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1
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Kuragano T. Treatment of Anemia Associated with Chronic Kidney Disease: Plea for Considering Physiological Erythropoiesis. Int J Mol Sci 2024; 25:7322. [PMID: 39000429 PMCID: PMC11242251 DOI: 10.3390/ijms25137322] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2024] [Revised: 06/21/2024] [Accepted: 06/25/2024] [Indexed: 07/16/2024] Open
Abstract
Traditionally, the treatment of anemia associated with chronic kidney disease (CKD) involves prescribing erythropoiesis-stimulating agents (ESAs) or iron preparations. The effectiveness and safety of ESAs and iron have been established. However, several clinical issues, such as hyporesponsiveness to ESAs or defective iron utilization for erythropoiesis, have been demonstrated. Recently, a new class of therapeutics for renal anemia known as hypoxia-inducible factor (HIF)/proline hydroxylase (PH) inhibitors has been developed. Several studies have reported that HIF-PH inhibitors have unique characteristics compared with those of ESAs. In particular, the use of HIF-PH inhibitors may maintain target Hb concentration in patients treated with a high dose of ESAs without increasing the dose. Furthermore, several recent studies have demonstrated that patients with CKD with defective iron utilization for erythropoiesis had a high risk of cardiovascular events or premature death. HIF-PH inhibitors increase iron transport and absorption from the gastrointestinal tract; thus, they may ameliorate defective iron utilization for erythropoiesis in patients with CKD. Conversely, several clinical problems, such as aggravation of thrombotic and embolic complications, diabetic retinal disease, and cancer, have been noted at the time of HIF-PH inhibitor administration. Recently, several pooled analyses of phase III trials have reported the non-inferiority of HIF-PH inhibitors regarding these clinical concerns compared with ESAs. The advantages and issues of anemia treatment by ESAs, iron preparations, and HIF-PH inhibitors must be fully understood. Moreover, patients with anemia and CKD should be treated by providing a physiological erythropoiesis environment that is similar to that of healthy individuals.
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Affiliation(s)
- Takahiro Kuragano
- Division of Kidney and Dialysis, Hyogo Medical University, Hyogo 663-8501, Japan
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2
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Yuan XM, Sultana N, Ghosh-Laskar M, Li W. Elevated Hepcidin Expression in Human Carotid Atheroma: Sex-Specific Differences and Associations with Plaque Vulnerability. Int J Mol Sci 2024; 25:1706. [PMID: 38338987 PMCID: PMC10855936 DOI: 10.3390/ijms25031706] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2023] [Revised: 01/19/2024] [Accepted: 01/27/2024] [Indexed: 02/12/2024] Open
Abstract
Hepcidin is upregulated by increased body iron stores and inflammatory cytokines. It is associated with cardiovascular events, arterial stiffness, and increased iron accumulation in human atheroma with hemorrhage. However, it is unknown whether the expression of hepcidin in human carotid plaques is related to plaque severity and whether hepcidin expression differs between men and women. Carotid samples from 58 patients (38 males and 20 females) were immunostained with hepcidin, macrophages, ferritin, and transferrin receptor. Immunocytochemistry of hepcidin was performed on THP-1 macrophages exposed to iron or 7betahydroxycholesterol. Hepcidin expression significantly increases with the progression of human atherosclerotic plaques. Plaques of male patients have significantly higher levels of hepcidin. Expressions of hepcidin are significantly correlated with the accumulation of CD68-positive macrophages and transferrin receptor 1 (TfR1) and apoptosis. In vitro, hepcidin is significantly increased in macrophages exposed to iron and moderately increased following 7-oxysterol treatment. In the cultured cells, suppression of hepcidin protected against macrophage cell death, lysosomal membrane permeabilization, and oxidative stress. Hepcidin may play a crucial role in the development and progression of atherosclerosis. The differential expression of hepcidin in male and female patients and its significant correlations with plaque severity, highlight the potential of hepcidin as a biomarker for risk stratification and therapeutic targeting in atherosclerosis.
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Affiliation(s)
- Xi-Ming Yuan
- Occupational and Environmental Medicine, Department of Health, Medicine and Caring Sciences, Linköping University, 581 85 Linköping, Sweden;
| | - Nargis Sultana
- Laboratory Medicine, Linköping University Hospital, 581 85 Linköping, Sweden;
| | | | - Wei Li
- Obstetrics and Gynaecology in Linköping, Department of Biomedical and Clinical Sciences, Linköping University, 581 85 Linköping, Sweden
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3
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Patino E, Akchurin O. Erythropoiesis-independent effects of iron in chronic kidney disease. Pediatr Nephrol 2022; 37:777-788. [PMID: 34244852 DOI: 10.1007/s00467-021-05191-9] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/07/2021] [Revised: 05/23/2021] [Accepted: 06/08/2021] [Indexed: 12/19/2022]
Abstract
Chronic kidney disease (CKD) leads to alterations of iron metabolism, which contribute to the development of anemia and necessitates iron supplementation in patients with CKD. Elevated hepcidin accounts for a significant iron redistribution in CKD. Recent data indicate that these alterations in iron homeostasis coupled with therapeutic iron supplementation have pleiotropic effects on many organ systems in patients with CKD, far beyond the traditional hematologic effects of iron; these include effects of iron on inflammation, oxidative stress, kidney fibrosis, cardiovascular disease, CKD-mineral and bone disorder, and skeletal growth in children. The effects of iron supplementation appear to be largely dependent on the route of administration and on the specific iron preparation. Iron-based phosphate binders exemplify the opportunity for using iron for both traditional (anemia) and novel (hyperphosphatemia) indications. Further optimization of iron therapy in patients with CKD may inform new approaches to the treatment of CKD complications and potentially allow modification of disease progression.
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Affiliation(s)
- Edwin Patino
- Department of Medicine, Division of Nephrology and Hypertension, Weill Cornell Medical College, New York, NY, USA
| | - Oleh Akchurin
- Department of Pediatrics, Division of Pediatric Nephrology, Weill Cornell Medical College, New York, NY, USA. .,New York-Presbyterian Hospital, New York-Presbyterian Phyllis and David Komansky Children's Hospital, Weill Cornell Medicine, 505 East 70th Street - HT 388, New York, NY, 10021, USA.
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Liu B, Yang Q, Zhao L, Shui H, Si X. Vitamin D receptor gene polymorphism predicts left ventricular hypertrophy in maintenance hemodialysis. BMC Nephrol 2022; 23:32. [PMID: 35033017 PMCID: PMC8761333 DOI: 10.1186/s12882-021-02640-3] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2021] [Accepted: 12/13/2021] [Indexed: 01/04/2023] Open
Abstract
Background To verify that the single nucleotide polymorphisms (SNP) of vitamin D receptor (VDR) may lead to genetic susceptibility to left ventricular hypertrophy (LVH), the present study was designed to study four SNPs of VDR associated with LVH in maintenance hemodialysis (MHD) patients of Han nationality. Methods 120 MHD patients were recruited at Department of Nephrology, Zhongnan Hospital of Wuhan University to analyze the expression of genotype, allele and haplotype of Fok I, Bsm I, Apa I and Taq I in blood samples, and to explore their correlation with blood biochemical indexes and ventricular remodeling. Results The results showed that the risks of CVD included gender, dialysis time, heart rate, SBP, glycated hemoglobin, calcium, iPTH and CRP concentration. Moreover, LAD, LVDd, LVDs, IVST and LVMI in B allele of Bsm I increased significantly. Fok I, Apa I and Taq I polymorphisms have no significant difference between MHD with LVH and without LVH. Further study showed that VDR expression level decreased significantly in MHD patients with LVH, and the B allele was positively correlated with VDR Expression. Conclusion VDR Bsm I gene polymorphism may predict cardiovascular disease risk of MDH patients, and provided theoretical basis for early detection and prevention of cardiovascular complications.
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Affiliation(s)
- Bingman Liu
- Department of Nephrology, Zhongnan Hospital of Wuhan University, No.169 Donghu Road, Wuchang District, Wuhan, 430071, China
| | - Qingqing Yang
- Department of Nephrology, Zhongnan Hospital of Wuhan University, No.169 Donghu Road, Wuchang District, Wuhan, 430071, China
| | - Liangyu Zhao
- Department of Nephrology, Zhongnan Hospital of Wuhan University, No.169 Donghu Road, Wuchang District, Wuhan, 430071, China
| | - Hua Shui
- Department of Nephrology, Zhongnan Hospital of Wuhan University, No.169 Donghu Road, Wuchang District, Wuhan, 430071, China
| | - Xiaoyun Si
- Department of Nephrology, Zhongnan Hospital of Wuhan University, No.169 Donghu Road, Wuchang District, Wuhan, 430071, China.
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Afsar RE, Kanbay M, Ibis A, Afsar B. In-depth review: is hepcidin a marker for the heart and the kidney? Mol Cell Biochem 2021; 476:3365-3381. [PMID: 33942218 DOI: 10.1007/s11010-021-04168-4] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2021] [Accepted: 04/21/2021] [Indexed: 12/15/2022]
Abstract
Iron is an essential trace element involved in oxidation-reduction reactions, oxygen transport and storage, and energy metabolism. Iron in excess can be toxic for cells, since iron produces reactive oxygen species and is important for survival of pathogenic microbes. There is a fine-tuning in the regulation of serum iron levels, determined by intestinal absorption, macrophage iron recycling, and mobilization of hepatocyte stores versus iron utilization, primarily by erythroid cells in the bone marrow. Hepcidin is the major regulatory hormone of systemic iron homeostasis and is upregulated during inflammation. Hepcidin metabolism is altered in chronic kidney disease. Ferroportin is an iron export protein and mediates iron release into the circulation from duodenal enterocytes, splenic reticuloendothelial macrophages, and hepatocytes. Systemic iron homeostasis is controlled by the hepcidin-ferroportin axis at the sites of iron entry into the circulation. Hepcidin binds to ferroportin, induces its internalization and intracellular degradation, and thus inhibits iron absorption from enterocytes, and iron release from macrophages and hepatocytes. Recent data suggest that hepcidin, by slowing or preventing the mobilization of iron from macrophages, may promote atherosclerosis and may be associated with increased cardiovascular disease risk. This article reviews the current data regarding the molecular and cellular pathways of systemic and autocrine hepcidin production and seeks the answer to the question whether changes in hepcidin translate into clinical outcomes of all-cause and cardiovascular mortality, and cardiovascular and renal end-points.
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Affiliation(s)
- Rengin Elsurer Afsar
- Department of Nephrology, Faculty of Medicine, Suleyman Demirel University, Isparta, Turkey.
| | - Mehmet Kanbay
- Department of Nephrology, Faculty of Medicine, Koc University, Istanbul, Turkey
| | - Avsin Ibis
- Department of Nephrology, Afyon Kocatepe Devlet Hastanesi, Afyon, Turkey
| | - Baris Afsar
- Department of Nephrology, Faculty of Medicine, Suleyman Demirel University, Isparta, Turkey
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Xu Y, Wang Y, Hu H, Li J, Tian T. Relationship between serum hepcidin levels and cardiovascular disease in patients with maintenance hemodialysis. Physiol Int 2020; 107:491-500. [PMID: 33355540 DOI: 10.1556/2060.2020.00040] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2020] [Accepted: 07/06/2020] [Indexed: 11/19/2022]
Abstract
Background To investigate the serum level of hepcidin and its relationship with cardiovascular disease (CVD) in maintenance hemodialysis (MHD) patients. Methods Blood was obtained from 75 MHD patients before undergoing hemodialysis and 20 healthy controls. Serum hepcidin, advanced oxidation protein products (AOPP) and interleukin (IL)-6 were measured by enzyme-linked immunosorbant assay (ELISA). Spearman correlation, and binary logistic regression linear regression analyses were used to assess the relationship between serum hepcidin and other parameters. Results The serum level of hepcidin, AOPP and IL-6 was significantly up-regulated in MHD patients compared with the control (P < 0.05). Furthermore, serum hepcidin levels in patients with CVD were higher than those in patients without CVD (P < 0.05). In all MHD patients, serum hepcidin level was correlated positively with erythropoietin (EPO) dose per week (ρ = 0.251, P = 0.030), EPO resistance index (ρ = 0.268, P = 0.020), ferritin (ρ = 0.814, P < 0.001), transferin saturation (TSAT, ρ = 0.263, P = 0.023), AOPP (ρ = 0.280, P = 0.049), high sensitive C reactive protein (ρ = 0.151, P = 0.006), IL-6 (ρ = 0.340, P = 0.003) and left ventricular mass index (LVMI, ρ = 0.290, P = 0.033). Moreover, it was negatively correlated with serum pre-albumin (ρ = -0.266, P = 0.021), total iron-binding capacity (TIBC, ρ = -0.458, P < 0.001), unsaturated iron-binding capacity (UIBC, ρ = -0.473, P < 0.001) and transferrin (ρ = -0.487, P < 0.001). Linear regression analysis showed that ferritin (β = 0.708, P < 0.001), TIBC (β = -0.246, P = 0.032) and IL-6 (β = 0.209, P = 0.041) were independently associated with hepcidin. Results of binary logistic regression analysis suggested that higher serum hepcidin level (>249.2 ng/mL) was positively and independently related to CVD (OR = 1.32, 95% CI [1.20-9.56], P = 0.043). Conclusions Serum hepcidin level is associated with CVD in MHD patients, indicating that hepcidin may be a novel biomarker and therapeutic target for CVD.
