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 - 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 - Fitchett, David A1 - Zinman, Bernard A1 - Wanner, Christoph A1 - Lachin, John M. A1 - Hantel, Stefan A1 - Salsali, Afshin A1 - Johansen, Odd Erik A1 - Woerle, Hans J. A1 - Broedl, Uli C. A1 - Inzucchi, Silvio E. T1 - Heart failure outcomes with empagliflozin in patients with type 2 diabetes at high cardiovascular risk: results of the EMPA-REG OUTCOME (R) trial JF - European Heart Journal N2 - Aims We previously reported that in the EMPA-REG OUTCOME(R) trial, empagliflozin added to standard of care reduced the risk of 3-point major adverse cardiovascular events, cardiovascular and all-cause death, and hospitalization for heart failure in patients with type 2 diabetes and high cardiovascular risk. We have now further investigated heart failure outcomes in all patients and in subgroups, including patients with or without baseline heart failure. Methods and results Patients were randomized to receive empagliflozin 10 mg, empagliflozin 25 mg, or placebo. Seven thousand and twenty patients were treated; 706 (10.1%) had heart failure at baseline. Heart failure hospitalization or cardiovascular death occurred in a significantly lower percentage of patients treated with empagliflozin 265/4687 patients (5.7%)] than with placebo 198/2333 patients (8.5%)] hazard ratio, HR: 0.66 (95% confidence interval: 0.55-0.79); P < 0.001], corresponding to a number needed to treat to prevent one heart failure hospitalization or cardiovascular death of 35 over 3 years. Consistent effects of empagliflozin were observed across subgroups defined by baseline characteristics, including patients with vs. without heart failure, and across categories of medications to treat diabetes and/or heart failure. Empagliflozin improved other heart failure outcomes, including hospitalization for or death from heart failure 2.8 vs. 4.5%; HR: 0.61 (0.47-0.79); P < 0.001] and was associated with a reduction in all-cause hospitalization 36.8 vs. 39.6%; HR: 0.89 (0.82-0.96); P = 0.003]. Serious adverse events and adverse events leading to discontinuation were reported by a higher proportion of patients with vs. without heart failure at baseline in both treatment groups, but were no more common with empagliflozin than with placebo. Conclusion In patients with type 2 diabetes and high cardiovascular risk, empagliflozin reduced heart failure hospitalization and cardiovascular death, with a consistent benefit in patients with and without baseline heart failure. KW - Cotransporter 2 inhibition KW - Placebo-controlled trial KW - Blood pressure KW - Double-blind KW - Mellitus KW - Weight KW - Collaboration KW - Guidelines KW - Mortality KW - Diseases KW - Cardiovascular disease KW - Hospitalization Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-188900 VL - 37 IS - 19 ER - TY - JOUR A1 - Weidemann, Frank A1 - Maier, Sebastian K. G. A1 - Störk, Stefan A1 - Brunner, Thomas A1 - Liu, Dan A1 - Hu, Kai A1 - Seydelmann, Nora A1 - Schneider, Andreas A1 - Becher, Jan A1 - Canan-Kühl, Sima A1 - Blaschke, Daniela A1 - Bijnens, Bart A1 - Ertl, Georg A1 - Wanner, Christoph A1 - Nordbeck, Peter T1 - Usefulness of an implantable loop recorder to detect clinically relevant arrhythmias in patients with advanced fabry cardiomyopathy JF - The American Journal of Cardiology N2 - Patients with genetic cardiomyopathy that involves myocardial hypertrophy often develop clinically relevant arrhythmias that increase the risk of sudden death. Consequently, guidelines for medical device therapy were established for hypertrophic cardiomyopathy, but not for conditions with only anecdotal evidence of arrhythmias, like Fabry cardiomyopathy. Patients with Fabry cardiomyopathy progressively develop myocardial fibrosis, and sudden cardiac death occurs regularly. Because 24-hour Holier electrocardiograms (ECGs) might not detect clinically important arrhythmias, we tested an implanted loop recorder for continuous heart rhythm surveillance and determined its impact on therapy. This prospective study included 16 patients (12 men) with advanced Fabry cardiomyopathy, relevant hypertrophy, and replacement fibrosis in "loco typico." No patients previously exhibited clinically relevant arrhythmias on Holier ECGs. Patients received an implantable loop recorder and were prospectively followed with telemedicine for a median of 1.2 years (range 0.3 to 2.0 years). The primary end point was a clinically meaningful event, which required a therapy change, captured with the loop recorder. Patients submitted