Association between serum hepcidin-25 and primary resistance to erythropoiesis-stimulating agents in chronic kidney disease: a secondary analysis of the HERO trial

Joel Gummer, Robert Trengove, Elaine M. Pascoe, Sunil V. Badve, Alan Cass, Philip Clarke, Stephen P. McDonald, Alicia T. Morrish, Eugenie Pedagogos, Vlado Perkovic, Donna Reidlinger, Anish Scaria, Rowan Walker, Liza A. Vergara, Carmel M. Hawley, David W. Johnson, John K. Olynyk, Paolo Ferrari, on behalf of the HERO Study Collaborative Group

Research output: Contribution to journalArticle

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).

Conclusion: 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.

LanguageEnglish
Pages548-554
Number of pages7
JournalNephrology
Volume22
Issue number7
DOIs
StatePublished - 1 Jul 2017

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Hematinics
Hepcidins
Pentoxifylline
Chronic Renal Insufficiency
Erythropoietin
Serum
Placebos
Hemoglobins
Anemia
Iron
Patient Isolation
Transferrin
Ferritins
Liquid Chromatography
Dialysis
Mass Spectrometry
Randomized Controlled Trials
Biomarkers
Hormones

Cite this

Gummer, J., Trengove, R., Pascoe, E. M., Badve, S. V., Cass, A., Clarke, P., ... on behalf of the HERO Study Collaborative Group (2017). Association between serum hepcidin-25 and primary resistance to erythropoiesis-stimulating agents in chronic kidney disease: a secondary analysis of the HERO trial. Nephrology, 22(7), 548-554. DOI: 10.1111/nep.12815
Gummer, Joel ; Trengove, Robert ; Pascoe, Elaine M. ; Badve, Sunil V. ; Cass, Alan ; Clarke, Philip ; McDonald, Stephen P. ; Morrish, Alicia T. ; Pedagogos, Eugenie ; Perkovic, Vlado ; Reidlinger, Donna ; Scaria, Anish ; Walker, Rowan ; Vergara, Liza A. ; Hawley, Carmel M. ; Johnson, David W. ; Olynyk, John K. ; Ferrari, Paolo ; on behalf of the HERO Study Collaborative Group. / Association between serum hepcidin-25 and primary resistance to erythropoiesis-stimulating agents in chronic kidney disease : a secondary analysis of the HERO trial. In: Nephrology. 2017 ; Vol. 22, No. 7. pp. 548-554
@article{868b3b774e7c48888976d283d5bebe18,
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). Conclusion: 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.",
keywords = "anaemia, chronic kidney disease, erythropoiesis stimulating agents, hepcidin-25, randomised controlled trial",
author = "Joel Gummer and Robert Trengove and Pascoe, {Elaine M.} and Badve, {Sunil V.} and Alan Cass and Philip Clarke and McDonald, {Stephen P.} and Morrish, {Alicia T.} and Eugenie Pedagogos and Vlado Perkovic and Donna Reidlinger and Anish Scaria and Rowan Walker and Vergara, {Liza A.} and Hawley, {Carmel M.} and Johnson, {David W.} and Olynyk, {John K.} and Paolo Ferrari and {on behalf of the HERO Study Collaborative Group}",
year = "2017",
month = "7",
day = "1",
doi = "10.1111/nep.12815",
language = "English",
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pages = "548--554",
journal = "Nephrology",
issn = "1320-5358",
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Gummer, J, Trengove, R, Pascoe, EM, Badve, SV, Cass, A, Clarke, P, McDonald, SP, Morrish, AT, Pedagogos, E, Perkovic, V, Reidlinger, D, Scaria, A, Walker, R, Vergara, LA, Hawley, CM, Johnson, DW, Olynyk, JK, Ferrari, P & on behalf of the HERO Study Collaborative Group 2017, 'Association between serum hepcidin-25 and primary resistance to erythropoiesis-stimulating agents in chronic kidney disease: a secondary analysis of the HERO trial' Nephrology, vol 22, no. 7, pp. 548-554. DOI: 10.1111/nep.12815

Association between serum hepcidin-25 and primary resistance to erythropoiesis-stimulating agents in chronic kidney disease : a secondary analysis of the HERO trial. / Gummer, Joel; Trengove, Robert; Pascoe, Elaine M.; Badve, Sunil V.; Cass, Alan; Clarke, Philip; McDonald, Stephen P.; Morrish, Alicia T.; Pedagogos, Eugenie; Perkovic, Vlado; Reidlinger, Donna; Scaria, Anish; Walker, Rowan; Vergara, Liza A.; Hawley, Carmel M.; Johnson, David W.; Olynyk, John K.; Ferrari, Paolo; on behalf of the HERO Study Collaborative Group.

In: Nephrology, Vol. 22, No. 7, 01.07.2017, p. 548-554.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Association between serum hepcidin-25 and primary resistance to erythropoiesis-stimulating agents in chronic kidney disease

T2 - Nephrology

AU - Gummer,Joel

AU - Trengove,Robert

AU - Pascoe,Elaine M.

AU - Badve,Sunil V.

AU - Cass,Alan

AU - Clarke,Philip

AU - McDonald,Stephen P.

AU - Morrish,Alicia T.

AU - Pedagogos,Eugenie

AU - Perkovic,Vlado

AU - Reidlinger,Donna

AU - Scaria,Anish

AU - Walker,Rowan

AU - Vergara,Liza A.

AU - Hawley,Carmel M.

AU - Johnson,David W.

AU - Olynyk,John K.

AU - Ferrari,Paolo

AU - on behalf of the HERO Study Collaborative Group

PY - 2017/7/1

Y1 - 2017/7/1

N2 - 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). Conclusion: 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.

AB - 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). Conclusion: 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.

KW - anaemia

KW - chronic kidney disease

KW - erythropoiesis stimulating agents

KW - hepcidin-25

KW - randomised controlled trial

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U2 - 10.1111/nep.12815

DO - 10.1111/nep.12815

M3 - Article

VL - 22

SP - 548

EP - 554

JO - Nephrology

JF - Nephrology

SN - 1320-5358

IS - 7

ER -