Association between serum alkaline phosphatase and primary resistance to erythropoiesis stimulating agents in chronic kidney disease

A secondary analysis of the HERO trial

Sunil V. Badve, Lei Zhang, Jeff S. Coombes, Elaine M. Pascoe, Alan Cass, Philip Clarke, Paolo Ferrari, 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, Emmanuel D'Almeida, Rob Fassett, Carl Kirkpatrick & 2 others Richard Phoon, On behalf of the HERO Study Collaborative Group

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Abstract

Background: Erythropoiesis stimulating agent (ESA)-resistant anemia is common in chronic kidney disease (CKD). Objectives: To evaluate the determinants of severity of ESA resistance in patients with CKD and primary ESA-resistance. 

Design: Secondary analysis of a randomized controlled trial (the Handling Erythropoietin Resistance with Oxpentifylline, HERO) 

Setting and patients: 53 adult patients with CKD stage 4 or 5 and primary ESA-resistant anemia (hemoglobin ≤120g/L, ESA resistance index [ERI] ≥1.0IU/kg/week/gHb for erythropoietin or ≥0.005μg/kg/week/gHb for darbepoeitin, no cause for ESA-resistance identified). 

Measurements: Iron studies, parathyroid hormone, albumin, liver enzymes, phosphate or markers of oxidative stress and inflammation. 

Methods: Participants were divided into tertiles of ERI. Multinomial logistic regression was used to analyse the determinants of ERI tertiles. 

Results: All patients, except one, were receiving dialysis for end-stage kidney disease. The mean±SD ERI values in the low (n=18), medium (n=18) and high (n=17) ERI tertiles were 1.4±0.3, 2.3±0.2 and 3.5±0.8IU/kg/week/gHb, respectively (P<0.001). There were no significant differences observed in age, gender, ethnicity, cause of kidney disease, diabetes, iron studies, parathyroid hormone, albumin, liver enzymes, phosphate or markers of oxidative stress and inflammation between the ERI tertiles. The median [inter-quartile range] serum alkaline phosphatase concentrations in the low, medium and high ERI tertiles were 89 [64,121], 99 [76,134 and 148 [87,175] U/L, respectively (P=0.054). There was a weak but statistically significant association between ERI and serum alkaline phosphatase (R2=0.06, P=0.03). Using multinomial logistic regression, the risk of being in the high ERI tertile relative to the low ERI tertile increased with increasing serum alkaline phosphatase levels (P=0.02). No other variables were significantly associated with ERI. 

Limitations: Small sample size; bone-specific alkaline phosphatase, other markers of bone turnover and bone biopsies not evaluated. 

Conclusions: Serum alkaline phosphatase was associated with severity of ESA resistance in ESA-resistant patients with CKD. Large prospective studies are required to confirm this association. 

Original languageEnglish
Article number33
Pages (from-to)1-10
Number of pages10
JournalCanadian Journal of Kidney Health and Disease
Volume2
DOIs
Publication statusPublished - 18 Aug 2015

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Hematinics
Pentoxifylline
Erythropoietin
Chronic Renal Insufficiency
Alkaline Phosphatase
Serum
Parathyroid Hormone
Anemia
Albumins
Oxidative Stress
Iron
Logistic Models
Phosphates
Inflammation
Bone and Bones
Bone Remodeling
Liver
Kidney Diseases
Enzymes
Sample Size

