@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{LocatelliSpasovskiDimkovicetal.2014, author = {Locatelli, Francesco and Spasovski, Goce and Dimkovic, Nada and Wanner, Christoph and Dellanna, Frank and Pontoriero, Giuseppe}, title = {The effects of colestilan versus placebo and sevelamer in patients with CKD 5D and hyperphosphataemia: a 1-year prospective randomized study}, series = {Nephrology Dialysis Transplantation}, volume = {29}, journal = {Nephrology Dialysis Transplantation}, number = {5}, doi = {10.1093/ndt/gft476}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-121114}, pages = {1061-73}, year = {2014}, abstract = {BACKGROUND: This study compared the effects of short-term titrated colestilan (a novel non-absorbable, non-calcium, phosphate binder) with placebo, and evaluated the safety and efficacy of colestilan over 1 year compared with sevelamer, in patients with chronic kidney disease (CKD) 5D. METHODS: This prospective multicentre study comprised a 4-week phosphate binder washout period, a 16-week short-term, flexible-dose, treatment period (including a 4-week placebo-controlled withdrawal period) and a 40-week extension treatment phase. RESULTS: At Week 16 (the end of the 4-week placebo-controlled withdrawal period), serum phosphorus level was 0.43 mmol/L (1.32 mg/dL) lower with colestilan than placebo (P < 0.001; primary end point). Serum LDL-C level was also lower with colestilan than with placebo (P < 0.001). Both colestilan and sevelamer produced significant reductions from baseline in serum phosphorus levels (P < 0.001), maintained for 1 year, and the proportion of patients achieving target levels of ≤1.78 mmol/L (5.5 mg/dL) or ≤1.95 mmol/L (6.0 mg/dL) at study end were similar (65.3 and 73.3\%, respectively, for colestilan, and 66.9 and 77.4\%, respectively, for sevelamer). Serum calcium level remained stable in the colestilan group but tended to increase slightly in the sevelamer group (end-of-study increase of 0.035 mmol/L over baseline). Both binders produced similar reductions from baseline in LDL-C level (P < 0.001), and responder rates after 1 year, using a target of <1.83 mmol/L (70 mg/dL) or <2.59 mmol/L (100 mg/dL) were similar in both groups (50.7 and 85.3\% for colestilan and 54.0 and 80.6\% for sevelamer). Colestilan was generally well tolerated. CONCLUSIONS: Colestilan is effective and safe for the treatment of hyperphosphataemia in patients with CKD 5D, and affords similar long-term phosphorus and cholesterol reductions/responder rates to sevelamer.}, language = {en} } @article{FruchartDavignonHermansetal.2014, author = {Fruchart, Jean-Charles and Davignon, Jean and Hermans, Michael P. and Al-Rubeaan, Khalid and Amarenco, Pierre and Assmann, Gerd and Barter, Philip and Betteridge, John and Bruckert, Eric and Cuevas, Ada and Farnier, Michel and Ferrannini, Ele and Fioretto, Paola and Genest, Jacques and Ginsberg, Henry N. and Gotto Jr., Antonio M. and Hu, Dayi and Kadowaki, Takashi and Kodama, Tatsuhiko and Krempf, Michel and Matsuzawa, Yuji and N{\´u}{\~n}ez-Cort{\´e}s, Jes{\´u}s Mill{\´a}n and Monfil, Calos Calvo and Ogawa, Hisao and Plutzky, Jorge and Rader, Daniel J. and Sadikot, Shaukat and Santos, Raul D. and Shlyakhto, Evgeny and Sritara, Piyamitr and Sy, Rody and Tall, Alan and Tan, Chee Eng and Tokg{\"o}zoğlu, Lale and Toth, Peter P. and Valensi, Paul and Wanner, Christoph and Zambon, Albertro and Zhu, Junren and Zimmet, Paul}, title = {Residual macrovascular risk in 2013: what have we learned?}, series = {Cardiovascual Diabetology}, volume = {13}, journal = {Cardiovascual Diabetology}, number = {26}, issn = {1475-2840}, doi = {10.1186/1475-2840-13-26}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-117546}, year = {2014}, abstract = {Cardiovascular disease poses a major challenge for the 21st century, exacerbated by the pandemics of obesity, metabolic syndrome and type 2 diabetes. While best standards of care, including high-dose statins, can ameliorate the risk of vascular complications, patients remain at high risk of cardiovascular events. The Residual Risk Reduction Initiative (R(3)i) has previously highlighted atherogenic dyslipidaemia, defined as the imbalance between proatherogenic triglyceride-rich apolipoprotein B-containing-lipoproteins and antiatherogenic apolipoprotein A-I-lipoproteins (as in high-density lipoprotein, HDL), as an important modifiable contributor to lipid-related residual cardiovascular risk, especially in