@article{KraftDrechslerGunrebenetal.2014, author = {Kraft, Peter and Drechsler, Christiane and Gunreben, Ignaz and Heuschmann, Peter Ulrich and Kleinschnitz, Christoph}, title = {Regulation of Blood Coagulation Factors XI and XII in Patients with Acute and Chronic Cerebrovascular Disease: A Case-Control Study}, series = {Cerebrovascular Diseases}, volume = {38}, journal = {Cerebrovascular Diseases}, number = {5}, issn = {1015-9770}, doi = {10.1159/000368434}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-199076}, pages = {337-343}, year = {2014}, abstract = {Background: Animal models have implicated an integral role for coagulation factors XI (FXI) and XII (FXII) in thrombus formation and propagation of ischemic stroke (IS). However, it is unknown if these molecules contribute to IS pathophysiology in humans, and might be of use as biomarkers for IS risk and severity. This study aimed to identify predictors of altered FXI and FXII levels and to determine whether there are differences in the levels of these coagulation factors between acute cerebrovascular events and chronic cerebrovascular disease (CCD). Methods: In this case-control study, 116 patients with acute ischemic stroke (AIS) or transitory ischemic attack (TIA), 117 patients with CCD, and 104 healthy volunteers (HVs) were enrolled between 2010 and 2013 at our University hospital. Blood sampling was undertaken once in the CCD and HV groups and on days 0, 1, and 3 after stroke onset in patients with AIS or TIA. Correlations between serum FXI and FXII levels and demographic and clinical parameters were tested by linear regression and analysis of variance. Results: The mean age of AIS/TIA patients was 70 ± 12. Baseline clinical severity measured with NIHSS and Barthel Index was 4.8 ± 6.0 and 74 ± 30, respectively. More than half of the patients had an AIS (58\%). FXI levels were significantly correlated with different leukocyte subsets (p < 0.05). In contrast, FXII serum levels showed no significant correlation (p > 0.1). Neither FXI nor FXII levels correlated with CRP (p > 0.2). FXII levels were significantly higher in patients with CCD compared with those with AIS/TIA (mean ± SD 106 ± 26\% vs. 97 ± 24\%; univariate analysis: p < 0.05); these differences did not reach significance in multivariate analysis adjusted for sex and age. FXI levels did not differ significantly between study groups. Sex and age were significantly associated with FXI and/or FXII levels in patients with AIS/TIA (p < 0.05). In contrast, no statistical significant influence was found for treatment modality (thrombolysis or not), pre-treatment with platelet inhibitors, and severity of stroke. Conclusions: In this study, there was no differential regulation of FXI and FXII levels between disease subtypes but biomarker levels were associated with patient and clinical characteristics. FXI and FXII levels might be no valid biomarker for predicting stroke risk.}, language = {en} } @article{SchneiderGutjahrLengsfeldRitzetal.2014, author = {Schneider, Andreas and Gutjahr-Lengsfeld, Lena and Ritz, Eberhard and Scharnagl, Hubert and Gelbrich, G{\"o}tz and Pilz, Stefan and Macdougall, Iain C. and Wanner, Christoph and Drechsler, Christiane}, title = {Longitudinal Assessments of Erythropoietin-Stimulating Agent Responsiveness and the Association with Specific Clinical Outcomes in Dialysis Patients}, series = {Nephron Clinical Practice}, volume = {128}, journal = {Nephron Clinical Practice}, number = {1-2}, issn = {1660-2110}, doi = {10.1159/000367975}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-196511}, pages = {147-152}, year = {2014}, abstract = {Background: Dose requirements of erythropoietin-stimulating agents (ESAs) can vary considerably over time and may be associated with cardiovascular outcomes. We aimed to longitudinally assess ESA responsiveness over time and to investigate its association with specific clinical end points in a time-dependent approach. Methods: The German Diabetes and Dialysis study (4D study) included 1,255 diabetic dialysis patients, of whom 1,161 were receiving ESA treatment. In those patients, the erythropoietin resistance index (ERI) was assessed every 6 months during a median follow-up of 4 years. The association between the ERI and cardiovascular end points was analyzed by time-dependent Cox regression analyses with repeated ERI measures. Results: Patients had a mean age of 66 ± 8.2 years; 53\% were male. During follow-up, a total of 495 patients died, of whom 136 died of sudden death and 102 of infectious death. The adjusted and time-dependent risk for sudden death was increased by 19\% per 5-unit increase in the ERI (hazard ratio, HR = 1.19, 95\% confidence interval, CI = 1.07-1.33). Similarly, mortality increased by 25\% (HR = 1.25, 95\% CI = 1.18-1.32) and infectious death increased by 27\% (HR = 1.27, 95\% CI = 1.13-1.42). Further analysis revealed that lower 25-hydroxyvitamin D levels were associated with lower ESA responsiveness (p = 0.046). Conclusions: In diabetic dialysis patients, we observed that time-varying erythropoietin resistance is associated with sudden death, infectious complications and all-cause mortality. Low 25-hydroxyvitamin D levels may contribute to a lower ESA responsiveness.