Publications by authors named "Tomas Ganz"

247 Publications

The pyruvate kinase activator mitapivat reduces hemolysis and improves anemia in a β-thalassemia mouse model.

J Clin Invest 2021 Apr 6. Epub 2021 Apr 6.

Department of Medicine, University of Verona, Verona, Italy.

Anemia in β-thalassemia is related to ineffective erythropoiesis and reduced red cell survival. Excess free heme and accumulation of unpaired α-globin chains impose substantial oxidative stress on β-thalassemic erythroblasts and erythrocytes, impacting cell metabolism. We hypothesized that increased pyruvate kinase activity induced by mitapivat (AG-348) in the Hbbth3/+ mouse model for β-thalassemia would reduce chronic hemolysis and ineffective erythropoiesis through stimulation of red cell glycolytic metabolism. Oral mitapivat administration ameliorated ineffective erythropoiesis and anemia in Hbbth3/+ mice. Increased ATP, reduced reactive oxygen species production, and reduced markers of mitochondrial dysfunction associated with improved mitochondrial clearance suggested enhanced metabolism following mitapivat administration in β-thalassemia. The amelioration of responsiveness to erythropoietin resulted in reduced soluble erythroferrone, increased liver Hamp expression, and diminished liver iron overload. Mitapivat reduced duodenal Dmt1 expression potentially by activating the pyruvate kinase M2HIF2α axis, representing a mechanism additional to Hamp in controlling iron absorption and preventing β-thalassemia-related liver iron overload. In ex vivo studies on erythroid precursors from patients with β-thalassemia, mitapivat enhanced erythropoiesis, promoted erythroid maturation, and decreased apoptosis. Overall, pyruvate kinase activation as a treatment modality for β-thalassemia in preclinical model systems had multiple beneficial effects in the erythropoietic compartment and beyond, providing a strong scientific basis for further clinical trials.
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http://dx.doi.org/10.1172/JCI144206DOI Listing
April 2021

Amelioration of chronic kidney disease-associated anemia by vadadustat in mice is not dependent on erythroferrone.

Kidney Int 2021 Mar 31. Epub 2021 Mar 31.

Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA.

Vadadustat is an investigational hypoxia-inducible factor prolyl hydroxylase inhibitor that increases endogenous erythropoietin production, and has been shown to decrease hepcidin levels, ameliorate iron restriction, and increase hemoglobin concentrations in anemic patients with chronic kidney disease (CKD). In studies of physiological responses to other erythropoietic stimuli, erythropoietin induced erythroblast secretion of erythroferrone (ERFE), which acts on the liver to suppress hepcidin production and mobilize iron for erythropoiesis. We therefore investigated whether vadadustat effects on erythropoiesis and iron metabolism are dependent on ERFE. Wild type and ERFE knockout mice with and without CKD were treated with vadadustat or vehicle. In both wild type and ERFE knockout CKD models, vadadustat was similarly effective, as evidenced by normalized hemoglobin concentrations, increased expression of duodenal iron transporters, lower serum hepcidin levels, and decreased tissue iron concentrations. This is consistent with ERFE-independent increased iron mobilization. Vadadustat treatment also lowered serum urea nitrogen and creatinine concentrations and decreased expression of kidney fibrosis markers. Lastly, vadadustat affected fibroblast growth factor 23 (FGF23) profiles: in non-CKD mice, vadadustat increased plasma total FGF23 out of proportion to intact FGF23, consistent with the known effects of hypoxia-inducible factor-1α and erythropoietin on FGF23 production and metabolism. However, in the mice with CKD, vadadustat markedly decreased both total and intact FGF23, effects likely contributed to by the reduced loss of kidney function. Thus, in this CKD model, vadadustat ameliorated anemia independently of ERFE, improved kidney parameters, and decreased FGF23. How vadadustat affects CKD progression in humans warrants future studies.
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http://dx.doi.org/10.1016/j.kint.2021.03.019DOI Listing
March 2021

Erythropoiesis stimulating agents are associated with serum fibroblast growth factor 23 metabolism in patients on hemodialysis.

Clin Kidney J 2021 Mar 23;14(3):943-949. Epub 2020 Jun 23.

Department of Chemistry, Kurume University, School of Medicine, Kurume, Japan.

