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Acute kidney injury (AKI) is a very common condition with high morbidity and mortality, which can be seen in 5-7% of all hospitalized patients and in up to 57% of all intensive care unit admissions. Despite recent advances in clinical care, the prevalence of AKI has been shown to increase with virtually no change in mortality. AKI is a complex syndrome occurring in a variety of clinical settings. Early detection is crucial to prevent irreversible loss of renal function. The pathogenesis of AKI is highly multifactorial and complex, including vasoconstriction, reactive oxygen species formation, cell death, abnormal immune modulators and growth factors. Emerging evidence from both human and animal studies suggests that dysregulation of iron metabolism may play a potentially important role in AKI. Therefore, targeting the iron homeostasis may provide a new therapeutic intervention for AKI. New therapeutic strategies including iron chelation therapy, targeting iron metabolism related proteins and direct inhibitors of ferroptosis are imperative to improve the outcomes of patients. Taking into consideration the complexity of AKI, one intervention may not be enough for therapeutic success. Future preclinical studies in animal disease models followed by well-designed clinical trials should be conducted to extend findings from animal AKI models to humans., Competing Interests: Declaration of competing interest The authors declare no conflict of interests., (Copyright © 2020 Medical University of Bialystok. Published by Elsevier B.V. All rights reserved.)

The increased usage of intravenous iron in hemodialysis patients during recent years has led to increasing concern over the potential development of iron overload. Current methods for detecting iron overload, transferrin saturation, and serum ferritin are neither sensitive nor specific. Labile plasma iron (LPI) represents a component of nontransferrin-bound iron and may be a more accurate indicator of impending iron overload. We studied whether LPI measured can serve as an early indicator of impending iron overload and mortality in hemodialysis patients. Chronic hemodialysis patients from two medical centers in Israel and Poland who received intravenous iron were included. Baseline clinical and laboratory parameters were recorded. LPI was measured before and 48 hours after a single IV administration. Correlation of positive LPI with laboratory parameters and 2-year mortality was evaluated. One hundred and one hemodialysis patients were included in the study. LPI became positive post-administration in 18 (17.8%) patients. Ferritin levels >526 ng/mL and monthly iron doses >250 mg were associated with positive LPI after intravenous iron. At a 2-year follow-up, higher mortality was observed in the positive LPI group (61.1% compared to 25.3%, P ≤ .05), although this effect was not statistically significant after multivariate adjustment. A substantial number of hemodialysis patients have positive LPI after intravenous iron administration. LPI positively correlates with laboratory parameters that are currently in routine clinical use for detecting iron overload and with higher intravenous iron dose. Further studies should be conducted to establish the clinical implications of LPI monitoring in hemodialysis patients., (© 2019 International Society for Apheresis, Japanese Society for Apheresis, and Japanese Society for Dialysis Therapy.)

Purpose: The aim of the study was to assess GDF-15 and iron status in patients in early stages of chronic kidney disease with a particular emphasis on elderly population in association of classic iron status parameters with novel iron homeostasis biomarkers and inflammatory parameters., Methods: Serum concentrations of GDF-15, iron (Fe), transferrin saturation, soluble transferrin receptor (sTfR), hepcidin, high-sensitive C-reactive protein (hsCRP), interleukin 6 (IL-6), and hemoglobin were measured in 56 patients ≥65 years of age and in 31 <65 years of age., Results: In patients ≥65 years, serum concentrations of GDF-15 and hsCRP were significantly higher in comparison with younger group. There was no statistically significant difference in hemoglobin, iron, hepcidin, and sTfR concentration between the two studied groups. In both groups GDF-15 was significantly correlated with hemoglobin, eGFR, hsCRP, and IL-6. GDF-15 was significantly higher in patients with anemia in comparison with their non-anemic counterparts. In multivariate analysis, hemoglobin was found to be a predictor of log GDF-15 (beta value = 0.36, P = 0.006, R (2) = 37 %)., Conclusions: An intricate interplay between renal function, anemia, and GDF-15 concentrations awaits further studies, as there are few data regarding pathophysiological role of GDF-15 in diabetes, kidney disease, and other comorbidities. Further understanding regarding the signaling pathways of GDF-15 may help to discover next pieces in the exciting puzzle of GDF-15. Finally, as studies dealing with normal level of GDF-15 in the healthy aged are lacking, it is possible that the higher values of GDF-15 values found in the present study represent values of GDF-15 according to age more than CKD levels.