}, language = {en} } @article{SeydelmannLiuKraemeretal.2016, author = {Seydelmann, Nora and Liu, Dan and Kr{\"a}mer, Johannes and Drechsler, Christiane and Hu, Kai and Nordbeck, Peter and Schneider, Andreas and St{\"o}rk, Stefan and Bijnens, Bart and Ertl, Georg and Wanner, Christoph and Weidemann, Frank}, title = {High-Sensitivity Troponin: A Clinical Blood Biomarker for Staging Cardiomyopathy in Fabry Disease}, series = {Journal of the American Heart Association}, volume = {5}, journal = {Journal of the American Heart Association}, number = {e002839}, doi = {10.1161/JAHA.115.002839}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-165682}, year = {2016}, abstract = {Background High-sensitivity troponin (hs-TNT), a biomarker of myocardial damage, might be useful for assessing fibrosis in Fabry cardiomyopathy. We performed a prospective analysis of hs-TNT as a biomarker for myocardial changes in Fabry patients and a retrospective longitudinal follow-up study to assess longitudinal hs-TNT changes relative to fibrosis and cardiomyopathy progression. Methods and Results For the prospective analysis, hs-TNT from 75 consecutive patients with genetically confirmed Fabry disease was analyzed relative to typical Fabry-associated echocardiographic findings and total myocardial fibrosis as measured by late gadolinium enhancement (LE) on magnetic resonance imaging. Longitudinal data (3.9±2.0 years), including hs-TNT, LE, and echocardiographic findings from 58 Fabry patients, were retrospectively collected. Hs-TNT level positively correlated with LE (linear correlation coefficient, 0.72; odds ratio, 32.81 [95\% CI, 3.56-302.59]; P=0.002); patients with elevated baseline hs-TNT (>14 ng/L) showed significantly increased LE (median: baseline, 1.9 [1.1-3.3] \%; follow-up, 3.2 [2.3-4.9] \%; P<0.001) and slightly elevated hs-TNT (baseline, 44.7 [30.1-65.3] ng/L; follow-up, 49.1 [27.6-69.5] ng/L; P=0.116) during follow-up. Left ventricular wall thickness and EF of patients with elevated hs-TNT were decreased during follow-up, indicating potential cardiomyopathy progression. Conclusions hs-TNT is an accurate, easily accessible clinical blood biomarker for detecting replacement fibrosis in patients with Fabry disease and a qualified predictor of cardiomyopathy progression. Thus, hs-TNT could be helpful for staging and follow-up of Fabry patients.}, language = {en} } @article{AllignolSchumacherWanneretal.2011, author = {Allignol, Arthur and Schumacher, Martin and Wanner, Christoph and Drechsler, Christiane and Beyersmann, Jan}, title = {Understanding competing risks: a simulation point of view}, series = {BMC Medical Research Methodology}, volume = {11}, journal = {BMC Medical Research Methodology}, number = {86}, doi = {10.1186/1471-2288-11-86}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-142811}, pages = {1-13}, year = {2011}, abstract = {Background: Competing risks methodology allows for an event-specific analysis of the single components of composite time-to-event endpoints. A key feature of competing risks is that there are as many hazards as there are competing risks. This is not always well accounted for in the applied literature. Methods: We advocate a simulation point of view for understanding competing risks. The hazards are envisaged as momentary event forces. They jointly determine the event time. Their relative magnitude determines the event type. 'Empirical simulations' using data from a recent study on cardiovascular events in diabetes patients illustrate subsequent interpretation. The method avoids concerns on identifiability and plausibility known from the latent failure time approach. Results: The 'empirical simulations' served as a proof of concept. Additionally manipulating baseline hazards and treatment effects illustrated both scenarios that require greater care for interpretation and how the simulation point of view aids the interpretation. The simulation algorithm applied to real data also provides for a general tool for study planning. Conclusions: There are as many hazards as there are competing risks. All of them should be analysed. This includes estimation of baseline hazards. Study planning must equally account for these aspects.