies lasting 105 (4 men) and 205 (6 men) days in 10 men simulating a flight to Mars. We controlled dietary intake of all constituents for months at salt intakes of 12, 9, and 6 g/d and collected all urine. The subjects' daily menus consisted of 27 279 individual servings, of which 83.0% were completely consumed, 16.5% completely rejected, and 0.5% incompletely consumed. Urinary recovery of dietary salt was 92% of recorded intake, indicating long-term steady-state sodium balance in both studies. Even at fixed salt intake, 24-hour urine collection for sodium excretion (UNaV) showed infradian rhythmicity. We defined a ±25 mmol deviation from the average difference between recorded sodium intake and UNaV as the prediction interval to accurately classify a 3-g difference in salt intake. Because of the biological variability in UNaV, only every other daily urine sample correctly classified a 3-g difference in salt intake (49%). By increasing the observations to 3 consecutive 24-hour collections and sodium intakes, classification accuracy improved to 75%. Collecting seven 24-hour urines and sodium intake samples improved classification accuracy to 92%. We conclude that single 24-hour urine collections at intakes ranging from 6 to 12 g salt per day were not suitable to detect a 3-g difference in individual salt intake. Repeated measurements of 24-hour UNaV improve precision. This knowledge could be relevant to patient care and the conduct of intervention trials.
EVALuna2:3790

A guide for easy- and difficult-to-treat hypertension - Schmieder, Roland; Volpe, Massimo; Waeber, Bernard; Ruilope, Luis M. (International Journal of Cardiology, 2014)
Although the blood pressure (BP) of many patients can be controlled using standard combinations, treatment of hypertension frequently represents a clinical challenge to the primary care physician. This article will review best practices for managing patients with easy- and difficult-to-treat hypertension, including preferred antihypertensive combinations, optimizing adherence and persistence, recognizing white-coat hypertension, and intensifying therapy for treatment-resistant patients. Each physician must decide based on his or her own level of experience at what point a patient becomes too challenging and would benefit from referral to a hypertension specialist for more intensive management and to complete the exclusion of secondary forms of arterial hypertension. With intensive pharmacotherapy, many patients with difficult-to-treat hypertension can achieve BP control. If it fails, interventional strategies (e.g., renal denervation) are a valid option to get BP controlled.
EVALuna2:3680

Aktueller Standard der Blutdruckmessung – Stellungnahme der Deutschen Hochdruckliga e. V. DHL® – Deutsche Gesellschaft für Hypertonie und Prävention - Eckert, Siegfried; Ott, Christian; Büchner, Nikolaus; Dechend, Ralf; Lüders, Stephan; Mengden, Thomas; Sanner, Bernd (Deutsche Medizinische Wochenschrift, 2019)
Arterial hypertension is one of the most prevalent chronic diseases, and a major risk factor for cardiovascular diseases. It is essential to perform the blood pressure measurement under standardized conditions in the office/clinical setting, otherwise inaccuracy of blood pressure values may lead to poor blood pressure control or misdiagnosis. Compliance with these standards by a trained observer is of crucial importance for a reliable and accurate blood pressure measurement in clinical practice. Regardless of the standardized assessment, it has to be kept in mind that available devices on the market may not measure blood pressure accurate enough. Therefore, a validated (e.âŠg. German Hypertension League Quality Seal) blood pressure monitor should be used. Out-of-office (home and ambulatory) blood pressure measurements provide important information beyond determining resting office/clinical BP.
CRIS-Team Scopus Importer:2019-11-05
Keywords: blood pressure measurement; standard/standardized measurement; validation/validated devices

Aktueller Stand der Durchführung von Nierenersatztherapien auf deutschen Intensivstationen - Willam, Carsten; Meersch, Melanie; Herbst, Larissa; Heering, Peter; Schmitz, Michael; Oppert, Michael; John, Stefan; Jörres, Achim; Zarbock, Alexander; Janssens, Uwe; Kindgen-Milles, Detlef (Medizinische Klinik - Intensivmedizin und Notfallmedizin, 2021)
About 50% of all critically ill patients develop acute kidney injury (AKI) and approximately 15% receive renal replacement therapy (RRT). Although RRT is frequently used in intensive care units in Germany, it is currently unknown which RRT procedures are available, which qualification the involved staff has, which anticoagulation strategies are used and how RRT doses are prescribed. To investigate quality and structural characteristics of the performance of RRT in intensive care units throughout Germany, the German Interdisciplinary Society of Intensivists (Deutsche Interdisziplinäre Vereinigung für Intensiv- und Notfallmedizin [DIVI]) performed an inquiry among their members. A total of 897 members participated in the survey in which practical aspects were queried. In 69.1% of the cases, RRT was performed in hospitals with more than 400 beds and in 74.5% in university hospitals or other primary care hospitals. Furthermore, 93.3% of clinics are equipped with continuous and 75.8% with intermittent renal replacement devices. In 91.9%, indication for initiation of RRT was performed by trained physicians specialized in intensive care medicine or nephrologists. Intermittent as well as continuous modalities are both present in three-quarters of cases, which allows for individualized therapy. However, the documentation of dialysis dose needs to be improved.
CRIS-Team Scopus Importer:2021-07-09
Keywords: Acute kidney injury; Hemodialysis; Hemofiltration; Intensive care medicine; Renal replacement therapy

Alcohol-mediated renal denervation in patients with hypertension in the absence of antihypertensive medications - Pathak, Atul; Rudolph, Ulrike M.; Saxena, Manish; Zeller, Thomas; Müller-Ehmsen, Jochen; Lipsic, Erik; Schmieder, Roland; Sievert, Horst; Halbach, Marcel; Sharif, Faisal; Parise, Helen; Fischell, Tim A.; et al. (EuroIntervention, 2023)
BACKGROUND: Ultrasound and radiofrequency renal denervation (RDN) have been shown to safely lower blood pressure (BP) in hypertension. AIMS: The TARGET BP OFF-MED trial investigated the efficacy and safety of alcohol-mediated renal denervation (RDN) in the absence of antihypertensive medications. METHODS: This randomised, blinded, sham-controlled trial was conducted in 25 centres in Europe and the USA. Patients with a 24-hour systolic BP of 135-170 mmHg, an office systolic BP 140-180 mmHg and diastolic BP ≥90 mmHg on 0-2 antihypertensive medications were enrolled. The primary efficacy endpoint was the change in mean 24-hour systolic BP at 8 weeks. Safety endpoints included major adverse events up to 30 days. RESULTS: A total of 106 patients were randomised; the baseline mean office BP following medication washout was 159.4/100.4±10.9/7.0 mmHg (RDN) and 160.1/98.3±11.0/6.1 mmHg (sham), respectively. At 8 weeks post-procedure, the mean (±standard deviation) 24-hour systolic BP change was â2.9±7.4 mmHg (p=0.009) versus â1.4±8.6 mmHg (p=0.25) in the RDN and sham groups, respectively (mean between-group difference: 1.5 mmHg; p=0.27). There were no differences in safety events between groups. After 12 months of blinded follow-up, with medication escalation, patients achieved similar office systolic BP (RDN: 147.9±18.5 mmHg; sham: 147.8±15.1 mmHg; p=0.68) with a significantly lower medication burden in the RDN group (mean daily defined dose: 1.5±1.5 vs 2.3±1.7; p=0.017). CONCLUSIONS: In this trial, alcohol-mediated RDN was delivered safely but was not associated with significant BP differences between groups. Medication burden was lower in the RDN group up to 12 months.
CRIS-Team Scopus Importer:2023-09-29

Alcohol-Mediated Renal Denervation Using the Peregrine System Infusion Catheter for Treatment of Hypertension - Mahfoud, Felix; Renkin, Jean; Sievert, Horst; Bertog, Stefan; Ewen, Sebastian; Böhm, Michael; Lengelé, Jean Philippe; Wojakowski, Wojciech; Schmieder, Roland; van der Giet, Markus; Parise, Helen; Haratani, Nicole; et al. (Jacc-Cardiovascular Interventions, 2020)
Objectives: The aim of this multicenter, open-label trial was to evaluate the safety and efficacy of alcohol-mediated renal denervation using a novel catheter system (the Peregrine System Infusion Catheter) for the infusion of dehydrated alcohol as a neurolytic agent into the renal periarterial space. Background: The number of hypertensive patients with uncontrolled blood pressure (BP) remains unacceptably low. The renal sympathetic nervous system has been identified as an attractive therapeutic target. Methods: Forty-five patients with uncontrolled hypertension on ≥3 antihypertensive medications underwent bilateral renal denervation using the Peregrine Catheter with 0.6 ml alcohol infused per renal artery. Results: All patients were treated as intended. Mean 24-h ambulatory BP reduction at 6 months versus baseline was −11 mm Hg (95% confidence interval [CI]: −15 to −7 mm Hg) for systolic BP and −7 mm Hg (95% CI: −9 to −4 mm Hg) for diastolic BP (p < 0.001 for both). Office systolic BP was reduced by −18/−10 mm Hg (95% CI: −25 to −12/−13 to −6 mm Hg) at 6 months. Antihypertensive medications were reduced in 23% and increased in 5% of patients at 6 months. Adherence to the antihypertensive regimen remained stable over time. The primary safety endpoint, defined as the absence of periprocedural major vascular complications, major bleeding, acute kidney injury, or death within 1 month, was met in 96% of patients (95% CI: 85% to 99%). Two patients had major adverse events of periprocedural access-site pseudoaneurysms, with major bleeding in one. There were no deaths or instances of myocardial infarction, stroke, transient ischemic attack, or renal artery stenosis. Transient microleaks were noted in 42% and 49% of the left and right main renal arteries, respectively. There were 2 cases of minor vessel dissection that resolved without treatment. Conclusions: Primary results from this trial suggest that alcohol-mediated renal denervation using the Peregrine Catheter safely reduces blood pressure and as such may represent a novel approach for the treatment of hypertension.
CRIS-Team Scopus Importer:2020-02-18
Keywords: alcohol; catheter; hypertension; neurolysis; renal denervation

Alcohol-mediated renal sympathetic neurolysis for the treatment of hypertension: The Peregrine™ infusion catheter - Bertog, Stefan; Sharma, Alok; Mahfoud, Felix; Pathak, Atul; Schmieder, Roland; Sievert, Kolja; Papademetriou, Vasilios; Weber, Michael A.; Haratani, Nicole; Lobo, Melvin D.; Saxena, Manish; Kandzari, David E.; et al. (Cardiovascular Revascularization Medicine, 2020)
Renal sympathetic denervation using conventional non-irrigated radiofrequency catheters has potential technical shortcomings, including limited penetration depth and incomplete circumferential nerve damage, potentially impacting therapeutic efficacy. Against this background, second generation multi-electrode, radiofrequency and ultrasound renal denervation systems have been developed to provide more consistent circumferential nerve ablation. Irrigated catheters may allow deeper penetration while minimizing arterial injury. In this context, catheter-based chemical denervation, with selective infusion of alcohol, a potent neurolytic agent, into the perivascular space, may minimize endothelial, intimal and medial injury while providing circumferential neurolysis. Animal studies demonstrate pronounced renal norepinephrine level reductions and consistent renal nerve injury after perivascular alcohol infusion using the Peregrine Catheter. Early clinical studies demonstrated significant blood pressure reductions and a reasonable safety profile. Randomized sham-controlled trials (NCT03503773, NCT02910414) are underway to examine whether the aforementioned theoretical advantages of alcohol-medicated denervation with the Peregrine System™ Kit translate into clinical benefits.
CRIS-Team Scopus Importer:2020-12-18
Keywords: Alcohol-mediated neurolysis; Chemical neurolysis; Hypertension; Renal denervation; Sympathetic nervous system

Aldosterone antagonists and renal denervation: friends or foes? - Mahfoud, Felix; Ruilope, Luis M.; Bohm, Michael; Schmieder, Roland (Hypertension, 2015)
EVALuna2:3735

Alpha8 Integrin (Itga8) Signalling Attenuates Chronic Renal Interstitial Fibrosis by Reducing Fibroblast Activation, Not by Interfering with Regulation of Cell Turnover - Marek, Ines; Lichtneger, Till-Simon; Cordasic, Nada; Hilgers, Karl Friedrich; Volkert, Gudrun; Fahlbusch, Fabian; Rascher, Wolfgang; Menendez-Castro, Carlos; Hartner, Andrea (PLoS ONE, 2016)
The ?8 integrin (Itga8) chain contributes to the regulation of cell proliferation and apoptosis in renal glomerular cells. In unilateral ureteral obstruction Itga8 is de novo expressed in the tubulointerstitium and a deficiency of Itga8 results in more severe renal fibrosis after unilateral ureteral obstruction. We hypothesized that the increased tubulointerstitial damage after unilateral ureteral obstruction observed in mice deficient for Itga8 is associated with altered tubulointerstitial cell turnover and apoptotic mechanisms resulting from the lack of Itga8 in cells of the tubulointerstitium. Induction of unilateral ureteral obstruction was achieved by ligation of the right ureter in mice lacking Itga8. Unilateral ureteral obstruction increased proliferation and apoptosis rates of tubuloepithelial and interstitial cells, however, no differences were observed in the tubulointerstitium of mice lacking Itga8 and wild type controls regarding fibroblast or proliferating cell numbers as well as markers of endoplasmic reticulum stress and apoptosis after unilateral ureteral obstruction. In contrast, unilateral ureteral obstruction in mice lacking Itga8 led to more pronounced tubulointerstitial cell activation i.e. to the appearance of more phospho-SMAD2/3-positive cells and more ?-smooth muscle actin-positive cells in the tubulointerstitium. Furthermore, a more severe macrophage and T-cell infiltration was observed in these animals compared to controls. Thus, Itga8 seems to attenuate tubulointerstitial fibrosis in unilateral ureteral obstruction not via regulation of cell turnover, but via regulation of TGF-? signalling, fibroblast activation and/or immune cell infiltration.
EVALuna2:3858

Alternative splicing and nonsense-mediated mRNA decay contribute to regulation of LOXL1 expression in response to cellular stress in pseudoexfoliation - Berner, Daniel; Zenkel, Matthias; Pasutto, Francesca; Schoedel, Johannes; Reis, André; Kruse, Friedrich; Schlötzer-Schrehardt, Ursula (2017)
EVALuna2:34538

Alternative splicing of SMPD1 coding for acid sphingomyelinase in major depression - Rhein, Cosima; Reichel, Martin; Kramer, Marcel; Rotter, Andrea; Lenz, Bernd; Mühle, Christiane; Gulbins, Erich; Kornhuber, Johannes (Journal of Affective Disorders, 2017)
BACKGROUND: Major depressive disorder (MDD) is a psychiatric disorder characterized by key symptoms that include depressed mood and a loss of interest and pleasure. A recently developed pathogenic model of MDD involves disturbed neurogenesis in the hippocampus, where the acid sphingomyelinase (ASM)/ceramide system plays an important role and is proposed as a molecular target for antidepressant action. Because alternative splicing of SMPD1 mRNA, coding for ASM, is relevant for the regulation of ASM enzymatic activity, we investigated the frequency of alternatively spliced ASM isoforms in peripheral blood cells of MDD patients versus healthy controls. METHODS: Because the full-length transcript variant 1 of SMPD1 (termed ASM-1) is the only known form within the splicing pattern that encodes an enzymatically fully active ASM, we determined a fraction of splice isoforms deviating from ASM-1 using PCR amplification and capillary electrophoresis with laser-induced fluorescence analysis. RESULTS: ASM alternative splicing events occurred significantly less frequently in MDD patients compared to healthy subjects. After 5 days of antidepressant treatment, the frequency of alternatively spliced ASM isoforms decreased in those patients who were treated with a functional inhibitor of ASM activity (FIASMA) but remained constant in MDD patients treated with other antidepressant drugs. This effect was more pronounced when healthy male volunteers were treated with the FIASMAs fluoxetine or paroxetine, in contrast to a placebo group. LIMITATIONS: Patients were treated with different antidepressant drugs, depending on individual parameters and disease courses. CONCLUSIONS: This study shows that the ASM alternative splicing pattern could be a biological target with diagnostic relevance and could serve as a novel biomarker for MDD.
EVALuna2:33501

A Modified Surgical Technique for Kidney Transplantation in Mice - Yin, Decheng; Fu, Jian; Chen, Rongjun; Shushakova, Nelli; Allabauer, Ida; Wei, Xinyi; Schiffer, Mario; Dudziak, Diana; Rong, Song; Hörning, André (Journal of Visualized Experiments, 2022)
Kidney transplantation in mice is a complicated and challenging surgery procedure. There are very few publications demonstrating the key steps of this operation. Therefore, this article introduces the technique and points out the surgical caveats associated with this operation. In addition, important modifications in comparison to the conventional procedure are demonstrated. Firstly, a patch of the abdominal aorta is cut and prepared so that the proximal bifurcations of the renal artery, including the ureteral artery are transected together with the donor kidney en bloc. This reduces the risk of a ureter necrosis and avoids the development of a urinary tract occlusion. Secondly, a new method of the vascular anastomosis is demonstrated that allows the operator to flexibly increase or decrease the size of the anastomosis after renal transplant reperfusion has already been initiated. This avoids the development of vessel strictures and intraabdominal bleeding. Thirdly, a technique that enables the anastomosis of the delicate donor ureter and the recipient bladder that does not cause a trauma is shown. Adopting this protocol can shorten the operation time and reduces the damage to the recipient's bladder, thereby significantly increasing the operation success rate for the recipient mice.
CRIS-Team Scopus Importer:2022-08-19

A multinational clinical approach to assessing the effectiveness of catheter-based ultrasound renal denervation: The RADIANCE-HTN and REQUIRE clinical study designs - Mauri, Laura; Kario, Kazuomi; Basile, Jan; Daemen, Joost; Davies, Justin; Kirtane, Ajay J.; Mahfoud, Felix; Schmieder, Roland; Weber, Michael; Nanto, Shinsuke; Azizi, Michel (American Heart Journal, 2018)
Catheter-based renal denervation is a new approach to treat hypertension via modulation of the renal sympathetic nerves. Although nonrandomized and small, open-label randomized studies resulted in significant reductions in office blood pressure 6months after renal denervation with monopolar radiofrequency catheters, the first prospective, randomized, sham-controlled study (Symplicity HTN-3) failed to meet its blood pressure efficacy end point. New clinical trials with new catheters have since been designed to address the limitations of earlier studies. Accordingly, the RADIANCE-HTN and REQUIRE studies are multicenter, blinded, randomized, sham-controlled trials designed to assess the blood pressure-lowering efficacy of the ultrasound-based renal denervation system (Paradise) in patients with established hypertension either on or off antihypertensive medications, is designed to evaluate patients in 2 cohorts-SOLO and TRIO, in the United States and Europe. The SOLO cohort includes patients with essential hypertension, at low cardiovascular risk, and either controlled on 1 to 2 antihypertensive medications or uncontrolled on 0 to 2 antihypertensive medications. Patients undergo a 4-week medication washout period before randomization to renal denervation (treatment) or renal angiogram (sham). The TRIO cohort includes patients with hypertension resistant to at least 3 antihypertensive drugs including a diuretic. Patients will be stabilized on a single-pill, triple-antihypertensive-drug combination for 4weeks before randomization to treatment or sham. Reduction in daytime ambulatory systolic blood pressure (primary end point) will be assessed at 2months in both cohorts. A predefined medication escalation protocol, as needed for blood pressure control, is implemented between 2 and 6months in both cohorts by a study staff member blinded to the randomization process. At 6months, daytime ambulatory blood pressure and antihypertensive treatment score will be assessed. REQUIRE is designed to evaluate patients with resistant hypertension on standard of care medication in Japan and Korea. Reduction in 24-hour ambulatory systolic blood pressure will be assessed at 3months (primary end point). Both studies are enrolling patients, and their results are expected in 2018.
EVALuna2:4042

ANALYZING THE EFFECT OF MICROPLASTIC PARTICLES ON HUMAN PODOCYTES - Yarbakht, Melina; Sarau, George; Kling, Lasse; Müller-Deile, Janina; Kotb, Ahmed; Christiansen, Silke; Schiffer, Mario (NEPHROLOGY DIALYSIS TRANSPLANTATION, 2021)
CRIS-Team WoS Importer:2021-12-03

Androglobin gene expression patterns and FOXJ1-dependent regulation indicate its functional association with ciliogenesis - Koay, Teng Wei; Osterhof, Carina; Orlando, Ilaria M.C.; Keppner, Anna; Andre, Daniel; Yousefian, Schayan; Alonso, María Suárez; Correia, Miguel; Markworth, Robert; Schödel, Johannes; Hankeln, Thomas; Hoogewijs, David (Journal of Biological Chemistry, 2021)
Androglobin (ADGB) represents the latest addition to the globin superfamily in metazoans. The chimeric protein comprises a calpain domain and a unique circularly permutated globin domain. ADGB expression levels are most abundant in mammalian testis, but its cell-type-specific expression, regulation, and function have remained unexplored. Analyzing bulk and single-cell mRNA-Seq data from mammalian tissues, we found that—in addition to the testes—ADGB is prominently expressed in the female reproductive tract, lungs, and brain, specifically being associated with cell types forming motile cilia. Correlation analysis suggested coregulation of ADGB with FOXJ1, a crucial transcription factor of ciliogenesis. Investigating the transcriptional regulation of the ADGB gene, we characterized its promoter using epigenomic datasets, exogenous promoter-dependent luciferase assays, and CRISPR/ dCas9-VPR-mediated activation approaches. Reporter gene assays revealed that FOXJ1 indeed substantially enhanced luciferase activity driven by the ADGB promoter. ChIP assays confirmed binding of FOXJ1 to the endogenous ADGB promoter region. We dissected the minimal sequence required for FOXJ1-dependent regulation and fine mapped the FOXJ1 binding site to two evolutionarily conserved regions within the ADGB promoter. FOXJ1 overexpression significantly increased endogenous ADGB mRNA levels in HEK293 and MCF-7 cells. Similar results were observed upon RFX2 overexpression, another key transcription factor in ciliogenesis. The complex transcriptional regulation of the ADGB locus was illustrated by identifying a distal enhancer, responsible for synergistic regulation by RFX2 and FOXJ1. Finally, cell culture studies indicated an ADGB-dependent increase in the number of ciliated cells upon overexpression of the full-length protein, confirming a ciliogenesis-associated role of ADGB in mammals.
CRIS-Team Scopus Importer:2021-04-02

A New Diagnostic Approach to HLA Testing in Kidney Transplant Patients Using Renal Epithelial Cells - Herrmann, Markus; Bach, Christian; Knaup, Karl; Schiffer, Mario; Spriewald, B.; Wiesener, M. S. (AMERICAN JOURNAL OF TRANSPLANTATION, 2020)
CRIS-Team WoS Importer:2020-10-16

A NEW DIAGNOSTIC APPROACH TO HLA TESTING IN KIDNEY TRANSPLANT RECIPIENTS USING CULTURED URINE DERIVED TUBULAR CELLS - Spriewald, Bernd M.; Herrmann, Markus; Bach, Christian; Knaup, Karl; Krumbiegel, Mandy; Reis, André; Schiffer, Mario; Wiesener, Michael (HLA, 2020)
CRIS-Team WoS Importer:2020-03-24

Angiotensin pathways under therapy with empagliflozin in patients with chronic heart failure - Bosch, Agnes; Poglitsch, Marko; Kannenkeril, Dennis; Kolwelter, Julie; Striepe, Kristina; Ott, Christian; Rauh, Manfred; Schiffer, Mario; Achenbach, Stephan; Schmieder, Roland (ESC Heart Failure, 2023)
Aims: Large outcome studies demonstrated a reduction of heart failure hospitalization or cardiovascular death in patients with chronic heart failure (CHF). The renin–angiotensin system (RAS) is a key player in fluid and sodium regulation. The classic angiotensin-converting enzyme–angiotensin II–angiotensin-1 receptor axis (Ang I–ACE–Ang II receptor axis) is predominantly angiotensin II (Ang-II) induced and promotes vasoconstriction. In contrast, the angiotensin-converting-enzyme-2–angiotensin-(1-7)–Mas axis (Mas-axis) is mediated by the metabolites angiotensin-1-7 (Ang-(1-7)) and angtiotensin-1-5 (Ang-(1-5)) and exerts cardioprotective effects. Methods: We previously investigated the effect of empagliflozin on the systemic haemodynamic in patients with stable CHF (NYHA II–III) in a randomized placebo-controlled clinical trial ‘Analysing the Effect of Empagliflozin on Reduction of Tissue Sodium Content in Patients With Chronic Heart Failure (ELSI)’. In a post hoc analysis, we now analysed whether empagliflozin has an effect on the RAS by measuring detailed RAS profiles (LC-MS/MS-based approach) in 72 patients from ELSI. We compared RAS parameters after 1-month and 3-months treatment with empagliflozin or placebo to baseline. The secondary goal was to analyse whether the effect of empagliflozin on RAS parameters was dependent on angiotensin-receptor-blocking (ARB) or angiotensin-converting-enzyme-inhibitor (ACEI) co-medication. Results: Empagliflozin medication induced a significant rise in Ang-II [68.5 pmol/L (21.3–324.2) vs. 131.5 pmol/L (34.9–564.0), P = 0.001], angiotensin-I (Ang-I) [78.7 pmol/L (21.5–236.6) vs. 125.9 pmol/L (52.6–512.9), P < 0.001], Ang-(1-7) [3.0 pmol/L (3.0–15.0) vs. 10.1 pmol/L (3.0–31.3), P = 0.006], and Ang-(1-5) [5.4 pmol/L (2.0–22.9) vs. 9.9 pmol/L (2.8–36.4), P = 0.004], which was not observed in the placebo group (baseline to 3-months treatment). A significant rise in Ang-II (206.4 pmol/L (64.2–750.6) vs. 568.2 pmol/L (164.7–1616.4), P = 0.001), Ang-(1-7) (3.0 pmol/L (3.0–14.1) vs. 15.0 pmol/L (3.0–31.3), P = 0.017), and Ang-(1-5) [12.2 pmol/L (3.8–46.6) vs. 36.4 pmol/L (11.1–90.7), P = 0.001] under empagliflozin treatment was only seen in the subgroup of patients with ARB co-medication, whereas no change of Ang-II (16.7 pmol/L (2.0–60.8) vs. 26.4 pmol/L (10.7–63.4), P = 0.469), Ang-(1-7) (6.6 pmol/L (3.0–20.7) vs. 10.5 pmol/L (3.0–50.5), P = 0.221), and Ang-(1-5) (2.7 pmol/L (2.0–8.4) vs. 2.8 pmol/L (2.0–6.9), P = 0.851) was observed in patients with empagliflozin that were on ACEI co-medication (baseline to 3-months treatment). Conclusions: Our data indicate that empagliflozin might lead to an activation of both the Ang I–ACE–Ang II receptor axis and the Mas-axis pathway. Activation of the Ang I–ACE–Ang II receptor axis and the protective Mas-axis pathway after initiating treatment with empagliflozin was only seen in patients with ARB co-medication, in contrast to co-medication with ACEI.
CRIS-Team Scopus Importer:2023-02-24
Keywords: Angiotensin profiles; Cardioprotective effects; Chronic heart failure; Empagliflozin; Renin–angiotensin system

ANGIOTENSIN PROFILES IN PATIENTS WITH HYPERTENSION AND TYPE 2 DIABETES WITH COMBINATION THERAPY OF EMPAGLIFLOZIN AND LINAGLIPTIN VERSUS METFORMIN AND INSULIN GLARGINE - Bosch, Agnes; Poglitsch, Marko; Kannenkeril, Dennis; Ott, Christian; Pietschner, Robert; Striepe, Kristina; Schiffer, Mario; Schmieder, Roland (JOURNAL OF HYPERTENSION, 2022)
CRIS-Team WoS Importer:2022-07-29

ANGIOTENSIN PROFILES IN PATIENTS WITH HYPERTENSION AND TYPE 2 DIABETES WITH COMBINATION THERAPY OF EMPAGLIFLOZIN AND LINAGLIPTIN VERSUS METFORMIN AND INSULIN GLARGINE - Bosch, Agnes; Poglitsch, Marko; Kannenkeril, Dennis; Ott, Christian; Pietschner, Robert; Striepe, Kristina; Schiffer, Mario; Schmieder, Roland (Journal of Hypertension, 2022)
OBJECTIVE: The renin-angiotensin system (RAS) plays a key role in the physiological regulation of blood pressure. Patients with type-2-diabetes-mellitus (T2DM) and hypertension are known to have increased RAS activity. However, the precise role of RAS activation after SGLT2-inhibitor therapy is unknown. The classic RAS comprises the ACE-AngII-AT1R-axis (classic-axis) that promotes vasoconstriction. The Angiotensin-converting-enzyme-2-angiotensin-(1-7)-Mas axis (Mas-axis) with its components Angiotensin-(1-7) (Ang-1-7) and Angiotensin-(1-5) (Ang-1-5) is an endogenous negative regulatory pathway of the classic-axis, which can reduce its harmful effects. DESIGN AND METHOD: Angiotensin profiles were determined in 55 patients with hypertension and T2DM from our double blind, randomized, placebo controlled clinical trial "Effects of Empagliflozin+Linagliptin (E+L) vs Metformin+Insulin Glargine (M+I) on Renal and Vascular Changes in Type 2 Diabetes'' (ELMI) at baseline and three months after application of either E+L or M+I. An LC-MS/MS based approach was used to simultaneously quantify individual angiotensin metabolites (Attoquant Diagnostics, Vienna, Austria). RESULTS: In the E+L group medication induced a rise in Ang-I, Ang-(1-7) and a trend to a rise in Ang-II between baseline and treatment, which was not present in the M+I group (table).Comparison between the E+L and M+I group revealed that change between baseline and treatment was significantly different for Ang I (p = 0.002) and Ang-(1-7) (p = 0.002) between the groups. No difference in change between baseline and treatment was found for Ang II (p = 0.182) and Ang-(1-5) (p = 0.224) between the E+L and M+I group. CONCLUSIONS: In patients with hypertension and T2DM three months of therapy with E+L led to a rise of classic and protective components of the RAS, which was not present in the M+I group. The biological consequence of this complex RAS activation remains to be elucidated.
CRIS-Team Scopus Importer:2022-09-09

