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Objective Classic androgens such as dehydroepiandrosterone, androstenedione, and testosterone are generally measured for diagnosis and treatment monitoring in children and adolescents with hyperandrogenism, as can occur in congenital adrenal hyperplasia, premature pubarche, or polycystic ovarian syndrome. However, adrenally-derived 11-oxygenated androgens also contribute to the androgen pool and should therefore be considered in clinical management. Nevertheless, paediatric reference intervals are lacking. Therefore, we developed a serum assay to establish reference intervals for four 11-oxygenated androgens in addition to four classic androgens. Design Reference interval study for serum 11-oxygenated androgens in children. Methods We developed and validated a sensitive liquid chromatography-tandem mass spectrometry assay and quantified eight serum androgens, including four 11-oxygenated androgens, in serum of 256 healthy children (aged 0-17 years old). An age-dependency for all androgens was observed, and therefore we divided the cohort based on age (prepubertal [ n = 133; 94 boys, 39 girls] and pubertal [ n = 123; 52 boys, 71 girls]) to compute reference intervals (2.5th-97.5th percentiles). Results In the prepubertal group, there was no significant sex-difference for any of the measured androgens. In the pubertal group, androstenedione, testosterone, and dihydrotestosterone showed a significant difference between boys and girls. In contrast, adrenal androgens dehydroepiandrosterone, 11-hydroxyandrostenedione, 11-ketoandrostenedione, 11-hydroxytestosterone, and 11-ketotestosterone did not. Conclusions We developed and validated an assay for 11-oxygenated androgens, in addition to four classic androgens and established reference intervals. This enables a comprehensive evaluation of serum androgen status in children with clinical symptoms of hyperandrogenism. [ABSTRACT FROM AUTHOR]

X-linked sideroblastic anaemia (XLSA) arises from pathogenic variants in the 5-aminolevulinate synthase 2 (ALAS2) gene, encoding ALAS2. Although dysregulation of the EPO-ERFE-hepcidin axis has been shown for different iron-loading anaemias,[[6], [10]] our findings for the various iron biomarkers suggest ineffective erythropoiesis in well-treated XLSA patients is less obvious. Iron parameters differed among patients, with some patients showing levels outside the reference interval: median ferritin was 154 g/L (IQR 101-317), transferrin saturation (TSAT) 46% (IQR 41-55), and hepcidin/ferritin-ratio was 14.9 pmol/ g (IQR 9.1-27.6). [Extracted from the article]

The hormone hepcidin plays an important role in intestinal iron absorption and cellular release. Cord blood hepcidin values reflect fetal hepcidin status, at least at the time of delivery, but are not available for the Belgian population. Therefore, we aimed (1) to provide the first data on cord blood hepcidin levels in a Belgian cohort and (2) to determine variables associated with cord blood hepcidin concentrations. A cross-sectional, observational study was performed at the University Hospital Leuven, Belgium. Cord blood samples were analyzed using a combination of weak cation exchange chromatography and time-of-flight mass spectrometry. Descriptive statistics, Spearman correlation tests, and Mann–Whitney U tests were performed. In total, 61 nonhemolyzed cord blood samples were analyzed. The median hepcidin level was 17.6 μg/L (IQR: 18.1; min-max: 3.9–54.7). A moderate correlation was observed between cord blood hepcidin and cord blood ferritin (r = 0.493) and hemoglobin (r = −0.342). Cord blood hepcidin was also associated with mode of delivery (p = 0.01), with higher hepcidin levels for vaginal deliveries. Nonetheless, larger studies are needed to provide more evidence on the actual clinical value and benefit of cord blood hepcidin measurements. [ABSTRACT FROM AUTHOR]

Purpose: Menstrual cycle phase affects resting hepcidin levels, but such effects on the hepcidin response to exercise are still unclear. Thus, we investigated the hepcidin response to running during three different menstrual cycle phases. Methods: Twenty-one endurance-trained eumenorrheic women performed three identical interval running protocols during the early-follicular phase (EFP), late-follicular phase (LFP), and mid-luteal phase (MLP). The protocol consisted of 8 × 3 min bouts at 85% of the maximal aerobic speed, with 90-s recovery. Blood samples were collected pre-exercise and at 0 h, 3 h and 24 h post-exercise. Results: Data presented as mean ± SD. Ferritin were lower in the EFP than the LFP (34.82 ± 16.44 vs 40.90 ± 23.91 ng/ml, p = 0.003), while iron and transferrin saturation were lower during the EFP (58.04 ± 19.70 µg/dl, 14.71 ± 5.47%) compared to the LFP (88.67 ± 36.38 µg/dl, 22.22 ± 9.54%; p < 0.001) and the MLP (80.20 ± 42.05 µg/dl, 19.87 ± 10.37%; p = 0.024 and p = 0.045, respectively). Hepcidin was not affected by menstrual cycle (p = 0.052) or menstrual cycle*time interaction (p = 0.075). However, when comparing hepcidin at 3 h post-exercise, a moderate and meaningful effect size showed that hepcidin was higher in the LFP compared to the EFP (3.01 ± 4.16 vs 1.26 ± 1.25 nMol/l; d = 0.57, CI = 0.07–1.08). No effect of time on hepcidin during the EFP was found either (p = 0.426). Conclusion: The decrease in iron, ferritin and TSAT levels during the EFP may mislead the determination of iron status in eumenorrheic athletes. However, although the hepcidin response to exercise appears to be reduced in the EFP, it shows no clear differences between the phases of the menstrual cycle (clinicaltrials.gov: NCT04458662). [ABSTRACT FROM AUTHOR]

Iron-refractory iron deficiency anemia (IRIDA) is an autosomal recessive inherited form of iron deficiency anemia characterized by discrepantly high hepcidin levels relative to body iron status. However, patients with monoallelic exonic TMPRSS6 variants have also been reported to express the IRIDA phenotype. The pathogenesis of an IRIDA phenotype in these patients is unknown and causes diagnostic uncertainty. Therefore, we retrospectively summarized the data of 16 patients (4 men, 12 women) who expressed the IRIDA phenotype in the presence of only a monoallelic TMPRSS6 variant. Eight unaffected relatives with identical exonic TMPRSS6 variants were used as controls. Haplotype analysis was performed to assess the (intra)genetic differences between patients and relatives. The expression and severity of the IRIDA phenotype were highly variable. Compared with their relatives, patients showed lower Hb, MCV, and TSAT/hepcidin ratios and inherited a different wild-type allele. We conclude that IRIDA in monoallelic TMPRSS6-affected patients is a phenotypically and genotypically heterogeneous disease that is more common in female patients. We hypothesize that allelic imbalance, polygenetic inheritance, or modulating environmental factors and their complex interplay are possible causes. This explorative study is the first step toward improved insights into the pathophysiology and improved diagnostic accuracy for patients presenting with IRIDA and a monoallelic exonic TMPRSS6 variant. [ABSTRACT FROM AUTHOR]