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Affiliation(s)
- Y Xu
- 1Hemodialysis Center, Shanghai Yangsi Hospital, Pudong New Area, Shanghai, China
| | - Y Wang
- 2Hemodialysis Center, Yantai Affiliated Hospital of Binzhou Medical University, Yantai City, Shandong Province, China
| | - H Hu
- 1Hemodialysis Center, Shanghai Yangsi Hospital, Pudong New Area, Shanghai, China
| | - J Li
- 1Hemodialysis Center, Shanghai Yangsi Hospital, Pudong New Area, Shanghai, China
| | - T Tian
- 1Hemodialysis Center, Shanghai Yangsi Hospital, Pudong New Area, Shanghai, China
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7
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Yang Q, Liu W, Zhang S, Liu S. The cardinal roles of ferroportin and its partners in controlling cellular iron in and out. Life Sci 2020; 258:118135. [DOI: 10.1016/j.lfs.2020.118135] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2020] [Revised: 07/14/2020] [Accepted: 07/20/2020] [Indexed: 12/12/2022]
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Kuragano T, Joki N, Hase H, Kitamura K, Murata T, Fujimoto S, Fukatsu A, Inoue T, Itakura Y, Nakanishi T. Low transferrin saturation (TSAT) and high ferritin levels are significant predictors for cerebrovascular and cardiovascular disease and death in maintenance hemodialysis patients. PLoS One 2020; 15:e0236277. [PMID: 32877424 PMCID: PMC7467218 DOI: 10.1371/journal.pone.0236277] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2020] [Accepted: 07/01/2020] [Indexed: 12/17/2022] Open
Abstract
Patients with high serum ferritin and low transferrin saturation (TSAT) levels could be considered as presenting with dysutilization of iron for erythropoiesis. However, the long-term safety of iron administration in these patients has not been well established. An observational multicenter study was performed over 3 years. In 805 patients undergoing maintenance hemodialysis (MHD), we defined dysutilization of iron for erythropoiesis in patients with lower TSAT (<20%) and higher ferritin (≥100 ng/mL) levels. A time-dependent Cox hazard model was used for the evaluation of the association between dysutilization of iron for erythropoiesis and adverse events and survival. Patients with low TSAT levels showed an increased risk of cerebrovascular and cardiovascular disease (CCVD) and death compared to patients with normal or higher TSAT levels. Patients with low ferritin and high TSAT levels had a significantly lower risk of CCVD and death compared with patients with high ferritin and low TSAT levels. Higher TSAT levels were associated with male gender, age, the absence of diabetes, low levels of high-sensitivity CRP, and low β2 microglobulin levels, but not with intravenous iron administration or ferritin levels. Although patients with low TSAT levels had a significantly higher risk of CCVD or death, high TSAT levels were not linked with iron administration. Patients, who were suspected of dysutilization of iron for erythropoiesis, had a higher risk of CCVD and death. The administration of iron should be performed cautiously for improving TSAT levels, as iron administration could sustain TSAT levels for a short term.
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Affiliation(s)
- Takahiro Kuragano
- Department of Internal Medicine, Division of Kidney and Dialysis, Hyogo College of Medicine, Nisinomiya, Japan
- * E-mail:
| | - Nobuhiko Joki
- Department of Nephrology, Toho University Ohashi Medical Center, Tokyo, Japan
| | - Hiroki Hase
- Department of Nephrology, Toho University Ohashi Medical Center, Tokyo, Japan
| | - Kenichiro Kitamura
- The Third Department of Internal Medicine Faculty of Medicine, The University of Yamanashi, Yamanashi, Japan
| | - Toshiaki Murata
- Department of Nephrology, Murakami karin dou Hospital, Fukuoka, Japan
| | - Shouichi Fujimoto
- Department of Hemovascular Medicine and Artificial Organs, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan
| | - Atushi Fukatsu
- Department of Nephrology, Hekinan Municipal Hospital, Hekinan, Japan
| | - Toru Inoue
- Department of Internal Medicine, Yuseikai Clinic, Osaka, Japan
| | | | - Takeshi Nakanishi
- Department of Internal Medicine, Division of Kidney and Dialysis, Hyogo College of Medicine, Nisinomiya, Japan
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9
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Nakanishi T, Nanami M, Kuragano T. The pathogenesis of CKD complications; Attack of dysregulated iron and phosphate metabolism. Free Radic Biol Med 2020; 157:55-62. [PMID: 31978539 DOI: 10.1016/j.freeradbiomed.2020.01.024] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/29/2019] [Revised: 01/07/2020] [Accepted: 01/20/2020] [Indexed: 01/17/2023]
Abstract
Chronic kidney disease (CKD) patients have a tremendously higher risk of developing cardiovascular disease (CVD) and infection than the non-CKD population, which could be caused by intertwining actions of hyperphosphatemia and CKD associated misdistribution of iron. CVD is often associated with vascular calcification, which has been attributed to hyperphosphatemia, and could be initiated in mitochondria, inducing apoptosis, and accelerated by reactive oxygen species (ROS). The production of ROS is principally linked to intracellular ferrous iron. For infection, the virulence and pathogenicity of a pathogen is directly related to its capacity to acquire iron for proliferation and to escape or subvert the host's immune response. Iron administration for renal anemia can sometimes be overdosed, which could decrease host immune mechanisms through its direct effect on neutrophils, macrophages and T cell function. Hyperphosphatemia has been demonstrated to be associated with an increased incidence of infection. We hypothesized two possible mechanisms: 1) fibroblast growth factor-23 levels are increased in parallel with serum phosphate levels and directly impair leukocyte recruitment and host defense mechanisms, and 2) circulating non-transferrin-bound iron (NTBI) is increased due to decreased iron binding capacity of the carrier protein transferrin in high-phosphate conditions. From these observations, maintaining an adequate serum range of phosphate levels and minimizing intracellular iron accumulation could attenuate the development of CKD complications.
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Affiliation(s)
- Takeshi Nakanishi
- Department of Nephrology, Sumiyoshigawa Hospital, Japan; Department of Internal Medicine, Division of Kidney and Dialysis, Hyogo College of Medicine, Japan.
| | - Masayoshi Nanami
- Department of Internal Medicine, Division of Kidney and Dialysis, Hyogo College of Medicine, Japan.
| | - Takahiro Kuragano
- Department of Internal Medicine, Division of Kidney and Dialysis, Hyogo College of Medicine, Japan.
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10
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Wunderer F, Traeger L, Sigurslid HH, Meybohm P, Bloch DB, Malhotra R. The role of hepcidin and iron homeostasis in atherosclerosis. Pharmacol Res 2020; 153:104664. [PMID: 31991168 PMCID: PMC7066581 DOI: 10.1016/j.phrs.2020.104664] [Citation(s) in RCA: 61] [Impact Index Per Article: 12.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/27/2019] [Revised: 12/20/2019] [Accepted: 01/24/2020] [Indexed: 02/06/2023]
Abstract
Atherosclerotic cardiovascular disease is a major burden on global health and a leading cause of death worldwide. The pathophysiology of this chronic disease is complex, involving inflammation, lipoprotein oxidation and accumulation, plaque formation, and calcification. In 1981, Dr. Jerome Sullivan formulated the 'Iron Hypothesis', suggesting that higher levels of stored iron promote cardiovascular diseases, whereas iron deficiency may have an atheroprotective effect. This hypothesis has stimulated research focused on clarifying the role of iron in the development of atherosclerosis. However, preclinical and clinical studies have produced contradictory results and the observation that patients with hemochromatosis do not appear to have an increased risk of atherosclerosis seemed incongruous with Sullivan's initial hypothesis. The 'paradox' of systemic iron overload not being accompanied by an increased risk for atherosclerosis led to a refinement of the iron hypothesis focusing on intracellular macrophage iron. More recent in vitro and animal studies have elucidated the complex signaling pathways regulating iron, with a particular focus on hepcidin, the master regulator of body iron homeostasis. Bone morphogenetic protein (BMP) signaling is the major pathway that is required for induction of hepcidin expression in response to increasing levels of iron. Strong links between iron homeostasis, BMP signaling, inflammation and atherosclerosis have been established in both mechanistic and human studies. This review summarizes the current understanding of the role of iron homeostasis and hepcidin in the development of atherosclerosis and discusses the BMP-hepcidin-ferroportin axis as a novel therapeutic target for the treatment of cardiovascular disease.
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Affiliation(s)
- Florian Wunderer
- Department of Anesthesiology, Intensive Care Medicine and Pain Therapy, University Hospital Frankfurt, Goethe University, Frankfurt, Germany
| | - Lisa Traeger
- Anesthesia Center for Critical Care Research of the Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital and Harvard Medical School, Boston
| | - Haakon H. Sigurslid
- Cardiovascular Research Center and the Cardiology Division of the Department of medicine, Massachusetts General Hospital and Harvard Medical School, Boston
| | - Patrick Meybohm
- Department of Anesthesiology, Intensive Care Medicine and Pain Therapy, University Hospital Frankfurt, Goethe University, Frankfurt, Germany
- Department of Anaesthesiology, University Hospital Wuerzburg, Wuerzburg, Germany
| | - Donald B. Bloch
- Anesthesia Center for Critical Care Research of the Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital and Harvard Medical School, Boston
- Division of Rheumatology, Allergy and Immunology of the Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston
| | - Rajeev Malhotra
- Cardiovascular Research Center and the Cardiology Division of the Department of medicine, Massachusetts General Hospital and Harvard Medical School, Boston
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Ghafourian K, Shapiro JS, Goodman L, Ardehali H. Iron and Heart Failure: Diagnosis, Therapies, and Future Directions. JACC Basic Transl Sci 2020; 5:300-313. [PMID: 32215351 PMCID: PMC7091506 DOI: 10.1016/j.jacbts.2019.08.009] [Citation(s) in RCA: 61] [Impact Index Per Article: 12.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/11/2019] [Revised: 08/29/2019] [Accepted: 08/29/2019] [Indexed: 12/11/2022]
Abstract
To date, 3 clinical trials have shown symptomatic benefit from the use of intravenous (IV) iron in patients with heart failure (HF) with low serum iron. This has led to recommendations in support of the use of IV iron in this population. However, the systemic and cellular mechanisms of iron homeostasis in cardiomyocyte health and disease are distinct, complex, and poorly understood. Iron metabolism in HF appears dysregulated, but it is still unclear whether the changes are maladaptive and pathologic or compensatory and protective for the cardiomyocytes. The serum markers of iron deficiency in HF do not accurately reflect cellular and mitochondrial iron levels, and the current definition based on the ferritin and transferrin saturation values is broad and inclusive of patients who do not need IV iron. This is particularly relevant in view of the potential risks that are associated with the use of IV iron. Reliable markers of cellular iron status may differentiate subgroups of HF patients who would benefit from cellular and mitochondrial iron chelation rather than IV iron.