Angiotensin profiles in patients with type 2 diabetes and combination therapy of empagliflozin and linagliptin versus metformin and insulin glargine - Bosch, Agnes; Poglitsch, M.; Kannenkeril, Dennis; Ott, Christian; Striepe, Kristina; Schmieder, Roland (DIABETOLOGIA, 2021)
CRIS-Team WoS Importer:2021-10-01

An intermediate-effect size variant in UMOD confers risk for chronic kidney disease - Olinger, Eric; Schaeffer, Céline; Kidd, Kendrah; Elhassan, Elhussein A.E.; Cheng, Yurong; Dufour, Inès; Schiano, Guglielmo; Mabillard, Holly; Pasqualetto, Elena; Hofmann, Patrick; Fuster, Daniel G.; Kistler, Andreas D.; et al. (Proceedings of the National Academy of Sciences of the United States of America, 2022)
The kidney-specific gene UMOD encodes for uromodulin, the most abundant protein excreted in normal urine. Rare large-effect variants in UMOD cause autosomal dominant tubulointerstitial kidney disease (ADTKD), while common low-impact variants strongly associate with kidney function and the risk of chronic kidney disease (CKD) in the general population. It is unknown whether intermediate-effect variants in UMOD contribute to CKD. Here, candidate intermediate-effect UMOD variants were identified using large-population and ADTKD cohorts. Biological and phenotypical effects were investigated using cell models, in silico simulations, patient samples, and international databases and biobanks. Eight UMOD missense variants reported in ADTKD are present in the Genome Aggregation Database (gnomAD), with minor allele frequency (MAF) ranging from 1025 to 1023. Among them, the missense variant p.Thr62Pro is detected in ∼1/1,000 individuals of European ancestry, shows incomplete penetrance but a high genetic load in familial clusters of CKD, and is associated with kidney failure in the 100,000 Genomes Project (odds ratio [OR] = 3.99 [1.84 to 8.98]) and the UK Biobank (OR = 4.12 [1.32 to 12.85). Compared with canonical ADTKD mutations, the p.Thr62Pro carriers displayed reduced disease severity, with slower progression of CKD and an intermediate reduction of urinary uromodulin levels, in line with an intermediate trafficking defect in vitro and modest induction of endoplasmic reticulum (ER) stress. Identification of an intermediate-effect UMOD variant completes the spectrum of UMOD-associated kidney diseases and provides insights into the mechanisms of ADTKD and the genetic architecture of CKD.
CRIS-Team Scopus Importer:2022-09-02
Keywords: Autosomal Dominant Tubulointerstitial Kidney Disease; ER stress; genetic architecture; rare disease; uromodulin

ANNOYANCE DUE TO NOISE TRIGGERS VASCULAR CHANGES IN THE RENAL HEMODYNAMIC - Bosch, Agnes; Kannenkeril, Dennis; Ott, Christian; Harazny, Joanna M.; Striepe, Kristina; Karg, Marina V.; Jung, Susanne; Kolwelter, Julie; Schmieder, Roland (JOURNAL OF HYPERTENSION, 2021)
CRIS-Team WoS Importer:2021-07-30

Anoctamin 1 induces calcium-activated chloride secretion and proliferation of renal cyst-forming epithelial cells - Buchholz, Björn; Faria, Diana; Schley, Gunnar; Schreiber, Rainer; Eckardt, Kai-Uwe; Kunzelmann, Karl (Kidney International, 2014)
Polycystic kidney diseases are characterized by multiple bilateral renal cysts that gradually enlarge and lead to a decline in renal function. Cyst enlargement is driven by transepithelial chloride secretion, stimulated by enhanced levels of cyclic adenosine monophosphate, which activates apical cystic fibrosis transmembrane conductance regulator chloride channels. However, chloride secretion by calcium-dependent chloride channels, activated through stimulation of purinergic receptors, also has a major impact. To identify the molecular basis of calcium-dependent chloride secretion in cyst expansion, we determined the role of anoctamin 1 and 6, two recently discovered calcium-activated chloride channels both of which are expressed in epithelial cells. We found that anoctamin 1, which plays a role in epithelial fluid secretion and proliferation, is strongly expressed in principal-like MDCK cells (PLCs) forming cysts within a collagen matrix, in an embryonic kidney cyst model, and in human autosomal dominant polycystic kidney disease tissue. Knockdown of anoctamin 1 but not anoctamin 6 strongly diminished the calcium-dependent chloride secretion of PLCs. Moreover, two inhibitors of anoctamin ion channels, tannic acid and a more selective inhibitor of anoctamin 1, significantly inhibited PLC cyst growth and cyst enlargement in an embryonic kidney cyst model. Knockdown of ANO1 by morpholino analogs also attenuated embryonic cyst growth. Thus, calcium-activated chloride secretion by anoctamin 1 appears to be a crucial component of renal cyst growth.
EVALuna2:3642

Anoctamin 6 is localized in the primary cilium of renal tubular cells and is involved in apoptosis-dependent cyst lumen formation - Forschbach, V.; Goppelt-Strübe, Margarete; Kunzelmann, K.; Schreiber, R.; Piedagnel, Remi; Kraus, Andre; Eckardt, Kai-Uwe; Buchholz, Björn (Cell Death & Disease, 2015)
Primary cilia are antenna-like structures projected from the apical surface of various mammalian cells including renal tubular cells. Functional or structural defects of the cilium lead to systemic disorders comprising polycystic kidneys as a key feature. Here we show that anoctamin 6 (ANO6), a member of the anoctamin chloride channel family, is localized in the primary cilium of renal epithelial cells in vitro and in vivo. ANO6 was not essential for cilia formation and had no effect on in vitro cyst expansion. However, knockdown of ANO6 impaired cyst lumen formation of MDCK cells in three-dimensional culture. In the absence of ANO6, apoptosis was reduced and epithelial cells were incompletely removed from the center of cell aggregates, which form in the early phase of cystogenesis. In line with these data, we show that ANO6 is highly expressed in apoptotic cyst epithelial cells of human polycystic kidneys. These data identify ANO6 as a cilium-associated protein and suggest its functional relevance in cyst formation.

Anoctamins control Ca2+ signaling in micro domains of plasma membranes and are expressed in the primary cilium - Schreiber, R.; Cabrita, I.; Fonseca, A.; Benedetto, R.; Wanitchakod, P.; Sirianant, L.; Forschbach, V.; Buchholz, Björn; Kunzeimann, K. (Acta Physiologica, 2017)

A noninvasive diagnostic approach to retrospective donor HLA typing in kidney transplant patients using urine - Bach, Christian; Knaup, Karl; Herrmann, Markus; Krumbiegel, Mandy; Pfister, Frederick; Büttner-Herold, Maike; Steffen, Martin; Zecher, Daniel; Lopau, Kai; Schneider, Karen; Dieterle, Anne; Amann, Kerstin Ute; et al. (Transplant International, 2021)
Antibody-mediated rejection (AMR) is a major obstacle to long-term kidney transplantation. AMR is mostly caused by donor specific HLA antibodies, which can arise before or any time after transplantation. Incomplete donor HLA typing and unavailability of donor DNA regularly preclude the assessment of donor-specificity of circulating anti-HLA antibodies. In our centre, this problem arises in approximately 20% of all post-transplant HLA-antibody assessments. We demonstrate that this diagnostic challenge can be resolved by establishing donor renal tubular cell cultures from recipient´s urine as a source of high-quality donor DNA. DNA was then verified for genetic origin and purity by fluorescence in situ hybridization and short tandem repeat analysis. Two representative cases highlight the diagnostic value of this approach which is corroborated by analysis of ten additional patients. The latter were randomly sampled from routine clinical care patients with available donor DNA as controls. In all 12 cases, we were able to perform full HLA typing of the respective donors confirmed by cross-comparison to results from the stored 10 donor DNAs. We propose that this noninvasive diagnostic approach for HLA typing in kidney transplant patients is valuable to determine donor specificity of HLA antibodies, which is important in clinical assessment of suspected AMR.
CRIS-Team Scopus Importer:2021-06-25
Keywords: antibody-mediated rejection; HLA typing; HLA-antibody post-transplantation; rejection

A novel direct adenosine monophosphate kinase activator ameliorates disease progression in preclinical models of Autosomal Dominant Polycystic Kidney Disease - Dagorn, Pascale Gluais; Buchholz, Björn; Kraus, Andre; Batchuluun, Battsetseg; Bange, Hester; Blockken, Laura; Steinberg, Gregory R.; Moller, David E.; Hallakou-Bozec, Sophie (Kidney International, 2023)
Autosomal dominant polycystic kidney disease (ADPKD) mainly results from mutations in the PKD1 gene, which encodes polycystin 1. It is the most common inherited kidney disease and is characterized by a progressive bilateral increase in cyst number and size, often leading to kidney failure. The cellular energy sensor and regulator adenosine monophosphate stimulated protein kinase (AMPK) has been implicated as a promising new therapeutic target. To address this hypothesis, we determined the effects of a potent and selective clinical stage direct allosteric AMPK activator, PXL770, in canine and patient-derived 3D cyst models and an orthologous mouse model of ADPKD. PXL770 induced AMPK activation and dose-dependently reduced cyst growth in principal-like Madin-Darby Canine Kidney cells stimulated with forskolin and kidney epithelial cells derived from patients with ADPKD stimulated with desmopressin. In an inducible, kidney epithelium-specific Pkd1 knockout mouse model, PXL770 produced kidney AMPK pathway engagement, prevented the onset of kidney failure (reducing blood urea by 47%), decreased cystic index by 26% and lowered the kidney weight to body weight ratio by 35% compared to untreated control Pkd1 knockout mice. These effects were accompanied by a reduction of markers of cell proliferation (-48%), macrophage infiltration (-53%) and tissue fibrosis (-37%). Thus, our results show the potential of direct allosteric AMPK activation in the treatment of ADPKD and support the further development of PXL770 for this indication.
CRIS-Team Scopus Importer:2023-04-21
Keywords: ADPKD; AMPK; fibrosis; inflammation; mitochondria; PXL770

An update on the role of the inflammasomes in the pathogenesis of kidney diseases - Darisipudi, Murthy N.; Knauf, Felix (Pediatric Nephrology, 2016)
Innate immune response pathways play a critical role as the first line of defense. Initiation of an immune response requires sensors that can detect noxious stimuli within the cellular microenvironment. Inflammasomes are signaling platforms that are assembled in response to both microbe-specific and nonmicrobial antigens. Upon activation, proinflammatory cytokines are released to engage immune defenses and to trigger an inflammatory cell death referred to as pyroptosis. The aim of this review is to provide an overview of the current knowledge of the role of the inflammasomes in the pathogenesis of kidney diseases. As crystal deposition in the kidney is a frequent cause of acute kidney injury and chronic kidney disease in children, recent insights into mechanisms of inflammasome activation by renal crystals are highlighted. This may be of particular interest to pediatric patients and nephrologists in need of new therapeutic approaches. Lastly, current data findings that inflammasomes are not only of major importance in host defense but are also a key regulator of the intestinal microbiota and the progression of systemic diseases are reviewed.
EVALuna2:3813

Aortic stiffness is not only associated with structural but also functional parameters of retinal microcirculation - Dąbrowska, Edyta; Harazny, Joanna M.; Miszkowska-Nagórna, Eliza; Stefański, Adrian; Graff, Beata; Kunicka, Katarzyna; Świerblewska, Ewa; Rojek, Agnieszka; Szyndler, Anna; Gąsecki, Dariusz; Wolf, Jacek; Gruchała, Marcin; et al. (Microvascular Research, 2020)
Objective: The aim of the study was to test the hypothesis that alterations in large arteries are associated with microvascular remodelling and decreased retinal capillary blood flow. Methods: The study group comprised of 88 patients with essential hypertension and 32 healthy controls. Retinal microcirculation was evaluated by scanning laser Doppler flowmetry. Macrovascular changes were assessed on the basis of arterial stiffness measurement (carotid-femoral pulse wave velocity), its hemodynamic consequences (central pulse pressure, augmentation pressure, augmentation index) and intima media thickness of common carotid artery. Results: Pulse wave velocity was inversely correlated to mean retinal capillary blood flow in hypertensive patients (R = −0.32, p < 0.01). This relationship remained significant in multivariate regression analysis after adjustment for age, sex, central systolic blood pressure (BP) and body mass index (β = −31.27, p < 0.001). Lumen diameter (LD) of retinal arterioles was significantly smaller in hypertensive then normotensive subjects (79.4 vs. 83.8, p = 0.03). Central and brachial systolic, diastolic and mean BPs were significantly correlated with LD and outer diameter of retinal arterioles. The relationship between LD and central BPs remained significant in multivariate analysis (β = −0.15, p = 0.03 for cSBP; β = −0.22, p = 0.04 for cDBP; β = −0.21, p = 0.03 for cMBP). Moreover, in a subgroup with cardiac damage central and brachial pulse pressure were positively associated with retinal wall thickness, wall cross sectional area, and wall to lumen ratio. Conclusion: In conclusion, the study provides a strong evidence that microcirculation is coupled with macrocirculation not only in terms of structural but also functional parameters.
CRIS-Team Scopus Importer:2020-01-21
Keywords: Aortic stiffness; Microcirculation; Pulse wave velocity; Scanning laser Doppler flowmetry

AORTIC STIFFNESS IS NOT ONLY ASSOCIATED WITH STRUCTURAL BUT ALSO WITH FUNCTIONAL PARAMETERS OF MICROCIRCULATION - Dabrowska, E.; Harazny, J. M.; Miszkowska-Nagorna, E.; Stefanski, A.; Graff, B.; Szyndler, A.; Kunicka, K.; Swierblewska, E.; Rojek, A.; Gasecki, D.; Schmieder, Roland; Laurent, S.; et al. (JOURNAL OF HYPERTENSION, 2019)
CRIS-Team WoS Importer:2019-09-20

A paired-kidney allocation study found superior survival with HLA-DR compatible kidney transplants in the Eurotransplant Senior Program - de Fijter, Johan; Dreyer, Geertje; Mallat, Marko; Budde, Klemens; Pratschke, Johann; Klempnauer, Jürgen; Zeier, Martin; Arns, Wolfgang; Hugo, Christian; Rump, Lars Christian; Hauser, Ingeborg; Schenker, Peter; et al. (Kidney International, 2023)
The Eurotransplant Senior Program (ESP) has expedited the chance for elderly patients with kidney failure to receive a timely transplant. This current study evaluated survival parameters of kidneys donated after brain death with or without matching for HLA-DR antigens. This cohort study evaluated the period within ESP with paired allocation of 675 kidneys from donors 65 years and older to transplant candidates 65 years and older, the first kidney to 341 patients within the Eurotransplant Senior DR-compatible Program and 334 contralateral kidneys without (ESP) HLA-DR antigen matching. We used Kaplan-Meier estimates and competing risk analysis to assess all cause mortality and kidney graft failure, respectively. The log-rank test and Cox proportional hazards regression were used for comparisons. Within ESP, matching for HLA-DR antigens was associated with a significantly lower five-year risk of mortality (hazard ratio 0.71; 95% confidence interval 0.53-0.95) and significantly lower cause-specific hazards for kidney graft failure and return to dialysis at one year (0.55; 0.35-0.87) and five years (0.73; 0.53-0.99) post-transplant. Allocation based on HLA-DR matching resulted in longer cold ischemia (mean difference 1.00 hours; 95% confidence interval: 0.32-1.68) and kidney offers with a significantly shorter median dialysis vintage of 2.4 versus 4.1 yrs. in ESP without matching. Thus, our allocation based on HLA-DR matching improved five-year patient and kidney allograft survival. Hence, our paired allocation study suggests a superior outcome of HLA-DR matching in the context of old-for-old kidney transplantation.
CRIS-Team Scopus Importer:2023-08-11
Keywords: allocation; Eurotransplant Senior Program; histocompatibility; HLA-DR matching; kidney transplantation; old-for-old allocation

A PHD inhibitor prevents changes in the phosphoproteome and capillary rarefaction by CsA: treatment option for CKD? - Schley, Gunnar; Goppelt-Strübe, Margarete (Kidney International, 2022)
Labes et al. analyze the phosphoproteome in a mouse model of chronic cyclosporine A nephrotoxicity and detect significant changes in the angiogenic pathway. Furthermore, they observe reduced hemoglobin levels and capillary rarefaction in the kidney. The authors show that coadministration of the hypoxia-inducible factor prolyl hydroxylase inhibitor daprodustat almost completely prevents changes of the phosphoproteome and capillary rarefaction, suggesting that prolyl hydroxylase domain enzyme inhibitors may preserve microvasculature of the kidney, which is commonly impaired in chronic kidney disease.
CRIS-Team Scopus Importer:2022-10-07

Apolipoprotein A-IV concentrations and clinical outcomes in a large chronic kidney disease cohort: Results from the GCKD study - Schwaiger, Johannes P.; Kollerits, Barbara; Steinbrenner, Inga; Weissensteiner, Hansi; Schoenherr, Sebastian; Forer, Lukas; Kotsis, Fruzsina; Lamina, Claudia; Schneider, Markus; Schultheiss, Ulla T.; Wanner, Christoph; Koettgen, Anna; et al. (Journal of Internal Medicine, 2022)
Background Chronic kidney disease (CKD) represents a chronic proinflammatory state and is associated with very high cardiovascular risk. Apolipoprotein A-IV (apoA-IV) has antiatherogenic, antioxidative, anti-inflammatory and antithrombotic properties and levels increase significantly during the course of CKD. Objectives We aimed to investigate the association between apoA-IV and all-cause mortality and cardiovascular outcomes in the German Chronic Kidney Disease study. Methods This was a prospective cohort study including 5141 Caucasian patients with available apoA-IV measurements and CKD. The majority of the patients had an estimated glomerular filtration rate (eGFR) of 30-60 ml/min/1.73m(2) or an eGFR >60 ml/min/1.73m(2) in the presence of overt proteinuria. Median follow-up was 6.5 years. The association of apoA-IV with comorbidities at baseline and endpoints during follow-up was modelled adjusting for major confounders. Results Mean apoA-IV concentrations of the entire cohort were 28.9 +/- 9.8 mg/dl. Patients in the highest apoA-IV quartile had the lowest high-sensitivity C-reactive protein values despite the highest prevalence of diabetes, albuminuria and the lowest eGFR. Each 10 mg/dl higher apoA-IV translated into lower odds of prevalent cardiovascular disease (1289 cases, odds ratio = 0.80, 95% confidence interval [CI] 0.72-0.86, p = 0.0000003). During follow-up, each 10 mg/dl higher apoA-IV was significantly associated with a lower risk for all-cause mortality (600 cases, hazard ratio [HR] = 0.81, 95% CI 0.73-0.89, p = 0.00004), incident major adverse cardiovascular events (506 cases, HR = 0.88, 95% CI 0.79-0.99, p = 0.03) and death or hospitalizations due to heart failure (346 cases, HR = 0.84, 95% CI 0.73-0.96, p = 0.01). Conclusions These data support a link between elevated apoA-IV concentrations and reduced inflammation in moderate CKD. ApoA-IV appears to be an independent risk marker for reduced all-cause mortality, cardiovascular events and heart failure in a large cohort of patients with CKD.
CRIS-Team WoS Importer:2022-01-14

APOLIPOPROTEIN A-IV CONCENTRATIONS AND CLINICAL OUTCOMES IN CHRONIC KIDNEY DISEASE PATIENTS: RESULTS FROM THE GERMAN CHRONIC KIDNEY DISEASE (GCKD) STUDY - Schwaiger, J. P.; Kollerits, B.; Steinbrenner, I.; Weissensteiner, H.; Schoenherr, S.; Forer, L.; Kotsis, F.; Schneider, Markus; Schultheiss, U. T.; Wanner, C.; Koettgen, A.; Eckardt, Kai-Uwe; et al. (ATHEROSCLEROSIS, 2021)
CRIS-Team WoS Importer:2021-09-24

A polygenic score for reduced kidney function and adverse outcomes in a cohort with chronic kidney disease - Steinbrenner, Inga; Yu, Zhi; Jin, Jin; Schultheiss, Ulla T.; Kotsis, Fruzsina; Grams, Morgan E.; Coresh, Josef; Wuttke, Matthias; Kronenberg, Florian; Eckardt, Kai-Uwe; Chatterjee, Nilanjan; Sekula, Peggy; et al. (Kidney International, 2023)
CRIS-Team Scopus Importer:2023-01-20
Keywords: chronic kidney disease; kidney function; polygenic score

APPLICATION OF A CENTRAL ILIAC ARTERIOVENOUS COUPLER DEVICE IN SEVERE TREATMENT-RESISTANT ARTERIAL HYPERTENSION: A FOUR-YEAR FOLLOW-UP - Jung, Susan; Ott, Christian; Karg, M.; Bosch, A.; Schmid, M.; Schlundt, Christian; Achenbach, Stephan; Schmieder, Roland (2018)
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Application of a central iliac arteriovenous coupler device in severe treatment-resistant hypertension: a 3.5-year follow-up - Jung, Susanne; Ott, Christian; Karg, Marina V.; Bosch, Agnes; Schmid, Michael; Schlundt, Christian; Achenbach, Stephan; Schmieder, Roland (Journal of Hypertension, 2018)
OBJECTIVE: In patients with resistant hypertension, percutaneous placement of an iliac arteriovenous coupler device leads to a reduction of blood pressure (BP) via decreased total vascular resistance and improved arterial compliance. However, long-term efficacy and safety need to be further explored. We report on the first case of 3.5-year follow-up in a patient who underwent implantation of an iliac arteriovenous coupler device. RESULTS: A patient with resistant hypertension was admitted to hospital. Despite treatment with six anti-hypertensive drugs, his BP was poorly controlled. Previously, he had undergone renal denervation, which did not cause a significant BP decrease. Therefore, an arteriovenous coupler device was implanted, leading to an immediate and significant BP decrease. The patient was discharged with an office BP of 122/71 mmHg. After 3 months, there was a sustained BP decrease (-14/9 mmHg), whereas later, it was fluctuant (office BP: 147-173/85-95 mmHg, ABPM: 153-166/81-94 mmHg) probably due to medication non-adherence confirmed by a urinary toxicological screening test. Follow-up right heart catheterization showed changes in hemodynamic parameters related to volume congestion, which were accompanied by progressive dyspnea and weight gain. This was controlled by an optimized diuretic therapy. Additionally, an invasive closure maneuver was performed, leading to an immediate BP increase after closure and a similar decrease after re-opening of the anastomosis, verifying its proper long-term function. CONCLUSION: The implantation of an iliac arteriovenous coupler device appears to be a promising and effective method to decrease BP and therefore reduce cardiovascular risk in patients with severe, treatment-resistant hypertension.
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Application of Acoustic Radiation Force Impulse (ARFI) Elastography in Imaging of Delayed Onset Muscle Soreness (DOMS): A Comparative Analysis With 3T MRI - Hotfiel, Thilo; Kellermann, Marion; Swoboda, Bernd; Wildner, Dane; Golditz, Tobias; Grim, Casper; Raithel, Martin; Uder, Michael; Heiß, Rafael (Journal of Sport Rehabilitation, 2017)
DOMS is one of the most common reasons for impaired muscle performance in sports and is associated with reduced muscle strength and frequently observed both in professional and recreational athletes.To emphasize the diagnostic value of Acoustic Radiation Force Impulse (ARFI) in imaging of Delayed Onset Muscle Soreness by comparing findings to high-resolution 3T MRI T2 weighted sequences.Case series.Laboratory environment.Fifteen healthy students (7 female, 8 male, age 24 ± 4 years, height 178 ± 10 cm, body weight 67 ± 12 kg).ARFI values, represented as shear wave velocities (SWV) of the gastrocnemius muscle (GM) and soleus muscle (SM), as well as conventional ultrasound, high-resolution 3T MRI, creatine kinase activity, extension range of the ankle joint, calf circumference and muscle soreness were assessed before (baseline) and 60 hours after (post-intervention, PI) a standardized eccentric exercise.ARFI SWV values of the GM revealed a statistically significant decrease of 19.1% between baseline (2.2 ± 0.26 m/s) and PI (1.78 ± 0.24 m/s); p=0.008. At follow-up, the MRI investigations showed intramuscular oedema for the GM in all participants corresponding to a significant raise in T2 signal intensity (p=0.001) and in T2-time values (p=0.004).ARFI elastography seems to be an additional sensitive diagnostic modality in the diagnostic work up of DOMS. Intramuscular SWV could represent an additional imaging marker for the assessment and monitoring of ultrastructural muscle injuries and therefore be helpful for individual training composition in elite sports.
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Application of win ratio methodology in the Global SYMPLICITY Registry for patients with atrial fibrillation or obstructive sleep apnea - Mahfoud, F.; Mancia, G.; Ukena, C.; Schmieder, Roland; Narkiewicz, K.; Ruilope, L.; Schlaich, M.; Williams, B.; Fahy, M.; Boehm, M. (EUROPEAN HEART JOURNAL, 2021)
CRIS-Team WoS Importer:2021-12-10

A prediction model for the decline in renal function in people with type 2 diabetes mellitus: study protocol. - Gregorich, Mariella; Heinzel, Andreas; Kammer, Michael; Meiselbach, Heike; Böger, Carsten A.; Mayer, Gert; Heinze, Georg; Oberbauer, Rainer; Eckardt, Kai-Uwe (Diagnostic and Prognostic Research, 2021)
BACKGROUND: Chronic kidney disease (CKD) is a well-established complication in people with diabetes mellitus. Roughly one quarter of prevalent patients with diabetes exhibit a CKD stage of 3 or higher and the individual course of progression is highly variable. Therefore, there is a clear need to identify patients at high risk for fast progression and the implementation of preventative strategies. Existing prediction models of renal function decline, however, aim to assess the risk by artificially grouped patients prior to model building into risk strata defined by the categorization of the least-squares slope through the longitudinally fluctuating eGFR values, resulting in a loss of predictive precision and accuracy. METHODS: This study protocol describes the development and validation of a prediction model for the longitudinal progression of renal function decline in Caucasian patients with type 2 diabetes mellitus (DM2). For development and internal-external validation, two prospective multicenter observational studies will be used (PROVALID and GCKD). The estimated glomerular filtration rate (eGFR) obtained at baseline and at all planned follow-up visits will be the longitudinal outcome. Demographics, clinical information and laboratory measurements available at a baseline visit will be used as predictors in addition to random country-specific intercepts to account for the clustered data. A multivariable mixed-effects model including the main effects of the clinical variables and their interactions with time will be fitted. In application, this model can be used to obtain personalized predictions of an eGFR trajectory conditional on baseline eGFR values. The final model will then undergo external validation using a third prospective cohort (DIACORE). The final prediction model will be made publicly available through the implementation of an R shiny web application. DISCUSSION: Our proposed state-of-the-art methodology will be developed using multiple multicentre study cohorts of people with DM2 in various CKD stages at baseline, who have received modern therapeutic treatment strategies of diabetic kidney disease in contrast to previous models. Hence, we anticipate that the multivariable prediction model will aid as an additional informative tool to determine the patient-specific progression of renal function and provide a useful guide to early on identify individuals with DM2 at high risk for rapid progression.
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Keywords: Prediction modeling; Type 2 diabetes mellitus; Chronic kidney disease; Mixed model; Prognosis; Risk calculator

A randomised study of the impact of the SGLT2 inhibitor dapagliflozin on microvascular and macrovascular circulation - Ott, Christian; Jumar, Agnes; Striepe, Kristina; Friedrich, Stefanie; Karg, Margarete; Bramlage, Peter; Schmieder, Roland (Cardiovascular Diabetology, 2017)
The sodium-glucose cotransporter 2 inhibitor, dapagliflozin, has been shown to improve diabetic control and reduce blood pressure in patients with type 2 diabetes mellitus. Its effects on micro- and macrovascular structure and function have not yet been reported.This was a prospective, single-centre, placebo-controlled, double-blind, randomised crossover phase IIIb study conducted between March 2014 and February 2015. After a 4-week run-in/washout phase, patients (N = 59) received 6 weeks of either dapagliflozin 10 mg or placebo once daily. They then underwent a 1-week washout before crossing over to the other treatment. Changes in retinal capillary flow (RCF) and arteriole remodelling were evaluated using scanning laser Doppler flowmetry, while micro- and macrovascular parameters in the systemic circulation were assessed using pulse wave analysis.Six weeks of dapagliflozin treatment resulted in improvements in diabetes control, including blood glucose and insulin resistance, and reduced office and 24-h ambulatory blood pressure values. RCF decreased from 324 AU at baseline to 308 AU after treatment with dapagliflozin (p = 0.028), while there was little difference after the placebo (318 AU; p = 0.334). Furthermore, the arteriole remodelling that was seen after the placebo phase was not evident after the dapagliflozin phase. Central systolic and diastolic blood pressure values were significantly lower after 6 weeks of dapagliflozin, by 3.0 and 2.2 mmHg, respectively (p = 0.035 and 0.020, respectively vs. baseline).Six weeks of dapagliflozin treatment resulted in numerous beneficial effects. In addition to achieving superior diabetes control and blood pressure, parameters associated with the early stages of vascular remodelling were also improved. Trial registration http://www.clinicaltrials.gov (NCT02383238).
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A role for the alpha-8 integrin chain (itga8) in glomerular homeostasis of the kidney. - Marek, Ines; Hilgers, Karl Friedrich; Rascher, Wolfgang; Wölfle, Joachim; Hartner, Andrea (Molecular and Cellular Pediatrics, 2020)
Glomerulonephritis results in a dysregulation of glomerular cells and may end up in chronic alterations and subsequent loss of renal function. Therefore, understanding mechanisms, which contribute to maintain glomerular integrity, is a pivotal prerequisite for therapeutic interventions. The alpha-8 integrin chain seems to be an important player to maintain glomerular homeostasis by conferring mechanical stability and functional support for the renal capillary tuft.
EVALuna2:383426
Keywords: itga8; Glomerular homeostasis; Mesangial cells; Glomerulonephritis

