TY - JOUR A1 - Gerhardt, Louisa M. S. A1 - Kordsmeyer, Maren A1 - Sehner, Susanne A1 - Güder, Gülmisal A1 - Störk, Stefan A1 - Edelmann, Frank A1 - Wachter, Rolf A1 - Pankuweit, Sabine A1 - Prettin, Christiane A1 - Ertl, Georg A1 - Wanner, Christoph A1 - Angermann, Christiane E. T1 - Prevalence and prognostic impact of chronic kidney disease and anaemia across ACC/AHA precursor and symptomatic heart failure stages JF - Clinical Research in Cardiology N2 - Background The importance of chronic kidney disease (CKD) and anaemia has not been comprehensively studied in asymptomatic patients at risk for heart failure (HF) versus those with symptomatic HF. We analysed the prevalence, characteristics and prognostic impact of both conditions across American College of Cardiology/American Heart Association (ACC/AHA) precursor and HF stages A–D. Methods and results 2496 participants from three non-pharmacological German Competence Network HF studies were categorized by ACC/AHA stage; stage C patients were subdivided into C1 and C2 (corresponding to NYHA classes I/II and III, respectively). Overall, patient distribution was 8.1%/35.3%/32.9% and 23.7% in ACC/AHA stages A/B/C1 and C2/D, respectively. These subgroups were stratified by the absence ( – ) or presence ( +) of CKD (estimated glomerular filtration rate [eGFR] < 60 mL/min/1.73m2) and anaemia (haemoglobin in women/men < 12/ < 13 g/dL). The primary outcome was all-cause mortality at 5-year follow-up. Prevalence increased across stages A/B/C1 and C2/D (CKD: 22.3%/23.6%/31.6%/54.7%; anaemia: 3.0%/7.9%/21.7%/33.2%, respectively), with concordant decreases in median eGFR and haemoglobin (all p < 0.001). Across all stages, hazard ratios [95% confidence intervals] for all-cause mortality were 2.1 [1.8–2.6] for CKD + , 1.7 [1.4–2.0] for anaemia, and 3.6 [2.9–4.6] for CKD + /anaemia + (all p < 0.001). Population attributable fractions (PAFs) for 5-year mortality related to CKD and/or anaemia were similar across stages A/B, C1 and C2/D (up to 33.4%, 30.8% and 34.7%, respectively). Conclusions Prevalence and severity of CKD and anaemia increased across ACC/AHA stages. Both conditions were individually and additively associated with increased 5-year mortality risk, with similar PAFs in asymptomatic patients and those with symptomatic HF. KW - anaemia KW - ACC/AHA classification KW - chronic kidney disease KW - comorbidity KW - heart failure KW - mortality Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-323990 VL - 112 IS - 7 ER - TY - JOUR A1 - Krieter, Detlef H. A1 - Rüth, Marieke A1 - Lemke, Horst-Dieter A1 - Wanner, Christoph T1 - Clinical performance comparison of two medium cut-off dialyzers JF - Therapeutic Apheresis and Dialysis N2 - Introduction Medium-cut-off (MCO) dialyzers may beneficially impact outcomes in patients on hemodialysis. Methods In a randomized, controlled trial in maintenance hemodialysis patients, the new Nipro ELISIO-17HX MCO dialyzer was compared to the Baxter Theranova 400 filter regarding middle molecule removal. Furthermore, the suitability of two assays for free lambda-light chain (λFLC) detection (Freelite vs. N-Latex) was verified. Results ELISIO-HX achieved slightly lower reduction ratios for β2-microglobulin (71.8 ± 6.0 vs. 75.3 ± 5.8%; p = 0.001), myoglobin (54.7 ± 8.6 vs. 64.9 ± 8.7%; p < 0.001), and kappa-FLC (62.1 ± 8.8 vs. 56.3 ± 7.7%; p = 0.021). λFLC reduction ratios were more conclusive with the Freelite assay and not different between ELISIO-HX and Theranova (28.4 ± 3.9 vs. 38.7 ± 13.4%; p = 0.069). The albumin loss of Theranova was considerably higher (2.14 ± 0.45 vs. 0.77 ± 0.25 g; p = 0.001) and the Global Removal ScoreLoss alb largely inferior (30.6 ± 7.4 vs. 82.4 ± 29.2%/g; p = 0.006) to ELISIO-HX. Conclusions The new ELISIO-HX expands the choice of dialyzers for MCO hemodialysis. KW - dialysis adequacy KW - medium cut-off dialyzer KW - hemodialysis KW - free light chains KW - end-stage kidney disease Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-318643 VL - 27 IS - 2 SP - 284 EP - 292 ER - TY - JOUR A1 - van der Veen, Sanne J. A1 - Vlietstra, Wytze J. A1 - van Dussen, Laura A1 - van Kuilenburg, André B.P. A1 - Dijkgraaf, Marcel G. W. A1 - Lenders, Malte A1 - Brand, Eva A1 - Wanner, Christoph A1 - Hughes, Derralynn A1 - Elliott, Perry M. A1 - Hollak, Carla E. M. A1 - Langeveld, Mirjam T1 - Predicting the development of anti-drug antibodies against recombinant alpha-galactosidase A in male patients with classical Fabry disease JF - International Journal of Molecular Sciences N2 - Fabry Disease (FD) is a rare, X-linked, lysosomal storage disease that mainly causes renal, cardiac and cerebral complications. Enzyme replacement therapy (ERT) with recombinant alpha-galactosidase A is available, but approximately 50% of male patients with classical FD develop inhibiting anti-drug antibodies (iADAs) that lead to reduced biochemical responses and an accelerated loss of renal function. Once immunization has occurred, iADAs tend to persist and tolerization is hard to achieve. Here we developed a pre-treatment prediction model for iADA development in FD using existing data from 120 classical