}, language = {en} } @article{DrechslerMeinitzerPilzetal.2011, author = {Drechsler, Christiane and Meinitzer, Andreas and Pilz, Stefan and Krane, Vera and Tomaschitz, Andreas and Ritz, Eberhard and M{\"a}rz, Winfried and Wanner, Christoph}, title = {Homoarginine, heart failure, and sudden cardiac death in haemodialysis patients}, series = {European Journal of Heart Failure}, volume = {13}, journal = {European Journal of Heart Failure}, number = {8}, doi = {10.1093/eurjhf/hfr056}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-140495}, pages = {852-859}, year = {2011}, abstract = {Aims Sudden cardiac death (SCD) is a major contributor to the excess mortality of patients on maintenance dialysis. Homoarginine deficiency may lead to decreased nitric oxide availability and endothelial dysfunction. Based on this rationale we assessed whether homoarginine deficiency is a risk factor for SCD in dialysis patients. Methods and results This study examined the association of homoarginine with cardiovascular outcomes in 1255 diabetic haemodialysis patients from the German diabetes and dialysis study. During a median of 4 years of follow-up, hazard ratios (HR) (95\% CI) for reaching the following pre-specified, adjudicated endpoints were determined: SCD, myocardial infarction, stroke, death due to heart failure, and combined cardiovascular events. There was a strong association of low homoarginine concentrations with the presence of congestive heart failure and left ventricular hypertrophy as well as increased levels of brain natriuretic peptide. Per unit decrease in homoarginine, the risk of SCD increased three-fold (HR 3.1, 95\% CI 2.0-4.9), attenuating slightly in multivariate models (HR 2.4; 95\% CI 1.5-3.9). Patients in the lowest homoarginine quintile experienced a more than two-fold increased risk of SCD, and more than three-fold increased risk of heart failure death than patients in the highest quintile, which accounted for the high incidence of combined cardiovascular events. Low homoarginine showed a trend towards increased risk of stroke, however, myocardial infarction was not meaningfully affected. Conclusion Low homoarginine is a strong risk factor for SCD and death due to heart failure in haemodialysis patients. Further studies are needed to elucidate the underlying mechanisms, offering the potential to develop new interventional strategies.}, language = {en} } @article{IyengarSedorFreedmanetal.2015, author = {Iyengar, Sudha K. and Sedor, John R. and Freedman, Barry I. and Kao, W. H. Linda and Kretzler, Matthias and Keller, Benjamin J. and Abboud, Hanna E. and Adler, Sharon G. and Best, Lyle G. and Bowden, Donald W. and Burlock, Allison and Chen, Yii-Der Ida and Cole, Shelley A. and Comeau, Mary E. and Curtis, Jeffrey M. and Divers, Jasmin and Drechsler, Christiane and Duggirala, Ravi and Elston, Robert C. and Guo, Xiuqing and Huang, Huateng and Hoffmann, Michael Marcus and Howard, Barbara V. and Ipp, Eli and Kimmel, Paul L. and Klag, Michael J. and Knowler, William C. and Kohn, Orly F. and Leak, Tennille S. and Leehey, David J. and Li, Man and Malhotra, Alka and M{\"a}rz, Winfried and Nair, Viji and Nelson, Robert G. and Nicholas, Susanne B. and O'Brien, Stephen J. and Pahl, Madeleine V. and Parekh, Rulan S. and Pezzolesi, Marcus G. and Rasooly, Rebekah S. and Rotimi, Charles N. and Rotter, Jerome I. and Schelling, Jeffrey R. and Seldin, Michael F. and Shah, Vallabh O. and Smiles, Adam M. and Smith, Michael W. and Taylor, Kent D. and Thameem, Farook and Thornley-Brown, Denyse P. and Truitt, Barbara J. and Wanner, Christoph and Weil, E. Jennifer and Winkler, Cheryl A. and Zager, Philip G. and Igo, Jr, Robert P. and Hanson, Robert L. and Langefeld, Carl D.}, title = {Genome-wide association and trans-ethnic meta-analysis for advanced diabetic kidney disease: Family Investigation of Nephropathy and Diabetes (FIND)}, series = {PLoS Genetics}, volume = {11}, journal = {PLoS Genetics}, number = {8}, doi = {10.1371/journal.pgen.1005352}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-180545}, pages = {e1005352}, year = {2015}, abstract = {Diabetic kidney disease (DKD) is the most common etiology of chronic kidney disease (CKD) in the industrialized world and accounts for much of the excess mortality in patients with diabetes mellitus. Approximately 45\% of U.S. patients with incident end-stage kidney disease (ESKD) have DKD. Independent of glycemic control, DKD aggregates in families and has higher incidence rates in African, Mexican, and American Indian ancestral groups relative to European populations. The Family Investigation of Nephropathy and Diabetes (FIND) performed a genome-wide association study (GWAS) contrasting 6,197 unrelated individuals with advanced DKD with healthy and diabetic individuals lacking nephropathy of European American, African American, Mexican American, or American Indian ancestry. A large-scale replication and trans-ethnic meta-analysis included 7,539 additional European American, African American and