Association of higher erythropoiesis stimulating agent dose and mortality in children on dialysis

Lestz, Rachel; Fivush, Barbara A.; Atkinson, Meredith A.

doi:10.1007/s00467-014-2820-9

Cited by 15 publications

(17 citation statements)

References 29 publications

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“…In light of clinical trial data in adults regarding the adverse effects of using escalating ESA doses to treat resistant anemia [35,36], along with recent observational evidence in children on dialysis that higher ESA doses are associated with an increased risk for mortality [27,37], there is a need for adjunctive anemia therapies with the potential to delay the need for ESA initiation or allow effective use of lower doses to maintain adequate HGB levels and avoid the need for red blood cell transfusions. Elevated hepcidin levels may be useful to identify anemic patients who may respond to IV iron administration, a task for which traditional iron indices are of limited utility [38].…”

Section: Discussionmentioning

confidence: 99%

“…RNA interference and gene silencing technologies to inhibit hepcidin gene transcription are under development in animal models, but are still quite remote from clinical application in humans [39–41]. Anti-hepcidin monoclonal antibodies and L-RNA aptamers (Spiegelmers) which can inhibit hepcidin activity and overcome erythropoietin resistance in animal models have been developed, with some currently in Phase I human clinical trials [35–37]. Interventions to prevent the endocytosis of ferroportin in response to binding by hepcidin are also in pre-clinical development [39,40].…”

Section: Discussionmentioning

confidence: 99%

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Hepcidin and risk of anemia in CKD: a cross-sectional and longitudinal analysis in the CKiD cohort

et al. 2014

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Background Hepcidin, a key iron regulatory protein, is elevated in patients with chronic kidney disease (CKD). Its role in the development and progression of the anemia of CKD in children remains poorly defined. Methods Cross-sectional and longitudinal study in children aged 1–16 years with stage 2–4 CKD in the Chronic Kidney Disease in Children (CKiD) cohort (n=133) with hepcidin measured at baseline and hemoglobin (HGB) measured annually in follow-up. Anemia was defined as HGB < 5th percentile for age/sex OR treatment with an erythropoiesis stimulating agent (ESA). Results Hepcidin levels correlated negatively with glomerular filtration rate (GFR) (r=−0.22, p=0.01) and positively with ferritin (r=0.67, p<0.001). At the lower end of the GFR spectrum at baseline (10th percentile, 27.5 ml/min/1.73m2), higher hepcidin was associated with a 0.87 g/dL decrease in HGB during follow-up (95% CI −1.69, −0.05 g/dL, p=0.038). At higher GFR percentiles there was no significant association between baseline hepcidin and HGB during follow-up. Among 90 non-anemic subjects at baseline, 23.3% developed incident anemia. In subjects with GFR ≤ the median, a higher hepcidin level was associated with an increased risk for incident anemia (at 10th %ile GFR, HR 3.471, 95% CI 1.228, 9.810, p=0.019; at 25th %ile GFR HR 2.641, 95% CI 1.213, 5.750, p=0.014; at 50th %ile GFR, HR 1.953, 95% CI 1.011, 3.772, p=0.046). Among subjects with GFR in the 75th percentile or above, incrementally higher baseline hepcidin was not associated with increased anemia risk. Conclusions Higher hepcidin levels are associated with a decreased HGB and an increased risk for incident anemia, and this association is most significant among subjects with lower GFR.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Hepcidin and risk of anemia in CKD: a cross-sectional and longitudinal analysis in the CKiD cohort

et al. 2014

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“…Indeed, upregulation of HIF in the kidneys will drive secretion of erythropoietin (EPO), which dose dependently increases FGF23 mRNA and total protein (9). This might further explain the adverse effects of EPO or erythropoiesis stimulating agents during the course of CKD progression (47,82,84). This also suggests that multiorgan normoxic and hypoxic HIF-1␣ stabilization occurring in CKD might represent an alternative therapeutic target.…”

