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Urinary Neutrophil Gelatinase-Associated Lipocalin/Hepcidin-25 Ratio for Early Identification of Patients at Risk for Renal Replacement Therapy After Cardiac Surgery: A Substudy of the BICARBONATE Trial.
Elitok, S, Kuppe, H, Devarajan, P, Bellomo, R, Isermann, B, Westphal, S, Kube, J, Albert, C, Ernst, M, Kropf, S, et al
Anesthesia and analgesia. 2021;(6):1510-1519
Abstract
BACKGROUND Acute kidney injury requiring renal replacement therapy (AKI-RRT) is strongly associated with mortality after cardiac surgery; however, options for early identification of patients at high risk for AKI-RRT are extremely limited. Early after cardiac surgery, the predictive ability for AKI-RRT even of one of the most extensively evaluated novel urinary biomarkers, neutrophil gelatinase-associated lipocalin (NGAL), appears to be only moderate. We aimed to determine whether the NGAL/hepcidin-25 ratio (urinary concentrations of NGAL divided by that of hepcidin-25) early after surgery may compare favorably to NGAL for identification of high-risk patients after cardiac surgery. METHODS This is a prospective substudy of the BICARBONATE trial, a multicenter parallel-randomized controlled trial comparing perioperative bicarbonate infusion for AKI prevention to usual patient care. At a tertiary referral center, 198 patients at increased kidney risk undergoing cardiac surgery with cardiopulmonary bypass were included into the present study. The primary outcome measure was defined as AKI-RRT. Secondary outcomes were in-hospital mortality and long-term mortality. We compared area under the curve of the receiver operating characteristic (AUC-ROC) of urinary NGAL with that of the urinary NGAL/hepcidin-25 ratio within 60 minutes after end of surgery. We compared adjusted AUC and performed cross-validated reclassification statistics of the (logarithmic) urinary NGAL/hepcidin-25 ratio adjusted to Cleveland risk score/EuroScore, cross-clamp time, age, volume of packed red blood cells, and (logarithmic) urinary NGAL concentration. The association of the NGAL/hepcidin-25 ratio with long-term patient survival was assessed using Cox proportional hazard regression analysis adjusting for EuroScore, aortic cross-clamp time, packed red blood cells and urinary NGAL. RESULTS Patients with AKI-RRT (n = 13) had 13.7-times higher NGAL and 3.3-times lower hepcidin-25 concentrations resulting in 46.9-times higher NGAL/hepcidin-25 ratio early after surgery compared to patients without AKI-RRT. The NGAL/hepcidin-25 ratio had higher AUC-ROC compared with NGAL for risk of AKI-RRT and in-hospital mortality (unadjusted AUC-ROC difference 0.087, 95% confidence interval [CI], 0.036-0.138, P < .001; 0.082, 95% CI, 0.018-0.146, P = .012). For AKI-RRT, the NGAL/hepcidin-25 ratio increased adjusted category-free net reclassification improvement (cfNRI; 0.952, 95% CI, 0.437-1.468; P < .001) and integrated discrimination improvement (IDI; 0.040, 95% CI, 0.008-0.073; P = .016) but not AUC difference. For in-hospital mortality, the ratio improved AUC of the reference model (AUC difference 0.056, 95% CI, 0.003-0.108; P = .037) and cfNRI but not IDI. The urinary NGAL/hepcidin-25 ratio remained significantly associated with long-term mortality after adjusting for the model covariates. CONCLUSIONS The urinary NGAL/hepcidin-25 ratio appears to early identify high-risk patients and outperform NGAL after cardiac surgery. Confirmation of our findings in other cardiac surgery centers is now needed.
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Effects of altitude and recombinant human erythropoietin on iron metabolism: a randomized controlled trial.