Cite this

Badve, Sunil V. ; Zhang, Lei ; Coombes, Jeff S. ; Pascoe, Elaine M. ; Cass, Alan ; Clarke, Philip ; Ferrari, Paolo ; 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. ; D'Almeida, Emmanuel ; Fassett, Rob ; Kirkpatrick, Carl ; Phoon, Richard ; On behalf of the HERO Study Collaborative Group. / Association between serum alkaline phosphatase and primary resistance to erythropoiesis stimulating agents in chronic kidney disease : A secondary analysis of the HERO trial. In: Canadian Journal of Kidney Health and Disease. 2015 ; Vol. 2. pp. 1-10.
@article{1658013a0be34d84b47929b1ac1fff27,
title = "Association between serum alkaline phosphatase and primary resistance to erythropoiesis stimulating agents in chronic kidney disease: A secondary analysis of the HERO trial",
abstract = "Background: Erythropoiesis stimulating agent (ESA)-resistant anemia is common in chronic kidney disease (CKD). Objectives: To evaluate the determinants of severity of ESA resistance in patients with CKD and primary ESA-resistance. Design: Secondary analysis of a randomized controlled trial (the Handling Erythropoietin Resistance with Oxpentifylline, HERO) Setting and patients: 53 adult patients with CKD stage 4 or 5 and primary ESA-resistant anemia (hemoglobin ≤120g/L, ESA resistance index [ERI] ≥1.0IU/kg/week/gHb for erythropoietin or ≥0.005μg/kg/week/gHb for darbepoeitin, no cause for ESA-resistance identified). Measurements: Iron studies, parathyroid hormone, albumin, liver enzymes, phosphate or markers of oxidative stress and inflammation. Methods: Participants were divided into tertiles of ERI. Multinomial logistic regression was used to analyse the determinants of ERI tertiles. Results: All patients, except one, were receiving dialysis for end-stage kidney disease. The mean±SD ERI values in the low (n=18), medium (n=18) and high (n=17) ERI tertiles were 1.4±0.3, 2.3±0.2 and 3.5±0.8IU/kg/week/gHb, respectively (P<0.001). There were no significant differences observed in age, gender, ethnicity, cause of kidney disease, diabetes, iron studies, parathyroid hormone, albumin, liver enzymes, phosphate or markers of oxidative stress and inflammation between the ERI tertiles. The median [inter-quartile range] serum alkaline phosphatase concentrations in the low, medium and high ERI tertiles were 89 [64,121], 99 [76,134 and 148 [87,175] U/L, respectively (P=0.054). There was a weak but statistically significant association between ERI and serum alkaline phosphatase (R2=0.06, P=0.03). Using multinomial logistic regression, the risk of being in the high ERI tertile relative to the low ERI tertile increased with increasing serum alkaline phosphatase levels (P=0.02). No other variables were significantly associated with ERI. Limitations: Small sample size; bone-specific alkaline phosphatase, other markers of bone turnover and bone biopsies not evaluated. Conclusions: Serum alkaline phosphatase was associated with severity of ESA resistance in ESA-resistant patients with CKD. Large prospective studies are required to confirm this association. ",
keywords = "Alkaline phosphatase, Anemia, Biological marker, Chronic kidney disease, Erythropoiesis stimulating agents, Randomized controlled trial, Risk factors",
author = "Badve, {Sunil V.} and Lei Zhang and Coombes, {Jeff S.} and Pascoe, {Elaine M.} and Alan Cass and Philip Clarke and Paolo Ferrari 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 Emmanuel D'Almeida and Rob Fassett and Carl Kirkpatrick and Richard Phoon and {On behalf of the HERO Study Collaborative Group}",
year = "2015",
month = "8",
day = "18",
doi = "10.1186/s40697-015-0066-5",
language = "English",
volume = "2",
pages = "1--10",
journal = "Canadian Journal of Kidney Health and Disease",
issn = "2054-3581",
publisher = "BioMed Central",

}

Badve, SV, Zhang, L, Coombes, JS, Pascoe, EM, Cass, A, Clarke, P, Ferrari, P, McDonald, SP, Morrish, AT, Pedagogos, E, Perkovic, V, Reidlinger, D, Scaria, A, Walker, R, Vergara, LA, Hawley, CM, Johnson, DW, D'Almeida, E, Fassett, R, Kirkpatrick, C, Phoon, R & On behalf of the HERO Study Collaborative Group 2015, 'Association between serum alkaline phosphatase and primary resistance to erythropoiesis stimulating agents in chronic kidney disease: A secondary analysis of the HERO trial', Canadian Journal of Kidney Health and Disease, vol. 2, 33, pp. 1-10. https://doi.org/10.1186/s40697-015-0066-5

Association between serum alkaline phosphatase and primary resistance to erythropoiesis stimulating agents in chronic kidney disease : A secondary analysis of the HERO trial. / Badve, Sunil V.; Zhang, Lei; Coombes, Jeff S.; Pascoe, Elaine M.; Cass, Alan; Clarke, Philip; Ferrari, Paolo; 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.; D'Almeida, Emmanuel; Fassett, Rob; Kirkpatrick, Carl; Phoon, Richard; On behalf of the HERO Study Collaborative Group.

In: Canadian Journal of Kidney Health and Disease, Vol. 2, 33, 18.08.2015, p. 1-10.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

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

T2 - A secondary analysis of the HERO trial

AU - Badve, Sunil V.

AU - Zhang, Lei

AU - Coombes, Jeff S.

AU - Pascoe, Elaine M.