The association between chronic kidney disease (CKD) and cardiovascular disease (CVD) is well established, and there is mounting evidence of interorgan cross talk that may accelerate pathologic processes and the progression of organ dysfunction in both systems. This process, termed cardiorenal syndrome (CRS) by the Acute Dialysis Quality Initiative, is considered a major health problem: patients with CKD and CVD are at much higher risk of mortality than patients with either condition alone. To date, the majority of CRS research has focused on neurohormonal mechanisms and hemodynamic alterations. However, mounting evidence suggests that abnormalities in the normal pathophysiology of the bone-mineral axis, iron, and erythropoietin play a role in accelerating CKD and CVD. The goal of this article is to review the role and interrelated effects of the bone-mineral axis and anemia in the pathogenesis of chronic CRS., (Copyright © 2015 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Background: In patients after kidney transplantation, anemia is relatively common and is associated with impaired kidney function, subclinical inflammatory state, and immunosuppressive treatment. Zonulin-prehaptoglobin-2, a newly discovered protein, is necessary for integrity of intracellular tight junctions in the gut. Taking into consideration iron metabolism, including its absorption in the gut, we designed a cross-sectional study to look for the possible interactions among zonulin, iron status, and anemia in kidney transplant recipients., Methods: The study was performed on 72 stable kidney transplant recipients and 22 healthy volunteers. Zonulin, iron status, and inflammatory markers were assessed with the use of commercially available kits., Results: Zonulin was significantly lower in kidney allograft recipients than in healthy volunteers (P < .001). Zonulin correlated with systolic blood pressure (r = -0.33; P < .05), thyroid-binding globulin (r = 0.24; P < .05), hematocrit (r = 0.28; P < .005), hemoglobin (r = 0.32; P < .01), total protein (r = -0.33; P < .01), erythrocyte count (r = 0.26; P < .05), and fasting glucose (r = -0.25; P < .05). Zonulin was not affected by sex, type of immunosuppressive therapy, presence of diabetes, coronary artery disease, heart failure, hypertension, or cause of end-stage renal disease. Zonulin was not related to any of the iron parameters studied. In multiple regression analysis, predictors of zonulin were total protein and thyroglobulin-binding protein, explaining 46% of variation., Conclusions: Zonulin, with its poorly defined function, does not seem to play a role in the anemia in kidney allograft recipients; however, it seems to be related to the absorption process in the gut.

Background: Neutrophil gelatinase-associated lipocalin (NGAL) binds small, iron-carrying molecules - siderophores. On the other hand, hepcidin is a small defensin-like peptide produced by hepatocytes, modulated in response to anaemia, hypoxia, or inflammation. We tested the hypothesis that NGAL may be related to hepcidin, not only to iron metabolism, in 182 prevalent haemodialysed patients., Methods: Iron status (iron, total iron-binding capacity, ferritin, total saturation of transferrin, TSAT), complete blood count, creatinine, albumin, serum lipids were assessed using standard laboratory methods. Soluble receptor of transferrin, high-sensitivity C-reactive protein (hsCRP), tumour necrosis factor-alpha, interleukin-6, prohepcidin, hepcidin and NGAL were measured in serum using commercially available kits., Results: Serum NGAL, prohepcidin, hepcidin levels were significantly higher in haemodialysed patients over healthy volunteers (579.11 +/- 213.95 vs. 78.43 +/- 32.21 ng/ml, p < 0.001, 320.54 +/- 182.65 vs. 98.65 +/- 34.32 ng/ml, p < 0.01, 155.30 +/- 94.05 vs. 23.65 +/- 12.76 ng/ml, p < 0.001, respectively). Serum NGAL correlated strongly with residual renal function (r = -0.54, p < 0.001), Kt/V (r = 0.41, p < 0.001), hepcidin (r = -0.28, p < 0.01), serum creatinine (r = 0.63, p < 0.001), iron (r = 0.25, p < 0.01), TSAT (r = 0.30, p < 0.001), ferritin (r = 0.33, p < 0.001), hsCRP (r = 0.32, p < 0.001). In multiple regression analysis, residual renal function, hepcidin, creatinine and hsCRP were predictors of serum NGAL in haemodialysed patients., Conclusions: NGAL is highly induced in dialysed patients. NGAL could reflect both kidney function and iron metabolism. Taking into account the antimicrobial properties of NGAL, further studies are needed to address the role of NGAL in iron metabolism and inflammation in renal failure., ((c) 2010 S. Karger AG, Basel.)

