Association between serum alkaline phosphatase and primary resistance to erythropoiesis stimulating agents in chronic kidney disease: a secondary analysis of the HERO trial.
BACKGROUND
Erythropoiesis stimulating agent (ESA)-resistant anemia is common in chronic kidney disease (CKD).


OBJECTIVE
To evaluate the determinants of severity of ESA resistance in patients with CKD and primary ESA-resistance.


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


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


METHODS
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 ± 0.8 IU/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 (R(2) = 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.


CONCLUSIONS
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. (


BACKGROUND
Australian New Zealand Clinical Trials Registry 12608000199314).
Australasian Kidney Trials Network, University of Queensland, Brisbane, Australia ; Department of Nephrology, Princess Alexandra Hospital, Brisbane, Australia ; Department of Nephrology, Level 2, ARTS Building, Princess Alexandra Hospital, Ipswich Road, Woolloongabba, Queensland 4102 Australia.
Sunil V
SV
Badve
Australasian Kidney Trials Network, University of Queensland, Brisbane, Australia ; Department of Nephrology, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, China.
Lei
L
Zhang
School of Human Movement Studies, University of Queensland, Brisbane, Australia.
Jeff S
JS
Coombes
Australasian Kidney Trials Network, University of Queensland, Brisbane, Australia.
Elaine M
EM
Pascoe
Australasian Kidney Trials Network, University of Queensland, Brisbane, Australia ; Menzies School of Health Research, Darwin, Australia.
Alan
A
Cass
Centre for Health Policy, Programs & Economics, University of Melbourne, Melbourne, Australia.
Philip
P
Clarke
Department of Nephrology, Prince of Wales Hospital, Sydney, Australia.
Paolo
P
Ferrari
Department of Nephrology and Transplantation Services, University of Adelaide at Central Northern Adelaide Renal and Transplantation Services, Adelaide, Australia.
Stephen P
SP
McDonald
Australasian Kidney Trials Network, University of Queensland, Brisbane, Australia.
Alicia T
AT
Morrish
Department of Nephrology, Royal Melbourne Hospital, Melbourne, Australia.
Eugenie
E
Pedagogos
Australasian Kidney Trials Network, University of Queensland, Brisbane, Australia ; The George Institute for Global Health, Sydney, Australia.
Vlado
V
Perkovic
Australasian Kidney Trials Network, University of Queensland, Brisbane, Australia.
Donna
D
Reidlinger
Australasian Kidney Trials Network, University of Queensland, Brisbane, Australia.
Anish
A
Scaria
Department of Renal Medicine, The Alfred Hospital, Melbourne, Australia.
Rowan
R
Walker
Australasian Kidney Trials Network, University of Queensland, Brisbane, Australia.
Liza A
LA
Vergara
Australasian Kidney Trials Network, University of Queensland, Brisbane, Australia ; Department of Nephrology, Princess Alexandra Hospital, Brisbane, Australia.
Carmel M
CM
Hawley
Australasian Kidney Trials Network, University of Queensland, Brisbane, Australia ; Department of Nephrology, Princess Alexandra Hospital, Brisbane, Australia.
David W
DW
Johnson
Alkaline phosphatase; Anemia; Biological marker; Chronic kidney disease; Erythropoiesis stimulating agents; Randomized controlled trial; Risk factors