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Key Words
- 6MWT, 6-min walk test
- CKD, chronic kidney disease
- DMT1, divalent metal transporter 1 protein
- FCM, ferric carboxymaltose
- FGF, fibroblast growth factor
- Fpn1, ferroportin 1
- Hb, hemoglobin
- I/R, ischemia/reperfusion
- ID, iron deficiency
- IV, intravenous
- LVEF, left ventricular ejection fraction
- NTBI, non–transferrin-bound iron
- NYHA, New York Heart Association
- PGA, Patient Global Assessment
- RCT, randomized clinical trial
- ROS, reactive oxygen species
- TSAT, transferrin saturation
- TfR1, transferrin receptor protein 1
- VO2, peak oxygen uptake
- heart failure
- intravenous iron
- iron chelation
- iron deficiency
- sTfR, soluble transferrin receptor
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Affiliation(s)
| | | | | | - Hossein Ardehali
- Feinberg Cardiovascular and Renal Research Institute, Northwestern University, Chicago, Illinois
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12
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Abstract
Iron is an essential element that is indispensable for life. The delicate physiological body iron balance is maintained by both systemic and cellular regulatory mechanisms. The iron-regulatory hormone hepcidin assures maintenance of adequate systemic iron levels and is regulated by circulating and stored iron levels, inflammation and erythropoiesis. The kidney has an important role in preventing iron loss from the body by means of reabsorption. Cellular iron levels are dependent on iron import, storage, utilization and export, which are mainly regulated by the iron response element-iron regulatory protein (IRE-IRP) system. In the kidney, iron transport mechanisms independent of the IRE-IRP system have been identified, suggesting additional mechanisms for iron handling in this organ. Yet, knowledge gaps on renal iron handling remain in terms of redundancy in transport mechanisms, the roles of the different tubular segments and related regulatory processes. Disturbances in cellular and systemic iron balance are recognized as causes and consequences of kidney injury. Consequently, iron metabolism has become a focus for novel therapeutic interventions for acute kidney injury and chronic kidney disease, which has fuelled interest in the molecular mechanisms of renal iron handling and renal injury, as well as the complex dynamics between systemic and local cellular iron regulation.
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13
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Vela D. Systemic and local hepcidin as emerging and important peptides in renal homeostasis and pathology. Biofactors 2019; 45:118-134. [PMID: 30461080 DOI: 10.1002/biof.1468] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/11/2018] [Revised: 09/20/2018] [Accepted: 09/26/2018] [Indexed: 12/14/2022]
Abstract
Recent data suggest that the importance of hepcidin goes beyond its classical role in controlling systemic iron metabolism. Local hepcidins are emerging as important peptides for organ homeostasis in the brain, heart, blood vessels, and in cancer as well. Similarly, accumulating data indicate that hepcidin does seem to be an important factor in renal homeostasis. This review encompasses present knowledge concerning the role of hepcidin in renoprotection and its use as a biomarker of kidney diseases. Understanding the role of hepcidin in kidneys is important due to its relevance for kidney physiology and its potential therapeutic application in kidney pathologies. © 2018 BioFactors, 45(2):118-134, 2019.
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Affiliation(s)
- Driton Vela
- Department of Physiology, Faculty of Medicine, University of Prishtina, Prishtina, Kosova
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14
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Nakanishi T, Kuragano T, Nanami M, Nagasawa Y, Hasuike Y. Misdistribution of iron and oxidative stress in chronic kidney disease. Free Radic Biol Med 2019; 133:248-253. [PMID: 29958932 DOI: 10.1016/j.freeradbiomed.2018.06.025] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/30/2018] [Revised: 06/19/2018] [Accepted: 06/21/2018] [Indexed: 12/17/2022]
Abstract
Chronic kidney disease (CKD) patients have an extremely high risk of developing cardiovascular diseases (CVD) compared to the general population. Systemic inflammation associated with oxidative stress could be an important determinant of morbidity and mortality associated with CVD. We suspected that dysregulation of iron metabolism should be considered in these patients. Anemia is prevalent in CKD patients and is often treated with erythropoiesis-stimulating agents (ESAs) and iron. In addition, iron administration sometimes causes iron overdose. Excessive iron in the cytosol and mitochondria can accelerate the formation of a highly toxic reactive oxygen species, hydroxyl radicals, which damage lipids, proteins, and DNA. In this review, we propose the following four major reasons for oxidative stress in CKD patients: 1) iron is sequestered in cells by proinflammatory cytokines and hepcidin; 2) the reduction in frataxin increases "free" iron in mitochondria; 3) the accumulation of 5-aminolevulinic acid, a heme precursor, has toxic effects on iron and mitochondrial metabolism; and 4) the elevated levels of the metabolic hormone, leptin, promote hepatic hepcidin production. Although an efficient therapy for preventing oxidative stress in these patients has not yet been well defined, we propose that ESAs for renal anemia may ameliorate these causes of oxidative stress. Further clinical trials are necessary to clarify the effectiveness of ESAs on oxidative stress in CKD patients.
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Affiliation(s)
- Takeshi Nakanishi
- Department of Nephrology, Gojinkai-Sumiyoshigawa Hospital, Japan; Department of Internal Medicine, Division of Kidney and Dialysis, Hyogo College of Medicine, Japan.
| | - Takahiro Kuragano
- Department of Internal Medicine, Division of Kidney and Dialysis, Hyogo College of Medicine, Japan.
| | - Masayoshi Nanami
- Department of Internal Medicine, Division of Kidney and Dialysis, Hyogo College of Medicine, Japan.
| | - Yasuyuki Nagasawa
- Department of Internal Medicine, Division of Kidney and Dialysis, Hyogo College of Medicine, Japan.
| | - Yukiko Hasuike
- Department of Internal Medicine, Division of Kidney and Dialysis, Hyogo College of Medicine, Japan.
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15
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Wang X, Sheng L, Ye P, Cao R, Yang X, Xiao W, Zhang Y, Bai Y, Wu H. The association between Hepcidin and arterial stiffness in a community-dwelling population. Lipids Health Dis 2018; 17:244. [PMID: 30373612 PMCID: PMC6206657 DOI: 10.1186/s12944-018-0866-6] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2018] [Accepted: 09/11/2018] [Indexed: 11/10/2022] Open
Abstract
Background An association of hepcidin with cardiovascular (CV) disease and atherosclerosis has been reported in different patient groups. However, it has not been well described clinically the association between hepcidin and arterial stiffness. In this study,We analysed the possible mechanism of Hepcidin and arterial stiffness. Methods This article related measurements of plasma hepcidin and arterial stiffness (carotid–femoral pulse wave velocity [PWV]) in a community-based sample. Results After a median follow-up interval of 4.8 years, multiple linear regression analysis revealed that hepcidin was independently associated with carotid–femoral PWV (β = 1.498, P < 0.001). In a multivariable linear regression analysis, HDL3-C levels were negatively and independently associated with hepcidin at baseline (β = − 0.857, P = 0.024). HDL2-C was not associated with hepcidin at baseline (β = − 1.121, P = 0.133). Conclusions We found an association between baseline hepcidin and follow-up arterial stiffness that was independent of age, gender and other vascular risk factors. We also identified an association between hepcidin and HDL3-C at baseline, which indicates that the HDL3-C level may reflect the change in cholesterol efflux from peripheral arteries and partly explain the relationship between hepcidin and the change of arterial stiffness.
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Affiliation(s)
- Xiaona Wang
- Department of Geriatric Cardiology, Chinese PLA General Hospital, Fuxing Road #28, Beijing, 100853, China
| | - Li Sheng
- Department of Geriatric Cardiology, Chinese PLA General Hospital, Fuxing Road #28, Beijing, 100853, China
| | - Ping Ye
- Department of Geriatric Cardiology, Chinese PLA General Hospital, Fuxing Road #28, Beijing, 100853, China.
| | - Ruihua Cao
- Department of Geriatric Cardiology, Chinese PLA General Hospital, Fuxing Road #28, Beijing, 100853, China
| | - Xu Yang
- Department of Geriatric Cardiology, Chinese PLA General Hospital, Fuxing Road #28, Beijing, 100853, China
| | - Wenkai Xiao
- Department of Geriatric Cardiology, Chinese PLA General Hospital, Fuxing Road #28, Beijing, 100853, China
| | - Yun Zhang
- Department of Geriatric Cardiology, Chinese PLA General Hospital, Fuxing Road #28, Beijing, 100853, China
| | - Yongyi Bai
- Department of Geriatric Cardiology, Chinese PLA General Hospital, Fuxing Road #28, Beijing, 100853, China
| | - Hongmei Wu
- Department of Geriatric Cardiology, Chinese PLA General Hospital, Fuxing Road #28, Beijing, 100853, China
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16
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Ueda N, Takasawa K. Impact of Inflammation on Ferritin, Hepcidin and the Management of Iron Deficiency Anemia in Chronic Kidney Disease. Nutrients 2018; 10:nu10091173. [PMID: 30150549 PMCID: PMC6163440 DOI: 10.3390/nu10091173] [Citation(s) in RCA: 142] [Impact Index Per Article: 20.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2018] [Revised: 08/08/2018] [Accepted: 08/17/2018] [Indexed: 12/16/2022] Open
Abstract
Iron deficiency anemia (IDA) is a major problem in chronic kidney disease (CKD), causing increased mortality. Ferritin stores iron, representing iron status. Hepcidin binds to ferroportin, thereby inhibiting iron absorption/efflux. Inflammation in CKD increases ferritin and hepcidin independent of iron status, which reduce iron availability. While intravenous iron therapy (IIT) is superior to oral iron therapy (OIT) in CKD patients with inflammation, OIT is as effective as IIT in those without. Inflammation reduces predictive values of ferritin and hepcidin for iron status and responsiveness to iron therapy. Upper limit of ferritin to predict iron overload is higher in CKD patients with inflammation than in those without. However, magnetic resonance imaging studies show lower cutoff levels of serum ferritin to predict iron overload in dialysis patients with apparent inflammation than upper limit of ferritin proposed by international guidelines. Compared to CKD patients with inflammation, optimal ferritin levels for IDA are lower in those without, requiring reduced iron dose and leading to decreased mortality. The management of IDA should differ between CKD patients with and without inflammation and include minimization of inflammation. Further studies are needed to determine the impact of inflammation on ferritin, hepcidin and therapeutic strategy for IDA in CKD.
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Affiliation(s)
- Norishi Ueda
- Department of Pediatrics, Public Central Hospital of Matto Ishikawa, 3-8 Kuramitsu, Hakusan, Ishikawa 924-8588, Japan.
| | - Kazuya Takasawa
- Department of Internal Medicine, Public Central Hospital of Matto Ishikawa, 3-8 Kuramitsu, Hakusan, Ishikawa 924-8588, Japan.
- Department of Internal Medicine, Public Tsurugi Hospital, Ishikawa 920-2134, Japan.
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17
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Batar B, Bavunoglu I, Hacioglu Y, Cengiz M, Mutlu T, Yavuzer S, Yavuzer H, Cuhadar Ercelebi D, Erhan D, Unal S, Tunckale A, Guven M. The role of TMPRSS6 gene variants in iron-related hematological parameters in Turkish patients with iron deficiency anemia. Gene 2018; 673:201-205. [PMID: 29928945 DOI: 10.1016/j.gene.2018.06.055] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2018] [Revised: 05/07/2018] [Accepted: 06/18/2018] [Indexed: 10/28/2022]
Abstract
TMPRSS6 gene mutations can result in iron deficiency anemia (IDA) and cause an increased iron-regulatory hormone, hepcidin, levels. TMPRSS6 encodes a serine protease, matriptase-2, which functions as negative regulatory protein of hepcidin transcription. Thus, TMPRSS6 variations might be risk factors for IDA. The aim of the study was to investigate the association of rs855791, rs4820268, rs5756506, rs2235324, rs2413450, rs2111833, rs228919, and rs733655 SNPs in TMPRSS6 gene with IDA susceptibility and iron-related clinical parameters. The study consisted of 150 IDA patients and 100 healthy controls. We analyzed the genotype distributions by using Real-Time polymerase chain reaction (Real-Time PCR) technique. We did not find any statistically differences for all SNPs between patients and controls (P > 0.05). In IDA patients, variations rs855791 and rs2413450 were associated with increased RBC (P = 0.03) and TIBC (P = 0.04), respectively. Also, increased of TIBC for rs4820268 (P < 0.05). On the other hand, in control group, rs5756506 was associated with two parameters, Hb (P = 0.02) and Hct (P = 0.03). We did not find markedly hepcidin levels in IDA patients compared to controls (P = 0.32). Our findings suggest that TMPRSS6 variations may not be risk factors for IDA. However, TMPRSS6 polymorphisms are associated with increased many iron-related hematological parameters.