Breenfeldt Andersen, A, Bonne, TC, Bejder, J, Jung, G, Ganz, T, Nemeth, E, Olsen, NV, Huertas, JR, Nordsborg, NB
American journal of physiology. Regulatory, integrative and comparative physiology. 2021;(2):R152-R161
Abstract
Current markers of iron deficiency (ID), such as ferritin and hemoglobin, have shortcomings, and hepcidin and erythroferrone (ERFE) could be of clinical relevance in relation to early assessment of ID. Here, we evaluate whether exposure to altitude-induced hypoxia (2,320 m) alone, or in combination with recombinant human erythropoietin (rHuEPO) treatment, affects hepcidin and ERFE levels before alterations in routine ID biomarkers and stress erythropoiesis manifest. Two interventions were completed, each comprising a 4-wk baseline, a 4-wk intervention at either sea level or altitude, and a 4-wk follow-up. Participants (n = 39) were randomly assigned to 20 IU·kg body wt-1 rHuEPO or placebo injections every second day for 3 wk during the two intervention periods. Venous blood was collected weekly. Altitude increased ERFE (P ≤ 0.001) with no changes in hepcidin or routine iron biomarkers, making ERFE of clinical relevance as an early marker of moderate hypoxia. rHuEPO treatment at sea level induced a similar pattern of changes in ERFE (P < 0.05) and hepcidin levels (P < 0.05), demonstrating the impact of accelerated erythropoiesis and not of other hypoxia-induced mechanisms. Compared with altitude alone, concurrent rHuEPO treatment and altitude exposure induced additive changes in hepcidin (P < 0.05) and ERFE (P ≤ 0.001) parallel with increases in hematocrit (P < 0.001), demonstrating a relevant range of both hepcidin and ERFE. A poor but significant correlation between hepcidin and ERFE was found (R2 = 0.13, P < 0.001). The findings demonstrate that hepcidin and ERFE are more rapid biomarkers of changes in iron demands than routine iron markers. Finally, ERFE and hepcidin may be sensitive markers in an antidoping context.
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Testosterone Administration During Energy Deficit Suppresses Hepcidin and Increases Iron Availability for Erythropoiesis.
Hennigar, SR, Berryman, CE, Harris, MN, Karl, JP, Lieberman, HR, McClung, JP, Rood, JC, Pasiakos, SM
The Journal of clinical endocrinology and metabolism. 2020;(4)
Abstract
CONTEXT Severe energy deprivation markedly inhibits erythropoiesis by restricting iron availability for hemoglobin synthesis. OBJECTIVE The objective of this study was to determine whether testosterone supplementation during energy deficit increased indicators of iron turnover and attenuated the decline in erythropoiesis compared to placebo. DESIGN This was a 3-phase, randomized, double-blind, placebo-controlled trial. SETTING The study was conducted at the Pennington Biomedical Research Center. PATIENTS OR OTHER PARTICIPANTS Fifty healthy young males. INTERVENTION(S): Phase 1 was a 14-day free-living eucaloric controlled-feeding phase; phase 2 was a 28-day inpatient phase where participants were randomized to 200 mg testosterone enanthate/week or an isovolumetric placebo/week during an energy deficit of 55% of total daily energy expenditure; phase 3 was a 14-day free-living, ad libitum recovery period. MAIN OUTCOME MEASURE(S): Indices of erythropoiesis, iron status, and hepcidin and erythroferrone were determined. RESULTS Hepcidin declined by 41%, indicators of iron turnover increased, and functional iron stores were reduced with testosterone administration during energy deficit compared to placebo. Testosterone administration during energy deficit increased circulating concentrations of erythropoietin and maintained erythropoiesis, as indicated by an attenuation in the decline in hemoglobin and hematocrit with placebo. Erythroferrone did not differ between groups, suggesting that the reduction in hepcidin with testosterone occurs through an erythroferrone-independent mechanism. CONCLUSION These findings indicate that testosterone suppresses hepcidin, through either direct or indirect mechanisms, to increase iron turnover and maintain erythropoiesis during severe energy deficit. This trial was registered at www.clinicaltrials.gov as #NCT02734238.