Background: This study aimed to determine associations among short- and long-acting erythropoiesis stimulating agents (ESAs), changes in serum fibroblast growth factor 23 (FGF23) and biomarkers of iron metabolism.

Methods: Among 108 patients on hemodialysis (HD), 44 received every 2 weeks or monthly doses of continuous erythropoiesis receptor activator (CERA), 31 received weekly doses of darbepoetin-α, 24 received three doses per week of epoetin-β and 9 were not treated with an ESA. Intact and C-terminal FGF23 and transferrin saturation (TSAT), ferritin, erythroferrone and hepcidin 25 were measured in blood samples collected before the HD session at the end of the dialysis week (baseline, Day 0) and on Days 3, 5, 7 and 14 thereafter.

Results: Levels of ferritin, hepcidin 25 and erythroferrone as well as TSAT were significantly decreased or elevated in patients treated with CERA compared with other types of ESAs. Levels of C-terminal FGF23 increased in all groups during the observation period. Levels of intact FGF23 and ratios of intact FGF23 to C-terminal FGF23 gradually decreased between Days 3 and 7 in the CERA but not in the other groups. Multivariate models associated changes in hepcidin 25 and phosphate with those of intact FGF23.

Conclusion: The long-acting ESA CERA might influence levels of intact FGF23 by increasing FGF23 cleavage in patients on HD in association with prolonged hepcidin 25 suppression.
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http://dx.doi.org/10.1093/ckj/sfaa042DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7986323PMC
March 2021

Commentary on the AGA Clinical Practice Guidelines on the Gastrointestinal Evaluation of Iron Deficiency Anemia.

Gastroenterology 2021 Mar 3. Epub 2021 Mar 3.

Divisions of Pulmonary and Critical Care, and David Geffen School of Medicine at UCLA, Los Angeles, CA, USA; Divisions of Hematology-Oncology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.

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http://dx.doi.org/10.1053/j.gastro.2021.03.001DOI Listing
March 2021

Increase of plasma erythroferrone levels during high-altitude exposure: A sub-analysis of the TOP OF HOMe study.

Am J Hematol 2021 May 9;96(5):E179-E181. Epub 2021 Mar 9.

Internal Medicine IV - Nephrology and Hypertension, Saarland University Medical Center, Homburg, Germany.

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http://dx.doi.org/10.1002/ajh.26130DOI Listing
May 2021

Pursuing Orally Bioavailable Hepcidin Analogues via Cyclic -Methylated Mini-Hepcidins.

Biomedicines 2021 Feb 8;9(2). Epub 2021 Feb 8.

School of Biomedical Sciences, Faculty of Medicine, The University of Queensland, Brisbane, QLD 4072, Australia.

The peptide hormone hepcidin is one of the key regulators of iron absorption, plasma iron levels, and tissue iron distribution. Hepcidin functions by binding to and inducing the internalisation and subsequent lysosomal degradation of ferroportin, which reduces both iron absorption in the gut and export of iron from storage to ultimately decrease systemic iron levels. The key interaction motif in hepcidin has been localised to the highly conserved N-terminal region, comprising the first nine amino acid residues, and has led to the development of mini-hepcidin analogs that induce ferroportin internalisation and have improved drug-like properties. In this work, we have investigated the use of head-to-tail cyclisation and -methylation of mini-hepcidin as a strategy to increase oral bioavailability by reducing proteolytic degradation and enhancing membrane permeability. We found that backbone cyclisation and -methylation was well-tolerated in the mini-hepcidin analogues, with the macrocylic analogues often surpassing their linear counterparts in potency. Both macrocyclisation and backbone -methylation were found to improve the stability of the mini-hepcidins, however, there was no effect on membrane-permeabilizing activity.
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http://dx.doi.org/10.3390/biomedicines9020164DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7915682PMC
February 2021

Parenteral iron therapy and phosphorus homeostasis: A review.

Am J Hematol 2021 May 9;96(5):606-616. Epub 2021 Feb 9.

Center for Bone Health and Division of Endocrinology and Diabetes, Children's Hospital of Philadelphia and University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA.

