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1.
Vet Sci ; 10(2)2023 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-36851425

RESUMO

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.

2.
Int J Mol Sci ; 23(3)2022 Jan 25.
Artigo em Inglês | MEDLINE | ID: mdl-35163276

RESUMO

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.


Assuntos
Injúria Renal Aguda/metabolismo , Hepcidinas/metabolismo , Injúria Renal Aguda/induzido quimicamente , Injúria Renal Aguda/fisiopatologia , Animais , Hemina/metabolismo , Hemoglobinas/metabolismo , Hemólise/fisiologia , Hepcidinas/fisiologia , Ferro/metabolismo , Rim/metabolismo , Rim/patologia , Túbulos Renais Distais/metabolismo , Camundongos , Camundongos Knockout , Estresse Oxidativo
3.
Sci Rep ; 12(1): 1199, 2022 01 24.
Artigo em Inglês | MEDLINE | ID: mdl-35075227

RESUMO

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.


Assuntos
Glomerulosclerose Segmentar e Focal/metabolismo , Ferro/metabolismo , Túbulos Renais Distais/metabolismo , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Animais , Captopril/uso terapêutico , Desferroxamina/uso terapêutico , Modelos Animais de Doenças , Feminino , Glomerulosclerose Segmentar e Focal/dietoterapia , Glomerulosclerose Segmentar e Focal/tratamento farmacológico , Masculino , Camundongos , Receptores de Superfície Celular/metabolismo , Sideróforos/uso terapêutico
4.
Am J Physiol Renal Physiol ; 316(3): F606-F614, 2019 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-30623722

RESUMO

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.


Assuntos
Taxa de Filtração Glomerular/fisiologia , Sobrecarga de Ferro/metabolismo , Ferro/urina , Rim/metabolismo , Adulto , Feminino , Humanos , Sobrecarga de Ferro/urina , Rim/fisiopatologia , Túbulos Renais Proximais/metabolismo , Túbulos Renais Proximais/fisiopatologia , Masculino
5.
PLoS One ; 10(10): e0140062, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26445018

RESUMO

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.


Assuntos
Anemia/sangue , Inflamação/sangue , Falência Renal Crônica/sangue , Falência Renal Crônica/complicações , Adolescente , Adulto , Anemia/complicações , Anemia/epidemiologia , Pesos e Medidas Corporais , Criança , Feminino , Ferritinas/sangue , Guatemala/epidemiologia , Hepcidinas/sangue , Humanos , Inflamação/complicações , Inflamação/epidemiologia , Ferro/sangue , Falência Renal Crônica/epidemiologia , Masculino , Adulto Jovem
6.
Eur J Immunol ; 45(9): 2553-67, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-26046550

RESUMO

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.


Assuntos
Caenorhabditis elegans/efeitos dos fármacos , Infecções por Enterobacteriaceae/patologia , Mucosa Intestinal/patologia , Intestinos/patologia , Ferro da Dieta/administração & dosagem , Salmonelose Animal/metabolismo , Proteínas de Fase Aguda/biossíntese , Proteínas de Fase Aguda/imunologia , Animais , Peso Corporal/imunologia , Caenorhabditis elegans/imunologia , Caenorhabditis elegans/metabolismo , Caenorhabditis elegans/microbiologia , Citrobacter rodentium/imunologia , Dieta/métodos , Infecções por Enterobacteriaceae/imunologia , Infecções por Enterobacteriaceae/metabolismo , Infecções por Enterobacteriaceae/microbiologia , Fezes/microbiologia , Feminino , Imunidade Inata , Mucosa Intestinal/imunologia , Mucosa Intestinal/metabolismo , Mucosa Intestinal/microbiologia , Intestinos/imunologia , Intestinos/microbiologia , Ferro da Dieta/efeitos adversos , Complexo Antígeno L1 Leucocitário/biossíntese , Complexo Antígeno L1 Leucocitário/imunologia , Lipocalina-2 , Lipocalinas/biossíntese , Lipocalinas/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Proteínas Oncogênicas/biossíntese , Proteínas Oncogênicas/imunologia , Salmonelose Animal/imunologia , Salmonelose Animal/microbiologia , Salmonelose Animal/mortalidade , Salmonella typhimurium/imunologia , Análise de Sobrevida
7.
J Int Soc Sports Nutr ; 11(1): 14, 2014 Apr 09.
Artigo em Inglês | MEDLINE | ID: mdl-24716892

RESUMO

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.

9.
PLoS One ; 8(12): e78964, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-24339866

RESUMO

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.


