Emrich, Insa E.

Ganz, Tomas

Heine, Gunnar H.

Scheuer, Anja

Wagenpfeil, Stefan

American Journal of Hematology

English

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5. Cheson BD, Bennett JM, Kopecky KJ, et al. Revised recommendations ofthe International Working Group for diagnosis, standardization ofresponse criteria, treatment outcomes, and reporting standards for thera-peutic trials in acute myeloid leukemia. J Clin Oncol. 2003;21:4642-4649.6. Zheng B, Yu SF, Del Rosario G, et al. An anti-CLL-1 antibody-drug con-jugate for the treatment of acute myeloid leukemia. Clin Cancer Res.2019;25:1358-1368.7. Leipold DD, Figueroa I, Masih S, et al. Preclinical pharmacokinetics andpharmacodynamics of DCLL9718A: an antibody-drug conjugate forthe treatment of acute myeloid leukemia. MAbs. 2018;10:1312-1321.8. Saber H, Simpson N, Ricks TK, Leighton JK. An FDA oncology analysisof toxicities associated with PBD-containing antibody-drug conjugates.Regul Toxicol Pharmacol. 2019;107:104429.9. Ngai LL, Ma C, Maguire O, et al. Bimodal expression of potential drugtarget CLL-1 (CLEC12A) on CD34+ blasts of AML patients. Eur J Haem.2021. In press.SUPPORTING INFORMATIONAdditional supporting information may be found online in theSupporting Information section at the end of this article.Received: NaN Month Revised: 13 February 2021 Accepted: 15 February2021DOI: 10.1002/ajh.26130Increase of plasmaerythroferrone levels duringhigh-altitude exposure: A sub-analysis of the TOP OFHOMe studyTo the Editor:In recent years, erythroferrone (ERFE) has been described as the keyendocrine regulator that connects erythropoiesis with iron metabolism.1In animal models, erythropoietin (EPO), which is the main driver oferythropoiesis, will induce ERFE production, which subsequently sup-presses hepcidin synthesis, probably by inhibiting the hepaticBMP/SMAD pathway.1 Low hepcidin itself will allow increased ironrelease from enterocytes and iron-recycling macrophages and thus aug-ment iron availability for erythropoiesis. The same pathways are of clini-cal importance for the pathophysiology of iron disorders in humans,particularly in patients suffering from ineffective erythropoiesis.1However, the specific roles of EPO and ERFE in physiologicalresponses in healthy individuals who are exposed to high-altitude areless well understood.2,3In a field experiment, eight healthy volunteers living in Homburg,Germany (233 meters above sea level [MASL]) spent 4 days at the“Schneefernerhaus” (Garmisch-Partenkirchen, Germany), an environ-mental research station at 2656 MASL. Our study was initially designedto study phosphorus regulation at high-altitude. We thereforerandomized the eight volunteers into two groups, who were subse-quently put either on a normal phosphorus diet (1300–1400 mg phos-phorus/day) or on a low phosphorus diet (700–800 mg phosphorus/day). Detailed information about the project and the baseline character-istics are summarized in an earlier publication of our group, whichfocused upon phosphorus regulation at high-altitude.4 The mean atmo-spheric air pressure at 233 and 2656 MASL is 1012 hPa (212.01 hPaoxygen partial pressure) and 740 hPa (155.03 hPa oxygen partialpressure).Before, during and after high-altitude exposure, blood and urinesamples were collected twice (Time Point [TP] 1–2), seven times(TP 3–9) and three-times (TP 10–12), respectively, for measurementsof plasma ERFE, hepcidin and EPO; at day 2, maximal aerobic exercisewas performed (10 km high-altitude hiking with a total ascent of700 m), directly before TP 6.We discarded the hepcidin, ERFE and EPO measurements afterTP 9 from further analysis, as earlier work from our group suggestedthat a short-term increase in plasma EPO will increase plasma ERFEfor approximately 7 days5; thus, we did not expect plasma ERFE toreturn to baseline values within 48 h (i.e., at TP 10–12) after high-altitude exposure.The study was approved by the local ethics committee and con-ducted in concordance with the