Hepcidin is the predominant negative regulator of iron absorption in the small intestine, iron transport across the placenta, and iron release from the macrophages. Iron supplementation is often introduced in dialyzed patients to replete or to maintain iron stores, particularly in patients treated with erythropoietin-stimulating agents. The aim of this study was to assess hepcidin levels in 12 hemodialyzed (HD) patients (6 females, 6 males, mean age 64 years, mean time on HD 36 months) before and after intravenous iron therapy. Prohepcidin and hepcidin were studied using commercially available kits from DRG Instruments GmbH, Marburg, Germany (ELISA method), and Bachem, St. Helens, UK (RIA method). Soluble receptor of transferrin was studied using a kit from R&D, Abington, UK. We found a significant rise in hemoglobin concentration, hematocrit, ferritin, serum iron, transferrin saturation and a fall in soluble receptor of transferrin. Serum hepcidin and prohepcidin as well as urinary prohepcidin increased significantly after the therapy. In conclusion, hepcidin levels are influenced by iron supplementation in HD patients. Further examinations of hepcidin as a marker of iron deficiency using new validated measurement techniques are required. It remains to be seen if assay of hepcidin will be of help in identifying patients unresponsive to oral iron or requiring intravenous iron supplementation., ((c) 2009 S. Karger AG, Basel.)

Maintaining the correct iron balance is crucial for health. Our understanding of the molecular control of iron metabolism has increased dramatically over the past 5 years due to the discovery of hepcidin. This is a circulating antimicrobial peptide mainly synthesized in the liver, which has been recently proposed as a factor regulating the uptake of dietary iron and its mobilization from macrophages and hepatic stores. Inflammation causes an increase of production of hepcidin, which is a potent mediator of anemia of chronic diseases. Anemia in chronic kidney disease is mainly due to erythropoietin deficiency but these patients often have a chronic inflammatory state. The aim of this review is to summarize the current knowledge dealing with a possible role of hepcidin in iron metabolism and its regulation, particularly in kidney disease. In addition, current methods of determination of hepcidin are reviewed., (Copyright 2007 S. Karger AG, Basel.)

Hepcidin is a small defensin-like peptide whose production by hepatocytes is modulated in response to anemia, hypoxia, or inflammation. Hepcidin could also act as an indicator of functional iron deficiency in these patients. Cross-sectional study was performed to assess hepcidin correlations with renal function, iron status, and hsCRP in patients with chronic renal failure on conservative treatment, on hemodialyses, and in kidney transplant recipients. Iron status, complete blood count, creatinine, albumin, lipids were assessed using standard laboratory methods. GFR was estimated using MDRD formula. Hepcidin and high sensitivity CRP were measured using commercially available kits. Ferritin and hepcidin were higher in hemodialyzed patients, kidney transplant recipients, and patients with chronic renal failure over controls. In patients with chronic renal failure, hepcidin correlated significantly with total protein, albumin, creatinine, and eGRF. In kidney transplant recipients, hepcidin correlated significantly in univariate analysis, with total protein, ferritin, time after transplantation, creatinine, eGRF and tended to correlate with cholesterol. In hemodialyzed patients hepcidin, correlated significantly with triglycerides, albumin, creatinine, urea, residual renal function, and hsCRP. In healthy volunteers, hepcidin was related to triglycerides and ferritin. Multiple regression analysis in hemodialyzed patients showed that hepcidin was independently related to creatinine, triglycerides, and residual renal function. Multiple regression analysis in kidney transplant recipients showed that hepcidin was independently related only to GFR and ferritin. Elevated hepcidin in all groups of patients studied may be due to low grade inflammation, frequently encountered in this population and mainly to impaired renal function., ((c) 2006 Wiley-Liss, Inc.)