Kidney iron deposition may play a role in the progression of tubulointerstitial injury during chronic kidney disease. Here, we studied the molecular mechanisms of kidney iron loading in experimental focal segmental glomerulosclerosis (FSGS) and investigated the effect of iron-reducing interventions on disease progression. Thy-1.1 mice were injected with anti-Thy-1.1 monoclonal antibody (mAb) to induce proteinuria. Urine, blood and tissue were collected at day (D)1, D5, D8, D15 and D22 after mAb injection. Thy-1.1 mice were subjected to captopril (CA), iron-deficient (ID) diet or iron chelation (deferoxamine; DFO). MAb injection resulted in significant albuminuria at all time points (p < 0.01). Kidney iron loading, predominantly in distal tubules, increased in time, along with urinary kidney injury molecule-1 and 24p3 concentration, as well as kidney mRNA expression of Interleukin-6 (Il-6) and Heme oxygenase-1 (Ho-1). Treatment with CA, ID diet or DFO significantly reduced kidney iron deposition at D8 and D22 (p < 0.001) and fibrosis at D22 (p < 0.05), but not kidney Il-6. ID treatment increased kidney Ho-1 (p < 0.001). In conclusion, kidney iron accumulation coincides with progression of tubulointerstitial injury in this model of FSGS. Reduction of iron loading halts disease progression. However, targeted approaches to prevent excessive kidney iron loading are warranted to maintain the delicate systemic and cellular iron balance. [ABSTRACT FROM AUTHOR]

Objective: The opportunistic pathogen Streptococcus gallolyticus is one of the few intestinal bacteria that has been consistently linked to colorectal cancer (CRC). This study aimed to identify novel S. gallolyticus -induced pathways in colon epithelial cells that could further explain how S. gallolyticus contributes to CRC development. Design and Results: Transcription profiling of in vitro cultured CRC cells that were exposed to S. gallolyticus revealed the specific induction of oxidoreductase pathways. Most prominently, CYP1A and ALDH1 genes that encode phase I biotransformation enzymes were responsible for the detoxification or bio-activation of toxic compounds. A common feature is that these enzymes are induced through the Aryl hydrocarbon receptor (AhR). Using the specific inhibitor CH223191, we showed that the induction of CYP1A was dependent on the AhR both in vitro using multiple CRC cell lines as in vivo using wild-type C57bl6 mice colonized with S. gallolyticus. Furthermore, we showed that CYP1 could also be induced by other intestinal bacteria and that a yet unidentified diffusible factor from the S. galloltyicus secretome (SGS) induces CYP1A enzyme activity in an AhR-dependent manner. Importantly, priming CRC cells with SGS increased the DNA damaging effect of the polycyclic aromatic hydrocarbon 3-methylcholanthrene. Conclusion: This study shows that gut bacteria have the potential to modulate the expression of biotransformation pathways in colonic epithelial cells in an AhR-dependent manner. This offers a novel theory on the contribution of intestinal bacteria to the etiology of CRC by modifying the capacity of intestinal epithelial or (pre-)cancerous cells to (de)toxify dietary components, which could alter intestinal susceptibility to DNA damaging events. [ABSTRACT FROM AUTHOR]

Phlebotomies are performed in hereditary hemochromatosis (HH) to maintain normal iron concentrations. Proton-pump inhibitors (PPIs) can reduce the number of phlebotomies in patients with HH. However, in patients without HH, the iron concentrations do not appear to be compromised when using PPIs. Therefore, we aim to explain the differences in iron absorption between patients with and without HH. In 10 p.cysteine282tyrosine (p.C282Y) homozygous HH patients with normalized iron stores and 10 healthy control subjects (HCs), the iron parameters and hepcidin concentrations were determined before ingestion of a pharmacological dose of 50 mg iron [ferric iron (Fe3+)] polymaltose and hourly for 4 h afterward. This was repeated after 7 days of treatment with pantoprazole 40 mg once daily. Serum iron concentrations and transferrin saturation percentages dropped significantly during PPI use in the patients with HH, whereas no changes were observed in the HCs. Hepcidin concentrations were lower in the patients with HH compared with the HCs both before and during PPI use. In both groups, hepcidin levels did not significantly decrease during the treatment. Seven-day PPI use significantly reduces iron absorption in patients with HH but not in HCs. Changes in hepcidin concentrations could not explain these different PPI effects on iron absorption probably due to a small sample size. NEW & NOTEWORTHY This study confirms that lowering gastric acidity by proton pump inhibitors results in a reduction in iron absorption in patients with hemochromatosis and not in healthy control subjects. The presupposition that a decrease in hepcidin concentration in healthy control subjects in response to lowering gastric acidity can explain the difference in iron absorption between these groups could not be confirmed probably because of a small sample size. [ABSTRACT FROM AUTHOR]

We present a p.C282Y homozygous patient with high hepcidin levels and normal iron parameters during systemic inflammation. This suggests that in the absence of a proper functioning HFE, resulting in blockage of the BMP/SMAD pathway, the innate low hepcidin concentration can be upregulated by inflammation, probably via the JAK/STAT3 pathway. [ABSTRACT FROM AUTHOR]

The use of oral contraceptives (OCs) by female athletes may lead to improved iron status, possibly through the regulation of hepcidin by sex hormones. The present work investigates the response of hepcidin and interleukin‐6 (IL‐6) to an interval exercise in both phases of the OC cycle. Sixteen endurance‐trained OC users (age 25.3 ± 4.7 years; height 162.4 ± 5.7 cm; body mass 56.0 ± 5.7 kg; body fat percentage 24.8 ± 6.0%; peak oxygen consumption [VO2peak]: 47.4 ± 5.5 mL min−1 kg−1) followed an identical interval running protocol during the withdrawal and active pill phases of the OC cycle. This protocol consisted of 8 × 3 minutes bouts at 85% VO2peak speed with 90 seconds recovery intervals. Blood samples were collected pre‐exercise, and at 0 hour, 3 hours, and 24 hours post‐exercise. Pre‐exercise 17β‐estradiol was lower (P =.001) during the active pill than the withdrawal phase (7.91 ± 1.81 vs 29.36 ± 6.45 pg/mL [mean ± SEM]). No differences were seen between the OC phases with respect to hepcidin or IL‐6 concentrations, whether taking all time points together or separately. However, within the withdrawal phase, hepcidin concentrations were higher at 3 hours post‐exercise (3.33 ± 0.95 nmol/L) than at pre‐exercise (1.04 ± 0.20 nmol/L; P =.005) and 0 hour post‐exercise (1.41 ± 0.38 nmol/L; P =.045). Within both OC phases, IL‐6 was higher at 0 hour post‐exercise than at any other time point (P <.05). Similar trends in hepcidin and IL‐6 concentrations were seen at the different time points during both OC phases. OC use led to low 17β‐estradiol concentrations during the active pill phase but did not affect hepcidin. This does not, however, rule out estradiol affecting hepcidin levels. [ABSTRACT FROM AUTHOR]

