Factors associated with 1-year changes in serum fibroblast growth factor 23 levels in pediatric patients with chronic kidney disease.

BACKGROUND: Fibroblast growth factor 23 (FGF23) levels increase as kidney function decreases and are associated with increased mortality in patients with chronic kidney disease (CKD). Inflammation has also been shown to increase FGF23 production in adults; however, this has not been validated in pediatric patients with CKD. Furthermore, previous studies on children involved a single measurement of FGF23 without a follow-up, and a few studies have examined changes in FGF23 levels. METHODS: We measured the levels of serum intact FGF23, tumor necrosis factor-α (TNF-α), and interleukin-6 as parameters of inflammation and other variables related to bone metabolism at baseline and after 1 year in 62 pediatric patients with CKD (stages 2-5D, 1-16 years old). Factors related to changes in FGF23 levels were investigated. RESULTS: The median age of patients at the evaluation was 10.5 years (interquartile range 6.0-14.0), and the estimated glomerular filtration rate (eGFR) was 59.0 mL/min/1.73 m2 (45.1-69.3). Primary diseases included congenital anomalies of the kidney and urinary tract, ischemic kidney, and glomerulonephritis. The baseline value of FGF23 was 66.5 pg/mL (48.3-96.4), and percent change in FGF23 levels after 1 year was 8.5% (- 29.9-74.7). The percent change in FGF23 levels showed a negative correlation with that in eGFR (P = 0.010), and a positive correlation with that in TNF-α levels (P = 0.035). A multivariate linear regression analysis identified TNF-α as an independent factor increasing FGF23 levels. CONCLUSIONS: An increase in TNF-α levels is associated with elevation of FGF23 levels in pediatric patients with CKD.

Saccharated ferric oxide attenuates haematopoietic response induced by epoetin beta pegol in patients undergoing haemodialysis.

BACKGROUND: Decreased erythropoietin levels and impaired iron metabolism due to excessive hepcidin levels are responsible for renal anaemia in patients undergoing haemodialysis. Recently, erythroferrone (ERFE) has been identified as a factor that regulates hepcidin. In addition, fibroblast growth factor 23 (FGF23), which has been recognized as a phosphorus-regulating hormone, appears to be involved in haematopoietic regulation. Clarification of the detailed mechanism of haematopoiesis could lead to the improvement of renal anaemia treatment. METHODS: Epoetin beta pegol (CERA) was administered to patients undergoing haemodialysis at week 0, and the same amount of CERA with saccharated ferric oxide (SFO) was administered at week 4. The changes in haematopoiesis-related biomarkers, including ERFE, intact FGF23 (iFGF23), C-terminal FGF23 (cFGF23), and inflammatory markers, were examined. RESULTS: Administration of CERA increased ERFE levels, decreased hepcidin levels, and stimulated iron usage for haematopoiesis, leading to an increase in reticulocytes (Ret) and haemoglobin (Hb). Simultaneous administration of SFO with CERA (CERA + SFO) significantly attenuated the responses of ERFE, Ret, and Hb compared with CERA alone. Although iFGF23 levels were not affected by either CERA or CERA + SFO, cFGF23 was significantly elevated from baseline after CERA. Since cFGF23 levels were not affected by CERA + SFO, cFGF23 levels after CERA + SFO were significantly lower than those after CERA alone. The ratio of iFGF23 to cFGF23 (i/cFGF23 ratio) was significantly higher after CERA + SFO than that after CERA alone. In addition, high-sensitivity C-reactive protein (hsCRP) levels were significantly higher after CERA + SFO than after CERA alone. CONCLUSION: Administration of SFO suppressed haematopoietic responses induced by CERA. Elevation of i/cFGF23 ratio and hsCRP could account for the inhibitory effects of SFO on haematopoiesis. TRIAL REGISTRATION: This study was registered with the University Hospital Medical Information Network (ID UMIN000016552 ).

Efficacy of corticosteroid therapy for IgA nephropathy patients stratified by kidney function and proteinuria.

