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2. A Novel Hypoxia-Inducible Factor−Prolyl Hydroxylase Inhibitor (GSK1278863) for Anemia in CKD: A 28-Day, Phase 2A Randomized Trial

Author

Borsukov, Alexey V., Marasaev, Vyacheslav V., Prasad, Gullipalli, Timokhovskaya, Galina Y., Kolmakova, Elena V., Dobronravov, Vladimir A., Zakharova, Elena V., Abraham, Georgi, Packham, David, Zateyshchikov, Dmitry A., Arutyunov, Gregory P., Volgina, Galina V., Lipatov, Kirill S., Perlin, Dmitry V., Cooper, Bruce, Kumar Saha, Tarun, Zagrebelnaya, Olga A., Mehta, Kalpana S., Koziolova, Natalya A., Fassett, Rob, Alexeeva, Narina P., Lysenko, Lidia V., Brigandi, Richard A., Johnson, Brendan, Oei, Coreen, Westerman, Mark, Olbina, Gordana, de Zoysa, Janak, Roger, Simon D., Sahay, Manisha, Cross, Nicholas, McMahon, Lawrence, Guptha, Veerabhadra, Smolyarchuk, Elena A., Singh, Narinder, Russ, Steven F., and Kumar, Sanjay

Published
2016
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20. Erythropoiesis-driven regulation of hepcidin in human red cell disorders is better reflected through concentrations of soluble transferrin receptor rather than growth differentiation factor 15

Author

Fertrin, Kleber Yotsumoto, Lanaro, Carolina, Franco-Penteado, Carla Fernanda, de Albuquerque, Dulcinéia Martins, de Mello, Mariana Rezende Bandeira, Pallis, Flávia Rubia, Bezerra, Marcos André Cavalcanti, Hatzlhofer, Betania Lucena Domingues, Olbina, Gordana, Olalla Saad, Sara Terezinha, da Silva Araújo, Aderson, Westerman, Mark, and Costa, Fernando Ferreira

Published
2014
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25. Early reversal of pediatric-neonatal septic shock by community physicians is associated with improved outcome

Author

Han, Yong Y., Carcillo, Joseph A., Dragotta, Michelle A., Bills, Debra M., Watson, R. Scott, Westerman, Mark E., and Orr, Richard A.

Subjects
Septic shock -- Care and treatment
Abstract

Objective. Experimental and clinical studies of septic shock support the concept that early resuscitation with fluid and inotropic therapies improves survival in a time-dependent manner. The new American College of Critical Care Medicine-Pediatric Advanced Life Support (ACCM-PALS) Guidelines for hemodynamic support of newborns and children in septic shock recommend this therapeutic approach. The objective of this study was to determine whether early septic shock reversal and use of resuscitation practice consistent with the new ACCM-PALS Guidelines by community physicians is associated with improved outcome. Methods. A 9-year (January 1993-December 2001) retrospective cohort study was conducted of 91 infants and children who presented to local community hospitals with septic shock and required transport to Children's Hospital of Pittsburgh. Shock reversal (defined by return of normal systolic blood pressure and capillary refill time), resuscitation practice concurrence with ACCM-PALS Guidelines, and hospital mortality were measured. Results. Overall, 26 (29%) patients died. Community physicians successfully achieved shock reversal in 24 (26%) patients at a median time of 75 minutes (when the transport team arrived at the patient's bedside), which was associated with 96% survival and >9-fold increased odds of survival (9.49 [1.07-83.89]). Each additional hour of persistent shock was associated with >2-fold increased odds of mortality (2.29 [1.19-4.44]). Nonsurvivors, compared with survivors, were treated with more inotropic therapies (dopamine/dobutamine [42% vs 20%] and epinephrine/norepinephrine [42% vs 6%]) but not increased fluid therapy (median volume; 32.9 mL/kg vs 20.0 mL/kg). Resuscitation practice was consistent with ACCM-PALS Guidelines in only 27 (30%) patients; however, when practice was in agreement with guideline recommendations, a lower mortality was observed (8% vs 38%). Conclusions. Early recognition and aggressive resuscitation of pediatric-neonatal septic shock by community physicians can save lives. Educational programs that promote ACCM-PALS recommended rapid, stepwise escalations in fluid as well as inotropic therapies may have value in improving outcomes in these children. Pediatrics 2003;112:793-799; fluid resuscitation, inotropes, interfacility transport, hydrocortisone., ABBREVIATIONS. ACCM, American College of Critical Care Medicine; AHA, American Heart Association; PALS, Pediatric Advanced Life Support; CHP, Children's Hospital of Pittsburgh; SBP, systolic blood pressure; PRISM, Pediatric Risk of [...]