male FD patients from three European centers, treated with ERT. We found that nonsense and frameshift mutations in the α-galactosidase A gene (p = 0.05), higher plasma lysoGb3 at baseline (p < 0.001) and agalsidase beta as first treatment (p = 0.006) were significantly associated with iADA development. Prediction performance of a Random Forest model, using multiple variables (AUC-ROC: 0.77) was compared to a logistic regression (LR) model using the three significantly associated variables (AUC-ROC: 0.77). The LR model can be used to determine iADA risk in individual FD patients prior to treatment initiation. This helps to determine in which patients adjusted treatment and/or immunomodulatory regimes may be considered to minimize iADA development risk. KW - Fabry disease KW - enzyme replacement therapy KW - anti-drug antibodies KW - prediction model Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-285687 SN - 1422-0067 VL - 21 IS - 16 ER - TY - JOUR A1 - Wagenhäuser, Laura A1 - Rickert, Vanessa A1 - Sommer, Claudia A1 - Wanner, Christoph A1 - Nordbeck, Peter A1 - Rost, Simone A1 - Üçeyler, Nurcan T1 - X-chromosomal inactivation patterns in women with Fabry disease JF - Molecular Genetics & Genomic Medicine N2 - Background Although Fabry disease (FD) is an X-linked lysosomal storage disorder caused by mutations in the α-galactosidase A gene (GLA), women may develop severe symptoms. We investigated X-chromosomal inactivation patterns (XCI) as a potential determinant of symptom severity in FD women. Patients and Methods We included 95 women with mutations in GLA (n = 18 with variants of unknown pathogenicity) and 50 related men, and collected mouth epithelial cells, venous blood, and skin fibroblasts for XCI analysis using the methylation status of the androgen receptor gene. The mutated X-chromosome was identified by comparison of samples from relatives. Patients underwent genotype categorization and deep clinical phenotyping of symptom severity. Results 43/95 (45%) women carried mutations categorized as classic. The XCI pattern was skewed (i.e., ≥75:25% distribution) in 6/87 (7%) mouth epithelial cell samples, 31/88 (35%) blood samples, and 9/27 (33%) skin fibroblast samples. Clinical phenotype, α-galactosidase A (GAL) activity, and lyso-Gb3 levels did not show intergroup differences when stratified for X-chromosomal skewing and activity status of the mutated X-chromosome. Conclusions X-inactivation patterns alone do not reliably reflect the clinical phenotype of women with FD when investigated in biomaterial not directly affected by FD. However, while XCI patterns may vary between tissues, blood frequently shows skewing of XCI patterns. KW - Fabry disease KW - Fabry genotype KW - Fabry phenotype KW - female Fabry patients KW - X-chromosomal inactivation Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-312795 VL - 10 IS - 9 ER - TY - JOUR A1 - Köping, Maria A1 - Shehata-Dieler, Wafaa A1 - Schneider, Dieter A1 - Cebulla, Mario A1 - Oder, Daniel A1 - Müntze, Jonas A1 - Nordbeck, Peter A1 - Wanner, Christoph A1 - Hagen, Rudolf A1 - Schraven, Sebastian P. T1 - Characterization of vertigo and hearing loss in patients with Fabry disease JF - Orphanet Journal of Rare Diseases N2 - Background Fabry Disease (FD) is an X-linked hereditary lysosomal storage disorder which leads to a multisystemic intralysosomal accumulation of globotriaosylceramid (Gb3). Besides prominent renal and cardiac organ involvement, patients commonly complain about vestibulocochlear symptoms like high-frequency hearing loss, tinnitus and vertigo. However, comprehensive data especially on vertigo remain scarce. The aim of this study was to examine the prevalence and characteristics of vertigo and hearing loss in patients with FD, depending on renal and cardiac parameters and get hints about the site and the pattern of the lesions. Methods Single-center study with 57 FD patients. Every patient underwent an oto-rhino-laryngological examination as well as videonystagmography and vestibular evoked myogenic potentials (VEMPs) and audiological measurements using pure tone audiometry and auditory brainstem response audiometry (ABR). Renal function was measured by eGFR, cardiac impairment was graduated by NYHA class. Results More than one out of three patients (35.1%) complained about hearing loss, 54.4% about vertigo and 28.1% about both symptom. In 74% a sensorineural hearing loss of at least 25 dB was found, ABR could exclude any retrocochlear lesion. Caloric testing showed abnormal values in 71.9%, VEMPs were pathological in 68%. A correlation between the side or the shape of hearing loss and pathological vestibular testing could not be revealed. Conclusions Hearing loss and vertigo show a high prevalence in FD. While hearing loss seems due to a cochlear lesion, peripheral vestibular as well as central nervous pathologies cause vertigo. Thus, both the site of lesion and the pathophysiological patterns seem to differ. KW - Fabry disease KW - vertigo KW - VEMP KW - cardiomyopathy KW - chronic kidney disease KW - lysosomal storage disorder Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-222818 VL - 13 