BACKGROUND: Steroid therapy is one of the important therapies for IgA nephropathy (IgAN), but the features of the IgAN patients who have the benefit from this therapy remained unclear. METHODS: This retrospective observational study, using data of 874 patients with IgAN analyzed the proteinuria and kidney function of IgAN patients who had beneficial effect by steroid therapy. Two advantages of the present study were a large cohort and a long observational period. RESULTS: Corticosteroid therapy had ameliorated the kidney prognosis [incident rate ratio (IRR) 0.57 (95%CI 0.34-0.92), P = 0.029]. Because of interaction between kidney function and use of corticosteroid (P = 0.047), stratification analysis by kidney function revealed that prognosis of kidney function in IgAN patients whose eGFR was less than 60 ml/min/1.73m2 was ameliorated by corticosteroid therapy [IRR 0.50 (95%CI 0.26-0.97), P = 0.015); while, there was no change of kidney prognosis in IgAN patients whose eGFR was above 60 ml/min/1.73 m2. To make the target of corticosteroid therapy for IgAN patients more clear, IgAN patients, whose eGFR were less than 60 ml/min/1.73 m2, were stratified by proteinuria (1 g/day). In IgAN patients whose eGFR were under 60 ml/min/1.73 m2 and whose proteinuria were over 1.0 g/day, corticosteroid therapy seemed to ameliorate kidney function [IRR 0.39 (95%CI 0.19-0.86), P < 0.05]; while, there was obviously no change by corticosteroid therapy in IgAN patients whose eGFR were less than 60 ml/min/1.73 m2 and whose proteinuria were less than 1.0 g/day. CONCLUSION: Our results suggested that steroid therapy was especially effective for IgAN patients whose eGFR was less than 60 ml/min/1.73 m2 and whose proteinuria was more than 1.0 g/day.

Inhibition of the Mammalian Target of Rapamycin May Augment the Increase in Soluble Klotho Levels in Renal Transplantation Recipients.

BACKGROUND/AIMS: α-Klotho is mainly expressed in the kidneys, and its soluble form can prevent vascular calcifications. Inhibition of the mammalian target of rapamycin (mTOR) upregulates Klotho. We assessed serial changes in the levels of soluble Klotho (sKlotho) in recipients before and after renal transplantation and investigated the effects of an mTOR inhibitor. METHODS: Serum sKlotho levels were measured in 36 recipients before and 1 year after transplantation and compared between those taking everolimus and those not taking everolimus. RESULTS: sKlotho levels were higher after transplantation than before transplantation (369.3 vs. 211.8 pg/mL). After transplantation, sKlotho levels were significantly higher in recipients taking everolimus than in those not taking everolimus (536.7 vs. 332.4 pg/mL). CONCLUSION: Our results suggest that mTOR inhibition may augment the increase in sKlotho levels in transplant recipients. Further studies are needed to examine whether mTOR inhibitors suppress the development of vascular complications via upregulation of Klotho expression in renal transplant recipients.

Current Topics in Vascular Access: Superficialization of Arteriovenous Fistula.

BACKGROUND: An arteriovenous fistula (AVF) is considered the gold standard modality of vascular access (VA) for maintenance hemodialysis (HD) because of its superior patency, few complications, provision of high quality of life, and low risk of patient mortality. The rapid growth of the aging population and the high prevalence of comorbidities, particularly diabetes mellitus and peripheral vascular disease, in patients requiring HD inevitably deteriorate the ability to construct and maintain a conventional AVF because of these patients' insufficient vascular adaptability. Furthermore, a substantial proportion of patients undergoing HD encounter non-maturation AVF failure and mis-cannulation-related complications, resulting in the need for a temporary VA procedure. Superficialization of the AVF is an alternative form of VA that facilitates the construction of an autologous fistula by maximizing the availability of a deeply located vein. Superficialization is also utilized in VA revision to improve the cannulability of an arterialized vein. SUMMARY: Superficialization involves various approaches, including tunnel transposition, elevation, lipectomy, and liposuction. Tunnel transposition and elevation are prerequisites for construction of an alternative autologous AVF, especially a one- or two-stage transposed brachial-basilic AVF, which is widely recognized as preferential to an arteriovenous graft in patients who cannot undergo conventional AVF installation. Elevation, lipectomy, and liposuction are also employed as revisional interventions for approximating the depth of the arterialized vein and ensuring a sufficient cannulable segment in the forearm and upper arm area. More recently, modified minimally invasive techniques for each superficialization procedure have been introduced to avoid postoperative complications. Amid the growing methodological diversity of superficialization, increasingly more studies have been performed in an attempt to clarify its feasibility and outcomes. On the whole, most superficialization procedures have acceptable patency and safety profiles. However, the preferable superficialization approach varies in accordance with both the influence of the anatomic location and the inherent advantages and limitations of each procedure. Key Messages: Both careful assessment of a patient's vascular adaptability and adequate comprehension of the various superficialization modalities that are available will enable optimal establishment of an autologous AVF in individual patients. This could lead to better outcomes and more successful management of HD.