AU - Cass, Alan

AU - Clarke, Philip

AU - Ferrari, Paolo

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 - D'Almeida, Emmanuel

AU - Fassett, Rob

AU - Kirkpatrick, Carl

AU - Phoon, Richard

AU - On behalf of the HERO Study Collaborative Group

PY - 2015/8/18

Y1 - 2015/8/18

N2 - Background: Erythropoiesis stimulating agent (ESA)-resistant anemia is common in chronic kidney disease (CKD). Objectives: To evaluate the determinants of severity of ESA resistance in patients with CKD and primary ESA-resistance. Design: Secondary analysis of a randomized controlled trial (the Handling Erythropoietin Resistance with Oxpentifylline, HERO) Setting and patients: 53 adult patients with CKD stage 4 or 5 and primary ESA-resistant anemia (hemoglobin ≤120g/L, ESA resistance index [ERI] ≥1.0IU/kg/week/gHb for erythropoietin or ≥0.005μg/kg/week/gHb for darbepoeitin, no cause for ESA-resistance identified). Measurements: Iron studies, parathyroid hormone, albumin, liver enzymes, phosphate or markers of oxidative stress and inflammation. Methods: Participants were divided into tertiles of ERI. Multinomial logistic regression was used to analyse the determinants of ERI tertiles. Results: All patients, except one, were receiving dialysis for end-stage kidney disease. The mean±SD ERI values in the low (n=18), medium (n=18) and high (n=17) ERI tertiles were 1.4±0.3, 2.3±0.2 and 3.5±0.8IU/kg/week/gHb, respectively (P<0.001). There were no significant differences observed in age, gender, ethnicity, cause of kidney disease, diabetes, iron studies, parathyroid hormone, albumin, liver enzymes, phosphate or markers of oxidative stress and inflammation between the ERI tertiles. The median [inter-quartile range] serum alkaline phosphatase concentrations in the low, medium and high ERI tertiles were 89 [64,121], 99 [76,134 and 148 [87,175] U/L, respectively (P=0.054). There was a weak but statistically significant association between ERI and serum alkaline phosphatase (R2=0.06, P=0.03). Using multinomial logistic regression, the risk of being in the high ERI tertile relative to the low ERI tertile increased with increasing serum alkaline phosphatase levels (P=0.02). No other variables were significantly associated with ERI. Limitations: Small sample size; bone-specific alkaline phosphatase, other markers of bone turnover and bone biopsies not evaluated. Conclusions: Serum alkaline phosphatase was associated with severity of ESA resistance in ESA-resistant patients with CKD. Large prospective studies are required to confirm this association. 

AB - Background: Erythropoiesis stimulating agent (ESA)-resistant anemia is common in chronic kidney disease (CKD). Objectives: To evaluate the determinants of severity of ESA resistance in patients with CKD and primary ESA-resistance. Design: Secondary analysis of a randomized controlled trial (the Handling Erythropoietin Resistance with Oxpentifylline, HERO) Setting and patients: 53 adult patients with CKD stage 4 or 5 and primary ESA-resistant anemia (hemoglobin ≤120g/L, ESA resistance index [ERI] ≥1.0IU/kg/week/gHb for erythropoietin or ≥0.005μg/kg/week/gHb for darbepoeitin, no cause for ESA-resistance identified). Measurements: Iron studies, parathyroid hormone, albumin, liver enzymes, phosphate or markers of oxidative stress and inflammation. Methods: Participants were divided into tertiles of ERI. Multinomial logistic regression was used to analyse the determinants of ERI tertiles. Results: All patients, except one, were receiving dialysis for end-stage kidney disease. The mean±SD ERI values in the low (n=18), medium (n=18) and high (n=17) ERI tertiles were 1.4±0.3, 2.3±0.2 and 3.5±0.8IU/kg/week/gHb, respectively (P<0.001). There were no significant differences observed in age, gender, ethnicity, cause of kidney disease, diabetes, iron studies, parathyroid hormone, albumin, liver enzymes, phosphate or markers of oxidative stress and inflammation between the ERI tertiles. The median [inter-quartile range] serum alkaline phosphatase concentrations in the low, medium and high ERI tertiles were 89 [64,121], 99 [76,134 and 148 [87,175] U/L, respectively (P=0.054). There was a weak but statistically significant association between ERI and serum alkaline phosphatase (R2=0.06, P=0.03). Using multinomial logistic regression, the risk of being in the high ERI tertile relative to the low ERI tertile increased with increasing serum alkaline phosphatase levels (P=0.02). No other variables were significantly associated with ERI. Limitations: Small sample size; bone-specific alkaline phosphatase, other markers of bone turnover and bone biopsies not evaluated. Conclusions: Serum alkaline phosphatase was associated with severity of ESA resistance in ESA-resistant patients with CKD. Large prospective studies are required to confirm this association. 

KW - Alkaline phosphatase

KW - Anemia

KW - Biological marker

KW - Chronic kidney disease

KW - Erythropoiesis stimulating agents

KW - Randomized controlled trial

KW - Risk factors

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U2 - 10.1186/s40697-015-0066-5

DO - 10.1186/s40697-015-0066-5

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EP - 10

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JF - Canadian Journal of Kidney Health and Disease

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