Assuntos
Anemia/sangue , Anemia/epidemiologia , Medula Óssea/metabolismo , Doenças Transmissíveis/sangue , Doenças Transmissíveis/epidemiologia , Hepcidinas/sangue , Deficiências de Ferro , Pré-Escolar , Eritropoese , Feminino , Humanos , Hipóxia/sangue , Incidência , Lactente , Malaui/epidemiologia , Masculino , Análise Multivariada
10.
PLoS One ; 8(10): e75518, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-24124495

RESUMO

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.


Assuntos
Hepcidinas/sangue , Espectrometria de Massas/métodos , Isoformas de Proteínas/sangue , Humanos , Reprodutibilidade dos Testes , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz
11.
Haematologica ; 98(3): 448-54, 2013 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-23065507

RESUMO

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.


Assuntos
Anemia/sangue , Hepcidinas/sangue , Fatores Etários , Idoso de 80 Anos ou mais , Anemia/diagnóstico , Anemia/epidemiologia , Comorbidade , Feminino , Humanos , Masculino , Países Baixos/epidemiologia , Vigilância da População , Estudos Prospectivos
12.
Clin Chem ; 59(3): 527-35, 2013 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-23232066

RESUMO

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.


Assuntos
Peptídeos Catiônicos Antimicrobianos/sangue , Ritmo Circadiano , Ferro da Dieta/administração & dosagem , Adolescente , Adulto , Suplementos Nutricionais , Feminino , Ferritinas/sangue , Hepcidinas , Humanos , Masculino , Pessoa de Meia-Idade , Transferrina/análise
13.
Transfusion ; 53(8): 1670-7, 2013 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-23176175

RESUMO

BACKGROUND: Blood donors that meet the hemoglobin (Hb) criteria for donation may have undetected subclinical iron deficiency. The aim of this study was to assess the prevalence of subclinical iron deficiency in whole blood donors with Hb levels above cutoff levels for donation by measuring zinc protoporphyrin (ZPP) levels. In addition, prevalence rates based on other iron variables were assessed for comparison. STUDY DESIGN AND METHODS: The study population comprised 5280 Dutch whole blood donors, who passed the Hb criteria for donation. During donor screening, Hb levels were measured in capillary samples (finger prick), and venous blood samples were taken for measurements of ZPP and other iron variables. These variables included ferritin, transferrin saturation, soluble transferrin receptor (sTfR), hepcidin, red blood cell mean corpuscular volume (MCV), and mean cell Hb (MCH). RESULTS: With a ZPP cutoff level of at least 100 µmol/mol heme, subclinical iron deficiency was present in 6.9% of male donors and in 9.8% of female donors. Based on other iron variables, iron deficiency was also observed. Prevalence rates ranged from 4.8% (based on transferrin saturation) to 27.4% (based on hepcidin concentration) in men and from 5.6% (based on sTfR concentration) to 24.7% (based on hepcidin concentration) in women. CONCLUSION: Results from this study showed that subclinical iron deficiency is prevalent among blood donors that meet the Hb criteria for blood donation, based on ZPP levels and on other iron variables. This finding needs attention because these donors are at increased risk of developing iron deficiency affecting Hb formation and other cellular processes.


Assuntos
Anemia Ferropriva/epidemiologia , Doadores de Sangue , Hemoglobinas/metabolismo , Protoporfirinas/sangue , Adolescente , Adulto , Idoso , Anemia Ferropriva/sangue , Anemia Ferropriva/diagnóstico , Doenças Assintomáticas , Biomarcadores/sangue , Seleção do Doador , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Países Baixos/epidemiologia , Prevalência , Adulto Jovem
14.
Nephrol Dial Transplant ; 28(12): 3062-71, 2013 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-23147161

RESUMO

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.


Assuntos
Biomarcadores/metabolismo , Doenças Cardiovasculares/metabolismo , Hepcidinas/metabolismo , Falência Renal Crônica/complicações , Diálise Renal/efeitos adversos , Proteína C-Reativa/metabolismo , Doenças Cardiovasculares/diagnóstico , Doenças Cardiovasculares/etiologia , Doenças Cardiovasculares/mortalidade , Estudos de Coortes , Feminino , Seguimentos , Humanos , Inflamação/etiologia , Inflamação/metabolismo , Inflamação/mortalidade , Masculino , Pessoa de Meia-Idade , Prognóstico , Modelos de Riscos Proporcionais , Taxa de Sobrevida
15.
Clin Chem Lab Med ; 51(7): 1395-401, 2013 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-23241678

RESUMO

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.


