Impact of serum hepcidin and inflammatory markers on resistance to erythropoiesis-stimulating therapy in haemodialysis patients

Sewefy, D A El; Farweez, Botheina Ahmed Thabet; Behairy, Maha; Yassin, N.

doi:10.1007/s11255-018-2062-z

Cited by 13 publications

(22 citation statements)

References 57 publications

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“…28 Higher serum hepcidin levels, along with higher levels of inflammatory markers, such as C-reactive protein and interleukin-6, are frequently observed in patients on hemodialysis compared with healthy controls. 54,55 In patients with NDD CKD, serum hepcidin levels were not associated with anemia in patients with earlier stages of CKD, but serum hepcidin was significantly associated with anemia in patients with later stages of CKD. 56 Reduced renal excretion of hepcidin has been observed in patients with CKD, which may also contribute to the higher observed hepcidin levels.…”

Section: Iron Deficiency In Patients With Anemia Of Ckdmentioning

confidence: 99%

Iron metabolism and management: focus on chronic kidney disease

Agarwal

2021

Kidney International Supplements

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Anemia is common in patients with chronic kidney disease (CKD) and results from the dysregulation of iron metabolism and erythropoiesis. Hepcidin is a key regulator of iron availability and leads to iron sequestration during the state of iron repletion. Decreases in the level of hepcidin in the presence of hypoxia and/or iron limitation allow for greater iron availability for erythropoiesis. However, kidney excretion of hepcidin decreases as the severity of CKD increases, whereas production of hepcidin is increased under inflammatory conditions often present in patients with CKD, both of which contribute to anemia. Assessment of iron status is, therefore, essential in the treatment of anemia. However, current laboratory tests for the determination of the adequate supply of iron have many limitations, including diurnal variation in the levels of biomarkers, lack of standardized reference methods across laboratories, and confounding by the presence of inflammation. In addition, the current treatment paradigm for anemia of CKD can further disrupt iron homeostasis; for example, treatment with erythropoiesis-stimulating agents in the absence of supplemental iron can induce functional iron deficiency. Moreover, supplemental iron can further increase levels of hepcidin. Several novel therapies, including hypoxia-inducible factor prolyl hydroxylase inhibitors and hepcidin inhibitors/antagonists, have shown promise in attenuating the levels and/or activity of hepcidin in anemia of CKD, thus ensuring the availability of iron for erythropoiesis.

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Section: Iron Deficiency In Patients With Anemia Of Ckdmentioning

confidence: 99%

Iron metabolism and management: focus on chronic kidney disease

Agarwal

2021

Kidney International Supplements

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“…Also, Ashby et al reported that ESAs decreased hepcidin levels in HD patients, as measured by applying a radioimmunoassay for total hepcidin [14]. Conversely, El Sewefy et al concluded that hepcidin was a predictor of ESAs hyporesponsiveness after using an enzyme‐linked immunoassay for total hepcidin measurement [24]. The noteworthy discrepancies between our results and the observation of Ashby et al and El Sewefy et al might be partially explained by the exploitation of different methods that measure either total hepcidin or the bioactive isoform of hepcidin.…”

Section: Discussionmentioning

confidence: 99%

Factors associated with hepcidin‐25 levels in maintenance hemodialysis patients

2021

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This study aimed to investigate the factors that are independently associated with hepcidin-25 and its relationship with doses of erythropoiesis-stimulating agents (ESAs) and intravenous iron in stable maintenance hemodialysis patients (smHD) stratified by ESAs administration. In 103 adult smHD (ESAs therapy (N = 64) and ESAs-free (N = 39)), median values of biologically active hepcidin-25 (chemiluminescent direct ELISA assay) and ferritin levels were significantly higher whereas red blood cell count, hemoglobin, and hematocrit values were lower in ESAs therapy compared to ESAs-free group (P < .001, for all). Our results suggest that ESAs-independent smHD exhibit supposedly normal hepcidin-25 levels and preserved iron homeostasis, with a lower degree of anemia. The results of our multivariable model indicate that hepcidin-25 levels are independently and positively associated with iron stores and inflammation, and inversely with active erythropoiesis, regardless of ESAs administration.Maintenance ESAs and the intravenous iron dose were not related to hepcidin-25 levels.