data regularly (14 +/- 11 times per month). During follow-up, 21 events were detected (including 4 asystole, i.e., ECG pauses >= 3 seconds) and 7 bradycardia events; 5 episodes of intermittent atrial fibrillation (>3 minutes) and 5 episodes of ventricular tachycardia (3 sustained and 2 nonsustained). Subsequently, as defined in the primary end point, 15 events leaded to a change of therapy. These patients required therapy with a pacemaker or cardioverter defibrillator implantation and/or anticoagulation therapy for atrial fibrillation. In conclusion, clinically relevant arrhythmias that require further device and/or medical therapy are often missed with Holier ECGs in patients with advanced stage Fabry cardiomyopathy, but they can be detected by telemonitoring with an implantable loop recorder. KW - Cardiovascular magnetic-resonance KW - Coronary artery disease KW - Ventricular-arrhythmias KW - Task force KW - Management KW - Enzyme replacement therapy KW - Hypertrophic cardiomyopathy KW - Myocardial fibrosis KW - Guidelines KW - Manifestation Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-188093 VL - 118 IS - 2 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 - TY - JOUR A1 - Busch, Martin A1 - Nadal, Jennifer A1 - Schmid, Matthias A1 - Paul, Katharina A1 - Titze, Stephanie A1 - Hübner, Silvia A1 - Köttgen, Anna A1 - Schultheiss, Ulla T. A1 - Baid-Agrawal, Seema A1 - Lorenzen, Johan A1 - Schlieper, Georg A1 - Sommerer, Claudia A1 - Krane, Vera A1 - Hilge, Robert A1 - Kielstein, Jan T. A1 - Kronenberg, Florian A1 - Wanner, Christoph A1 - Eckardt, Kai-Uwe A1 - Wolf, Gunter T1 - Glycaemic control and antidiabetic therapy in patients with diabetes mellitus and chronic kidney disease - cross-sectional data from the German Chronic Kidney Disease (GCKD) cohort JF - BMC Nephrology N2 - Background Diabetes mellitus (DM) is the leading cause of end-stage renal disease. Little is known about practice patterns of anti-diabetic therapy in the presence of chronic kidney disease (CKD) and correlates with glycaemic control. We therefore aimed to analyze current antidiabetic treatment and correlates of metabolic control in a large contemporary prospective cohort of patients with diabetes and CKD. Methods The German Chronic Kidney Disease (GCKD) study enrolled 5217 patients aged 18–74 years with an estimated glomerular filtration rate (eGFR) between 30–60 mL/min/1.73 m2 or proteinuria >0.5 g/d. The use of diet prescription, oral anti-diabetic medication, and insulin was assessed at baseline. HbA1c, measured centrally, was the main outcome measure. Results At baseline, DM was present in 1842 patients (35 %) and the median HbA1C was 7.0 % (25th–75th percentile: 6.8–7.9 %), equalling 53 mmol/mol (51, 63); 24.2 % of patients received dietary treatment only, 25.5 % oral antidiabetic drugs but not insulin, 8.4 % oral antidiabetic drugs with insulin, and 41.8 % insulin alone. Metformin was used by 18.8 %. Factors associated with an HbA1C level >7.0 % (53 mmol/mol) were higher BMI (OR = 1.04 per increase of 1 kg/m2, 95 % CI 1.02–1.06), hemoglobin (OR = 1.11 per increase of 1 g/dL, 95 % CI 1.04–1.18), treatment with insulin alone (OR = 5.63, 95 % CI 4.26–7.45) or in combination with oral antidiabetic agents (OR = 4.23, 95 % CI 2.77–6.46) but not monotherapy with metformin, DPP-4 inhibitors, or glinides. Conclusions Within the GCKD cohort of patients with CKD stage 3 or overt proteinuria, antidiabetic treatment patterns were highly variable with a remarkably high proportion of more than 50 % receiving insulin-based therapies. Metabolic control was overall satisfactory, but insulin use was associated with higher HbA1C levels. KW - Chronic kidney disease KW - Glycaemic control KW - Hemoglobin A1C KW - Insulin therapy KW - Oral antidiabetic drugs KW - Diabetes mellitus Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-164687 VL - 17 IS - 59 ER - TY - JOUR A1 - Dienemann, Thomas A1 - Fujii, Naohiko A1 - Orlandi, Paula A1 - Nessel, Lisa A1 - Furth, Susan L. A1 - Hoy, Wendy E. A1 - Matsuo, Seiichi A1 - Mayer, Gert A1 - Methven, Shona A1 - Schaefer, Franz A1 - Schaeffner, Elke S. A1 - Solá, Laura A1 - Stengel, Bénédicte A1 - Wanner, Christoph A1 - Zhang, Luxia A1 - Levin, Adeera A1 - Eckardt, Kai-Uwe A1 - Feldman, Harold I. T1 - International Network of Chronic Kidney Disease cohort studies (iNET-CKD): a global network of chronic kidney disease cohorts JF - BMC Nephrology N2 - Background Chronic kidney disease (CKD) is a global health burden, yet it is still underrepresented within public health agendas in many countries. Studies focusing