Effect of Deferoxamine on Post-Transfusion Iron, Inflammation, and In Vitro Microbial Growth in a Canine Hemorrhagic Shock Model: A Randomized Controlled Blinded Pilot Study.

Red blood cell (RBC) transfusion is associated with recipient inflammation and infection, which may be triggered by excessive circulating iron. Iron chelation following transfusion may reduce these risks. The aim of this study was to evaluate the effect of deferoxamine on circulating iron and inflammation biomarkers over time and in vitro growth of Escherichia coli (E. coli) following RBC transfusion in dogs with atraumatic hemorrhage. Anesthetized dogs were subject to atraumatic hemorrhage and transfusion of RBCs, then randomized to receive either deferoxamine or saline placebo of equivalent volume (n = 10 per group) in a blinded fashion. Blood was sampled before hemorrhage and then 2, 4, and 6 h later. Following hemorrhage and RBC transfusion, free iron increased in all dogs over time (both p < 0.001). Inflammation biomarkers interleukin-6 (IL6), CXC motif chemokine-8 (CXCL8), interleukin-10 (IL10), and keratinocyte-derived chemokine (KC) increased in all dogs over time (all p < 0.001). Logarithmic growth of E. coli clones within blood collected 6 h post-transfusion was not different between groups. Only total iron-binding capacity was different between groups over time, being significantly increased in the deferoxamine group at 2 and 4 h post-transfusion (both p < 0.001). In summary, while free iron and inflammation biomarkers increased post-RBC transfusion, deferoxamine administration did not impact circulating free iron, inflammation biomarkers, or in vitro growth of E. coli when compared with placebo.

Trends in the early care of infants with myelomeningocele in the United States 2012-2018.

PURPOSE: The early care of children with spina bifida has changed with the increasing availability of fetal surgery and evidence that fetal repair improves the long-term outcomes of children with myelomeningocele. We sought to determine current trends in the prevalence and early care of children with myelomeningocele using a national administrative database. METHODS: This is a retrospective, cross-sectional cohort study of infants with spina bifida admitted within the first 28 days of life using the 2012-2018 Healthcare Cost and Utilization Project National Inpatient Database. Patients with spina bifida were identified by ICD code and stratified into a cohort with a coded neonatal repair of the defect and those without a coded repair. This database had no identifier specific for fetal surgery, but it is likely that a substantial number of infants without a coded repair had fetal surgery. RESULTS: We identified 5,090 patients with a coded repair and 5,715 without a coded repair. The overall prevalence of spina bifida was 3.94 per 10,000 live births. The percentage of patients without neonatal repair increased during the study period compared to those with repair (p = 0.0002). The cohort without neonatal repair had a higher risk of death (p < 0.001), prematurity (p < 0.001), and low birth weight (p < 0.001). More shunts were placed in patients who underwent neonatal repair (p < 0.001). Patients without neonatal repair were less likely to have public insurance (p = 0.0052) and more likely to reside in zip codes within the highest income quartile (p = 0.0002). CONCLUSIONS: The prevalence of spina bifida from 2012 to 2018 was 3.94 per 10,000 live births, with an increasing number of patients without neonatal repair of the defect, suggesting increased utilization of fetal surgery. Patients without neonatal repair had a higher risk of death, prematurity, and low birth weight but were more likely to have commercial insurance and reside in high-income zip codes.

Investigating the Molecular Mechanisms of Renal Hepcidin Induction and Protection upon Hemoglobin-Induced Acute Kidney Injury.