insulin-resistant conditions. As part of its mission to improve awareness and clinical management of atherogenic dyslipidaemia, the R(3)i has identified three key priorities for action: i) to improve recognition of atherogenic dyslipidaemia in patients at high cardiometabolic risk with or without diabetes; ii) to improve implementation and adherence to guideline-based therapies; and iii) to improve therapeutic strategies for managing atherogenic dyslipidaemia. The R(3)i believes that monitoring of non-HDL cholesterol provides a simple, practical tool for treatment decisions regarding the management of lipid-related residual cardiovascular risk. Addition of a fibrate, niacin (North and South America), omega-3 fatty acids or ezetimibe are all options for combination with a statin to further reduce non-HDL cholesterol, although lacking in hard evidence for cardiovascular outcome benefits. Several emerging treatments may offer promise. These include the next generation peroxisome proliferator-activated receptor alpha agonists, cholesteryl ester transfer protein inhibitors and monoclonal antibody therapy targeting proprotein convertase subtilisin/kexin type 9. However, long-term outcomes and safety data are clearly needed. In conclusion, the R(3)i believes that ongoing trials with these novel treatments may help to define the optimal management of atherogenic dyslipidaemia to reduce the clinical and socioeconomic burden of residual cardiovascular risk.}, 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{ZinmanInzucchiLachinetal.2014, author = {Zinman, Bernard and Inzucchi, Silvio E. and Lachin, John M. and Wanner, Christoph and Ferrari, Roberto and Fitchett, David and Bluhmki, Erich and Hantel, Stefan and Kempthorne-Rawson, Joan and Newman, Jennifer and Johansen, Odd Erik and Woerle, Hans-Juergen and Broedl, Uli C.}, title = {Rationale, design, and baseline characteristics of a randomized, placebo-controlled cardiovascular outcome trial of empagliflozin (EMPA-REG OUTCOME (TM))}, series = {Cardiovascular Diabetology}, volume = {13}, journal = {Cardiovascular Diabetology}, number = {102}, issn = {1475-2840}, doi = {10.1186/1475-2840-13-102}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-116036}, year = {2014}, abstract = {Background: Evidence concerning the importance of glucose lowering in the prevention of cardiovascular (CV) outcomes remains controversial. Given the multi-faceted pathogenesis of atherosclerosis in diabetes, it is likely that any intervention to mitigate this risk must address CV risk factors beyond glycemia alone. The SGLT-2 inhibitor empagliflozin improves glucose control, body weight and blood pressure when used as monotherapy or add-on to other antihyperglycemic agents in patients with type 2 diabetes. The aim of the ongoing EMPA-REG OUTCOME (TM) trial is to determine the long-term CV safety of empagliflozin, as well as investigating potential benefits on macro-/microvascular outcomes. Methods: Patients who were drug naive (HbA(1c) >= 7.0\% and <= 9.0\%), or on background glucose-lowering therapy (HbA(1c) >= 7.0\% and <= 10.0\%), and were at high risk of CV events, were randomized (1:1:1) and treated with empagliflozin 10 mg, empagliflozin 25 mg, or placebo (double blind, double dummy) superimposed upon the standard of care. The primary outcome is time to first occurrence of CV death, non-fatal myocardial infarction, or non-fatal stroke. CV events will be prospectively adjudicated by an independent Clinical Events Committee. The trial will continue until >= 691 confirmed primary outcome events have occurred, providing a power of 90\% to yield an upper limit of the adjusted 95\% CI for a hazard ratio of <1.3 with a one-sided a of 0.025, assuming equal risks between placebo and empagliflozin (both doses pooled). Hierarchical testing for superiority will follow for the primary outcome and key secondary outcomes (time to first occurrence of CV death, non-fatal myocardial infarction, non-fatal stroke or hospitalization for unstable angina pectoris) where non-inferiority is achieved. Results: Between Sept 2010 and April 2013, 592 clinical sites randomized and treated 7034 patients (41\% from Europe, 20\% from North America, and 19\% from Asia). At baseline, the mean age was 63 +/- 9 years, BMI 30.6 +/- 5.3 kg/m(2), HbA1c 8.1 +/- 0.8\%, and eGFR 74 +/- 21 ml/min/1.73 m(2). The study is expected to report in 2015. Discussion: EMPA REG OUTCOME (TM) will determine the CV safety of empagliflozin in a cohort of patients with type 2 diabetes and high CV risk, with the potential to show cardioprotection.