Arrythmias and heart rate increase in the LEADER trial and relation to risk of cardiovascular events - Husain, M.; Bain, S. C.; Mann, Johannes; Nauck, M.; Poulter, N.; Baeres, F. M. M.; Goldman, B.; Thomsen, A. Bloch; Marso, S. (EUROPEAN HEART JOURNAL, 2018)
CRIS-Team WoS Importer:2019-03-15

Arterial Hyper- and Hypotension associated with psychiatric medications: a risk assessment based on the summaries of product characteristics (SmPCs) - Freudenmann, Roland W.; Freudenmann, Ninja; Zurowski, Bartosz; Schönfeldt-Lecuona, Carlos; Maier, Ludwig; Schmieder, Roland; Lange-Asschenfeldt, Christian; Gahr, Maximilian (Deutsche Medizinische Wochenschrift, 2017)
Introduction Psychiatric medications are well-known triggers of clinically relevant blood pressure changes. Therefore, we aimed at creating ranking lists for their risk of causing arterial hyper- or hypotension. Methods We analyzed 784 Summaries of Product characteristics (SmPCs, available online from "Rote Liste" or "Gelbe Liste" websites) from 105 psychiatric medications registered in adult psychiatry in Germany and extracted the standardized reported risks of increasing or decreasing arterial blood pressure. Results According to the SmPCs, atomoxetine had the highest risk of arterial hypertension ("very frequent", > 10 %), and another 15 substances followed in the category "frequent" (> 1 %): duloxetine, milnacipran, venlafaxine, bupropion, citalopram, tranylcypromine (particularly with certain diets), reboxetine, methylphenidate, clozapine, paliperidone, risperidone, buprenorphine+naloxone, memantine, galantamine, and rivastigmine. Conversely, 7 substances, namely amitriptyline, tranylcypromine, chlorprothixen, flupentixol, levomepromazine, olanzapine and trimipramine had the highest reported risk of low blood pressure ("very frequent"), and another 25 substances had the risk "frequent". No risk of hypertension or hypotension was documented for many other substances. Incidentally, we observed that the reported effects on blood pressure for single substances (e. g. citalopram) markedly differed between the SmPCs from different manufacturers, rendering a clear risk assessment impossible for many medications. Discussion According to the German SmPc, many psychiatric medications are associated with the risk of arterial hypertension and, even more so, hypotension. We hardly observed substance group effects, such as high blood pressure with noradrenergic antidepressants. Commonly used tables summarising secondary causes of arterial hypertension should be revised in terms of psychiatric medications. Our rank orders of risk may aid choosing the best psychiatric medications in patients with known hypertension or at risk for syncope, as well as when blood pressure changes occur under psychiatric pharmacotherapy. A definitive risk assessment however requires controlled studies.
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Arteriovenous fistula thrombosis is associated with increased all-cause and cardiovascular mortar in haemodialysis patients from the AURORA trial - Girerd, Sophie; Girerd, Nicolas; Frimat, Luc; Holdaas, Hallvard; Jardine, Alan G.; Schmieder, Roland; Fellstrom, Bengt; Settembre, Nicla; Malikov, Sergei; Rossignol, Patrick; Zannad, Faiez (Clinical Kidney Journal, 2020)
Background. The impact of arteriovenous fistula (AVF) or graft (AVG) thrombosis on mortality has been sparsely studied. This study investigated the association between AVF/AVG thrombosis and all-cause and cardiovascular mortality.
CRIS-Team WoS Importer:2020-05-02

Assessment of Hypertension-Mediated Organ Damage - OTT, Christian; Schmieder, Roland (Elsevier, 2023)
The individual impact of arterial hypertension on several hypertension-mediated organ damages (HMODs) varies widely. This chapter mainly addresses HMODs with arterial hypertension being the most important attributable risk factor. HMOD can be detected in an early subclinical (asymptomatic) stage, but once HMOD, even intermediate, has developed, these conditions are by far overwriting any risk prediction from the cardiovascular (CV) risk factor scores. Hence, the specific impact of HMOD is particular in (younger and middle-aged) patients with a probable reclassification of their individual risk estimation. A variety of techniques are available nowadays to diagnose HMOD of the brain, heart, eyes, kidneys, and vasculature in different organs, but with differences in sensitivity and specificity as well as applicability is limited depending on the availability of the various techniques and the reimbursement strategy of the national health care systems. The clinical importance of HMOD is also underlined by the fact that regression of HMOD is clinically a useful tool for evaluation of the efficacy of (more aggressive and immediate) antihypertensive treatment in individual patients. Therefore this chapter also emphasizes the consequences of HMOD regression by antihypertensive treatment, and attempts to establish whether or not changes of HMOD have related prognostic significance.
CRIS-Team Scopus Importer:2023-11-24
Keywords: blood pressure; brain; eye; heart; hypertension-mediated organ damage (HMOD); kidney; vasculature

Assessment of Plasma Oxalate Concentration in Patients With CKD - Pfau, Anja; Wytopil, Monika; Chauhan, Kinsuk; Reichel, Martin; Coca, Steve G.; Aronson, Peter S.; Eckardt, Kai-Uwe; Knauf, Felix (Kidney International Reports, 2020)
Introduction: Alterations in oxalate homeostasis are associated with kidney stone disease and progression of chronic kidney disease (CKD). However, accurate measurement of plasma oxalate (POx) concentrations in large patient cohorts is challenging as prompt acidification of samples has been deemed necessary. In the present study, we investigated the effects of variations in sample handling on POx results and examined an alternative strategy to the established preanalytical procedures. Methods: The effect of storage time at room temperature (RT) and maintenance of samples at −80°C was tested. POx was measured in 1826 patients enrolled in the German Chronic Kidney Disease (GCKD) study, an ongoing multicenter, prospective, observational cohort study. Results: We demonstrate that POx concentrations increased rapidly when samples were maintained at RT. This was most relevant for POx <10 μM, as concentrations more than doubled within a few hours. Immediate freezing on dry ice and storage at −80°C provided stable results and allowed postponement of acidification for >1 year. In the patients of the lowest estimated glomerular filtration rate (eGFR) quartile, median POx was 2.7 μM (interquartile range [IQR] <2.0–4.2) with a median eGFR of 25.1 ml/min per 1.73 m2 (IQR 20.3–28.1). Conclusion: We conclude that immediate freezing and maintenance of plasma samples at -80°C facilitates the sample collection process and allows accurate POx assessment in large cohorts. The present study may serve as a reference for sample handling to assess POx in clinical trials and to determine its role in CKD progression.
CRIS-Team Scopus Importer:2020-11-20
Keywords: chronic kidney disease; clinical trials; P; P; preanalytical conditions

Assessment of Use and Preferences Regarding Internet-Based Health Care Delivery: Cross-Sectional Questionnaire Study - Paslakis, Georgios; Fischer-Jacobs, Josefine; Pape, Lars; Schiffer, Mario; Gertges, Raoul; Tegtbur, Uwe; Zimmermann, Tanja; Noehre, Mariel; De Zwaan, Martina (Journal of Medical Internet Research, 2019)
Background: There has been an incremental increase in the use of technology in health care delivery. Feasibility, acceptability, and efficacy of interventions based on internet technologies are supported by a growing body of evidence.
CRIS-Team WoS Importer:2019-05-24

Association Between Dietary Patterns and Kidney Function in Patients With Chronic Kidney Disease: A Cross-Sectional Analysis of the German Chronic Kidney Disease Study - Heindel, Judith; Baid-Agrawal, Seema; Rebholz, Casey M.; Nadal, Jennifer; Schmid, Matthias; Schaeffner, Elke; Schneider, Markus; Meiselbach, Heike; Kaesler, Nadine; Bergmann, Manuela; Ernst, Sabine; Krane, Vera; et al. (Journal of Renal Nutrition, 2019)
Objective: In the general population, “healthy” dietary patterns are associated with improved health outcomes, but data on associations between observance of specific dietary patterns and kidney function in patients with chronic kidney disease (CKD) are sparse. Methods: Dietary intake was evaluated using food frequency questionnaires in patients with moderately severe CKD under nephrology care enrolled into the observational multicenter German CKD study. The Dietary Approaches to Stop Hypertension (DASH) diet score, Mediterranean diet score, and German Food Pyramid Index (GFPI) were calculated and their association with estimated glomerular filtration rate (eGFR) and albuminuria was assessed by multivariable linear regression analysis, adjusted for gender, age, body mass index, energy intake, smoking status, alcohol intake, education, high-density lipoprotein-cholesterol (HDL- cholesterol), low-density lipoprotein-cholesterol (LDL-cholesterol), hypertension, and diabetes mellitus. Results: A total of 2,813 patients (41% women; age 60.1 ± 11.6 years) were included in the analysis. High DASH diet score and GFPI were associated with lower systolic blood pressure and lower intake of antihypertensive medication, higher HDL, and lower uric acid levels. Mediterranean-style diet was associated with lower prevalence of diabetes mellitus. Higher DASH and Mediterranean diet scores were associated with higher eGFR (β-coefficient = 1.226, P <.001; β-coefficient = 0.932, P =.007, respectively). In contrast, GFPI was not associated with eGFR. For the individual components of the dietary patterns, higher intake of nuts and legumes, cereals, fish, and polyunsaturated fats was associated with higher eGFR and higher intake of dairy, composed of low- and whole-fat dairy, was associated with lower eGFR. No association was found between dietary patterns and albuminuria. Conclusion: Higher observance of the DASH or Mediterranean diet, but not German food pyramid recommendations, was associated with higher eGFR among patients with CKD. Improving dietary habits may offer an opportunity to better control comorbidities and kidney function decline in patients with CKD.
CRIS-Team Scopus Importer:2019-12-27

Association between exercise frequency with renal and cardiovascular outcomes in diabetic and non-diabetic individuals at high cardiovascular risk - Boehm, Michael; Schumacher, Helmut; Werner, Christian; Teo, Koon K.; Lonn, Eva M.; Mahfoud, Felix; Speer, Thimoteus; Mancia, Giuseppe; Redon, Josep; Schmieder, Roland; Sliwa, Karen; Marx, Nikolaus; et al. (Cardiovascular Diabetology, 2022)
Background: Guidelines recommend physical activity to reduce cardiovascular (CV) events. The association between physical activity and progression of chronic kidney disease (CKD) with and without diabetes is unknown. We assessed the association of self-reported physical activity with renal and CV outcomes in high-risk patients aged ≥ 55 years over a median follow-up of 56 months in post-hoc analysis of a previously randomized trial program. Methods: Analyses were done with Cox regression analysis, mixed models for repeated measures, ANOVA and χ2-test. 31,312 patients, among them 19,664 with and 11,648 without diabetes were analyzed. Results: Physical activity was inversely associated with renal outcomes (doubling of creatinine, end-stage kidney disease (ESRD)) and CV outcomes (CV death, myocardial infarction, stroke, heart failure hospitalization). Moderate activity (at least 2 times/week to every day) was associated with lower risk of renal outcomes and lower incidence of new albuminuria (p < 0.0001 for both) compared to lower exercise levels. Similar results were observed for those with and without diabetes without interaction for renal outcomes (p = 0.097–0.27). Physical activity was associated with reduced eGFR decline with a moderate association between activity and diabetes status (p = 0.05). Conclusions: Moderate physical activity was associated with improved kidney outcomes with a threshold at two sessions per week. The association of physical activity with renal outcomes did not meaningfully differ with or without diabetes but absolute benefit of activity was even greater in people with diabetes. Thus, risks were similar between those with diabetes undertaking high physical activity and those without diabetes but low physical activity. Clinical trial registration: http://clinicaltrials.gov.uniqueidentifier:NCT00153101.
CRIS-Team Scopus Importer:2022-01-28
Keywords: Cardiovascular outcomes; Physical activity; Renal outcomes; Secondary prevention

Association of a coding polymorphism in Fc gamma receptor 2A and graft survival in re-transplant candidates - Fuernrohr, Barbara G.; Weiss, Katrin M.; Harre, Ulrike; Wiesener, Michael S.; Spriewald, Bernd M.; Arnold, Martin (Human Immunology, 2015)
The family of Fc gamma receptors (Fc?Rs) is involved in mediating immunological effector functions. Fc?Rs are differentially expressed on immune cells and can act either activating or inhibitory, with Fc?R2A belonging to the first group. The polymorphism H131R (rs1801274) in FCGR2A has been associated with acute rejection and can shift the overall balance between activating and inhibitory Fc?Rs. Anti-HLA allo-antibodies in transplant recipients have been identified as risk factor for organ survival after transplantation. In this study we genotyped FCGR2A H131R in 200 patients who had undergone kidney transplantation and experienced loss of graft function. FCGR2A polymorphism was related to graft survival and anti-HLA antibodies. Graft survival was calculated as the time interval between transplantation and return to chronic dialysis after transplantation. The gene frequency of FCGR2A R/R131 was found significantly more often in patients with earlier (?60months) compared to patients with later (>60months) graft failure. Overall patients homozygous for R/R131 had a significantly shorter graft survival, compared to H/H131 or H/R131 which is even more pronounced, when anti-HLA antibodies were present. These data suggest, that FCGR2A polymorphisms constitute a risk factor for graft loss following kidney transplantation and that this effect is related to anti-HLA antibodie
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Association of donor hypertension and recipient renal function in living donor kidney transplantation: A single-center retrospective study - Dienemann, Thomas; Schellenberg, Jana; Heller, Katharina; Daniel, Christoph; Amann, Kerstin Ute; Hilgers, Karl Friedrich; Schiffer, Mario; Weidemann, Alexander (Clinical Transplantation, 2019)
Transplant centers now accept living donors with well-controlled hypertension. Little is known whether hypertension in living donors affects recipient's kidney function. We aimed to examine potential differences in kidneys from hypertensive donors compared to normotensive donors with respect to renal function over 36 months and histologic findings at transplantation (T0) and 12 months after transplantation (T1). Retrospective single-center analysis of 174 living donor-recipient pairs (age > 18; transplantation date 1/2008-3/2016). Hypertension in donors was defined as being on antihypertensive medication. All biopsies were assessed by the same blinded, experienced renal pathologist. Biopsies were scored for glomerulosclerosis, IFTA, and arteriosclerosis. Regression models were used to examine the relationship of donor hypertension with renal function and histologic changes. Hypertensive donors were significantly older than normotensive donors. Chronic changes such as tubular atrophy and atherosclerosis were more evident in kidneys from hypertensive donors at T0 as well as T1. Donor hypertension was independently associated with histologic changes at T0 and T1 but not with renal function over the follow period. Despite more pronounced histologic changes in kidneys from hypertensive living donors, these grafts exhibited a similar functional outcome. However, they subsequently might be at a greater risk and warrant thorough follow-up care.
CRIS-Team WoS Importer:2019-09-27

Association of mineral and bone biomarkers with adverse cardiovascular outcomes and mortality in the German Chronic Kidney Disease (GCKD) cohort - Reimer, Katharina Charlotte; Nadal, Jennifer; Meiselbach, Heike; Schmid, Matthias; Schultheiss, Ulla T.; Kotsis, Fruzsina; Stockmann, Helena; Friedrich, Nele; Nauck, Matthias; Krane, Vera; Eckardt, Kai-Uwe; Schneider, Markus; et al. (Bone Research, 2023)
Mineral and bone disorder (MBD) in chronic kidney disease (CKD) is tightly linked to cardiovascular disease (CVD). In this study, we aimed to compare the prognostic value of nine MBD biomarkers to determine those associated best with adverse cardiovascular (CV) outcomes and mortality. In 5 217 participants of the German CKD (GCKD) study enrolled with an estimated glomerular filtration rate (eGFR) between 30–60 mL·min−1 per 1.73 m2 or overt proteinuria, serum osteoprotegerin (OPG), C-terminal fibroblast growth factor-23 (FGF23), intact parathyroid hormone (iPTH), bone alkaline phosphatase (BAP), cross-linked C-telopeptide of type 1 collagen (CTX1), procollagen 1 intact N-terminal propeptide (P1NP), phosphate, calcium, and 25-OH vitamin D were measured at baseline. Participants with missing values among these parameters (n = 971) were excluded, leaving a total of 4 246 participants for analysis. During a median follow-up of 6.5 years, 387 non-CV deaths, 173 CV deaths, 645 nonfatal major adverse CV events (MACEs) and 368 hospitalizations for congestive heart failure (CHF) were observed. OPG and FGF23 were associated with all outcomes, with the highest hazard ratios (HRs) for OPG. In the final Cox regression model, adjusted for CV risk factors, including kidney function and all other investigated biomarkers, each standard deviation increase in OPG was associated with non-CV death (HR 1.76, 95% CI: 1.35–2.30), CV death (HR 2.18, 95% CI: 1.50–3.16), MACE (HR 1.38, 95% CI: 1.12–1.71) and hospitalization for CHF (HR 2.05, 95% CI: 1.56–2.69). Out of the nine biomarkers examined, stratification based on serum OPG best identified the CKD patients who were at the highest risk for any adverse CV outcome and mortality.
CRIS-Team Scopus Importer:2023-11-10

Association of mitochondrial DNA copy number with metabolic syndrome and type 2 diabetes in 14 176 individuals - Fazzini, F.; Lamina, C.; Raftopoulou, Athina; Koller, A.; Fuchsberger, C.; Pattaro, C.; Del Greco, F. M.; Doettelmayer, P.; Fendt, L.; Fritz, J.; Meiselbach, Heike; Schoenherr, S.; et al. (Journal of Internal Medicine, 2021)
Background Mitochondria play an important role in cellular metabolism, and their dysfunction is postulated to be involved in metabolic disturbances. Mitochondrial DNA is present in multiple copies per cell. The quantification of mitochondrial DNA copy number (mtDNA-CN) might be used to assess mitochondrial dysfunction.
CRIS-Team WoS Importer:2021-03-12

Association of Noise Annoyance with Measured Renal Hemodynamic Changes - Kannenkeril, Dennis; Jung, Susanne; Ott, Christian; Striepe, Kristina; Kolwelter, Julie; Schmieder, Roland; Bosch, Agnes (Kidney & Blood Pressure Research, 2021)
Background: Chronic mental stress is recognized as a modifiable risk factor for cardiovascular disease. The aim of this study was to demonstrate that noise annoyance-induced stress is associated with changes in renal hemodynamics. Methods: Renal hemodynamic parameters were measured using steady-state input clearance with infusion of para-aminohippuric acid and inulin in individuals with normal, high normal, and elevated blood pressure. All individuals ranked subjective annoyance due to noise in everyday life on a 7-grade Likert scale. The median of all rankings was used as a cutoff point to divide the group into noise-annoyed and non-noise-annoyed individuals. Different renal hemodynamic parameters were calculated based on the Gomez equation. Results: Noise-annoyed individuals (n = 58) showed lower renal plasma flow (599 +/- 106 vs. 663 +/- 124 mL/min, p = 0.009), lower renal blood flow (1,068 +/- 203 vs. 1,172 +/- 225 mL/min, p = 0.047), higher filtration fraction (22.7 +/- 3.3 vs. 21.3 +/- 3.0, p = 0.012), higher renal vascular resistance (88.9 +/- 25.6 vs. 75.8 +/- 22.9 mm Hg/[mL/min], p = 0.002), and higher resistance of afferent arteriole (2,439.5 +/- 1,253.4 vs. 1,849.9 +/- 1,242.0 dyn s(-1) cm(-5), p = 0.001) compared to non-noise-annoyed individuals (n = 55). There was no difference in measured glomerular filtration rate (133 +/- 11.8 vs. 138 +/- 15 mL/min, p = 0.181), resistance of efferent arteriole (2,419.4 +/- 472.2 vs. 2,245.8 +/- 370.3 dyn s(-1) cm(-5), p = 0.060), and intraglomerular pressure (64.0 +/- 3.1 vs. 64.6 +/- 3.5 mm Hg, p = 0.298) between the groups. After adjusting for age, renal plasma flow, renal blood flow, and renal vascular resistance remained significantly different between the groups, with a trend in increased afferent arteriolar resistance and filtration fraction. Conclusion: In this study, noise annoyance was associated with reduced renal perfusion attributed to increased renal vascular resistance predominantly at the afferent site. Long-term consequences of this renal hemodynamic pattern due to noise annoyance need to be investigated.
CRIS-Team WoS Importer:2021-05-14

Association of osteopontin with kidney function and kidney failure in chronic kidney disease patients: the GCKD study - Steinbrenner, Inga; Sekula, Peggy; Kotsis, Fruzsina; Von Cube, Maja; Cheng, Yurong; Nadal, Jennifer; Schmid, Matthias; Schneider, Markus; Krane, Vera; Nauck, Matthias; Eckardt, Kai-Uwe; Schultheiss, Ulla T. (Nephrology Dialysis Transplantation, 2022)
Background Osteopontin (OPN), synthesized in the thick ascending limb of Henle's loop and in the distal tubule, is involved in the pathogenesis of kidney fibrosis, a hallmark of kidney failure (KF). In a cohort of chronic kidney disease (CKD) patients, we evaluated OPN's association with kidney markers and KF. Methods OPN was measured from baseline serum samples of German Chronic Kidney Disease study participants. Cross-sectional regression models for estimated glomerular filtration rate (eGFR) and urinary albumin-to-creatinine ratio (UACR) as well as Cox regression models for all-cause mortality and KF were evaluated to estimate the OPN effect. Additionally, the predictive ability of OPN and time-dependent population-attributable fraction were evaluated. Results Over a median follow-up of 6.5 years, 471 KF events and 629 deaths occurred among 4950 CKD patients. One-unit higher log(OPN) was associated with 5.5 mL/min/1.73 m(2) lower eGFR [95% confidence interval (95% CI) -6.4 to -4.6] and 1% change in OPN with 0.7% higher UACR (estimated effect 0.7, 95% CI 0.6-0.8). Moreover, higher OPN levels were associated with a higher risk of KF [hazard ratio (HR) 1.4, 95% CI 1.2-1.7] and all-cause mortality (HR 1.5, 95% CI 1.3-1.8). After 6 years, 31% of the KF events could be attributed to higher OPN levels (95% CI 3%-56%). Conclusions In this study, higher OPN levels were associated with kidney function markers worsening and a higher risk for adverse outcomes. A larger proportion of KF could be attributed to higher OPN levels, warranting further research on OPN with regards to its role in CKD progression and possible treatment options.
CRIS-Team WoS Importer:2022-07-22

ASSOCIATION OF SERUM UROMODULIN WITH DEATH, CARDIOVASCULAR AND RENAL EVENTS: RESULTS FROM THE GERMAN CHRONIC KIDNEY DISEASE (GCKD) STUDY - Steubl, Dominik; Schneider, Markus; Meiselbach, Heike; Nadal, Jennifer; Saritas, Turgay; Krane, Vera; Sommerer, Claudia; Baid-Agrawal, Seema; Koettgen, Anna; Eckardt, Kai-Uwe; Scherberich, Juergen (NEPHROLOGY DIALYSIS TRANSPLANTATION, 2019)
CRIS-Team WoS Importer:2019-11-26

Association of Serum Uromodulin with Death, Cardiovascular Events, and Kidney Failure in CKD - Steubl, Dominik; Schneider, Markus; Meiselbach, Heike; Nadal, Jennifer; Schmid, Matthias C.; Saritas, Turgay; Krane, Vera; Sommerer, Claudia; Baid-Agrawal, Seema; Voelkl, Jakob; Kotsis, Fruzsina; Köttgen, Anna; et al. (Clinical Journal of the American Society of Nephrology, 2020)
BACKGROUND AND OBJECTIVES: Uromodulin is exclusively produced by tubular epithelial cells and released into urine and serum. Higher serum uromodulin has been associated with lower risk for kidney failure in Chinese patients with CKD and with lower risk for mortality in the elderly and in patients undergoing coronary angiography. We hypothesized that lower serum uromodulin is associated with mortality, cardiovascular events, and kidney failure in white patients with CKD. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We measured serum uromodulin in 5143 participants enrolled in the German CKD (GCKD) study. The associations of baseline serum uromodulin with all-cause mortality, major adverse cardiovascular events (MACE; a composite of cardiovascular mortality, nonfatal myocardial infarction or stroke, or incident peripheral vascular disease), and kidney failure (dialysis or transplantation) were evaluated using multivariable Cox proportional hazard regression analyses in a cohort study design, adjusting for demographics, eGFR, albuminuria, cardiovascular risk factors, and medication. RESULTS: The mean age of participants was 60±12 years, 60% were male. Mean serum uromodulin concentration was 98±60 ng/ml, eGFR was 49±18 ml/min per 1.73 m2, and 78% had eGFR <60 ml/min per 1.73 m2. Participants in lower serum uromodulin quartiles had lower eGFR and higher albuminuria, prevalence of diabetes, hypertension, coronary artery disease, and more frequent history of stroke at baseline. During a follow-up of 4 years, 335 participants died, 417 developed MACE, and 229 developed kidney failure. In multivariable analysis, the highest serum uromodulin quartile was associated with lower hazard for mortality (hazard ratio [HR], 0.57; 95% CI, 0.38 to 0.87), MACE (HR, 0.63; 95% CI, 0.45 to 0.90), and kidney failure (HR, 0.24; 95% CI, 0.10 to 0.55) compared with the lowest quartile. CONCLUSIONS: Higher serum uromodulin is independently associated with lower risk for mortality, cardiovascular events, and kidney failure in white patients with CKD. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: Deutsches Register für Klinische Studien (DRKS; German national database of clinical studies), DRKS00003971.
CRIS-Team Scopus Importer:2020-05-26
Keywords: albuminuria; cardiovascular diseases; chronic; chronic kidney disease; confidence intervals; coronary angiography; coronary artery disease; diabetes mellitus; end-stage renal disease; epithelial cells; glomerular filtration rate; hypertension; myocardial infarction; peripheral vascular diseases; regression analysis; renal insufficiency; risk factors; stroke; Tamm–Horsfall protein; tubular function; uromodulin

Association of the metabolic syndrome with mortality and major adverse cardiac events: A large chronic kidney disease cohort - Pammer, Lorenz M.; Lamina, Claudia; Schultheiss, Ulla T.; Kotsis, Fruzsina; Kollerits, Barbara; Stockmann, Helena; Lipovsek, Jan; Meiselbach, Heike; Busch, Martin; Kronenberg, Florian; Eckardt, Kai-Uwe (Journal of Internal Medicine, 2021)
Background Metabolic syndrome with its key components insulin resistance, central obesity, dyslipidaemia, and hypertension is associated with a high risk for cardiovascular events and all-cause mortality in the general population. However, evidence that these findings apply to patients with chronic kidney disease (CKD) with moderately reduced estimated glomerular filtration rate and/or albuminuria is limited. Objectives We aimed to investigate the association between metabolic syndrome and its components with all-cause mortality and cardiovascular outcomes in CKD patients. Methods Prospective observation of a cohort of 5110 CKD patients from the German Chronic Kidney Disease study with 3284 (64.3%) of them having a metabolic syndrome at baseline. Results During the follow-up of 6.5 years, 605 patients died and 650 patients experienced major cardiovascular events. After extended data adjustment, patients with a metabolic syndrome had a higher risk for all-cause mortality (hazard ratio [HR] = 1.26, 95% confidence interval [CI]: 1.04-1.54) and cardiovascular events (HR = 1.48, 95% CI: 1.22-1.79). The risk increased steadily with a growing number of metabolic syndrome components (increased waist circumference, glucose, triglycerides, hypertension and decreased HDL cholesterol): HR per component = 1.09 (95% CI: 1.02-1.17) for all-cause mortality, and 1.23 (95% CI: 1.15-1.32) for cardiovascular events. This resulted in hazard ratios between 1.50 and 2.50 in the case of four or five components present. Analysis of individual components of metabolic syndrome showed that the glucose component led to the highest increase in risk for all-cause mortality (HR = 1.68, 95% CI: 1.38-2.03) and cardiovascular events (HR = 1.81, 95% CI: 1.51-2.18), followed by the HDL cholesterol and triglyceride components. Conclusions We observed a high prevalence of metabolic syndrome among patients with moderate CKD. Metabolic syndrome increases the risk for all-cause mortality and cardiovascular events. The glucose and lipid components seem to be the main drivers for the association with outcomes.
CRIS-Team WoS Importer:2021-08-13