Hemolysis is known to cause acute kidney injury (AKI). The iron regulatory hormone hepcidin, produced by renal distal tubules, is suggested to exert a renoprotective role during this pathology. We aimed to elucidate the molecular mechanisms of renal hepcidin synthesis and its protection against hemoglobin-induced AKI. In contrast to known hepatic hepcidin induction, incubation of mouse cortical collecting duct (mCCDcl1) cells with IL-6 or LPS did not induce Hamp1 mRNA expression, whereas iron (FeS) and hemin significantly induced hepcidin synthesis (p < 0.05). Moreover, iron/heme-mediated hepcidin induction in mCCDcl1 cells was caused by the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway, as indicated by increased nuclear Nrf2 translocation and induced expression of Nrf2 downstream targets GCLM (p < 0.001), NQO1 (p < 0.001), and TXNRD1 (p < 0.005), which could be prevented by the known Nrf2 inhibitor trigonelline. Newly created inducible kidney-specific hepcidin KO mice demonstrated a significant reduction in renal Hamp1 mRNA expression. Phenylhydrazine (PHZ)-induced hemolysis caused renal iron loading and oxidative stress in both wildtype (Wt) and KO mice. PHZ treatment in Wt induced inflammatory markers (IL-6, TNFα) but not Hamp1. However, since PHZ treatment also significantly reduced systemic hepcidin levels in both Wt and KO mice (both p < 0.001), a dissection between the roles of systemic and renal hepcidin could not be made. Combined, the results of our study indicate that there are kidney-specific mechanisms in hepcidin regulation, as indicated by the dominant role of iron and not inflammation as an inducer of renal hepcidin, but also emphasize the complex interplay of various iron regulatory mechanisms during AKI on a local and systemic level.

Kidney tubule iron loading in experimental focal segmental glomerulosclerosis.

Kidney iron deposition may play a role in the progression of tubulointerstitial injury during chronic kidney disease. Here, we studied the molecular mechanisms of kidney iron loading in experimental focal segmental glomerulosclerosis (FSGS) and investigated the effect of iron-reducing interventions on disease progression. Thy-1.1 mice were injected with anti-Thy-1.1 monoclonal antibody (mAb) to induce proteinuria. Urine, blood and tissue were collected at day (D)1, D5, D8, D15 and D22 after mAb injection. Thy-1.1 mice were subjected to captopril (CA), iron-deficient (ID) diet or iron chelation (deferoxamine; DFO). MAb injection resulted in significant albuminuria at all time points (p < 0.01). Kidney iron loading, predominantly in distal tubules, increased in time, along with urinary kidney injury molecule-1 and 24p3 concentration, as well as kidney mRNA expression of Interleukin-6 (Il-6) and Heme oxygenase-1 (Ho-1). Treatment with CA, ID diet or DFO significantly reduced kidney iron deposition at D8 and D22 (p < 0.001) and fibrosis at D22 (p < 0.05), but not kidney Il-6. ID treatment increased kidney Ho-1 (p < 0.001). In conclusion, kidney iron accumulation coincides with progression of tubulointerstitial injury in this model of FSGS. Reduction of iron loading halts disease progression. However, targeted approaches to prevent excessive kidney iron loading are warranted to maintain the delicate systemic and cellular iron balance.

Code Blue Events in the Neonatal and Pediatric Intensive Care Units at a Tertiary Care Children's Hospital.

OBJECTIVE: The authors aim to compare all code blue events, regardless of the need for chest compressions, in the neonatal intensive care unit (NICU) versus the pediatric intensive care unit (PICU). We hypothesize that code events in the two units differ, reflecting different disease processes. STUDY DESIGN: This is a retrospective analysis of 107 code events using the code narrator, which is an electronic medical record of real-time code documentation, from April 2018 to March 2019. Events were divided into two groups, NICU and PICU. Neonatal resuscitation program algorithm was used for NICU events and a pediatric advanced life-support algorithm was used for PICU events. Events and outcomes were compared using univariate analysis. The Mann-Whitney test and linear regressions were done to compare the total code duration, time from the start of code to airway insertion, and time from airway insertion to end of code event. RESULTS: In the PICU, there were almost four times more code blue events per month and more likely to involve patients with seizures and no chronic condition. NICU events more often involved ventilated patients and those under 2 months of age. The median code duration for NICU events was 2.5 times shorter than for PICU events (11.5 vs. 29 minutes), even when adjusted for patient characteristics. Survival to discharge was not different in the two groups. CONCLUSION: Our study suggests that NICU code events as compared with PICU code events are more likely to be driven by airway problems, involve patients <2 months of age, and resolve quickly once airway is taken care of. This supports the use of a ventilation-focused neonatal resuscitation program for patients in the NICU. KEY POINTS: · Code blue events are four times more common in PICU.. · NICU code events are 2.5 times shorter in duration compared with PICU events.. · NICU code events are more likely to be attributed to a problem with an airway..

Neonatal Birth Trauma: Analysis of Yearly Trends, Risk Factors, and Outcomes.