Section: Mechanisms For Fgf23 Regulation By Inflammationmentioning

confidence: 97%

Ironing out the cross talk between FGF23 and inflammation

David

Francis

Babitt

2017

American Journal of Physiology-Renal Physiology

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The bone-secreted hormone fibroblast growth factor 23 (FGF23) has an essential role in phosphate homeostasis by regulating expression of the kidney proximal tubule sodium-phosphate cotransporters as well as parathyroid hormone levels. Induction of FGF23 early in chronic kidney disease (CKD) helps to maintain normal phosphorous levels. However, high FGF23 levels become pathological as kidney disease progresses and are associated with an increased risk of CKD progression, cardiovascular events, and death. The factors responsible for increasing FGF23 levels early in CKD are unknown, but recent work has proposed a role for inflammation and disordered iron homeostasis. Notably, FGF23 has recently been shown to elicit an inflammatory response and to display immunomodulatory properties. Here, we will review emerging evidence on the cross talk between inflammation, iron, FGF23, and bone and mineral metabolism and discuss the relevance for CKD patients.

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“…Unlike the current study, they did not find an association between all-cause hospitalizations and hemoglobin, perhaps because of differences between the 2 studies including that the previous study was limited to children 12 years of age and older, producing a smaller overall cohort. Lestz et al 22 identified an association between higher ESA dosing and mortality in children on chronic dialysis that was independent of hemoglobin level. Our current study adjusted for EPO dosing and still found a lower risk for all-cause mortality in children with a hemoglobin level $12 g/dl.…”

Section: Discussionmentioning

confidence: 99%

Hemoglobin of 12 g/dl and above is not associated with increased cardiovascular morbidity in children on hemodialysis

Rheault

Molony

Nevins

et al. 2017

Kidney International

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In adults on chronic hemodialysis, achieving a hemoglobin concentration of 12g/dl and above with erythropoiesis stimulating agents leads to increased cardiovascular events and mortality, but this may not be true in children. Therefore, we conducted a retrospective cohort study of pediatric patients (under 18) from the Centers for Medicare and Medicaid Services End Stage Renal Disease (ESRD) Clinical Performance Measures (CPM) project (2000 to 2008) merged with the United States Renal Data System. Hemoglobin was determined from the Clinical Performance Measures data, and beginning annually on January 1st of the next year, patients were followed for up to 1 year. We determined the outcomes (mortality, hospitalization, and cardiovascular events) during follow-up by hemoglobin group at baseline. Models were adjusted for demographic and clinical characteristics of 1569 children studied. The hemoglobin 12 g/dl and above group was older, had fewer years of ESRD, and was more often transplanted. Inpatient and outpatient visits for congestive heart failure, cardiomyopathy, and valvular heart disease were most common in the hemoglobin under 10g/dl group and the frequency of these diagnoses decreased with increasing hemoglobin. The hazard ratio of all-cause mortality (0.33, 95% confidence interval 0.14-0.81) and the adjusted relative rate of all-cause hospitalizations (0.81, 0.74-0.89) were significantly lower in the hemoglobin 12 g/dl and above group. Cardiovascular hospitalizations were significantly higher in the hemoglobin under 10g/dl group (1.31, 1.05-1.64). Thus, in children on hemodialysis, hemoglobin 12g/dl and above is not associated with increased cardiovascular visits, mortality, or all-cause and cardiovascular-related hospitalizations.

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Association of higher erythropoiesis stimulating agent dose and mortality in children on dialysis

Cited by 15 publications

References 29 publications

Hepcidin and risk of anemia in CKD: a cross-sectional and longitudinal analysis in the CKiD cohort

Hepcidin and risk of anemia in CKD: a cross-sectional and longitudinal analysis in the CKiD cohort

Ironing out the cross talk between FGF23 and inflammation

Hemoglobin of 12 g/dl and above is not associated with increased cardiovascular morbidity in children on hemodialysis

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