Associations between genetic risk variants for kidney diseases and kidney disease etiology - Wunnenburger, Sebastian; Schultheiss, Ulla T.; Walz, Gerd; Hausknecht, Birgit; Ekici, Arif Bülent; Kronenberg, Florian; Eckardt, Kai-Uwe; Kottgen, Anna; Wuttke, Matthias (Scientific Reports, 2017)
Chronic kidney disease (CKD) is a global health problem with a genetic component. Genome-wide association studies have identified variants associated with specific CKD etiologies, but their genetic overlap has not been well studied. This study examined SNP associations across different CKD etiologies and CKD stages using data from 5,034 CKD patients of the German Chronic Kidney Disease study. In addition to confirming known associations, a systemic lupus erythematosus-associated risk variant at TNXB was also associated with CKD attributed to type 1 diabetes (p = 2.5 × 10(-)(7)), a membranous nephropathy-associated variant at HLA-DQA1 was also associated with CKD attributed to systemic lupus erythematosus (p = 5.9 × 10(-)(6)), and an IgA risk variant at HLA-DRB1 was associated with both CKD attributed to granulomatosis with polyangiitis (p = 2.0 × 10(-4)) and to type 1 diabetes (p = 4.6 × 10(-11)). Associations were independent of additional risk variants in the respective genetic regions. Evaluation of CKD stage showed a significant association of the UMOD risk variant, previously identified in population-based studies for association with kidney function, for advanced (stage >=G3b) compared to early-stage CKD (<=stage G2). Shared genetic associations across CKD etiologies and stages highlight the role of the immune response in CKD. Association studies with detailed information on CKD etiology can reveal shared genetic risk variants.
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Associations of urinary sodium excretion with cardiovascular events in individuals with and without hypertension: a pooled analysis of data from four studies - Mente, Andrew; O'Donnell, Martin; Rangarajan, Sumathy; Dagenais, Gilles; Lear, Scott; McQueen, Matthew; Diaz, Rafael; Avezum, Alvaro; Lopez-Jaramillo, Patricio; Lanas, Fernando; Li, Wei; Lu, Yin; et al. (Lancet, 2016)
Several studies reported a U-shaped association between urinary sodium excretion and cardiovascular disease events and mortality. Whether these associations vary between those individuals with and without hypertension is uncertain. We aimed to explore whether the association between sodium intake and cardiovascular disease events and all-cause mortality is modified by hypertension status.In this pooled analysis, we studied 133,118 individuals (63,559 with hypertension and 69,559 without hypertension), median age of 55 years (IQR 45-63), from 49 countries in four large prospective studies and estimated 24-h urinary sodium excretion (as group-level measure of intake). We related this to the composite outcome of death and major cardiovascular disease events over a median of 4.2 years (IQR 3.0-5.0) and blood pressure.Increased sodium intake was associated with greater increases in systolic blood pressure in individuals with hypertension (2.08 mm Hg change per g sodium increase) compared with individuals without hypertension (1.22 mm Hg change per g; pinteraction<0.0001). In those individuals with hypertension (6835 events), sodium excretion of 7 g/day or more (7060 [11%] of population with hypertension: hazard ratio [HR] 1.23 [95% CI 1.11-1.37]; p<0.0001) and less than 3 g/day (7006 [11%] of population with hypertension: 1.34 [1.23-1.47]; p<0.0001) were both associated with increased risk compared with sodium excretion of 4-5 g/day (reference 25% of the population with hypertension). In those individuals without hypertension (3021 events), compared with 4-5 g/day (18,508 [27%] of the population without hypertension), higher sodium excretion was not associated with risk of the primary composite outcome (>= 7 g/day in 6271 [9%] of the population without hypertension; HR 0.90 [95% CI 0.76-1.08]; p=0.2547), whereas an excretion of less than 3 g/day was associated with a significantly increased risk (7547 [11%] of the population without hypertension; HR 1.26 [95% CI 1.10-1.45]; p=0.0009).Compared with moderate sodium intake, high sodium intake is associated with an increased risk of cardiovascular events and death in hypertensive populations (no association in normotensive population), while the association of low sodium intake with increased risk of cardiovascular events and death is observed in those with or without hypertension. These data suggest that lowering sodium intake is best targeted at populations with hypertension who consume high sodium diets.Full funding sources listed at end of paper (see Acknowledgments).
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A Symptom Checker App Is Better at Classifying Inflammatory Disease Than Physicians Who Are Presented Identical Information - 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. (ARTHRITIS & RHEUMATOLOGY, 2022)
CRIS-Team WoS Importer:2023-01-13

Atherosclerotic renovascular disease: a clinical practice document by the European Renal Best Practice (ERBP) board of the European Renal Association (ERA) and the Working Group Hypertension and the Kidney of the European Society of Hypertension (ESH) - Sarafidis, Pantelis A.; Theodorakopoulou, Marieta; Ortiz, Alberto; Fernandez-Fernandez, Beatriz; Nistor, Ionut; Schmieder, Roland; Arici, Mustafa; Saratzis, Athanasios; Van Der Niepen, Patricia; Halimi, Jean Michel; Kreutz, Reinhold; Januszewicz, Andrzej; et al. (Nephrology Dialysis Transplantation, 2023)
Atherosclerotic renovascular disease (ARVD) is the most common type of renal artery stenosis. It represents a common health problem with clinical presentations relevant to many medical specialties and carries a high risk for future cardiovascular and renal events, as well as overall mortality. The available evidence regarding the management of ARVD is conflicting. Randomized controlled trials failed to demonstrate superiority of percutaneous transluminal renal artery angioplasty (PTRA) with or without stenting in addition to standard medical therapy compared with medical therapy alone in lowering blood pressure levels or preventing adverse renal and cardiovascular outcomes in patients with ARVD, but they carried several limitations and met important criticism. Observational studies showed that PTRA is associated with future cardiorenal benefits in patients presenting with high-risk ARVD phenotypes (i.e. flash pulmonary oedema, resistant hypertension or rapid loss of kidney function). This clinical practice document, prepared by experts from the European Renal Best Practice (ERBP) board of the European Renal Association (ERA) and from the Working Group on Hypertension and the Kidney of the European Society of Hypertension (ESH), summarizes current knowledge in epidemiology, pathophysiology and diagnostic assessment of ARVD and presents, following a systematic literature review, key evidence relevant to treatment, with an aim to support clinicians in decision making and everyday management of patients with this condition.
CRIS-Team Scopus Importer:2023-12-15
Keywords: angioplasty; atherosclerotic renovascular disease; epidemiology; renal artery stenosis; revascularization

A Tight Control of Non-Canonical TGF-β Pathways and MicroRNAs Downregulates Nephronectin in Podocytes - Sopel, Nina; Ohs, Alexandra; Schiffer, Mario; Müller-Deile, Janina (Cells, 2022)
Nephronectin (NPNT) is an extracellular matrix protein in the glomerular basement membrane that is produced by podocytes and is important for the integrity of the glomerular filtration barrier. Upregulated transforming growth factor β (TGF-β) and altered NPNT are seen in different glomerular diseases. TGF-β downregulates NPNT and upregulates NPNT-targeting microRNAs (miRs). However, the pathways involved were previously unknown. By using selective inhibitors of the canonical, SMAD-dependent, and non-canonical TGF-β pathways, we investigated NPNT transcription, translation, secretion, and regulation through miRs in podocytes. TGF-β decreased NPNT mRNA and protein in cultured human podocytes. TGF-β-dependent regulation of NPNT was meditated through intracellular signaling pathways. Under baseline conditions, non-canonical pathways predominantly regulated NPNT post-transcriptionally. Podocyte NPNT secretion, however, was not dependent on canonical or non-canonical TGF-β pathways. The canonical TGF-β pathway was also dispensable for NPNT regulation after TGF-β stimulation, as TGF-β was still able to downregulate NPNT in the presence of SMAD inhibitors. In contrast, in the presence of different non-canonical pathway inhibitors, TGF-β stimulation did not further decrease NPNT expression. Moreover, distinct non-canonical TGF-β pathways mediated TGF-β-induced upregulation of NPNT-targeting miR-378a-3p. Thus, we conclude that post-transcriptional fine-tuning of NPNT expression in podocytes is mediated predominantly through non-canonical TGF-β pathways.
CRIS-Team Scopus Importer:2022-01-21
Keywords: MicroRNAs; Nephronectin; Podocytes; Podocytopathies; Post-transcriptional regulation; TGF-β

AT II Receptor Blockade and Renal Denervation: Different Interventions with Comparable Renal Effects? - Rodionova, Kristina; Hindermann, Martin; Hilgers, Karl Friedrich; Ott, Christian; Schmieder, Roland; Schiffer, Mario; Amann, Kerstin Ute; Veelken, Roland; Ditting, Tilmann (Kidney & Blood Pressure Research, 2021)
Background: Angiotensin II (Ang II) and the renal sympathetic nervous system exert a strong influence on renal sodium and water excretion. We tested the hypothesis that already low doses of an Ang II inhibitor (candesartan) will result in similar effects on tubular sodium and water reabsorption in congestive heart failure (CHF) as seen after renal denervation (DNX). Methods: Measurement of arterial blood pressure, heart rate (HR), renal sympathetic nerve activity (RSNA), glomerular filtration rate (GFR), renal plasma flow (RPF), urine volume, and urinary sodium. To assess neural control of volume homeostasis, 21 days after the induction of CHF via myocardial infarction rats underwent volume expansion (0.9% NaCL; 10% body weight) to decrease RSNA. CHF rat and controls with or without DNX or pretreated with the Ang II type-1 receptor antagonist candesartan (0.5 ug i.v.) were studied. Results: CHF rats excreted only 68 + 10.2% of the volume load (10% body weight) in 90 min. CHF rats pretreated with candesartan or after DNX excreted from 92 to 103% like controls. Decreases of RSNA induced by volume expansion were impaired in CHF rats but unaffected by candesartan pointing to an intrarenal drug effect. GFR and RPF were not significantly different in controls or CHF. Conclusion: The prominent function of increased RSNA - retaining salt and water - could no longer be observed after renal Ang II receptor blockade in CHF rats.
CRIS-Team WoS Importer:2021-06-11
Keywords: Renal sympathetic innervation; Angiotensin II; Congestive heart failure; Renal nerve ablation; Renal function

Attenuation of Splanchnic Autotransfusion Following Noninvasive Ultrasound Renal Denervation: A Novel Marker of Procedural Success - Saxena, Manish; Shour, Tariq; Shah, Mussadiq; Wolff, Christopher B.; Julu, Peter O.O.; Kapil, Vikas; Collier, David J.; Ng, Fu Liang; Gupta, Ajay; Balawon, Armida; Pheby, Jane; Zak, Anne; et al. (Journal of the American Heart Association, 2018)
BACKGROUND: Renal denervation has no validated marker of procedural success. We hypothesized that successful renal denervation would reduce renal sympathetic nerve signaling demonstrated by attenuation of α-1-adrenoceptor-mediated autotransfusion during the Valsalva maneuver. METHODS AND RESULTS: In this substudy of the Wave IV Study: Phase II Randomized Sham Controlled Study of Renal Denervation for Subjects With Uncontrolled Hypertension, we enrolled 23 subjects with resistant hypertension. They were randomized either to bilateral renal denervation using therapeutic levels of ultrasound energy (n=12) or sham application of diagnostic ultrasound (n=11). Within-group changes in autonomic parameters, office and ambulatory blood pressure were compared between baseline and 6 months in a double-blind manner. There was significant office blood pressure reduction in both treatment (16.1±27.3 mm Hg, P<0.05) and sham groups (27.9±15.0 mm Hg, P<0.01) because of which the study was discontinued prematurely. However, during the late phase II (Iii) of Valsalva maneuver, renal denervation resulted in substantial and significant reduction in mean arterial pressure (21.8±25.2 mm Hg, P<0.05) with no significant changes in the sham group. Moreover, there were significant reductions in heart rate in the actively treated group at rest (6.0±11.5 beats per minute, P<0.05) and during postural changes (supine 7.2±8.4 beats per minute, P<0.05, sit up 12.7±16.7 beats per minute, P<0.05), which were not observed in the sham group. CONCLUSIONS: Blood pressure reduction per se is not necessarily a marker of successful renal nerve ablation. Reduction in splanchnic autotransfusion following renal denervation has not been previously demonstrated and denotes attenuation of (renal) sympathetic efferent activity and could serve as a marker of procedural success. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT02029885.
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Attitudes of medical staff potentially participating in the organ donation process towards organ donation and transplantation in Bavaria - Grammenos, D.; Bein, T.; Briegel, J.; Eckardt, Kai-Uwe; Gerresheim, G.; Lang, C.; Niess, C.; Zeman, F.; Breidenbach, T. (Deutsche Medizinische Wochenschrift, 2014)
Background: Organ donation rates in Germany are lower than in other countries and have declined further after manipulations of the waiting lists in some German transplant centers became public. Attitudes and commitment of medical personnel are crucial for successful organ donation. Therefore, we studied the attitudes of hospital staff towards organ donation and transplantation. Method: In 50 Bavarian hospitals, medical professionals working in units relevant to organ donation were asked to respond to an anonymous questionnaire. Results: 2983 questionnaires could be evaluated. The majority of all respondents had a positive attitude towards organ donation; 71 % were willing to donate their organs after brain death and 57 % were willing to accept a transplant in case of organ failure. Rates of positive attitude were lower among nurses than among physicians. 28 % indicated that recent developments had a negative impact on their attitude and of those approximately half evaluated the work of transplant centers negatively. Overall only 23 % considered organ allocation as fair. The majority of nurses and a large proportion of physicians considered themselves as not well informed. Conclusion: The current loss of confidence into organ donation and transplantation also affects the attitude of medical personnel. Intensified measures of information and full transparency of all procedures are urgently needed.
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Author Correction: Novel diagnostic and therapeutic techniques reveal changed metabolic profiles in recurrent focal segmental glomerulosclerosis (Scientific Reports, (2021), 11, 1, (4577), 10.1038/s41598-021-83883-w) - Müller-Deile, Janina; Sarau, George; Kotb, Ahmed M.; Jaremenko, Christian; Rolle-Kampczyk, Ulrike E.; Daniel, Christoph; Kalkhof, Stefan; Christiansen, Silke H.; Schiffer, Mario (Scientific Reports, 2021)
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
CRIS-Team Scopus Importer:2021-06-04

Author Correction: Rare genetic variants affecting urine metabolite levels link population variation to inborn errors of metabolism (Nature Communications, (2021), 12, 1, (964), 10.1038/s41467-020-20877-8) - Cheng, Yurong; Schlosser, Pascal; Hertel, Johannes; Sekula, Peggy; Spiekerkoetter, Ute; Mielke, Johanna; Freitag, Daniel F.; Schmidts, Miriam; Oefner, Peter J.; Kronenberg, Florian; Eckardt, Kai-Uwe; Thiele, Ines; et al. (Nature Communications, 2021)
The original version of the Supplementary Data associated with this Article included two incorrect column labels in Supplementary Data 3 and 6 files. All numeric content remains unchanged. The HTML has been updated to include a corrected version of Supplementary Data 3 and 6; the original version of Supplementary Data 3 and 6 with the incorrectly labelled column headers can be found as Supplementary Information associated with this Correction.
CRIS-Team Scopus Importer:2021-10-22

Author Reply to Comment on “Assessment of Plasma Oxalate Concentration in Patients With CKD” by Oka et al. - Pfau, Anja; Wytopil, Monika; Chauhan, Kinsuk; Reichel, Martin; Coca, Steve; Aronson, Peter S.; Eckardt, Kai-Uwe; Knauf, Felix (Kidney International Reports, 2021)
CRIS-Team Scopus Importer:2021-04-16

Autosomal-dominant polycystic kidney disease (ADPKD): executive summary from a Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference - Chapman, Arlene B.; Devuyst, Olivier; Eckardt, Kai-Uwe; Gansevoort, Ron T.; Harris, Tess; Horie, Shigeo; Kasiske, Bertram L.; Odland, Dwight; Pei, York; Perrone, Ronald D.; Pirson, Yves; Schrier, Robert W.; et al. (Kidney International, 2015)
Autosomal-dominant polycystic kidney disease (ADPKD) affects up to 12 million individuals and is the fourth most common cause for renal replacement therapy worldwide. There have been many recent advances in the understanding of its molecular genetics and biology, and in the diagnosis and management of its manifestations. Yet, diagnosis, evaluation, prevention, and treatment vary widely and there are no broadly accepted practice guidelines. Barriers to translation of basic science breakthroughs to clinical care exist, with considerable heterogeneity across countries. The Kidney Disease: Improving Global Outcomes Controversies Conference on ADPKD brought together a panel of multidisciplinary clinical expertise and engaged patients to identify areas of consensus, gaps in knowledge, and research and health-care priorities related to diagnosis; monitoring of kidney disease progression; management of hypertension, renal function decline and complications; end-stage renal disease; extrarenal complications; and practical integrated patient support. These are summarized in this review.
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Autosomal dominant tubulointerstitial kidney disease: diagnosis, classification, and management-A KDIGO consensus report - Eckardt, Kai-Uwe; Alper, Seth L.; Antignac, Corinne; Bleyer, Anthony J.; Chauveau, Dominique; Dahan, Karin; Deltas, Constantinos; Hosking, Andrew; Kmoch, Stanislav; Rampoldi, Luca; Wiesener, Michael; Wolf, Matthias T.; et al. (Kidney International, 2015)
Rare autosomal dominant tubulointerstitial kidney disease is caused by mutations in the genes encoding uromodulin (UMOD), hepatocyte nuclear factor-1? (HNF1B), renin (REN), and mucin-1 (MUC1). Multiple names have been proposed for these disorders, including 'Medullary Cystic Kidney Disease (MCKD) type 2', 'Familial Juvenile Hyperuricemic Nephropathy (FJHN)', or 'Uromodulin-Associated Kidney Disease (UAKD)' for UMOD-related diseases and 'MCKD type 1' for the disease caused by MUC1 mutations. The multiplicity of these terms, and the fact that cysts are not pathognomonic, creates confusion. Kidney Disease: Improving Global Outcomes (KDIGO) proposes adoption of a new terminology for this group of diseases using the term 'Autosomal Dominant Tubulointerstitial Kidney Disease' (ADTKD) appended by a gene-based subclassification, and suggests diagnostic criteria. Implementation of these recommendations is anticipated to facilitate recognition and characterization of these monogenic diseases. A better understanding of these rare disorders may be relevant for the tubulointerstitial fibrosis component in many forms of chronic kidney disease.
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Autosomal dominant tubulointerstitial kidney diseases (ADTKD) - Knaup, Karl; Wiesener, M. S. (Nephrologe, 2019)
Hereditary kidney diseases, particularly those with onset in adulthood, are underdiagnosed due to various reasons, with the exception of autosomal dominant polycystic kidney disease (ADPKD). Among these the autosomal dominant tubulointerstitial kidney diseases (ADTKD) form the largest heterogeneous group of hereditary diseases in adulthood. In cases of negative or unknown family history and a frequently not carried out kidney biopsy, which additionally often only achieves an insufficient differentiation between ADTKD and other potential disease entities, only a molecular genetic analysis leads to a clear classification of the disease. This article describes the clinical phenotype of ADTKD, the subtypes with the so far identified causal heterozygous mutations in 5 candidate genes, as well as the possible differential diagnoses and pathomechanisms. In addition, the already existing treatment approaches for delaying the progression of renal insufficiency are presented. The future necessary measures and results of clinical and also basic research, which could lead the way to specific and therefore more effective treatment interventions are discussed.
CRIS-Team WoS Importer:2019-03-15

Azilsartan compared to ACE inhibitors in anti-hypertensive therapy: one-year outcomes of the observational EARLY registry - Gitt, Anselm K.; Bramlage, Peter; Potthoff, Sebastian A.; Baumgart, Peter; Mahfoud, Felix; Buhck, Hartmut; Ehmen, Martina; Ouarrak, Taoufik; Senges, Jochen; Schmieder, Roland (Bmc Cardiovascular Disorders, 2016)
Azilsartan medoxomil (AZL-M), has been demonstrated to be more effective than the other sartans currently in use; however, there is insufficient information available comparing it with ACE-inhibitors. Therefore, we aimed to compare the efficacy, safety, and tolerability of AZL-M with that of ACE-inhibitors in a real life clinical setting.The EARLY registry is a prospective, observational, national, multicentre registry with a follow-up period of 12 months. There were two principal objectives: 1) documentation of the achievement of target BP values set according to recent national and international guidelines, and 2) description of the safety profile of AZL-M.A total of 3 849 patients with essential arterial hypertension were recruited from primary care offices in Germany. Patients who initiated monotherapy at baseline comprising either AZL-M or an ACE-inhibitor were included at a ratio of seven to three. Results demonstrated that a blood pressure target of <140/90 mmHg was achieved by a significantly greater proportion of patients in the AZL-M group (61.1 %) compared with the ACE-inhibitor group (56.4 %; p < 0.05; OR, 1.21; 95 % CI, 1.03-1.42), with this finding maintained after adjusting for differences in baseline characteristics. AZL-M appeared to have an equivalent safety profile to the ACE-inhibitors, with a similar incidence of adverse events in the two patient groups (p = 0.73).These data add to the results of previous randomized controlled clinical trials suggesting that, compared with other agents that target the renin-angiotensin system, AZL-M provides statistically significant albeit small improvements in blood pressure control.
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Balancing wobbles in the body sodium - Titze, Jens; Rakova, Natalia; Kopp, Christoph; Dahlmann, Anke; Jantsch, Jonathan; Luft, Friedrich C. (Nephrology Dialysis Transplantation, 2016)
Sodium balance is achieved within a matter of days and everything that enters should come out; sodium stores are of questionable relevance and sodium accumulation is accompanied by weight gain. Careful balance studies oftentimes conflicted with this view, and long-term studies suggested that total body sodium (TBNa) fluctuates independent of intake or body weight. We recently performed the opposite experiment in that we fixed sodium intake for weeks at three levels of sodium intake and collected all urine made. We found weekly (circaseptan) patterns in sodium excretion that were inversely related to aldosterone and directly related to cortisol. TBNa was not dependent on sodium intake, but instead exhibited far longer (greater than or equal to monthly) infradian rhythms independent of extracellular water, body weight or blood pressure. To discern the mechanisms further, we delved into sodium magnetic resonance imaging (Na-MRI) to identify sodium storage clinically. We found that sodium stores are greater in men than in women, increase with age and are higher in hypertensive than normotensive persons. We have suggestive evidence that these sodium stores can be mobilized, also in dialysis patients. The observations are in accordance with our findings that immune cells regulate a hypertonic interface in the skin interstitium that could serve as a protective barrier. Returning to our balance studies, we found that due to biological variability in 24-h sodium excretion, collecting urine for a day could not separate 12, 9 or 6 g/day sodium intakes with the precision of tossing a coin. Every other daily urine sampling correctly classified a 3-g difference in salt intake less than half the time, making the gold standard 24-h urine collection of little value in predicting salt intake. We suggest that wobbles in expected outcomes can lead to novel clinical insights even with respect to banal salt questions.
EVALuna2:3836

Basal nitric oxide activity is an independent determinant of arteriolar structure in the human retinal circulation - Ritt, Martin; Harazny, Joanna M.; Ott, Christian; Raff, Ulrike; Schneider, Markus; Michelson, Georg; Schmieder, Roland (Journal of Hypertension, 2011)
Experimental data indicate that nitric oxide might play a role in structure and remodeling of peripheral small arteries and arterioles. We hypothesized that retinal arteriolar structure is modulated by basal nitric oxide activity.The study cohort comprised 97 male untreated patients with normal and elevated blood pressure but without clinical evidence for cardiovascular disease. The changes of retinal capillary blood flow (RCF) to nitric oxide synthase inhibitor N-monomethyl-L-arginine (L-NMMA), that reflects basal nitric oxide activity of retinal vasculature, and to flicker light, that in part nitric oxide dependently provokes retinal vasodilatation, and parameters of retinal arteriolar structure, for example wall-to-lumen ratio (WLR), were assessed noninvasively and in vivo by scanning laser Doppler flowmetry.Participants were stratified according to the median WLR of retinal arterioles into two groups. In the group with WLR above the median RCF in response to infusion of L-NMMA decreased to a smaller extent (-3.82 ± 26 vs. -26.0 ± 45 arbitrary units and -0.83 ± 8.4 vs. -5.88 ± 11%, P = 0.004 and P = 0.015; respectively), whereas RCF in response to flicker light did not differ significantly compared to the counter group (22.2 ± 56 vs. 39.8 ± 51 arbitrary units and 7.42 ± 15 vs. 11.9 ± 14%, P = 0.112 and P = 0.149). In the whole study cohort WLR of retinal arterioles was related with the decrease of RCF to L-NMMA infusion [when expressed in absolute terms (r = 0.252, P = 0.013) and in percentage change (r = 0.213, P = 0.036)] and inversely related with the change of RCF to flicker light [when expressed in absolute terms (r = -0.203, P = 0.048) but not clearly when expressed in percentage change (r = -0.161, P = 0.120)]. Adjustment for major cardiovascular risk factors and changes of systemic hemodynamics in response to L-NMMA infusion revealed an independent relationship between WLR of retinal arterioles and percentage change of RCF to L-NMMA infusion (ß = 0.300, P = 0.007).Basal nitric oxide activity emerged as an independent determinant of arteriolar remodeling in the human retinal circulation in vivo.
EVALuna2:3475

Baseline Characteristics and Prescription Patterns of Standard Drugs in Patients with Angiographically Determined Coronary Artery Disease and Renal Failure (CAD-REF Registry) - Reinecke, Holger; Breithardt, Guenter; Engelbertz, Christiane; Schmieder, Roland; Fobker, Manfred; Pinnschmidt, Hans O.; Schmitz, Boris; Bruland, Philipp; Wegscheider, Karl; Pavenstaedt, Hermann; Brand, Eva (PLoS ONE, 2016)
Chronic kidney disease (CKD) is strongly associated with coronary artery disease (CAD). We established a prospective observational nationwide multicenter registry to evaluate current treatment and outcomes in patients with both CKD and angiographically documented CAD.In 32 cardiological centers 3,352 CAD patients with >=50% stenosis in at least one coronary artery were enrolled and classified according to their estimated glomerular filtration rate and proteinuria into one of five stages of CKD or as a control group.2,723 (81.2%) consecutively enrolled patients suffered from CKD. Compared to controls, CKD patients had a higher prevalence of diabetes, hypertension, peripheral artery diseases, heart failure, and valvular heart disease (each p<0.001). Myocardial infarctions (p = 0.02), coronary bypass grafting, valve replacements and pacemaker implantations had been recorded more frequently (each p<0.001). With advanced CKD, the number of diseased coronary vessels and the proportion of patients with reduced left ventricular ejection fraction (LVEF) increased significantly (both p<0.001). Percutaneous coronary interventions were performed less frequently (p<0.001) while coronary bypass grafting was recommended more often (p = 0.04) with advanced CKD. With regard to standard drugs in CAD treatment, prescriptions were higher in our registry than in previous reports, but beta-blockers (p = 0.008), and angiotensin-converting-enzyme inhibitors and/or angiotensin-receptor blockers (p<0.001) were given less often in higher CKD stages. In contrast, in the subgroup of patients with moderately to severely reduced LVEF the prescription rates did not differ between CKD stages. In-hospital mortality increased stepwise with each CKD stage (p = 0.02).In line with other studies comprising CKD cohorts, patients' morbidity and in-hospital mortality increased with the degree of renal impairment. Although cardiologists' drug prescription rates in CAD-REF were higher than in previous studies, they were still lower especially in advanced CKD stages compared to cohorts treated by nephrologists.
EVALuna2:3832

B CELL DENSITY IN RENAL GRAFTS CORRELATES WITH REJECTION, FIBROSIS, POLYOMA NEPHROPATHY AND DONOR CHARACTERISTICS - Johnsdorf, J.; Scheffner, I.; Khalifa, A.; Schmitz, J.; Schiffer, Mario; Kunzendorf, U.; Kribben, A.; Gwinner, W.; Braesen, J. H. (TRANSPLANT INTERNATIONAL, 2019)
CRIS-Team WoS Importer:2019-10-29

Beliefs about immunosuppressant medication and correlates in a German kidney transplant population - Bünemann, Maybrit; Bauer-Hohmann, Maximilian; Klewitz, Felix; Kyaw Tha Tun, Eva Marie; Tegtbur, Uwe; Pape, Lars; Schiffer, Lena; Schiffer, Mario; de Zwaan, Martina; Nöhre, Mariel (Journal of psychosomatic research, 2020)
Objective: A common reason for organ rejection after transplantation is the lack of adherence regarding immunosuppressive medication (ISM). A variety of different aspects can promote non-adherent behavior, including the relationship between perceived benefits and concerns regarding ISM (“necessity-concerns-framework”). Little is known about the variables associated with this framework. Methods: As part of this cross-sectional study, 570 patients after kidney transplantation who participated in a structured multimodal follow-up program (KTx360°) were examined in two transplant centers in Lower Saxony. We used the Beliefs about Medicines Questionnaire (BMQ) to evaluate the patients' believes and concerns regarding their ISM. Results: The mean age of the participants was 51.9 (SD 14.17) years, 58.4% were men, and 25.8% had ≥12 years of school attendance. The mean time since transplantation was 65.9 months. In patients undergoing kidney transplantation, the perceived benefit of ISM mostly exceeded the concerns. We found an association between lower perceived benefits and greater concerns and lower adherence. Also, a higher perceived necessity was significantly associated with higher age and lower levels of depression and anxiety. Greater concerns were significantly associated with more symptoms of depression and anxiety, lower perceived social support, and lower kidney functioning (eGFR). Conclusion: Even though patients after kidney transplantation usually acknowledge the importance of their ISM, they still have considerable concerns that are associated with less adherence and various psychosocial risk factors. Further longitudinal studies are needed to assess the extent to which beliefs about medication are variable and can be individually addressed to improve adherence.
CRIS-Team Scopus Importer:2020-03-17
Keywords: Adherence; Beliefs about medicines; Immunosuppressive medication; Kidney transplantation; Renal transplantation