OBJECTIVE: To evaluate the trends, proportions, risk factors, resource utilization, and outcomes of neonatal birth trauma in the US. STUDY DESIGN: This cross-sectional study of in-hospital births used the Nationwide Inpatient Sample for 2006-2014. We divided the cases by type of birth trauma: scalp injuries and major birth trauma. Linear regression for yearly trends and logistic regression were used for risk factors and outcomes. A generalized linear model was used, with a Poisson distribution for the length of stay and a gamma distribution for total spending charges. RESULTS: A total of 982 033 weighted records with neonatal birth trauma were found. The prevalence rate increased by 23% from (from 25.3 to 31.1 per 1000 hospital births). Scalp injuries composed 80% of all birth traumas and increased yearly from 19.87 to 26.46 per 1000 hospital births. Major birth trauma decreased from 5.44 to 4.67 per 1000 hospital births due to decreased clavicular fractures, brachial plexus injuries, and intracranial hemorrhage. There were significant differences in demographics and risk factors between the 2 groups. Compared with scalp injuries, major birth trauma was associated with higher odds of hypoxic-ischemic encephalopathy, seizures, need for mechanical ventilation, meconium aspiration, and sepsis. Length of stay was increased by 56%, and total charges were almost doubled for major birth trauma. CONCLUSIONS: Neonatal birth trauma increased over the study period secondary to scalp injuries. Major birth trauma constitutes a significant health burden. Scalp injuries are also associated with increased morbidity and might be markers of brain injury in some cases.

Improved Maternal and Infant Outcomes with Serial, Self-Reported Early Prenatal Substance Use Screening.

INTRODUCTION: Most screening tools identifying women with substance use are not validated, used once in pregnancy, and are not reflective of continued substance use. We hypothesized that serial early prenatal substance screening leads to decreased substance use by the end of pregnancy and improved outcomes. METHODS: This is a retrospective cohort study of mothers and their infants between 1/2015 and 12/2017. A self-reported substance screening tool was administered on the first prenatal visit and subsequent visits until delivery. For analysis, mothers were divided into three groups based on the trimester of their first screen and adjusted for demographics and risk factors. RESULTS: Early first trimester screening resulted in 52% of mothers having ≥ 3 screens throughout pregnancy vs. 6% of mothers with late third trimester screens (p < 0.001). Compared to third trimester screening, there was a five-fold decrease of any substance use at second trimester, a seven-fold decrease at first trimester, and a nine-fold decrease for marijuana at first trimester. Compared to third trimester screening, there was a significant five-fold increase of negative maternal urine drug screen, 3 ½ -fold increase in well newborn diagnosis, and a five-fold increase of no infant morphine treatment at first trimester. DISCUSSION: We identified improved maternal and infant outcomes with serial early prenatal substance use screening. Early maternal substance use identification is crucial for immediate referral for prevention and treatment, and for social and community services. Further research is needed on universal serial early prenatal screenings.

Iron handling by the human kidney: glomerular filtration and tubular reabsorption both contribute to urinary iron excretion.

In physiological conditions, circulating iron can be filtered by the glomerulus and is almost completely reabsorbed by the tubular epithelium to prevent urinary iron wasting. Increased urinary iron concentrations have been associated with renal injury. However, it is not clear whether increased urinary iron concentrations in patients are the result of increased glomerular iron filtration and/or insufficient tubular iron reabsorption and if these processes contribute to renal injury. We measured plasma and urine iron parameters and urinary tubular injury markers in healthy human subjects ( n = 20), patients with systemic iron overload ( n = 20), and patients with renal tubular dysfunction ( n = 18). Urinary iron excretion parameters were increased in both patients with systemic iron overload and tubular dysfunction, whereas plasma iron parameters were only increased in patients with systemic iron overload. In patients with systemic iron overload, increased urinary iron levels were associated with elevated circulating iron, as indicated by transferrin saturation (TSAT), and increased body iron, as suggested by plasma ferritin concentrations. In patients with tubular dysfunction, enhanced urinary iron and transferrin excretion were associated with distal tubular injury as indicated by increased urinary glutathione S-transferase pi 1-1 (GSTP1-1) excretion. In systemic iron overload, elevated urinary iron and transferrin levels were associated with increased injury to proximal tubules, indicated by increased urinary kidney injury marker 1 (KIM-1) excretion. Our explorative study demonstrates that both glomerular filtration of elevated plasma iron levels and insufficient tubular iron reabsorption could increase urinary iron excretion and cause renal injury.

