title: Association between serum hepcidin-25 and primary resistance to erythropoiesis-stimulating agents in chronic kidney disease: a secondary analysis of the HERO trial.
abstract: BACKGROUND
  Pentoxifylline has been shown to increase haemoglobin levels in patients with chronic kidney disease (CKD) and erythropoietin-stimulating agent (ESA)-hyporesponsive anaemia in the Handling Erythropoietin Resistance with Oxpentifylline multicentre double-blind, randomized controlled trial. The present sub-study evaluated the effects of pentoxifylline on the iron-regulatory hormone hepcidin in patients with ESA-hyporesponsive CKD.
  
  
  METHODS
  This sub-study included 13 patients in the pentoxifylline arm (400 mg daily) and 13 in the matched placebo arm. Hepcidin-25 was measured by ultra performance liquid chromatography/quadrupole time-of-flight mass spectrometry following isolation from patient serum. Serum hepcidin-25, serum iron biomarkers, haemoglobin and ESA dosage were compared within and between the two groups.
  
  
  RESULTS
  Hepcidin-25 concentration at 4 months adjusted for baseline did not differ significantly in pentoxifylline versus placebo treated patients (adjusted mean difference (MD) -7.9 nmol, P = 0.114), although the difference between the groups mean translated into a >25% reduction of circulating hepcidin-25 due to pentoxifylline compared with the placebo baseline. In paired analysis, serum hepcidin-25 levels were significantly decreased at 4 months compared with baseline in the pentoxifylline group (-5.47 ± 2.27 nmol/l, P < 0.05) but not in the placebo group (2.82 ± 4.29 nmol/l, P = 0.24). Pentoxifylline did not significantly alter serum ferritin (MD 55.4 mcg/l), transferrin saturation (MD 4.04%), the dosage of ESA (MD -9.93 U/kg per week) or haemoglobin concentration (MD 5.75 g/l).
  
  
  CONCLUSIONS
  The reduction of circulating hepcidin-25 due to pentoxifylline did not reach statistical significance; however, the magnitude of the difference suggests that pentoxifylline may be a clinically and biologically meaningful modulator of hepcidin-25 in dialysis of patients with ESA-hyporesponsive anaemia.
authors.affiliation: Separation Science and Metabolomics Laboratory and Metabolomics Australia, Murdoch University Node, Perth, Australia.
authors.forename: Joel
authors.initials: J
authors.lastname: Gummer
authors.affiliation: Separation Science and Metabolomics Laboratory and Metabolomics Australia, Murdoch University Node, Perth, Australia.
authors.forename: Robert
authors.initials: R
authors.lastname: Trengove
authors.affiliation: Australasian Kidney Trials Network, University of Queensland, Brisbane, Australia.
authors.forename: Elaine M
authors.initials: EM
authors.lastname: Pascoe
authors.affiliation: Australasian Kidney Trials Network, University of Queensland, Brisbane, Australia.|Department of Nephrology, St George Hospital, Sydney, Australia.
authors.forename: Sunil V
authors.initials: SV
authors.lastname: Badve
authors.affiliation: Australasian Kidney Trials Network, University of Queensland, Brisbane, Australia.|Menzies School of Health Research, Darwin, Australia.
authors.forename: Alan
authors.initials: A
authors.lastname: Cass
authors.affiliation: Centre for Health Policy, Programs and Economics, University of Melbourne, Melbourne, Australia.
authors.forename: Philip
authors.initials: P
authors.lastname: Clarke
authors.affiliation: Department of Nephrology and Transplantation Services, University of Adelaide at Central Northern Adelaide Renal and Transplantation Services, Adelaide, Australia.
authors.forename: Stephen P
authors.initials: SP
authors.lastname: McDonald
authors.affiliation: Australasian Kidney Trials Network, University of Queensland, Brisbane, Australia.
authors.forename: Alicia T
authors.initials: AT
authors.lastname: Morrish
authors.affiliation: Department of Nephrology, Royal Melbourne Hospital, Melbourne, Australia.
authors.forename: Eugenie
authors.initials: E
authors.lastname: Pedagogos
authors.affiliation: Australasian Kidney Trials Network, University of Queensland, Brisbane, Australia.|The George Institute for Global Health, Sydney, Australia.
authors.forename: Vlado
authors.initials: V
authors.lastname: Perkovic
authors.affiliation: Australasian Kidney Trials Network, University of Queensland, Brisbane, Australia.
authors.forename: Donna
authors.initials: D
authors.lastname: Reidlinger
authors.affiliation: Australasian Kidney Trials Network, University of Queensland, Brisbane, Australia.
authors.forename: Anish
authors.initials: A
authors.lastname: Scaria
authors.affiliation: Department of Renal Medicine, The Alfred Hospital, Melbourne, Australia.
authors.forename: Rowan
authors.initials: R
authors.lastname: Walker
authors.affiliation: Australasian Kidney Trials Network, University of Queensland, Brisbane, Australia.
authors.forename: Liza A
authors.initials: LA
authors.lastname: Vergara
authors.affiliation: Australasian Kidney Trials Network, University of Queensland, Brisbane, Australia.|Department of Nephrology, Princess Alexandra Hospital, Brisbane, Australia.
authors.forename: Carmel M
authors.initials: CM
authors.lastname: Hawley
authors.affiliation: Australasian Kidney Trials Network, University of Queensland, Brisbane, Australia.|Department of Nephrology, Princess Alexandra Hospital, Brisbane, Australia.
authors.forename: David W
authors.initials: DW
authors.lastname: Johnson
authors.affiliation: Department of Gastroenterology, Fremantle and Fiona Stanley Hospitals, Perth, Australia.|School of Veterinary Sciences, Murdoch University, Perth, Australia.|School of Biomedical Sciences and Curtin Health Innovation Research Institute, Curtin University, Perth, Australia.
authors.forename: John K
authors.initials: JK
authors.lastname: Olynyk
authors.affiliation: Department of Nephrology, Prince of Wales Hospital, Sydney, Australia.|Clinical School, University of New South Wales, Sydney, Australia.
authors.forename: Paolo
authors.initials: P
authors.lastname: Ferrari
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000740:Anemia / Q000097:blood / Q000175:diagnosis / Q000188:drug therapy*; D015415:Biomarkers / Q000097:blood; D000068256:Darbepoetin alfa / Q000009:adverse effects / Q000627:therapeutic use*; D004311:Double-Blind Method; D004351:Drug Resistance; D004920:Erythropoiesis / Q000187:drug effects*; D005260:Female; D006397:Hematinics / Q000009:adverse effects / Q000627:therapeutic use*; D006454:Hemoglobins / Q000378:metabolism; D064451:Hepcidins / Q000097:blood*; D006801:Humans; D007501:Iron / Q000097:blood; D008297:Male; D008875:Middle Aged; D010431:Pentoxifylline / Q000009:adverse effects / Q000627:therapeutic use*; D051436:Renal Insufficiency, Chronic / Q000097:blood / Q000175:diagnosis / Q000628:therapy*; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D015415:Biomarkers; D006397:Hematinics; D006454:Hemoglobins; D064451:Hepcidins; C545475:hepcidin 25, human; D000068256:Darbepoetin alfa; D007501:Iron; D010431:Pentoxifylline
keywords: anaemia; chronic kidney disease; erythropoiesis stimulating agents; hepcidin-25; randomised controlled trial