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Affiliation(s)
- Bahadir Batar
- Department of Medical Biology, Medical Faculty of Namik Kemal University, Tekirdag, Turkey.
| | - Isil Bavunoglu
- Department of Internal Medicine, Medical Faculty of Cerrahpasa, Istanbul University, Istanbul, Turkey
| | - Yalcin Hacioglu
- Department of Family Medicine, Istanbul Education and Research Hospital, Istanbul, Turkey
| | - Mahir Cengiz
- Department of Internal Medicine, Medical Faculty of Cerrahpasa, Istanbul University, Istanbul, Turkey
| | - Tuba Mutlu
- Department of Medical Biology, Medical Faculty of Cerrahpasa, Istanbul University, Istanbul, Turkey
| | - Serap Yavuzer
- Department of Internal Medicine, Medical Faculty of Cerrahpasa, Istanbul University, Istanbul, Turkey
| | - Hakan Yavuzer
- Department of Internal Medicine, Medical Faculty of Cerrahpasa, Istanbul University, Istanbul, Turkey
| | - Dilek Cuhadar Ercelebi
- Department of Internal Medicine, Medical Faculty of Cerrahpasa, Istanbul University, Istanbul, Turkey
| | - Duygu Erhan
- Department of Medical Biology, Medical Faculty of Cerrahpasa, Istanbul University, Istanbul, Turkey
| | - Selin Unal
- Department of Medical Biology, Medical Faculty of Cerrahpasa, Istanbul University, Istanbul, Turkey
| | - Aydin Tunckale
- Department of Internal Medicine, Medical Faculty of Cerrahpasa, Istanbul University, Istanbul, Turkey
| | - Mehmet Guven
- Department of Medical Biology, Medical Faculty of Cerrahpasa, Istanbul University, Istanbul, Turkey
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18
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Relation between high serum hepcidin-25 level and subclinical atherosclerosis and cardiovascular mortality in hemodialysis patients. Anatol J Cardiol 2018; 19:117-122. [PMID: 29339674 PMCID: PMC5864805 DOI: 10.14744/anatoljcardiol.2017.8019] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
OBJECTIVE In hemodialysis (HD) patients, cardiovascular disease (CVD) is the major cause of mortality and morbidity. In atherosclerotic diseases, iron gets accumulated in the arterial wall. Hepcidin is an important hormone in iron metabolism. Furthermore, hepcidin is associated with atherosclerotic disease. Therefore, this study aims to investigate the relation of serum hepcidin-25 (SH-25) and sub-clinic atherosclerosis measured by carotid intima-media thickness (CIMT) and mortality in HD patients. METHODS We enrolled 82 HD patients in a cross-control study. We measured SH-25 using ELISA kit and CIMT using high-resolution real-time ultrasonography. After 4 years of first assessment, we investigated the relation between all-cause and cardiovascular mortality and SH-25 and CIMT. RESULTS Two patients were excluded because of renal transplantation. The survivors were younger (53.7±15.1 vs. 65.2±15.5; p<0.05) and CIMT was lower (0.83±0.2 vs. 0.95±0.2; p<0.05); however, there was no significant difference in SH-25 levels between the groups (29.1±13 vs. 32.4±22.4; p=0.767). The patients who died of CVD were significantly older (63.7±16.1 vs. 53.7±15.1; p<0.05) and had significantly higher CIMT (0.94±0.2 vs. 83±0.2; p<0.05). The SH-25 levels were statistically significantly higher in patients who died of CVD (40.3±25 vs. 29.1±13; p<0.05). Linear regression analysis showed a positive correlation between CIMT and SH-25 in the study population and in those who died from CVD (r=0.41; p<0.05 and r=0.606; p<0.05, respectively). CONCLUSION This study suggests that hepcidin is effective in cardiovascular mortality and pathophysiology of subclinical atherosclerosis in HD patients.
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19
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Associations of plasma hepcidin with mortality risk in patients with coronary artery disease. Oncotarget 2017; 8:109497-109508. [PMID: 29312624 PMCID: PMC5752537 DOI: 10.18632/oncotarget.22722] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2017] [Accepted: 07/06/2017] [Indexed: 12/18/2022] Open
Abstract
Background Increased blood hepcidin may be associated with the presence and promotion of atherosclerosis, the association of hepcidin with mortality among coronary artery disease (CAD) patients remains unknown. We sought to assess the relationship of hepcidin and all-cause and cardiovascular disease (CVD) mortality among CAD patients with and without acute coronary syndrome (ACS). Methods and Results This study included 759 patients with ACS and 526 patients with stable CAD. After an average follow-up of 4.1 years, 154 deaths were recorded, 114 were due to CVD. After adjusting for CVD risk factors and inflammatory markers, the plasma hepcidin was positively associated with all-cause and CVD mortality in the ACS patients, the multivariable-adjusted hazard ratios (HRs) across tertiles of hepcidin were 1.00, 2.18 (95% CI 1.23-3.94), and 2.82 (95% CI 1.59-5.12) for all-cause mortality (Ptrend=0.006), and 1.00, 2.20 (95% CI 1.12-4.05), and 2.64 (95% CI 1.41-5.65) for CVD mortality (Ptrend=0.01). The C-index and net reclassification improvement when including hepcidin in traditional CVD models were 1.6% and 21.5% for all-cause mortality, 1.4% and 23.5% for CVD mortality, respectively, (P<0.001). Conclusions Plasma hepcidin was positively associated with mortality in ACS patients. Hepcidin may be a potential biomarker for risk prediction in ACS patients.
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Liu WS, Chu DC, Chan HL, Li SY, Liu CK, Yang CY, Chen YW, Lee PC, Lai YT, Lin CC. Fixed dose of long-acting erythropoietic stimulating agents at higher frequency improves appetite, reduces inflammation and corrects anaemia in patients on haemodialysis. Clin Exp Pharmacol Physiol 2017; 43:875-82. [PMID: 27385380 DOI: 10.1111/1440-1681.12618] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2015] [Revised: 06/14/2016] [Accepted: 07/03/2016] [Indexed: 12/21/2022]
Abstract
Anaemia is an important issue in patients undergoing haemodialysis. We aimed to identify a better dosing schedule of a fixed monthly dose of continuous erythropoietin receptor activator (CERA) in patients with chronic kidney disease (CKD) on haemodialysis. The CERA dosing schedule included 100 μg once monthly for 2 months, 50 μg twice monthly for 2 months and then 100 μg once monthly for two months. The effectiveness was determined by comparing haematocrit, nutritional status (serum protein and albumin) and inflammatory markers (tumour necrosis factor (TNF)-α, interleukin (IL)-1, IL-6 and Hepcidin) at the beginning of the study with those at the end of the study. Forty-seven out of 67 patients completed the trial. At the end, haematocrit was significantly higher (34.51 vs 33.22%, P=.004), levels of inflammatory markers were significantly lower (TNF-α (30.71 vs 35.67 ng/mL, P=.007), IL-6 (5.12 vs 7.95 ng/mL, P=.033), hepcidin (60.39 vs 74.39 ng/mL, P=.002)), blood glucose levels were significantly lower (112.40 vs 139.02 mg/dL, P=.003) and albumin was significantly higher (4.11 vs 3.98, P=.001). Patients with a better than average response had a lower initial number of red blood cells (3.3 vs 3.6 × 10(6) /mm(3) , P=.025) and a lower IL-1 (3.8 vs 12.9 ng/mL, P=.01). They also had significantly lower blood glucose levels at the end. (91.3 vs 124.0 mg/dL, P=.03). We demonstrate that a fixed monthly dose of CERA at a twice monthly dosing schedule improves nutrition, reduces the inflammation and corrects anaemia in patients on haemodialysis. This finding may provide a new strategy for treating CKD-related anaemia.
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Affiliation(s)
- Wen-Sheng Liu
- Division of Nephrology, Department of Medicine, Taipei City Hospital, Zhong-Xing Branch, Taipei, Taiwan.,School of Medicine, National Yang-Ming University, Taipei, Taiwan.,Institute of Environmental and Occupational Health Sciences, School of Medicine, National Yang-Ming University, Taipei, Taiwan.,College of Science and Engineering, Fu Jen Catholic University, New Taipei City, Taiwan
| | - Da-Chen Chu
- Institute of Public Health and Community Medicine Research Centre, National Yang-Ming University, Taipei, Taiwan.,Department of Health Care Management, National Taipei University of Nursing and Health Sciences, Taipei, Taiwan.,Department of Neurosurgery, Taipei City Hospital, Taipei, Taiwan
| | - Hsiang-Lin Chan
- Department of Child Psychiatry, Chang Gung Memorial Hospital and University, Taoyuan, Taiwan
| | - Szu-Yuan Li
- School of Medicine, National Yang-Ming University, Taipei, Taiwan.,Division of Nephrology, and Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Chih-Kuang Liu
- College of Medicine & Graduate Institute of Business Administration, Fu Jen Catholic University, New Taipei City, Taiwan
| | - Chih-Yu Yang
- School of Medicine, National Yang-Ming University, Taipei, Taiwan.,Division of Nephrology, and Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Yu-Wei Chen
- School of Medicine, National Yang-Ming University, Taipei, Taiwan.,Division of Nephrology, and Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Pui-Ching Lee
- School of Medicine, National Yang-Ming University, Taipei, Taiwan.,Division of Nephrology, and Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Yen-Ting Lai
- Department of Physical Medicine and Rehabilitation, National Taiwan University Hospital Hsin-Chu Branch, Hsinchu, Taiwan.,Department of Nursing, Yuanpei University, Hsinchu, Taiwan
| | - Chih-Ching Lin
- School of Medicine, National Yang-Ming University, Taipei, Taiwan.,Division of Nephrology, and Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
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21
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Petrulienė K, Žiginskienė E, Kuzminskis V, Nedzelskienė I, Bumblytė IA. Hepcidin serum levels and resistance to recombinant human erythropoietin therapy in hemodialysis patients. MEDICINA-LITHUANIA 2017; 53:90-100. [PMID: 28416170 DOI: 10.1016/j.medici.2017.03.001] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/25/2015] [Revised: 11/25/2016] [Accepted: 03/20/2017] [Indexed: 02/09/2023]
Abstract
OBJECTIVE The aim of this study was to analyze the factors that are associated with the response to erythropoiesis-stimulating agents (ESAs) and its association with hospitalization and mortality rates; to evaluate the serum hepcidin level and its associations with iron profile, inflammatory markers, ESA responsiveness, and mortality; and to determine independent factors affecting ERI and hepcidin. MATERIALS AND METHODS To evaluate a dose-response effect of ESAs we used the erythropoietin resistance index (ERI). Patients were stratified in two groups: nonresponders and responders (ERI>15, n=20, and ERI ≤15U/kg/week/g per 100mL, n=153, respectively). Hematological data, hepcidin levels, iron parameters, inflammatory markers, hospitalization and mortality rates were compared between the groups. Multiple regression analysis was used to determine independent factors affecting ERI and hepcidin. RESULTS C-reactive protein (CRP) (β=0.078, P=0.007), albumin (β=-0.436, P=0.004), body mass index (β=-0.374, P<0.001), and hospitalization rate per year (β=3.017, P<0.001) were found to be significant determinants of ERI in maintenance hemodialysis (MHD) patients. Inadequate dialysis was associated with higher ERI. Patients with concomitant oncological diseases had higher ERI (31.2±12.4 vs 9.7±8.1U/kg/week/g per 100mL, P=0.002). The hepcidin level was 158.51±162.57 and 120.65±67.28ng/mL in nonresponders and responders, respectively (P=0.33). Hepcidin correlated directly with ERI, dose of ESAs, ferritin and inversely with Hb, transferrin saturation, and albumin. ERI (β=4.869, P=0.002) and ferritin (β=0.242, P=0.003) were found to be significant determinants of hepcidin in MHD patients. The hospitalization rate per year was 2.35±1.8 and 1.04±1.04 in nonresponders and responders, respectively (P=0.011). The mean length of one hospitalization was 25.12±21.26 and 10.82±17.25 days, respectively (P=0.012). Death occurred in 30% of the patients from the responders' group and in 50% from the nonresponders' group (P=0.289). The mean hepcidin concentration of patients who died was 141.9±129.62ng/mL and who survived, 132.98±109.27ng/mL (P=0.797). CONCLUSIONS CRP, albumin, BMI, and hospitalization rate per year were found to be significant determinants of ERI in MHD patients. Inadequate dialysis was associated with higher epoetin requirements. There were no difference in patient mortality by ERI, but a significant difference in hospitalization rates and mean length of one hospitalization was revealed. A significant positive relation between hepcidin and ERI was revealed. ERI and ferritin were found to be significant determinants of hepcidin in MHD patients. Hepcidin was not related to mortality.