Outcome of neonates with gastroschisis at different gestational ages using a national database.

BACKGROUND/PURPOSE: The optimal time for delivery of neonates with a prenatal diagnosis of gastroschisis (GS) is controversial. We compared the outcomes for GS at three different gestational ages (GAs), 33-34 weeks, 35-36 weeks, and ≥ 37 weeks. METHODS: We analyze hospital discharge data of neonates with GS using the 2006, 2009 and 2012 Healthcare Cost and Utilization Project Kids' Inpatient Database (HCUPKIDS). Multivariable analysis was used to compare the association between GS outcomes and the three GAs. RESULTS: Significantly higher number of 33-34 week infants had coexisting morbidities like respiratory distress syndrome, bronchopulmonary dysplasia, small bowel atresia, stenosis, or stricture, large bowel atresia and/or stenosis, malrotation, and atrial septal defect. In multivariable logistic regression, 33-34 week infants had higher NEC (p value = 0.002, 95% CI1.64-10.32), small bowel resection (0.024, 1.12-5.25) and pRBCs transfusion (0.024, 1.05-2.11). No differences were found between 35-36 weeks and ≥37 weeks gest infants for NEC, malabsorption, small bowel resection, TPN cholestasis, sepsis, CLABSI, number of pRBCs transfusion, length of stay and total charges. CONCLUSION: We did not show benefit for delivering early and in the absence of data, delivery at ≥37 weeks was noninferior to 35-36 weeks. We suggest that waiting for spontaneous onset of labor may be a better approach to balance the effects of prematurity and possible ongoing in utero bowel damage/stillbirth. LEVELS OF EVIDENCE: Level 3 (Retrospective comparative study).

The Growth Attainment, Hematological, Iron Status and Inflammatory Profile of Guatemalan Juvenile End-Stage Renal Disease Patients.

BACKGROUND: Stunting, anemia and inflammation are frequently observed in children with end-stage renal disease (ESRD). OBJECTIVES: To assess anthropometric, hematological and inflammatory data and to study their potential interrelationship in Guatemalan juveniles undergoing hemodialysis (HD) and peritoneal dialysis (PD). METHODS: 54 juveniles 7-20 years of age were recruited in FUNDANIER, Guatemala City: 27 on HD and 27 PD. Hemoglobin, serum iron, transferrin, serum transferrin receptor (sTfR), serum ferritin, transferrin saturation and iron-binding capacity, white blood cell count (WBC), erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), as well as IL-6, IL-1 and TNF-α, weight and height were determined by standard methods. Hepcidin-25 (Hep-25) was assessed by weak cation exchange time-of-flight mass-spectrometry. RESULTS: 92% and 55% of HD and PD children, respectively, were stunted and 95% and 85% were anemic. Among iron status biomarkers, serum ferritin was massively increased and significantly higher in the HD group compared to the PD group. Hep-25 was also greatly elevated in both groups. 41% of HD patients showed increments in three or more inflammatory biomarkers, while it was 2 or less in all PD subjects. CONCLUSIONS: The degree of stunting, the prevalence and severity of anemia in Guatemalan juvenile ESRD far exceed the national statistics for this low-income Central American country. Ferritin and Hep-25 concentrations were elevated, with the latter to an extraordinary magnitude. Additional biomarkers of inflammation not directly related to iron status were elevated as well. The role of both disease- and environment-related factors in combination best explains the magnitude of the biomarker abnormalities.

Low dietary iron intake restrains the intestinal inflammatory response and pathology of enteric infection by food-borne bacterial pathogens.

Orally administrated iron is suspected to increase susceptibility to enteric infections among children in infection endemic regions. Here we investigated the effect of dietary iron on the pathology and local immune responses in intestinal infection models. Mice were held on iron-deficient, normal iron, or high iron diets and after 2 weeks they were orally challenged with the pathogen Citrobacter rodentium. Microbiome analysis by pyrosequencing revealed profound iron- and infection-induced shifts in microbiota composition. Fecal levels of the innate defensive molecules and markers of inflammation lipocalin-2 and calprotectin were not influenced by dietary iron intervention alone, but were markedly lower in mice on the iron-deficient diet after infection. Next, mice on the iron-deficient diet tended to gain more weight and to have a lower grade of colon pathology. Furthermore, survival of the nematode Caenorhabditis elegans infected with Salmonella enterica serovar Typhimurium was prolonged after iron deprivation. Together, these data show that iron limitation restricts disease pathology upon bacterial infection. However, our data also showed decreased intestinal inflammatory responses of mice fed on high iron diets. Thus additionally, our study indicates that the effects of iron on processes at the intestinal host-pathogen interface may highly depend on host iron status, immune status, and gut microbiota composition.