Phosphorus has an essential role in cellular and extracellular metabolism; maintenance of normal phosphorus homeostasis is critical. Phosphorus homeostasis can be affected by diet and certain medications; some intravenous iron formulations can induce renal phosphate excretion and hypophosphatemia, likely through increasing serum concentrations of intact fibroblast growth factor 23. Case studies provide insights into two types of hypophosphatemia: acute symptomatic and chronic hypophosphatemia, while considering the role of pre-existing conditions and comorbidities, medications, and intravenous iron. This review examines phosphorus homeostasis and hypophosphatemia, with emphasis on effects of iron deficiency and iron replacement using intravenous iron formulations.
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http://dx.doi.org/10.1002/ajh.26100DOI Listing
May 2021

Erythroferrone structure, function, and physiology: Iron homeostasis and beyond.

J Cell Physiol 2021 Jul 28;236(7):4888-4901. Epub 2020 Dec 28.

Department of Medicine, David Geffen School of Medicine at UCLA, University of California, Los Angeles, California, USA.

Erythroferrone (ERFE) is the main erythroid regulator of hepcidin, the homeostatic hormone controlling plasma iron levels and total body iron. When the release of erythropoietin from the kidney stimulates the production of new red blood cells, it also increases the synthesis of ERFE in bone marrow erythroblasts. Increased ERFE then suppresses hepcidin synthesis, thereby mobilizing cellular iron stores for use in heme and hemoglobin synthesis. Recent mechanistic studies have shown that ERFE suppresses hepcidin transcription by inhibiting bone morphogenetic protein signaling in hepatocytes. In ineffective erythropoiesis, pathological overproduction of ERFE by an expanded population of erythroblasts suppresses hepcidin and causes iron overload, even in non-transfused patients. ERFE may be a useful biomarker of ineffective erythropoiesis and an attractive target for treating its systemic effects.
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http://dx.doi.org/10.1002/jcp.30247DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8026552PMC
July 2021

Isolation and thermal stabilization of mouse ferroportin.

FEBS Open Bio 2021 Jan 17;11(1):26-34. Epub 2020 Dec 17.

Structural Biology Program, Centenary Institute, Sydney, NSW, Australia.

Ferroportin (Fpn) is an essential mammalian iron transporter that is negatively regulated by the hormone hepcidin. Our current molecular understanding of Fpn-mediated iron efflux and regulation is limited due to a lack of biochemical, biophysical and high-resolution structural studies. A critical step towards understanding the transport mechanism of Fpn is to obtain sufficient quantities of pure and stable protein for downstream studies. As such, we detail here an expression and purification protocol for mouse Fpn yielding milligram quantities of pure protein. We have generated deletion constructs exhibiting enhanced thermal stability and which retained iron-transport activity and hepcidin responsiveness, providing a platform for further biophysical studies of Fpn.
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http://dx.doi.org/10.1002/2211-5463.13039DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7780100PMC
January 2021

The role of hepcidin in fetal iron homeostasis.

Authors:
Tomas Ganz

Blood 2020 09;136(13):1474-1475

University of California, Los Angeles.

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http://dx.doi.org/10.1182/blood.2020007382DOI Listing
September 2020

Prognostic associations of plasma hepcidin in women with early breast cancer.

Breast Cancer Res Treat 2020 Dec 22;184(3):927-935. Epub 2020 Sep 22.

Lunenfeld-Tanenbaum Research Institute, Department of Medicine, Mount Sinai Hospital, Toronto, ON, Canada.

Purpose: Iron is essential to energy metabolism, cell proliferation and DNA synthesis, and sufficient iron availability may be required for tumor growth. The hormone hepcidin is a systemic regulator of iron concentration in plasma. Intra-tumor RNA expression of hepcidin has been linked to shorter metastasis-free survival in women with early breast cancer, but the prognostic implications of this inflammatory marker and iron-regulating plasma peptide in the blood are unknown.

Methods: Using an ELISA assay, hepcidin was measured in the banked blood of 518 women who were recruited from 1989 to 1996 for a prospective cohort study of diet and lifestyle factors in breast cancer. Blood samples were obtained 4-12 weeks post-operatively, prior to treatment with chemotherapy or tamoxifen.