American Indian DKD cases and non-nephropathy controls. Within ethnic group meta-analysis of discovery GWAS and replication set results identified genome-wide significant evidence for association between DKD and rs12523822 on chromosome 6q25.2 in American Indians (P = 5.74x10\(^{-9}\)). The strongest signal of association in the trans-ethnic meta-analysis was with a SNP in strong linkage disequilibrium with rs12523822 (rs955333; P = 1.31x10\(^{-8}\)), with directionally consistent results across ethnic groups. These 6q25.2 SNPs are located between the SCAF8 and CNKSR3 genes, a region with DKD relevant changes in gene expression and an eQTL with IPCEF1, a gene co-translated with CNKSR3. Several other SNPs demonstrated suggestive evidence of association with DKD, within and across populations. These data identify a novel DKD susceptibility locus with consistent directions of effect across diverse ancestral groups and provide insight into the genetic architecture of DKD.}, language = {en} } @article{KraftDrechslerSchuhmannetal.2015, author = {Kraft, Peter and Drechsler, Christiane and Schuhmann, Michael K. and Gunreben, Ignaz and Kleinschnitz, Christoph}, title = {Characterization of Peripheral Immune Cell Subsets in Patients with Acute and Chronic Cerebrovascular Disease: A Case-Control Study}, series = {International Journal of Molecular Science}, volume = {16}, journal = {International Journal of Molecular Science}, number = {10}, doi = {10.3390/ijms161025433}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-126319}, pages = {25433-25449}, year = {2015}, abstract = {Immune cells (IC) play a crucial role in murine stroke pathophysiology. However, data are limited on the role of these cells in ischemic stroke in humans. We therefore aimed to characterize and compare peripheral IC subsets in patients with acute ischemic stroke/transient ischemic attack (AIS/TIA), chronic cerebrovascular disease (CCD) and healthy volunteers (HV). We conducted a case-control study of patients with AIS/TIA (n = 116) or CCD (n = 117), and HV (n = 104) who were enrolled at the University Hospital W{\"u}rzburg from 2010 to 2013. We determined the expression and quantity of IC subsets in the three study groups and performed correlation analyses with demographic and clinical parameters. The quantity of several IC subsets differed between the AIS/TIA, CCD, and HV groups. Several clinical and demographic variables independently predicted the quantity of IC subsets in patients with AIS/TIA. No significant changes in the quantity of IC subsets occurred within the first three days after AIS/TIA. Overall, these findings strengthen the evidence for a pathophysiologic role of IC in human ischemic stroke and the potential use of IC-based biomarkers for the prediction of stroke risk. A comprehensive description of IC kinetics is crucial to enable the design of targeted treatment strategies.}, language = {en} } @article{KraftDrechslerGunrebenetal.2014, author = {Kraft, Peter and Drechsler, Christiane and Gunreben, Ignaz and Nieswandt, Bernhard and Stoll, Guido and Heuschmann, Peter Ulrich and Kleinschnitz, Christoph}, title = {Von Willebrand Factor Regulation in Patients with Acute and Chronic Cerebrovascular Disease: A Pilot, Case-Control Study}, series = {PLoS ONE}, volume = {9}, journal = {PLoS ONE}, number = {6}, issn = {1932-6203}, doi = {10.1371/journal.pone.0099851}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-119588}, pages = {e99851}, year = {2014}, abstract = {Background and Purpose In animal models, von Willebrand factor (VWF) is involved in thrombus formation and propagation of ischemic stroke. However, the pathophysiological relevance of this molecule in humans, and its potential use as a biomarker for the risk and severity of ischemic stroke remains unclear. This study had two aims: to identify predictors of altered VWF levels and to examine whether VWF levels differ between acute cerebrovascular events and chronic cerebrovascular disease (CCD). Methods A case-control study was undertaken between 2010 and 2013 at our University clinic. In total, 116 patients with acute ischemic stroke (AIS) or transitory ischemic attack (TIA), 117 patients with CCD, and 104 healthy volunteers (HV) were included. Blood was taken at days 0, 1, and 3 in patients with AIS or TIA, and once in CCD patients and HV. VWF serum levels were measured and correlated with demographic and clinical parameters by multivariate linear regression and ANOVA. Results Patients with CCD (158±46\%) had significantly higher VWF levels than HV (113±36\%, P<0.001), but lower levels than AIS/TIA patients (200±95\%, P<0.001). Age, sex, and stroke severity influenced VWF levels (P<0.05). Conclusions VWF levels differed across disease subtypes and patient characteristics. Our study confirms increased VWF levels as a risk factor for cerebrovascular disease and, moreover, suggests that it may represent a potential biomarker for stroke severity, warranting further investigation.