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3. 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

Author

Claus, Melissa A., Smart, Lisa, Raisis, Anthea L., Sharp, Claire R., Abraham, Sam, Gummer, Joel P. A., Mead, Martin K., Bradley, Damian L., Van Swelm, Rachel, Wiegerinck, Erwin T. G., Litton, Edward, Claus, Melissa A., Smart, Lisa, Raisis, Anthea L., Sharp, Claire R., Abraham, Sam, Gummer, Joel P. A., Mead, Martin K., Bradley, Damian L., Van Swelm, Rachel, Wiegerinck, Erwin T. G., and Litton, Edward

Abstract

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.

Published
2023

4. 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

Author

Claus, Melissa A., primary, Smart, Lisa, additional, Raisis, Anthea L., additional, Sharp, Claire R., additional, Abraham, Sam, additional, Gummer, Joel P. A., additional, Mead, Martin K., additional, Bradley, Damian L., additional, Van Swelm, Rachel, additional, Wiegerinck, Erwin T. G., additional, and Litton, Edward, additional

Published
2023
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7. Toxic iron species in lower-risk myelodysplastic syndrome patients : course of disease and effects on outcome

Author

Hoeks, Marlijn, Bagguley, Tim, van Marrewijk, Corine, Smith, Alex, Bowen, David, Culligan, Dominic, Kolade, Seye, Symeonidis, Argiris, Garelius, Hege, Spanoudakis, Michail, Langemeijer, Saskia, Roelofs, Rian, Wiegerinck, Erwin, Tatic, Aurelia, Killick, Sally, Panagiotidis, Panagiotis, Stanca, Oana, Hellström-Lindberg, Eva, Cermak, Jaroslav, van der Klauw, Melanie, Wouters, Hanneke, van Kraaij, Marian, Blijlevens, Nicole, Swinkels, Dorine W., de Witte, Theo, Stauder, R., Walder, A., Pfeilstöcker, M., Schoenmetzler-Makrai, A., Burgstaller, S., Thaler, J., Mandac Rogulj, I., Krejci, M., Voglova, J., Rohon, P., Jonasova, A., Cermak, J., Mikulenkova, D., Hochova, I., Jensen, P. D., Holm, M. S., Kjeldsen, L., Dufva, I. H., Vestergaard, H., Re, D., Slama, B., Fenaux, P., Choufi, B., Cheze, S., Klepping, D., Salles, B., de Renzis, B., Willems, L., De Prost, D., Gutnecht, J., Courby, S., Siguret, V., Tertian, G., Pascal, L., Chaury, M., Wattel, E., Guerci, A., Legros, L., Itzykson, R., Ades, L., Isnard, F., Sanhes, L., Benramdane, R., Stamatoullas, A., Amé, S., Beyne-Rauzy, O., Gyan, E., Platzbecker, U., Badrakan, C., Germing, U., Lübbert, M., Schlenk, R., Kotsianidis, I., Tsatalas, C., Pappa, V., Galanopoulos, A., Michali, E., Panagiotidis, P., Viniou, N., Katsigiannis, A., Roussou, P., Terpos, E., Kostourou, A., Kartasis, Z., Pouli, A., Palla, K., Briasoulis, V., Hatzimichael, E., Vassilopoulos, G., Symeonidis, A., Kourakli, A., Zikos, P., Anagnostopoulos, A., Kotsopoulou, M., Megalakaki, K., Protopapa, M., Vlachaki, E., Konstantinidou, P., Stemer, G., Nemetz, A., Gotwin, U., Cohen, O., Koren, M., Levy, E., Greenbaum, U., Gino-Moor, S., Price, M., Ofran, Y., Winder, A., Goldshmidt, N., Elias, S., Sabag, R., Hellman, I., Ellis, M., Braester, A., Rosenbaum, H., Berdichevsky, S., Itzhaki, G., Wolaj, O., Yeganeh, S., Katz, O., Filanovsky, K., Dali, N., Mittelman, M., Malcovati, L., Fianchi, L., vd Loosdrecht, A., Matthijssen, V., Herbers, A., Pruijt, H., Aboosy, N., de Vries, F., Velders, G., Jacobs, E., Langemeijer, S., MacKenzie, M., Lensen, C., Kuijper, P., Madry, K., Camara, M., Almeida, A., Vulkan, G., Stanca Ciocan, O., Tatic, A., Savic, A., Pedro, C., Xicoy, B., Leiva, P., Munoz, J., Betes, V., Benavente, C., Lozano, M., Martinez, M., Iniesta, P., Bernal, T., Diez Campelo, M., Tormo, D., Andreu Lapiedra, R., Sanz, G., Hesse Sundin, E., Garelius, H., Karlsson, C., Antunovic, P., Jönsson, A., Brandefors, L., Nilsson, L., Kozlowski, P., Hellstrom-Lindberg, E., Grövdal, M., Larsson, K., Wallvik, J., Lorenz, F., Ejerblad, E., Culligan, D., Craddock, C., Kolade, S., Cahalin, P., Killick, S., Ackroyd, S., Wong, C., Warren, A., Drummond, M., Hall, C., Rothwell, K., Green, S., Ali, S., Bowen, D., Karakantza, M., Dennis, M., Jones, G., Parker, J., Bowen, A., Radia, R., Das-Gupta, E., Vyas, P., Nga, E., Creagh, D., Ashcroft, J., Mills, J., Bond, L., Life Course Epidemiology (LCE), and VU University medical center