Results: Hepcidin was not associated with time to distant breast cancer recurrence (primary outcome) nor time to death from any cause. However, a pre-planned interaction test of body mass index (BMI) was statistically significant (p < 0.01). Among obese women (BMI > 30 kg/m), higher hepcidin was associated with a shorter time to distant breast cancer recurrence in both uni- and multivariable analyses (adjusted HR 1.84; 95% CI 1.04-3.25). For overall survival, a similar pattern was seen in the univariable model but the effect was diminished in a multivariable analysis. Plasma hepcidin was not associated with high-sensitivity C-reactive protein, but it was significantly associated (r ≥ 0.32) with iron indices, including total iron (p < 0.01), transferrin (p < 0.01) and soluble transferrin receptor (p < 0.01).

Conclusions: Hepcidin may be associated with poor breast cancer outcome in obese women, however, replication is required. The biologic basis for this prognostic association requires further research.
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http://dx.doi.org/10.1007/s10549-020-05903-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7883934PMC
December 2020

ACVR1/JAK1/JAK2 inhibitor momelotinib reverses transfusion dependency and suppresses hepcidin in myelofibrosis phase 2 trial.

Blood Adv 2020 09;4(18):4282-4291

Gilead Sciences, Inc., Foster City, CA.

Momelotinib (MMB) is a JAK1/2 and ACVR1 inhibitor with demonstrated clinical activity in all 3 hallmarks of myelofibrosis (MF): anemia, constitutional symptoms, and splenomegaly. In this phase 2 open-label translational biology study (NCT02515630) of 41 transfusion-dependent patients with MF, we explored mechanisms underlying the favorable activity of MMB on MF-associated iron-restricted anemia, including its impact on serum hepcidin levels, and markers of iron storage and availability, erythropoiesis, and inflammation. A transfusion-independent response (TI-R), defined as red blood cell transfusion independence (TI) ≥12 weeks at any time on study, occurred in 17 patients (41%; 95% confidence interval [CI], 26%-58%), including 14 patients (34%; 95% CI, 20%-51%) who achieved TI-R by week 24. In addition, 78% of TI nonresponse (TI-NR) patients achieved a ≥50% decrease in transfusion requirement for ≥8 weeks. Adverse events (AEs) were consistent with previous studies of MMB in MF, with cough, diarrhea, and nausea as the most common. Twenty-one patients experienced grade ≥3 AEs, most commonly anemia and neutropenia. Consistent with preclinical data, daily MMB treatment led to an acute and persistent decrease in blood hepcidin associated with increased iron availability and markers of erythropoiesis. Baseline characteristics associated with TI-R were lower inflammation and hepcidin as well as increased markers of erythropoiesis and bone marrow function. Overall, the study demonstrates that MMB treatment decreases hepcidin in conjunction with improving iron metabolism and erythropoiesis, suggesting a mechanistic explanation for the reduced transfusion dependency observed in transfusion-dependent MF patients treated with MMB, thereby addressing the key unmet medical need in the MF population.
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http://dx.doi.org/10.1182/bloodadvances.2020002662DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7509854PMC
September 2020

Expression of Iron-Regulatory Hormone Hepcidin and Iron Transporters Ferroportin and ZIP8 in Patients With and Without Chronic Rhinosinusitis.

Otolaryngol Head Neck Surg 2020 Dec 4;163(6):1270-1273. Epub 2020 Aug 4.

Department of Head and Neck Surgery, University of California Los Angeles David Geffen School of Medicine, Los Angeles, California, USA.

Airway epithelia express intrinsic antimicrobial and nutrient-sequestering factors, which contribute to the host defense of the respiratory tract. Hepcidin is an endogenous peptide hormone that serves as a key regulator of iron metabolism, and ferroportin and ZIP8 are iron transporters. All exhibit innate antimicrobial activity. The purpose of this pilot study is to determine if molecules involved in iron regulation are expressed within sinus epithelia and to compare levels of expression between patients with and without chronic rhinosinusitis (CRS). Sinus mucosa was obtained from patients with (n = 19) and without (n = 14) CRS. Real-time polymerase chain reaction following RNA extraction was used to quantify expression of hepcidin, ferroportin, and ZIP8 mRNA. Hepcidin, ferroportin, and ZIP8 were all detected in the sinus epithelia of patients with and without CRS. However, only ZIP8 was significantly changed in CRS, with a 2.5-fold mean increase in mRNA expression relative to controls ( = .005). These findings suggest that ZIP8 may play a role in the innate epithelial defense of the paranasal sinuses.
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http://dx.doi.org/10.1177/0194599820939910DOI Listing
December 2020

Iron Administration, Infection, and Anemia Management in CKD: Untangling the Effects of Intravenous Iron Therapy on Immunity and Infection Risk.