Declaration of Helsinki. All partici-pants provided written informed consent.Note, ERFE was measured from plasma samples by an enzyme-linked sandwich immunosorbent assay described previously.5Hepcidin was measured by an enzyme-linked immunosorbent assay(DRG hepcidin 25; DRG International Inc., USA). All other metaboliteswere measured according to the standardized methods of theSaarland University central laboratory.Statistical analyses were performed by SPSS 20. Continuous data arepresented as median (interquartile range [IQR]). Comparison as time prog-ressed was performed by linear mixed model analysis, with prespecifiedtime points as the dependent variable and high-altitude exposure(TP 3–9) versus no high-altitude exposure (TP 1–2) as the independentvariable. Two-sided p values <.05 were considered significant.As shown before, EPO increased compared to baseline (TP 1: 7.12[6.06; 11.36] mIU/mL) soon after arriving at 2656 MASL, reaching itshighest levels at TP 5 (20.80 [17.48; 21.59] mIU/mL). After descendingto 233 MASL, EPO returned to baseline. Plasma hepcidin initiallyincreased from 8.36 [8.03; 22.03] ng/mL to 22.30 [11.03; 44.06] ng/mLat TP 4 and subsequently decreased. Compared to levels measured at233 MASL (TP 1: 2.56 [1.00; 5.88] ng/mL), plasma ERFE successivelyincreased at high altitude, reaching its peak at TP 8 (10.30 [5.87; 17.47]ng/mL) (Figure 1, Table S2), and remaining elevated after a return to lowaltitude until TP 12. Strenuous physical exercise had no immediate effectupon either EPO, hepcidin or ERFE. In subgroup analyses, the changes inERFE were particularly pronounced in individuals randomized to lowphosphorus intake (Tables S1A and S1B).In the linear mixed model analysis, plasma EPO was significantlyassociated with high-altitude exposure (Estimate 7.78 CI [5.59; 9.97];p < .001). Plasma hepcidin, however, showed no association with high-altitude exposure (Estimate 0.52 CI [−5.55; 6.58]; p = .858). WhileCORRESPONDENCE E179plasma ERFE tended to be higher at high-altitude, level of significancewas marginally missed (Estimate 2.06 CI [−0.03; 4.16]; p = .053).In line with previous data by Robach et al.,2 we observed thathigh-altitude exposure will increase plasma ERFE and lower plasmahepcidin. We deliberately chose a more moderate altitude (Robachet al.: 3800 MASL; TOP of HOMe: 2656 MASL) and longer exposure(Robach et al.: 15 h; TOP of HOMe: 4 days). Our findings expand theresults from Robach et al. to more common physiological conditions,as many people are exposed to altitudes of 2700 MASL either pro-fessionally or during their leisure time; moreover, an altitude of2700 MASL corresponds to the air pressure in a commercial airliner.Apparently, such an altitude causes an increase in EPO that is suffi-cient to stimulate ERFE secretion.To our knowledge, the only other study that analyzed the impact ofhigh-altitude exposure on plasma ERFE was reported by Garvican-Lewiset al., who simulated high-altitude exposure during 21 subsequent nights(“live high, train low”).3 In individuals who did not receive additional phar-macological treatment, simulated high-altitude exposure did not augmentplasma ERFE. However, the participants were exposed to simulated highaltitude only for a part of the day, which may explain the findings.3While ERFE may be expressed in skeletal muscles, strenuousmountain hiking did not affect ERFE in our study. These observationsare in agreement with a study of 29 healthy athletes, in whom a mara-thon run did not consistently increase ERFE levels.6As a limitation of this analysis, we cannot provide repetitive measure-ments of parameters of iron metabolism – such as ferritin or transferrinsaturation – or of erythropoiesis – such as hemoglobin, reticulocyte hemo-globin content and reticulocyte counts. Moreover, the study group wasrelatively small, which limits the validity of subgroups analyses.In conclusion, our study expands the observations by Robachet al., as we confirm that high- altitude