}, language = {en} } @article{DrechslerRitzTomaschitzetal.2013, author = {Drechsler, Christiane and Ritz, Eberhard and Tomaschitz, Andreas and Pilz, Stefan and Sch{\"o}nfeld, Stephan and Blouin, Katja and Bidlingmaier, Martin and Hammer, Fabian and Krane, Vera and M{\"a}rz, Winfried and Allolio, Bruno and Fassnacht, Martin and Wanner, Christoph}, title = {Aldosterone and cortisol affect the risk of sudden cardiac death in haemodialysis patients}, series = {European Heart Journal}, volume = {34}, journal = {European Heart Journal}, doi = {10.1093/eurheartj/ehs361}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-132562}, pages = {578-585}, year = {2013}, abstract = {Background: Sudden cardiac death is common and accounts largely for the excess mortality of patients on maintenance dialysis. It is unknown whether aldosterone and cortisol increase the incidence of sudden cardiac death in dialysis patients. Methods and results: We analysed data from 1255 diabetic haemodialysis patients participating in the German Diabetes and Dialysis Study (4D Study). Categories of aldosterone and cortisol were determined at baseline and patients were followed for a median of 4 years. By Cox regression analyses, hazard ratios (HRs) were determined for the effect of aldosterone, cortisol, and their combination on sudden death and other adjudicated cardiovascular outcomes. The mean age of the patients was 66 ± 8 years (54\% male). Median aldosterone was <15 pg/mL (detection limit) and cortisol 16.8 µg/dL. Patients with aldosterone levels >200 pg/mL had a significantly higher risk of sudden death (HR: 1.69; 95\% CI: 1.06-2.69) compared with those with an aldosterone <15 pg/mL. The combined presence of high aldosterone (>200 pg/mL) and high cortisol (>21.1 µg/dL) levels increased the risk of sudden death in striking contrast to patients with low aldosterone (<15 pg/mL) and low cortisol (<13.2 µg/dL) levels (HR: 2.86, 95\% CI: 1.32-6.21). Furthermore, all-cause mortality was significantly increased in the patients with high levels of both hormones (HR: 1.62, 95\% CI: 1.01-2.62). Conclusions: The joint presence of high aldosterone and high cortisol levels is strongly associated with sudden cardiac death as well as all-cause mortality in haemodialysed type 2 diabetic patients. Whether a blockade of the mineralocorticoid receptor decreases the risk of sudden death in these patients must be examined in future trials.}, language = {en} } @article{DrechslerSchmiedekeNiemannetal.2013, author = {Drechsler, Christiane and Schmiedeke, Benjamin and Niemann, Markus and Schmiedeke, Daniel and Kr{\"a}mer, Johannes and Turkin, Irina and Blouin, Katja and Emmert, Andrea and Pilz, Stefan and Obermayer-Pietsch, Barbara and Wiedemann, Frank and Breunig, Frank and Wanner, Christoph}, title = {Potential role of vitamin D deficiency on Fabry cardiomyopathy}, series = {Journal of Inherited Metabolic Disease}, volume = {37}, journal = {Journal of Inherited Metabolic Disease}, number = {2}, doi = {10.1007/s10545-013-9653-8}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-132102}, pages = {289-295}, year = {2013}, abstract = {Patients with Fabry disease frequently develop left ventricular (LV) hypertrophy and renal fibrosis. Due to heat intolerance and an inability to sweat, patients tend to avoid exposure to sunlight. We hypothesized that subsequent vitamin D deficiency may contribute to Fabry cardiomyopathy. This study investigated the vitamin D status and its association with LV mass and adverse clinical symptoms in patients with Fabry disease. 25-hydroxyvitamin D (25[OH]D) was measured in 111 patients who were genetically proven to have Fabry disease. LV mass and cardiomyopathy were assessed by magnetic resonance imaging and echocardiography. In cross-sectional analyses, associations with adverse clinical outcomes were determined by linear and binary logistic regression analyses, respectively, and were adjusted for age, sex, BMI and season. Patients had a mean age of 40 ± 13 years (42 \% males), and a mean 25(OH)D of 23.5 ± 11.4 ng/ml. Those with overt vitamin D deficiency (25[OH]D ≤ 15 ng/ml) had an adjusted six fold higher risk of cardiomyopathy, compared to those with sufficient 25(OH)D levels >30 ng/ml (p = 0.04). The mean LV mass was distinctively different with 170 ± 75 g in deficient, 154 ± 60 g in moderately deficient and 128 ± 58 g in vitamin D sufficient patients (p = 0.01). With increasing severity of vitamin D deficiency, the median levels of proteinuria increased, as well as the prevalences of depression, edema, cornea verticillata and the need for medical pain therapy. In conclusion, vitamin D deficiency was strongly associated with cardiomyopathy and adverse clinical symptoms in patients with Fabry disease. Whether vitamin D supplementation improves complications of Fabry disease, requires a randomized controlled trial.