Kidney Med 2020 May-Jun;2(3):341-353. Epub 2020 Mar 27.

Division of Nephrology, Indiana University Health, Indianapolis, IN.

Patients with chronic kidney disease (CKD) are at increased risk for infection, attributable to immune dysfunction, increased exposure to infectious agents, loss of cutaneous barriers, comorbid conditions, and treatment-related factors (eg, hemodialysis and immunosuppressant therapy). Because iron plays a vital role in pathogen reproduction and host immunity, it is biologically plausible that intravenous iron therapy and/or iron deficiency influence infection risk in CKD. Available data from preclinical experiments, observational studies, and randomized controlled trials are summarized to explore the interplay between intravenous iron and infection risk among patients with CKD, particularly those receiving maintenance hemodialysis. The current evidence base, including data from a recent randomized controlled trial, suggests that proactive judicious use of intravenous iron (in a manner that minimizes the accumulation of non-transferrin-bound iron) beneficially replaces iron stores while avoiding a clinically relevant effect on infection risk. In the absence of an urgent clinical need, intravenous iron therapy should be avoided in patients with active infection. Although serum ferritin concentration and transferrin saturation can help guide clinical decision making about intravenous iron therapy, definition of an optimal iron status and its precise determination in individual patients remain clinically challenging in CKD and warrant additional study.
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http://dx.doi.org/10.1016/j.xkme.2020.01.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7380433PMC
March 2020

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

J Appl Lab Med 2020 09;5(5):943-953

Intrinsic LifeSciences LLC, La Jolla, CA.

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.
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http://dx.doi.org/10.1093/jalm/jfaa038DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7497288PMC
September 2020

The Authors Reply.

Kidney Int Rep 2020 Jul 4;5(7):1119-1120. Epub 2020 May 4.

Veterans Affairs, Greater Los Angeles Healthcare System, Los Angeles, California, USA.

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http://dx.doi.org/10.1016/j.ekir.2020.04.023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7335947PMC
July 2020

Iron overload causes a mild and transient increase in acute lung injury.

Physiol Rep 2020 06;8(12):e14470

Department of Medicine, David Geffen School of Medicine, UCLA, Los Angeles, CA, USA.

Recent studies have demonstrated a strong link between acute respiratory distress syndrome (ARDS) and the levels of iron and iron-related proteins in the lungs. However, the role of iron overload in ARDS development has yet to be characterized. In this study, we compared the highly iron-overloaded hepcidin knockout mice (HKO) to their iron-sufficient wild-type (WT) littermates in a model of sterile acute lung injury (ALI) induced by treatment with oropharyngeal (OP) LPS. There were no major differences in systemic inflammatory response or airway neutrophil infiltration between the two groups at the time of maximal injury (days 2 and 3) or during the recovery phase (day 7). Hepcidin knockout mice had transiently increased bronchoalveolar lavage fluid (BALF) protein and MPO activity in the lung and BALF on day 3, indicating worse vascular leakage and increased neutrophil activity, respectively. The increased ALI severity in iron-overloaded mice may be a result of increased apoptosis of lung tissue, as evidenced by an increase in cleaved capsase-3 protein in lung homogenates from HKO mice versus WT mice on day 3. Altogether, our data suggest that even severe iron overload has a relatively minor and transient effect in LPS-induced ALI.
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http://dx.doi.org/10.14814/phy2.14470DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7322498PMC
June 2020

Maternal hepcidin determines embryo iron homeostasis in mice.

Blood 2020 11;136(19):2206-2216

Center for Iron Disorders, Department of Medicine, David Geffen School of Medicine and.

