Cox regression results.

<p>P-splines to explore the functional form of the effect of ferritin values (ng/mL) on the log hazard ratio for the risk of all-cause mortality and cardiovascular or sepsis-related mortality in patients with C-reactive protein <0.5 mg/dL and ≥0.5 mg/dL during follow-up, adjusted for age, sex, diabetes mellitus and time-dependent albumin and hemoglobin. Dashed lines are the pointwise 95% CI. The rugplot at the bottom of the figures displays the number of measurements.</p

Iron Supplementation and Mortality in Incident Dialysis Patients: An Observational Study

<div><p>Background</p><p>Studies on the association between iron supplementation and mortality in dialysis patients are rare and conflicting.</p><p>Methods</p><p>In our observational single-center cohort study (INVOR study) we prospectively studied 235 incident dialysis patients. Time-dependent Cox proportional hazards models using all measured laboratory values for up to 7.6 years were applied to study the association between iron supplementation and all-cause mortality, cardiovascular and sepsis-related mortality. Furthermore, the time-dependent association of ferritin levels with mortality in patients with normal C-reactive protein (CRP) levels (<0.5 mg/dL) and elevated CRP levels (≧0.5 mg/dL) was evaluated by using non-linear P-splines to allow flexible modeling of the association.</p><p>Results</p><p>One hundred and ninety-one (81.3%) patients received intravenous iron, 13 (5.5%) patients oral iron, whereas 31 (13.2%) patients were never supplemented with iron throughout the observation period. Eighty-two (35%) patients died during a median follow-up of 34 months, 38 patients due to cardiovascular events and 21 patients from sepsis. Baseline CRP levels were not different between patients with and without iron supplementation. However, baseline serum ferritin levels were lower in patients receiving iron during follow up (median 93 <i>vs</i> 251 ng/mL, p<0.001). Iron supplementation was associated with a significantly reduced all-cause mortality [HR (95%CI): 0.22 (0.08–0.58); p = 0.002] and a reduced cardiovascular and sepsis-related mortality [HR (95%CI): 0.31 (0.09–1.04); p = 0.06]. Increasing ferritin concentrations in patients with normal CRP were associated with a decreasing mortality, whereas in patients with elevated CRP values ferritin levels>800 ng/mL were linked with increased mortality.</p><p>Conclusions</p><p>Iron supplementation is associated with reduced all-cause mortality in incident dialysis patients. While serum ferritin levels up to 800 ng/mL appear to be safe, higher ferritin levels are associated with increased mortality in the setting of concomitant inflammation.</p></div

Survival curves for a) all-cause mortality and b) cardiovascular or sepsis-related mortality stratified for iron supplementation.

<p>Adjusted for age, sex, time-dependent type of renal replacement therapy, diabetes, time-dependent C-reactive protein, albumin and hemoglobin. The number of patients at risk for each year of observation is given with the last observation time at 91 months. “% surv” indicates the percentage of survivors for each 12-month interval.</p

Clinical characteristics of patients at baseline and during follow-up stratified for iron supplementation during follow-up.

<p>Mean ±SD [25^th, 50^th and 75^th percentile for cases of non-normal distribution] or number (%).</p>a<p>p<0.05;</p>b<p>p<0.01;</p>c<p>p<0.005;</p>d<p>p<0.001, comparison between patients who ever received iron supplementation and patients who never received iron supplementation during the observation period.</p><p>* <b>Coronary artery disease (CAD)</b>: myocardial infarction (MI), percutaneous transluminal coronary angioplasty (PTCA), aortocoronary bypass (ACBP).</p><p>** <b>Cardiovascular disease (CVD)</b>: myocardial infarction (MI), percutaneous transluminal coronary angioplasty (PTCA), aortocoronary bypass (ACBP), coronary artery stenosis ≥50%, ischemic cerebral infarction, transient ischemic attack (TIA)/PRIND.</p><p>*** <b>Peripheral arterial disease (PAD)</b>: vascular stenosis, percutaneous transluminal angioplasty (PTA), peripheral bypass, amputation.</p>‡<p>Follow-up time was calculated as the time from the start of dialysis until the patient died or the end of the observation period was reached.</p>#<p><b>Cardiovascular mortality</b>: myocardial infarction (MI), heart failure, sudden death, ischemic stroke, hemorrhagic stroke.</p><p>Clinical characteristics of patients at baseline and during follow-up stratified for iron supplementation during follow-up.</p

Association between iron supplementation and all-cause mortality and cardiovascular or sepsis-related mortality using time-dependent Cox proportional hazards models^*.

<p><b>*</b> Adjusted for age, sex, diabetes mellitus and the time-dependent variables type of renal replacement therapy, C-reactive protein, albumin and hemoglobin.</p><p>** <b>Cardiovascular or sepsis mortality</b>: myocardial infarction (MI), heart failure, sudden death, ischemic stroke, hemorrhagic stroke, sepsis.</p><p>Association between iron supplementation and all-cause mortality and cardiovascular or sepsis-related mortality using time-dependent Cox proportional hazards models^{<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0114144#nt111" target="_blank">*</a>}.</p

Association between iron supplementation and all-cause mortality in patients with diabetes mellitus and without diabetes mellitus using time-dependent Cox proportional hazards models^*.