Benefits and Risks of Aliskiren Treatment in Patients With Type 2 Diabetes: Analyses of the 3A Registry - Kistner, Iris; Zeymer, Uwe; Dechend, Ralf; Hagedorn, Ina; Riemer, Thomas; Bramlage, Peter; Pittrow, David; Senges, Jochen; Schmieder, Roland (Journal of Clinical Hypertension, 2016)
The authors sought to retrospectively analyze the real-world evidence on aliskiren in diabetic patients with or without concomitant renin-angiotensin system (RAS) blocker use based on the Registry for Ambulant Therapy With RAS Inhibitors in Hypertension Patients in Germany (3A). Of 14,986 patients included, 3772 patients had diabetes and 28.5% received aliskiren, 14.3% received angiotensin-converting enzyme (ACE) inhibitors/angiotensin receptor blockers (ARBs), 35.4% received aliskiren plus an ACE inhibitor/ARB, and 10.5% received other drugs. Ambulatory blood pressure (BP) monitoring (baseline BP 148±15.8/84.0±10.9 mm Hg) revealed stronger diastolic BP reduction for aliskiren plus ACE inhibitor/ARB than aliskiren alone in the low (2.8±0.5 vs 0.6±0.6; P=.004) and intermediate (5.9±0.5 vs 4.5±0.5; P=.04) baseline BP groups. There was a lesser ambulatory BP reduction observed for patients receiving non-RAS in the high baseline category for both systolic (12.5±1.8 vs 17.1±1.0; P=.02) and diastolic (6.9±1.0 vs 9.8±0.6; P=.01) BP. In patients with hypertension and type 2 diabetes, aliskiren was beneficial in lowering BP, with no observed increases in major adverse effects compared with RAS-blocking therapy alone.
EVALuna2:3853

Biallelic ANKS6 mutations cause late-onset ciliopathy with chronic kidney disease through YAP dysregulation - Schwarz, Hannah; Popp, Bernt; Airik, Rannar; Torabi Sarijalo, Nasrin; Knaup, Karl; Stoeckert, Johanna; Wiech, Thorsten; Amann, Kerstin Ute; Wiesmann da Silva Reis, André; Schiffer, Mario; Schueler, Markus; Wiesener, Michael (Human Molecular Genetics, 2021)
Nephronophthisis-related ciliopathies (NPHP-RC) comprises a group of inherited kidney diseases, caused by mutations in genes encoding proteins localizing to primary cilia. NPHP-RC represents one of the most frequent monogenic causes of renal failure within the first three decades of life, but its molecular disease mechanisms remain unclear. Here, we identified biallelic ANKS6 mutations in two affected siblings with late-onset chronic kidney disease by whole-exome sequencing. We employed patient-derived fibroblasts generating an in vitro model to study the precise biological impact of distinct human ANKS6 mutations, completed by immunohistochemistry studies on renal biopsy samples. Functional studies using patient-derived cells showed an impaired integrity of the ciliary inversin compartment with reduced cilia length. Further analyses demonstrated that ANKS6 deficiency leads to a dysregulation of Hippo-signaling through nuclear yes-associated protein (YAP) imbalance and disrupted ciliary localization of YAP. In addition, an altered transcriptional activity of canonical Wnt target genes and altered expression of non-phosphorylated (active) beta-catenin and phosphorylated glycogen synthase kinase 3 beta were observed. Upon ciliation, ANKS6 deficiency revealed a deranged subcellular localization and expression of components of the endocytic recycling compartment. Our results demonstrate that ANKS6 plays a key role in regulating the Hippo pathway, and ANKS6 deficiency is linked to dysregulation of signaling pathways. Our study provides molecular clues in understanding pathophysiological mechanisms of NPHP-RC and may offer new therapeutic targets.
CRIS-Team WoS Importer:2022-05-13

Biallelic Expression of Mucin-1 in Autosomal Dominant Tubulointerstitial Kidney Disease: Implications for Nongenetic Disease Recognition - Knaup, Karl; Hackenbeck, Thomas; Popp, Bernt; Stoeckert, Johanna; Wenzel, Andrea; Büttner-Herold, Maike; Pfister, Frederick; Schüler, Markus; Seven, Didem; May, Annette M.; Halbritter, Jan; Gröne, Hermann Josef; et al. (Journal of the American Society of Nephrology, 2018)
BACKGROUND: Providing the correct diagnosis for patients with tubulointerstitial kidney disease and secondary degenerative disorders, such as hypertension, remains a challenge. The autosomal dominant tubulointerstitial kidney disease (ADTKD) subtype caused by MUC1 mutations (ADTKD-MUC1) is particularly difficult to diagnose, because the mutational hotspot is a complex repeat domain, inaccessible with routine sequencing techniques. Here, we further evaluated SNaPshot minisequencing as a technique for diagnosing ADTKD-MUC1 and assessed immunodetection of the disease-associated mucin 1 frameshift protein (MUC1-fs) as a nongenetic technique. METHODS: We re-evaluated detection of MUC1 mutations by targeted repeat enrichment and SNaPshot minisequencing by haplotype reconstruction via microsatellite analysis in three independent ADTKD-MUC1 families. Additionally, we generated rabbit polyclonal antibodies against MUC1-fs and evaluated immunodetection of wild-type and mutated allele products in human kidney biopsy specimens. RESULTS: The detection of MUC1 mutations by SNaPshot minisequencing was robust. Immunostaining with our MUC1-fs antibodies and an MUC1 antibody showed that both proteins are readily detectable in human ADTKD-MUC1 kidneys, with mucin 1 localized to the apical membrane and MUC1-fs abundantly distributed throughout the cytoplasm. Notably, immunohistochemical analysis of MUC1-fs expression in clinical kidney samples facilitated reliable prediction of the disease status of individual patients. CONCLUSIONS: Diagnosing ADTKD-MUC1 by molecular genetics is possible, but it is technically demanding and labor intensive. However, immunohistochemistry on kidney biopsy specimens is feasible for nongenetic diagnosis of ADTKD-MUC1 and therefore, a valid method to select families for further diagnostics. Our data are compatible with the hypothesis that specific molecular effects of MUC1-fs underlie the pathogenesis of this disease.
EVALuna2:34428

BKPYV-SPECIFIC T CELLS REDUCE VIRAL LOAD IN A PRIMARY TUBULAR CELL MODEL - Wasielewski, E.; Lippler, Susanne; Knaup, Karl; Gary, Regina; Aigner, Michael; Kremer, Anna-Lena; Pfister, Felix; Amann, Kerstin Ute; Schiffer, Mario; Mackensen, Andreas; Wiesener, Michael (TRANSPLANT INTERNATIONAL, 2021)
CRIS-Team WoS Importer:2021-10-15

Blood pressure and Cardiorenal Outcomes With Finerenone in Chronic Kidney Disease in Type 2 Diabetes - Ruilope, Luis M.; Agarwal, Rajiv; Anker, Stefan D.; Filippatos, Gerasimos; Pitt, Bertram; Rossing, Peter; Sarafidis, Pantelis; Schmieder, Roland; Joseph, Amer; Rethemeier, Nicole; Nowack, Christina; Bakris, George L. (Hypertension, 2022)
BACKGROUND: Chronic kidney disease is frequently associated with hypertension and poorly controlled blood pressure can lead to chronic kidney disease progression. Finerenone, a nonsteroidal mineralocorticoid receptor antagonist, significantly improves cardiorenal outcomes in patients with chronic kidney disease and type 2 diabetes. This analysis explored the relationship between office systolic blood pressure (SBP) and cardiorenal outcomes with finerenone in FIDELIO-DKD trial (Finerenone in Reducing Kidney Failure and Disease Progression in Diabetic Kidney Disease).
CRIS-Team WoS Importer:2022-11-18

Blood pressure and LDL-cholesterol targets for prevention of recurrent strokes and cognitive decline in the hypertensive patient: design of the European Society of Hypertension-Chinese Hypertension League Stroke in Hypertension Optimal Treatment randomize - 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, 2014)
The SBP values to be achieved by antihypertensive therapy in order to maximize reduction of cardiovascular outcomes are unknown; neither is it clear whether in patients with a previous cardiovascular event, the optimal values are lower than in the low-to-moderate risk hypertensive patients, or a more cautious blood pressure (BP) reduction should be obtained. Because of the uncertainty whether 'the lower the better' or the 'J-curve' hypothesis is correct, the European Society of Hypertension and the Chinese Hypertension League have promoted a randomized trial comparing antihypertensive treatment strategies aiming at three different SBP targets in hypertensive patients with a recent stroke or transient ischaemic attack. As the optimal level of low-density lipoprotein cholesterol (LDL-C) level is also unknown in these patients, LDL-C-lowering has been included in the design.The European Society of Hypertension-Chinese Hypertension League Stroke in Hypertension Optimal Treatment trial is a prospective multinational, randomized trial with a 3 × 2 factorial design comparing: three different SBP targets (1, <145-135; 2, <135-125; 3, <125 mmHg); two different LDL-C targets (target A, 2.8-1.8; target B, <1.8 mmol/l). The trial is to be conducted on 7500 patients aged at least 65 years (2500 in Europe, 5000 in China) with hypertension and a stroke or transient ischaemic attack 1-6 months before randomization. Antihypertensive and statin treatments will be initiated or modified using suitable registered agents chosen by the investigators, in order to maintain patients within the randomized SBP and LDL-C windows. All patients will be followed up every 3 months for BP and every 6 months for LDL-C. Ambulatory BP will be measured yearly.Primary outcome is time to stroke (fatal and non-fatal). Important secondary outcomes are: time to first major cardiovascular event; cognitive decline (Montreal Cognitive Assessment) and dementia. All major outcomes will be adjudicated by committees blind to randomized allocation. A Data and Safety Monitoring Board has open access to data and can recommend trial interruption for safety.It has been calculated that 925 patients would reach the primary outcome after a mean 4-year follow-up, and this should provide at least 80% power to detect a 25% stroke difference between SBP targets and a 20% difference between LDL-C targets.
EVALuna2:3699

Blood pressure and low-density lipoprotein-cholesterol lowering for prevention of strokes and cognitive decline: a review of available trial evidence - 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, 2014)
It is well established by a large number of randomized controlled trials that lowering blood pressure (BP) and low-density lipoprotein cholesterol (LDL-C) by drugs are powerful means to reduce stroke incidence, but the optimal BP and LDL-C levels to be achieved are largely uncertain. Concerning BP targets, two hypotheses are being confronted: first, the lower the BP, the better the treatment outcome, and second, the hypothesis that too low BP values are accompanied by a lower benefit and even higher risk. It is also unknown whether BP lowering and LDL-C lowering have additive beneficial effects for the primary and secondary prevention of stroke, and whether these treatments can prevent cognitive decline after stroke.A review of existing data from randomized controlled trials confirms that solid evidence on optimal BP and LDL-C targets is missing, possible interactions between BP and LDL-C lowering treatments have never been directly investigated, and evidence in favour of a beneficial effect of BP or LDL-C lowering on cognitive decline is, at best, very weak.A new, large randomized controlled trial is needed to determine the optimal level of BP and LDL-C for the prevention of recurrent stroke and cognitive decline.
EVALuna2:3698

Blood pressure control in chronic kidney disease: A cross-sectional analysis from the German Chronic Kidney Disease (GCKD) study - Schneider, Markus; Hilgers, Karl Friedrich; 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)
We assessed the prevalence, awareness, treatment and control of hypertension in patients with moderate chronic kidney disease (CKD) under nephrological care in Germany. In the German Chronic Kidney Disease (GCKD) study, 5217 patients under nephrology specialist care were enrolled from 2010 to 2012 in a prospective observational cohort study. Inclusion criteria were an estimated glomerular filtration rate (eGFR) of 30-60 mL/min/1.73 m2 or overt proteinuria in the presence of an eGFR>60 mL/min/1.73 m2. Office blood pressure was measured by trained study personnel in a standardized way and hypertension awareness and medication were assessed during standardized interviews. Blood pressure was considered as controlled if systolic < 140 and diastolic < 90 mmHg. In 5183 patients in whom measurements were available, mean blood pressure was 139.5 ± 20.4 / 79.3 ± 11.8 mmHg; 4985 (96.2%) of the patients were hypertensive. Awareness and treatment rates were > 90%. However, only 2456 (49.3%) of the hypertensive patients had controlled blood pressure. About half (51.0%) of the patients with uncontrolled blood pressure met criteria for resistant hypertension. Factors associated with better odds for controlled blood pressure in multivariate analyses included younger age, female sex, higher income, low or absent proteinuria, and use of certain classes of antihypertensive medication. We conclude that blood pressure control of CKD patients remains challenging even in the setting of nephrology specialist care, despite high rates of awareness and medication use.
EVALuna2:156740

Blood pressure in chronic kidney disease: conclusions from a Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference - Cheung, Alfred K.; Chang, Tara I.; Cushman, William C.; Furth, Susan L.; Ix, Joachim H.; Pecoits-Filho, Roberto; Perkovic, Vlado; Sarnak, Mark J.; Tobe, Sheldon W.; Tomson, Charles R.V.; Cheung, Michael; Wheeler, David C.; et al. (Kidney International, 2019)
In September 2017, KDIGO (Kidney Disease: Improving Global Outcomes) convened a Controversies Conference titled Blood Pressure in Chronic Kidney Disease (CKD). The purpose of the meeting was to consider which recommendations from the 2012 KDIGO Clinical Practice Guideline for the Management of Blood Pressure in CKD should be reevaluated based on new evidence from clinical trials. Participants included a multidisciplinary panel of clinical and scientific experts. Discussions focused on the optimal means for measuring blood pressure (BP) as well as managing BP in CKD patients. Consistent with the 2012 Guideline, the conference did not address BP management in patients on maintenance dialysis.
CRIS-Team Scopus Importer:2019-05-02
Keywords: blood pressure measurement; blood pressure targets; cardiovascular events; guideline; treatment threshold

Blood Pressure Pattern and Target Organ Damage in Patients With Chronic Kidney Disease - Scheppach, Johannes B.; Raff, Ulrike; Toncar, Sebastian; Ritter, Christian; Klink, Thorsten; Stoerk, Stefan; Wanner, Christoph; Schlieper, Georg; Saritas, Turgay; Reinartz, Sebastian D.; Floege, Juergen; Janka, Rolf Matthias; et al. (Hypertension, 2018)
In patients with chronic kidney disease, data on blood pressure (BP) pattern and its association with target organ damage, which indicates elevated cardiovascular risk, are sparse. In 305 treated hypertensive chronic kidney disease patients, we assessed BP pattern, left ventricular mass (magnetic resonance imaging), intima-media thickness (ultrasound), 24-hour-pulse wave velocity and 24-hour-central augmentation index (Mobil-O-Graph). Controlled hypertension (normal office and ambulatory BP) was found in 41% and sustained uncontrolled hypertension (elevated office and ambulatory BP) in 30% of patients. Misclassification of BP status occurred in 29%: white coat uncontrolled hypertension (elevated office but normal ambulatory BP) was detected in 11% and masked uncontrolled hypertension (normal office but elevated ambulatory BP) in 18% of patients. Left ventricular mass was increased in white coat uncontrolled hypertension (+11.2 g), masked uncontrolled hypertension (+9.4 g), and sustained uncontrolled hypertension (+16.6 g) compared with controlled hypertension. Intima-media thickness was similar across all 4 BP groups. Twenty-four hour-pulse wave velocity and 24-hour-central augmentation index were increased in masked uncontrolled hypertension (+0.5 m/sec and +2.5%) and sustained uncontrolled hypertension (+0.5 m/sec and +2.9%) compared with controlled hypertension. In conclusion, based on office BP measurements, misclassification of true BP status occurred in almost one-third of chronic kidney disease patients. Both types of misclassification (white coat uncontrolled hypertension and masked uncontrolled hypertension) were associated with parameters of target organ damage. Ambulatory BP monitoring should be used routinely to identify chronic kidney disease patients at high cardiovascular risk.
EVALuna2:34688

Blood pressure profile, sympathetic nervous system activity, and subclinical target organ damage in patients with polycythemia vera - Jóźwik-Plebanek, Katarzyna; Dobrowolski, Piotr; Lewandowski, Jacek; Narkiewicz, Krzysztof; Sikorska, Anna; Siński, Maciej; Eisenhofer, Graeme; Schmieder, Roland; Januszewicz, Magdalena; Windyga, Jerzy; Prejbisz, Aleksander; Januszewicz, Andrzej (Polish Archives of Internal Medicine, 2020)
INTRODUCTION: Polycythemia vera (PV) is a rare myeloproliferative disease associated with an increased prevalence of hypertension and increased risk of cardiovascular complications. However, the precise mechanisms leading to the elevation of blood pressure (BP) and secondary target organ damage remain poorly understood. OBJECTIVES: The study aimed to evaluate BP profile, assess the activity of the sympathetic nervous system and the renin-angiotensin system, and provide a comprehensive assessment of subclinical target organ damage in patients with PV. PATIENTS AND METHODS: Twenty consecutive patients with newly diagnosed PV and 20 control subjects were included. The following were assessed: BP, levels of catecholamines, urinary and plasma O-methylated catecholamine metabolites, concentrations of aldosterone and renin. We also assessed microneurography sympathetic nervous system activity (MSNA) and baroreflex control of heart rate as well as subclinical target organ damage. RESULTS: At similar levels of BP, BP variability was decreased in the PV group (mean [SD] 24-hour systolic BP, 9 [3] vs 12 [3] mm Hg; P = 0.003). Patients with PV had lower norepinephrine excretion (mean [SD], 16.54 [6.32] vs 25.46 [12.88] μg/d; P = 0.03) as well as decreased MSNA as assessed by microneurography compared with controls (mean [SD] MSNA, 30.7 [8.7] bursts/min vs 38.7 [5.4] bursts/min; P = 0.007 and MSNA 51.8 [11] bursts/100 beats vs 61.1 [11.3] bursts/100 heart beats; P = 0.04). Baroreflex control of HR was unaltered in the PV group. Increased hemoglobin levels and red blood cell count correlated with decreased retinal capillary flow in patients with PV. CONCLUSIONS: Patients with PV, characterized by high hemoglobin concentrations and hematocrit levels had lower sympathetic nervous activity and decreased BP variability as compared with controls. There was no relationship between hemoglobin plasma concentration, hematocrit level, and target organ damage.
CRIS-Team Scopus Importer:2020-09-18
Keywords: Blood pressure profile; Organ damage; Polycythemia vera

Blood pressure reduction after renal denervation in patients with or without chronic kidney disease - Günes-Altan, Merve; Schmid, Axel; Ott, Christian; Bosch, Agnes; Pietschner, Robert; Schiffer, Mario; Uder, Michael; Schmieder, Roland; Kannenkeril, Dennis (Clinical Kidney Journal, 2024)
Background. Renal denervation (RDN) has emerged as an adjacent option for the treatment of hypertension. This analysis of the Erlanger registry aimed to compare the blood pressure (BP)-lowering effects and safety of RDN in patients with and without chronic kidney disease (CKD). Methods. In this single-center retrospective analysis, 47 patients with and 127 without CKD underwent radiofrequency-, ultrasound- or alcohol-infusion-based RDN. Office and 24-h ambulatory BP and estimated glomerular filtration rate (eGFR) were measured at baseline, and after 6 and 12 months. Results. A total of 174 patients with a mean age of 59.0 ± 10 years were followed up for 12 months. At baseline, mean eGFR was 55.8 ± 21 mL/min/1.73 m2 in patients with CKD and 87.3 ± 13 mL/min/1.73 m2 in patients without CKD. There was no significant eGFR decline in either of the groups during 12 months of follow-up. In patients without CKD, office systolic and diastolic BP were reduced by –15.3 ± 17.5/–7.9 ± 10.8 mmHg 6 months after RDN and by –16.1 ± 18.2/–7.7 ± 9.6 mmHg 12 months after RDN. In patients with CKD, office systolic and diastolic BP were reduced by –10.7 ± 24.0/–5.8 ± 13.2 mmHg 6 months after RDN and by –15.1 ± 24.9/–5.9 ± 12.9 mmHg 12 months after RDN. Accordingly, in patients without CKD, 24-h ambulatory systolic and diastolic BP were reduced by –7.2 ± 15.8/–4.9 ± 8.8 mmHg 6 months after RDN and by –9.0 ± 17.0/–6.2 ± 9.8 mmHg 12 months after RDN. In patients with CKD, 24-h systolic and diastolic BP were reduced by –7.4 ± 12.9/–4.2 ± 9.9 mmHg 6 months after RDN and by –8.0 ± 14.0/–3.6 ± 9.6 mmHg 12 months after RDN. There was no difference in the reduction of office and 24-h ambulatory BP between the two groups at any time point (all P > .2). Similar results have been found for the 6 months data. With exception of rare local adverse events, we did not observe any safety signals. Conclusion. According to our single-center experience, we observed a similar reduction in 24-h, day and night-time ambulatory BP as well as in-office BP in patients with and without CKD at any time point up to 12 months. We conclude that RDN is an effective and safe treatment option for patients with hypertension and CKD.
CRIS-Team Scopus Importer:2024-01-26
Keywords: blood pressure; chronic kidney disease; hypertension; post-hoc analysis; renal denervation

BLOOD PRESSURE REDUCTION AFTER RENAL DENERVATION IN PATIENTS WITH OR WITHOUT CHRONIC KIDNEY DISEASE: THE ERLANGER EXPERIENCE - Schmid, Axel; Ott, Christian; Bosch, Agnes; Schiffer, Mario; Uder, Michael; Schmieder, Roland; Kannenkeril, Dennis (JOURNAL OF HYPERTENSION, 2023)
CRIS-Team WoS Importer:2023-03-17

Blood pressure reduction in higher cardiovascular risk patients in the Global SYMPLICITY Registry - Rodriguez, O.; Mahfoud, F.; Schmieder, Roland; Schlaich, M.; Narkiewicz, K.; Ruilope, L.; Williams, B.; Fahy, M.; Mancia, G.; Boehm, M. (European Heart Journal, 2022)
CRIS-Team WoS Importer:2023-03-03

Blunted transcriptional response to skeletal muscle ischemia in rats with chronic kidney disease: potential role for impaired ischemia-induced angiogenesis - Heiß, Rafael; Fahlbusch, Fabian B.; Jacobi, Johannes; Daniel, Christoph; Ekici, Arif Bülent; Cordasic, Nada; Amann, Kerstin Ute; Hilgers, Karl Friedrich; Hartner, Andrea (Physiological Genomics, 2017)
Chronic kidney disease (CKD) is associated with increased cardiovascular morbidity and mortality. Previous studies indicated an impairment of ischemia-induced angiogenesis in skeletal muscle of rats with CKD. We performed a systematic comparison of early gene expression in response to ischemia in rats with or without CKD to identify potential molecular mechanisms underlying impaired angiogenesis in CKD. CKD was induced in male rats by 5/6 nephrectomy (SNX); control rats were sham operated (sham). Eight weeks later, ischemia of the right limb was induced by ligation and resection of the femoral artery. Rats were sacrificed 24 hours after the onset of ischemia, and RNA was extracted from the musculus soleus of the ischemic and the nonischemic hindlimb. To identify differentially expressed transcripts, RNA was analyzed employing Affymetrix GeneChip Rat Genome 230 2.0 Arrays. RT-PCR analysis of selected genes was performed to validate observed changes. Hindlimb ischemia up-regulated 239 genes in CKD and 299 genes in control rats (66% overlap) whereas only a few genes were down-regulated (14 in CKD and 34 in controls), compared with the non-ischemic limb of the same animals. Comparison between the ischemic limbs of CKD and controls revealed down-regulation of 65 genes in CKD; 37 of these genes were also among the ischemia-induced genes in controls. Analysis of functional groups (other than angiogenesis) pointed to genes involved in leukocyte recruitment and fatty acid metabolism. Transcript expression profiling points to a relatively small number of differentially expressed genes which may underlie the impaired post-ischemic angiogenesis in CKD.
EVALuna2:3946

Brain function and metabolism in patients with long-term tacrolimus therapy after kidney transplantation in comparison to patients after liver transplantation - Pflugrad, Henning; Nösel, Patrick; Ding, Xiaoqi; Schmitz, Birte; Lanfermann, Heinrich; Barg-Hock, Hannelore; Klempnauer, Jürgen; Schiffer, Mario; Weissenborn, Karin (PLoS ONE, 2020)
Background About 50% of the patients 5–7 years after kidney transplantation show impairment of memory, attention and executive function. Tacrolimus frequently induces neurological complications in the first few weeks after transplantation. Furthermore, tacrolimus treatment is associated with impaired cognitive function in the long-term in patients after liver transplantation. We hypothesize that long-term tacrolimus therapy is associated with cognitive dysfunction and alterations of brain structure and metabolism in patients after kidney transplantation. Methods Twenty-one patients 10 years after kidney transplantation underwent cognitive testing, magnetic resonance imaging and whole brain 31-phosphor magnetic resonance spectroscopy for the assessment of brain function, structure and energy metabolism. Using a cross-sectional study design the results were compared to those of patients 1 (n = 11) and 5 years (n = 10) after kidney transplantation, and healthy controls (n = 17). To further analyze the share of transplantation, tacrolimus therapy and kidney dysfunction on the results patients after liver transplantation (n = 9) were selected as a patient control group. Results Patients 1 and 10 years after kidney transplantation (p = 0.02) similar to patients 10 years after liver transplantation (p<0.01) showed significantly worse cognitive function than healthy controls. In contrast to patients after liver transplantation patients after kidney transplantation showed significantly reduced adenosine triphosphate levels in the brain compared to healthy controls (p≤0.01). Patients 1 and 5 years after kidney transplantation had significantly increased periventricular hyperintensities compared to healthy controls (p<0.05). Conclusions Our data indicate that cognitive impairment in the long-term after liver and kidney transplantation cannot exclusively be explained by CNI neurotoxicity.
CRIS-Team Scopus Importer:2020-03-20

Building a network of ADPKD reference centres across Europe: the EuroCYST initiative - Petzold, Katja; Gansevoort, Ron T.; Ong, Albert C. M.; Devuyst, Olivier; Rotar, Laura; Eckardt, Kai-Uwe; Koettgen, Anna; Pirson, Yves; Remuzzi, Giuseppe; Sandford, Richard; Tesar, Vladimir; Ecder, Tevfik; et al. (Nephrology Dialysis Transplantation, 2014)
Autosomal dominant polycystic kidney disease (ADPKD) is the most common monogenic inherited kidney disease, affecting an estimated 600 000 individuals in Europe. The disease is characterized by age-dependent development of a multiple cysts in the kidneys, ultimately leading to end-stage renal failure and the need of renal replacement therapy in the majority of patients, typically by the fifth or sixth decade of life. The variable disease course, even within the same family, remains largely unexplained. Similarly, assessing disease severity and prognosis in an individual with ADPKD remains difficult. Epidemiological studies are limited due to the fragmentation of ADPKD research in Europe.The EuroCYST initiative aims: (i) to harmonize and develop common standards for ADPKD research by starting a collaborative effort to build a network of ADPKD reference centres across Europe and (ii) to establish a multicentric observational cohort of ADPKD patients. This cohort will be used to study factors influencing the rate of disease progression, disease modifiers, disease stage-specific morbidity and mortality, health economic issues and to identify predictive disease progression markers. Overall, 1100 patients will be enrolled in 14 study sites across Europe. Patients will be prospectively followed for at least 3 years. Eligible patients will not have participated in a pharmaceutical clinical trial 1 year before enrolment, have clinically proven ADPKD, an estimated glomerular filtration rate (eGFR) of 30 mL/min/1.73 m(2) and above, and be able to provide written informed consent. The baseline visit will include a physical examination and collection of blood, urine and DNA for biomarker and genetic studies. In addition, all participants will be asked to complete questionnaires detailing self-reported health status, quality of life, socioeconomic status, health-care use and reproductive planning. All subjects will undergo annual follow-up. A magnetic resonance imaging (MRI) scan will be carried out at baseline, and patients are encouraged to undergo a second MRI at 3-year follow-up for qualitative and quantitative kidney and liver assessments.The ADPKD reference centre network across Europe and the observational cohort study will enable European ADPKD researchers to gain insights into the natural history, heterogeneity and associated complications of the disease as well as how it affects the lives of patients across Europe.
EVALuna:27100

Can Gene Expression Analysis in Zero-Time Biopsies Predict Kidney Transplant Rejection? - Vonbrunn, Eva; Angeloni, Miriam; Büttner-Herold, Maike; Müller-Deile, Janina; Heller, Katharina M.; Bleich, Erik; Söllner, Stefan; Amann, Kerstin Ute; Ferrazzi, Fulvia; Daniel, Christoph (Frontiers in Medicine, 2022)
Zero-time biopsies are taken to determine the quality of the donor organ at the time of transplantation. Histological analyses alone have so far not been able to identify parameters that allow the prediction of subsequent rejection episodes or graft survival. This study investigated whether gene expression analyses of zero-time biopsies might support this prediction. Using a well-characterized cohort of 26 zero-time biopsies from renal transplant patients that include 4 living donor (LD) and 22 deceased donor (DD) biopsies that later developed no rejection (Ctrl, n = 7), delayed graft function (DGF, n = 4), cellular (T-cell mediated rejection; TCMR, n = 8), or antibody-mediated rejection (ABMR, n = 7), we analyzed gene expression profiles for different types of subsequent renal transplant complication. To this end, RNA was isolated from formalin-fixed, paraffin-embedded (FFPE) sections and gene expression profiles were quantified. Results were correlated with transplant data and B-cell, and plasma cell infiltration was assessed by immunofluorescence microscopy. Both principal component analysis and clustering analysis of gene expression data revealed marked separation between LDs and DDs. Differential expression analysis identified 185 significant differentially expressed genes (adjusted p < 0.05). The expression of 68% of these genes significantly correlated with cold ischemia time (CIT). Furthermore, immunoglobulins were differentially expressed in zero-time biopsies from transplants later developing rejection (TCMR + ABMR) compared to non-rejected (Ctrl + DGF) transplants. In addition, immunoglobulin expression did not correlate with CIT but was increased in transplants with previous acute renal failure (ARF). In conclusion, gene expression profiles in zero-time biopsies derived from LDs are markedly different from those of DDs. Pre-transplant ARF increased immunoglobulin expression, which might be involved in triggering later rejection events. However, these findings must be confirmed in larger cohorts and the role of early immunoglobulin upregulation in zero-biopsies needs further clarification.
CRIS-Team Scopus Importer:2022-04-29
Keywords: inflammation; kidney transplantation; mRNA expression; outcome; zero-time biopsy