on the natural history of CKD are challenging to design and conduct, because of the long time-course of disease progression, a wide variation in etiologies, and a large amount of clinical variability among individuals with CKD. With the difference in health-related behaviors, healthcare delivery, genetics, and environmental exposures, this variability is greater across countries than within one locale and may not be captured effectively in a single study. Methods Studies were invited to join the network. Prerequisites for membership included: 1) observational designs with a priori hypotheses and defined study objectives, patient-level information, prospective data acquisition and collection of bio-samples, all focused on predialysis CKD patients; 2) target sample sizes of 1,000 patients for adult cohorts and 300 for pediatric cohorts; and 3) minimum follow-up of three years. Participating studies were surveyed regarding design, data, and biosample resources. Results Twelve prospective cohort studies and two registries covering 21 countries were included. Participants age ranges from >2 to >70 years at inclusion, CKD severity ranges from stage 2 to stage 5. Patient data and biosamples (not available in the registry studies) are measured yearly or biennially. Many studies included multiple ethnicities; cohort size ranges from 400 to more than 13,000 participants. Studies’ areas of emphasis all include but are not limited to renal outcomes, such as progression to ESRD and death. Conclusions iNET-CKD (International Network of CKD cohort studies) was established, to promote collaborative research, foster exchange of expertise, and create opportunities for research training. Participating studies have many commonalities that will facilitate comparative research; however, we also observed substantial differences. The diversity we observed across studies within this network will be able to be leveraged to identify genetic, behavioral, and health services factors associated with the course of CKD. With an emerging infrastructure to facilitate interactions among the investigators of iNET-CKD and a broadly defined research agenda, we are confident that there will be great opportunity for productive collaborative investigations involving cohorts of individuals with CKD. KW - Cohort study KW - Network KW - CKD KW - Epidemiology KW - Diversity Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-164604 VL - 17 ER - TY - JOUR A1 - Lenders, Malte A1 - Weidemann, Frank A1 - Kurschat, Christine A1 - Canaan-Kühl, Sima A1 - Duning, Thomas A1 - Stypmann, Jörg A1 - Schmitz, Boris A1 - Reiermann, Stefanie A1 - Krämer, Johannes A1 - Blaschke, Daniela A1 - Wanner, Christoph A1 - Brand, Stefan-Martin A1 - Brand, Eva T1 - Alpha-Galactosidase A p.A143T, a non-Fabry disease-causing variant JF - Orphanet Journal of Rare Diseases N2 - Background Fabry disease (FD) is an X-linked multisystemic disorder with a heterogeneous phenotype. Especially atypical or late-onset type 2 phenotypes present a therapeutical dilemma. Methods To determine the clinical impact of the alpha-Galactosidase A (GLA) p.A143T/ c.427G > A variation, we retrospectively analyzed 25 p.A143T patients in comparison to 58 FD patients with other missense mutations. Results p.A143T patients suffering from stroke/ transient ischemic attacks had slightly decreased residual GLA activities, and/or increased lyso-Gb3 levels, suspecting FD. However, most male p.A143T patients presented with significant residual GLA activity (~50 % of reference), which was associated with normal lyso-Gb3 levels. Additionally, p.A143T patients showed less severe FD-typical symptoms and absent FD-typical renal and cardiac involvement in comparison to FD patients with other missense mutations. Two tested female p.A143T patients with stroke/TIA did not show skewed X chromosome inactivation. No accumulation of neurologic events in family members of p.A143T patients with stroke/transient ischemic attacks was observed. Conclusions We conclude that GLA p.A143T seems to be most likely a neutral variant or a possible modifier instead of a disease-causing mutation. Therefore, we suggest that p.A143T patients with stroke/transient ischemic attacks of unknown etiology should be further evaluated, since the diagnosis of FD is not probable and subsequent ERT or chaperone treatment should not be an unreflected option. KW - Fabry disease KW - genotype KW - lyso-Gb3 KW - variant of unknown significance KW - GLA mutation KW - late-onset KW - stroke Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-166559 VL - 11 IS - 54 ER -