<p><b>*</b> Adjusted for age, sex and the time-dependent variables type of renal replacement therapy, C-reactive protein, albumin and hemoglobin.</p><p>Association between iron supplementation and all-cause mortality in patients with diabetes mellitus and without diabetes mellitus using time-dependent Cox proportional hazards models^{<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0114144#nt113" target="_blank">*</a>}.</p

Association between time-dependent ferritin and all-cause mortality and cardiovascular or sepsis-related mortality in patients with C-reactive protein <0.5 mg/dL and ≧0.5 mg/dL during follow-up using time-dependent Cox proportional hazards models.

<p>Shown for each model are estimated HRs for the linear component of the non-linear P-spline and HRs for ferritin measurements per 100 ng/mL increase.</p><p><b>*</b> Adjusted for age, sex, diabetes mellitus and time-dependent albumin and hemoglobin.</p><p>** <b>Cardiovascular or sepsis mortality</b>: myocardial infarction (MI), heart failure, sudden death, ischemic stroke, hemorrhagic stroke, sepsis.</p><p>Association between time-dependent ferritin and all-cause mortality and cardiovascular or sepsis-related mortality in patients with C-reactive protein <0.5 mg/dL and ≧0.5 mg/dL during follow-up using time-dependent Cox proportional hazards models.</p

Image_1_Cilgavimab/Tixagevimab as alternative therapeutic approach for BA.2 infections.jpg

ObjectivesThe identification of the SARS-CoV-2 Omicron variants BA.1 and BA.2 immediately raised concerns about the efficacy of currently used monoclonal antibody therapies. Here, we analyzed the activity of Sotrovimab and Regdanvimab, which are used in clinics for treatment of moderate to severe SARS-CoV-2 infections, and Cilgavimab/Tixagevimab, which are approved for prophylactic use, against BA.1 and BA.2 in a 3D model of primary human bronchial epithelial cells.MethodsPrimary human airway epithelia (HAE) cells in a 3D tissue model were infected with clinical isolates of SARS-CoV-2 Delta, BA.1 or BA.2. To mimic the therapeutic use of mAbs, we added Regdanvimab, Sotrovimab or Cilgavimab/Tixagevimab 6 h after infection. In order to mirror the prophylactic use of Cilgavimab/Tixagevimab, we added this compound 6 h prior to infection to the fully differentiated, pseudostratified epithelia cultured in air-liquid interphase (ALI).ResultsWe observed that Sotrovimab, but not Regdanvimab, is active against BA.1; however, both antibodies lose their efficacy against BA.2. In contrast, we found that BA.2 was sensitive to neutralization by the approved prophylactic administration and the therapeutic use, which is not yet permitted, of Cilgavimab/Tixagevimab.ConclusionImportantly, while the use of Tixagevimab/Cilgavimab is effective in controlling BA.2 but not BA.1 infection, monoclonal antibodies (mAbs) with efficacy against BA.1 are ineffective to reduce BA.2 virus replication in a human lung model. Our data may have implications on the variant specific clinical use of monoclonal antibodies.</p

Image_2_Cilgavimab/Tixagevimab as alternative therapeutic approach for BA.2 infections.jpg

ObjectivesThe identification of the SARS-CoV-2 Omicron variants BA.1 and BA.2 immediately raised concerns about the efficacy of currently used monoclonal antibody therapies. Here, we analyzed the activity of Sotrovimab and Regdanvimab, which are used in clinics for treatment of moderate to severe SARS-CoV-2 infections, and Cilgavimab/Tixagevimab, which are approved for prophylactic use, against BA.1 and BA.2 in a 3D model of primary human bronchial epithelial cells.MethodsPrimary human airway epithelia (HAE) cells in a 3D tissue model were infected with clinical isolates of SARS-CoV-2 Delta, BA.1 or BA.2. To mimic the therapeutic use of mAbs, we added Regdanvimab, Sotrovimab or Cilgavimab/Tixagevimab 6 h after infection. In order to mirror the prophylactic use of Cilgavimab/Tixagevimab, we added this compound 6 h prior to infection to the fully differentiated, pseudostratified epithelia cultured in air-liquid interphase (ALI).ResultsWe observed that Sotrovimab, but not Regdanvimab, is active against BA.1; however, both antibodies lose their efficacy against BA.2. In contrast, we found that BA.2 was sensitive to neutralization by the approved prophylactic administration and the therapeutic use, which is not yet permitted, of Cilgavimab/Tixagevimab.ConclusionImportantly, while the use of Tixagevimab/Cilgavimab is effective in controlling BA.2 but not BA.1 infection, monoclonal antibodies (mAbs) with efficacy against BA.1 are ineffective to reduce BA.2 virus replication in a human lung model. Our data may have implications on the variant specific clinical use of monoclonal antibodies.</p

Percentage of subjects with values outside of the normal range for biomarkers in hemodialysis and peritoneal dialysis patients.

<p>HD, hemodialysis; PD, peritoneal dialysis; Hb, hemoglobin; TIBC, total iron binding capacity; sTfR, soluble transferrin receptor; Hep-25, hepcidin-25; WBC, white blood cell count; CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; IL-6, Interleukin-6; IL-10, Interleukin-10; TNF-α = tumor necrosis factor alpha.</p><p>* P-value was calculated with original data.</p><p>Percentage of subjects with values outside of the normal range for biomarkers in hemodialysis and peritoneal dialysis patients.</p