@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{DrechslerMeinitzerPilzetal.2011,
  author    = {Drechsler, Christiane and Meinitzer, Andreas and Pilz, Stefan and Krane, Vera and Tomaschitz, Andreas and Ritz, Eberhard and M{\"a}rz, Winfried and Wanner, Christoph},
  title     = {Homoarginine, heart failure, and sudden cardiac death in haemodialysis patients},
  series = {European Journal of Heart Failure},
  volume    = {13},
  journal   = {European Journal of Heart Failure},
  number    = {8},
  doi       = {10.1093/eurjhf/hfr056},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-140495},
  pages     = {852-859},
  year      = {2011},
  abstract  = {Aims Sudden cardiac death (SCD) is a major contributor to the excess mortality of patients on maintenance dialysis. Homoarginine deficiency may lead to decreased nitric oxide availability and endothelial dysfunction. Based on this rationale we assessed whether homoarginine deficiency is a risk factor for SCD in dialysis patients. Methods and results This study examined the association of homoarginine with cardiovascular outcomes in 1255 diabetic haemodialysis patients from the German diabetes and dialysis study. During a median of 4 years of follow-up, hazard ratios (HR) (95\% CI) for reaching the following pre-specified, adjudicated endpoints were determined: SCD, myocardial infarction, stroke, death due to heart failure, and combined cardiovascular events. There was a strong association of low homoarginine concentrations with the presence of congestive heart failure and left ventricular hypertrophy as well as increased levels of brain natriuretic peptide. Per unit decrease in homoarginine, the risk of SCD increased three-fold (HR 3.1, 95\% CI 2.0-4.9), attenuating slightly in multivariate models (HR 2.4; 95\% CI 1.5-3.9). Patients in the lowest homoarginine quintile experienced a more than two-fold increased risk of SCD, and more than three-fold increased risk of heart failure death than patients in the highest quintile, which accounted for the high incidence of combined cardiovascular events. Low homoarginine showed a trend towards increased risk of stroke, however, myocardial infarction was not meaningfully affected. Conclusion Low homoarginine is a strong risk factor for SCD and death due to heart failure in haemodialysis patients. Further studies are needed to elucidate the underlying mechanisms, offering the potential to develop new interventional strategies.},
  language  = {en}
}
@article{DrechslerRitzTomaschitzetal.2013,
  author    = {Drechsler, Christiane and Ritz, Eberhard and Tomaschitz, Andreas and Pilz, Stefan and Sch{\"o}nfeld, Stephan and Blouin, Katja and Bidlingmaier, Martin and Hammer, Fabian and Krane, Vera and M{\"a}rz, Winfried and Allolio, Bruno and Fassnacht, Martin and Wanner, Christoph},
  title     = {Aldosterone and cortisol affect the risk of sudden cardiac death in haemodialysis patients},
  series = {European Heart Journal},
  volume    = {34},
  journal   = {European Heart Journal},
  doi       = {10.1093/eurheartj/ehs361},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-132562},
  pages     = {578-585},
  year      = {2013},
  abstract  = {Background: Sudden cardiac death is common and accounts largely for the excess mortality of patients on maintenance dialysis. It is unknown whether aldosterone and cortisol increase the incidence of sudden cardiac death in dialysis patients. Methods and results: We analysed data from 1255 diabetic haemodialysis patients participating in the German Diabetes and Dialysis Study (4D Study). Categories of aldosterone and cortisol were determined at baseline and patients were followed for a median of 4 years. By Cox regression analyses, hazard ratios (HRs) were determined for the effect of aldosterone, cortisol, and their combination on sudden death and other adjudicated cardiovascular outcomes. The mean age of the patients was 66 ± 8 years (54\% male). Median aldosterone was <15 pg/mL (detection limit) and cortisol 16.8 µg/dL. Patients with aldosterone levels >200 pg/mL had a significantly higher risk of sudden death (HR: 1.69; 95\% CI: 1.06-2.69) compared with those with an aldosterone <15 pg/mL. The combined presence of high aldosterone (>200 pg/mL) and high cortisol (>21.1 µg/dL) levels increased the risk of sudden death in striking contrast to patients with low aldosterone (<15 pg/mL) and low cortisol (<13.2 µg/dL) levels (HR: 2.86, 95\% CI: 1.32-6.21). Furthermore, all-cause mortality was significantly increased in the patients with high levels of both hormones (HR: 1.62, 95\% CI: 1.01-2.62). Conclusions: The joint presence of high aldosterone and high cortisol levels is strongly associated with sudden cardiac death as well as all-cause mortality in haemodialysed type 2 diabetic patients. Whether a blockade of the mineralocorticoid receptor decreases the risk of sudden death in these patients must be examined in future trials.},
  language  = {en}
}
@article{DrechslerSchmiedekeNiemannetal.2013,
  author    = {Drechsler, Christiane and Schmiedeke, Benjamin and Niemann, Markus and Schmiedeke, Daniel and Kr{\"a}mer, Johannes and Turkin, Irina and Blouin, Katja and Emmert, Andrea and Pilz, Stefan and Obermayer-Pietsch, Barbara and Wiedemann, Frank and Breunig, Frank and Wanner, Christoph},