Subjects
Adult, Male, 0301 basic medicine, Cancer Research, medicine.medical_specialty, Iron Overload, Iron, Cancer development and immune defence Radboud Institute for Molecular Life Sciences [Radboudumc 2], Vascular damage Radboud Institute for Health Sciences [Radboudumc 16], Ferroportin, Lower risk, Gastroenterology, Article, Cancer development and immune defence Radboud Institute for Health Sciences [Radboudumc 2], 03 medical and health sciences, 0302 clinical medicine, Hepcidin, Internal medicine, Humans, Medicine, Blood Transfusion, Prospective Studies, Aged, Soluble transferrin receptor, biology, business.industry, Transferrin saturation, Hematology, Middle Aged, Erythroferrone, Prognosis, 3. Good health, Survival Rate, Ferritin, Renal disorders Radboud Institute for Molecular Life Sciences [Radboudumc 11], 030104 developmental biology, Oncology, Myelodysplastic Syndromes, 030220 oncology & carcinogenesis, biology.protein, Erythropoiesis, Female, business, Myelodysplastic syndrome, Follow-Up Studies, Rare cancers Radboud Institute for Health Sciences [Radboudumc 9]
Abstract

Red blood cell transfusions (RBCT) remain the cornerstone of supportive care in lower-risk myelodysplastic syndrome (LRMDS) [1]. Transfusion dependency in LRMDS patients is associated with inferior outcomes, mainly attributed to severe bone marrow failure [2]. However, iron toxicity, due to frequent RBCT or ineffective erythropoiesis, may be an additional negative prognostic factor [3,4,5,6]. Recently, much progress has been made in unraveling the iron metabolism. The peptide hormone hepcidin is the key regulator by inhibiting iron uptake through degradation of ferroportin, a cellular iron exporter [7]. Erythroferrone and GDF15, produced by erythroblasts, inhibit hepcidin production, which leads to increased uptake and cellular release of iron for the purpose of erythropoiesis [8]. The pathophysiology of iron metabolism in MDS is still not completely understood. Exceedingly high reactive oxygen species (ROS) levels are associated with iron toxicity, disease development, and progression in MDS patients [9,10,11,12]. Malondialdehyde (MDA), resulting from lipid peroxidation of polyunsaturated fatty acids, is a biomarker of oxidative stress [10, 12]. Currently, little is known about the prognostic impact of ROS in MDS patients. The aim of this study is twofold: (1) describe iron and oxidative stress parameters over time in LRMDS patients and (2) to assess their effect on overall and progression-free survival. The EUMDS registry prospectively collects observational data on newly diagnosed LRMDS patients from 148 centers in 16 countries in Europe and Israel as of January 2008. All patients provided informed consent. Clinical data were collected at baseline and at each six-monthly follow-up visit. Serum samples were collected prospectively at each visit from 256 patients included in six participating countries. Conventional iron parameters were measured with routine assays. We additionally analyzed hepcidin, growth differentiation factor 15 (GDF15), soluble transferrin receptor (sTfR), non-transferrin bound iron (NTBI), labile plasma iron (LPI), and MDA. Subjects were prospectively followed until death, loss to follow-up, or withdrawal of consent. All iron parameters were measured centrally at the department of Laboratory Medicine of the Radboudumc, Nijmegen, The Netherlands. Serum samples were collected just prior to transfusion in transfusion-dependent patients and stored at −80 °C. Details on the assays and reference ranges of hepcidin, GDF15, sTfR, NTBI, LPI, and MDA are provided in the supplement. The Spearman rank test was used to evaluate correlations between iron parameters. We stratified the results by transfusion dependency per visit and the presence of ring sideroblasts. When evaluating temporal changes in iron parameters, with linear quantile mixed models, we excluded patients from the timepoint they received iron chelation therapy. Overall survival (OS) was defined as the time from MDS diagnosis to death or, in case of progression-free survival, to date of progression or death; patients still alive at the end of follow-up were censored. Time-dependent Kaplan–Meier curves and cox proportional hazards models were used. In total, 256 consecutive patients, were included in this study. Over five six-monthly visits, 1040 samples were collected. Table 1 describes the patient characteristics. Most patients without ring sideroblasts were transfusion-independent at diagnosis (nonRS-TI; 55.9%), 18.8% with ring sideroblasts were transfusion-independent (RS-TI), 18.4% without ring sideroblasts were transfusion-dependent (nonRS-TD), and 7% with ring sideroblasts were transfusion-dependent patients (RS-TD). The median follow-up time was 6.6 years (95% CI 5.9–7.0). LPI was positively correlated with transferrin saturation (TSAT) (r = 0.15, p < 0.001, Fig. S1). LPI values increased exponentially at TSAT values above 80%. This effect was most pronounced in the transfusion-dependent groups, but also observed in the RS-TI group. MDA was weakly correlated with NTBI (r = 0.09, p = 0.069) and negatively correlated with hemoglobin level (r = −0.1, p = 0.033). GDF15 and hepcidin were negatively correlated in the RS-TI and nonRS-TD group and significantly negatively correlated in the RS-TD group (r = −0.34, p = 0.007, Fig. S2). Serum ferritin levels were elevated in all subgroups with a mean value of 858 µg/L at visit 5. The highest serum ferritin levels were observed in the RS-TD group (mean value at visit 5: 2092 µg/L, Table S1). Serum ferritin increased significantly per visit in the RS-TD group (beta 454.46 µg/L; 95% CI 334.65–574.27), but not in the other groups (Table S2). All subgroups, except for the nonRS-TI, had elevated TSAT levels. TSAT levels were most markedly increased in the RS-TD group with a mean TSAT of 88% at visit 5 (Table S1). In both transfusion-dependent groups the median increase per visit was significant (Table S2). LPI was elevated in the RS-TD group exclusively with a mean value of 0.59 µmol/L at visit 5 (Table S1). NTBI was elevated in all subgroups, with the highest values in the RS-TD group (Table S1). The increase in median NTBI level was significant in both transfusion-dependent groups (Table S2). Hepcidin levels were markedly elevated in the nonRS-TD group. Interestingly, hepcidin levels were lower in the RS-TD group, probably reflecting ineffective erythropoiesis, likewise supported by lower hepcidin/ferritin ratios in RS groups (Table S1). Median hepcidin levels increased over time in the transfusion-dependent subgroups only (Table S2). GDF15 levels, analyzed in the light of its potential role in hepcidin suppression, were increased in all subgroups (Table S1). The RS subgroups had higher GDF15 levels compared to the nonRS groups, reflecting increased erythropoiesis. Mean sTfR levels were within the reference range in all subgroups except for the RS-TI group, which showed elevated levels, reflecting...