Published
2003

38. Clinical Immunoassay for Human Hepcidin Predicts Iron Deficiency in First-Time Blood Donors.

Author

Gutschow, Patrick, Huiling Han, Olbina, Gordana, Westerman, Keith, Nemeth, Elizabeta, Ganz, Tomas, Copeland, Karen, Westerman, Mark, and Ostland, Vaughn

Subjects
HEPCIDIN, IRON deficiency anemia diagnosis, IRON in the blood, BLOOD donors, IRON deficiency
Abstract

Background: Serum markers currently used as indicators of iron status have clinical limitations. Hepcidin, a key regulator of iron homeostasis, is reduced in iron deficiency (ID) and increased in iron overload. We describe the first CLIA-validated immunoassay with excellent accuracy and precision to quantify human serum hepcidin. Its diagnostic utility for detecting ID in first-time blood donors was demonstrated. Methods: A monoclonal competitive ELISA (C-ELISA) was developed for the quantitation of human hepcidin and validated according to CLIA guidelines. Sera from nonanemic first-time blood donors (n=292) were analyzed for hepcidin, ferritin, transferrin, and serum iron. Logistic regression served to determine the utility of hepcidin as a predictor of ID. Results: The C-ELISA was specific for human hepcidin and had a low limit of quantitation (4.0 ng/mL). The hepcidin concentration measured with the monoclonal C-ELISA was strongly correlated with a previously established, extensively tested polyclonal C-ELISA (Blood 2008;112:4292-7) (r=0.95, P<0.001). The area under the receiver operating characteristic curve for hepcidin as a predictor of ID, defined by 3 ferritin concentration thresholds, was >0.9. For predicting ID defined by ferritin <15 ng/mL, hepcidin <10 ng/mL yielded sensitivity of 93.1% and specificity of 85.5%, whereas the same hepcidin cutoff for ferritin <30 ng/mL yielded sensitivity of 67.6% and specificity of 91.7%. Conclusion: The clinical measurement of serum hepcidin concentrations was shown to be a potentially useful tool for diagnosing ID. [ABSTRACT FROM AUTHOR]

Published
2020
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39. Hepcidin Status at 2 Months in Infants Fed Breast Milk Compared with Formula.

Author

Verhaeghe, Rebecca, George, Kandie, Westerman, Mark, Olbina, Gordana, McCann, Diane, Parrow, Nermi, Pincus, Elisa, Havranek, Tomas, and Fleming, Robert E.

Subjects
BREAST milk, HEPCIDIN, INFANTS, IRON in the body, INFANT formulas
Abstract

Introduction: The basis for the superior absorption of iron from breast milk compared with infant formulas is unclear. The hormone hepcidin downregulates dietary iron absorption. Hepcidin production increases with increased body iron status (reflected in serum ferritin levels). We hypothesized that serum hepcidin levels are suppressed relative to iron status in infants fed breast milk compared with formula. Methods: Subjects were healthy infants presenting for routine 2-month clinic visit and strictly fed either breast milk or standard infant formula. Urinary hepcidin and ferritin levels (reflective of serum levels) were analyzed and compared across the breast milk- and formula-fed groups. The relationship between urinary hepcidin and ferritin levels within each group was analyzed by linear regression. Results: Twenty-four subjects were enrolled in each group. The median urinary hepcidin level in the group fed breast milk was lower than in formula (130 vs. 359 ng hepcidin/mg creatinine, p < 0.05). However, the median ferritin levels were similar (2.1 vs. 1.9 ng/mL). Within each group, urinary hepcidin correlated with urinary ferritin (r = 0.5, p < 0.05 for each group); however, the slope of the regression line was lower in the group fed breast milk compared with formula (p < 0.005). Conclusion: Despite similar urinary ferritin levels, urinary hepcidin levels are lower at 2 months in infants fed breast milk compared with infants fed formula. Hepcidin levels correlate with iron status in each group; however, this relationship is relatively dampened in infants fed breast milk. We speculate that relatively lower infant hepcidin contributes to the superior efficiency of iron absorption from breast milk. [ABSTRACT FROM AUTHOR]