ER - TY - JOUR A1 - Lau, Kolja A1 - Üçeyler, Nurcan A1 - Cairns, Tereza A1 - Lorenz, Lora A1 - Sommer, Claudia A1 - Schindehütte, Magnus A1 - Amann, Kerstin A1 - Wanner, Christoph A1 - Nordbeck, Peter T1 - Gene variants of unknown significance in Fabry disease: Clinical characteristics of c.376AG (p.Ser126Gly) JF - Molecular Genetics & Genomic Medicine N2 - Background Anderson–Fabry disease (FD) is an X-linked lysosomal storage disorder with varying organ involvement and symptoms, depending on the underlying mutation in the alpha-galactosidase A gene (HGNC: GLA). With genetic testing becoming more readily available, it is crucial to precisely evaluate pathogenicity of each genetic variant, in order to determine whether there is or might be not a need for FD-specific therapy in affected patients and relatives at the time point of presentation or in the future. Methods This case series investigates the clinical impact of the specific GLA gene variant c.376A>G (p.Ser126Gly) in five (one heterozygous and one homozygous female, three males) individuals from different families, who visited our center between 2009 and 2021. Comprehensive neurological, nephrological and cardiac examinations were performed in all cases. One patient received a follow-up examination after 12 years. Results Index events leading to suspicion of FD were mainly unspecific neurological symptoms. However, FD-specific biomarkers, imaging examinations (i.e., brain MRI, heart MRI), and tissue-specific diagnostics, including kidney and skin biopsies, did not reveal evidence for FD-specific symptoms or organ involvement but showed normal results in all cases. This includes findings from 12-year follow-up in one patient with renal biopsy. Conclusion These findings suggest that p.Ser126Gly represents a benign GLA gene variant which per se does not cause FD. Precise clinical evaluation in individuals diagnosed with genetic variations of unknown significance should be performed to distinguish common symptoms broadly prevalent in the general population from those secondary to FD. KW - diagnosis in Fabry disease KW - Fabry disease KW - gene variant KW - genotype/phenotype correlation KW - lysosomal storage disease Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-312817 VL - 10 IS - 5 ER - TY - JOUR A1 - Reidenberg, Bruce E. A1 - Wanner, Christoph A1 - Polsky, Bruce A1 - Castanheira, Mariana A1 - Shelip, Alla A1 - Stalleicken, Dirk A1 - Pfaffle, Antony E. T1 - Postmarketing experience with Neutrolin® (taurolidine, heparin, calcium citrate) catheter lock solution in hemodialysis patients JF - European Journal of Clinical Microbiology & Infectious Diseases N2 - Catheter-related bloodstream infections (CRBSI) are major complications for patients with life-threatening conditions requiring chronic vascular catheterization. The wide range of etiologic microbes and the ongoing development of resistance to antimicrobials with specific mechanisms of action make this an appropriate target for applying a nonspecific antimicrobial therapeutic. Taurolidine hydrolyzes into two antimicrobial moieties, formaldehyde and methylene glycol, which react with microbial surfaces. NeutrolinA (R) (taurolidine, heparin, calcium citrate) was recently introduced in Germany as an antimicrobial catheter lock solution. This postmarketing experience collected data on 201 patients at 20 centers from January 2014 through September 2016. Likely CRBSI was observed in 13 episodes in 47,118 days (0.2759 per 1000 days [0.1468, 0.4718]). Thrombosed catheter was observed in seven catheters in 47,118 days (0.1486 per 1000 days [0.0595, 0.3061]). No adverse drug reactions that led to the discontinuation of NeutrolinA (R) use were reported. Two patients experienced occasional transient dysgeusia. NeutrolinA (R), when used in conjunction with guideline-based catheter care, showed reduction in the rate of both CRBSI and catheter thrombosis relative to recent historical controls. KW - Taurolidine KW - Postmarketing Experience KW - Catheter Lock Solution KW - Calcium Citrate KW - Catheter-related Bloodstream Infections (CRBSI) Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-225091 VL - 37 IS - 4 ER - TY - JOUR A1 - Rosenstock, Julio A1 - Perkovic, Vlado A1 - Alexander, John H. A1 - Cooper, Mark E. A1 - Marx, Nikolaus A1 - Pencina, Michael J. A1 - Toto, Robert D. A1 - Wanner, Christoph A1 - Zinman, Bernard A1 - Baanstra, David A1 - Pfarr, Egon A1 - Mattheus, Michaela A1 - Broedl, Uli C. A1 - Woerle, Hans-Jürgen A1 - George, Jyothis T. A1 - von Eynatten, Maximilian A1 - McGuire, Darren K. T1 - Rationale, design, and baseline characteristics of the CArdiovascular safety and Renal Microvascular outcomE study with LINAgliptin - (CARMELINA®): a randomized, double-blind, placebo-controlled clinical trial in patients with type 2 diabetes and high cardio-renal risk JF - Cardiovascular Diabetology N2 - Background: Cardiovascular (CV) outcome trials in type 2 diabetes (T2D) have underrepresented patients with chronic kidney disease (CKD), leading to uncertainty regarding their kidney efficacy and safety. The CARMELINA (R) trial aims to evaluate the effects of