Objectives: Hepcidin measurement advances insights in pathophysiology, diagnosis, and treatment of iron disorders, but requires analytically sound and standardized measurement procedures (MPs). Recent development of a two-level secondary reference material (sRM) for hepcidin assays allows worldwide standardization. However, no proficiency testing (PT) schemes to ensure external quality assurance (EQA) exist and the absence of a high calibrator in the sRM set precludes optimal standardization. Methods: We developed a pilot PT together with the Dutch EQA organization Stichting Kwaliteitsbewaking Medische Laboratoriumdiagnostiek (SKML) that included 16 international hepcidin MPs. The design included 12 human serum samples that allowed us to evaluate accuracy, linearity, precision and standardization potential. We manufactured, value-assigned, and validated a high-level calibrator in a similar manner to the existing low- and middle-level sRM. Results: The pilot PT confirmed logistical feasibility of an annual scheme. Most MPs demonstrated linearity (R2>0.99) and precision (duplicate CV>12.2%), although the need for EQA was shown by large variability in accuracy. The high-level calibrator proved effective, reducing the inter-assay CV from 42.0% (unstandardized) to 14.0%, compared to 17.6% with the two-leveled set. The calibrator passed international homogeneity criteria and was assigned a value of 9.07±0.24 nmol/L. Conclusions: We established a framework for future PT to enable laboratory accreditation, which is essential to ensure quality of hepcidin measurement and its use in patient care. Additionally, we showed optimized standardization is possible by extending the current sRM with a third high calibrator, although international implementation of the sRM is a prerequisite for its success. [ABSTRACT FROM AUTHOR]

The effect of exercise modality and intensity on Interleukin-6 (IL-6), iron status, and hepcidin levels was investigated. Ten trained male triathletes performed 4 exercise trials including low-intensity continuous running (L-R), low-intensity continuous cycling (L-C), high-intensity interval running (H-R), and high-intensity interval cycling (H-C). Both L-R and L-C consisted of 40 min continuous exercise performed at 65% of peak running velocity (vVO2peak) and cycling power output (pVO2peak), while H-R and H-C consisted of 8 × 3-min intervals performed at 85% vVO2peak and pVO2peak. Venous blood samples were drawn pre-, post-, and 3 hr postexercise. Significant increases in postexercise IL-6 were seen within each trial (p < .05) and were significantly greater in H-R than L-R (p < .05). Hepcidin levels were significantly elevated at 3 hr postexercise within each trial (p < .05). Serum iron levels were significantly elevated (p < .05) immediately postexercise in all trials except L-C. These results suggest that, regardless of exercise mode or intensity, postexercise increases in IL-6 may be expected, likely influencing a subsequent elevation in hepcidin. Regardless, the lack of change in postexercise serum iron levels in L-C may indicate that reduced hemolysis occurs during weight-supported, low-intensity activity. [ABSTRACT FROM AUTHOR]

The effect of exercise modality and intensity on Interleukin-6 (IL-6), iron status, and hepcidin levels was investigated. Ten trained male triathletes performed 4 exercise trials including low-intensity continuous running (L-R), low-intensity continuous cycling (L-C), high-intensity interval running (H-R), and high-intensity interval cycling (H-C). Both L-R and L-C consisted of 40 min continuous exercise performed at 65% of peak running velocity (vVO2peak) and cycling power output (pVO2peak), while H-R and H-C consisted of 8 Ã 3-min intervals performed at 85% vVO2peak and pVO2peak. Venous blood samples were drawn pre-, post-, and 3 hr postexercise. Significant increases in postexercise IL-6 were seen within each trial (p < .05) and were significantly greater in H-R than L-R (p < .05). Hepcidin levels were significantly elevated at 3 hr postexercise within each trial (p < .05). Serum iron levels were significantly elevated (p < .05) immediately postexercise in all trials except L-C. These results suggest that, regardless of exercise mode or intensity, postexercise increases in IL-6 may be expected, likely influencing a subsequent elevation in hepcidin. Regardless, the lack of change in postexercise serum iron levels in L-C may indicate that reduced hemolysis occurs during weight-supported, low-intensity activity. [ABSTRACT FROM AUTHOR]

Introduction: Iron deficiency is a treatable cause of severe anaemia in low-and-middle-income-countries (LMIC). Diagnosing it remains challenging as peripheral blood markers poorly reflect bone-marrow iron deficiency (BM-ID), especially in the context of HIV-infection. Methods: Severely anaemic (haemoglobin ≤70g/l) HIV-infected adults were recruited at Queen Elizabeth Central Hospital, Blantyre, Malawi. BM-ID was evaluated. Accuracy of blood markers (including hepcidin, mean corpuscular volume, mean cellular haemoglobin concentration, serum iron, serum ferritin, soluble transferrin receptor (sTfR), sTfR index, sTfR–ratio) to detect BM-ID was evaluated by ROC area under the curve (AUCROC). Results: Seventy-three patients were enrolled and 35 (48.0%) had BM-ID. Although hepcidin and MCV performed best (AUCROC of 0.593 and 0.545 respectively) all markers performed poorly in identifying BM-ID (ROC<0.6). The AUCROC of hepcidin in males was 0.767 (sensitivity 80%, specificity 78%) and in women 0.490 (sensitivity 60%, specificity 61%). Conclusion: BM-ID deficiency was common in severely anaemic HIV-infected patients. It is an important and potential treatable contributor to severe anaemia but lack of definitive biomarkers makes it difficult to accurately assess iron status in these patients. Further investigation of the potential of hepcidin is needed, including exploration of the differences in hepcidin results between males and females. [ABSTRACT FROM AUTHOR]