}, language = {en} } @article{SchneiderSchneiderScharnagletal.2013, author = {Schneider, Andreas and Schneider, Markus P. and Scharnagl, Hubert and Jardine, Alan G. and Wanner, Christoph and Drechsler, Christiane}, title = {Predicting erythropoietin resistance in hemodialysis patients with type 2 diabetes}, series = {BMC Nephrology}, volume = {14}, journal = {BMC Nephrology}, number = {67}, doi = {10.1186/1471-2369-14-67}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-128695}, year = {2013}, abstract = {Background: Resistance to ESAs (erythropoietin stimulating agents) is highly prevalent in hemodialysis patients with diabetes and associated with an increased mortality. The aim of this study was to identify predictors for ESA resistance and to develop a prediction model for the risk stratification in these patients. Methods: A post-hoc analysis was conducted of the 4D study, including 1015 patients with type 2 diabetes undergoing hemodialysis. Determinants of ESA resistance were identified by univariate logistic regression analyses. Subsequently, multivariate models were performed with stepwise inclusion of significant predictors from clinical parameters, routine laboratory and specific biomarkers. Results: In the model restricted to clinical parameters, male sex, shorter dialysis vintage, lower BMI, history of CHF, use of ACE-inhibitors and a higher heart rate were identified as independent predictors of ESA resistance. In regard to routine laboratory markers, lower albumin, lower iron saturation, higher creatinine and higher potassium levels were independently associated with ESA resistance. With respect to specific biomarkers, higher ADMA and CRP levels as well as lower Osteocalcin levels were predictors of ESA resistance. Conclusions: Easily obtainable clinical parameters and routine laboratory parameters can predict ESA resistance in diabetic hemodialysis patients with good discrimination. Specific biomarkers did not meaningfully further improve the risk prediction of ESA resistance. Routinely assessed data can be used in clinical practice to stratify patients according to the risk of ESA resistance, which may help to assign appropriate treatment strategies.}, language = {en} } @article{DrechslerKolleritzMeinitzeretal.2013, author = {Drechsler, Christiane and Kolleritz, Barbara and Meinitzer, Andreas and M{\"a}rz, Winfried and Ritz, Eberhard and K{\"o}nig, Paul and Neyer, Ulrich and Pilz, Stefan and Wanner, Christoph and Kronenberg, Florian}, title = {Homoarginine and Progression of Chronic Kidney Disease: Results from the Mild to Moderate Kidney Disease Study}, series = {PLoS ONE}, volume = {8}, journal = {PLoS ONE}, number = {5}, organization = {MMKD Study Group}, doi = {10.1371/journal.pone.0063560}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-130979}, pages = {e63560}, year = {2013}, abstract = {Background: Homoarginine is an amino acid derivative mainly synthesized in the kidney. It is suggested to increase nitric oxide availability, enhance endothelial function and to protect against cardiovascular diseases. We aimed to investigate the relation between homoarginine, kidney function and progression of chronic kidney disease (CKD). Methods: We measured plasma homoarginine concentrations in baseline samples of the Mild to Moderate Kidney Disease (MMKD) Study, a prospective cohort study of 227 patients with CKD in Europe. Homoarginine concentrations were available in 182 of the baseline samples and in 139 of the prospectively-followed patients. We correlated homoarginine concentrations to parameters of kidney function. The association between homoarginine and progression of CKD was assessed during a follow-up of up to seven years (median 4.45 years, interquartile range 2.54-5.19) using Cox regression analysis. Progression of CKD was defined as doubling of baseline serum creatinine and/or end-stage renal disease. Results: Study participants were at baseline on average 47 \(\pm\)13 years old and 65\% were male. Mean \(\pm\) standard deviation of homoarginine concentrations were \(2.5 \pm 1.1 \mu mol/L\) and concentrations were incrementally lower at lower levels of GFR with mean concentrations of \(2.90 \pm 1.02 \mu mol/L\) (GFR. 90 ml/min), \(2.64 \pm 1.06 \mu mol/L\) (GFR 60-90 ml/min), \(2.52 \pm 1.24 \mu mol/L\) (GFR 30-60 ml/min) and \(2.05 \pm 0.78 \mu mol/L\) (GFR, 30 ml/min), respectively (p = 0.002). The age-and sex-adjusted risk to reach the renal endpoint was significantly higher by 62\% with each decrease by one standard deviation (\(1.1 \mu mol/L\)) of homoarginine (HR 1.62, 95\% CI 1.16-2.27, p = 0.005). This association was independent of proteinuria (HR 1.56, 95\% CI 1.11-2.20, p = 0.01), and was slightly attenuated when adjusting for GFR (HR 1.40 (95\% CI 0.98-1.98, p = 0.06). Conclusions: Homoarginine concentrations are directly correlated with kidney function and are significantly associated with the progression of CKD. Low homoarginine concentrations might be an early indicator of kidney failure and a potential target for the prevention of disease progression which needs further investigations.