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Affiliation(s)
- Kristina Petrulienė
- Department of Nephrology, Medical Academy, Lithuanian University of Health Sciences, Kaunas, Lithuania.
| | - Edita Žiginskienė
- Department of Nephrology, Medical Academy, Lithuanian University of Health Sciences, Kaunas, Lithuania
| | - Vytautas Kuzminskis
- Department of Nephrology, Medical Academy, Lithuanian University of Health Sciences, Kaunas, Lithuania
| | - Irena Nedzelskienė
- Department of Odontology, Medical Academy, Lithuanian University of Health Sciences, Kaunas, Lithuania
| | - Inga Arūnė Bumblytė
- Department of Nephrology, Medical Academy, Lithuanian University of Health Sciences, Kaunas, Lithuania
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22
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Tessitore N, Poli A, Bedogna V, Corazza L, Campostrini N, Atti M, Sereni L, Castagna A, Girelli D, Pessolano G, Lupo A. A single dialysis session of hemodiafiltration with sorbent-regenerated endogenous ultrafiltrate reinfusion (HFR) removes hepcidin more efficiently than bicarbonate hemodialysis: a new approach to containing hepcidin burden in dialysis patients? J Nephrol 2017; 31:297-306. [PMID: 28353202 DOI: 10.1007/s40620-017-0383-0] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2016] [Accepted: 02/22/2017] [Indexed: 12/22/2022]
Abstract
BACKGROUND Most hemodialysis patients have high Hepcidin-25 levels, which may be involved in the pathogenesis of several uremic complications related to an altered iron biology. The hemodialysis procedure itself can influence Hepcidin-25 levels by removing Hepcidin-25 and maybe stimulating its production due to a pro-inflammatory effect. METHODS To assess the relationship between dialysis-related inflammation and intradialysis changes in Hepcidin-25, we performed a crossover trial in 28 hemodialysis patients to compare the effects on serum levels of Hepcidin-25 and inflammatory markers activated during dialysis [Tumor Necrosis Factor-α (TNF-α), Interleukin-6, C-reactive protein (CRP), Pentraxin-3] of a single dialysis session using a technique capable of reducing inflammation, HFR (Hemo Filtrate Reinfusion: a hemodiafiltration system combining convection, diffusion and adsorption) or bicarbonate-dialysis using either the same low-flux membrane as in the diffusion stage of HFR (LFBD) or a high-flux membrane (HFBD). RESULTS HFR achieved a greater reduction in Hepcidin-25 levels than both LFBD [-72% (95% CI: -11 to -133), p = 0.022] and HFBD [-137% (95% CI: -2 to -272), p = 0.047], conceivably due to both a greater removal (because of its convective/adsorptive component) and a lower inflammation-related Hepcidin-25 production. HFR also led to a greater decrease in TNF-α than LFBD [-277% (95% CI: -59 to -494), p = 0.014], while the two methods induced similar changes in Interleukin-6, CRP and Pentraxin-3 levels. CONCLUSIONS Our findings suggest that a single bicarbonate-dialysis session can upregulate Hepcidin-25 synthesis and that HFR can fully overcome this effect, enabling a greater Hepcidin-25 removal during dialysis. Adequately-designed studies are needed, however, to establish whether the beneficial effect of HFR emerging from our study could reduce Hepcidin-25 (and TNF-α) burden and improve clinically-relevant outcomes. TRIAL REGISTRATION ISRCTN15957905.
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Affiliation(s)
- Nicola Tessitore
- Emodialisi Borgo Roma, Nephrology Section, Department of Medicine, University of Verona, Piazzale LA Scuro 10, 37134, Verona, Italy.
| | - Albino Poli
- Department of Diagnostic and Public Health, University of Verona, Verona, Italy
| | - Valeria Bedogna
- Emodialisi Borgo Roma, Nephrology Section, Department of Medicine, University of Verona, Piazzale LA Scuro 10, 37134, Verona, Italy
| | | | - Natascia Campostrini
- Internal Medicine Section, Department of Medicine, University of Verona, Verona, Italy
| | | | | | - Annalisa Castagna
- Internal Medicine Section, Department of Medicine, University of Verona, Verona, Italy
| | - Domenico Girelli
- Internal Medicine Section, Department of Medicine, University of Verona, Verona, Italy
| | - Giuseppina Pessolano
- Emodialisi Borgo Roma, Nephrology Section, Department of Medicine, University of Verona, Piazzale LA Scuro 10, 37134, Verona, Italy
| | - Antonio Lupo
- Emodialisi Borgo Roma, Nephrology Section, Department of Medicine, University of Verona, Piazzale LA Scuro 10, 37134, Verona, Italy
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Abstract
In chronic hemodialysis patients, a disruption in iron metabolism ranging from absolute to functional deficiency, with compartmentalization of this metal into macrophages, is often observed. Chronic inflammation indeed often causes an upregulation of the iron hormone hepcidin, thereby reducing iron absorption and availability to the erythron. We systematically reviewed the literature on the role of genetic risk factors on iron metabolism in hemodialysis. In this setting, mutations in the HFE gene of hereditary hemochromatosis may confer an adaptive benefit by decreasing hepcidin release, thus improving iron availability to erythropoiesis, anemia control, and the response to erythropoiesis stimulating agents and iron itself, and reducing the side effects of these therapies. The HFE protein together with Transferrin receptor-2 may also have a direct role on erythroid differentiation and iron uptake in erythroid cells. In addition, other genetic determinants of iron status, such as variants in Matriptase-2 (TMPRSS6), have been shown to influence iron metabolism in chronic hemodialysis patients, most likely acting through hepcidin regulation. Although data must be confirmed in larger prospective studies, this favorable shift in iron metabolism balance possibly results in reduced mortality, in particular because of cardiovascular and infective diseases. Further genetic studies may offer a valuable tool to test these hypotheses and guide personalized clinical management and the research of new therapies.
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Affiliation(s)
- Luca Valenti
- Department of Pathophysiology and Transplantation, Internal Medicine and Metabolic Diseases, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Università degli Studi di Milano, Milano, Italy
| | - Serena Pelusi
- Department of Pathophysiology and Transplantation, Internal Medicine and Metabolic Diseases, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Università degli Studi di Milano, Milano, Italy
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Kang E, Kim S, Lee HJ, Park I, Kim H, Shin GT. Tumor necrosis factor α is a risk factor for infection in peritoneal dialysis patients. Korean J Intern Med 2016; 31:722-9. [PMID: 27000486 PMCID: PMC4939502 DOI: 10.3904/kjim.2015.230] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/20/2015] [Revised: 08/24/2015] [Accepted: 08/28/2015] [Indexed: 11/27/2022] Open
Abstract
BACKGROUND/AIMS It has been shown that circulating tumor necrosis factor α (TNF-α) is elevated in end stage renal disease patients; however, the relationship between TNF-α and the development of infection in these patients is unknown. In this study, we investigated the association of plasma TNF-α and interleukin 6 (IL-6) with infection in peritoneal dialysis (PD) patients. We also evaluated the association of their plasma levels with the production by peripheral blood mononuclear cells (PBMC), and with various clinical parameters. METHODS We enrolled 32 patients on maintenance PD and 10 healthy controls. Plasma and PBMC were isolated from blood. PBMC were stimulated with lipopolysaccharide in vitro. RESULTS Mean follow-up duration was 775 days. Six patients developed organ infections (five pneumonia and one liver abscess), and six patients developed PD peritonitis and eight developed exit site infection. Plasma TNF-α and IL-6 levels were significantly elevated in organ infections but not in peritonitis or in exit site infection. Plasma TNF-α was the only significant risk factor for organ infections and pneumonia in multivariate regression analysis. Patients with high plasma TNF-α levels showed a significantly greater cumulative hazard rate for organ infections compared to those with low TNF-α levels. Plasma TNF-α levels correlated with TNF-α production by PBMC and showed an inverse association with Kt/V. CONCLUSIONS This is the first study showing that plasma TNF-α is a significant risk factor for infection in PD patients.
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Affiliation(s)
- Eunjung Kang
- Department of Nephrology, Ajou University School of Medicine, Suwon, Korea
| | - Seihran Kim
- Department of Nephrology, Ajou University School of Medicine, Suwon, Korea
| | - Hwa Jung Lee
- Department of Nephrology, Ajou University School of Medicine, Suwon, Korea
| | - Inhwee Park
- Department of Nephrology, Ajou University School of Medicine, Suwon, Korea
| | - Heungsoo Kim
- Department of Nephrology, Ajou University School of Medicine, Suwon, Korea
| | - Gyu-Tae Shin
- Department of Nephrology, Ajou University School of Medicine, Suwon, Korea
- Correspondence to Gyu-Tae Shin, M.D. Department of Nephrology, Ajou University School of Medicine, 164 World cup-ro, Yeongtong-gu, Suwon 16499, Korea Tel: +82-31-219-5133 Fax: +82-31-219-5137 E-mail:
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Yousaf F, Spinowitz B. Hypoxia-Inducible Factor Stabilizers: a New Avenue for Reducing BP While Helping Hemoglobin? Curr Hypertens Rep 2016; 18:23. [DOI: 10.1007/s11906-016-0629-6] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
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Macdougall IC, Bircher AJ, Eckardt KU, Obrador GT, Pollock CA, Stenvinkel P, Swinkels DW, Wanner C, Weiss G, Chertow GM, Adamson JW, Akizawa T, Anker SD, Auerbach M, Bárány P, Besarab A, Bhandari S, Cabantchik I, Collins AJ, Coyne DW, de Francisco ÁL, Fishbane S, Gaillard CA, Ganz T, Goldsmith DJ, Hershko C, Jankowska EA, Johansen KL, Kalantar-Zadeh K, Kalra PA, Kasiske BL, Locatelli F, Małyszko J, Mayer G, McMahon LP, Mikhail A, Nemeth E, Pai AB, Parfrey PS, Pecoits-Filho R, Roger SD, Rostoker G, Rottembourg J, Singh AK, Slotki I, Spinowitz BS, Tarng DC, Tentori F, Toblli JE, Tsukamoto Y, Vaziri ND, Winkelmayer WC, Wheeler DC, Zakharova E. Iron management in chronic kidney disease: conclusions from a “Kidney Disease: Improving Global Outcomes” (KDIGO) Controversies Conference. Kidney Int 2016; 89:28-39. [DOI: 10.1016/j.kint.2015.10.002] [Citation(s) in RCA: 167] [Impact Index Per Article: 18.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2015] [Revised: 09/22/2015] [Accepted: 09/29/2015] [Indexed: 12/21/2022]
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Kali A, Yayar O, Erdogan B, Eser B, Buyukbakkal M, Ercan Z, Merhametsiz O, Haspulat A, Gök Oğuz E, Canbakan B, Ayli MD. Is hepcidin-25 a predictor of atherosclerosis in hemodialysis patients? Hemodial Int 2015; 20:191-7. [PMID: 26374145 DOI: 10.1111/hdi.12355] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
Atherosclerotic cardiovascular disease is an important cause of mortality and morbidity in hemodialysis patients. Iron accumulation in arterial wall macrophages is increased in atherosclerotic lesions. Hepcidin is a key hepatic hormone regulating iron balance. It inhibits iron release from macrophages and iron absorption from enterocytes by binding and inactivating the cellular iron exporter ferroportin. The aim of this study is to investigate the relation of hepcidin-25, iron parameters, and atherosclerosis measured by carotid intima media thickness (CIMT) in hemodialysis patients. Eighty-two hemodialysis patients were enrolled in this cross-sectional study. Predialysis blood samples were centrifuged at 1500 g and 4°C for 10 minutes and stored at -80°C for the measurement of hepcidin-25. DRG hepcidin enzyme-linked immunosorbent assay kit was used for the measurement of hepcidin-25. Ultrasonographical B-mode imaging of bilateral carotid arteries was performed with a high-resolution real-time ultrasonography (Mindray DC7). Mean age of the study population was 57.90 ± 16.08 years and 43.9% were men. Total study population was grouped into two according to median value of hepcidin-25. There was no difference between groups with respect to age, dialysis vintage, and C-reactive protein. CIMT was found to be statistically significantly higher in low hepcidin-25 group. In correlation analysis, CIMT was found to be correlated with age (P < 0.01, R = 0.33) and hepcidin-25 (P < 0.01, R = 0.46). In linear regression analysis, age (β = 0.31) and hepcidin-25 (β = 0.44) were found to be the determinants of CIMT in hemodialysis patients. Our results implicate that hepcidin may take part in pathophysiology of atherosclerosis and cardiovascular disease in hemodialysis patients.