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Association of Hepcidin With Anemia Parameters in Incident Dialysis Patients: Differences Between Dialysis Modalities.
Lim, JH, Park, YW, Lee, SH, Do, JY, Kim, SH, Han, S, Jung, HY, Choi, JY, Cho, JH, Kim, CD, et al
Therapeutic apheresis and dialysis : official peer-reviewed journal of the International Society for Apheresis, the Japanese Society for Apheresis, the Japanese Society for Dialysis Therapy. 2020;(1):4-16
Abstract
Hepcidin's relationships with other variables are unclear. We evaluated associations of serum hepcidin with clinical parameters in ESRD patients. Ninety-nine incident dialysis patients, including 57 on peritoneal dialysis (PD) and 42 on HD, were prospectively followed for 6 months. Serum hepcidin levels significantly increased during initial 6 months of dialysis. In the multivariate regression model, independent predictors of serum hepcidin levels in ESRD patients before maintenance dialysis were interleukin-6, ferritin, phosphate, iron, and aspartate transaminase. Six months after initiating dialysis, serum hepcidin levels were independently predicted by ferritin, total iron binding capacity (TIBC), and aspartate transaminase in all patients, whereas by ferritin and TIBC in PD patients, and ferritin, TIBC, and 24-h urine volume in HD patients. Serum hepcidin levels are differentially associated with anemia parameters in PD compared with HD patients. Urine volume was an independent predictor of hepcidin levels in early HD patients.
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Effect of cholecalciferol on serum hepcidin and parameters of anaemia and CKD-MBD among haemodialysis patients: a randomized clinical trial.
Obi, Y, Yamaguchi, S, Hamano, T, Sakaguchi, Y, Shimomura, A, Namba-Hamano, T, Mikami, S, Nishi, O, Tanaka, M, Kamoto, A, et al
Scientific reports. 2020;(1):15500
Abstract
In this multicentre double-blind randomized clinical trial, we investigated the effects of oral cholecalciferol supplementation on serum hepcidin and parameters related to anaemia and CKD-MBD among haemodialysis patients. Participants were assigned in a 2:2:1:1 ratio to either (1) thrice-weekly 3,000-IU cholecalciferol, (2) once-monthly cholecalciferol (equivalent to 9,000 IU/week), (3) thrice-weekly placebo, or (4) once-monthly placebo. We also examined the effect modifications by selected single nucleotide polymorphisms in vitamin D-related genes. Out of 96 participants, 94 were available at Month 3, and 88 completed the 6-month study. After adjustment for baseline values, serum hepcidin levels were higher at Day 3 in the combined cholecalciferol (vs. placebo) group, but were lower at Month 6 with increased erythropoietin resistance. Cholecalciferol increased serum 1,25(OH)2D levels, resulting in a greater proportion of patients who reduced the dose of active vitamin D at Month 6 (31% vs. 10% in the placebo group). Cholecalciferol also suppressed intact PTH only among patients with severe vitamin D deficiency. In conclusion, cholecalciferol supplementation increases serum hepcidin-25 levels in the short term and may increase erythropoietin resistance in the long term among haemodialysis patients. Both thrice-weekly and once-monthly supplementation effectively increases serum 1,25(OH)2D levels, and hence, reduces active vitamin D drugs.Clinical Trial Registry: This study was registered at ClinicalTrials.gov and University Hospital Medical Information Network Clinical Trials Registry (UMIN-CTR) as NCT02214563 (registration date: 12/08/2014) and UMIN000011786 (registration date: 15/08/2014), respectively (please refer to the links below). ClinicalTrials.gov: https://clinicaltrials.gov/ct2/show/record/NCT02214563 . UMIN-CTR: https://upload.umin.ac.jp/cgi-open-bin/ctr/ctr.cgi?function=brows&action=brows&type=summary&recptno=R000017152&language=E .