Iron disorders are associated with adverse pregnancy outcomes, yet iron homeostatic mechanisms during pregnancy are poorly understood. In humans and rodents, the iron-regulatory hormone hepcidin is profoundly decreased in pregnant mothers, which is thought to ensure adequate iron availability for transfer across placenta. However, the fetal liver also produces hepcidin, which may regulate fetal iron endowment by controlling placental iron export. To determine the relative contribution of maternal vs embryo hepcidin to the control of embryo iron endowment in iron-sufficient or iron-overloaded mice, we generated combinations of mothers and embryos that had or lacked hepcidin. We found that maternal, but not embryonic, hepcidin determined embryo and placental iron endowment in a healthy pregnancy. We further determined that inflammation can counteract pregnancy-dependent suppression of maternal hepcidin. To establish how essential maternal hepcidin suppression is for embryo iron homeostasis, we mimicked the range of maternal hepcidin activity by administering a hepcidin peptide mimetic to pregnant mice. This also allowed us to determine the effect of isolated maternal hepcidin excess on pregnancy, in the absence of other confounding effects of inflammation. Higher doses of hepcidin agonist caused maternal iron restriction and anemia, lower placenta and embryo weight, embryo anemia, and increased embryo mortality. Low agonist doses did not cause maternal anemia but still adversely affected the embryo, causing anemia, tissue iron deficiency (including in the brain), and decreased weight. Our studies demonstrate that suppression of maternal hepcidin during pregnancy is essential for maternal and embryo iron homeostasis and health.
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http://dx.doi.org/10.1182/blood.2020005745DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7645983PMC
November 2020

Author Correction: Identification of erythroferrone as an erythroid regulator of iron metabolism.

Nat Genet 2020 Apr;52(4):463

Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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http://dx.doi.org/10.1038/s41588-019-0548-yDOI Listing
April 2020

Drugging erythroferrone to treat anemias.

Authors:
Tomas Ganz

Blood 2020 02;135(8):516-518

University of California, Los Angeles.

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http://dx.doi.org/10.1182/blood.2019004678DOI Listing
February 2020

Fetal and amniotic fluid iron homeostasis in healthy and complicated murine, macaque, and human pregnancy.

JCI Insight 2020 02 27;5(4). Epub 2020 Feb 27.

Center for Iron Disorders, and.

Adequate iron supply during pregnancy is essential for fetal development. However, how fetal or amniotic fluid iron levels are regulated during healthy pregnancy, or pregnancies complicated by intraamniotic infection or inflammation (IAI), is unknown. We evaluated amniotic fluid and fetal iron homeostasis in normal and complicated murine, macaque, and human pregnancy. In mice, fetal iron endowment was affected by maternal iron status, but amniotic fluid iron concentrations changed little during maternal iron deficiency or excess. In murine and macaque models of inflamed pregnancy, the fetus responded to maternal systemic inflammation or IAI by rapidly upregulating hepcidin and lowering iron in fetal blood, without altering amniotic fluid iron. In humans, elevated cord blood hepcidin with accompanying hypoferremia was observed in pregnancies with antenatal exposure to IAI compared with those that were nonexposed. Hepcidin was also elevated in human amniotic fluid from pregnancies with IAI compared with those without IAI, but amniotic fluid iron levels did not differ between the groups. Our studies in mice, macaques, and humans demonstrate that amniotic fluid iron is largely unregulated but that the rapid induction of fetal hepcidin by inflammation and consequent fetal hypoferremia are conserved mechanisms that may be important in fetal host defense.
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http://dx.doi.org/10.1172/jci.insight.135321DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7101151PMC
February 2020

Elevated Fibroblast Growth Factor 23 Levels Are Associated With Greater Diastolic Dysfunction in ESRD.

Kidney Int Rep 2019 Dec 9;4(12):1748-1751. Epub 2019 Aug 9.

Veterans Affairs, Greater Los Angeles Healthcare System, Los Angeles, California, USA.

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http://dx.doi.org/10.1016/j.ekir.2019.07.022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6895593PMC
December 2019

Effects of maternal iron status on placental and fetal iron homeostasis.

J Clin Invest 2020 02;130(2):625-640

Center for Iron Disorders, Department of Medicine, and.