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Affiliation(s)
- Alaaddin Kali
- Department of Nephrology, Diskapi Yildirim Beyazid Research and Training Hospital, Ankara, Turkey
| | - Ozlem Yayar
- Department of Nephrology, Diskapi Yildirim Beyazid Research and Training Hospital, Ankara, Turkey
| | - Bulent Erdogan
- Department of Nephrology, Diskapi Yildirim Beyazid Research and Training Hospital, Ankara, Turkey
| | - Baris Eser
- Department of Nephrology, Diskapi Yildirim Beyazid Research and Training Hospital, Ankara, Turkey
| | - Mehmet Buyukbakkal
- Department of Nephrology, Diskapi Yildirim Beyazid Research and Training Hospital, Ankara, Turkey
| | - Zafer Ercan
- Department of Nephrology, Diskapi Yildirim Beyazid Research and Training Hospital, Ankara, Turkey
| | - Ozgur Merhametsiz
- Department of Nephrology, Diskapi Yildirim Beyazid Research and Training Hospital, Ankara, Turkey
| | - Ayhan Haspulat
- Department of Nephrology, Diskapi Yildirim Beyazid Research and Training Hospital, Ankara, Turkey
| | - Ebru Gök Oğuz
- Department of Nephrology, Diskapi Yildirim Beyazid Research and Training Hospital, Ankara, Turkey
| | - Basol Canbakan
- Department of Nephrology, Diskapi Yildirim Beyazid Research and Training Hospital, Ankara, Turkey
| | - Mehmet D Ayli
- Department of Nephrology, Diskapi Yildirim Beyazid Research and Training Hospital, Ankara, Turkey
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Iron Stores, Hepcidin, and Aortic Stiffness in Individuals with Hypertension. PLoS One 2015; 10:e0134635. [PMID: 26244503 PMCID: PMC4526526 DOI: 10.1371/journal.pone.0134635] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2015] [Accepted: 07/11/2015] [Indexed: 11/19/2022] Open
Abstract
Background & Aims Iron accumulation within the arterial wall has been hypothesized to promote atherosclerosis progression. Aim of this study was to evaluate whether the hormone hepcidin and iron stores are associated with arterial stiffness in subjects with essential hypertension. Methods Circulating hepcidin, ferritin, and mutations in the hemochromatosis gene were compared between subjects included in the first vs. third tertile (n=284 each) of carotid-femoral pulse wave velocity (PWV) in an unselected cohort of patients with arterial hypertension. Results At univariate logistic regression analysis, high PWV was associated with higher ferritin levels (p=0.010), but lower hepcidin (p=0.045), and hepcidin ferritin/ratio (p<0.001). Hemochromatosis mutations predisposing to iron overload were associated with high PWV (p=0.025). At multivariate logistic regression analysis, high aortic stiffness was associated with older age, male sex, lower BMI, higher systolic blood pressure and heart rate, hyperferritinemia (OR 2.05, 95% c.i. 1.11-3.17 per log ng/ml; p=0.022), and lower circulating hepcidin concentration (OR 0.29, 95% c.i. 0.16-0.51 per log ng/ml; p<0.001). In subgroup analyses, high PWV was associated with indices of target organ damage, including micro-albuminuria (n=125, p=0.038), lower ejection fraction (n=175, p=0.031), cardiac diastolic dysfunction (p=0.004), and lower S wave peak systolic velocity (p<0.001). Ferritin was associated with cardiac diastolic dysfunction, independently of confounders (p=0.006). Conclusions In conclusion, hyperferritinemia is associated with high aortic stiffness and cardiac diastolic dysfunction, while low circulating hepcidin with high aortic stiffness.
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Li H, Feng SJ, Su LL, Wang W, Zhang XD, Wang SX. Serum hepcidin predicts uremic accelerated atherosclerosis in chronic hemodialysis patients with diabetic nephropathy. Chin Med J (Engl) 2015; 128:1351-7. [PMID: 25963357 PMCID: PMC4830316 DOI: 10.4103/0366-6999.156781] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2014] [Indexed: 12/17/2022] Open
Abstract
BACKGROUND Hepcidin, as a regulator of body iron stores, has been recently discovered to play a critical role in the pathogenesis of anemia of chronic disease. Atherosclerotic cardiovascular disease is the most common complication and the leading cause of death in chronic hemodialysis (CHD) patients. In the current study, we aimed to explore the relationship between serum hepcidin and uremic accelerated atherosclerosis (UAAS) in CHD patients with diabetic nephropathy (CHD/DN). METHODS A total of 78 CHD/DN and 86 chronic hemodialyzed nondiabetic patients with chronic glomerulonephritis (CHD/non-DN) were recruited in this study. The level of serum hepcidin-25 was specifically measured by liquid chromatography-tandem mass spectrometry. Serum levels of interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) were measured by enzyme-linked immunosorbent assay. RESULTS High serum level of hepcidin-25 was seen in CHD patients. Serum hepcidin-25 in CHD/DN was significantly higher than that in CHD/non-DN patients. Serum hepcidin-25 was positively correlated with ferritin, high-sensitivity C-reactive protein (hs-CRP), TNF-α, and IL-6 in CHD/DN patients. CHD/DN patients exhibited higher common carotid artery intima media thickness (CCA-IMT), hs-CRP, and hepcidin-25 levels than that in CHD/non-DN patients. Moreover, in CHD/DN patients, CCA-IMT was positively correlated with serum hepcidin, hs-CRP, and low-density lipoprotein-cholesterol. On multiple regression analysis, serum hepcidin and hs-CRP level exhibited independent association with IMT in CHD/DN patients. CONCLUSIONS These findings suggest possible linkage between iron metabolism and hepcidin modulation abnormalities that may contribute to the development of UAAS in CHD/DN patients.
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Affiliation(s)
- Han Li
- Department of Blood Purification, Beijing Chao-Yang Hospital, Capital Medical University; Nephrology Faculty, Capital Medical University, Beijng 100020, China
- Institute of Uro-Nephrology, Beijing Chao-Yang Hospital, Capital Medical University, Beijng 100020, China
| | - Su-Juan Feng
- Department of Blood Purification, Beijing Chao-Yang Hospital, Capital Medical University; Nephrology Faculty, Capital Medical University, Beijng 100020, China
- Institute of Uro-Nephrology, Beijing Chao-Yang Hospital, Capital Medical University, Beijng 100020, China
| | - Lu-Lu Su
- Institute of Uro-Nephrology, Beijing Chao-Yang Hospital, Capital Medical University, Beijng 100020, China
| | - Wei Wang
- Institute of Uro-Nephrology, Beijing Chao-Yang Hospital, Capital Medical University, Beijng 100020, China
| | - Xiao-Dong Zhang
- Institute of Uro-Nephrology, Beijing Chao-Yang Hospital, Capital Medical University, Beijng 100020, China
| | - Shi-Xiang Wang
- Department of Blood Purification, Beijing Chao-Yang Hospital, Capital Medical University; Nephrology Faculty, Capital Medical University, Beijng 100020, China
- Institute of Uro-Nephrology, Beijing Chao-Yang Hospital, Capital Medical University, Beijng 100020, China
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Effect of protoconized therapy for renal anemia on adverse events of patients with maintenance hemodialysis. Int J Artif Organs 2014; 37:865-74. [PMID: 25450320 DOI: 10.5301/ijao.5000370] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/24/2014] [Indexed: 12/19/2022]
Abstract
PURPOSE We evaluate the effect of the protoconized anemia therapy on adverse events using the Hb and ferritin levels of individual patients undergoing maintenance hemodialysis (MHD). METHODS Design: A randomized, parallel group, multi-center study. PATIENTS Two hundred sixty-six MHD patients. Intervention group: The doses of erythropoietin, iron, and vitamin C were adjusted every month based on the ferritin and hemoglobin (Hb) levels according to the protocol. Non-intervention group: The attending physician determined the doses of erythropoietin and iron. RESULTS The maintenance rate of target Hb and ferritin levels were significantly higher in the Intervention group than in the Non-intervention group. The frequency of hospitalization was significantly lower for patients with a higher maintenance rate of target Hb levels than for those with a lower maintenance rate. CONCLUSIONS Using an anemia treatment protocol according to the individual Hb and ferritin levels of hemodialysis patients might stabilize the Hb and ferritin levels, which in turn could contribute to the lower frequency of adverse events in MHD patients.
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Morikami Y, Fujimori A, Okada S, Kumei M, Mizobuchi N, Sakai M. Twice-monthly administration of a lower dose of epoetin beta pegol can maintain adequate hemoglobin levels in hemodialysis patients. Ther Apher Dial 2014; 19:138-43. [PMID: 25402974 DOI: 10.1111/1744-9987.12248] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
Epoetin beta pegol is a continuous erythropoietin receptor activator (CERA) with a long half-life. Although CERA has been shown to maintain adequate hemoglobin (Hb) levels at prolonged dosing intervals, the optimal dosing schedule remains unclear. We therefore compared the efficacy of maintaining hemoglobin levels with administration of twice-monthly CERA (TWICE) versus once-monthly CERA (ONCE). Twenty hemodialysis patients receiving epoetin beta (EPO) were enrolled in this crossover study. Patients were assigned to either the TWICE or the ONCE group based on matching Hb levels and EPO doses. After 6 months of treatment, the CERA dosage was interchanged between the groups and the study was continued for an additional 6 months. The effect of the different regimens on iron metabolism was also assessed during the first 6 months of the study. Hb levels significantly increased in the TWICE group, allowing for a reduction in CERA dosage, while the dose of CERA required to maintain Hb levels in the ONCE group remained unchanged. After the interchange, a decrease in Hb levels with incremental increase in CERA dosage was observed in the TWICE→ONCE group, with the opposite effect observed in the ONCE→TWICE group. Although increases in ferritin and hepcidin-25 levels in the ONCE group were noted at one month, they disappeared at 6 months. Although Hb levels were maintained in both the ONCE and TWICE groups, a twice-monthly administration was advantageous, as it required a lower dose of CERA.