CAN WE IDENTIFY GLOMERULAR HYPERFILTRATION IN PATIENTS WITH TYPE 2 DIABETES BY CLINICAL PARAMETERS? - Kolwelter, Julie; Striepe, Kristina; Kannenkeril, Dennis; Jung, Susanne; Bosch, Agnes; Ott, Christian; Schmieder, Roland (JOURNAL OF HYPERTENSION, 2021)
CRIS-Team WoS Importer:2021-07-30

Capillary vascular density in the retina of hypertensive patients is associated with a non-dipping pattern independent of mean ambulatory blood pressure - Nolde, Janis M.; Frost, Shaun; Kannenkeril, Dennis; Lugo-Gavidi, Leslie Marisol; Chan, Justine; Joyson, Anu; Azzam, Omar; Carnagarin, Revathy; Kiuchi, Marcio G.; Vignarajan, Janardhan; Schlaich, Markus P. (Journal of Hypertension, 2021)
Background: A nocturnal non-dipping pattern has been associated with hypertension-mediated organ damage (HMOD), morbidity and mortality. Retinal imaging through application of modern technologies including optical coherence tomography angiography (OCT-A) can provide detailed insights into early vascular damage. In this observational study, we investigated the relationship of microscopic vascular density in the retina measured with OCT-A and nocturnal blood pressure (BP) dipping.
CRIS-Team WoS Importer:2021-08-20

CAPILLARY VASCULAR DENSITY IN THE RETINA OF HYPERTENSIVE SUBJECTS IS ASSOCIATED WITH A NON-DIPPING PATTERN INDEPENDENT OF MEAN AMBULATORY BLOOD PRESSURE - Nolde, J. M.; Frost, S.; Kannenkeril, Dennis; Lugo-Gavidia, L. M.; Chan, J.; Joyson, A.; Azzam, O.; Carnagarin, R.; Kiuchi, M. G.; Vignarajan, J.; Schlaich, M. P. (ATHEROSCLEROSIS, 2021)
CRIS-Team WoS Importer:2021-09-24

Cardiac effects of hypertension - Schmieder, Roland; Nitschmann, S. (Internist, 2015)
EVALuna2:3766

Cardiac Imaging and Management of Cardiac Disease in Asymptomatic Renal Transplant Candidates: A Current Update - Lioudaki, Eirini; Androvitsanea, Ariadni; Petrakis, Ioannis; Bakogiannis, Constantinos; Androulakis, Emmanuel (Diagnostics, 2022)
Given the high cardiovascular risk accompanying end-stage kidney disease, it would be of paramount importance for the clinical nephrologist to know which screening method(s) identify high-risk patients and whether screening asymptomatic transplant candidates effectively reduces cardiovascular risk in the perioperative setting as well as in the longer term. Within this review, key studies concerning the above questions are reported and critically analyzed. The lack of unified screening criteria and of a prognostically sufficient screening cardiovascular effect for renal transplant candidates sets the foundation for a personalized patient approach in the near future and highlights the need for well-designed studies to produce robust evidence which will address the above questions.
CRIS-Team Scopus Importer:2022-11-04
Keywords: cardiovascular screening; chronic kidney disease; coronary angiography; end-stage kidney disease; renal transplantation; timing

Cardiovascular and health cost impacts of cuff blood pressure underestimation and overestimation of invasive aortic systolic blood pressure - Fonseca, Ricardo; Palmer, Andrew J.; Picone, Dean S.; Cox, Ingrid A.; Schultz, Martin G.; Black, J. Andrew; Bos, Willem J.W.; Cheng, Hao Min; Chen, Chen Huan; Cremer, Antoine; Dwyer, Nathan; Hughes, Alun D.; et al. (Journal of Hypertension, 2023)
OBJECTIVE: Hypertension management is directed by cuff blood pressure (BP), but this may be inaccurate, potentially influencing cardiovascular disease (CVD) events and health costs. This study aimed to determine the impact on CVD events and related costs of the differences between cuff and invasive SBP. METHODS: Microsimulations based on Markov modelling over one year were used to determine the differences in the number of CVD events (myocardial infarction or coronary death, stroke, atrial fibrillation or heart failure) predicted by Framingham risk and total CVD health costs based on cuff SBP compared with invasive (aortic) SBP. Modelling was based on international consortium data from 1678 participants undergoing cardiac catheterization and 30 separate studies. Cuff underestimation and overestimation were defined as cuff SBP less than invasive SBP and cuff SBP greater than invasive SBP, respectively. RESULTS: The proportion of people with cuff SBP underestimation versus overestimation progressively increased as SBP increased. This reached a maximum ratio of 16 : 1 in people with hypertension grades II and III. Both the number of CVD events missed (predominantly stroke, coronary death and myocardial infarction) and associated health costs increased stepwise across levels of SBP control, as cuff SBP underestimation increased. The maximum number of CVD events potentially missed (11.8/1000 patients) and highest costs (241 300 USD/1000 patients) were seen in people with hypertension grades II and III and with at least 15 mmHg of cuff SBP underestimation. CONCLUSION: Cuff SBP underestimation can result in potentially preventable CVD events being missed and major increases in health costs. These issues could be remedied with improved cuff SBP accuracy.
CRIS-Team Scopus Importer:2023-09-08

Cardiovascular and renal outcomes by baseline albuminuria status and renal function: Results from the LEADER randomized trial - Mosenzon, Ofri; Bain, Stephen C.; Heerspink, Hiddo J. L.; Idorn, Thomas; Mann, Johannes; Persson, Frederik; Pratley, Richard E.; Rasmussen, Soren; Rossing, Peter; Von Scholten, Bernt Johan; Raz, Itamar (Diabetes Obesity & Metabolism, 2020)
Aim: To assess cardiorenal outcomes by baseline urinary albumin-to-creatinine ratio (UACR) and estimated glomerular filtration rate (eGFR) in the contemporary LEADER cohort. Materials and methods: LEADER was a multinational, double-blind trial. Patients with type 2 diabetes and high cardiovascular (CV) risk were randomized 1:1 to the glucagon-like peptide-1 analogue liraglutide (≤1.8 mg daily; n = 4668) or placebo (n = 4672) plus standard care and followed for 3.5 to 5 years. Primary composite outcomes were time to first non-fatal myocardial infarction, non-fatal stroke or CV death. Post hoc Cox regression analyses of outcomes by baseline UACR and eGFR subgroups were conducted with adjustment for baseline variables. Results: In the LEADER population, 1598 (17.5%), 2917 (31.9%), 1200 (13.1%), 1611 (17.6%), 845 (9.2%) and 966 (10.6%) had UACR = 0, >0 to <15, 15 to <30, 30 to <100, 100 to <300 and ≥300 mg/g, respectively. Increasing UACR and decreasing eGFR were linked with higher risks of the primary outcome, heart failure hospitalization, a composite renal outcome and death (P-values for the Cochran-Armitage test for trends were all <.0001). Across UACR and eGFR subgroups, risks of cardiorenal events and death were generally lower or similar with liraglutide versus placebo. Conclusions: In a contemporary type 2 diabetes population, increasing baseline UACR and declining eGFR were linked with higher risks of cardiorenal events and death.
CRIS-Team Scopus Importer:2020-08-14
Keywords: albuminuria; cardiovascular outcomes; glomerular filtration rate; liraglutide; mortality; renal outcomes

Cardiovascular changes in the NZB/W F1 mouse model of lupus nephritis - Böhme, Romy; Daniel, Christoph; Ferrazzi, Fulvia; Angeloni, Miriam; Ekici, Arif Bülent; Winkler, Thomas; Hilgers, Karl Friedrich; Wellmann, Ute; Voll, Reinhard E.; Amann, Kerstin Ute (Frontiers in Cardiovascular Medicine, 2023)
Background: Patients with systemic lupus erythematosus (SLE), an autoimmune disease, have a higher risk of cardiovascular (CV) disease and death. In addition, up to 40%–50% of SLE patients develop lupus nephritis (LN) and chronic kidney disease, which is an additional CV risk factor. Thus, the individual contributions of LN and other SLE-specific factors to CV events are unclear. Methods: In this study, we investigated the effect of LN on the development of CV changes using the female NZBxNZW F1 (NZB/W) mouse model of lupus-like disease, with female NZW mice as controls. Standard serologic, morphologic, immunohistologic, and molecular analyses were performed. In a separate group of NZB/W mice, systolic blood pressure (BP) was measured during the course of the disease using tail plethysmography. Results: Our data show marked CV changes in NZB/W mice, i.e., increased heart weight, hypertrophy of the left ventricle (LV) and septum, and increased wall thickness of the intramyocardial arteries and the aorta, which correlated with the progression of renal damage, but not with the age of the mice. In addition, systolic BP was increased in NZB/W mice only when kidney damage progressed and proteinuria was present. Pathway analysis based on gene expression data revealed a significant upregulation of the response to interferon beta in NZB/W mice with moderate kidney injury compared with NZB mice. Furthermore, IFI202b and IL-6 mRNA expression is correlated with CV changes. Multiple linear regression analysis demonstrated serum urea as a surrogate marker of kidney function and IFI202b expression as an independent predictor for LV wall thickness. In addition, deposition of complement factors CFD and C3c in hearts from NZB/W mice was seen, which correlated with the severity of kidney disease. Conclusions: Thus, we postulate that the pathogenesis of CV disease in SLE is affected by renal impairment, i.e., LN, but it can also be partly influenced by lupus-specific cardiac expression of pro-inflammatory factors and complement deposition.
CRIS-Team Scopus Importer:2023-08-18
Keywords: autoimmune disease; cardiovascular disease; IL-15; interferon-related; renal disease; systemic lupus erythematosus

Cardiovascular Mortality Can Be Predicted by Heart Rate Turbulence in Hemodialysis Patients - Braunisch, Matthias C.; Mayer, Christopher C.; Bauer, Axel; Lorenz, Georg; Haller, Bernhard; Rizas, Konstantinos D.; Hagmair, Stefan; von Stülpnagel, Lukas; Hamm, Wolfgang; Günthner, Roman; Angermann, Susanne; Matschkal, Julia; et al. (Frontiers in Physiology, 2020)
Background: Excess mortality in hemodialysis patients is mostly of cardiovascular origin. We examined the association of heart rate turbulence (HRT), a marker of baroreflex sensitivity, with cardiovascular mortality in hemodialysis patients. Methods: A population of 290 prevalent hemodialysis patients was followed up for a median of 3 years. HRT categories 0 (both turbulence onset [TO] and slope [TS] normal), 1 (TO or TS abnormal), and 2 (both TO and TS abnormal) were obtained from 24 h Holter recordings. The primary end-point was cardiovascular mortality. Associations of HRT categories with the endpoints were analyzed by multivariable Cox regression models including HRT, age, albumin, and the improved Charlson Comorbidity Index for hemodialysis patients. Multivariable linear regression analysis identified factors associated with TO and TS. Results: During the follow-up period, 20 patients died from cardiovascular causes. In patients with HRT categories 0, 1 and 2, cardiovascular mortality was 1, 10, and 22%, respectively. HRT category 2 showed the strongest independent association with cardiovascular mortality with a hazard ratio of 19.3 (95% confidence interval: 3.69–92.03; P < 0.001). Age, calcium phosphate product, and smoking status were associated with TO and TS. Diabetes mellitus and diastolic blood pressure were only associated with TS. Conclusion: Independent of known risk factors, HRT assessment allows identification of hemodialysis patients with low, intermediate, and high risk of cardiovascular mortality. Future prospective studies are needed to translate risk prediction into risk reduction in hemodialysis patients.
CRIS-Team Scopus Importer:2020-03-17
Keywords: baroreflex; cardiovascular mortality; heart rate turbulence; hemodialysis; mortality risk prediction

Cardiovascular outcomes and achieved blood pressure in patients with and without diabetes at high cardiovascular risk - Böhm, Michael; Schumacher, Helmut; Teo, Koon K.; Lonn, Eva M.; Mahfoud, Felix; Mann, Johannes; Mancia, Giuseppe; Redon, Josep; Schmieder, Roland; Marx, Nikolaus; Sliwa, Karen; Weber, Michael A.; et al. (European Heart Journal, 2019)
AIMS: Studies have shown a non-linear relationship between systolic blood pressure (SBP) and diastolic blood pressure (DBP) and outcomes, with increased risk observed at both low and high blood pressure (BP) levels. We hypothesized that the BP-risk association is different in individuals with and without diabetes at high cardiovascular risk. METHODS AND RESULTS: We identified patients with (N = 11 487) or without diabetes (N = 19 450), from 30 937 patients, from 133 centres in 44 countries with a median follow-up of 56 months in the ONTARGET/TRANSCEND studies. Patients had a prior history of stroke, myocardial infarction (MI), peripheral artery disease, or were high-risk diabetics. Patients in ONTARGET had been randomized to ramipril 10 mg daily, telmisartan 80 mg daily, or the combination of both. Patients in TRANSCEND were ACE intolerant and randomized to telmisartan 80 mg daily or matching placebo. We analysed the association of mean achieved in-trial SBP and DBP with the composite outcome of cardiovascular death, MI, stroke and hospitalization for congestive heart failure (CHF), the components of the composite, and all-cause death. Data were analysed by Cox regression and restricted cubic splines, adjusting for risk markers including treatment allocation and accompanying cardiovascular treatments. In patients with diabetes, event rates were higher across the whole spectrum of SBP and DBP compared with those without diabetes (P < 0.0001 for the primary composite outcome, P < 0.01 for all other endpoints). Mean achieved in-trial SBP ≥160 mmHg was associated with increased risk for the primary outcome [diabetes/no diabetes: adjusted hazard ratio (HR) 2.31 (1.93-2.76)/1.66 (1.36-2.02) compared with non-diabetics with SBP 120 to <140 mmHg], with similar findings for all other endpoints in patients with diabetes, and for MI and stroke in patients without diabetes. In-trial SBP <120 mmHg was associated with increased risk for the combined outcome in patients with diabetes [HR 1.53 (1.27-1.85)], and for cardiovascular death and all-cause death in all patients. In-trial DBP ≥90 mmHg was associated with increased risk for the primary outcome [diabetes/no diabetes: HR 2.32 (1.91-2.82)/1.61 (1.35-1.93) compared with non-diabetics with DBP 70 to <80 mmHg], with similar findings for all other endpoints, but not for CHF hospitalizations in patients without diabetes. In-trial DBP <70 mmHg was associated with increased risk for the combined outcome in all patients [diabetes/no diabetes: HR 1.77 (1.51-2.06)/1.30 (1.16-1.46)], and also for all other endpoints except stroke. CONCLUSION: High on treatment BP levels (≥160 or ≥90 mmHg) are associated with increased risk of cardiovascular outcomes and death. Also low levels (<120 or <70 mmHg) are associated with increased cardiovascular outcomes (except stroke) and death. Patients with diabetes have consistently higher risks over the whole BP range, indicating that achieving optimal BP goals is most impactful in this group. These data favour guidelines taking lower BP boundaries into consideration, in particular in diabetes. CLINICAL TRIAL REGISTRATION: http://clinicaltrials.gov.Unique identifier: NCT00153101.
EVALuna2:118635

Cardiovascular outcomes, bleeding risk, and achieved blood pressure in patients on long-term anticoagulation with the thrombin antagonist dabigatran or warfarin: Data from the RE-LY trial - Böhm, Michael; Brueckmann, Martina; Eikelboom, John W.; Ezekowitz, Michael; Fräßdorf, Mandy; Hijazi, Ziad; Hohnloser, Stefan H.; Mahfoud, Felix; Schmieder, Roland; Schumacher, Helmut; Wallentin, Lars; Yusuf, Salim (European Heart Journal, 2020)
Aims A J-shaped association of cardiovascular events to achieved systolic (SBP) and diastolic (DBP) blood pressure was shown in high-risk patients. This association on oral anticoagulation is unknown. This analysis from RELY assessed the risks of death, stroke or systemic emboli, and bleeding according to mean achieved SBP and DBP in atrial fibrillation on oral anticoagulation. Methods RE-LY patients were followed for 2 years and recruited between 22 December 2005 until 15 December 2007. and results 18.113 patients were randomized in 951 centres in 54 countries and 18,107 patients with complete blood pressure (BP) data were analysed with a median follow-up of 2.0 years and a complete follow-up in 99.9%. The association between achieved mean SBP and DBP on all-cause death, stroke and systemic embolic events (SSE), major, and any bleeding were explored. On treatment, SBP >140 mmHg and <120 mmHg was associated with all-cause death compared with SBP 120-130 mmHg (reference). For SSE, risk was unchanged at SBP <110 mmHg but increased at 140-160 mmHg (adjusted hazard ratio (HR) 1.81; 1.40-2.33) and SBP >_160 mmHg (HR 3.35; 2.09-5.36). Major bleeding events were also increased at <110 mmHg and at 110 to <120 mmHg. Interestingly, there was no increased risk of major bleeding at SBP >130 mmHg. Similar patterns were observed for DBP with an increased risk at <70 mmHg (HR 1.55; 1.35-1.78) and >90 mmHg (HR 1.88; 1.43-2.46) for all-cause death compared to 70 to <80 mmHg (reference). Risk for any bleeding was increased at low DBP <70 mmHg (HR 1.46; 1.37-1.56) at DBP 80 to <90 mmHg (HR 1.13; 1.06-1.31) without increased risk at higher achieved DBP. Dabigatran 150 mg twice daily showed an advantage in all patients for all-cause death and SSE and there was an advantage for 110 mg dabigatran twice daily for major bleeding and any bleeding irrespective of SBP or DBP achieved. Similar results were obtained for baseline BP, time-updated BP, and BP as time-varying covariate. Conclusion Low achieved SBP associates with increased risk of death, SSE, and bleeding in patients with atrial fibrillation on oral anticoagulation. Major bleeding events did not occur at higher BP. Low BP might identify high-risk patients not only for death but also for high bleeding risks.
CRIS-Team Scopus Importer:2020-09-18
Keywords: Anticoagulation; Atrial fibrillation; Bleeding; Blood pressure; Hypertension; Novel anticoagulants; Stroke; Systemic embolism

Cardiovascular outcomes in patients at high cardiovascular risk with previous myocardial infarction or stroke - Boehm, Michael; Schumacher, Helmut; Teo, Koon K.; Lonn, Eva M.; Lauder, Lucas; Mancia, Giuseppe; Redon, Josep; Schmieder, Roland; Sliwa, Karen; Marx, Nikolaus; Weber, Michael A.; Williams, Bryan; et al. (Journal of Hypertension, 2021)
Background: Guidelines recommend to start blood pressure (BP)-lowering drugs also according to cardiovascular risk including history of cardiovascular events. We hypothesized that in patients with a history of myocardial infarction (MI), stroke, both or none of those, the index events predict the next event and have different SBP risk associations to different cardiovascular outcomes. Design and measurements: In this pooled posthoc, nonprespecified analysis, we assessed outcome data from high-risk patients aged 55 years or older with a history of cardiovascular events or proven cardiovascular disease, randomized to the Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial and to Telmisartan Randomized Assessment Study in ACE Intolerant Subjects with Cardiovascular Disease Trial investigating telmisartan, ramipril and their combination with a median follow-up of 56 months. Standardized office BP was measured every 6 months. Associations of mean achieved BP on treatment were investigated on MI, stroke and cardiovascular death. We identified patients with previous MI (N = 13 487), stroke (N = 4985), both (N = 1509) or none (N = 10 956) of these index events. Analyses were done by Cox regression, analysis of variance and Chi(2)-test. 30 937 patients with complete data were enrolled between 1 December 2001 and 31 July 2003, and followed until 31 July 2008. Data of both trials were pooled as the outcomes were similar. Results: Patients with MI as index event had a higher risk to experience a second MI [hazard ratio 1.42 (confidence interval (CI) 1.20-1.69), P < 0.0001] compared with patients with no events but no increased risk for a stroke as a next event [hazard ratio 0.95 (CI 0.73-1.23), n.s.]. The risk was roughly doubled when they had both, MI and stroke before [hazard ratio 2.07 (CI 1.58-2.71), P < 0.0001]. Patients with a stroke history had a roughly three-fold higher likelihood to experience a second stroke [hazard ratio 2.89 (CI 2.37-3.53) P < 0.0001] but not MI [hazard ratio 1.07 (CI 0.88-1.32), n.s.]. Both types of index events increased roughly three-fold the risk of a second stroke compared with no previous events. The SBP-risk relationship was not meaningfully altered by the event history. After MI and stroke the risk for subsequent events and cardiovascular death was increased over the whole SBP spectrum. A J-shape relationship between BP and outcome was only observed for cardiovascular death. Conclusion: Previous MI and previous stroke are associated with increased risk for the same event in the future, independent of achieved SBP. Thus, secondary prevention may also be chosen according to the event history of patients.
CRIS-Team WoS Importer:2021-07-23

Cardiovascular Risk Reduction After Renal Denervation According to Time in Therapeutic Systolic Blood Pressure Range - Mahfoud, Felix; Mancia, Giuseppe; Schmieder, Roland; Ruilope, Luis; Narkiewicz, Krzysztof; Schlaich, Markus; Williams, Bryan; Ribichini, Flavio; Weil, Joachim; Kao, Hsien Li; Rodriguez-Leor, Oriol; Noory, Elias; et al. (Journal of the American College of Cardiology, 2022)
Background: Renal denervation (RDN) has been shown to lower blood pressure (BP), but its effects on cardiovascular events have only been preliminarily evaluated. Time in therapeutic range (TTR) of BP is associated with cardiovascular events. Objectives: This study sought to assess the impact of catheter-based RDN on TTR and its association with cardiovascular outcomes in the GSR (Global SYMPLICITY Registry). Methods: Patients with uncontrolled hypertension were enrolled and treated with radiofrequency RDN. Office and ambulatory systolic blood pressure (OSBP and ASBP) were measured at 3, 6, 12, 24, and 36 months postprocedure and used to derive TTR. TTR through 6 months was assessed as a predictor of cardiovascular events from 6 to 36 months using a Cox proportional hazard regression model. Results: As of March 1, 2022, 3,077 patients were enrolled: 42.2% were female; mean age was 60.5 ± 12.2 years; baseline OSBP was 165.6 ± 24.8 mm Hg; and baseline ASBP was 154.3 ± 18.7 mm Hg. Patients were prescribed 4.9 ± 1.7 antihypertensive medications at baseline and 4.8 ± 1.9 at 36 months. At 36 months, mean changes were −16.7 ± 28.4 and −9.0 ± 20.2 mm Hg for OSBP and ASBP, respectively. TTR through 6 months was 30.6%. A 10% increase in TTR after RDN through 6 months was associated with significant risk reductions from 6 to 36 months of 15% for major adverse cardiovascular events (P < 0.001), 11% cardiovascular death (P = 0.010), 15% myocardial infarction (P = 0.023), and 23% stroke (P < 0.001). Conclusions: There were sustained BP reductions and higher TTR through 36 months after RDN. A 10% increase in TTR through 6 months was associated with significant risk reductions in major cardiovascular events from 6 to 36 months. (Global SYMPLICITY Registry [GSR] DEFINE; NCT01534299)
CRIS-Team Scopus Importer:2022-11-11
Keywords: cardiovascular death; hypertension; myocardial infarction; risk reduction; stroke

Cardiovascular Risk Reduction With Liraglutide: An Exploratory Mediation Analysis of the LEADER Trial - Buse, John B.; Bain, Stephen C.; Mann, Johannes; Nauck, Michael A.; Nissen, Steven E.; Pocock, Stuart; Poulter, Neil R.; Pratley, Richard E.; Linder, Martin; Monk Fries, Tea; Orsted, David D.; Zinman, Bernard (Diabetes Care, 2020)
OBJECTIVE The Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results (LEADER) trial (reg. no.) demonstrated a reduced risk of cardiovascular (CV) events for patients with type 2 diabetes who received the glucagon-like peptide 1 receptor agonist liraglutide versus placebo. The mechanisms behind this CV benefit remain unclear. We aimed to identify potential mediators for the CV benefit observed with liraglutide in the LEADER trial. RESEARCH DESIGN AND METHODS We performed exploratory analyses to identify potential mediators of the effect of liraglutide on major adverse CV events (MACE; composite of CV death, nonfatal myocardial infarction, or nonfatal stroke) from the following candidates: glycated hemoglobin (HbA(1c)), body weight, urinary albumin-to-creatinine ratio (UACR), confirmed hypoglycemia, sulfonylurea use, insulin use, systolic blood pressure, and LDL cholesterol. These candidates were selected as CV risk factors on which liraglutide had an effect in LEADER such that a reduction in CV risk might result. We used two methods based on a Cox proportional hazards model and the new Vansteelandt method designed to use all available information from the mediator and to control for confounding factors. RESULTS Analyses using the Cox methods and Vansteelandt method indicated potential mediation by HbA(1c)(up to 41% and 83% mediation, respectively) and UACR (up to 29% and 33% mediation, respectively) on the effect of liraglutide on MACE. Mediation effects were small for other candidates. CONCLUSIONS These analyses identify HbA(1c)and, to a lesser extent, UACR as potential mediators of the CV effects of liraglutide. Whether either is a marker of an unmeasured factor or a true mediator remains a key question that invites further investigation.
CRIS-Team WoS Importer:2020-07-10

Catheter-based alcohol-mediated renal denervation for the treatment of uncontrolled hypertension: design of two sham-controlled, randomized, blinded trials in the absence (TARGET BP OFF-MED) and presence (TARGET BP I) of antihypertensive medications - Mahfoud, Felix; Weber, Michael; Schmieder, Roland; Lobo, Melvin D.; Blankestijn, Peter J.; Persu, Alexandre; Fischell, Tim A.; Parise, Helen; Pathak, Atul; Kandzari, David E. (American Heart Journal, 2021)
Background: Arterial hypertension is a common and life-threatening condition and poses a large global health burden. Device-based treatments have been developed as adjunctive or alternative therapy, to be used with or without antihypertensive medication for treating uncontrolled hypertension. The safety and feasibility of chemical renal denervation (RDN) using the Peregrine Catheter and alcohol were demonstrated in a first-in-man and open-label clinical trials, prompting the initiation of the ongoing TARGET BP OFF-MED and TARGET BP I trials. Design: The TARGET BP trials are randomized, blinded, sham-controlled trials designed to assess the safety and efficacy of alcohol-mediated RDN for the treatment of uncontrolled hypertension in the absence of antihypertensive medications (TARGET BP OFF-MED) or in addition to prescribed antihypertensive medications (TARGET BP I). Subjects with confirmed uncontrolled hypertension and suitable renal artery anatomy are randomized (1:1) to receive either RDN using the Peregrine Kit with alcohol (0.6 mL per renal artery) infused through the Peregrine Catheter or diagnostic renal angiography only (sham procedure). TARGET BP OFF-MED completed enrollment and randomized 96 subjects. TARGET BP I will randomize approximately 300 subjects and will transition to an open-label safety cohort of approximately 300 subjects receiving RDN once the primary efficacy endpoint of the Randomized Controlled Trial (RCT) cohort has been met. Primary endpoints are change in mean 24-hour ambulatory systolic blood pressure from baseline to 8 weeks (TARGET BP OFF-MED) and 3 months (TARGET BP I) post-procedure. Conclusion: The TARGET BP trials are the first large-scale, international, randomized trials aimed to investigate the safety and BP lowering efficacy of a novel RDN method, with perivascular alcohol delivery using the Peregrine Kit.
CRIS-Team Scopus Importer:2021-07-23