}, language = {en} } @article{OcakDrechslerVossenetal.2014, author = {Ocak, Gurbey and Drechsler, Christiane and Vossen, Carla Y. and Vos, Hans L. and Rosendaal, Frits R. and Reitsma, Pieter H. and Hoffmann, Michael M. and M{\"a}rz, Winfried and Ouwehand, Willem H. and Krediet, Raymond T. and Boeschoten, Elisabeth W. and Dekker, Frido W. and Wanner, Christoph and Verduijn, Marion}, title = {Single Nucleotide Variants in the Protein C Pathway and Mortality in Dialysis Patients}, series = {PLOS ONE}, volume = {9}, journal = {PLOS ONE}, number = {5}, issn = {1932-6203}, doi = {10.1371/journal.pone.0097251}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-116265}, pages = {e97251}, year = {2014}, abstract = {Background: The protein C pathway plays an important role in the maintenance of endothelial barrier function and in the inflammatory and coagulant processes that are characteristic of patients on dialysis. We investigated whether common single nucleotide variants (SNV) in genes encoding protein C pathway components were associated with all-cause 5 years mortality risk in dialysis patients. Methods: Single nucleotides variants in the factor V gene (F5 rs6025; factor V Leiden), the thrombomodulin gene (THBD rs1042580), the protein C gene (PROC rs1799808 and 1799809) and the endothelial protein C receptor gene (PROCR rs867186, rs2069951, and rs2069952) were genotyped in 1070 dialysis patients from the NEtherlands COoperative Study on the Adequacy of Dialysis (NECOSAD) cohort) and in 1243 dialysis patients from the German 4D cohort. Results: Factor V Leiden was associated with a 1.5-fold (95\% CI 1.1-1.9) increased 5-year all-cause mortality risk and carriers of the AG/GG genotypes of the PROC rs1799809 had a 1.2-fold (95\% CI 1.0-1.4) increased 5-year all-cause mortality risk. The other SNVs in THBD, PROC, and PROCR were not associated with 5-years mortality. Conclusion: Our study suggests that factor V Leiden and PROC rs1799809 contributes to an increased mortality risk in dialysis patients.}, language = {en} } @article{KraftDrechslerGunrebenetal.2015, author = {Kraft, Peter and Drechsler, Christiane and Gunreben, Ignaz and Heuschmann, Peter Ulrich and Kleinschnitz, Christoph}, title = {Case-control study of platelet glycoprotein receptor Ib and IIb/IIIa expression in patients with acute and chronic cerebrovascular disease}, series = {PLoS ONE}, volume = {10}, journal = {PLoS ONE}, number = {3}, doi = {10.1371/journal.pone.0119810}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-148806}, pages = {e0119810}, year = {2015}, abstract = {Background Animal models have been instrumental in defining thrombus formation, including the role of platelet surface glycoprotein (GP) receptors, in acute ischemic stroke (AIS). However, the involvement of GP receptors in human ischemic stroke pathophysiology and their utility as biomarkers for ischemic stroke risk and severity requires elucidation. Aims To determine whether platelet GPIb and GPIIb/IIIa receptors are differentially expressed in patients with AIS and chronic cerebrovascular disease (CCD) compared with healthy volunteers (HV) and to identify predictors of GPIb and GPIIb/IIIa expression. Methods This was a case-control study of 116 patients with AIS or transient ischemic attack (TIA), 117 patients with CCD, and 104 HV who were enrolled at our University hospital from 2010 to 2013. Blood sampling was performed once in the CCD and HV groups, and at several time points in patients with AIS or TIA. Linear regression and analysis of variance were used to analyze correlations between platelet GPIb and GPIIb/IIIa receptor numbers and demographic and clinical parameters. Results GPIb and GPIIb/IIIa receptor numbers did not significantly differ between the AIS, CCD, and HV groups. GPIb receptor expression level correlated significantly with the magnitude of GPIIb/IIIa receptor expression and the neutrophil count. In contrast, GPIIb/IIIa receptor numbers were not associated with peripheral immune-cell sub-population counts. Creactive protein was an independent predictor of GPIIb/IIIa (not GPIb) receptor numbers. Conclusions Platelet GPIb and GPIIb/IIIa receptor numbers did not distinguish between patient or control groups in this study, negating their potential use as a biomarker for predicting stroke risk.