linagliptin, a DPP-4 inhibitor, on both CV and kidney outcomes in a study population enriched for cardio-renal risk. Methods: CARMELINA (R) is a randomized, double-blind, placebo-controlled clinical trial conducted in 27 countries in T2D patients at high risk of CV and/or kidney events. Participants with evidence of CKD with or without CV disease and HbA1c 6.5-10.0% (48-86 mmol/mol) were randomized 1:1 to receive linagliptin once daily or matching placebo, added to standard of care adjusted according to local guidelines. The primary outcome is time to first occurrence of CV death, non-fatal myocardial infarction, or non-fatal stroke. The key secondary outcome is a composite of time to first sustained occurrence of end-stage kidney disease, >= 40% decrease in estimated glomerular filtration rate (eGFR) from baseline, or renal death. CV and kidney events are prospectively adjudicated by independent, blinded clinical event committees. CARMELINA (R) was designed to continue until at least 611 participants had confirmed primary outcome events. Assuming a hazard ratio of 1.0, this provides 90% power to demonstrate non-inferiority of linagliptin versus placebo within the pre-specified non-inferiority margin of 1.3 at a one-sided a-level of 2.5%. If non-inferiority of linagliptin for the primary outcome is demonstrated, then its superiority for both the primary outcome and the key secondary outcome will be investigated with a sequentially rejective multiple test procedure. Results: Between July 2013 and August 2016, 6980 patients were randomized and took >= 1 dose of study drug (40.6, 33.1, 16.9, and 9.4% from Europe, South America, North America, and Asia, respectively). At baseline, mean +/- SD age was 65.8 +/- 9.1 years, HbA1c 7.9 +/- 1.0%, BMI 31.3 +/- 5.3 kg/m(2), and eGFR 55 +/- 25 mL/min/1.73 m(2). A total of 5148 patients (73.8%) had prevalent kidney disease (defined as eGFR < 60 mL/min/1.73 m(2) or macroalbuminuria [albumin-to-creatinine ratio > 300 mg/g]) and 3990 patients (57.2%) had established CV disease with increased albuminuria; these characteristics were not mutually exclusive. Microalbuminuria (n = 2896 [41.5%]) and macroalbuminuria (n = 2691 [38.6%]) were common. Conclusions: CARMELINA (R) will add important information regarding the CV and kidney disease clinical profile of linagliptin by including an understudied, vulnerable cohort of patients with T2D at highest cardio-renal risk. KW - Diabetes mellitus KW - type 2 KW - Cardiovascular diseases KW - Diabetic nephropathies KW - Dipeptidyl-peptidase IV inhibitors KW - Linagliptin KW - Clinical trial KW - phase IV KW - Research design KW - Treatment outcome Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-226996 VL - 17 ER - TY - JOUR A1 - Krieter, Detlef H. A1 - Jeyaseelan, Jarline A1 - Rüth, Marieke A1 - Lemke, Horst-Dieter A1 - Wanner, Christoph A1 - Drechsler, Christiane T1 - Clinical hemocompatibility of double-filtration lipoprotein apheresis comparing polyethersulfone and ethylene-vinyl alcohol copolymer membranes JF - Artificial Organs N2 - 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. KW - lipoprotein(a) KW - biocompatibility KW - fractionation membranev KW - hypercholesterolemia KW - LDL cholesterol KW - lipoprotein apheresis Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-258307 VL - 45 IS - 9 ER - TY - JOUR A1 - Reinecke, Holger A1 - Jürgensmeyer, Sabine A1 - Engelbertz, Christiane A1 - Gerss, Joachim A1 - Kirchhof, Paulus A1 - Breithardt, Günter A1 - Bauersachs, Rupert A1 - Wanner, Christoph T1 - Design and rationale of a randomised controlled trial comparing apixaban to phenprocoumon in patients with atrial fibrillation on chronic haemodialysis: the AXADIA-AFNET 8 study JF - BMJ open N2 - Introduction Patients with end-stage kidney disease requiring maintenance haemodialysis treatment experience a dramatic cardiovascular morbidity and mortality. Due to the high atherosclerotic and arteriosclerotic burden and profound alterations in haemostasis, they frequently suffer and die from both thromboembolic and bleeding events. This is a particular concern in patients on haemodialysis with atrial fibrillation (AF). Controlled trials on the optimal anticoagulation in patients with AF on haemodialysis are not available. The randomised controlled phase IIIb AXADIA-AFNET 8 trial will evaluate the safety and efficacy of the factor Xa inhibitor apixaban in patients with AF requiring haemodialysis. Methods and analysis A total of 222 patients will be randomised in an open-labelled, 1:1 design to receive either apixaban 2.5mg twice daily or dose-adjusted vitamin K antagonist therapy (target international normalised ratio 2.0-3.0). All patients will be treated and followed up for a minimum of 6 months up to a maximum of 24 months. The primary outcome is major or clinically relevant, non-major bleedings or death of any cause. Secondary outcomes include stroke, cardiovascular death and other thromboembolic events, thus exploring the efficacy of apixaban. The first patient was randomised in June 2017. Ethics and dissemination The study protocol was approved by the Ethical Committee of the