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Serum hepcidin potentially identifies iron deficiency in survivors of critical illness at the time of hospital discharge.
Shah, A, Wray, K, James, T, Shine, B, Morovat, R, Stanworth, S, McKechnie, S, Kirkbride, R, Griffith, DM, Walsh, TS, et al
British journal of haematology. 2019;(2):279-281
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A first-in-human phase 1 study of a hepcidin monoclonal antibody, LY2787106, in cancer-associated anemia.
Vadhan-Raj, S, Abonour, R, Goldman, JW, Smith, DA, Slapak, CA, Ilaria, RL, Tiu, RV, Wang, X, Callies, S, Cox, J, et al
Journal of hematology & oncology. 2017;(1):73
Abstract
BACKGROUND Hepcidin plays a central role in iron homeostasis and erythropoiesis. Neutralizing hepcidin with a monoclonal antibody (mAb) may prevent ferroportin internalization, restore iron efflux from cells, and allow transferrin-mediated iron transport to the bone marrow. This multicenter, phase 1 study evaluated the safety, pharmacokinetics (PK), pharmacodynamics (PD), and efficacy of a fully humanized mAb (LY2787106) with high affinity for hepcidin in cancer patients with anemia. METHODS Thirty-three patients with hepcidin levels ≥5 ng/mL received LY2787106 either every 3 weeks (19 patients, dose range 0.3-10 mg/kg) (part A) or weekly (14 patients, dose 10 mg/kg) (part B). LY2787106 PK/PD markers of iron and hematology biology were measured. RESULTS LY2787106 clearance (32 mL/h) and volume of distribution (7.7 L) were independent of dose and time, leading to a dose-proportional increase in concentration with dose. Consistent dose-dependent increases in serum iron, and transferrin saturation were seen at the 3 and 10 mg/kg dose levels, typically peaking within 24 h after LY2787106 administration and returning to baseline by day 8. CONCLUSIONS Our findings indicate that LY2787106 was well tolerated in cancer patients with anemia and that targeting the hepcidin-ferroportin pathway by neutralizing hepcidin resulted in transient iron mobilization, thus supporting the role of hepcidin in iron regulation. TRIAL REGISTRATION ClinicalTrial.gov, NCT01340976.
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Hepcidin levels and gastric cancer risk in the EPIC-EurGast study.
Jakszyn, P, Fonseca-Nunes, A, Lujan-Barroso, L, Aranda, N, Tous, M, Arija, V, Cross, A, Bueno-de-Mesquita, HBA, Weiderpass, E, Kühn, T, et al
International journal of cancer. 2017;(5):945-951
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Abstract
Hepcidin is the main regulator of iron homeostasis and dysregulation of proteins involved in iron metabolism has been associated with tumorogenesis. However, to date, no epidemiological study has researched the association between hepcidin levels and gastric cancer risk. To further investigate the relationship between hepcidin levels and gastric cancer risk, we conducted a nested case-control study (EURGAST) within the multicentric European Prospective Investigation into Cancer and Nutrition study. The study included 456 primary incident gastric adenocarcinoma cases and 900 matched controls that occurred during an average of 11 years of follow-up. We measured serum levels of hepcidin-25, iron, ferritin, transferrin and C-reactive protein. Odds ratios (ORs) and 95% confidence intervals (CIs) for the risk of gastric cancer by hepcidin levels were estimated from multivariable conditional logistic regression models. Mediation effect of the ferritin levels on the hepcidin-gastric cancer pathway was also evaluated. After adjusting for relevant confounders, we observed a statistically significant inverse association between gastric cancer and hepcidin levels (OR 5 ng/l = 0.96, 95% CI = 0.93-0.99). No differences were found by tumor localization or histological type. In mediation analysis, we found that the direct effect of hepcidin only represents a nonsignificant 38% (95% CI: -69%, 91%). In summary, these data suggest that the inverse association of hepcidin levels and gastric cancer risk was mostly accounted by ferritin levels. Further investigation including repeated measures of hepcidin is needed to clarify their role in gastric carcinogenesis.