Purpose: To investigate the effects of acute exercise on serum hepcidin and iron (sFe) in active women. Changes in interleukin-6 (IL-6), hepcidin, ferritin, and sFe in response to 2 different exercise durations were compared. Methods: Twelve women age 19-32 yr performed 2 treadmill runs (60 and 120 min) at 65% of VO2max. Blood samples were obtained before, immediately after, and 3, 6, 9, and 24 hr after exercise. Two-way repeated-measures ANOVA was conducted to examine changes in measured variables. Significance was accepted at p < .05. Results: Significant effects for trial were observed for hepcidin (60 min: 1.15 ± 0.48 nmol/L; 120 min: 2.28 ± 1.44 nmol/L) and for time, with hepcidin significantly increased 3 hr postexercise in both trials (60 min: 3 hr - 1.99 ± 2.00 nmol/L; 120 min: 3 hr - 4.60 ± 4.61 nmol/L). Significant main effects for time occurred for sFe, ferritin, and IL-6. sFe was significantly decreased 9 hr postexercise compared with 3 and 24 hr postexercise. IL-6 was significantly increased immediately postexercise. Conclusions: Both runs resulted in significant increases in hepcidin 3 hr after exercise. Increases in hepcidin were preceded by significant increases in IL-6 immediately postexercise and followed by significant decreases in sFe 9 hr postexercise. It was concluded that endurance exercise increases the production of hepcidin, which affects sFe. The 2-hr exercise bout stimulated greater changes in serum hepcidin than the 1-hr bout. [ABSTRACT FROM AUTHOR]

Purpose: To investigate the effects of acute exercise on serum hepcidin and iron (sFe) in active women. Changes in interleukin-6 (IL-6), hepcidin, ferritin, and sFe in response to 2 different exercise durations were compared. Methods: Twelve women age 19-32 yr performed 2 treadmill runs (60 and 120 min) at 65% of VO2max. Blood samples were obtained before, immediately after, and 3, 6, 9, and 24 hr after exercise. Two-way repeated-measures ANOVA was conducted to examine changes in measured variables. Significance was accepted at p < .05. Results: Significant effects for trial were observed for hepcidin (60 min: 1.15 ± 0.48 nmol/L; 120 min: 2.28 ± 1.44 nmol/L) and for time, with hepcidin significantly increased 3 hr postexercise in both trials (60 min: 3 hr - 1.99 ± 2.00 nmol/L; 120 min: 3 hr - 4.60 ± 4.61 nmol/L). Significant main effects for time occurred for sFe, ferritin, and IL-6. sFe was significantly decreased 9 hr postexercise compared with 3 and 24 hr postexercise. IL-6 was significantly increased immediately postexercise. Conclusions: Both runs resulted in significant increases in hepcidin 3 hr after exercise. Increases in hepcidin were preceded by significant increases in IL-6 immediately postexercise and followed by significant decreases in sFe 9 hr postexercise. It was concluded that endurance exercise increases the production of hepcidin, which affects sFe. The 2-hr exercise bout stimulated greater changes in serum hepcidin than the 1-hr bout. [ABSTRACT FROM AUTHOR]

Urinary hepcidin, inflammation, and iron metabolism were examined during the 24 hr after exercise. Eight moderately trained athletes (6 men, 2 women) completed a 60-min running trial (15-min warm-up at 75-80% HRpeak + 45 min at 85-90% HRpeak) and a 60-min trial of seated rest in a randomized, crossover design. Venous blood and urine samples were collected pretrial, immediately posttrial, and at 3, 6, and 24 hr posttrial. Samples were analyzed for interleukin-6 (IL-6), C-reactive protein (CRP), serum iron, serum ferritin, and urinary hepcidin. The immediate postrun levels of IL-6 and 24-hr postrun levels of CRP were significantly increased from baseline (6.9 and 2.6 times greater, respectively) and when compared with the rest trial (p ≤ .05). Hepcidin levels in the run trial after 3, 6, and 24 hr of recovery were significantly greater (1.7-3.1 times) than the pre- and immediate postrun levels (p ≤ .05). This outcome was consistent in all participants, despite marked variation in the magnitude of rise. In addition, the 3-hr postrun levels of hepcidin were significantly greater than at 3 hr in the rest trial (3.0 times greater, p ≤ .05). Hepcidin levels continued to increase at 6 hr postrun but failed to significantly differ from the rest trial (p = .071), possibly because of diurnal influence. Finally, serum iron levels were significantly increased immediately postrun (1.3 times, p ≤ .05). The authors concluded that high-intensity exercise was responsible for a significant increase in hepcidin levels subsequent to a significant increase in IL-6 and serum iron. [ABSTRACT FROM AUTHOR]

In physiological conditions, circulating iron can be filtered by the glomerulus and is almost completely reabsorbed by the tubular epithelium to prevent urinary iron wasting. Increased urinary iron concentrations have been associated with renal injury. However, it is not clear whether increased urinary iron concentrations in patients are the result of increased glomerular iron filtration and/or insufficient tubular iron reabsorption and if these processes contribute to renal injury. We measured plasma and urine iron parameters and urinary tubular injury markers in healthy human subjects (n=20), patients with systemic iron overload (n=20), and patients with renal tubular dysfunction (n 18). Urinary iron excretion parameters were increased in both patients with systemic iron overload and tubular dysfunction, whereas plasma iron parameters were only increased in patients with systemic iron overload. In patients with systemic iron overload, increased urinary iron levels were associated with elevated circulating iron, as indicated by transferrin saturation (TSAT), and increased body iron, as suggested by plasma ferritin concentrations. In patients with tubular dysfunction, enhanced urinary iron and transferrin excretion were associated with distal tubular injury as indicated by increased urinary glutathione S-transferase pi 1-1 (GSTP1-1) excretion. In systemic iron overload, elevated urinary iron and transferrin levels were associated with increased injury to proximal tubules, indicated by increased urinary kidney injury marker 1 (KIM-1) excretion. Our explorative study demonstrates that both glomerular filtration of elevated plasma iron levels and insufficient tubular iron reabsorption could increase urinary iron excretion and cause renal injury [ABSTRACT FROM AUTHOR]