Long-term decline of the Amazon carbon sink.

Atmospheric carbon dioxide records indicate that the land surface has acted as a strong global carbon sink over recent decades, with a substantial fraction of this sink probably located in the tropics, particularly in the Amazon. Nevertheless, it is unclear how the terrestrial carbon sink will evolve as climate and atmospheric composition continue to change. Here we analyse the historical evolution of the biomass dynamics of the Amazon rainforest over three decades using a distributed network of 321 plots. While this analysis confirms that Amazon forests have acted as a long-term net biomass sink, we find a long-term decreasing trend of carbon accumulation. Rates of net increase in above-ground biomass declined by one-third during the past decade compared to the 1990s. This is a consequence of growth rate increases levelling off recently, while biomass mortality persistently increased throughout, leading to a shortening of carbon residence times. Potential drivers for the mortality increase include greater climate variability, and feedbacks of faster growth on mortality, resulting in shortened tree longevity. The observed decline of the Amazon sink diverges markedly from the recent increase in terrestrial carbon uptake at the global scale, and is contrary to expectations based on models.

A seven day running training period increases basal urinary hepcidin levels as compared to cycling.

BACKGROUND: This investigation compared the effects of an extended period of weight-bearing (running) vs. non-weight-bearing (cycling) exercise on hepcidin production and its implications for iron status. METHODS: Ten active males performed two separate exercise training blocks with either running (RTB) or cycling (CTB) as the exercise mode. Each block consisted of five training sessions (Day 1, 2, 4, 5, 6) performed over a seven day period that were matched for exercise intensity. Basal venous blood samples were obtained on Day 1 (D1), and on Recovery Days 3 (R3) and 7 (R7) to assess iron status, while basal and 3 h post-exercise urinary hepcidin levels were measured on D1, D2, D6, as well as R3 and R7 (basal levels only) for each condition. RESULTS: Basal urinary hepcidin levels were significantly elevated (p ≤ 0.05) at D2, R3 and R7 as compared to D1 in RTB. Furthermore, 3 h post-exercise urinary hepcidin levels on D1 were also significantly higher in RTB compared to CTB (p ≤ 0.05). In CTB, urinary hepcidin levels were not statistically different on D1 as compared to R7. Iron parameters were not significantly different at D1 compared to R3 and R7 during both conditions. CONCLUSIONS: These results suggest that basal hepcidin levels may increase over the course of an extended training program, especially if a weight-bearing exercise modality is undertaken. However, despite any variations in hepcidin production, serum iron parameters in both RTB and CTB were unaffected, possibly due to the short duration of each training block. In comparing running to cycling, non-weight-bearing activity may require more training sessions, or sessions of extended duration, before any significant changes in basal hepcidin levels appear. Chronic elevations in hepcidin levels may help to explain the high incidence of iron deficiency in athletes.

Low hepcidin levels in severely anemic malawian children with high incidence of infectious diseases and bone marrow iron deficiency.

INTRODUCTION: A reliable diagnostic biomarker of iron status is required for severely anemic children living in malarious areas because presumptive treatment with iron may increase their infection risk if they are not iron deficient. Current biomarkers are limited because they are altered by host inflammation. In this study hepcidin concentrations were assessed in severely anemic children living in a highly malarious area of Malawi and evaluated against bone marrow iron in order to determine the usefulness of hepcidin as a point of care test. METHODS: 207 severely anemic children were assessed for levels of hepcidin, ferritin, serum transferrin receptor, erythropoietin, hematological indices, C-reactive protein, interleukin-6, malaria parasites and HIV infection. Deficiency of bone marrow iron stores was graded and erythroblast iron incorporation estimated. Interaction of covariates was assessed by structural-equation-modeling. RESULTS AND CONCLUSION: Hepcidin was a poor predictor of bone marrow iron deficiency (sensitivity 66.7%; specificity 48.5%), and of iron incorporation (sensitivity 54.2%; specificity 61.8%), and therefore would have limitations as a point of care test in this category of children. As upregulation of hepcidin by inflammation and iron status was blunted by erythropoietin in this population, enhanced iron absorption through the low hepcidin values may increase infection risk. Current recommendations to treat all severely anemic children living in malarious areas with iron should therefore be reconsidered.