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Impact of iron deficiency diagnosis using hepcidin mass spectrometry dosage methods on hospital stay and costs after a prolonged ICU stay: Study protocol for a multicentre, randomised, single-blinded medico-economic trial.
Lasocki, S, Puy, H, Mercier, G, Lehmann, S, ,
Anaesthesia, critical care & pain medicine. 2017;(6):391-396
Abstract
BACKGROUND Iron deficiency (ID) is frequent but difficult to diagnose in critically ill patients. ID may be responsible for prolonged post-ICU hospital stays, since it results in fatigue, muscle weakness and anaemia. Hepcidin, the key iron metabolism hormone, may be a good marker of ID in these patients. The aim of this study is to determine whether using mass spectrometry hepcidin determination to diagnose (and treat) ID after prolonged ICU stays may reduce patients' subsequent hospital stays and costs in comparison with conventional (ferritin) methods. METHODS This is a randomised, controlled, single-blinded, multicentre medico-economic study. Hepcidin quantification will be performed in anaemic (WHO criteria) critically ill adults about to be discharged, after a stay ≥5days. In the intervention arm (hepcidin) results will be given to the ICU-physicians, and not in the control arm. ID Treatment will be recommended in intervention arm: IV iron when hepcidin is <20μg/L; IV iron+erythropoietin when hepcidin is between 20-41μg/L; in the control arm: IV iron when ferritin <300μg/L and Transferrin saturation <20%. The primary endpoint will be the number of days spent in hospital 90 days after ICU discharge and the direct hospital costs. Secondary endpoints will be anaemia and iron deficiency on D15, fatigue and the proportion of patients alive and at home on D30 and D90. DISCUSSION The results of this study will show whether diagnosing iron deficiency using MS hepcidin determination methods is liable to reduce patients' post-ICU hospital stay and costs, as well as their anaemia and fatigue.
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Effects of lanthanum carbonate and calcium carbonate on fibroblast growth factor 23 and hepcidin levels in chronic hemodialysis patients.
Chang, YM, Tsai, SC, Shiao, CC, Liou, HH, Yang, CL, Tung, NY, Hsu, KS, Chen, IL, Liu, MC, Kao, JL, et al
Clinical and experimental nephrology. 2017;(5):908-916
Abstract
BACKGROUND Phosphate binders have an impact on fibroblast growth factor 23 (FGF23); however, the effect of phosphate binders on serum hepcidin has not been explored. We conducted a 24-week multicenter randomized controlled trial to investigate the effects of lanthanum carbonate or calcium carbonate monotherapy on serum phosphate, FGF23, and hepcidin levels in chronic hemodialysis patients. METHODS Forty-six patients were recruited, and daily dietary phosphorus was controlled between 600-800 mg. Serum calcium, phosphate, albumin, alkaline phosphatase (ALP), FGF23, intact parathyroid hormone (iPTH), hepcidin, high-sensitivity CRP (hsCRP), 25(OH)D, 1,25(OH)2D, fetuin-A, and osteopontin were checked as scheduled. RESULTS Twenty-five patients completed the study. Mean serum FGF23 level was significantly decreased after a 24-week treatment with lanthanum (8677.5 ± 7490.0 vs. 4692.8 ± 5348.3 pg/mL, p = 0.013, n = 13), but not with calcium (n = 12). The reduction of serum hepcidin in lanthanum group was positively correlated with the decrement of serum phosphate (r = 0.631, p = 0.021) and serum hsCRP (r = 0.670, p = 0.012) levels, respectively. Serum ALP, iPTH, vitamin D, fetuin-A, and osteopontin revealed no significant inter- or intragroup differences. CONCLUSIONS In summary, a decrease in serum FGF23 levels and a trend of decline in hepcidin levels were observed only in lanthanum group.