Background Iron status is a determinant of physical performance, but training may induce both low-grade inflammation and erythropoiesis, exerting opposing influences on hepcidin and iron metabolism. To our knowledge, the combined effects on iron absorption and utilization during training have not been examined directly in humans. Objective We hypothesized that 3 wk of exercise training in recreational male runners would decrease oral iron bioavailability by increasing inflammation and hepcidin concentrations. Design In a prospective intervention, nonanemic, iron-sufficient men (n = 10) completed a 34-d study consisting of a 16-d control phase and a 22-d exercise-training phase of 8 km running every second day. We measured oral iron absorption and erythroid iron utilization using oral 57Fe and intravenous 58Fe tracers administered before and during training. We measured hemoglobin mass (mHb) and total red blood cell volume (RCV) by carbon monoxide rebreathing. Iron status, interleukin-6 (IL-6), plasma hepcidin (PHep), erythropoietin (EPO), and erythroferrone were measured before, during, and after training. Results Exercise training induced inflammation, as indicated by an increased mean ± SD IL-6 (0.87 ± 1.1 to 5.17 ± 2.2 pg/mL; P < 0.01), while also enhancing erythropoiesis, as indicated by an increase in mean EPO (0.66 ± 0.42 to 2.06 ± 1.6 IU/L), mHb (10.5 ± 1.6 to 10.8 ± 1.8 g/kg body weight), and mean RCV (30.7 ± 4.3 to 32.7 ± 4.6 mL/kg) (all P < 0.05). Training tended to increase geometric mean iron absorption by 24% (P = 0.083), consistent with a decreased mean ± SD PHep (7.25 ± 2.14 to 5.17 ± 2.24 nM; P < 0.05). The increase in mHb and erythroid iron utilization were associated with the decrease in PHep (P < 0.05). Compartmental modeling indicated that iron for the increase in mHb was obtained predominantly (>80%) from stores mobilization rather than from increased dietary absorption. Conclusions In iron-sufficient men, mild intensification of exercise intensity increases both inflammation and erythropoiesis. The net effect is to decrease hepcidin concentrations and to tend to increase oral iron absorption. This trial was registered at clinicaltrials.gov as NCT01730521. [ABSTRACT FROM AUTHOR]

1 Experimental protocol performed in the EFP, LFP, and MLP of the menstrual cycle. EFP early-follicular phase, FSH follicle-stimulating hormone, LFP late-follicular phase, LH luteinizing hormone, MLP mid-luteal phase, 0 h, 0 h post-exercise, 3 h, 3 h post-exercise, 24 h, 24 h post-exercise Graph: Fig. [Extracted from the article]

Background: The safety of iron supplementation for young women is uncertain in malaria-endemic settings.Methods: This was a double-blind, randomized controlled noninferiority trial in rural Burkina Faso.Results: A total of 1959 nulliparae were assigned to weekly supplementation (60 mg iron and 2.8 mg folic acid) (n = 980) or 2.8 mg folic acid (n = 979) until first antenatal visit (ANC1), or 18 months if remaining nonpregnant. Three hundred fifteen women attended ANC1, and 916 remained nonpregnant. There was no difference at ANC1 in parasitemia prevalence (iron, 53.4% [95% confidence interval {CI}, 45.7%-61.0%]; control, 55.3% [95% CI, 47.3%-62.9%]; prevalence ratio, 0.97 [95% CI, .79-1.18]; P = .82), anemia (adjusted effect, 0.96 [95% CI, .83-1.10]; P = .52), iron deficiency (adjusted risk ratio [aRR], 0.84 [95% CI, .46-1.54]; P = .58), or plasma iron biomarkers. Outcomes in nonpregnant women were parasitemia (iron, 42.9% [95% CI, 38.3%-47.5%]; control, 39.2% [95% CI, 34.9%-43.7%]; prevalence ratio, 1.09 [95% CI, .93-1.28]; P = .282); anemia (aRR, 0.90 [95% CI, .78-1.05]; P = .17), and iron deficiency (aRR, 0.99 [95% CI, .77-1.28]; P = .96), with no iron biomarker differences.Conclusions: Weekly iron supplementation did not increase malaria risk, improve iron status, or reduce anemia in young, mostly adolescent menstruating women, nor in early pregnancy. World Health Organization Guidelines for universal supplementation for young nulliparous women may need reassessment.Clinical Trials Registration: NCT01210040. [ABSTRACT FROM AUTHOR]

Aims: Iron deficiency is common in patients with heart failure and associated with a poor cardiac function and higher mortality. How iron deficiency impairs cardiac function on a cellular level in the human setting is unknown. This study aims to determine the direct effects of iron deficiency and iron repletion on human cardiomyocytes.Methods and Results: Human embryonic stem cell-derived cardiomyocytes were depleted of iron by incubation with the iron chelator deferoxamine (DFO). Mitochondrial respiration was determined by Seahorse Mito Stress test, and contractility was directly quantified using video analyses according to the BASiC method. The activity of the mitochondrial respiratory chain complexes was examined using spectrophotometric enzyme assays. Four days of iron depletion resulted in an 84% decrease in ferritin (P < 0.0001) and significantly increased gene expression of transferrin receptor 1 and divalent metal transporter 1 (both P < 0.001). Mitochondrial function was reduced in iron-deficient cardiomyocytes, in particular ATP-linked respiration and respiratory reserve were impaired (both P < 0.0001). Iron depletion affected mitochondrial function through reduced activity of the iron-sulfur cluster containing complexes I, II and III, but not complexes IV and V. Iron deficiency reduced cellular ATP levels by 74% (P < 0.0001) and reduced contractile force by 43% (P < 0.05). The maximum velocities during both systole and diastole were reduced by 64% and 85%, respectively (both P < 0.001). Supplementation of transferrin-bound iron recovered functional and morphological abnormalities within 3 days.Conclusion: Iron deficiency directly affects human cardiomyocyte function, impairing mitochondrial respiration, and reducing contractility and relaxation. Restoration of intracellular iron levels can reverse these effects. [ABSTRACT FROM AUTHOR]

Background and Purpose: Anaemia of chronic disease (ACD) has been linked to iron-restricted erythropoiesis imposed by high circulating levels of hepcidin, a 25 amino acid hepatocyte-derived peptide that controls systemic iron homeostasis. Here, we report the engineering of the human lipocalin-derived, small protein-based anticalin PRS-080 hepcidin antagonist with high affinity and selectivity.Experimental Approach: Anticalin- and hepcidin-specific pharmacokinetic (PK)/pharmacodynamic modelling (PD) was used to design and select the suitable drug candidate based on t1/2 extension and duration of hepcidin suppression. The development of a novel free hepcidin assay enabled accurate analysis of bioactive hepcidin suppression and elucidation of the observed plasma iron levels after PRS-080-PEG30 administration in vivo.Key Results: PRS-080 had a hepcidin-binding affinity of 0.07 nM and, after coupling to 30 kD PEG (PRS-080-PEG30), a t1/2 of 43 h in cynomolgus monkeys. Dose-dependent iron mobilization and hepcidin suppression were observed after a single i.v. dose of PRS-080-PEG30 in cynomolgus monkeys. Importantly, in these animals, suppression of free hepcidin and subsequent plasma iron elevation were sustained during repeated s.c. dosing. After repeated dosing and followed by a treatment-free interval, all iron parameters returned to pre-dose values.Conclusions and Implications: In conclusion, we developed a dose-dependent and safe approach for the direct suppression of hepcidin, resulting in prolonged iron mobilization to alleviate iron-restricted erythropoiesis that can address the root cause of ACD. PRS-080-PEG30 is currently in early clinical development. [ABSTRACT FROM AUTHOR]