Landesaertzekammer, Westfalen-Lippe and the Medical Faculty of the University of Muenster, Muenster, Germany (reference number: 2016-598f-A). Written informed consent will be obtained from all patients prior to study participation, including their consent for long-term follow-up. AXADIA-AFNET 8 is an investigator-initiated trial. Sponsor is AFNET, Muenster, Germany. Study findings will be disseminated to Bristol-Myers Squibb, Munich, Germany, and Pfizer, Berlin, Germany, to the participating centres, at research conferences and in peer-reviewed journals. Trial registration numbers NCT02933697, Pre-results. KW - arial fibrillation KW - hemodialysis KW - cardiovascular morbidity KW - cardiovascular mortality KW - anticoagulation Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-225156 VL - 8 IS - 9 ER - TY - JOUR A1 - Schneider, Andreas A1 - Gutjahr-Lengsfeld, Lena A1 - Ritz, Eberhard A1 - Scharnagl, Hubert A1 - Gelbrich, Götz A1 - Pilz, Stefan A1 - Macdougall, Iain C. A1 - Wanner, Christoph A1 - Drechsler, Christiane T1 - Longitudinal Assessments of Erythropoietin-Stimulating Agent Responsiveness and the Association with Specific Clinical Outcomes in Dialysis Patients JF - Nephron Clinical Practice N2 - 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. KW - dialysis KW - erythropoietin KW - diabetes KW - epidemiology Y1 - 2014 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-196511 SN - 1660-2110 N1 - This publication is with permission of the rights owner freely accessible due to an Alliance licence and a national licence (funded by the DFG, German Research Foundation) respectively. VL - 128 IS - 1-2 ER - TY - JOUR A1 - de Zeeuw, Dick A1 - Akizawa, Tadao A1 - Agarwal, Rajiv A1 - Audhya, Paul A1 - Bakris, George L. A1 - Chin, Melanie A1 - Krauth, Melissa A1 - Lambers Heerspink, Hiddo J. A1 - Meyer, Colin J. A1 - McMurray, John J. A1 - Parving, Hans-Henrik A1 - Pergola, Pablo E. A1 - Remuzzi, Giuseppe A1 - Toto, Robert D. A1 - Vaziri, Nosratola D. A1 - Wanner, Christoph A1 - Warnock, David G. A1 - Wittes, Janet A1 - Chertow, Glenn M. T1 - Rationale and Trial Design of Bardoxolone Methyl Evaluation in Patients with Chronic Kidney Disease and Type 2 Diabetes: The Occurrence of Renal Events (BEACON) JF - American Journal of Nephrology N2 - Background: Chronic kidney disease (CKD) associated with type 2 diabetes mellitus constitutes a global epidemic complicated by considerable renal and cardiovascular morbidity and mortality, despite the provision of inhibitors of the renin-angiotensin-aldosterone system (RAAS). Bardoxolone methyl, a synthetic triterpenoid that reduces oxidative stress and inflammation through Nrf2 activation and inhibition of NF-κB was previously shown to increase estimated glomerular filtration rate (eGFR) in patients with CKD associated with type 2 diabetes mellitus. To date, no antioxidant or anti-inflammatory therapy has proved successful at slowing the progression of CKD. Methods: Herein, we describe the design of Bardoxolone Methyl Evaluation in Patients with Chronic Kidney Disease and Type 2 Diabetes: the Occurrence of Renal Events (BEACON) trial, a multinational, multicenter, double-blind, randomized, placebo-controlled Phase 3 trial designed to determine whether long-term administration of bardoxolone methyl (on a background of standard therapy, including RAAS inhibitors) safely reduces renal and cardiac morbidity and mortality. Results: The primary composite endpoint is time-to-first occurrence of either end-stage renal disease or cardiovascular death. Secondary endpoints include the change in eGFR and time to occurrence of cardiovascular events. Conclusion: BEACON will be the first event-driven trial to evaluate the effect of an oral antioxidant and anti-inflammatory drug in advanced CKD. KW - clinical trial KW - diabetes mellitus KW - glomerular filtration rate KW - trial design KW - bardoxolone methyl KW - Nrf2 KW - end-stage renal disease KW - cardiovascular death KW - chronic kidney disease Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-196832 SN - 0250-8095 SN - 1421-9670 N1 - This publication is with permission of the rights owner freely accessible due to an Alliance licence and a national licence (funded by the DFG, German Research Foundation) respectively. VL - 37 IS - 3 ER - TY - JOUR A1 - Wanner, Christoph A1 - Feldt-Rasmussen, Ulla A1 - Jovanovic, Ana A1 - Linhart, Aleš A1 - Yang, Meng A1 - Ponce, Elvira A1 - Brand, Eva A1 - Germain, Dominique P. A1 - Hughes, Derralynn A. A1 - Jefferies, John L. A1 - Martins, Anna Maria A1 - Nowak, Albina A1 - Vujkovac, Bojan A1 - Weidemann, Frank A1 - West, Michael L. A1 - Ortiz, Alberto T1 - Cardiomyopathy and kidney function in agalsidase beta-treated female Fabry patients: a pre-treatment vs. post-treatment analysis JF - ESC Heart Failure N2 - Long-term treatment effect studies in large female Fabry patient groups are challenging to design because of phenotype heterogeneity and lack of appropriate comparison groups, and have not been reported. We compared long-term cardiomyopathy and kidney function outcomes after agalsidase beta treatment with preceding treatment-naive outcomes. Methods and results