Misdistribution of iron and oxidative stress in chronic kidney disease.

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.

Imbalance of coagulation and fibrinolysis can predict vascular access failure in patients on hemodialysis after vascular access intervention.

OBJECTIVE: For patients with end-stage renal disease on hemodialysis, the durability of vascular access (VA) is still far from optimal, and access survival after intervention for access failure is an important aspect. Procoagulant status is a leading cause of access failure. Coagulation-fibrinolysis imbalance can occur in hemodialyzed patients, but the influence of the imbalance has not been fully elucidated. METHODS: We prospectively examined coagulation-fibrinolysis balance to assess the risk of access failure after the intervention of revascularization in a cohort of 462 hemodialysis patients. Thrombin-antithrombin complex (TAT) and plasmin-α2-plasmin inhibitor complex (PIC) are markers for coagulation and fibrinolysis. Median follow-up was 243 days. The end point was clinical access failure: revascularization or access revision. The survival curve for VA patency was assessed using the Kaplan-Meier method and compared using the log-rank test. Cox proportional hazards regression models that allowed adjustment for baseline differences in age, sex, dialysis vintage, diabetes mellitus, and various factors (quantity of blood flow, prothrombin time-international normalized ratio, fibrin degradation products, C-reactive protein, interleukin-6, tumor necrosis factor-α, and pentraxin-3) were used. RESULTS: The 162 patients who reached an end point had smaller access flow volume and smaller percentage of arteriovenous fistula and higher TAT/PIC ratio. Kaplan-Meier analysis indicated that the patients with elevated TAT/PIC ratio showed poorer outcome (P < .001). On Cox regression modeling, elevated TAT/PIC was an independent risk factor for access failure (hazard ratio, 1.58; P = .03). CONCLUSIONS: Our results suggest that coagulation-fibrinolysis imbalance is a significant risk factor for access failure and may predict VA failure in hemodialyzed patients after access intervention.

Deregulated iron metabolism in bone marrow from adenine-induced mouse model of chronic kidney disease.

Although the primary cause of anemia in chronic kidney disease (CKD) is lack of sufficient erythropoietin (EPO), other factors may be involved, including the deregulation of iron metabolism. To clarify the mechanism of deranged erythropoiesis in CKD, we evaluated bone marrow (BM) cells in adenine-induced CKD mice. They showed even higher EPO expression in the kidney. Hepatic hepcidin mRNA and plasma hepcidin and ferritin levels were increased. Flow cytometry revealed a decrease in the number of cells expressing transferrin receptor (TfR), or late erythroid progenitors in BM; these cells correspond to proerythroblasts, and basophilic and polychromatic erythroblasts. In CKD mice, levels of erythroferrone mRNA in BM and splenic cells were significantly decreased, and MafB protein levels in BM cells were significantly increased. These results suggest that, in BM, the decrease in TfR, which may be associated with increased MafB levels, and the decrease in erythroferrone increase hepatic hepcidin expression, which may perturb iron recycling and erythropoiesis.

Oral Versus Intravenous Iron Supplementation for the Treatment of Iron Deficiency Anemia in Patients on Maintenance Hemodialysis-Effect on Fibroblast Growth Factor-23 Metabolism.