Improved mass spectrometry assay for plasma hepcidin: detection and characterization of a novel hepcidin isoform.

Mass spectrometry (MS)-based assays for the quantification of the iron regulatory hormone hepcidin are pivotal to discriminate between the bioactive 25-amino acid form that can effectively block the sole iron transporter ferroportin and other naturally occurring smaller isoforms without a known role in iron metabolism. Here we describe the design, validation and use of a novel stable hepcidin-25(+40) isotope as internal standard for quantification. Importantly, the relative large mass shift of 40 Da makes this isotope also suitable for easy-to-use medium resolution linear time-of-flight (TOF) platforms. As expected, implementation of hepcidin-25(+40) as internal standard in our weak cation exchange (WCX) TOF MS method yielded very low inter/intra run coefficients of variation. Surprisingly, however, in samples from kidney disease patients, we detected a novel peak (m/z 2673.9) with low intensity that could be identified as hepcidin-24 and had previously remained unnoticed due to peak interference with the formerly used internal standard. Using a cell-based bioassay it was shown that synthetic hepcidin-24 was, like the -22 and -20 isoforms, a significantly less potent inducer of ferroportin degradation than hepcidin-25. During prolonged storage of plasma at room temperature, we observed that a decrease in plasma hepcidin-25 was paralleled by an increase in the levels of the hepcidin-24, -22 and -20 isoforms. This provides first evidence that all determinants for the conversion of hepcidin-25 to smaller inactive isoforms are present in the circulation, which may contribute to the functional suppression of hepcidin-25, that is significantly elevated in patients with renal impairment. The present update of our hepcidin TOF MS assay together with improved insights in the source and preparation of the internal standard, and sample stability will further improve our understanding of circulating hepcidin and pave the way towards further optimization and standardization of plasma hepcidin assays.

Plasma hepcidin levels and anemia in old age. The Leiden 85-Plus Study.

Hepcidin, an important regulator of iron homeostasis, is suggested to be causally related to anemia of inflammation. The aim of this study was to explore the role of plasma hepcidin in anemia among older persons from the general population. The Leiden 85-Plus Study is a population-based study of 85-year olds in Leiden, the Netherlands. Eighty-five-year old inhabitants of Leiden were enrolled between September 1997 and September 1999. At the age of 86, plasma hepcidin was determined with time of flight mass spectrometry in 490 participants [160 (32.7%) male, 114 (23.3%) with anemia]. Anemia was defined according to criteria of the World Health Organization (hemoglobin level <13 g/dL for men and hemoglobin <12 g/dL for women). The median plasma hepcidin level was 3.0 nM [interquartile range (IQR) 1.8-4.9]. We found strong correlations between plasma hepcidin and body iron status, C-reactive protein and erythropoietin levels. Significantly higher hepcidin levels were found in participants with anemia of inflammation (P<0.01), in participants with anemia of kidney disease (P=0.01), and in participants with unexplained anemia (P=0.01) than in participants without anemia. Participants with iron-deficiency anemia had significantly lower plasma hepcidin levels than participants without anemia (P<0.01). In conclusion, older persons with anemia of inflammation have higher hepcidin levels than their counterparts without anemia. The potential clinical value of hepcidin in future diagnostic algorithms for anemia has to be explored.

Diurnal rhythm rather than dietary iron mediates daily hepcidin variations.