  title     = {Potential role of vitamin D deficiency on Fabry cardiomyopathy},
  series = {Journal of Inherited Metabolic Disease},
  volume    = {37},
  journal   = {Journal of Inherited Metabolic Disease},
  number    = {2},
  doi       = {10.1007/s10545-013-9653-8},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-132102},
  pages     = {289-295},
  year      = {2013},
  abstract  = {Patients with Fabry disease frequently develop left ventricular (LV) hypertrophy and renal fibrosis. Due to heat intolerance and an inability to sweat, patients tend to avoid exposure to sunlight. We hypothesized that subsequent vitamin D deficiency may contribute to Fabry cardiomyopathy. This study investigated the vitamin D status and its association with LV mass and adverse clinical symptoms in patients with Fabry disease. 25-hydroxyvitamin D (25[OH]D) was measured in 111 patients who were genetically proven to have Fabry disease. LV mass and cardiomyopathy were assessed by magnetic resonance imaging and echocardiography. In cross-sectional analyses, associations with adverse clinical outcomes were determined by linear and binary logistic regression analyses, respectively, and were adjusted for age, sex, BMI and season. Patients had a mean age of 40 ± 13 years (42 \% males), and a mean 25(OH)D of 23.5 ± 11.4 ng/ml. Those with overt vitamin D deficiency (25[OH]D ≤ 15 ng/ml) had an adjusted six fold higher risk of cardiomyopathy, compared to those with sufficient 25(OH)D levels >30 ng/ml (p = 0.04). The mean LV mass was distinctively different with 170 ± 75 g in deficient, 154 ± 60 g in moderately deficient and 128 ± 58 g in vitamin D sufficient patients (p = 0.01). With increasing severity of vitamin D deficiency, the median levels of proteinuria increased, as well as the prevalences of depression, edema, cornea verticillata and the need for medical pain therapy. In conclusion, vitamin D deficiency was strongly associated with cardiomyopathy and adverse clinical symptoms in patients with Fabry disease. Whether vitamin D supplementation improves complications of Fabry disease, requires a randomized controlled trial.},
  language  = {en}
}
@article{DrechslerKolleritzMeinitzeretal.2013,
  author    = {Drechsler, Christiane and Kolleritz, Barbara and Meinitzer, Andreas and M{\"a}rz, Winfried and Ritz, Eberhard and K{\"o}nig, Paul and Neyer, Ulrich and Pilz, Stefan and Wanner, Christoph and Kronenberg, Florian},
  title     = {Homoarginine and Progression of Chronic Kidney Disease: Results from the Mild to Moderate Kidney Disease Study},
  series = {PLoS ONE},
  volume    = {8},
  journal   = {PLoS ONE},
  number    = {5},
  organization    = {MMKD Study Group},
  doi       = {10.1371/journal.pone.0063560},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-130979},
  pages     = {e63560},
  year      = {2013},
  abstract  = {Background: Homoarginine is an amino acid derivative mainly synthesized in the kidney. It is suggested to increase nitric oxide availability, enhance endothelial function and to protect against cardiovascular diseases. We aimed to investigate the relation between homoarginine, kidney function and progression of chronic kidney disease (CKD). Methods: We measured plasma homoarginine concentrations in baseline samples of the Mild to Moderate Kidney Disease (MMKD) Study, a prospective cohort study of 227 patients with CKD in Europe. Homoarginine concentrations were available in 182 of the baseline samples and in 139 of the prospectively-followed patients. We correlated homoarginine concentrations to parameters of kidney function. The association between homoarginine and progression of CKD was assessed during a follow-up of up to seven years (median 4.45 years, interquartile range 2.54-5.19) using Cox regression analysis. Progression of CKD was defined as doubling of baseline serum creatinine and/or end-stage renal disease. Results: Study participants were at baseline on average 47 \(\pm\)13 years old and 65\% were male. Mean \(\pm\) standard deviation of homoarginine concentrations were \(2.5 \pm 1.1 \mu mol/L\) and concentrations were incrementally lower at lower levels of GFR with mean concentrations of \(2.90 \pm 1.02 \mu mol/L\) (GFR. 90 ml/min), \(2.64 \pm 1.06 \mu mol/L\) (GFR 60-90 ml/min), \(2.52 \pm 1.24 \mu mol/L\) (GFR 30-60 ml/min) and \(2.05 \pm 0.78 \mu mol/L\) (GFR, 30 ml/min), respectively (p = 0.002). The age-and sex-adjusted risk to reach the renal endpoint was significantly higher by 62\% with each decrease by one standard deviation (\(1.1 \mu mol/L\)) of homoarginine (HR 1.62, 95\% CI 1.16-2.27, p = 0.005). This association was independent of proteinuria (HR 1.56, 95\% CI 1.11-2.20, p = 0.01), and was slightly attenuated when adjusting for GFR (HR 1.40 (95\% CI 0.98-1.98, p = 0.06). Conclusions: Homoarginine concentrations are directly correlated with kidney function and are significantly associated with the progression of CKD. Low homoarginine concentrations might be an early indicator of kidney failure and a potential target for the prevention of disease progression which needs further investigations.},
  language  = {en}
}