Published
2021

15. Afebrile Plasmodium falciparum parasitemia decreases absorption of fortification iron but does not affect systemic iron utilization: a double stable-isotope study in young Beninese women

Author

Cercamondi, Colin I., Egli, Ines M., Ahouandjinou, Ella, Dossa, Romain, Zeder, Christophe, Salami, Lamidhi, Tjalsma, Harold, Wiegerinck, Erwin, Tanno, Toshihiko, Hurrell, Richard F., Hounhouigan, Joseph, and Zimmermann, Michael B.

Subjects
Plasmodium falciparum -- Health aspects, Plasmodium falciparum -- Research, Iron deficiency anemia -- Risk factors, Iron deficiency anemia -- Research, Malaria -- Complications and side effects, Malaria -- Research, Food/cooking/nutrition, Health
Abstract

Background: Iron deficiency anemia (IDA) affects many young women in sub-Saharan Africa. Its etiology is multifactorial, but the major cause is low dietary iron bioavailability exacerbated by parasitic infections such as malaria. Objective: We investigated whether asymptomatic Plasmodium falciparum parasitemia in Beninese women would impair absorption of dietary iron or utilization of circulating iron. Design: Iron absorption and utilization from an iron-fortified sorghum-based meal were estimated by using oral and intravenous isotope labels in 23 afebrile women with a positive malaria smear (asexual P. falciparum parasitemia; >500 parasites/[micro]L blood). The women were studied while infected, treated, and then restudied 10 d after treatment. Iron status, hepcidin, and inflammation indexes were measured before and after treatment. Results: Treatment reduced low-grade inflammation, as reflected by decreases in serum ferritin, C-reactive protein, interleukin-6, interleukin-8, and interleukin-10 (P < 0.05); this was accompanied by a reduction in median serum hepcidin of [approximately equal to]50%, from 2.7 to 1.4 nmol/L (P < 0.005). Treatment decreased serum erythropoietin and growth differentiation factor 15 (P < 0.05). Clearance of parasitemia increased geometric mean dietary iron absorption (from 10.2% to 17.6%; P = 0.008) but did not affect systemic iron utilization (85.0% compared with 83.1%; NS). Conclusions: Dietary iron absorption is reduced by [approximately equal to]40% in asymptomatic P falciparum parasitemia, likely because of low-grade inflammation and its modulation of circulating hepeidin. Because asymptomatic parasitemia has a protracted course and is very common in malarial areas, this effect may contribute to IDA and blunt the efficacy of iron supplementation and fortification programs. This trial was registered at clinicaltrials.gov as NCT01108939. Am J Clin Nutr 2010;92:1385-92. doi: 10.3945/ajcn.2010.30051.

Published
2010

18. Effects of Exercise on Hepcidin Response and Iron Metabolism During Recovery.

Author

Peeling, Peter, Dawson, Brian, Goodman, Carmel, Landers, Grant, Wiegerinck, Erwin T., Swinkels, Dorine W., and Trinder, Debbie

Subjects
IRON metabolism, PEPTIDE hormones, RUNNING, CYTOKINES, INFLAMMATION, IRON in the body, EXERCISE physiology
Abstract