Assuntos
Anemia Ferropriva/sangue , Hepcidinas/sangue , Ferro/sangue , Período Pós-Parto/sangue , Trimestres da Gravidez/sangue , Adulto , Biomarcadores/sangue , Proteína C-Reativa/análise , Feminino , Ferritinas/sangue , Humanos , Gravidez , Estudos Prospectivos , Receptores da Transferrina/sangue , Fatores de Tempo
16.
PLoS One ; 7(7): e39783, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22808058

RESUMO

Hepcidin-25, the bioactive form of hepcidin, is a key regulator of iron homeostasis as it induces internalization and degradation of ferroportin, a cellular iron exporter on enterocytes, macrophages and hepatocytes. Hepcidin levels are increased in chronic hemodialysis (HD) patients, but as of yet, limited information on factors associated with hepcidin-25 in these patients is available. In the current cross-sectional study, potential patient-, laboratory- and treatment-related determinants of serum hepcidin-20 and -25, were assessed in a large cohort of stable, prevalent HD patients. Baseline data from 405 patients (62% male; age 63.7 ± 13.9 [mean SD]) enrolled in the CONvective TRAnsport STudy (CONTRAST; NCT00205556) were studied. Predialysis hepcidin concentrations were measured centrally with matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. Patient-, laboratory- and treatment related characteristics were entered in a backward multivariable linear regression model. Hepcidin-25 levels were independently and positively associated with ferritin (p<0.001), hsCRP (p<0.001) and the presence of diabetes (p = 0.02) and inversely with the estimated glomerular filtration rate (p = 0.01), absolute reticulocyte count (p = 0.02) and soluble transferrin receptor (p<0.001). Men had lower hepcidin-25 levels as compared to women (p = 0.03). Hepcidin-25 was not associated with the maintenance dose of erythropoiesis stimulating agents (ESA) or iron therapy. In conclusion, in the currently studied cohort of chronic HD patients, hepcidin-25 was a marker for iron stores and erythropoiesis and was associated with inflammation. Furthermore, hepcidin-25 levels were influenced by residual kidney function. Hepcidin-25 did not reflect ESA or iron dose in chronic stable HD patients on maintenance therapy. These results suggest that hepcidin is involved in the pathophysiological pathway of renal anemia and iron availability in these patients, but challenges its function as a clinical parameter for ESA resistance.


Assuntos
Peptídeos Catiônicos Antimicrobianos/sangue , Falência Renal Crônica/sangue , Falência Renal Crônica/fisiopatologia , Rim/fisiopatologia , Diálise Renal , Idoso , Biomarcadores/sangue , Proteína C-Reativa/metabolismo , Estudos Transversais , Eritropoese/efeitos dos fármacos , Eritropoetina/sangue , Feminino , Ferritinas/sangue , Taxa de Filtração Glomerular/efeitos dos fármacos , Hematínicos/uso terapêutico , Hepcidinas , Humanos , Ferro/metabolismo , Rim/efeitos dos fármacos , Rim/metabolismo , Falência Renal Crônica/terapia , Masculino , Pessoa de Meia-Idade , Fragmentos de Peptídeos/sangue
17.
Eur J Appl Physiol ; 112(5): 1889-98, 2012 May.
Artigo em Inglês | MEDLINE | ID: mdl-21922263

RESUMO

The effect of carbohydrate (CHO) consumption during prolonged endurance running on post-exercise inflammation and hepcidin levels was investigated. Eleven well-trained male endurance athletes completed a graded exercise test, followed by two experimental running trials in a randomized order. The two experimental trials consisted of a 90 min run at 75% of the peak oxygen uptake velocity (vVO(2peak)), while consuming a solution with either 6% CHO or a placebo (PLA) equivalent at 3 ml kg(-1) every 20 min. Serum interleukin-6 (IL-6), free hemoglobin (Hb), haptoglobin (Hp), hepcidin and iron parameters were assessed throughout the post-run recovery period. Serum iron and IL-6 were significantly elevated immediately post-run in both CHO and PLA (p ≤ 0.05), with no differences between trials. Serum-free Hb increased and Hp decreased significantly immediately post-run in both conditions (p ≤ 0.05). Serum soluble transferrin receptor levels were significantly below the baseline at 3 and 24 h post-run in both conditions (p ≤ 0.05). Serum hepcidin concentration recorded 3 h post-run in both conditions was significantly elevated (p ≤ 0.05), and had returned to the baseline by 24 h post-run (p ≤ 0.05). The use of a 6% CHO solution at 3 ml kg(-1) 20 min(-1) during endurance running did not attenuate the inflammatory response and subsequent increase in serum hepcidin levels during the post-run recovery period.