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“…In patients with NDD-CKD, a positive correlation was shown between hepcidin level and ESA dose [51], and between hepcidin and the ESA response index (ERI, the average ratio of weight-adjusted ESA dose to Hb used as a measure of ESA hyporesponse; Table 1) [52]. Interestingly, markers of inflammation are also correlated with ESA resistance and anemia [27,[52][53][54][55][56]. IL-6 and C-reactive protein (CRP) levels are significantly higher in patients who are hyporesponsive to ESAs [53,57], and IL-6 levels are a strong predictor of ESA resistance in patients on hemodialysis [57].…”

Section: Inflammationmentioning

confidence: 99%

“…IL-6 and C-reactive protein (CRP) levels are significantly higher in patients who are hyporesponsive to ESAs [53,57], and IL-6 levels are a strong predictor of ESA resistance in patients on hemodialysis [57]. Moreover, in a recent study, patients on hemodialysis in the highest tertile of ERI had higher mean IL-6, high-sensitivity (hs) CRP, ferritin, and hepcidin levels and lower Hb levels, RBC counts, and hematocrit than patients in lower tertiles [56].…”

Section: Inflammationmentioning

confidence: 99%

Managing Anemia across the Stages of Kidney Disease in Those Hyporesponsive to Erythropoiesis-Stimulating Agents

Weir

2021

Am J Nephrol

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Background: Patients with CKD frequently have anemia that results from iron-restricted erythropoiesis and inflammation. Anemia of CKD is currently managed with iron supplements and erythropoiesis-stimulating agents (ESAs) to promote erythropoiesis and with RBC transfusion in severe cases. Hyporesponse to ESAs, or the need for larger than usual doses to attain a given hemoglobin (Hb) level, is associated with increased morbidity and mortality and presents a pressing clinical challenge, particularly for patients on dialysis. This paper reviews ESA hyporesponse and potential new therapeutic options in the management of anemia of CKD. Summary: The most common causes of ESA hyporesponse include iron deficiency and inflammation, and to a lesser degree, secondary hyperparathyroidism, inadequate dialysis, malnutrition, and concomitant medications. Management of ESA hyporesponse is multipronged and involves treating low level infections, ensuring adequate nutrition, and optimizing iron status and dialysis modality, although some patients can remain refractory. Inflammation directly increases production and secretion of hepcidin, contributes to an impaired response to hypoxia, and suppresses proliferation of erythroid progenitors. Coordination of renal and hepatic erythropoietin (EPO) production and iron metabolism is under the control of hypoxia-inducible factors (HIF), which are in turn regulated by HIF-prolyl hydroxylases (HIF-PHs). HIF-PHs and hepcidin are therefore attractive potential drug targets particularly in patients with ESA hyporesponse. Several oral HIF-PH inhibitors have been evaluated in patients with anemia of CKD and have been shown to increase Hb and reduce hepcidin regardless of inflammation, iron status, or dialysis modality. These sustained effects are achieved through more modest increases in endogenous EPO compared with ESAs. Key Messages: Treatments that address ESA hyporesponse remain a significant unmet clinical need in patients with anemia of CKD. New therapies such as HIF-PH inhibitors have the potential to address fundamental aspects of ESA hyporesponse and provide a new therapeutic option in these patients.

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Impact of serum hepcidin and inflammatory markers on resistance to erythropoiesis-stimulating therapy in haemodialysis patients

Cited by 13 publications

References 57 publications

Iron metabolism and management: focus on chronic kidney disease

Iron metabolism and management: focus on chronic kidney disease

Factors associated with hepcidin‐25 levels in maintenance hemodialysis patients

Managing Anemia across the Stages of Kidney Disease in Those Hyporesponsive to Erythropoiesis-Stimulating Agents

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