Anaemia is a common complication of chronic kidney disease (CKD). In this setting, iron deficiency is frequent because of the combination of increased iron needs to sustain erythropoiesis with increased iron losses. Over the years, evidence has accumulated on the involvement of iron in influencing pulmonary vascular resistance, endothelial function, atherosclerosis progression and infection risk. For decades, iron therapy has been the mainstay of therapy for renal anaemia together with erythropoiesis-stimulating agents (ESAs). Despite its long-standing use, grey areas still surround the use of iron therapy in CKD. In particular, the right balance between either iron repletion with adequate therapy and the avoidance of iron overload and its possible negative effects is still a matter of debate. This is particularly true in patients having functional iron deficiency. The recent Proactive IV Iron Therapy in Haemodialysis Patients trial supports the use of intravenous (IV) iron therapy until a ferritin upper limit of 700 ng/mL is reached in haemodialysis patients on ESA therapy, with short dialysis vintage and minimal signs of inflammation. IV iron therapy has also been proven to be effective in the setting of heart failure (HF), where it improves exercise capacity and quality of life and possibly reduces the risk of HF hospitalizations and cardiovascular deaths. In this review we discuss the risks of functional iron deficiency and the possible benefits and risks of iron therapy for the cardiovascular system in the light of old and new evidence. [ABSTRACT FROM AUTHOR]

Background/aims: Zonulin is the only known regulator of intestinal permeability. It is also considered as a potential inflammatory marker in several conditions such as diabetes and inflammatory bowel syndrome. The aim of the study was to investigate zonulin levels in patients with early stages of CKD and its possible correlation with inflammation, anemia and iron status parameters. Methods: Eighty-eight patients with early stages of CKD and 23 healthy volunteers were enrolled in the study. Zonulin, hepcidin-25, soluble transferrin receptor, interleukin-6 and high-sensitivity C-reactive protein were measured using commercially available assays. Results: Zonulin was significantly lower among patients with CKD in comparison with healthy volunteers. There were no statistically significant differences in zonulin concentration between patients with and without inflammation. Zonulin was significantly correlated with hepcidin only in patients with inflammation. Zonulin was neither related to iron nor related to ferritin. Conclusions: Zonulin cannot be considered as an inflammatory marker in CKD. It does not play a role in the disturbances of iron metabolism in CKD. Its physiological role remains to be elucidated. [ABSTRACT FROM AUTHOR]

Iron deficiency anaemia is a global health problem that manifests as fatigue and poor physical endurance. Anaemia can be caused by dietary iron deficiency, blood loss or a combination of poor iron absorption and ineffective iron mobilization in patients with chronic disease. Nephrologists caring for patients with impaired renal function understand that iron treatment is necessary to provide adequate iron for erythropoiesis during the treatment of overt anaemia. However, a less wellunderstood health problemis iron deficiency, which creates symptoms that overlap with those of anaemia and often occurs in concert with chronic disease. Recently, several randomized controlled clinical trials have been conducted to investigate the effects of treatment with intravenous iron in heart failure patients with iron deficiency who may or may not also have anaemia. Given that heart and kidney disease are often comorbid, these clinical trials may have implications for the way nephrologists view their patients with iron deficiency. In this article, we review several clinical studies of intravenous iron therapy for patients with iron deficiency and heart failure and discuss possible implications for the treatment of patients with kidney disease. [ABSTRACT FROM AUTHOR]

Introduction: Fibroblast growth factor 23 (FGF-23) levels are elevated in impaired renal function. Inflammation and iron are potential regulators of FGF-23. The aim of the study was to evaluate the association between FGF-23 concentration, novel iron status biomarkers and inflammatory parameters among patients with early stages of chronic kidney disease (CKD).Material and Methods: The study population included 84 patients with CKD in the early stage. Serum hemoglobin, fibrinogen, creatinine, iron, transferrin saturation and ferritin levels were measured using standard laboratory methods. Commercially available kits were used to measure: intact FGF-23, hepcidin, soluble transferrin receptor (sTfR), interleukin 6 (IL-6) and high-sensitivity C-reactive protein (hsCRP).Results: In patients with CKD no differences in FGF-23 concentration according to iron status were observed. Lower iron concentration was associated with higher concentrations of hsCRP, IL-6 and fibrinogen. In univariate and multivariate analysis FGF-23 correlated with fibrinogen (r = -0.23, p < 0.05) and eGFR (r = -0.36, p < 0.05).Conclusions: FGF-23 is affected by kidney function and fibrinogen but not iron status parameters in the early stages of CKD. Our data are paving the way for further studies on the role of FGF-23 in iron metabolism, especially in early stages of CKD. [ABSTRACT FROM AUTHOR]