Urinary hepcidin, inflammation, and iron metabolism were examined during the 24 hr after exercise. Eight moderately trained athletes (6 men, 2 women) completed a 60-min running trial (15-min warm-up at 75-80% HRpeak + 45 min at 85-90% HRpeak) and a 60-min trial of seated rest in a randomized, crossover design. Venous blood and urine samples were collected pretrial, immediately posttrial, and at 3, 6, and 24 hr posttrial. Samples were analyzed for interleukin-6 (IL-6), C-reactive protein (CRP), serum iron, serum ferritin, and urinary hepcidin. The immediate postrun levels of IL-6 and 24-hr postrun levels of CRP were significantly increased from baseline (6.9 and 2.6 times greater, respectively) and when compared with the rest trial (p ≤ .05). Hepcidin levels in the run trial after 3, 6, and 24 hr of recovery were significantly greater (1.7-3.1 times) than the pre- and immediate postrun levels (p ≤ .05). This outcome was consistent in all participants, despite marked variation in the magnitude of rise. In addition, the 3-hr postrun levels of hepcidin were significantly greater than at 3 hr in the rest trial (3.0 times greater, p ≤ .05). Hepcidin levels continued to increase at 6 hr postrun but failed to significantly differ from the rest trial (p = .071), possibly because of diurnal influence. Finally, serum iron levels were significantly increased immediately postrun (1.3 times, p ≤ .05). The authors concluded that high-intensity exercise was responsible for a significant increase in hepcidin levels subsequent to a significant increase in IL-6 and serum iron. [ABSTRACT FROM AUTHOR]

Published
2009
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19. Low dietary iron intake restrains the intestinal inflammatory response and pathology of enteric infection by food-borne bacterial pathogens

Author

Kortman, Guus A M, Mulder, Michelle L. M, Richters, Thijs J W, Shanmugam, Nanda K N, Trebicka, Estela, Boekhorst, Jos, Timmerman, Harro M., Roelofs, Rian, Wiegerinck, Erwin T., Laarakkers, Coby M., Swinkels, Dorine W., Bolhuis, Albert, Cherayil, Bobby J., and Tjalsma, Harold

Subjects
Salmonella typhimurium, Article, Feces, Mice, Lipocalin-2, Animals, Intestinal Mucosa, Caenorhabditis elegans, Iron supplementation, Oncogene Proteins, Gut microbiome, Salmonella Infections, Animal, Body Weight, Enterobacteriaceae Infections, Survival Analysis, Immunity, Innate, Lipocalins, Diet, Intestines, Mice, Inbred C57BL, Citrobacter rodentium, Female, Intestinal pathogens, Leukocyte L1 Antigen Complex, Iron, Dietary, Acute-Phase Proteins
Abstract

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.

Published
2015

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

Author

van Raaij, Sanne E. G., Rennings, Alexander J., Biemond, Bart J., Schols, Saskia E. M., Wiegerinck, Erwin T. G., Roelofs, Hennie M. J., Hoorn, Ewout J., Walsh, Stephen B., Nijenhuis, Tom, Swinkels, Dorine W., and van Swelm, Rachel P. L.

Abstract

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 [ABSTRACT FROM AUTHOR]

Published
2019
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22. Low dietary iron intake restrains the intestinal inflammatory response and pathology of enteric infection by food-borne bacterial pathogens

Author

Kortman, Guus A. M., primary, Mulder, Michelle L. M., additional, Richters, Thijs J. W., additional, Shanmugam, Nanda K. N., additional, Trebicka, Estela, additional, Boekhorst, Jos, additional, Timmerman, Harro M., additional, Roelofs, Rian, additional, Wiegerinck, Erwin T., additional, Laarakkers, Coby M., additional, Swinkels, Dorine W., additional, Bolhuis, Albert, additional, Cherayil, Bobby J., additional, and Tjalsma, Harold, additional

Published
2015
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24. Low Hepcidin Levels in Severely Anemic Malawian Children with High Incidence of Infectious Diseases and Bone Marrow Iron Deficiency

Author

Jonker, Femkje A. M., primary, Calis, Job C. J., additional, Phiri, Kamija, additional, Kraaijenhagen, Rob J., additional, Brabin, Bernard J., additional, Faragher, Brian, additional, Wiegerinck, Erwin T., additional, Tjalsma, Harold, additional, Swinkels, Dorine W., additional, and Boele van Hensbroek, Michael, additional