Self-controlled pretreatment and post-treatment comparison (piecewise mixed linear modelling) included Fabry female patients ≥18 years at treatment initiation who received agalsidase beta (0.9–1.1 mg/kg every other week) for ≥2 years, with ≥2 pretreatment and ≥2 post-treatment outcome measurements during 10-year follow-up. Left ventricular posterior wall thickness (LVPWT)/interventricular septal thickness (IVST) and estimated glomerular filtration rate (eGFR, Chronic Kidney Disease Epidemiology Collaboration creatinine equation) analyses included 42 and 86 patients, respectively, aged 50.0 and 46.3 years at treatment initiation, respectively. LVPWT and IVST increased pretreatment (follow-up 3.5 years) but stabilized during 3.6 years of treatment (LVPWT: n = 38, slope difference [95% confidence interval (CI)] = - 0.41 [ - 0.68, - 0.15] mm/year, P\(_{pre–post difference}\)<0.01; IVST: n = 38, slope difference =-0.32 [-0.67, 0.02] mm/year, P\(_{pre–post difference}\) = 0.07). These findings were not modified by renal involvement or antiproteinuric agent use. Compared with the treatment-naive period (follow-up 3.6 years), eGFR decline remained modest and stabilized within normal ranges during 4.1 years of treatment (slope difference, 95% CI: -0.13 [-1.15, 0.89] mL/min/1.73m\(^2\)/year, P\(_{pre–post difference}\) = 0.80). Conclusions Cardiac hypertrophy, progressing during pretreatment follow-up, appeared to stabilize during sustained agalsidase beta treatment. eGFR decline remained within normal ranges. This suggests that treatment may prevent further Fabry-related progression of cardiomyopathy in female patients and maintain normal kidney function. KW - Agalsidase beta KW - Enzyme replacement therapy KW - Fabry disease KW - Cardiomyopathy KW - Kidney function KW - Female patients Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-235963 VL - 7 IS - 3 ER - TY - JOUR A1 - Grebe, Sören Jendrik A1 - Malzahn, Uwe A1 - Donhauser, Julian A1 - Liu, Dan A1 - Wanner, Christoph A1 - Krane, Vera A1 - Hammer, Fabian T1 - Quantification of left ventricular mass by echocardiography compared to cardiac magnet resonance imaging in hemodialysis patients JF - Cardiovascular Ultrasound N2 - Background: Left ventricular hypertrophy (LVH), defined by the left ventricular mass index (LVMI), is highly prevalent in hemodialysis patients and a strong independent predictor of cardiovascular events. Compared to cardiac magnetic resonance imaging (CMR), echocardiography tends to overestimate the LVMI. Here, we evaluate the diagnostic performance of transthoracic echocardiography (TTE) compared to CMR regarding the assessment of LVMI in hemodialysis patients. Methods: TTR and CMR data for 95 hemodialysis patients who participated in the MiREnDa trial were analyzed. The LVMI was calculated by two-dimensional (2D) TTE-guided M-mode measurements employing the American Society of Echocardiography (ASE) and Teichholz (Th) formulas, which were compared to the reference method, CMR. Results: LVH was present in 44% of patients based on LVMI measured by CMR. LVMI measured by echocardiography correlated moderately with CMR, ASE: r = 0.44 (0.34-0.62); Th: r = 0.44 (0.32-0.62). Compared to CMR, both echocardiographic formulas overestimated LVMI (mean increment LVMI (ASE-CMR): 19.5 +/- 19.48 g/m(2),p < 0.001; mean increment LVMI (Th-CMR): 15.9 +/- 15.89 g/m(2),p < 0.001). We found greater LVMI overestimation in patients with LVH using the ASE formula compared to the Th formula. Stratification of patients into CMR LVMI quartiles showed a continuous decrease in increment LVMI with increasing CMR LVMI quartiles for the Th formula (p < 0.001) but not for the ASE formula (p = 0.772). Bland-Altman analysis showed that the Th formula had a constant bias independent of LVMI. Both methods had good discrimination ability for the detection of LVH (ROC-AUC: 0.819 (0.737-0.901) and 0.808 (0.723-0.892) for Th and ASE, respectively). Conclusions: The ASE and Th formulas overestimate LVMI in hemodialysis patients. However, the overestimation is less with the Th formula, particularly with increasing LVMI. The results suggest that the Th formula should be preferred for measurement of LVMI in chronic hemodialysis patients. KW - Teichholz formula KW - ASE formula KW - echocardiography KW - left ventricular hypertrophy KW - left ventricular mass index KW - hemodialysis Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-229282 VL - 18 ER - TY - JOUR A1 - Macdougall, Iain C. A1 - Bircher, Andreas J. A1 - Eckhardt, Kai-Uwe A1 - Obrador, Gregorio T. A1 - Pollock, Carol A. A1 - Stenvinkel, Peter A1 - Swinkels, Dorine W. A1 - Wanner, Christoph A1 - Weiss, Günter A1 - Chertow, Glenn M. T1 - Iron management in chronic kidney disease: conclusions from a "Kidney Disease: Improving Global Outcomes" (KDIGO) Controversies Conference JF - Kidney International N2 - Before the introduction of erythropoiesis-stimulating agents (ESAs) in 1989, repeated transfusions given to patients with end-stage renal disease caused iron overload, and the need for supplemental iron was rare. However, with the widespread introduction of ESAs, it was recognized