Published
2020
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40. Evidence of Relative Iron Deficiency in Platelet- and Plasma-Pheresis Donors Correlates With Donation Frequency

Author

Li, Huihui, Condon, Frances, Kessler, Debra, Nandi, Vijay, Rebosa, Mark, Westerman, Mark, Shaz, Beth H., and Ginzburg, Yelena

Subjects
Male, Time Factors, Plateletpheresis, Blood Donors, Pilot Projects, Iron Deficiencies, Plasmapheresis, Article, White People, Cross-Sectional Studies, Hepcidins, Case-Control Studies, Ferritins, Humans, Erythropoiesis
Abstract

BACKGROUND: The loss of iron stores and resulting iron deficiency is well documented in whole blood or red blood cell donors. We hypothesized that relative iron deficiency also occurs as a result of more frequent platelet- and plasma-pheresis (apheresis) donation. MATERIALS AND METHODS: To test this hypothesis, we proposed a pilot cross-sectional study to analyze erythropoiesis- and iron-related parameters in white male apheresis donors: (1) relative to controls, (2) in correlation with apheresis donation frequency, and (3) in correlation with pre-donation platelet count. RESULTS: Fifty eligible apheresis donors and eight controls were enrolled in the study. Apheresis donors were found to have a lower serum ferritin and serum hepcidin and exhibited evidence of iron restricted erythropoiesis relative to controls. Furthermore, among donors, lower MCV, CH(r), hepcidin concentration, and serum ferritin were observed in more frequent apheresis donors. Correlations between donation frequency and hepcidin and ferritin were noted in apheresis donors. CONCLUSIONS: This pilot study demonstrates that apheresis donors are relatively iron deficient compared to controls and supports the premise that frequent apheresis donation correlates with relatively iron restricted erythropoiesis. An analysis of iron- and erythropoiesis-related parameters in a broader population of frequent apheresis donors (i.e., female and non-white donors) may demonstrate larger deficits and an even greater potential benefit of iron replacement.

Published
2016

41. Urinary Biomarkers may Complement the Cleveland Score for Prediction of Adverse Kidney Events After Cardiac Surgery: A Pilot Study.

Author

Albert, Christian, Haase, Michael, Albert, Annemarie, Kropf, Siegfried, Bellomo, Rinaldo, Westphal, Sabine, Westerman, Mark, Braun-Dullaeus, Rüdiger Christian, and Haase-Fielitz, Anja

Subjects
LIPOCALINS, CARDIAC surgery, ADVERSE health care events, BIOMARKERS, BIOLOGICAL tags, ACUTE kidney failure, PROXIMAL kidney tubules
Abstract

Background: The ability of urinary biomarkers to complement established clinical risk prediction models for postoperative adverse kidney events is unclear. We assessed the effect of urinary biomarkers linked to suspected pathogenesis of cardiac surgery-induced acute kidney injury (AKI) on the performance of the Cleveland Score, a risk assessment model for postoperative adverse kidney events. Methods: This pilot study included 100 patients who underwent open-heart surgery. We determined improvements to the Cleveland Score when adding urinary biomarkers measured using clinical laboratory platforms (neutrophil gelatinase-associated lipocalin [NGAL], interleukin-6) and those in the preclinical stage (hepcidin-25, midkine, alpha-1 microglobulin), all sampled immediately post-surgery. The primary endpoint was major adverse kidney events (MAKE), and the secondary endpoint was AKI. We performed ROC curve analysis, assessed baseline model performance (odds ratios [OR], 95% CI), and carried out statistical reclassification analyses to assess model improvement. Results: NGAL (OR [95% CI] per 20 concentration-units wherever applicable): (1.07 [1.01-1.14]), Interleukin-6 (1.51 [1.01-2.26]), midkine (1.01 [1.00-1.02]), 1-hepcidin- 25 (1.08 [1.00-1.17]), and NGAL/hepcidin-ratio (2.91 [1.30-6.49]) were independent predictors of MAKE and AKI (1.38 [1.03-1.85], 1.08 [1.01-1.15], 1.01 [1.00-1.02], 1.09 [1.01-1.18], and 3.45 [1.54-7.72]). Category-free net reclassification improvement identified interleukin-6 as a model-improving biomarker for MAKE and NGAL for AKI. However, only NGAL/hepcidin-25 improved model performance for event- and event-free patients for MAKE and AKI. Conclusions: NGAL and interleukin-6 measured immediately post cardiac surgery may complement the Cleveland Score. The combination of biomarkers with hepcidin-25 may further improve diagnostic discrimination. [ABSTRACT FROM AUTHOR]