}, language = {en} } @article{UeceylerHomolaGonzalezetal.2014, author = {{\"U}{\c{c}}eyler, Nurcan and Homola, Gy{\"o}rgy A. and Gonz{\´a}lez, Hans Guerrero and Kramer, Daniela and Wanner, Christoph and Weidemann, Frank and Solymosi, L{\´a}szl{\´o} and Sommer, Claudia}, title = {Increased Arterial Diameters in the Posterior Cerebral Circulation in Men with Fabry Disease}, doi = {10.1371/journal.pone.0087054}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-112614}, year = {2014}, abstract = {A high load of white matter lesions and enlarged basilar arteries have been shown in selected patients with Fabry disease, a disorder associated with an increased stroke risk. We studied a large cohort of patients with Fabry disease to differentially investigate white matter lesion load and cerebral artery diameters. We retrospectively analyzed cranial magnetic resonance imaging scans of 87 consecutive Fabry patients, 20 patients with ischemic stroke, and 36 controls. We determined the white matter lesion load applying the Fazekas score on fluid-attenuated inversion recovery sequences and measured the diameters of cerebral arteries on 3D-reconstructions of the time-of-flight-MR-angiography scans. Data of different Fabry patient subgroups (males - females; normal - impaired renal function) were compared with data of patients with stroke and controls. A history of stroke or transient ischemic attacks was present in 4/30 males (13\%) and 5/57 (9\%) females with Fabry disease, all in the anterior circulation. Only one man with Fabry disease showed confluent cerebral white matter lesions in the Fazekas score assessment (1\%). Male Fabry patients had a larger basilar artery (p<0.01) and posterior cerebral artery diameter (p<0.05) compared to male controls. This was independent of disease severity as measured by renal function and did not lead to changes in arterial blood flow properties. A basilar artery diameter of >3.2 mm distinguished between men with Fabry disease and controls (sensitivity: 87\%, specificity: 86\%, p<0.001), but not from stroke patients. Enlarged arterial diameters of the posterior circulation are present only in men with Fabry disease independent of disease severity.}, language = {en} } @article{WagnerKraemerBlohmetal.2014, author = {Wagner, Martin and Kr{\"a}mer, Johannes and Blohm, Elisabeth and Vergho, Dorothee and Weidemann, Frank and Breunig, Frank and Wanner, Christoph}, title = {Kidney function as an underestimated factor for reduced health related quality of life in patients with Fabry disease}, doi = {10.1186/1471-2369-15-188}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-111159}, year = {2014}, abstract = {Background: Impairments of health related quality of life (HRQoL) are frequently observed in Fabry disease (FD) and are known to be related to neuropathic pain and cardiovascular events. This study aimed to explore the role of chronic kidney disease (CKD) in a large cohort of patients with FD. Methods: In 96 patients (53\% female; age 40 ± 12 yrs) with genetically proven FD, HRQoL was assessed by the Medical Outcomes Study (SF-36) questionnaire. All patients were na{\"i}ve to enzyme replacement therapy. Three categories for kidney dysfunction were chosen, eGFR ≥/<60 ml/min/1.73 m2 or need of renal replacement therapy (RRT). Minor (e.g. arrhythmia, angina pectoris, etc.) and major (e.g. myocardial infarction, coronary artery bypass, stroke or implantable cardioverter-defibrillator) vascular events as well as pain and pain therapy were considered in linear regression analyses with the dimensions of HRQoL. Results: Ten patients (10\%) had impaired kidney function and a further nine were on RRT (9.4\%). Kidney function and pain emerged as the main factors associated with lower scores on the SF 36, in particular on physical components (PCS beta-coefficients for CKD -6.2, for RRT -11.8, for pain -9.1, p < 0.05, respectively), while controlling for gender, vascular event and pain-therapy. Relationships were found for mental aspects of HRQoL. Age and history of vascular events were not related to HRQoL. Conclusion: Cardiovascular events and pain are important factors related to HRQoL, social functioning and depression. Our study highlights impaired chronic kidney disease, in particular after initiation of RRT, as a strong determinant of reduced HRQoL in FD.}, language = {en} }