that supplemental iron was necessary to optimize hemoglobin response and allow reduction of the ESA dose for economic reasons and recent concerns about ESA safety. Iron supplementation was also found to be more efficacious via intravenous compared to oral administration, and the use of intravenous iron has escalated in recent years. The safety of various iron compounds has been of theoretical concern due to their potential to induce iron overload, oxidative stress, hypersensitivity reactions, and a permissive environment for infectious processes. Therefore, an expert group was convened to assess the benefits and risks of parenteral iron, and to provide strategies for its optimal use while mitigating the risk for acute reactions and other adverse effects. KW - chronic kidney disease KW - hypersensitivity KW - infections KW - iron KW - overload KW - oxidative stress Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-191467 VL - 89 IS - 1 ER - TY - JOUR A1 - Rothe, Hansjörg A1 - Brandenburg, Vincent A1 - Haun, Margot A1 - Kollerits, Barbara A1 - Kronenberg, Florian A1 - Ketteler, Markus A1 - Wanner, Christoph T1 - Ecto-5 ' -Nucleotidase CD73 (NT5E), vitamin D receptor and FGF23 gene polymorphisms may play a role in the development of calcific uremic arteriolopathy in dialysis patients - Data from the German Calciphylaxis Registry JF - PLoS One N2 - Introduction: Calciphylaxis/calcific uremic arteriolopathy affects mainly end-stage kidney disease patients but is also associated with malignant disorders such as myeloma, melanoma and breast cancer. Genetic risk factors of calciphylaxis have never been studied before. Methods: We investigated 10 target genes using a tagging SNP approach: the genes encoding CD73/ ecto-5'-nucleotidase (purinergic pathway), Matrix Gla protein, Fetuin A, Bone Gla protein, VKORC1 (all related to intrinsic calcification inhibition), calcium-sensing receptor, FGF23, Klotho, vitamin D receptor, stanniocalcin 1 (all related to CKD-MBD). 144 dialysis patients from the German calciphylaxis registry were compared with 370 dialysis patients without history of CUA. Genotyping was performed using iPLEX Gold MassARRAY(Sequenom, San Diego, USA), KASP genotyping chemistry (LGC, Teddington, Middlesex, UK) or sequencing. Statistical analysis comprised logistic regression analysis with adjustment for age and sex. Results: 165 SNPs were finally analyzed and 6 SNPs were associated with higher probability for calciphylaxis (OR>1) in our cohort. Nine SNPs of three genes (CD73, FGF23 and Vitamin D receptor) reached nominal significance (p< 0.05), but did not reach statistical significance after correction for multiple testing. Of the CD73 gene, rs4431401 (OR = 1.71, 95%CI 1.08-2.17, p = 0.023) and rs9444348 (OR = 1.48, 95% CI 1.11-1.97, p = 0.008) were associated with a higher probability for CUA. Of the FGF23 and VDR genes, rs7310492, rs11063118, rs13312747 and rs17882106 were associated with a higher probability for CUA. Conclusion: Polymorphisms in the genes encoding CD73, vitamin D receptor and FGF23 may play a role in calciphylaxis development. Although our study is the largest genetic study on calciphylaxis, it is limited by the low sample sizes. It therefore requires replication in other cohorts if available. KW - single nucleotide polymorphisms KW - calcification KW - medical dialysis KW - genotyping KW - cancer risk factors KW - vitamin D KW - chronic kidney disease KW - melanoma Y1 - 2017 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-171817 VL - 12 IS - 2 ER - TY - JOUR A1 - Üçeyler, Nurcan A1 - Schröter, Nils A1 - Kafke, Waldemar A1 - Kramer, Daniela A1 - Wanner, Christoph A1 - Weidemann, Frank A1 - Sommer, Claudia T1 - Skin Globotriaosylceramide 3 Load Is Increased in Men with Advanced Fabry Disease JF - PLoS ONE N2 - Background The X-chromosomally linked life-limiting Fabry disease (FD) is associated with deposits of the sphingolipid globotriaosylceramide 3 (Gb3) in various tissues. Skin is easily accessible and may be used as an additional diagnostic and follow-up medium. Our aims were to visualize skin Gb3 deposits in FD patients applying immunofluorescence and to determine if cutaneous Gb3 load correlates with disease severity. Methods At our Fabry Center for Interdisciplinary Therapy we enrolled 84 patients with FD and 27 healthy controls. All subjects underwent 5-mm skin punch biopsy at the lateral lower leg and the back. Skin samples were processed for immunohistochemistry using antibodies against CD77 (i.e. Gb3). Cutaneous Gb3 deposition was quantified in a blinded manner and correlated to clinical data. Results We found that Gb3 load was higher in distal skin of male FD patients compared to healthy controls (p<0.05). Men (p<0.01) and women (p<0.05) with a classic FD phenotype had higher distal skin Gb3 load than healthy controls. Men with advanced disease as reflected by impaired renal function, and men and women with small fiber neuropathy had more Gb3 deposits in distal skin samples than males with normal renal function (p<0.05) and without small fiber neuropathy. Gb3 deposits were not different between patients with and without enzyme