exposure will raise plasmaERFE not only at very high altitude >3800 m, but also at moder-ate altitude, to which healthy men and women are frequentlyexposed.ACKNOWLEDGMENTSWe thank Martina Wagner and Fabio Lizzi, Universität desSaarlandes Medical Center, for helpful discussion and advice. Theresults presented in this paper have not been published previouslyin whole or part. Open Access funding enabled and organized byProjekt DEAL.CONFLICT OF INTERESTT.G. is a scientific co-founder of Intrinsic LifeSciences and SilarusPharma, consultant for ADARx, Akebia, Pharmacosmos, Ionis, Gossa-mer Bio, Global Blood Therapeutics, American Regent, Disc Medicine,and Rockwell Scientific and inventor on patents related toerythroferrone. I.E.E., A.S., S.W. and G.H.H. have no conflicts ofinterest.PATIENT CONSENT STATEMENTAll participants provided written informed consent.REFERENCES1. Ganz T. Erythropoietic regulators of iron metabolism. Free Rad BiolMed. 2019;133:69-74.2. Robach P, Gammella E, Recalcati S, et al. Induction oferythroferrone in healthy humans by micro-dose recombinanterythropoietin or high-altitude exposure. Haematologica. 2020;106(2):384-390.3. Garvican-Lewis LA, Vuong VL, Govus AD, et al. Intravenous iron doesnot augment the hemoglobin mass response to simulated hypoxia. MedSci Sports Exerc. 2018;50:1669-1678.4. Emrich IE, Dederer J, Kircher A, et al. Does a rise in plasma erythropoi-etin after high-altitude exposure affect FGF23 in healthy volunteers ona normal or low-phosphorus diet? Nutr Metab Cardiovasc Dis. 2019;29(12):1361-1367.5. Ganz T, Jung G, Naeim A, et al. Immunoassay for human serumerythroferrone. Blood. 2017;130:1243-1246.6. Tomczyk M, Kortas J, Flis D, et al. Marathon run-induced changes inthe erythropoietin-erythroferrone-hepcidin axis are iron dependent. IntJ Environ Res Public Health. 2020;17(8):2781.F IGURE 1 Plasma levels oferythroferrone (ERFE), hepcidin anderythropoietin (EPO) at different timepoints: time points one and two at233 MASL, time points 3–9 at 2656MASL. Results are presented as medianE180 CORRESPONDENCESUPPORTING INFORMATIONAdditional supporting information may be found online in theSupporting Information section at the end of this article.DATA AVAILABILITY STATEMENTThe datasets generated and/or analyzed during the current study are notpublicly available due to organizational reasons, but they are availablefrom the corresponding author on reasonable request.Insa E. Emrich1 , Anja Scheuer2, Stefan Wagenpfeil3,Tomas Ganz4 , Gunnar H. Heine2,51Internal Medicine III - Cardiology, Angiology and Intensive CareMedicine, Saarland University Medical Center, Homburg, Germany2Internal Medicine IV – Nephrology and Hypertension, SaarlandUniversity Medical Center, Homburg, Germany3Institute for Medical Biometry, Epidemiology and Medical Informatics,Saarland University Medical Center, Homburg, Germany4Department of Medicine and Pathology, University of California, LosAngeles, California5Ageplesion Markus Krankenhaus, Frankfurt (Main), GermanyCorrespondenceInsa E. Emrich, Internal Medicine III – Cardiology, Angiology andIntensive Care Medicine, Saarland University Medical Center,Homburg, Germany.Email: insa.emrich@uks.euClinical trial registration: Our research work meets the WHO criteriaof clinical trials, and it was published on 14 August 2017 in the Ger-man Clinical Trials Register (registration number: DRKS 000 12 771).ORCIDInsa E. Emrich https://orcid.org/0000-0002-5048-3659Tomas Ganz https://orcid.org/0000-0002-2830-5469CORRESPONDENCE E181

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

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https://publikationen.sulb.uni-saarland.de/bitstream/20.500.11880/32358/1/American%20J%20Hematol%20-%202021%20-%20Emrich%20-%20Increase%20of%20plasma%20erythroferrone%20levels%20during%20high%e2%80%90altitude%20exposure%20%20A%20sub%e2%80%90analysis.pdf

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

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