Iron deficiency is common worldwide and is associated with adverse pregnancy outcomes. The increasing prevalence of indiscriminate iron supplementation during pregnancy also raises concerns about the potential adverse effects of iron excess. We examined how maternal iron status affects the delivery of iron to the placenta and fetus. Using mouse models, we documented maternal homeostatic mechanisms that protect the placenta and fetus from maternal iron excess. We determined that under physiological conditions or in iron deficiency, fetal and placental hepcidin did not regulate fetal iron endowment. With maternal iron deficiency, critical transporters mediating placental iron uptake (transferrin receptor 1 [TFR1]) and export (ferroportin [FPN]) were strongly regulated. In mice, not only was TFR1 increased, but FPN was surprisingly decreased to preserve placental iron in the face of fetal iron deficiency. In human placentas from pregnancies with mild iron deficiency, TFR1 was increased, but there was no change in FPN. However, induction of more severe iron deficiency in human trophoblast in vitro resulted in the regulation of both TFR1 and FPN, similar to what was observed in the mouse model. This placental adaptation that prioritizes placental iron is mediated by iron regulatory protein 1 (IRP1) and is important for the maintenance of mitochondrial respiration, thus ultimately protecting the fetus from the potentially dire consequences of generalized placental dysfunction.
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http://dx.doi.org/10.1172/JCI127341DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6994143PMC
February 2020

Anemia of Inflammation.

Authors:
Tomas Ganz

N Engl J Med 2019 Sep;381(12):1148-1157

From the Departments of Medicine and Pathology, David Geffen School of Medicine at UCLA, Los Angeles.

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http://dx.doi.org/10.1056/NEJMra1804281DOI Listing
September 2019

Novel Oral Iron Therapies for Iron Deficiency Anemia in Chronic Kidney Disease.

Adv Chronic Kidney Dis 2019 07;26(4):272-291

David Geffen School of Medicine, UCLA, Los Angeles, CA.

Iron deficiency anemia (IDA) is a frequent complication of chronic kidney disease (CKD) and is associated with adverse outcomes in these patients. Patients with CKD and IDA remain largely undertreated. Conventional oral iron agents are insufficiently effective due to poor absorption and cause gastrointestinal side effects; thus, novel oral iron preparations are needed. This article covers current treatment guidelines for patients with anemia and CKD and clinical trial data for iron-repletion agents currently in use, as well as for novel oral iron therapies in development. Ferric citrate, a novel oral iron-repletion agent approved for patients with non-dialysis-dependent CKD and IDA, demonstrated improvements in hemoglobin levels and iron parameters, with good tolerability in patients with non-dialysis-dependent CKD. When used as a phosphate binder, ferric citrate also improves hemoglobin and iron parameters in dialysis-dependent CKD, but additional trials are needed to evaluate its efficacy as an iron-repletion agent in this setting. Other novel oral iron preparations in development for IDA in patients with CKD include ferric maltol, which is approved in Europe and the United States for IDA in adult patients, and sucrosomial iron, which has been evaluated in IDA associated with CKD and several other clinical settings.
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http://dx.doi.org/10.1053/j.ackd.2019.05.002DOI Listing
July 2019

A variant erythroferrone disrupts iron homeostasis in -mutated myelodysplastic syndrome.

Sci Transl Med 2019 07;11(500)

Université de Paris, Paris 75006, France.

Myelodysplastic syndromes (MDS) with ring sideroblasts are hematopoietic stem cell disorders with erythroid dysplasia and mutations in the splicing factor gene. Patients with MDS with mutations often accumulate excessive tissue iron, even in the absence of transfusions, but the mechanisms that are responsible for their parenchymal iron overload are unknown. Body iron content, tissue distribution, and the supply of iron for erythropoiesis are controlled by the hormone hepcidin, which is regulated by erythroblasts through secretion of the erythroid hormone erythroferrone (ERFE). Here, we identified an alternative transcript in patients with MDS with the mutation. Induction of this transcript in primary -mutated bone marrow erythroblasts generated a variant protein that maintained the capacity to suppress hepcidin transcription. Plasma concentrations of ERFE were higher in patients with MDS with an gene mutation than in patients with wild-type MDS. Thus, hepcidin suppression by a variant ERFE is likely responsible for the increased iron loading in patients with -mutated MDS, suggesting that ERFE could be targeted to prevent iron-mediated toxicity. The expression of the variant transcript that was restricted to -mutated erythroblasts decreased in lenalidomide-responsive anemic patients, identifying variant ERFE as a specific biomarker of clonal erythropoiesis.
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http://dx.doi.org/10.1126/scitranslmed.aav5467DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8005358PMC
July 2019

Glutathione peroxidase 4 and vitamin E control reticulocyte maturation, stress erythropoiesis and iron homeostasis.