Published
2020
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42. Maternal Hepcidin Is Associated with Placental Transfer of Iron Derived from Dietary Heme and Nonheme Sources1234

Author

Young, Melissa F., Griffin, Ian, Pressman, Eva, McIntyre, Allison W., Cooper, Elizabeth, McNanley, Thomas, Harris, Z. Leah, Westerman, Mark, and O’Brien, Kimberly O.

Subjects
Adult, Young Adult, Adolescent, Hepcidins, Pregnancy, Iron, Humans, Female, Nutrient Physiology, Metabolism, and Nutrient-Nutrient Interactions, Heme, Maternal-Fetal Exchange, Antimicrobial Cationic Peptides, Diet
Abstract

The determinants of placental transport of dietary iron remain largely uncharacterized. The objective of this research was to elucidate determinants of fetal Fe transfer from maternally ingested dietary heme and non-heme Fe. The study was undertaken in 19 pregnant females (16-32 y) who ingested intrinsically labeled (58)Fe-heme and a nonheme Fe source ((57)FeSO(4)) during the third trimester of pregnancy. At delivery, maternal and cord blood was obtained to assess neonatal (57)Fe and (58)Fe enrichment as a function of maternal/neonatal Fe status [serum ferritin (SF), transferrin receptor, hemoglobin (Hb), total body Fe, and hepcidin]. There was a greater percentage of maternally absorbed (58)Fe tracer present in the neonates compared to the (57)Fe tracer (5.4 ± 2.4 vs. 4.0 ± 1.6; P0.0001). Net dietary nonheme Fe (mg) and heme Fe (mg) transferred to the fetus were both inversely correlated with measures of maternal serum hepcidin (P = 0.002, r(2) = 0.43; P = 0.004, r(2) = 0.39) and SF (P = 0.0008, r(2) = 0.49; P = 0.003, r(2) = 0.41) and directly associated with neonatal Hb (P = 0.004, r(2) = 0.39; P = 0.008, r(2) = 0.35). The results of this study suggest that during pregnancy there appears to be preferential fetal use of maternally ingested Fe derived from a dietary, animal-based heme source compared to Fe ingested as ferrous sulfate. Maternal serum hepcidin and maternal/neonatal Fe status may play a role in placental uptake of dietary heme and nonheme Fe.

Published
2011

43. Utilization of Iron from an Animal-Based Iron Source Is Greater Than That of Ferrous Sulfate in Pregnant and Nonpregnant Women123

Author

Young, Melissa F., Griffin, Ian, Pressman, Eva, McIntyre, Allison W., Cooper, Elizabeth, McNanley, Thomas, Harris, Z. Leah, Westerman, Mark, and O’Brien, Kimberly O.

Subjects
Adult, Young Adult, Adolescent, Pregnancy, Iron, Humans, Female, Nutrient Physiology, Metabolism, and Nutrient-Nutrient Interactions, Ferrous Compounds
Abstract