Anemia is more prevalent in renal transplant recipients than in GFR-matched chronic kidney disease patients. Hepcidin is a small defensin-like peptide whose production by hepatocytes is modulated in response to anemia, hypoxia or inflammation. Growth differentiation factor 15 (GDF15) was recently identified as a hepcidin-suppression factor that is expressed at high levels in patients with ineffective erythropoiesis. The aim of the study was to assess GDF15 levels with relation to iron parameters in 62 stable kidney allograft recipients maintained on triple immunosuppressive therapy. Methods: Complete blood count, urea, creatinine, and iron status were assessed by standard methods. We measured GDF15, hepcidin, hemojuvelin, IL-6 and NGAL with commercially available assays. Results: Mean levels of GDF15, NGAL, hepcidin and hemojuvelin were significantly higher in kidney allograft recipients when compared to the control group (p < 0.001 for all). GDF15 was significantly higher in patients with anemia according to the WHO definition when compared to their nonanemic counterparts (p < 0.05). GDF15 levels were not dependent on the type of immunosuppressive therapy. In univariate analysis GDF15 was related to kidney function (creatinine r = 0.39, p < 0.01, eGFR by MDRD r = -0.37, p < 0.01), urea (r = 0.39, p < 0.01), uric acid (r = 0.42, p < 0.01), hepcidin (r = -0.32, p < 0.01), IL-6 (r = 0.28, p < 0.05), hemoglobin (r = -0.32, p < 0.05), and NGAL (r = -0.35, p < 0.01). GDF15 was not related to serum iron, or ferritin. In multivariate analysis, hepcidin was found to be a predictor of GDF15. In conclusion, our preliminary data may suggest possible mutual relations between GDF15 and hepcidin in patients with kidney disease and that GDF15 might be involved in the pathogenesis of anemia in kidney allograft recipients. However, the role of inflammation should be also elucidated. Copyright © 2013 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Iron is the fourth most common element in the Earth’s crust and is crucial for life. Over the last few years, our understanding of iron metabolism has dramatically increased due to the discovery of hepcidin, which is produced by hepatocytes and modulated in response to anemia, hypoxia and inflammation. It has been found that anemia upregulates lipocalin 2 (NGAL; neutrophil gelatinase-associated lipocalin) in the liver and serum. The aim of this review is to summarize the current knowledge dealing with a possible role of hepcidin and NGAL in iron metabolism and its regulation, particularly in kidney disease. Elevated NGAL a few days after insult is a possible preventive or protective mechanism limiting renal injury. NGAL is an innate antibacterial factor as well as hepcidin. NGAL binds siderophores, thereby preventing iron uptake by bacteria. Hepcidin, an antibacterial defensin, prevents iron absorption from the gut and iron release from macrophages, leading to hypoferremia and anemia. Both proteins sequester iron, but by different mechanisms. However, these proteins involved in iron metabolism do not seem to be independently related. Taking into account the antimicrobial moieties of NGAL, further studies are needed to address the role of NGAL in iron metabolism and inflammation in renal failure. Copyright © 2010 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Chronic kidney disease (CKD) is one of the fastest-growing major causes of death internationally. Better treatment of CKD and its complications is crucial to reverse this negative trend. Anemia is a frequent complication of CKD and is associated with unfavorable clinical outcomes. It is a devastating complication of progressive kidney disease, that negatively affects also the quality of life. The prevalence of anemia increases in parallel with CKD progression. The aim of this review is to summarize the current knowledge on therapy of renal anemia. Iron therapy, blood transfusions, and erythropoietin stimulating agents are still the mainstay of renal anemia treatment. There are several novel agents on the horizon that might provide therapeutic opportunities in CKD. The potential therapeutic options target the hepcidin–ferroportin axis, which is the master regulator of iron homeostasis, and the BMP-SMAD pathway, which regulates hepcidin expression in the liver. An inhibition of prolyl hydroxylase is a new therapeutic option becoming available for the treatment of anemia in CKD patients. This new class of drugs stimulates the synthesis of endogenous erythropoietin and increases iron availability. We also summarized the effects of prolyl hydroxylase inhibitors on iron parameters, including hepcidin, as their action on the hematological parameters. They could be of particular interest in the out-patient population with CKD and patients with ESA hyporesponsiveness. However, current knowledge is limited and still awaits clinical validation. One should be aware of the potential risks and benefits of novel, sophisticated therapies. [ABSTRACT FROM AUTHOR]