BACKGROUND: The iron-regulating hormone hepcidin is a promising biomarker in the diagnosis of iron disorders. Concentrations of hepcidin have been shown to increase during the day in individuals who are following a regular diet. It is currently unknown whether these increases are determined by an innate rhythm or by other factors. We aimed to assess the effect of dietary iron on hepcidin concentrations during the day. METHODS: Within a 7-day interval, 32 volunteers received an iron-deficient diet on 1 day and the same diet supplemented with 65 mg ferrous fumarate at 0815 and 1145 on another day. Blood was drawn to assess ferritin, hepcidin-25, and transferrin saturation (TS) throughout both days at 4 time points between 0800 (fasted) and 1600. A linear mixed model for repeated data was used to analyze the effect of iron intake on TS and hepcidin concentrations. RESULTS: Baseline values of hepcidin at 0800 correlated significantly with ferritin (r = 0.61). During the day of an iron-deficient diet the mean TS was similar both in men and in women, whereas hepcidin increased. During the day with iron supplementation the mean TS was significantly higher both in men and in women, and the mean hepcidin was moderately but significantly higher in women (1.0 nmol/L, 95% CI, 0.2-1.8) but not in men (0.0 nmol/L, 95% CI, -0.8 to 0.8). CONCLUSIONS: Our data demonstrate that ferritin sets the basal hepcidin concentrations and suggest that innate diurnal rhythm rather than dietary iron mediates the daily hepcidin variations. These findings will be useful for optimizing sampling protocols and will facilitate the interpretation of hepcidin as an iron biomarker.

Hepcidin-25 is related to cardiovascular events in chronic haemodialysis patients.

BACKGROUND: The development of atherosclerosis may be enhanced by iron accumulation in macrophages. Hepcidin-25 is a key regulator of iron homeostasis, which downregulates the cellular iron exporter ferroportin. In haemodialysis (HD) patients, hepcidin-25 levels are increased. Therefore, it is conceivable that hepcidin-25 is associated with all-cause mortality and/or fatal and non-fatal cardiovascular (CV) events in this patient group. The aim of the current analysis was to study the relationship between hepcidin-25 and all-cause mortality and both fatal and non-fatal CV events in chronic HD patients. METHODS: Data from 405 chronic HD patients included in the CONvective TRAnsport STudy (NCT00205556) were studied (62% men, age 63.7 ± 13.9 years [mean ± SD]). The median (range) follow-up was 3.0 (0.8-6.6) years. Hepcidin-25 was measured with mass spectrometry. The relationship between hepcidin-25 and all-cause mortality or fatal and non-fatal CV events was investigated with multivariate Cox proportional hazard models. RESULTS: Median (interquartile range) hepcidin-25 level was 13.8 (6.6-22.5) nmol/L. During follow-up, 158 (39%) patients died from any cause and 131 (32%) had a CV event. Hepcidin-25 was associated with all-cause mortality in an unadjusted model [hazard ratio (HR) 1.14 per 10 nmol/L, 95% CI 1.03-1.26; P = 0.01], but not after adjustment for all confounders including high-sensitive C-reactive protein (HR 1.02 per 10 nmol/L, 95% CI 0.87-1.20; P = 0.80). At the same time, hepcidin-25 was significantly related to fatal and non-fatal CV events in a fully adjusted model (HR 1.24 per 10 nmol/L, 95% CI 1.05-1.46, P = 0.01). CONCLUSION: Hepcidin-25 was associated with fatal and non-fatal CV events, even after adjustment for inflammation. Furthermore, inflammation appears to be a significant confounder in the relation between hepcidin-25 and all-cause mortality. These findings suggest that hepcidin-25 might be a novel determinant of CV disease in chronic HD patients.

The iron regulatory hormone hepcidin is decreased in pregnancy: a prospective longitudinal study.

BACKGROUND: Iron deficiency is a commonly encountered problem in pregnancy and a frequently observed cause of pregnancy-associated anemia. We longitudinally assessed the iron regulatory hormone hepcidin during gestation and postpartum and related hepcidin to conventional indicators of iron status and inflammation. METHODS: Thirty-one healthy pregnant women were included and 81 blood samples from the three trimesters, directly and 6 weeks postpartum were analyzed for hemoglobin, the iron parameters: iron, total iron binding capacity, transferrin saturation, ferritin, soluble transferrin receptor and hepcidin, and CRP and leucocytes as markers of inflammation. RESULTS: Hepcidin concentration decreased gradually from the first to the second and third trimester to undetectable levels (≤ 0.5 nmol/L) which was paralleled by decreasing hemoglobin levels and changes in iron parameters indicative for iron deficiency. During gestation hepcidin levels correlated with iron parameters, but not with inflammatory markers. Postpartum, hepcidin increased immediately to levels similar as assessed at early pregnancy. CONCLUSIONS: We conclude that hepcidin levels were suppressed during the second and third trimester of pregnancy, which was likely determined by the occurrence of iron deficiency. These data give insight in iron homeostasis during normal pregnancy.