Catheter-based renal denervation for treatment of patients with treatment-resistant hypertension: 36 month results from the SYMPLICITY HTN-2 randomized clinical trial - Esler, Murray D.; Boehm, Michael; Sievert, Horst; Rump, Christian L.; Schmieder, Roland; Krum, Henry; Mahfoud, Felix; Schlaich, Markus P. (European Heart Journal, 2014)
The aim of this study was to determine long-term results of renal artery denervation for treatment of treatment-resistant hypertension in the SYMPLICITY HTN-2 study.SYMPLICITY HTN-2 randomized 106 subjects with treatment-resistant hypertension to renal denervation or medical therapy alone. At 6 months, 37 control subjects crossed over to renal denervation. Office blood pressure measurements, antihypertensive medication use, and safety events were followed every 6 months through 3 years.Follow-up was available at 36 months in 40 of 52 subjects in the initial renal denervation group and at 30 months in 30 of 37 subjects who crossed over and received renal denervation at 6 months. Baseline blood pressure was 184 ± 19/99 ± 16 mmHg in all treated subjects. At 30-month post-procedure, systolic blood pressure decreased 34 mmHg (95% CI: -40, -27, P < 0.01) and diastolic blood pressure decreased 13 mmHg (95% CI: -16, -10, P < 0.01). The systolic and diastolic blood pressure reduction at 36 months for the initial renal denervation group was -33 mmHg (95% CI: -40, -25, P < 0.01) and -14 mmHg (95% CI: -17, -10, P < 0.01), respectively. Procedural complications included one haematoma, and one renal artery dissection before energy delivery that was treated successfully. Later complications included two cases of acute renal failure, which fully resolved, 15 hypertensive events requiring hospitalization, and three deaths.Renal denervation resulted in sustained lowering of blood pressure at 3 years in a selected population of subjects with severe, treatment-resistant hypertension without serious safety concerns.NCT00888433.
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Catheter-based renal denervation in patients with uncontrolled hypertension in the absence of antihypertensive medications (SPYRAL HTN-OFF MED): a randomised, sham-controlled, proof-of-concept trial - Townsend, Raymond R.; Mahfoud, Felix; Kandzari, David E.; Kario, Kazuomi; Pocock, Stuart; Weber, Michael A.; Ewen, Sebastian; Tsioufis, Konstantinos; Tousoulis, Dimitrios; Sharp, Andrew S.P.; Watkinson, Anthony F.; Schmieder, Roland; et al. (Lancet, 2017)
Previous randomised renal denervation studies did not show consistent efficacy in reducing blood pressure. The objective of our study was to evaluate the effect of renal denervation on blood pressure in the absence of antihypertensive medications.SPYRAL HTN-OFF MED was a multicentre, international, single-blind, randomised, sham-controlled, proof-of-concept trial. Patients were enrolled at 21 centres in the USA, Europe, Japan, and Australia. Eligible patients were drug-naive or discontinued their antihypertensive medications. Patients with an office systolic blood pressure (SBP) of 150 mm Hg or greater and less than 180 mm Hg, office diastolic blood pressure (DBP) of 90 mm Hg or greater, and a mean 24-h ambulatory SBP of 140 mm Hg or greater and less than 170 mm Hg at second screening underwent renal angiography and were randomly assigned to renal denervation or sham control. Patients, caregivers, and those assessing blood pressure were blinded to randomisation assignments. The primary endpoint, change in 24-h blood pressure at 3 months, was compared between groups. Drug surveillance was done to ensure patient compliance with absence of antihypertensive medication. The primary analysis was done in the intention-to-treat population. Safety events were assessed at 3 months. This study is registered with ClinicalTrials.gov, number NCT02439749.Between June 25, 2015, and Jan 30, 2017, 353 patients were screened. 80 patients were randomly assigned to renal denervation (n=38) or sham control (n=42) and followed up for 3 months. Office and 24-h ambulatory blood pressure decreased significantly from baseline to 3 months in the renal denervation group: 24-h SBP -5·5 mm Hg (95% CI -9·1 to -2·0; p=0·0031), 24-h DBP -4·8 mm Hg (-7·0 to -2·6; p<0·0001), office SBP -10·0 mm Hg (-15·1 to -4·9; p=0·0004), and office DBP -5·3 mm Hg (-7·8 to -2·7; p=0·0002). No significant changes were seen in the sham-control group: 24-h SBP -0·5 mm Hg (95% CI -3·9 to 2·9; p=0·7644), 24-h DBP -0·4 mm Hg (-2·2 to 1·4; p=0·6448), office SBP -2·3 mm Hg (-6·1 to 1·6; p=0·2381), and office DBP -0·3 mm Hg (-2·9 to 2·2; p=0·8052). The mean difference between the groups favoured renal denervation for 3-month change in both office and 24-h blood pressure from baseline: 24-h SBP -5·0 mm Hg (95% CI -9·9 to -0·2; p=0·0414), 24-h DBP -4·4 mm Hg (-7·2 to -1·6; p=0·0024), office SBP -7·7 mm Hg (-14·0 to -1·5; p=0·0155), and office DBP -4·9 mm Hg (-8·5 to -1·4; p=0·0077). Baseline-adjusted analyses showed similar findings. There were no major adverse events in either group.Results from SPYRAL HTN-OFF MED provide biological proof of principle for the blood-pressure-lowering efficacy of renal denervation.Medtronic.
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Central arteriovenous anastomosis and hypertension - Authors' reply - Lobo, Melvin D.; Sobotka, Paul A.; Dolan, Eamon; Witkowski, Adam; Schmieder, Roland (Lancet, 2015)
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Central arteriovenous anastomosis for the treatment of patients with uncontrolled hypertension (the ROX CONTROL HTN study): a randomised controlled trial - Lobo, Melvin D.; Sobotka, Paul A.; Stanton, Alice; Cockcroft, John R.; Sulke, Neil; Dolan, Eamon; Van Der Giet, Markus; Hoyer, Joachim; Furniss, Stephen S.; Foran, John P.; Witkowski, Adam; Januszewicz, Andrzej; et al. (Lancet, 2015)
Hypertension contributes to cardiovascular morbidity and mortality. We assessed the safety and efficacy of a central iliac arteriovenous anastomosis to alter the mechanical arterial properties and reduce blood pressure in patients with uncontrolled hypertension.We enrolled patients in this open-label, multicentre, prospective, randomised, controlled trial between October, 2012, and April, 2014. Eligible patients had baseline office systolic blood pressure of 140 mm Hg or higher and average daytime ambulatory blood pressure of 135 mm Hg or higher systolic and 85 mm Hg or higher diastolic despite antihypertensive treatment. Patients were randomly allocated in a 1:1 ratio to undergo implantation of an arteriovenous coupler device plus current pharmaceutical treatment or to maintain current treatment alone (control). The primary endpoint was mean change from baseline in office and 24 h ambulatory systolic blood pressure at 6 months. Analysis was by modified intention to treat (all patients remaining in follow-up at 6 months). This trial is registered with ClinicalTrials.gov, number NCT01642498.83 (43%) of 195 patients screened were assigned arteriovenous coupler therapy (n=44) or normal care (n=39). Mean office systolic blood pressure reduced by 26·9 (SD 23·9) mm Hg in the arteriovenous coupler group (p<0·0001) and by 3·7 (21·2) mm Hg in the control group (p=0·31). Mean systolic 24 h ambulatory blood pressure reduced by 13·5 (18·8) mm Hg (p<0·0001) in arteriovenous coupler recipients and by 0·5 (15·8) mm Hg (p=0·86) in controls. Implantation of the arteriovenous coupler was associated with late ipsilateral venous stenosis in 12 (29%) of 42 patients and was treatable with venoplasty or stenting.Arteriovenous anastomosis was associated with significantly reduced blood pressure and hypertensive complications. This approach might be a useful adjunctive therapy for patients with uncontrolled hypertension.ROX Medical.
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Central arteriovenous anastomosis to treat resistant hypertension - Kapil, Vikas; Sobotka, Paul A.; Lobo, Mel D.; Schmieder, Roland (Current Opinion in Nephrology and Hypertension, 2017)
Novel, interventional treatments have emerged in the last decade for the treatment of resistant hypertension. This review focuses on a unique device that creates a fixed calibre, central iliac arteriovenous anastomosis that is significantly different in haemodynamic and safety profile from traditional haemodialysis fistulae. The background, physiology, and clinical data to date will be presented.The single, randomized, controlled clinical trial using the ROX coupler in patients with resistant hypertension demonstrated substantial reductions in both office and ambulatory blood pressure to 12-month postimplantation. There was a common, but manageable, adverse effect of upstream iliac venous stenosis causing ipsilateral lower limb oedema. There were no renal safety concerns. The mechanism of action is proposed to be mechanical by provision of a low-pressure parallel circuit attached to the high-pressure arterial system though detailed physiological evaluation is currently lacking.Preliminary data using the ROX coupler to form a central arteriovenous anastomosis are very encouraging. Concerns regarding the lack of sham control are to some extent mitigated by immediate on table blood pressure reduction with opening of the coupler and will be further addressed in the ongoing pivotal, sham-controlled ROX CONTROL Hypertension2 study which should provide further robust information regarding efficacy and safety.
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Central Iliac Arteriovenous Anastomosis for Uncontrolled Hypertension: One-Year Results From the ROX CONTROL HTN Trial - Lobo, Melvin D.; Ott, Christian; Sobotka, Paul A.; Saxena, Manish; Stanton, Alice; Cockcroft, John R.; Sulke, Neil; Dolan, Eamon; Van Der Giet, Markus; Hoyer, Joachim; Furniss, Stephen S.; Foran, John P.; et al. (Hypertension, 2017)
Creation of a central iliac arteriovenous anastomosis using a novel nitinol coupler device results in an immediate, significant reduction of blood pressure (BP). We present efficacy and safety findings at 12 months post-coupler insertion. This open-label, multicenter, prospective, randomized trial enrolled patients with a baseline office systolic BP >=140 mm Hg and average daytime ambulatory BP >=135/85 mm Hg. Subjects were randomly allocated to coupler implantation and continuing previous pharmacotherapy or to maintain previous treatment alone. At 12 months, 39 patients who had coupler therapy were included in the intention-to-treat analysis. Office-based systolic BP reduced by 25.1±23.3 mm Hg (baseline, 174±18 mm Hg; P<0.0001) post-coupler placement, and office diastolic BP reduced by 20.8±13.3 mm Hg (baseline, 100±13 mm Hg; P<0.0001). Mean 24-hour ambulatory BP reduced by 12.6±17.4/15.3±9.7 mm Hg (P<0.0001 for both). In a prespecified subset of patients who failed to respond adequately to prior renal denervation, coupler therapy led to highly significant reduction in office systolic/diastolic BP (30.7/24.1 mm Hg) and significant reduction in 24-hour ambulatory systolic/diastolic BP (12.4/14.4 mm Hg) at 12 months (n=9). After coupler therapy, 14 patients (33%) developed ipsilateral venous stenosis; all were treated successfully with venous stenting. These findings confirm the importance of arterial mechanics in the pathophysiology of hypertension and support the clinical use of a central iliac arteriovenous anastomosis.URL: http://www.clinicaltrials.gov. Unique identifier: NCT01642498.
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Central processing of afferent renal pathways—significance and implications - Rodionova, Kristina; Veelken, Roland (Pflügers Archiv: European Journal of Physiology, 2020)
CRIS-Team Scopus Importer:2020-09-25

Central pulse pressure is an independent determinant of vascular remodeling in the retinal circulation - Ott, Christian; Raff, Ulrike; Harazny, Joanna M.; Michelson, Georg; Schmieder, Roland (Hypertension, 2013)
Pulse pressure has been recognized as a risk factor for stroke. Moreover, it was shown that central pulse pressure relates more strongly to vascular disease and outcome than (peripheral) brachial pulse pressure. Because vascular remodeling in the retinal circulation mirrors the 1 in the cerebral circulation and represents an easy, noninvasive possibility to assess microvascular changes in humans, we analyzed the impact of central pulse pressure on retinal vascular structure in humans. The study cohort comprised 135 nondiabetic patients across a wide range of blood pressure values. Parameter of retinal arteriolar remodeling (wall-to-lumen ratio) was assessed noninvasively and in vivo by scanning laser Doppler flowmetry. Central pulse pressure and augmentation index normalized to a heart rate of 75 beats per minute were assessed by pulse wave analysis. Central pulse pressure correlated with wall-to-lumen ratio (r=0.302; P<0.001), central augmentation index normalized to a heart rate of 75 beats per minute correlated with wall-to-lumen ratio (r=0.190; P=0.028), and in accordance pulse pressure amplification (peripheral pulse pressure/central pulse pressure) was negatively correlated with wall-to-lumen ratio (r=-0.223; P=0.009). In contrast, central mean arterial pressure was not correlated with wall-to-lumen ratio (r=0.110; P=0.203). Multiple regression analysis revealed an independent relationship between wall-to-lumen ratio and central pulse pressure (?=0.277; P=0.009), but not with other classical cardiovascular risk factors. Thus, central pulse pressure, indicative of changes in large conduit arteries is an independent determinant of vascular remodeling in small retinal arterioles. Such a relationship indicates a coupling and crosstalk between the microvascular and macrovascular changes attributable to hypertension.
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Central pulse pressure predicts BP reduction after renal denervation in patients with treatment-resistant hypertension - Ott, Christian; Schmid, Axel; Toennes, Stefan W.; Ditting, Tilmann; Veelken, Roland; Uder, Michael; Schmieder, Roland (EuroIntervention, 2015)
Enhanced vascular ageing is associated with elevated central pulse pressure (cPP), an independent predictor of cardiovascular (CV) events. Although antihypertensive treatment strategies are effective, high residual CV risk remains indicative of advanced and largely irreversible vascular damage. Renal denervation (RDN) has been shown to reduce blood pressure (BP) to various extents in patients with treatment-resistant hypertension (TRH). We hypothesised that cPP predicts BP reduction after RDN.Sixty-three patients with true TRH underwent catheter-based RDN using the Symplicity Flex(TM) catheter and were followed for six months. At baseline, cPP was assessed by pulse wave analysis (SphygmoCor(TM)). Patients were stratified according to their median cPP (55 mmHg), and called "low cPP" (below the median) or "high cPP" (above the median). Office BP reduction six months after RDN was greater (-22±19/-13±11 vs. -12±20/-5±13 mmHg, p=0.038/0.014) and 24-hr ambulatory blood pressure (ABP) reduction tended to be greater (-11±13/-8±10 vs. -3±18/-4±10 mmHg, p=0.070/0.112) in patients with low cPP compared to those with high cPP. Only cPP (?=0.687, p=0.001) and baseline systolic BP (?=-0.564, p<0.001) were independent determinants of office systolic BP reduction after RDN.Our data suggest that cPP, indicative of the degree of large arterial stiffening, may be helpful to identify responders to RDN.
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cfNOMe - A single assay for comprehensive epigenetic analyses of cell-free DNA - Erger, Florian; Nörling, Deborah; Borchert, Domenica; Leenen, Esther; Habbig, Sandra; Wiesener, Michael S.; Bartram, Malte P.; Wenzel, Andrea; Becker, Christian; Toliat, Mohammad R.; Nürnberg, Peter; Beck, Bodo B.; et al. (Genome Medicine, 2020)
Cell-free DNA (cfDNA) analysis has become essential in cancer diagnostics and prenatal testing. We present cfNOMe, a two-in-one method of measuring cfDNA cytosine methylation and nucleosome occupancy in a single assay using non-disruptive enzymatic cytosine conversion and a custom bioinformatic pipeline. We show that enzymatic cytosine conversion better preserves cfDNA fragmentation information than does bisulfite conversion. Whereas previously separate experiments were required to study either epigenetic marking, cfNOMe delivers reliable results for both, enabling more comprehensive and inexpensive epigenetic cfDNA profiling. cfNOMe has the potential to advance biomarker discovery and diagnostic usage in diseases with systemic perturbations of cfDNA composition.
CRIS-Team Scopus Importer:2020-07-10
Keywords: Analysis software; Cell-free DNA; cfNOMe; Methylome; Nucleosome footprints

Challenges in Long-Term Follow-Up Care of Patients After Kidney Transplantation in Specialized Transplant Centers - Schiffer, Lena; Hartleib-Otto, Melanie; Lerch, Christian; Haller, Hermann; Pape, Lars; Schiffer, Mario (Gesundheitswesen, 2019)
Medical care after kidney transplantation requires a close follow-up in specialized transplant centers to minimize complications. Especially in bigger territorial states, the distance the patients have to cover is an underestimated problem for the patients. We performed a survey of 498 patients who underwent kidney transplantation at the transplant center of Hannover Medical School in Lower Saxony in order to find out the burden imposed by having to travel to one of the outpatient clinics affiliated with it for follow-ups. We found that 72% of the patients had to travel more than 100 km to reach the outpatient clinic and the costs for the trip were € 36.30 (standard deviation € 34.15). A distance between home and transplant center of more than 100 km reduced the motivation to attend the outpatient clinic significantly (p=0.023), whereas reimbursement of travel costs improved the motivation to attend the outpatient clinic only partially (p=0.012). We conclude that novel modern media-based care models like televisits could reduce patient burdens and optimize post-transplant care.
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Change of renal function after short-term use of cardioprotective agents in patients with type 2 diabetes is not accurately assessed by the change of estimated glomerular filtration rate: an observational study - Kolwelter, Julie; Striepe, Kristina; Bosch, Agnes; Kannenkeril, Dennis; Ott, Christian; Schiffer, Mario; Schmieder, Roland (Diabetology & Metabolic Syndrome, 2022)
Background After initiating cardioprotective agents, a fall of estimated glomerular filtration rate (eGFR) has been reported in several studies. Our goal was to evaluate the accuracy of change of Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) eGFR in patients with type 2 diabetes (T2D) after short-term pharmacological intervention with angiotensin-converting enzyme inhibitor, angiotensin-receptor blocker, gliptin or sodium-glucose cotransporter-2 inhibitor. Methods We analyzed 190 patients with T2D in the early stage of the disease, having no overt renal impairment by CKD-EPI equation. In each patient, we measured GFR (mGFR) by applying the constant infusion input clearance technique with sinistrin (Inutest; Fresenius, Linz, Austria) at baseline and after short-term (4-12 weeks) pharmacological intervention with cardioprotective agents (ramipril, telmisartan, linagliptin, metformin, empagliflozin) that potentially lead to an alteration of renal function. Simultaneously, a standardized analysis of serum creatinine was performed and eGFR was estimated by the CKD-EPI equation. Results Average mGFR was 111 +/- 20 ml/min/1.73m(2), whereas eGFR was lower with 93 +/- 13 ml/min/1.73m(2). The ratio eGFR/mGFR in relation to mGFR was almost curvilinear, showing an underestimation of renal function by eGFR in the upper normal range. At baseline only 80 patients (42%) lay within +/- 10% of mGFR and the concordance correlation coefficient (CCC) was extremely low (- 0.07). After short-term pharmacological intervention changes in eGFR and mGFR correlated with each other (r = 0.286, p < 0.001). For example, for a given mGFR of 111 ml/min/1.73m(2), a change of mGFR by +/- 10% corresponded to +/- 11 ml/min/1.73m(2), but the confidence interval of eGFR was 25 ml/min/1.73m(2). The CCC was low (0.22). Conclusion The agreement between eGFR by CKD-EPI and mGFR is modest and the change of renal function after short-term pharmacological intervention is not accurately and precisely reflected by the change of eGFR in patients with T2D in the early stage of their disease.
CRIS-Team WoS Importer:2022-08-05

Changes in 24-Hour Patterns of Blood Pressure in Hypertension Following Renal Denervation Therapy - Kario, Kazuomi; Weber, Michael A.; Mahfoud, Felix; Kandzari, David E.; Schmieder, Roland; Kirtane, Ajay J.; Boehm, Michael; Hettrick, Douglas A.; Townsend, Raymond R.; Tsioufis, Konstantinos P. (Hypertension, 2019)
CRIS-Team WoS Importer:2019-08-23

Changes in Albuminuria Predict Cardiovascular and Renal Outcomes in Type 2 Diabetes: A Post Hoc Analysis of the LEADER Trial - Persson, Frederik; Bain, Stephen C.; Mosenzon, Ofri; Heerspink, Hiddo J. L.; Mann, Johannes; Pratley, Richard; Raz, Itamar; Idorn, Thomas; Rasmussen, Soren; Von Scholten, Bernt Johan; Rossing, Peter (Diabetes Care, 2021)
OBJECTIVE A post hoc analysis to investigate the association between 1-year changes in albuminuria and subsequent risk of cardiovascular and renal events. RESEARCH DESIGN AND METHODS LEADER was a randomized trial of liraglutide up to 1.8 mg/day versus placebo added to standard care for 3.5-5 years in 9,340 participants with type 2 diabetes and high cardiovascular risk. We calculated change in urinary albumin-to-creatinine ratio (UACR) from baseline to 1 year in participants with >30% reduction (n = 2,928), 30-0% reduction (n = 1,218), or any increase in UACR (n = 4,124), irrespective of treatment. Using Cox regression, risks of major adverse cardiovascular events (MACE) and a composite nephropathy outcome (from 1 year to end of trial in subgroups by baseline UACR [<30 mg/g, 30-300 mg/g, or >= 300 mg/g]) were assessed. The analysis was adjusted for treatment allocation alone as a fixed factor and for baseline variables associated with cardiovascular and renal outcomes. RESULTS For MACE, hazard ratios (HRs) for those with >30% and 30-0% UACR reduction were 0.82 (95% CI 0.71, 0.94; P = 0.006) and 0.99 (0.82, 1.19; P = 0.912), respectively, compared with any increase in UACR (reference). For the composite nephropathy outcome, respective HRs were 0.67 (0.49, 0.93; P = 0.02) and 0.97 (0.66, 1.43; P = 0.881). Results were independent of baseline UACR and consistent in both treatment groups. After adjustment, HRs were significant and consistent in >30% reduction subgroups with baseline micro- or macroalbuminuria. CONCLUSIONS A reduction in albuminuria during the 1st year was associated with fewer cardiovascular and renal outcomes, independent of treatment. Albuminuria monitoring remains an important part of diabetes care, with great unused potential.
CRIS-Team WoS Importer:2021-04-09

Changes in blood pressure after crossover to ultrasound renal denervation in patients initially treated with sham in the RADIANCE-HTN SOLO trial - Mahfoud, Felix; Bloch, Michael J.; Azizi, Michel; Wang, Yale; Schmieder, Roland; Lobo, Melvin D.; Sharp, Andrew S. P.; Daemen, Joost; Basile, Jan; Weber, Michael A.; Scicli, Andrea P.; Mcclure, Candace K.; et al. (EuroIntervention, 2021)
Background: The multicentre, randomised, sham-controlled RADIANCE-HTN SOLO trial reported the blood pressure (BP)-lowering efficacy and safety of ultrasound renal denervation (RDN) in the absence (2 months) and presence (6 and 12 months) of antihypertensive medications in patients with mild-to-moderate hypertension.
CRIS-Team WoS Importer:2022-01-07

Changes in Plasma Renin Activity After Renal Artery Sympathetic Denervation - Mahfoud, Felix; Townsend, Raymond R.; Kandzari, David E.; Kario, Kazuomi; Schmieder, Roland; Tsioufis, Konstantinos; Pocock, Stuart; David, Shukri; Patel, Kiritkumar; Rao, Anjani; Walton, Antony; Bloom, Jason E.; et al. (Journal of the American College of Cardiology, 2021)
Background: The renin-angiotensin-aldosterone system plays a key role in blood pressure (BP) regulation and is the target of several antihypertensive medications. Renal denervation (RDN) is thought to interrupt the sympathetic-mediated neurohormonal pathway as part of its mechanism of action to reduce BP. Objectives: The purpose of this study was to evaluate plasma renin activity (PRA) and aldosterone before and after RDN and to assess whether these baseline neuroendocrine markers predict response to RDN. Methods: Analyses were conducted in patients with confirmed absence of antihypertensive medication. Aldosterone and PRA levels were compared at baseline and 3 months post-procedure for RDN and sham control groups. Patients in the SPYRAL HTN-OFF MED Pivotal trial were separated into 2 groups, those with baseline PRA ≥0.65 ng/ml/h (n = 110) versus <0.65 ng/ml/h (n = 116). Follow-up treatment differences between RDN and sham control groups were adjusted for baseline values using multivariable linear regression models. Results: Baseline PRA was similar between RDN and control groups (1.0 ± 1.1 ng/ml/h vs. 1.1 ± 1.1 ng/ml/h; p = 0.37). Change in PRA at 3 months from baseline was significantly greater for RDN compared with control subjects (−0.2 ± 1.0 ng/ml/h; p = 0.019 vs. 0.1 ± 0.9 ng/ml/h; p = 0.14), p = 0.001 for RDN versus control subjects, and similar differences were seen for aldosterone: RDN compared with control subjects (−1.2 ± 6.4 ng/dl; p = 0.04 vs. 0.4 ± 5.4 ng/dl; p = 0.40), p = 0.011. Treatment differences at 3 months in 24-h and office systolic blood pressure (SBP) for RDN versus control patients were significantly greater for patients with baseline PRA ≥0.65 ng/ml/h versus <0.65 ng/ml/h, despite similar baseline BP. Differences in office SBP changes according to baseline PRA were also observed earlier at 2 weeks post-RDN. Conclusions: Plasma renin activity and aldosterone levels for RDN patients were significantly reduced at 3 months when compared with baseline as well as when compared with sham control. Higher baseline PRA levels were associated with a significantly greater reduction in office and 24-h SBP. (SPYRAL PIVOTAL - SPYRAL HTN-OFF MED Study; NCT02439749)
CRIS-Team Scopus Importer:2021-06-11
Keywords: aldosterone; hypertension; plasma renin activity; renal denervation

Changes in Stroke Volume After Renal Denervation: Insight From Cardiac Magnetic Resonance Imaging - Lurz, Philip; Kresoja, Karl Patrik; Rommel, Karl Philipp; von Roeder, Maximilian; Besler, Christian; Lücke, Christian; Gutberlet, Matthias; Schmieder, Roland; Mahfoud, Felix; Thiele, Holger; Desch, Steffen; Fengler, Karl (Hypertension, 2020)
Recent trial results support catheter-based renal denervation (RDN) for treatment of hypertension, while the exact mechanisms causing blood pressure to fall remain incompletely understood. Cardiac magnetic resonance imaging was used to assess the effects of RDN on cardiac function in patients with hypertension undergoing RDN and compared with sham treatment. Cardiac magnetic resonance imaging was used to assess stroke volume index, cardiac index, heart rate, systemic vascular resistance index, and stroke work index from aortic flow measurements. Patients with resistant hypertension from a randomized, sham-controlled RDN trial underwent cardiac magnetic resonance imaging before RDN and at follow-up (randomized cohort). Results were then validated in a cohort of patients with resistant hypertension undergoing RDN and cardiac magnetic resonance imaging (validation cohort). In total, 162 patients were included 52 patients in the randomized trial (27 shams) and 110 patients in the validation cohort. In the randomized cohort, stroke volume index was reduced by 4.7±9.8 mL/m2 in the RDN cohort and remained unchanged in the sham cohort (P=0.008 for between-group comparison), while cardiac index and stroke work index tended to be reduced in RDN patients but not in sham patients (-0.10±5.9 versus 0.17±0.51 L/min per m2 and -7.1±12.5 versus -1.4±10.4 g/m2, P=0.08 for both). In contrast, systemic vascular resistance index and heart rate remained unchanged after RDN. In the validation cohort, reduction of stroke volume index was confirmed, and cardiac index and stroke work index were also reduced significantly, whereas systemic vascular resistance index and heart rate remained unchanged at follow-up. In this study of patients with resistant hypertension, RDN resulted in a reduction of stroke volume when compared with sham.
CRIS-Team Scopus Importer:2020-03-17
Keywords: blood pressure; hemodynamics; magnetic resonance imaging; renal denervation; stroke volume

Changes in T2 Relaxation Time Mapping of Intervertebral Discs Adjacent to Vertebrae after Kyphoplasty Correlate with the Physical Clinical Outcome of Patients - Wegener, Lisa; Werner, Felix; Kleyer, Arnd; Simon, David; Uder, Michael; Janka, Rolf Matthias; Trattnig, Siegfried; Welsch, Goetz H.; Pachowsky, Milena (Diagnostics, 2022)
(1) Background: To assess whether clinical outcomes correlate with tissue changes in the intervertebral discs (IVDs) after kyphoplasty as treatment for vertebral fractures, quantitative MRI was applied. (2) Methods: Quantitative T2 mapping acquired in a 3 T MRI scanner of the thoracolumbar spine was performed in 20 patients two years after kyphoplasty. The IVDs adjacent and nonadjacent to the treated vertebrae were divided into six regions of interest (ROI), which were further categorised into inner (ROI 2–5) and outer (ROI 1 and 6) parts of the IVDs, and the T2 values were analysed. T2 values of adjacent discs were correlated with the items of questionnaires evaluating the clinical outcome (i.e., 36-Item Short Form Survey). (3) Results: Lower T2 values in adjacent IVDs correlated with poorer physical outcome two years after kyphoplasty. The inner part of the IVDs adjacent to treated vertebrae showed statistically significant lower T2 values in segments L2/L3 and L3/L4 compared to nonadjacent ones. Patients with lower T2 values showed more pain and physical limitations in everyday life. (4) Conclusions: Quantitative T2 mapping can detect IVD degeneration in patients after kyphoplasty and correlates with the physical outcome. This technique could help to gain better insights into alterations in tissue composition following kyphoplasty and the consequences for the patients’ quality of life.
CRIS-Team Scopus Importer:2022-03-11
Keywords: Clinical outcome; Intervertebral disc; Kyphoplasty; MRI; T2 mapping

CHANGES IN THE KYNURENINE PATHWAY LEAD TO ALTERATIONS IN NAD BALANCE AND BIOENERGETICS PARAMETERS IN GLOMERULAR CELLS IN VITRO AND CONTRIBUTE TO PROTEINURIA IN A ZEBRAFISH MODEL - Bolanos-Palmieri, Patricia; Kotb, Ahmed; Schenk, Heiko; Baehre, Heike; Schroder, Patricia; Schiffer, Mario (NEPHROLOGY DIALYSIS TRANSPLANTATION, 2021)
CRIS-Team WoS Importer:2021-12-03

Characterizations of drug carrying magnetic nanoparticles for tumor therapy: Biological outcome and first immunological aspects - Dürr, Stephan; Tietze, Rainer; Lyer, Stefan; Janko, Christina; Schreiber, Eveline; Mann, Johannes; Turcu, R.; Gitter, K.; Odenbach, S.; Vasylyev, Serhiy; Herrmann, Martin; Peukert, Wolfgang; et al. (Magnetohydrodynamics, 2013)
Nanosized magnetic drug carriers offer a splendid prospect for directed drug application. The increased drug concentration in cancer tissue reached for this kind of application enables therapeutic effects on tumors that cannot be achieved using conventional chemotherapeutic treatment. Characterizing the drug targeting system and its behavior in vitro is necessary for understanding the biological outcome. In our studies, IRspectroscopy shows covalent binding of the biocompatible fatty acid layer. Although binding of mitoxantrone (MTO) to particles is hardly defined, considerable amounts of drug can be carried by nanoparticles. Furthermore, the nanosized drug carrier complex has to be investigated due to its biological outcome. Real-time cell analysis is useful to observe the therapeutic particles concerning their outcome in cell culture time-resolved up to several days. First experiments in concordance to a conventional assay show that the effectivity of nanoparticle bound MTO in cell culture is higher than treatment with pure MTO. A preliminary study demonstrates that the burden of the immune system is reduced by Magnetic Drug Targeting (MDT) vs. conventional chemotherapy. For a better understanding of MDT for cancer treatment, further studies have to be done to explain especially the binding behavior of superparamagnetic iron oxide nanoparticles to the respective chemotherapeutic agent.
Keywords: nano; magnetic; characterization; particle; agent