Background: Deferral for low hemoglobin (Hb) increases the likelihood that donors do not return for future donations. Zinc protoporphyrin (ZPP) has been described as a sensitive marker of iron-deficient erythropoiesis, before Hb decreases. It is a relatively cheap, rapid, and easy-to-perform measurement in a drop of whole blood. To assess the utility of ZPP measurement in donor management we examined whether ZPP and Hb levels among first-time donors differ from repeat donors. We further explored whether ZPP increases over subsequent donations at a donor population level and whether increasing ZPP levels coincide with decreasing Hb levels and donor deferral.Study Design and Methods: We included first-time (n = 4983) and repeat (n = 3533) whole blood donors from the ZPP and Iron in the Netherlands Cohort (ZINC) study. ZPP and Hb were measured at each subsequent donation during a 4-year period after inclusion in the study.Results: Median ZPP levels were higher in repeat than in first-time donors. In first-time donors, especially women, ZPP levels were increased with a corresponding decline in Hb levels over subsequent donations. ZPP levels were increased among first-time donors deferred for low Hb.Conclusion: Our results suggest that adding ZPP to Hb measurements in the daily blood collection setting, especially for first-time donors and first-time female donors may add to the identification of a donor subpopulation with low functional iron stores. [ABSTRACT FROM AUTHOR]

The Radboud Biobank offers disease-based biobanks a centralized facility to optimize the use and distribution of biomaterial for scientific research. Notably, two population biobanks are also included in this collection. All collections are professionally and sustainably maintained using high-quality and secure standardized protocols for ICT, legal-ethical aspects, sample collection, processing and storage, communication and distribution. The Radboud Biobank includes biomaterial (e.g. DNA, serum, plasma, tissue, urine and faeces - depending on the specific patient group), images, associated clinical data (patient, disease-specific and phenotypic data) and derived information (genotypic data, microarray gene expressions). Patient advocates and other relevant stakeholders are actively involved in the governance of the Radboud Biobank. [ABSTRACT FROM AUTHOR]

The Radboud Biobank offers disease-based biobanks a centralized facility to optimize the use and distribution of biomaterial for scientific research. Notably, two population biobanks are also included in this collection. All collections are professionally and sustainably maintained using high-quality and secure standardized protocols for ICT, legal-ethical aspects, sample collection, processing and storage, communication and distribution. The Radboud Biobank includes biomaterial (e.g. DNA, serum, plasma, tissue, urine and faeces - depending on the specific patient group), images, associated clinical data (patient, disease-specific and phenotypic data) and derived information (genotypic data, microarray gene expressions). Patient advocates and other relevant stakeholders are actively involved in the governance of the Radboud Biobank. [ABSTRACT FROM AUTHOR]

Background: Hepcidin is the central systemic regulator of iron metabolism, but its quantification in biological fluids is challenging. Rapid, accurate and user-friendly methods are needed. Our aim was to assess the ability of hepcidin as measured by three different c-ELISA assays to predict iron bioavailability in humans. Methods: The three assays used were commercially available DRG and Peninsula assays and the c-ELISA method performed at Radboud University Medical Centre, Nijmegen, The Netherlands (Hepcidinanalysis.com), validated by comparative measurements with time-of-flight mass spectrometry. We analyzed plasma samples (n = 37) selected to represent a broad range of hepcidin concentrations from a subgroup of healthy, iron-depleted women in a study assessing fractional absorption from iron supplements. Results: In single regressions, all three c-ELISA assays were predictors of fractional iron absorption: R2 = 0.363 (DRG), R2 = 0.281 (Peninsula) and R2 = 0.327 (Hepcidinanalysis. com). In multiple regressions, models including hepcidin measured with either DRG-, Peninsula or Hepcidinanalysis.com explained 55.7%, 44.5% and 52.5% of variance in fractional absorption, and hepcidin was a strong predictor of fractional absorption irrespective of the hepcidin assays used. However, we found significant differences in absolute values for hepcidin between different methods. Both the DRG assay’s (y = 0.61x + 0.87; R2 = 0.873) and the Peninsula assay’s measurements (y = 1.88x + 0.62; R2 = 0.770) were correlated with Hepcidinanalysis. com. Conclusions: The biological variability in plasma hepcidin, (inter-sample CV) was 5–10-fold higher for both the Peninsula and DRG assay than the analytical variably (inter-run within-sample CV) suggesting substantial discriminatory power to distinguish biological hepcidin variation. Between methods, prediction of iron bioavailability in generally healthy iron depleted subjects appears comparable. [ABSTRACT FROM AUTHOR]

Heme is an efficient source of iron in the diet, and heme preparations are used to prevent and cure iron deficiency anemia in humans and animals. However, the molecular mechanisms responsible for heme absorption remain only partially characterized. Here, we employed young iron-deficient piglets as a convenient animal model to determine the efficacy of oral heme iron supplementation and investigate the pathways of heme iron absorption. The use of bovine hemoglobin as a dietary source of heme iron was found to efficiently counteract the development of iron deficiency anemia in piglets, although it did not fully rebalance their iron status. Our results revealed a concerted increase in the expression of genes responsible for apical and basolateral heme transport in the duodenum of piglets fed a heme-enriched diet. In these animals the catalytic activity of heme oxygenase 1 contributed to the release of elemental iron from the protoporphyrin ring of heme within enterocytes, which may then be transported by the strongly expressed ferroportin across the basolateral membrane to the circulation. We hypothesize that the well-recognized high bioavailability of heme iron may depend on a split pathway mediating the transport of heme-derived elemental iron and intact heme from the interior of duodenal enterocytes to the bloodstream. [ABSTRACT FROM AUTHOR]

Patients with chronic kidney disease (CKD) and loss of kidney function are at increased risk for morbidity and mortality. The risks of CKD are attributed to "uremia," an increased concentration of uremic retention solutes (toxins) in the plasma. Recently, a colo-renal axis became clearly apparent and uremia has been associated with an altered gut microbiome composition and metabolism. There is a high prevalence of anemia in patients with CKD, for which patients are often treated with oral or intravenous iron. Recent in vivo and in vitro studies have reported adverse effects of oral iron supplementation on the gut microbiota composition, gut metabolome, and intestinal health, which in turn may result in an increased production of uremic toxins. It may also affect circulating levels of other microbe-derived molecules, that can act as mediators of immune regulation. Changes in body iron levels have also been reported to exert subtle effects on host immune function by modulating immune cell proliferation and differentiation, and by directly regulating cytokine formation and antimicrobial immune effector mechanisms. Based on the foregoing it is conceivable that oral iron supplementation in iron deficient predialysis CKD patients adversely changes gut microbiota composition, the gut and systemic metabolome, and host immunity and infection. Future studies are needed to confirm these hypotheses and to assess whether, compared to IV iron supplementation, oral iron supplementation negatively impacts on morbidity of CKD, and whether these adverse effects depend on the iron bioavailability of the iron formulation to the microbiota. [ABSTRACT FROM AUTHOR]