Published
2013
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30. Hepcidin in anemia of chronic heart failure

Author

Divakaran, Vijay, primary, Mehta, Sachin, additional, Yao, David, additional, Hassan, Saamir, additional, Simpson, Steven, additional, Wiegerinck, Erwin, additional, Swinkels, Dorine W., additional, Mann, Douglas L., additional, and Afshar-Kharghan, Vahid, additional

Published
2010
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33. Effect of the new HJV-L165X mutation on penetrance of HFE

Author

van Dijk, Boukje A. C., primary, Kemna, Erwin H. J. M., additional, Tjalsma, Harold, additional, Klaver, Siem M., additional, Wiegerinck, Erwin T. G., additional, Goossens, Jan-Pieter, additional, Slee, Peter H. Th. J., additional, Breuning, Martijn H., additional, and Swinkels, Dorine W., additional

Published
2007
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38. Hepcidin-25 in Chronic Hemodialysis Patients Is Related to Residual Kidney Function and Not to Treatment with Erythropoiesis Stimulating Agents.

Author

Van der Weerd, Neelke C., Grooteman, Muriel P. C., Bots, Michiel L., Van den Dorpel, Marinus A., Den Hoedt, Claire H., Mazairac, Albert H. A., Nubé, Menso J., Lars Penne, E., Gaillard, Carlo A., Wetzels, Jack F. M., Wiegerinck, Erwin T., Swinkels, Dorine W., Blankestijn, Peter J., and Ter Wee, Piet M.

Subjects
HEPCIDIN, HEMODIALYSIS patients, CARBOHYDRATE intolerance, ENTEROCYTES, LIVER cells
Abstract

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. [ABSTRACT FROM AUTHOR]

Published
2012
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39. Toxic iron species in lower-risk myelodysplastic syndrome patients: course of disease and effects on outcome.

Author

Hoeks M, Bagguley T, van Marrewijk C, Smith A, Bowen D, Culligan D, Kolade S, Symeonidis A, Garelius H, Spanoudakis M, Langemeijer S, Roelofs R, Wiegerinck E, Tatic A, Killick S, Panagiotidis P, Stanca O, Hellström-Lindberg E, Cermak J, van der Klauw M, Wouters H, van Kraaij M, Blijlevens N, Swinkels DW, and de Witte T

Subjects
Adult, Aged, Female, Follow-Up Studies, Humans, Iron Overload etiology, Iron Overload metabolism, Iron Overload pathology, Male, Middle Aged, Myelodysplastic Syndromes pathology, Myelodysplastic Syndromes therapy, Prognosis, Prospective Studies, Survival Rate, Blood Transfusion mortality, Iron adverse effects, Iron Overload mortality, Myelodysplastic Syndromes mortality
Published
2021
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41. Plasma hepcidin levels and anemia in old age. The Leiden 85-Plus Study.

Author

den Elzen WP, de Craen AJ, Wiegerinck ET, Westendorp RG, Swinkels DW, and Gussekloo J

Subjects
Age Factors, Aged, 80 and over, Anemia diagnosis, Anemia epidemiology, Comorbidity, Female, Humans, Male, Netherlands epidemiology, Population Surveillance, Prospective Studies, Anemia blood, Hepcidins blood
Abstract

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.

Published
2013
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42. [Iron deficiency anaemia due to a matriptase-2 mutation].

Author

Cuijpers ML, Wiegerinck ET, Brouwer R, de Witte TJ, and Swinkels DW

Subjects
Adult, Anemia, Iron-Deficiency drug therapy, Female, Hepcidins, Humans, Iron therapeutic use, Mutation genetics, Pedigree, Treatment Failure, Anemia, Iron-Deficiency enzymology, Anemia, Iron-Deficiency genetics, Antimicrobial Cationic Peptides blood, Membrane Proteins genetics, Membrane Proteins metabolism, Serine Endopeptidases genetics, Serine Endopeptidases metabolism
Abstract

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.

Published
2010

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