Heme iron absorption during pregnancy and the role of hepcidin in regulating dietary heme iron absorption remains largely unexplored. The objective of this research was to examine relative differences in heme (animal based) and nonheme (ferrous sulfate) iron utilization. This study was undertaken in 18 pregnant (ages 16-32 y; wk 32-35 of gestation) and 11 nonpregnant women (ages 18-27 y). Women were randomly assigned to receive both an animal-based heme meal (intrinsically labeled (58)Fe pork) and labeled ferrous sulfate ((57)Fe) fed on alternate days. Blood samples obtained 2 wk postdosing were used to assess iron status indicators and serum hepcidin and iron utilization based on RBC incorporation of iron isotopes. Heme iron utilization was significantly greater than nonheme iron utilization in the pregnant (47.7 ± 14.4 vs. 40.4 ± 13.2%) and nonpregnant women (50.1 ± 14.8 vs. 15.3 ± 9.7%). Among pregnant women, utilization of nonheme iron was associated with iron status, as assessed by the serum transferrin receptor concentration (P = 0.003; r(2) = 0.43). In contrast, heme iron utilization was not influenced by maternal iron status. In the group as a whole, women with undetectable serum hepcidin had greater nonheme iron utilization compared with women with detectable serum hepcidin (P = 0.02; n = 29); however, there were no significant differences in heme iron utilization. Our study suggests that iron utilization from an animal-based food provides a highly bioavailable source of dietary iron for pregnant and nonpregnant women that is not as sensitive to hepcidin concentrations or iron stores compared with ferrous sulfate.

Published
2010

44. Sequential evaluation of serum hepcidin in anemic myeloma patients: Study of correlations with myeloma treatment, disease variables, and anemia response

Author

Katodritou, Eirini Ganz, Tomas Terpos, Evangelos Verrou, Evgenia Olbina, Gordana Gastari, Vassiliki Hadjiaggelidou, Christina Varthaliti, Maria Georgiadou, Sofia Westerman, Mark Zervas, Konstantinos

Subjects
hemic and lymphatic diseases
Abstract

Hepcidin is a liver-derived hormone with a central role In Iron regulation and In anemia of Inflammation. Its correlations with disease variables, anemia response (AR), and responses to treatment have not been investigated In multiple myeloma (MM). A cohort of anemic MM patients undergoing treatment with Immunomodulatory drug (IMiDs)-based regimens (n = 18) or conventional chemotherapy (n = 16) was studied. Overall, hepcidin decreased significantly between baseline and treatment Cycles 2 and 4 (P < 0.05), and this was more profound In the IMiDs group compared with the conventional group. Baseline hepcidin Inversely correlated with baseline hemoglobin (Hb) and platelets (PLT) and positively correlated with beta 2M, ferritin, transferrin saturation (TSAT%), and International Scoring System (ISS) (P < 0.05). Abnormally high baseline hepcidin inversely correlated with duration of response (DOR) In all studied patients and In the conventional group. Abnormally high hepcidin before treatment Cycles 2 and 3 predicted for AR and disease response (DR), respectively, In all studied patients (P < 0.05). These results suggest that serum hepcidin correlates with significant MM variables and may serve as a surrogate marker for MM and as a predictor for response Indicators.

Published
2009

46. The Growth Differentiation Factor-15 Levels Are Increased in Patients with Compound Heterozygous Sickle Cell and Beta-Thalassemia, Correlate with Hepcidin-25/Ferritin Molar Ratio and with Markers of Hemolysis, Endothelial Dysfunction and Angiogenesis

Author

Papassotiriou, Ioannis, Larrisi, Katerina, Margeli, Alexandra, Christoulas, Dimitrios, Dimopoulou, Maria, Ostland, Vaughn, Poziopoulos, Christos, Westerman, Mark, Politou, Marianna, Voskaridou, Ersi, and Terpos, Evangelos

Published
2016
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50. Toward Worldwide Hepcidin Assay Harmonization: Identification of a Commutable Secondary Reference Material.

Author

van der Vorm, Lisa N., Hendriks, Jan C. M., Laarakkers, Coby M., Klaver, Siem, Armitage, Andrew E., Bamberg, Alison, Geurts-Moespot, Anneke J., Girelli, Domenico, Herkert, Matthias, Itkonen, Outi, Konrad, Robert J., Naohisa Tomosugi, Westerman, Mark, Bansal, Sukhvinder S., Campostrini, Natascia, Drakesmith, Hal, Fillet, Marianne, Olbina, Gordana, Pasricha, Sant-Rayn, and Pitts, Kelly R.

Published
2016
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