}, language = {en} } @article{SchneiderSchneiderKrieteretal.2015, author = {Schneider, Andreas and Schneider, Markus P. and Krieter, Detlef H. and Genser, Bernd and Scharnagl, Hubert and Stojakovic, Tatjana and Wanner, Christoph and Drechsler, Christiane}, title = {Effect of high-flux dialysis on circulating FGF-23 levels in end-stage renal disease patients: results from a randomized trial}, series = {PLoS ONE}, volume = {10}, journal = {PLoS ONE}, number = {5}, doi = {10.1371/journal.pone.0128079}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-148559}, pages = {e0128079}, year = {2015}, abstract = {Background In patients undergoing maintenance hemodialysis (HD), increased levels of circulating fibroblast growth factor-23 (FGF-23) are independently associated with cardiovascular events and mortality. Interventional strategies aiming to reduce levels of FGF-23 in HD patients are of particular interest. The purpose of the current study was to compare the impact of high-flux versus low-flux HD on circulating FGF-23 levels. Methods We conducted a post-hoc analysis of the MINOXIS study, including 127 dialysis patients randomized to low-flux (n = 62) and high-flux (n = 65) HD for 52 weeks. Patients with valid measures for FGF-23 investigated baseline and after 52 weeks were included. Results Compared to baseline, a significant increase in FGF-23 levels after one year of low-flux HD was observed (Delta plasma FGF-23: +4026 RU/ml; p < 0.001). In contrast, FGF-23 levels remained stable in the high flux group (Delta plasma FGF-23: +373 RU/ml, p = 0.70). The adjusted difference of the absolute change in FGF-23 levels between the two treatment groups was statistically significant (p < 0.01). Conclusions Over a period of 12 months, high-flux HD was associated with stable FGF-23 levels, whereas the low-flux HD group showed an increase of FGF-23. However, the implications of the different FGF 23 time-trends in patients on high flux dialysis, as compared to the control group, remain to be explored in specifically designed clinical trials.}, language = {en} } @article{KrieterJeyaseelanRuethetal.2021, author = {Krieter, Detlef H. and Jeyaseelan, Jarline and R{\"u}th, Marieke and Lemke, Horst-Dieter and Wanner, Christoph and Drechsler, Christiane}, title = {Clinical hemocompatibility of double-filtration lipoprotein apheresis comparing polyethersulfone and ethylene-vinyl alcohol copolymer membranes}, series = {Artificial Organs}, volume = {45}, journal = {Artificial Organs}, number = {9}, doi = {10.1111/aor.13944}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-258307}, pages = {1104-1113}, year = {2021}, abstract = {Activation of the complement system and leukocytes by blood-membrane interactions may further promote arteriosclerosis typically present in patients on lipoprotein apheresis. As clinical data on the hemocompatibility of lipoprotein apheresis are scarce, a controlled clinical study comparing two different types of plasma separation and fractionation membranes used in double-filtration lipoprotein apheresis was urgently needed, as its outcome may influence clinical decision-making. In a prospective, randomized, crossover controlled trial, eight patients on double-filtration lipoprotein apheresis were subjected to one treatment with recent polyethersulfone (PES) plasma separation and fractionation membranes and one control treatment using a set of ethylene-vinyl alcohol copolymer (EVAL) membranes. White blood cell (WBC) and platelet (PC) counts, complement factor C5a and thrombin-antithrombin III (TAT) concentrations were determined in samples drawn at defined times from different sites of the extracorporeal blood and plasma circuit. With a nadir at 25 minutes, WBCs in EVAL decreased to 33.5 ± 10.7\% of baseline compared with 63.8 ± 22.0\% at 20 minutes in PES (P < .001). The maximum C5a levels in venous blood reentering the patients were measured at 30 minutes, being 30.0 ± 11.2 µg/L with EVAL and 12.3 ± 9.0 µg/L with PES (P < .05). The highest C5a concentrations were found in plasma after the plasma filters (EVAL 56.1 ± 22.0 µg/L at 15 minutes vs PES 23.3 ± 15.2 µg/L at 10 minutes; P < .001). PC did not significantly decrease over time with both membrane types, whereas TAT levels did not rise until the end of the treatment without differences between membranes. Regarding lipoprotein(a) and low-density lipoprotein (LDL) cholesterol removal, both membrane sets performed equally. Compared with EVAL, PES membranes cause less leukocyte and complement system activation, the classical parameters of hemocompatibility of extracorporeal treatment procedures, at identical treatment efficacy. Better hemocompatibility may avoid inflammation-promoting effects through blood-material interactions in patients requiring double-filtration lipoprotein apheresis.}, language = {en} }