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Affiliation(s)
- Yuki Morikami
- Blood Purification and Kidney Center, Kohnan Hospital, Kobe, Japan
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Associations between serum hepcidin level, FGF-21 level and oxidative stress with arterial stiffness in CAPD patients. Int Urol Nephrol 2014; 46:2409-14. [PMID: 24908281 DOI: 10.1007/s11255-014-0753-7] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2014] [Accepted: 05/22/2014] [Indexed: 01/04/2023]
Abstract
BACKGROUND Patients on continuous ambulatory peritoneal dialysis (CAPD) and hemodialysis have accelerated atherosclerosis associated with an increase in cardiovascular morbidity and mortality. Atherosclerosis is associated with increased arterial stiffness (AS), endothelial dysfunction and elevated oxidative stress (OS) and inflammation. We aimed to investigate the relationship between oxidative stress status, arterial stiffness, hepcidin and fibroblast growth factor-21 (FGF-21) levels in CAPD patients. METHODS As a prospective observational study, we analyzed 56 CAPD patients, aged between 30 and 63 years. Serum hepcidin, FGF-21 levels, OS status and AS were determined. Arterial stiffness was measured by flow-mediated dilatation (FMD). Oxidative stress status was determined by total antioxidant status, total oxidant status (TOS) and oxidative stress index (OSI). RESULTS FMD was negatively correlated with TOS, OSI, hepcidin and FGF-21 (r: -0.313, p: 0.020; r: -0.0331, p: 0.014; r: -0.498, p < 0.001; r: -0.403, p: 0.002, respectively). OSI was positively correlated with hepcidin, parathormone and negatively correlated with FMD (r: 0.278, p: 0.040; r: 0.462, p < 0.001; r: -0.0331, p: 0.014, respectively). CONCLUSION There are many factors affecting arterial stiffness in CAPD patients. In our study, higher levels of OS status, hepcidin and FGF-21 were independent determinants of arterial stiffness in PD patients. Therefore, definition and improvement of these new parameters will be helpful to reduce the cardiovascular disease risk and mortality in CAPD patients.
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Iron and atherosclerosis: nailing down a novel target with magnetic resonance. J Cardiovasc Transl Res 2014; 7:533-42. [PMID: 24590608 DOI: 10.1007/s12265-014-9551-y] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/14/2013] [Accepted: 02/14/2014] [Indexed: 12/21/2022]
Abstract
Iron is an essential mineral in many proteins and enzymes in human physiology, with limited means of iron elimination to maintain iron balance. Iron accrual incurs various pathological mechanisms linked to cardiovascular disease. In atherosclerosis, iron catalyzes the creation of reactive oxygen free radicals that contribute to lipid modification, which is essential to atheroma formation. Inflammation further fuels iron-related pathologic processes associated with plaque progression. Given iron's role in atherosclerosis development, in vivo detection techniques sensitive iron are needed for translational studies targeting iron for earlier diagnosis and treatment. Magnetic resonance imaging is uniquely able to quantify iron in human tissues noninvasively and without ionizing radiation, offering appealing for longitudinal and interventional studies. Particularly intriguing is iron's complementary biology vs. calcium, which is readily detectable by computed tomography. This review summarizes the role of iron in atherosclerosis with considerable implications for novel diagnostic and therapeutic approaches.
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Del Vecchio L, Locatelli F. New treatment approaches in chronic kidney disease-associated anaemia. Expert Opin Biol Ther 2014; 14:687-96. [PMID: 24579747 DOI: 10.1517/14712598.2014.892577] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/23/2023]
Abstract
INTRODUCTION Erythropoiesis-stimulating agents (ESA) and iron are the main tools for treating anaemia associated with chronic kidney disease (CKD). Pharmaceutical research has focused on modified epoetins or different strategies to stimulate erythropoiesis with the idea of improving relative disadvantages of the molecules already available in the market. AREAS COVERED Following a literature search on PubMed using anaemia, haemoglobin, erythropoietin (EPO), hypoxia-inducible transcription factor (HIF) inhibitors and chronic kidney disease as keywords, we critically analysed new strategies for increasing erythropoiesis, looking in depth at their peculiar characteristics and possible advantages in the clinical setting. EXPERT OPINION In recent years the ESA market is facing a number of hurdles making it less appealing than before. Economic recession or stagnation has raised the need of sustainability of medical treatment. New treatments must bring clear benefits compared to existing drugs. In addition to this, ESA consumption has been progressively reduced, fearing possible risks of increased cardiovascular events especially when given at excessive doses. New drugs may also undergo premature stopping because of unexpected adverse reactions as for peginesatide. At present, the most promising approach to anaemia treatment in CKD patients is the manipulation of the HIF system. The regulation of activin A pathway is another option with good potential, also considering the additional advantage of increasing bone mass.
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Affiliation(s)
- Lucia Del Vecchio
- A Manzoni Hospital, Department of Nephrology, Dialysis, and Renal Transplant , Via dell'Eremo 9, 23900 Lecco , Italy
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Galesloot TE, Holewijn S, Kiemeney LA, de Graaf J, Vermeulen SH, Swinkels DW. Serum Hepcidin Is Associated With Presence of Plaque in Postmenopausal Women of a General Population. Arterioscler Thromb Vasc Biol 2014; 34:446-56. [DOI: 10.1161/atvbaha.113.302381] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Affiliation(s)
- Tessel E. Galesloot
- From the Department for Health Evidence (T.E.G., L.A.L.M.K., S.H.V.), Department of General Internal Medicine, Division of Vascular Medicine (S.H., J.d.G.), Department of Urology (L.A.L.M.K.), and Laboratory of Genetic, Endocrine and Metabolic Diseases, Department of Laboratory Medicine (D.W.S.), Radboud University Medical Center, Nijmegen, The Netherlands
| | - Suzanne Holewijn
- From the Department for Health Evidence (T.E.G., L.A.L.M.K., S.H.V.), Department of General Internal Medicine, Division of Vascular Medicine (S.H., J.d.G.), Department of Urology (L.A.L.M.K.), and Laboratory of Genetic, Endocrine and Metabolic Diseases, Department of Laboratory Medicine (D.W.S.), Radboud University Medical Center, Nijmegen, The Netherlands
| | - Lambertus A.L.M. Kiemeney
- From the Department for Health Evidence (T.E.G., L.A.L.M.K., S.H.V.), Department of General Internal Medicine, Division of Vascular Medicine (S.H., J.d.G.), Department of Urology (L.A.L.M.K.), and Laboratory of Genetic, Endocrine and Metabolic Diseases, Department of Laboratory Medicine (D.W.S.), Radboud University Medical Center, Nijmegen, The Netherlands
| | - Jacqueline de Graaf
- From the Department for Health Evidence (T.E.G., L.A.L.M.K., S.H.V.), Department of General Internal Medicine, Division of Vascular Medicine (S.H., J.d.G.), Department of Urology (L.A.L.M.K.), and Laboratory of Genetic, Endocrine and Metabolic Diseases, Department of Laboratory Medicine (D.W.S.), Radboud University Medical Center, Nijmegen, The Netherlands
| | - Sita H. Vermeulen
- From the Department for Health Evidence (T.E.G., L.A.L.M.K., S.H.V.), Department of General Internal Medicine, Division of Vascular Medicine (S.H., J.d.G.), Department of Urology (L.A.L.M.K.), and Laboratory of Genetic, Endocrine and Metabolic Diseases, Department of Laboratory Medicine (D.W.S.), Radboud University Medical Center, Nijmegen, The Netherlands
| | - Dorine W. Swinkels
- From the Department for Health Evidence (T.E.G., L.A.L.M.K., S.H.V.), Department of General Internal Medicine, Division of Vascular Medicine (S.H., J.d.G.), Department of Urology (L.A.L.M.K.), and Laboratory of Genetic, Endocrine and Metabolic Diseases, Department of Laboratory Medicine (D.W.S.), Radboud University Medical Center, Nijmegen, The Netherlands
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Morikami Y, Fujimori A, Okada S, Kumei M, Mizobuchi N, Sakai M. Comparison of 2-Week Versus 4-Week Dosing Intervals of Epoetin Beta Pegol on Erythropoiesis and Iron Metabolism in Hemodialysis Patients. Ther Apher Dial 2014; 18:414-20. [DOI: 10.1111/1744-9987.12164] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Affiliation(s)
- Yuki Morikami
- Blood Purification and Kidney Center; Konan Hospital; Kobe Japan
| | - Akira Fujimori
- Blood Purification and Kidney Center; Konan Hospital; Kobe Japan
| | - Shioko Okada
- Blood Purification and Kidney Center; Konan Hospital; Kobe Japan
| | - Mai Kumei
- Blood Purification and Kidney Center; Konan Hospital; Kobe Japan
| | | | - Makoto Sakai
- Department of Internal Medicine; Konan Hospital; Kobe Japan
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Samouilidou E, Pantelias K, Petras D, Tsirpanlis G, Bakirtzi J, Chatzivasileiou G, Tzanatos H, Grapsa E. Serum hepcidin levels are associated with serum triglycerides and interleukin-6 concentrations in patients with end-stage renal disease. Ther Apher Dial 2013; 18:279-83. [PMID: 24119290 DOI: 10.1111/1744-9987.12102] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/24/2023]
Abstract
Hepcidin has emerged as a peptide with a key role in the regulation of iron homeostasis in patients with chronic kidney disease (CKD), having a strong dependence on inflammation. Recent studies reveal that hepcidin may be also associated with the progression of atherosclerosis. This study was performed to analyze the relation of hepcidin to markers of atherosclerosis and inflammation in patients on dialysis. A total of 90 individuals were enrolled. Sixty patients with end-stage renal disease, who were on hemodialysis (HD) (N = 30) and peritoneal dialysis (N = 30) were compared with 30 normal controls (NC). Age, body mass index, time on dialysis, serum lipids, C-reactive protein (CRP) and interleukin-6 (IL-6) were measured and analyzed in correlation with hepcidin concentration. It was found that patients on HD and peritoneal dialysis have significantly higher (P < 0.0001) levels of hepcidin, CRP and IL-6 than NC. Hepcidin in dialysis patients is significantly related to age (r = 0.373, P = 0.012), serum triglycerides (r = 0.401, P = 0.005), HDL-C (r = -0.268, P = 0.048), CRP (r = 0.436, P = 0.0007) and IL-6 (r = 0.569, P < 0.0001). In multiple regression analysis, hepcidin correlated independently with triglycerides (β = 0.402, P = 0.041) and IL-6 (β = 0.559, P = 0.006). Moreover, patients with high triglycerides in combination with high IL-6 levels have significantly increased concentrations of hepcidin than those with low triglycerides and low IL-6 levels (P < 0.0001). Elevated levels of hepcidin in patients with CKD on dialysis may be related to the occurrence of high triglycerides and high IL-6 serum concentrations. This probably suggests that hepcidin may play a role to the progression of atherosclerosis and inflammation, but this hypothesis should be further evaluated.
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Wagner M, Ashby D. Hepcidin--a well-known iron biomarker with prognostic implications in chronic kidney disease. Nephrol Dial Transplant 2013; 28:2936-9. [PMID: 24046195 DOI: 10.1093/ndt/gft330] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Affiliation(s)
- Martin Wagner
- Institute of Clinical Epidemiology and Biometry, University of Würzburg, Würzburg, Germany
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The removal of serum hepcidin by different dialysis membranes. Int J Artif Organs 2013; 36:633-9. [PMID: 23918276 DOI: 10.5301/ijao.5000221] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/12/2013] [Indexed: 12/16/2022]
Abstract
PURPOSE Hepcidin has been suspected to be associated with anemia of chronic disease, which is commonly observed in patients with maintenance hemodialysis (MHD). As almost of hepcidin is bounded to protein, it is essential to clarify which kind of dialysis membrane can remove it efficiently. METHODS Ex vivo study: 50 mL of whole blood from healthy volunteers were circulated for 2 h in a microcircuit with mini-dialyzers (acrylonitrile-co-methallyl sulfonate (AN69) or polysulfone (PS)) without ultrafiltration. We measured hepcidin-25 levels at 0, 60, and 120 min in the blood samples. In vivo study: Blood samples were taken from 28 MHD patients at the start and end of HD sessions with PS or AN69. We measured serum levels of hepcidin 20, 22, and 25 by liquid chromatography tandem mass spectrometry, and also measured serum levels of urea nitrogen (UN), β2microglobulin (MG). RESULTS Ex vivo study: Although serum hepcidin 25 levels increased after the ex vivo session with PS, they significantly decreased with AN69. In vivo study: The reduction ratio of β2MG by PS was significantly higher than that of AN69. On the other hand, there was no significant difference in the reduction ratio of hepcidin 20, 22, and 25 between PS and AN69. CONCLUSIONS Both super-flux PS and AN69 similarly removed hepcidin 20 22, and 25. HD with PS might achieve a high removal ratio of hepcidin by enhanced diffusion performance and an increased clearance of small molecule solutes. On the other hand, AN69 might remove hepcidin by adsorption.