Purpose: The extent to which hepcidin regulation after acute bouts of exercise is influenced by baseline (resting) concentrations of key iron parameters remains uncertain. This investigation explored the influence of selected iron parameters and 25-km race walk time on 3-h post-exercise hepcidin-25 levels in international-level race walkers.Methods: Twenty-four male race walkers completed a graded exercise test and a 25-km race-walk trial. Throughout the 25-km race-walk, venous blood samples were collected pre-exercise, immediately post-exercise, and at 3-h post-exercise. Blood was analysed for serum ferritin, serum iron, Interleukin-6 (IL-6), and hepcidin-25 concentration.Results: IL-6 and hepcidin-25 increased (7.6- and 7.5-fold, respectively) in response to the 25-km race-walk trial (both p < 0.01). Significant individual relationships were evident between 3-h post-exercise hepcidin-25, baseline serum ferritin and serum iron (r > 0.62; p < 0.05). Multiple regression analysis showed that these two iron parameters, in addition to post-exercise IL-6 concentration and 25-km race-walk time, accounted for ~77% of the variance in 3-h post-exercise hepcidin-25 (p < 0.01). A median split by the cohort's baseline serum ferritin concentration (LOW: 58.0 vs. HIGH: 101.8 µg/L; p < 0.01) showed a significant between group difference in the 3-h post-exercise hepcidin-25 (LOW: 6.0 ± 3.6 vs. 11.3 ± 5.4 nM; p = 0.01), despite no differences in baseline serum iron, post-exercise IL-6, or 25-km race-walk time (all p > 0.05).Conclusion: Despite exercise activating numerous hepcidin regulators, baseline iron status appears to play a dominant role in the regulation of hepcidin-25 in elite-level athletes subsequent to endurance exercise. [ABSTRACT FROM AUTHOR]

Background: In the past, elevated estradiol levels were reported to downregulate the iron regulatory hormone hepcidin, thereby potentially improving iron metabolism. As estrogen plays a role in regulating the menstrual cycle and can influence the cytokine interleukin-6 (IL-6; a hepcidin up-regulator), this investigation examined the effects of estradiol supplementation achieved by the use of a monophasic oral contraceptive pill (OCP) on IL-6, hepcidin levels and iron status during the hormone-deplete versus hormone-replete phases within an oral contraceptive cycle (OCC). Methods: Fifteen healthy female OCP users were recruited and provided a venous blood sample on 2 separate mornings during a 28-day period. These included (a) days 2-4 of the OCC, representing a hormone-free withdrawal period (WD); (b) days 12-14 of the OCC, representing the end of the first week of active hormone therapy (AHT). Results: IL-6 and hepcidin levels were not significantly different at WD and AHT. Serum ferritin was significantly higher (p = 0.039) during AHT as compared to WD. Conclusions: Fluctuations in OCP hormones (estradiol and/or progestogen) had no effect on basal IL-6 and hepcidin levels in young women. Nevertheless, elevated ferritin levels recorded during AHT may indicate that OCP hormones can positively influence iron stores within an OCC despite unchanged hepcidin levels. [ABSTRACT FROM AUTHOR]

Aims: Heart failure (HF) is a common manifestation of patients with primary and secondary causes of iron overload, whereas in patients with established HF iron deficiency impairs outcome. Whether iron stores, either depleted or in overload, amplify the risk for new-onset HF among healthy individuals is unknown. The present study aimed to assess whether markers of iron status or the iron-regulatory hormone hepcidin are associated with new-onset HF or cardiovascular (CV) events in the general population.Methods and Results: In 6386 subjects from the Prevention of REnal and Vascular ENd-stage Disease (PREVEND) trial, a prospective, community-based, cohort study, markers of iron status and the iron-regulatory hormone hepcidin were measured. Mean age was 53.1 ± 12.0 years, and 50.7% of the cohort was female. During a median follow-up of 8.3 (interquartile range 7.8-8.9) years, 199 subjects (3.1%) were newly diagnosed with HF, 456 (7.1%) experienced a CV event, and 356 (5.6%) died from all causes. A higher annual HF incidence per ferritin quartile was observed in women (P < 0.001), but not in men (P for interaction 0.032). Multivariable analyses demonstrated ferritin levels to remain independently predictive for new-onset HF in women only (P = 0.024). This association persisted within strata defined by markers of the metabolic syndrome, markers of inflammation, or other markers of iron homeostasis, including hepcidin. No association between ferritin or hepcidin and incident CV events or all-cause mortality was observed in either sex.Conclusions: Increased serum ferritin levels independently amplify the risk for new-onset HF in women in the community. [ABSTRACT FROM AUTHOR]

Ferric pyrophosphate citrate (Triferic) is a water-soluble iron salt that is administered via dialysate to maintain iron balance and hemoglobin in hemodialysis patients. This double-blind, randomized, placebo-controlled, single-, ascending-dose study was conducted to evaluate the pharmacokinetics and safety of intravenous ferric pyrophosphate citrate in 48 healthy iron-replete subjects (drug, n = 36; placebo, n = 12). Single doses of 2.5, 5.0, 7.5, or 10 mg of ferric pyrophosphate citrate or placebo were administered over 4 hours, and single doses of 15 or 20 mg of ferric pyrophosphate citrate or placebo were administered over 12 hours via intravenous infusion. Serum total iron (sFetot), transferrin-bound iron (TBI), hepcidin-25, and biomarkers of oxidative stress and inflammation were determined using validated assays. Marked diurnal variation in sFetot was observed in placebo-treated subjects. Concentrations of sFetot and TBI increased rapidly after drug administration, with maximum serum concentrations (Cmax) reached at the end of infusion. Increases in baseline-corrected Cmax and area under the concentration-time curve from 0 to the time of the last quantifiable concentration (AUC0-t) were dose proportional up to 100% transferrin saturation. Iron was rapidly cleared (apparent terminal phase half-life 1.2-2 hours). No significant changes from baseline in serum hepcidin-25 concentration were observed at end of infusion for any dose. Biomarkers of oxidative stress and inflammation were unaffected. Intravenous doses of ferric pyrophosphate citrate were well tolerated. These results demonstrate that intravenous ferric pyrophosphate citrate is rapidly bound to transferrin and cleared from the circulation without increasing serum hepcidin levels or biomarkers of oxidative stress or inflammation. [ABSTRACT FROM AUTHOR]