Assuntos
Peptídeos Catiônicos Antimicrobianos/sangue , Carboidratos da Dieta/farmacologia , Exercício Físico/fisiologia , Inflamação/sangue , Ferro/sangue , Corrida/fisiologia , Citocinas/sangue , Carboidratos da Dieta/administração & dosagem , Teste de Esforço , Hemólise , Hepcidinas , Humanos , Masculino , Resistência Física/fisiologia , Adulto Jovem
18.
Am J Trop Med Hyg ; 84(1): 148-51, 2011 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-21212218

RESUMO

In malaria-endemic areas, iron deficiency and placental Plasmodium falciparum infection commonly coexist. In primigravidae and their newborns, hepcidin and other iron parameters were evaluated in groups and classified according to placental P. falciparum and maternal anemia status. Mothers had relatively high hepcidin levels considering their low iron status. In cord blood, levels of hepcidin, hemoglobin, and other iron parameters were also similar for groups. We conclude that maternal hepcidin is not significantly altered as a function of placental infection and/or anemia. Importantly, fetal hemoglobin and iron status were also unaffected, regardless of the presence of placental infection or maternal anemia.


Assuntos
Ferro/metabolismo , Malária Falciparum/metabolismo , Doenças Placentárias/metabolismo , Complicações Parasitárias na Gravidez/metabolismo , Adolescente , Peptídeos Catiônicos Antimicrobianos/sangue , Peptídeos Catiônicos Antimicrobianos/metabolismo , Feminino , Sangue Fetal/química , Hepcidinas , Homeostase/fisiologia , Humanos , Recém-Nascido de Baixo Peso , Recém-Nascido , Troca Materno-Fetal , Doenças Placentárias/parasitologia , Gravidez , Adulto Jovem
19.
Ned Tijdschr Geneeskd ; 154: A1038, 2010.
Artigo em Holandês | MEDLINE | ID: mdl-20719010

RESUMO

A 36-year old female patient who had had iron deficiency anaemia since her childhood showed no clear response to oral iron treatment. Elevated serum hepcidin levels were found after excluding other causes of iron deficiency. This is in contrast to what is expected in iron deficiency anaemia and indicates a primary defect in hepcidin regulation. Indeed, in the search for a defect in genes coding for hepcidin-regulating proteins the patient was found to be compound heterozygous for two different mutations in the TMPRSS6 gene. This leads to a dysfunctional matriptase-2 protein for which the gene codes. Consequently, liver cells cannot inhibit hepcidin production in the presence of low serum iron levels. High hepcidin levels result in less iron being absorbed from the bowel than is necessary for erythropoiesis. Therefore, patients with matriptase-2 deficiency respond poorly to oral iron treatment and have to be treated with intravenous iron.


Assuntos
Anemia Ferropriva/enzimologia , Anemia Ferropriva/genética , Peptídeos Catiônicos Antimicrobianos/sangue , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Serina Endopeptidases/genética , Serina Endopeptidases/metabolismo , Adulto , Anemia Ferropriva/tratamento farmacológico , Feminino , Hepcidinas , Humanos , Ferro/uso terapêutico , Mutação/genética , Linhagem , Falha de Tratamento
20.
J Clin Endocrinol Metab ; 94(12): 5102-7, 2009 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-19850683

RESUMO

CONTEXT: Obesity and iron deficiency are two of the most common nutritional disorders worldwide. Several studies found higher rates of iron deficiency in obese than in normal-weight children. Hepcidin represents the main inhibitor of intestinal iron absorption, and its expression is increased in adipose tissue of obese patients. Leptin is able, in vitro, to raise hepcidin expression. OBJECTIVES: Aims of this work were 1) to assess the association between poor iron status and obesity, 2) to investigate whether iron homeostasis of obese children may be modulated by serum hepcidin variations, and 3) to assess the potential correlation between leptin and serum hepcidin variations. METHODS: Iron status and absorption as well as hepcidin, leptin, and IL-6 levels were studied in 60 obese children and in 50 controls. RESULTS: Obese children showed lower iron and transferrin saturation (both P < 0.05) and higher hepcidin levels (P = 0.004) compared with controls. A direct correlation between hepcidin and obesity degree (P = 0.0015), and inverse correlations between hepcidin and iron (P = 0.04), hepcidin and transferrin saturation (P = 0.005), and hepcidin and iron absorption (P = 0.003) were observed. A correlation between leptin and hepcidin (P = 0.006) has been found. The correlation remained significant when adjusted for body mass index, sex, pubertal stage, and IL-6 values. CONCLUSIONS: We propose that in obese patients, increased hepcidin production, at least partly leptin mediated, represents the missing link between obesity and disrupted iron metabolism.


Assuntos
Peptídeos Catiônicos Antimicrobianos/sangue , Deficiências de Ferro , Ferro/sangue , Obesidade/genética , Absorção , Adolescente , Biomarcadores , Estatura , Índice de Massa Corporal , Peso Corporal , Criança , Feminino , Hepcidinas , Humanos , Interleucina-6/sangue , Ferro/metabolismo , Itália , Leptina/sangue , Masculino , Estado Nutricional , Transferrina/metabolismo
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