Characterizing Intraindividual Podocyte Morphology In Vitro with Different Innovative Microscopic and Spectroscopic Techniques - Kraus, Annalena; Rose, Victoria; Krüger, René; Sarau, George; Kling, Lasse; Schiffer, Mario; Christiansen, Silke; Müller-Deile, Janina (Cells, 2023)
Podocytes are critical components of the glomerular filtration barrier, sitting on the outside of the glomerular basement membrane. Primary and secondary foot processes are characteristic for podocytes, but cell processes that develop in culture were not studied much in the past. Moreover, protocols for diverse visualization methods mostly can only be used for one technique, due to differences in fixation, drying and handling. However, we detected by single-cell RNA sequencing (scRNAseq) analysis that cells reveal high variability in genes involved in cell type-specific morphology, even within one cell culture dish, highlighting the need for a compatible protocol that allows measuring the same cell with different methods. Here, we developed a new serial and correlative approach by using a combination of a wide variety of microscopic and spectroscopic techniques in the same cell for a better understanding of podocyte morphology. In detail, the protocol allowed for the sequential analysis of identical cells with light microscopy (LM), Raman spectroscopy, scanning electron microscopy (SEM) and atomic force microscopy (AFM). Skipping the fixation and drying process, the protocol was also compatible with scanning ion-conductance microscopy (SICM), allowing the determination of podocyte surface topography of nanometer-range in living cells. With the help of nanoGPS Oxyo®, tracking concordant regions of interest of untreated podocytes and podocytes stressed with TGF-β were analyzed with LM, SEM, Raman spectroscopy, AFM and SICM, and revealed significant morphological alterations, including retraction of podocyte process, changes in cell surface morphology and loss of cell-cell contacts, as well as variations in lipid and protein content in TGF-β treated cells. The combination of these consecutive techniques on the same cells provides a comprehensive understanding of podocyte morphology. Additionally, the results can also be used to train automated intelligence networks to predict various outcomes related to podocyte injury in the future.
CRIS-Team Scopus Importer:2023-05-26
Keywords: atomic force microscopy; filopodia; foot processes; light microscopy; nanoGPS tracking; podocytes; Raman spectroscopy; scanning electron microscopy; scanning ion-conductance microscopy; single-cell RNA sequencing

Characterizing renal involvement in Hermansky-Pudlak Syndrome in a zebrafish model - Schenk, H.; Mueller-Deile, J.; Schroder, P.; Bolanos-Palmieri, P.; Beverly-Staggs, L.; White, R.; Braesen, J. H.; Haller, H.; Schiffer, Mario (Scientific Reports, 2019)
Hermansky-Pudlak Syndrome (HPS) is a rare disease caused by mutations in the genes coding for various HPS proteins. HPS proteins are part of multi-subunit complexes involved in the biogenesis of organelles from the lysosomal-endosomal-system. In humans, this syndrome is characterized by the presence of albinism, platelet dysfunction and pulmonary fibrosis. The renal component to the disease remains unstudied and untreated in patients with HPS. Here we demonstrate that in humans, HPS proteins have a high renal expression with active transcription of HPS1, 3, 4 and 5 in human podocyte cell culture, suggesting that impaired function of HPS proteins could directly impact renal function. Therefore, we developed a zebrafish model to study the renal involvement of HPS proteins in proteinuric kidney disease. Remarkably, knockdown of HPS genes in zebrafish causes glomerular injury with edema, proteinuria and structural changes of the glomerular filtration barrier. Moreover, reduced expression of HPS proteins in zebrafish recapitulates other important disease hallmarks, like hypopigmentation and accumulation of intracellular debris characteristic of lysosomal disorders. In conclusion, we present a valid zebrafish model that highlights the previously underestimated relevance of renal disease in HPS. This draws attention to the therapeutic options available to manage this component of the syndrome.
CRIS-Team Scopus Importer:2019-12-10

Checklisten in der Hausarztpraxis – eine Entwicklungsstudie mit Vorher/Nachher-Vergleich - Saggau, Korbinian; Höfle, Anina; Schedlbauer, Angela; Hueber, Susann; Roos, Marco; Kühlein, Thomas; Heinmüller, Stefan (Zeitschrift für Allgemeinmedizin, 2021)
Background Quality assurance in Germany focuses on support processes (requirements of hygiene etc.) rather than on quality of care (QOC). Systems that do focus on QOC are referred to as “clinical governance” (CG). We understand CG as a process of professional self-reflection and management. An electronic checklist (eCL) for Chronic Obstructive Lung Disease (COPD) was developed reminding doctors of important aspects of care, assuring adequate documentation, and generating data at the same time. We describe the development of the eCL and a before/ after analysis of process-QOC for COPD-patients in a single group family practice. Methods Developmental study with a before/after-analysis. To capture QOC at baseline (t0) electronic health records (EHR) of COPDpatients were surveyed using a guideline-based questionnaire. Our intervention was an eCL, which can be used within the EHR. Doctors and practice assistants were trained in the application of the eCL, its use remained optional. One year (t1) and four years (t2) after implementation QOC was reanalysed. Results At t0 103 COPD patients were identified. For 58% a spirometry was documented. Smoking status was recorded in 56% and 34% were vaccinated against influenza. After introduction of the eCL due to some changes in the practice 80 patients at t1 and 49 patients at t2 were identified. For 71% (t1) and 63% (t2) a spirometry was documented. Smoking status was documented in 75% (t1) and 90% (t2). Influenza vaccination was documented in 33% (t1) and 55% (t2) of patients. Conclusions Development and implementation of an eCL in the setting of our office within the EHR was possible. Our results indicate that the provision of an eCL together with a short introduction can help improve QOC. The eCL allows doctors to perform CG autonomously.
CRIS-Team Scopus Importer:2021-04-19
Keywords: Checklist; Chronic disease; Evidence-based medicine; Family medicine; General practice

Chemokine CXCL13 as a New Systemic Biomarker for B-Cell Involvement in Acute T Cell-Mediated Kidney Allograft Rejection - Schiffer, Lena; Wiehler, Flavia; Bräsen, Jan Hinrich; Gwinner, Wilfried; Greite, Robert; Kreimann, Kirill; Thorenz, Anja; Derlin, Katja; Teng, Beina; Rong, Song; von Vietinghoff, Sibylle; Haller, Hermann; et al. (International Journal of Molecular Sciences, 2019)
The presence of B-cell clusters in allogenic T cell-mediated rejection (TCMR) of kidney allografts is linked to more severe disease entities. In this study we characterized B-cell infiltrates in patients with TCMR and examined the role of serum CXCL-13 in these patients and experimentally. CXCL-13 serum levels were analyzed in 73 kidney allograft recipients at the time of allograft biopsy. In addition, four patients were evaluated for CXCL13 levels during the first week after transplantation. ELISA was done to measure CXCL-13 serum levels. For further mechanistic understanding, a translational allogenic kidney transplant (ktx) mouse model for TCMR was studied in BalbC recipients of fully mismatched transplants with C57BL/6 donor kidneys. CXCL-13 serum levels were measured longitudinally, CD20 and CD3 composition and CXCL13 mRNA in tissue were examined by flow cytometry and kidneys were examined by histology and immunohistochemistry. We found significantly higher serum levels of the B-cell chemoattractant CXCL13 in patients with TCMR compared to controls and patients with borderline TCMR. Moreover, in patients with acute rejection within the first week after ktx, a >5-fold CXCL13 increase was measured and correlated with B-cell infiltrates in the biopsies. In line with the clinical findings, TCMR in mice correlated with increased systemic serum-CXCL13 levels. Moreover, renal allografts had significantly higher CXCL13 mRNA expression than isogenic controls and showed interstitial CD20+ B-cell clusters and CD3+ cell infiltrates accumulating in the vicinity of renal vessels. CXCL13 blood levels correlate with B-cell involvement in TCMR and might help to identify patients at risk of a more severe clinical course of rejection.
CRIS-Team Scopus Importer:2019-06-25
Keywords: allograft rejection; B-cell attracting chemokine; CXCL13; kidney transplantation; T cell-mediated rejection

Chemokine/Cytokine Levels Correlate with Organ Involvement in PR3-ANCA-Associated Vasculitis - Müller-Deile, Janina; Jaremenko, Christian; Haller, Hermann; Schiffer, Mario; Haubitz, Marion; Christiansen, Silke; Falk, Christine; Schiffer, Lena (Journal of Clinical Medicine, 2021)
Background: ANCA-associated vasculitis (AAV) is a rare small vessel disease characterized by multi-organ involvement. Biomarkers that can measure specific organ involvement are missing. Here, we ask whether certain circulating cytokines and chemokines correlate with renal involvement and if distinct cytokine/chemokine patterns can differentiate between renal, ear/nose/throat, joints, and lung involvement of AAV. Methods: Thirty-two sets of Birmingham vasculitis activity score (BVAS), PR3-ANCA titers, laboratory marker, and different cytokines were obtained from 17 different patients with AAV. BVAS, PR3-ANCA titers, laboratory marker, and cytokine concentrations were correlated to different organ involvements in active AAV. Results: Among patients with active PR3-AAV (BVAS > 0) and kidney involvement we found significant higher concentrations of chemokine ligand (CCL)-1, interleukin (IL)-6, IL21, IL23, IL-28A, IL33, monocyte chemoattractant protein 2 (MCP2), stem cell factor (SCF), thymic stromal lymphopoietin (TSLP), and thrombopoietin (TPO) compared to patients without PR3-ANCA-associated glomerulonephritis. Patients with ear, nose, and throat involvement expressed higher concentrations of MCP2 and of the (C-X-C motif) ligand-12 (CXCL-12) compared to patients with active AAV and no involvement of these organs. Conclusion: We identified distinct cytokine patterns for renal manifestation and for ear, nose and throat involvement of PR3-AAV. Distinct plasma cytokines might be used as non-invasive biomarkers of organ involvement in AAV.
CRIS-Team WoS Importer:2021-07-09

Chronic Kidney Disease - Diagnosis and Treatment - Galle, J.; Schmieder, Roland; Weinreich, T. (Diabetes Stoffwechsel und Herz, 2021)
Around five to eight million people in Germany are affected by chronic kidney disease (CKD), with incidence and prevalence continuing to rise and a high number of unknown cases. CKD is defined as persistent kidney damage associated with declining kidney function. Hypertension, diabetes, and obesity accelerate the process, resulting in increased risk of cardiovascular disease and mortality. CKD is diagnosed in screening tests (urine test or blood test) and imaging techniques for determining overall kidney function, and then classified into stages to enable appropriate therapy. This review article aims to summarise current knowledge on CKD and place it into a clinical context focusing on CKD classification, diagnosis, complications, essential current treatment options, and recommendations on when general practitioners should refer patients to a nephrologist.
CRIS-Team WoS Importer:2022-02-11

Chronic Kidney Disease (Not) on the Agenda - Eckardt, Kai-Uwe (Deutsches Ärzteblatt international, 2016)
EVALuna2:3845

Circadian rhythm and day to day variability of serum potassium concentration: a pilot study - Schmidt, Stefan; Ditting, T.; Deutsch, Birgit; Schutte, R.; Friedrich, S.; Kistner, I.; Ott, Christian; Raff, U.; Veelken, Roland; Schmieder, Roland (Journal of Nephrology, 2015)
Hyperkalemia is a common and life-threatening complication frequently seen in patients with acute kidney injury, end-stage renal disease and chronic heart failure. Cardiac arrest and ventricular fibrillation are possible consequences. Biosensors are currently being developed to measure serum potassium under ambulatory conditions and trigger an alarm if the potassium concentration exceeds normal limits. Only few studies exist on the circadian rhythm of potassium; and its dependence on age and kidney function is less clear.Our observational monocentric exploratory study included 30 subjects of which 15 had impaired renal function (RF) (GFR <60 ml/min/1.73 m(2)). Subjects were further categorized into three age groups: 18-39 years (N normal RF = 5, N impaired RF = 4), 40-59 years (N normal RF = 5, N impaired RF = 6), 60-80 years (N normal RF = 5, N impaired RF = 5). Serum potassium levels were measured every 2 h during a 24 h period and repeated once after 2, 4, or 6 days.In the 15 subjects with normal RF, the lowest mean potassium level (3.96 ± 0.14 mmol/l) was observed at 9 p.m. and the greatest (4.23 ± 0.23 mmol/l) at 1 p.m. In patients with impaired RF the lowest mean potassium level (4.20 ± 0.32 mmol/l) was observed at 9 p.m. and the highest (4.57 ± 0.46 mmol/l) at 3 p.m. The range between the mean of minimum and maximum was greater in patients with impaired RF (0.71 ± 0.45 mmol/l) than in subjects with normal RF (0.53 ± 0.14 mmol/l) [p < 0.001]. No difference in the circadian rhythm was found between the first and second examination.Our results indicate that patients with normal and impaired RF have comparable circadian patterns of serum potassium concentrations, but higher fluctuations in patients with impaired RF. These results have clinical relevance for developing an automatic biosensor to measure the potassium concentration in blood under ambulatory conditions in patients at high risk for potassium fluctuations.
EVALuna2:3700

Circulating factors cause proteinuria in parabiotic zebrafish - Müller-Deile, J.; Schenk, H.; Schroder, P.; Schulze, K.; Bolaños-Palmieri, P.; Siegerist, F.; Endlich, N.; Haller, H.; Schiffer, Mario (Kidney International, 2019)
Proteinuria can be induced by impairment of any component of the glomerular filtration barrier. To determine the role of circulating permeability factors on glomerular damage, we developed a parabiosis-based zebrafish model to generate a common circulation between zebrafish larvae. A morpholino-mediated knockdown of a podocyte specific gene (nephronectin) was induced in one zebrafish larva which was then fused to an un-manipulated fish. Notably, proteinuria and glomerular damage were present in the manipulated fish and in the parabiotically-fused partner. Thus, circulating permeability factors may be induced by proteinuria even when an induced podocyte gene dysregulation is the initiating cause.
CRIS-Team Scopus Importer:2019-05-14
Keywords: nephrotic syndrome; podocyte; proteinuria

Circulating uromodulin inhibits vascular calcification by interfering with pro-inflammatory cytokine signalling - Alesutan, Ioana; Luong, Trang T.D.; Schelski, Nadeshda; Masyout, Jaber; Hille, Susanne; Schneider, Markus; Graham, Delyth; Zickler, Daniel; Verheyen, Nicolas; Estepa, Misael; Pasch, Andreas; Maerz, Winfried; et al. (Cardiovascular Research, 2021)
AIMS: Uromodulin is produced exclusively in the kidney and secreted into both urine and blood. Serum levels of uromodulin are correlated with kidney function and reduced in chronic kidney disease (CKD) patients, but physiological functions of serum uromodulin are still elusive. This study investigated the role of uromodulin in medial vascular calcification, a key factor associated with cardiovascular events and mortality in CKD patients. METHODS AND RESULTS : Experiments were performed in primary human (HAoSMCs) and mouse (MOVAS) aortic smooth muscle cells, cholecalciferol overload and subtotal nephrectomy mouse models and serum from CKD patients. In three independent cohorts of CKD patients, serum uromodulin concentrations were inversely correlated with serum calcification propensity. Uromodulin supplementation reduced phosphate-induced osteo-/chondrogenic transdifferentiation and calcification of HAoSMCs. In human serum, pro-inflammatory cytokines tumour necrosis factor α (TNFα) and interleukin-1β (IL-1β) co-immunoprecipitated with uromodulin. Uromodulin inhibited TNFα and IL-1β-induced osteo-/chondrogenic signalling and activation of the transcription factor nuclear factor kappa-light-chain-enhancer of activated β cells (NF-kB) as well as phosphate-induced NF-kB-dependent transcriptional activity in HAoSMCs. In vivo, adeno-associated virus (AAV)-mediated overexpression of uromodulin ameliorated vascular calcification in mice with cholecalciferol overload. Conversely, cholecalciferol overload-induced vascular calcification was aggravated in uromodulin-deficient mice. In contrast, uromodulin overexpression failed to reduce vascular calcification during renal failure in mice. Carbamylated uromodulin was detected in serum of CKD patients and uromodulin carbamylation inhibited its anti-calcific properties in vitro. CONCLUSIONS : Uromodulin counteracts vascular osteo-/chondrogenic transdifferentiation and calcification, at least in part, through interference with cytokine-dependent pro-calcific signalling. In CKD, reduction and carbamylation of uromodulin may contribute to vascular pathology.
CRIS-Team Scopus Importer:2021-03-19
Keywords: Osteo-/chondrogenic transdifferentiation; Phosphate; Uromodulin; Vascular calcification; Vascular smooth muscle cells

CLINICAL EVENT REDUCTIONS IN HIGH-RISK HYPERTENSION PATIENTS TREATED WITH RENAL DENERVATION: 10-YEAR PROJECTIONS BASED ON 3-YEAR FOLLOW-UP FROM THE GLOBAL SYMPLICITY REGISTRY - Esler, Murray; Cao, Khoa; Lobo, Melvin; Sharp, Andrew S. P.; Kandzari, David E.; Mancia, Giuseppe; Bohm, Michael; Schmieder, Roland; Pietzch, Jan B. (JOURNAL OF HYPERTENSION, 2022)
CRIS-Team WoS Importer:2023-02-17

CLINICAL EVENT REDUCTIONS IN HIGH-RISK HYPERTENSION PATIENTS TREATED WITH RENAL DENERVATION: 10-YEAR PROJECTIONS BASED ON 3-YEAR FOLLOW-UP FROM THE GLOBAL SYMPLICITY REGISTRY - Esler, Murray; Cao, Khoa; Lobo, Melvin; Sharp, Andrew S.P.; Kandzari, David E.; Mancia, Giuseppe; Böhm, Michael; Schmieder, Roland; Pietzch, Jan B. (Journal of Hypertension, 2022)
OBJECTIVE: Clinical event rates over 3 years have been published for patients with uncontrolled hypertension treated with radiofrequency renal denervation (RDN) in the Global SYMPLICITY Registry (GSR). We estimated 10-year clinical event reductions following RDN vs. a simulated control group without RDN, for two high-risk subgroups and the full GSR cohort. DESIGN AND METHOD: A Markov model was used to compare projected 10-year clinical events [stroke, myocardial infarction (MI), cardiovascular death (CVD), heart failure (HF), all-cause death (ACD), and a composite of major adverse cardiac events (MACE, calculated as sum of stroke, MI, and CVD)] for RDN patients vs. a hypothetical control for the high atherosclerotic vascular disease risk (ASCVD) subgroup (n = 737; 69 ± 8 years), the type-2 diabetes mellitus (T2DM) subgroup (n = 1,007; 64 ± 10 years), and for all GSR patients (n = 2,651; 61 ± 12 years). The simulated control assumed maintenance of baseline office systolic blood pressure (oSBP) over time. The model was calibrated to 3-year stroke and MI events reported in the GSR and used published meta-regression data to calculate risk reduction based on cohort-specific changes in oSBP from baseline. Relative risks (RRs), events avoided, and numbers needed to treat (NNTs) were calculated at 3 and 10 years, along with the ratio of 10- vs. 3-year projected events avoided. RESULTS: 10-year MACE events were 35.8% vs. 48.5% (-12.7%, RR = 0.74) for RDN vs. control for all GSR patients, 37.8% vs. 52.4% (-14.6%, RR = 0.72) for the high ASCVD risk cohort, and 40.5% vs. 54.0% (-13.5%, RR = 0.75) for the T2DM cohort. Across all three cohorts, events avoided were highest for stroke and lowest for MI. 10-year NNTs for MACE were comparable between the three cohorts, estimated between 7 to 8. The ratio of model-projected MACE at 10- vs. 3-years was 5.20, 5.46, and 5.03 for the full GSR, high ASCVD risk, and T2DM cohorts, respectively. CONCLUSIONS: Model-based projections based on 3- year events observed in the GSR suggest meaningful event reductions after treatment with radiofrequency RDN at 10 years that might be up to 5-times higher than the projected events avoided at 3 years under the assumption of maintained treatment effect versus baseline.
CRIS-Team Scopus Importer:2022-09-09

Clinical event reductions in high-risk patients after renal denervation projected from the global SYMPLICITY registry - Schmieder, Roland; Mahfoud, Felix; Mancia, Giuseppe; Narkiewicz, Krzysztof; Ruilope, Luis; Hutton, David; Cao, Khoa; Hettrick, Douglas A.; Fahy, Martin; Schlaich, Markus P.; Bohm, Michael; Pietzsch, Jan B. (European Heart Journal - Quality of Care and Clinical Outcomes, 2022)
Aims Renal denervation has been shown to lower blood pressure in sham-controlled trials and represents a device-based treatment option for hypertension. We sought to project clinical event reductions after radiofrequency renal denervation using a novel modelling approach. Methods and results The Global SYMPLICITY Registry is a global, prospective all-comer registry to evaluate safety and efficacy after renal denervation. For this analysis, change in office systolic blood pressure from baseline was calculated from reported follow-up in the Global SYMPLICITY Registry. Relative risks for death and other cardiovascular events as well as numbers needed to treat for event avoidance were obtained for the respective blood pressure reductions based on previously reported meta-regression analyses for the full cohort and high-risk subgroups including type 2 diabetes, chronic kidney disease, resistant hypertension, and high basal cardiovascular risk. Average baseline office systolic blood pressure and reduction estimates for the full cohort (N = 2651) were 166 +/- 25 and -14.8 +/- 0.4 mmHg, respectively. Mean reductions in blood pressure ranged from -11.0–21.8 mmHg for the studied high-risk subgroups. Projected relative risks ranged from 0.57 for stroke in the resistant hypertension cohort to 0.92 for death in the diabetes cohort. Significant absolute reductions in major adverse cardiovascular events over 3 years compared with the projected control (8.6 +/- 0.7% observed vs. 11.7 +/- 0.9% for projected control; P < 0.01) were primarily due to reduced stroke incidence. The robustness of findings was confirmed in sensitivity and scenario analyses. Conclusion Model-based projections suggest radiofrequency renal denervation for patients with uncontrolled hypertension adds considerable clinical benefit across a spectrum of different cohort characteristics.
CRIS-Team WoS Importer:2022-10-21

Clinical impact of patient adherence to a fixed-dose combination of olmesartan, amlodipine and hydrochlorothiazide - Bramlage, Peter; Ketelhut, Reinhard; Fronk, Eva-Maria; Wolf, Wolf-Peter; Smolnik, Ruediger; Zemmrich, Claudia; Schmieder, Roland (Clinical Drug Investigation, 2014)
Recent findings from randomized clinical trials indicate an improved patient adherence and blood pressure (BP) control by using fixed-dose combinations (FDCs) in the treatment of hypertension. The aim of the present study was to verify those data in a large real-world sample of hypertensive patients and to cross-check adherence evaluation performed by physicians and patients self-assessment.A European multi-center, prospective, 24-week, non-interventional study was conducted including 14,979 patients with essential hypertension and new treatment with olmesartan, amlodipine and hydrochlorothiazide as an FDC. Patients' adherence was measured using the Morisky Medication Adherence Scale (MMAS-8) and a non-standardized questionnaire was used by physicians and patients for self-assessment.The mean age of the patients was 63.9 ± 11.78 years and 46.5 % were women. One or more cardiovascular risk factors were present in 71.9 % of patients and 94.7 % had been treated for hypertension before study entry. Mean adherence to medication by MMAS-8 improved from 6.0 to 6.9 at study end. Corresponding improvements of adherence were seen on physicians' and patients' self-assessments throughout the study. Mean decrease of systolic/diastolic BP was 26.4/12.8 mmHg without a relevant difference between the MMAS-8 adherence levels. BP target achievement improved from 55.3 to 67.7 % in patients with low versus high adherence. The overall rate of patients with adverse drug reactions was very low (1.76 %) but more frequent in patients with low adherence.Our data confirm previous clinical trial data on the improvement of medication adherence by switching antihypertensive combination therapy to an FDC and a subsequent improvement in BP target achievement. An observed trend toward a reduction in adverse drug reactions needs to be further investigated in clinical trials.
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Clinical Trial Design Principles and Outcomes Definitions for Device-Based Therapies for Hypertension: A Consensus Document From the Hypertension Academic Research Consortium - Kandzari, David E.; Mahfoud, Felix; Weber, Michael A.; Townsend, Raymond; Parati, Gianfranco; Fisher, Naomi D. L.; Lobo, Melvin D.; Bloch, Michael; Bohm, Michael; Sharp, Andrew S. P.; Schmieder, Roland; Azizi, Michel; et al. (Circulation, 2022)
The clinical implications of hypertension in addition to a high prevalence of both uncontrolled blood pressure and medication nonadherence promote interest in developing device-based approaches to hypertension treatment. The expansion of device-based therapies and ongoing clinical trials underscores the need for consistency in trial design, conduct, and definitions of clinical study elements to permit trial comparability and data poolability. Standardizing methods of blood pressure assessment, effectiveness measures beyond blood pressure alone, and safety outcomes are paramount. The Hypertension Academic Research Consortium (HARC) document represents an integration of evolving evidence and consensus opinion among leading experts in cardiovascular medicine and hypertension research with regulatory perspectives on clinical trial design and methodology. The HARC document integrates the collective information among device-based therapies for hypertension to better address existing challenges and identify unmet needs for technologies proposed to treat the world's leading cause of death and disability. Consistent with the Academic Research Consortium charter, this document proposes pragmatic consensus clinical design principles and outcomes definitions for studies aimed at evaluating device-based hypertension therapies.
CRIS-Team WoS Importer:2022-03-25

Clopidogrel significantly lowers the development of atherosclerosis in ApoE-deficient mice in vivo - Heim, Christian; Gebhardt, Julia; Ramsperger-Gleixner, Martina; Jacobi, Johannes; Weyand, Michael; Ensminger, Stephan M. (Heart and Vessels, 2016)

Clopidogrel significantly lowers the development of atherosclerosis in ApoE-deficient mice in vivo - Heim, Christian; Gebhardt, Julia; Ramsperger-Gleixner, Martina; Jacobi, Johannes; Weyand, Michael; Ensminger, Stephan M. (Heart and Vessels, 2016)
The anti-platelet drug clopidogrel has been shown to modulate adhesion molecule and cytokine expression, both playing an important role in the pathogenesis of atherosclerosis. The aim of this study was to investigate the impact of clopidogrel on the development and progression of atherosclerosis. ApoE(-/-) mice fed an atherogenic diet (cholesterol: 1 %) for 6 months received a daily dose of clopidogrel (1 mg/kg) by i.p. injection. Anti-platelet treatment was started immediately in one experimental group, and in another group clopidogrel was started 2 month after beginning of the atherogenic diet. Blood was analysed at days 30, 60 and 120 to monitor the lipid profile. After 6 months the aortic arch and brachiocephalic artery were analysed by Sudan IV staining for plaque size and by morphometry for luminal occlusion. Serum levels of various adhesion molecules were investigated by ELISA and the cellular infiltrate was analysed by immunofluorescence. After daily treatment with 1 mg/kg clopidogrel mice showed a significant reduction of atherosclerotic lesions in the thoracic aorta and within cross sections of the aortic arch [plaque formation 55.2 % (clopidogrel/start) vs. 76.5 % (untreated control) n = 8, P < 0.05]. After treatment with clopidogrel P-/E-selectin levels and cytokine levels of MCP-1 and PDGF? were significantly reduced as compared to controls. The cellular infiltrate showed significantly reduced macrophage and T-cell infiltration in clopidogrel-treated animals. These results show that clopidogrel can effectively delay the development and progression of 'de-novo' atherosclerosis. However, once atherosclerotic lesions were already present, anti-platelet treatment alone did not result in reverse remodelling of these lesions.
EVALuna2:16107

Cloth Masks May Prevent Transmission of COVID-19: An Evidence-Based, Risk-Based Approach - Clase, Catherine M.; Fu, Edouard L.; Joseph, Meera; Beale, Rupert C. L.; Dolovich, Myrna B.; Jardine, Meg; Mann, Johannes; Pecoits-Filho, Roberto; Winkelmayer, Wolfgang C.; Carrero, Juan J. (Annals of Internal Medicine, 2020)
CRIS-Team Scopus Importer:2021-04-19

Cloth Masks May Prevent Transmission of COVID-19 - Clase, Catherine M.; Fu, Edouard L.; Jardine, Meg; Mann, Johannes; Carrero, Juan J. (Annals of Internal Medicine, 2021)
CRIS-Team Scopus Importer:2021-05-21

CMV INFECTION WITH SIGHT THREATENING CMV RETINITIS REFRACTORY TO CONVENTIONAL TREATMENT: SALVAGE THERAPY WITH AUTOLOGOUS CMV-SPECIFIC T CELLS - A CASE REPORT - Herrmann, Markus; Gary, Regina; Bosch, J.; Winkler, Julia; Schiffer, Mario; Opgenoorth, M. (TRANSPLANT INTERNATIONAL, 2019)
CRIS-Team WoS Importer:2019-10-29