TY - JOUR A1 - Wagner, Martin A1 - Ashby, Damien R. A1 - Kurtz, Caroline A1 - Alam, Ahsan A1 - Busbridge, Mark A1 - Raff, Ulrike A1 - Zimmermann, Josef A1 - Heuschmann, Peter U. A1 - Wanner, Christoph A1 - Schramm, Lothar T1 - Hepcidin-25 in diabetic chronic kidney disease is predictive for mortality and progression to end stage renal disease JF - PLoS One N2 - Background Anemia is common and is associated with impaired clinical outcomes in diabetic chronic kidney disease (CKD). It may be explained by reduced erythropoietin (EPO) synthesis, but recent data suggest that EPO-resistance and diminished iron availability due to inflammation contribute significantly. In this cohort study, we evaluated the impact of hepcidin-25—the key hormone of iron-metabolism—on clinical outcomes in diabetic patients with CKD along with endogenous EPO levels. Methods 249 diabetic patients with CKD of any stage, excluding end-stage renal disease (ESRD), were enrolled (2003–2005), if they were not on EPO-stimulating agent and iron therapy. Hepcidin-25 levels were measured by radioimmunoassay. The association of hepcidin-25 at baseline with clinical variables was investigated using linear regression models. All-cause mortality and a composite endpoint of CKD progression (ESRD or doubling of serum creatinine) were analyzed by Cox proportional hazards models. Results Patients (age 67 yrs, 53% male, GFR 51 ml/min, hemoglobin 131 g/L, EPO 13.5 U/L, hepcidin-25 62.0 ng/ml) were followed for a median time of 4.2 yrs. Forty-nine patients died (19.7%) and forty (16.1%) patients reached the composite endpoint. Elevated hepcidin levels were independently associated with higher ferritin-levels, lower EPO-levels and impaired kidney function (all p<0.05). Hepcidin was related to mortality, along with its interaction with EPO, older age, greater proteinuria and elevated CRP (all p<0.05). Hepcidin was also predictive for progression of CKD, aside from baseline GFR, proteinuria, low albumin- and hemoglobin-levels and a history of CVD (all p<0.05). Conclusions We found hepcidin-25 to be associated with EPO and impaired kidney function in diabetic CKD. Elevated hepcidin-25 and EPO-levels were independent predictors of mortality, while hepcidin-25 was also predictive for progression of CKD. Both hepcidin-25 and EPO may represent important prognostic factors of clinical outcome and have the potential to further define “high risk” populations in CKD. KW - diabetes mellitus KW - inflammation KW - type 2 diabetes KW - hemoglobin KW - chronic kidney disease KW - anemia KW - ferritin KW - proteinuria Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-125514 VL - 10 IS - 4 ER - TY - JOUR A1 - Schneider, Andreas A1 - Schneider, Markus P. A1 - Krieter, Detlef H. A1 - Genser, Bernd A1 - Scharnagl, Hubert A1 - Stojakovic, Tatjana A1 - Wanner, Christoph A1 - Drechsler, Christiane T1 - Effect of high-flux dialysis on circulating FGF-23 levels in end-stage renal disease patients: results from a randomized trial JF - PLoS ONE N2 - 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. KW - chronic kidney disease KW - left ventricular hypertrophy KW - phosphate homeostasis KW - hemodialysis KW - mortality KW - fibroblast growth factor-23 KW - mineral metabolism KW - parathyroid hormone KW - cardiovascular events Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-148559 VL - 10 IS - 5 ER - TY - JOUR A1 - Kleikers, Pamela W. M. A1 - Hooijmans, Carlijn A1 - Göb, Eva A1 - Langhauser, Friederike A1 - Rewell, Sarah S. J. A1 - Radermacher, Kim A1 - Ritskes-Hoitinga, Merel A1 - Howells, David W. A1 - Kleinschnitz, Christoph A1 - Schmidt, Harald H. H. W. T1 - A combined pre-clinical meta-analysis and randomized confirmatory trial approach to improve data validity for therapeutic target validation JF - Scientific Reports N2 - Biomedical research suffers from a dramatically poor translational success. For example, in ischemic stroke, a condition with a high medical need, over a thousand experimental drug targets were unsuccessful. Here, we adopt methods from clinical research for a late-stage pre-clinical meta-analysis (MA) and randomized confirmatory trial (pRCT) approach. A profound body of literature suggests NOX\(_{2}\) to be a major therapeutic target in stroke. Systematic review and MA of all available NOX\(_{2}\)\(^{-/y}\) studies revealed a positive publication bias and lack of statistical power to detect a relevant reduction in infarct size. A fully powered multi-center pRCT rejects NOX\(_{2}\) as a target to improve neurofunctional outcomes or achieve a translationally relevant infarct size reduction. Thus stringent statistical thresholds, reporting negative data and a MA-pRCT approach can ensure biomedical data validity and overcome risks of bias. KW - focal cerebral ischemia KW - darbepoetin alpha KW - mice KW - translational stroke research KW - colony-stimulating factor KW - NADPH oxidase inhibitors KW - chronic kidney disease KW - diabetes mellitus KW - oxidative stress KW - search filter Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-151401 VL - 5 IS - 13428 ER -