Aims Heart failure (HF) is a common manifestation of patients with primary and secondary causes of iron overload, whereas in patients with established HF iron deficiency impairs outcome. Whether iron stores, either depleted or in overload, amplify the risk for new-onset HF among healthy individuals is unknown. The present study aimed to assess whether markers of iron status or the iron-regulatory hormone hepcidin are associated with new-onset HF or cardiovascular (CV) events in the general population. Methods and results In 6386 subjects from the Prevention of REnal and Vascular ENd-stage Disease (PREVEND) trial, a prospective, community-based, cohort study, markers of iron status and the iron-regulatory hormone hepcidin were measured. Mean age was 53.1±12.0 years, and 50.7% of the cohort was female. During a median follow-up of 8.3 (interquartile range 7.8-8.9) years, 199 subjects (3.1%) were newly diagnosed with HF, 456 (7.1%) experienced a CV event, and 356 (5.6%) died from all causes. A higher annual HF incidence per ferritin quartile was observed in women (P < 0.001), but not in men (P for interaction 0.032). Multivariable analyses demonstrated ferritin levels to remain independently predictive for new-onset HF in women only (P = 0.024). This association persisted within strata defined by markers of the metabolic syndrome, markers of inflammation, or other markers of iron homeostasis, including hepcidin. No association between ferritin or hepcidin and incident CV events or all-cause mortality was observed in either sex. Conclusions Increased serum ferritin levels independently amplify the risk for new-onset HF in women in the community. [ABSTRACT FROM AUTHOR]

Current treatment for newly diagnosed patients with hereditary hemochromatosis (HH) and iron overload consist of weekly phlebotomy or less frequent and more personalized erythrocytapheresis. Previous observations during phlebotomy suggest an increase in intestinal iron uptake caused by lowering of hepcidin as a result of intensive bloodletting. It is not known whether such an effect is present or even more pronounced using erythrocytapheresis since a larger amount of iron is extracted per procedure. In this study we aimed to assess the effect of erythrocytapheresis on the course of iron parameters, with special focus on serum hepcidin. We performed a retrospective proof-of-principle observational study, comparing serum iron parameters in 12 males during the depletion phase using either phlebotomy ( n = 6) or erythrocytapheresis ( n = 6). Decreases in serum ferritin over time were similar for both treatments but more pronounced using erythrocytapheresis when expressed per treatment procedure. Hemoglobin did not change during erythrocytapheresis, whereas during phlebotomy decreased with 10%. Increase of erythropoietin and soluble transferrin receptor and decrease in transferrin saturation were similar for both treatments. Reduction in serum hepcidin was higher (50% versus 25% of initial value) and occurred more early using phlebotomy (10 versus 20 weeks after start). In aggregate, compared to phlebotomy, the less frequent and more personalized erythrocytapheresis leads to a more pronounced decrease in serum ferritin per treatment procedure, without a larger decrease in serum hepcidin. This may be clinically relevant and may prevent an increase in intestinal iron uptake and an ensuing vicious circle of more frequent treatment procedures. J. Clin. Apheresis 31:564-570, 2016. © 2015 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Serum hepcidin concentration is regulated by iron status, inflammation, erythropoiesis and numerous other factors, but underlying processes are incompletely understood. We studied the association of common and rare single nucleotide variants (SNVs) with serum hepcidin in one Italian study and two large Dutch population-based studies. We genotyped common SNVs with genome-wide association study (GWAS) arrays and subsequently performed imputation using the 1000 Genomes reference panel. Cohort-specific GWAS were performed for log-transformed serum hepcidin, adjusted for age and gender, and results were combined in a fixed-effects meta-analysis (total N 6,096). Six top SNVs (p<5x10-6) were genotyped in 3,821 additional samples, but associations were not replicated. Furthermore, we meta-analyzed cohort-specific exome array association results of rare SNVs with serum hepcidin that were available for two of the three cohorts (total N 3,226), but no exome-wide significant signal (p<1.4x10-6) was identified. Gene-based meta-analyses revealed 19 genes that showed significant association with hepcidin. Our results suggest the absence of common SNVs and rare exonic SNVs explaining a large proportion of phenotypic variation in serum hepcidin. We recommend extension of our study once additional substantial cohorts with hepcidin measurements, GWAS and/or exome array data become available in order to increase power to identify variants that explain a smaller proportion of hepcidin variation. In addition, we encourage follow-up of the potentially interesting genes that resulted from the gene-based analysis of low-frequency and rare variants. [ABSTRACT FROM AUTHOR]

Background: Hepcidin regulates systemic iron homeostasis by downregulating the iron exporter ferroportin. Circulating hepcidin is mainly derived from the liver but hepcidin is also produced in the heart. We studied the differential and local regulation of hepcidin gene expression in response to myocardial infarction (MI) and/or chronic kidney disease (CKD). We hypothesized that cardiac hepcidin gene expression is induced by and regulated to severity of cardiac injury, either through direct (MI) or remote (CKD) stimuli, as well as through increased local iron content.Methods: Nine weeks after subtotal nephrectomy (SNX) or sham surgery (CON), rats were subjected to coronary ligation (CL) or sham surgery to realize 4 groups: CON, SNX, CL and SNX + CL. In week 16, the gene expression of hepcidin, iron and damage markers in cardiac and liver tissues was assessed by quantitative polymerase chain reaction and ferritin protein expression was studied by immunohistochemistry.Results: Cardiac hepcidin messenger RNA (mRNA) expression was increased 2-fold in CL (p = 0.03) and 3-fold in SNX (p = 0.01). Cardiac ferritin staining was not different among groups. Cardiac hepcidin mRNA expression correlated with mRNA expression levels of brain natriuretic peptide (β = 0.734, p < 0.001) and connective tissue growth factor (β = 0.431, p = 0.02). In contrast, liver hepcidin expression was unaffected by SNX and CL alone, while it had decreased 50% in SNX + CL (p < 0.05). Hepatic ferritin immunostaining was not different among groups.Conclusions: Our data indicate differences in hepcidin regulation in liver and heart and suggest a role for injury rather than iron as the driving force for cardiac hepcidin expression in renocardiac failure. [ABSTRACT FROM AUTHOR]

Acute kidney injury (AKI) is a common and often devastating condition among hospitalized patients and is associated with markedly increased hospital length of stay, mortality, and cost. The pathogenesis of AKI is complex, but animal models support an important role for catalytic iron in causing AKI. Catalytic iron, also known as labile iron, is a transitional pool of non-transferrin-bound iron that is readily available to participate in redox cycling. Initial findings related to catalytic iron and animal models of kidney injury have only recently been extended to human AKI. In this review, we discuss the role of catalytic iron in human AKI, focusing on recent translational studies in humans, assay considerations, and potential therapeutic targets for future interventional studies. [ABSTRACT FROM AUTHOR]