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Lobo JC, Stockler-Pinto MB, Farage NE, Faulin TDES, Abdalla DSP, Torres JPM, Velarde LGC, Mafra D. Reduced plasma zinc levels, lipid peroxidation, and inflammation biomarkers levels in hemodialysis patients: implications to cardiovascular mortality. Ren Fail 2013; 35:680-5. [PMID: 23650973 DOI: 10.3109/0886022x.2013.789960] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
Despite the fact that low plasma zinc (Zn) levels play important roles in the oxidative stress, the relationships between lipid peroxidation and inflammation biomarkers with low plasma Zn levels have not been investigated in chronic kidney disease (CKD) patients. The aim of this study was to evaluate the Zn plasma levels, electronegative LDL [LDL(-)] levels, and inflammation markers as predictors of cardiovascular (CV) mortality in hemodialysis (HD) patients. Forty-five HD patients (28 men, 54.2 ± 12.7 years, 62.2 ± 51.4 months on dialysis and BMI 24.3 ± 4.1 kg/m(2)) were studied and compared to 20 healthy individuals (9 men, 51.6 ± 15.6 years, BMI 25.2 ± 3.9 kg/m(2)) and followed for 24 months to investigate the risks for CV mortality. LDL(-) levels were measured by ELISA, plasma Zn levels by atomic absorption spectrophotometry, C-reactive protein (CRP) level by immunoturbidimetric method, and tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), monocyte chemotactic protein-1 (MCP-1), and plasminogen activator inhibitor-1 (PAI-1) levels by a multiplex assay kit. HD patients presented low plasma Zn levels (54.9 ± 16.1 μg/dL) and high-LDL(-) (0.18 ± 0.12 U/L) and TNF-α (5.5 ± 2.2 pg/mL) levels when compared to healthy subjects (78.8 ± 9.4μ g/dL, 0.10 ± 0.08U/L, 2.4 ± 1.1 pg/mL, respectively, p < 0.05). Zn plasma levels were negatively correlated to TNF-α (r = -0.49; p = 0.0001) and LDL(-) (r = -0.33; p = 0.008). During the 2 years, 24.4% of the patients died, all due to CV disease. Analysis by the Cox model showed that high CRP, TNF-α, IL-6 levels, and long duration of HD were significant predictors of mortality. In conclusion, reduced Zn levels were associated with lipid peroxidation and inflammation, and we confirm here in a Brazilian cohort of HD patients that inflammation markers are strong predictors of CV death.
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Affiliation(s)
- Julie Calixto Lobo
- Institute of Biophysic Carlos Chagas Filho, Health Sciense Centre, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.
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Pelusi S, Girelli D, Rametta R, Campostrini N, Alfieri C, Traglia M, Dongiovanni P, Como G, Toniolo D, Camaschella C, Messa P, Fargion S, Valenti L. The A736V TMPRSS6 polymorphism influences hepcidin and iron metabolism in chronic hemodialysis patients: TMPRSS6 and hepcidin in hemodialysis. BMC Nephrol 2013; 14:48. [PMID: 23433094 PMCID: PMC3585892 DOI: 10.1186/1471-2369-14-48] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2012] [Accepted: 02/14/2013] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Aim of this study was to evaluate whether the A736V TMPRSS6 polymorphism, a major genetic determinant of iron metabolism in healthy subjects, influences serum levels of hepcidin, the hormone regulating iron metabolism, and erythropoiesis in chronic hemodialysis (CHD). METHODS To this end, we considered 199 CHD patients from Northern Italy (157 with hepcidin evaluation), and 188 healthy controls without iron deficiency, matched for age and gender. Genetic polymorphisms were evaluated by allele specific polymerase chain reaction assays, and hepcidin quantified by mass spectrometry. RESULTS Serum hepcidin levels were not different between the whole CHD population and controls (median 7.1, interquartile range (IQR) 0.55-17.1 vs. 7.4, 4.5-17.9 nM, respectively), but were higher in the CHD subgroup after exclusion of subjects with relative iron deficiency (p = 0.04). In CHD patients, the A736V TMPRSS6 polymorphism influenced serum hepcidin levels in individuals positive for mutations in the HFE gene of hereditary hemochromatosis (p < 0.0001). In particular, the TMPRSS6 736 V variant was associated with higher hepcidin levels (p = 0.017). At multivariate analysis, HFE and A736V TMPRSS6 genotypes predicted serum hepcidin independently of ferritin and C reactive protein (p = 0.048). In patients without acute inflammation and overt iron deficiency (C reactive protein <1 mg/dl and ferritin >30 ng/ml; n = 86), hepcidin was associated with lower mean corpuscular volume (p = 0.002), suggesting that it contributed to iron-restricted erythropoiesis. In line with previous results, in patients without acute inflammation and severe iron deficiency the "high hepcidin" 736 V TMPRSS6 variant was associated with higher erythropoietin maintenance dose (p = 0.016), independently of subclinical inflammation (p = 0.02). CONCLUSIONS The A736V TMPRSS6 genotype influences hepcidin levels, erythropoiesis, and anemia management in CHD patients. Evaluation of the effect of TMPRSS6 genotype on clinical outcomes in prospective studies in CHD may be useful to predict the outcomes of hepcidin manipulation, and to guide treatment personalization by optimizing anemia management.
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Affiliation(s)
- Serena Pelusi
- Department of Pathophysiology and Transplantation, Internal Medicine, Università degli Studi di Milano, Fondazione IRCCS Ca' Granda Ospedale Policlinico Milano, Milano, Italy
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Shoji S, Inaba M, Tomosugi N, Okuno S, Ichii M, Yamakawa T, Kurihara S. Greater potency of darbepoetin-αthan erythropoietin in suppression of serum hepcidin-25 and utilization of iron for erythropoiesis in hemodialysis patients. Eur J Haematol 2013; 90:237-44. [DOI: 10.1111/ejh.12067] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/27/2012] [Indexed: 11/29/2022]
Affiliation(s)
| | | | - Naohisa Tomosugi
- Division of Advanced Medicine; Medical Research Institute; Kanazawa Medical University; Ishikawa; Japan
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Gözdemir E, Kaygusuz I, Kafali H. Is Hepcidin a New Cardiovascular Risk Marker in Polycystic Ovary Syndrome? Gynecol Obstet Invest 2013; 75:196-202. [DOI: 10.1159/000348497] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2012] [Accepted: 01/27/2013] [Indexed: 11/19/2022]
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Canavesi E, Alfieri C, Pelusi S, Valenti L. Hepcidin and HFE protein: Iron metabolism as a target for the anemia of chronic kidney disease. World J Nephrol 2012; 1:166-76. [PMID: 24175256 PMCID: PMC3782218 DOI: 10.5527/wjn.v1.i6.166] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/20/2011] [Revised: 05/24/2012] [Accepted: 09/25/2012] [Indexed: 02/06/2023] Open
Abstract
The anemia of chronic kidney disease and hemodialysis is characterized by chronic inflammation and release of cytokines, resulting in the upregulation of the iron hormone hepcidin, also increased by iron therapy and reduced glomerular filtration, with consequent reduction in iron absorption, recycling, and availability to the erythron. This response proves advantageous in the short-term to restrain iron availability to pathogens, but ultimately leads to severe anemia, and impairs the response to erythropoietin (Epo) and iron. Homozygosity for the common C282Y and H63D HFE polymorphisms influence iron metabolism by hampering hepcidin release by hepatocytes in response to increased iron stores, thereby resulting in inadequate inhibition of the activity of Ferroportin-1, inappropriately high iron absorption and recycling, and iron overload. However, in hemodialysis patients, carriage of HFE mutations may confer an adaptive benefit by decreasing hepcidin release in response to iron infusion and inflammation, thereby improving iron availability to erythropoiesis, anemia control, the response to Epo, and possibly survival. Therefore, anti-hepcidin therapies may improve anemia management in hemodialysis. However, HFE mutations directly favor hemoglobinization independently of hepcidin, and reduce macrophages activation in response to inflammation, whereas hepcidin might also play a beneficial anti-inflammatory and anti-microbic action during sepsis, so that direct inhibition of HFE-mediated regulation of iron metabolism may represent a valuable alternative therapeutic target. Genetic studies may offer a valuable tool to test these hypotheses and guide the research of new therapies.
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Affiliation(s)
- Elena Canavesi
- Elena Canavesi, Serena Pelusi, Luca Valenti, Internal Medicine, Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, via F Sforza 35, 20122 Milano, Italy
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van der Weerd NC, Grooteman MPC, Bots ML, van den Dorpel MA, den Hoedt CH, Mazairac AHA, Nubé MJ, Penne EL, Wetzels JFM, Wiegerinck ET, Swinkels DW, Blankestijn PJ, Ter Wee PM. Hepcidin-25 is related to cardiovascular events in chronic haemodialysis patients. Nephrol Dial Transplant 2012; 28:3062-71. [PMID: 23147161 DOI: 10.1093/ndt/gfs488] [Citation(s) in RCA: 56] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
BACKGROUND The development of atherosclerosis may be enhanced by iron accumulation in macrophages. Hepcidin-25 is a key regulator of iron homeostasis, which downregulates the cellular iron exporter ferroportin. In haemodialysis (HD) patients, hepcidin-25 levels are increased. Therefore, it is conceivable that hepcidin-25 is associated with all-cause mortality and/or fatal and non-fatal cardiovascular (CV) events in this patient group. The aim of the current analysis was to study the relationship between hepcidin-25 and all-cause mortality and both fatal and non-fatal CV events in chronic HD patients. METHODS Data from 405 chronic HD patients included in the CONvective TRAnsport STudy (NCT00205556) were studied (62% men, age 63.7 ± 13.9 years [mean ± SD]). The median (range) follow-up was 3.0 (0.8-6.6) years. Hepcidin-25 was measured with mass spectrometry. The relationship between hepcidin-25 and all-cause mortality or fatal and non-fatal CV events was investigated with multivariate Cox proportional hazard models. RESULTS Median (interquartile range) hepcidin-25 level was 13.8 (6.6-22.5) nmol/L. During follow-up, 158 (39%) patients died from any cause and 131 (32%) had a CV event. Hepcidin-25 was associated with all-cause mortality in an unadjusted model [hazard ratio (HR) 1.14 per 10 nmol/L, 95% CI 1.03-1.26; P = 0.01], but not after adjustment for all confounders including high-sensitive C-reactive protein (HR 1.02 per 10 nmol/L, 95% CI 0.87-1.20; P = 0.80). At the same time, hepcidin-25 was significantly related to fatal and non-fatal CV events in a fully adjusted model (HR 1.24 per 10 nmol/L, 95% CI 1.05-1.46, P = 0.01). CONCLUSION Hepcidin-25 was associated with fatal and non-fatal CV events, even after adjustment for inflammation. Furthermore, inflammation appears to be a significant confounder in the relation between hepcidin-25 and all-cause mortality. These findings suggest that hepcidin-25 might be a novel determinant of CV disease in chronic HD patients.
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Peffer K, den Heijer M, Holewijn S, de Graaf J, Swinkels DW, Verbeek AL, Atsma F. The effect of frequent whole blood donation on ferritin, hepcidin, and subclinical atherosclerosis. Transfusion 2012; 53:1468-74. [DOI: 10.1111/j.1537-2995.2012.03916.x] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2012] [Revised: 08/12/2012] [Accepted: 08/12/2012] [Indexed: 11/28/2022]
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POON PETERYAMKAU, SZETO CHEUKCHUN, KWAN BONNIECHINGHA, CHOW KAIMING, LEUNG CHIBON, LI PHILIPKAMTAO. Relationship between serum levels of tumour necrosis factor-related apoptosis-inducing ligand and the survival of Chinese peritoneal dialysis patients. Nephrology (Carlton) 2012; 17:466-71. [DOI: 10.1111/j.1440-1797.2012.01605.x] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
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