replacement therapy. Conclusions Immunofluorescence on minimally invasive skin punch biopsies may be useful as a tool for assessment and follow-up in FD patients. KW - biopsy KW - neuropathy KW - Fabry disease KW - renal system KW - immunofluorescence KW - enzyme replacement therapy KW - skin diseases KW - nerve fibers Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-178856 VL - 11 IS - 11 ER - TY - JOUR A1 - Ortiz, Alberto A1 - Abiose, Ademola A1 - Bichet, Daniel G. A1 - Cabrera, Gustavo A1 - Charrow, Joel A1 - Germain, Dominique P. A1 - Hopkin, Robert J. A1 - Jovanovic, Ana A1 - Linhart, Aleš A1 - Maruti, Sonia S. A1 - Mauer, Michael A1 - Oliveira, João P. A1 - Patel, Manesh R. A1 - Politei, Juan A1 - Waldek, Stephen A1 - Wanner, Christoph A1 - Yoo, Han-Wook A1 - Warnock, David G. T1 - Time to treatment benefit for adult patients with Fabry disease receiving agalsidase beta: data from the Fabry Registry JF - Journal of Medical Genetics N2 - Background Agalsidase beta is a form of enzyme replacement therapy for Fabry disease, a genetic disorder characterised by low alpha-galactosidase A activity, accumulation of glycosphingolipids and life-threatening cardiovascular, renal and cerebrovascular events. In clinical trials, agalsidase beta cleared glycolipid deposits from endothelial cells within 6 months; clearance from other cell types required sustained treatment. We hypothesised that there might be a 'lag time' to clinical benefit after initiating agalsidase beta treatment, and analysed the incidence of severe clinical events over time in patients receiving agalsidase beta. Methods The incidence of severe clinical events (renal failure, cardiac events, stroke, death) was studied in 1044 adult patients (641 men, 403 women) enrolled in the Fabry Registry who received agalsidase beta (average dose 1 mg/kg every 2 weeks) for up to 5 years. Results The incidence of all severe clinical events was 111 per 1000 person-years (95% CI 84 to 145) during the first 6 months. After 6 months, the incidence decreased and remained stable within the range of 40-58 events per 1000 patient-years. The largest decrease in incidence rates was among male patients and those aged >= 40 years when agalsidase beta was initiated. Conclusions Contrary to the expected increased incidence of severe clinical events with time, adult patients with Fabry disease had decreased incidence of severe clinical events after 6 months treatment with agalsidase beta 1 mg/kg every 2 weeks. KW - Enzyme replacement therapy KW - Natural-history data KW - Racial differences KW - Outcome survey KW - Galactosidase-A gene KW - Alpha-Galactosidase KW - Kidney function KW - Lag time Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-188241 VL - 53 IS - 7 ER - TY - JOUR A1 - Seydelmann, Nora A1 - Liu, Dan A1 - Krämer, Johannes A1 - Drechsler, Christiane A1 - Hu, Kai A1 - Nordbeck, Peter A1 - Schneider, Andreas A1 - Störk, Stefan A1 - Bijnens, Bart A1 - Ertl, Georg A1 - Wanner, Christoph A1 - Weidemann, Frank T1 - High-Sensitivity Troponin: A Clinical Blood Biomarker for Staging Cardiomyopathy in Fabry Disease JF - Journal of the American Heart Association N2 - 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. KW - biomarker KW - cardiomyopathy KW - fabry disease KW - myocardial fibrosis KW - troponin T Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-165682 VL - 5 IS - e002839 ER - TY - JOUR A1 - Perkovic, Vlado A1 - Agarwal, Rajiv A1 - Fioretto, Paola A1 - Hemmelgarn, Brenda R. A1 - Levin, Adeera A1 - Thomas, Merlin C. A1 - Wanner, Christoph A1 - Kasiske, Bertram L. A1 - Wheeler, David C. A1 - Groop, Per-Henrik T1 - Management of patients with diabetes and CKD: conclusions from a "Kidney Disease: Improving Global Outcomes" (KDIGO) controversies conference JF - Kidney International N2 - The prevalence of diabetes around the world has reached epidemic proportions and is projected to increase to 642 million people by 2040. Diabetes is already the leading cause of end-stage kidney disease (ESKD) in most developed countries, and the growth in the number of people with ESKD around the world parallels the increase in diabetes. The presence of kidney disease is associated with a markedly elevated risk of cardiovascular disease and death in people with diabetes. Several new therapies and novel investigational agents targeting chronic kidney disease patients with diabetes are now under development. This conference was convened to assess our current state of knowledge regarding optimal glycemic control, current antidiabetic agents and their safety, and new therapies being developed to improve kidney function and cardiovascular outcomes for this vulnerable population. KW - stage renal-disease KW - converting enzyme-inhibition KW - dietary sodium restriction KW - intensive glucose control KW - albumin excretion rate KW - blood pressure KW - cardiovascular outcomes KW - randomized trial KW - glycemic control KW - receptor KW - antidiabetic agents KW - cardiovascular disease KW - chronic kidney disease KW - diabetes KW - renoprotection KW - antagonist Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-186599 VL - 90 IS - 6 ER -