Haematologica 2020 04 27;105(4):937-950. Epub 2019 Jun 27.

Institute of Clinical Molecular Biology and Tumor Genetics, Helmholtz Zentrum München, Deutsches Forschungszentrum für Gesundheit und Umwelt (GmbH), München, Germany

Glutathione peroxidase 4 (GPX4) is unique as it is the only enzyme that can prevent detrimental lipid peroxidation by reducing lipid peroxides to the respective alcohols thereby stabilizing oxidation products of unsaturated fatty acids. During reticulocyte maturation, lipid peroxidation mediated by 15-lipoxygenase in humans and rabbits and by 12/15-lipoxygenase (ALOX15) in mice was considered the initiating event for the elimination of mitochondria but is now known to occur through mitophagy. Yet, genetic ablation of the gene in mice failed to provide evidence for this hypothesis. We designed a different genetic approach to tackle this open conundrum. Since either other lipoxygenases or non-enzymatic autooxidative mechanisms may compensate for the loss of , we asked whether ablation of in the hematopoietic system would result in the perturbation of reticulocyte maturation. Quantitative assessment of erythropoiesis indices in the blood, bone marrow (BM) and spleen of chimeric mice with ablated in hematopoietic cells revealed anemia with an increase in the fraction of erythroid precursor cells and reticulocytes. Additional dietary vitamin E depletion strongly aggravated the anemic phenotype. Despite strong extramedullary erythropoiesis reticulocytes failed to mature and accumulated large autophagosomes with engulfed mitochondria. -deficiency in hematopoietic cells led to systemic hepatic iron overload and simultaneous severe iron demand in the erythroid system. Despite extremely high erythropoietin and erythroferrone levels in the plasma, hepcidin expression remained unchanged. Conclusively, perturbed reticulocyte maturation in response to loss in hematopoietic cells thus causes ineffective erythropoiesis, a phenotype partially masked by dietary vitamin E supplementation.
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http://dx.doi.org/10.3324/haematol.2018.212977DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7109755PMC
April 2020

The Discovery of the Iron-Regulatory Hormone Hepcidin.

Authors:
Tomas Ganz

Clin Chem 2019 10 24;65(10):1330-1331. Epub 2019 Jun 24.

Departments of Medicine and Pathology, David Geffen School of Medicine at UCLA, Los Angeles, CA.

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http://dx.doi.org/10.1373/clinchem.2019.306407DOI Listing
October 2019

Mechanism of Action and Clinical Attributes of Auryxia (Ferric Citrate).

Drugs 2019 Jun;79(9):957-968

David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA.

Chronic kidney disease (CKD) is a major cause of morbidity and premature mortality and represents a significant global public health issue. Underlying this burden are the many complications of CKD, including mineral and bone disorders, anemia, and accelerated cardiovascular disease. Hyperphosphatemia and elevated levels of fibroblast growth factor 23 (FGF23) have been identified as key independent risk factors for the adverse cardiovascular outcomes that frequently occur in patients with CKD. Auryxia (ferric citrate; Keryx Biopharmaceuticals, Inc., Boston, MA, USA) is an iron-based compound with distinctive chemical characteristics and a mechanism of action that render it dually effective as a therapy in patients with CKD; it has been approved as a phosphate binder for the control of serum phosphate levels in adult CKD patients treated with dialysis and as an iron replacement product for the treatment of iron deficiency anemia in adult CKD patients not treated with dialysis. This review focuses on Auryxia, its mechanism of action, and the clinical attributes that differentiate it from other, non-pharmaceutical-grade, commercially available forms of ferric citrate and from other commonly used phosphate binder and iron supplement therapies for patients with CKD. Consistent with the chemistry and mechanism of action of Auryxia, multiple clinical studies have demonstrated its efficacy in both lowering serum phosphate levels and improving iron parameters in patients with CKD. Levels of FGF23 decrease significantly with Auryxia treatment, but the effects associated with the cardiovascular system remain to be evaluated in longer-term studies.
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http://dx.doi.org/10.1007/s40265-019-01125-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6562046PMC
June 2019

William Ganz and His Legacy.

Ann Intern Med 2019 05;170(10):734-735

University of California, San Francisco, San Francisco, California (P.G.).

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http://dx.doi.org/10.7326/L19-0033DOI Listing
May 2019