OBJECTIVE: Iron administration affects serum levels of intact (I-) fibroblast growth factor-23 (FGF23) and its cleavage product C-terminal (C-) FGF23 in iron-deficient patients on maintenance hemodialysis (MHD). The objective of this study was to compare the effect of oral or intravenous iron administration on serum levels of I-FGF23 and C-FGF23 in iron-deficient patients on MHD. DESIGN AND METHODS: A prospective randomized study. SUBJECTS: Participants on MHD with severe iron deficiency (n = 61). INTERVENTION: Participants were randomized to receive oral iron (50 mg of sodium ferrous citrate daily; oral group, n = 29) or intravenous iron (40 mg of saccharated ferric oxide weekly; IV group, n = 32). MAIN OUTCOME MEASURE: Changes in I-FGF23 and C-FGF23 after 10 weeks of treatment. RESULTS: Iron supplementation significantly increased hemoglobin, mean corpuscular volume, ferritin, and transferrin saturation rate, and decreased erythropoiesis-stimulating agent dose and erythropoiesis-stimulating agent resistance index value. Serum phosphate, calcium, and intact parathyroid hormone levels did not change significantly during the study. I-FGF23 levels increased significantly in the IV group and did not change in the oral group, whereas C-FGF23 levels were significantly reduced in both groups. Serum interleukin-6 and tumor necrosis factor-α levels were increased in both groups. Multiple regression analysis indicated the relationship between iron or erythropoiesis and FGF23 metabolism. CONCLUSION: Iron administration to patients on MHD with severe iron deficiency decreased C-FGF23 levels, whereas intravenous iron increased I-FGF23 levels though oral iron did not. If the target of chronic kidney disease-mineral and bone disorder therapy is reducing I-FGF23 levels, we suggest the use of oral iron.

Iron-induced calcification in human aortic vascular smooth muscle cells through interleukin-24 (IL-24), with/without TNF-alpha.

In CKD patients, arteriosclerotic lesions, including calcification, can occur in vascular smooth muscle cells in a process called Moenckeberg's medial arteriosclerosis. Iron overload induces several complications, including the acceleration of arteriosclerosis. However, the relationship between Moenckeberg's arteriosclerosis in vascular smooth muscle cells and iron accumulation has remained unknown. We tested the accelerated effect of iron on calcification in cultured human aortic vascular smooth muscle cells (HASMCs). After establishment of this model, we performed a microarray analysis using mRNA from early stage culture HASMCs after iron stimulation with or without TNF-alpha stimulation. The role of interleukin-24 (IL-24) was confirmed from candidate genes that might contribute to calcification. HASMCs demonstrated calcification induced by iron and TNF-alpha. Calcification of HASMCs was synergistically enhanced by stimulation with both iron and TNF-alpha. In the early phase of calcification, microarray analysis revealed up-regulation of IL-24. Stimulation of HASMCs by IL-24 instead of iron induced calcification. The anti-IL-24 antibody reversed the effect of IL-24, supporting the important role of IL-24 in HASMCs calcification. In conclusion, iron-induced calcification in vascular smooth muscle cells occurred via IL-24, IL-24 was increased during the calcification process induced by iron, and IL-24 itself caused calcification in the absence of iron.

Interplay of adipocyte and hepatocyte: Leptin upregulates hepcidin.

Conflicting evidence concerning leptin, an adipocyte-derived hormone, in atherogenesis and non-alcoholic fatty liver disease (NAFLD) has been reported. Iron metabolism and iron-mediated oxidative stress should be taken into consideration for the clarification of the pathogenesis of these diseases. In this study, we demonstrate that leptin receptor activation directly affects iron metabolism by the finding that serum levels of hepcidin, the master regulator of iron in the whole body, were significantly lower in leptin-deficient (ob/ob) and leptin receptor-deficient (db/db) mice. The administration of recombinant leptin to ob/ob mice for two weeks showed a significant increase in serum hepcidin and hepatic Hamp mRNA levels. Hamp mRNA levels were significantly correlated with hepatic iron content and BMP6 mRNA levels. Hepatic iron content was associated with the increase in mRNA levels of divalent metal transporter 1 and transferrin receptor. Our data provide evidence that the interplay of these two hormones could help improve the understanding of the pathogenesis of atherosclerosis and NAFLD.

Views of Japanese medical students on the work-life balance of female physicians.

OBJECTIVES: To survey medical students on their ideas of future work-life balance and discuss topics for next-generation medical education. METHODS: First-year (n=372, 34.9% female) and sixth-year medical students (n=311, 44.1% female) responded to a questionnaire on future self, marriage and childcare, and gender differences at the workplace. Responses were compared between academic years and gender. Responses were evaluated by gender and academic year using the Mann-Whitney U test.  Significance was set at p<0.01. RESULTS: The first-year and sixth-year students, regardless of gender, had different views on gender-related favorable treatment at workplaces {U=13464, p=0.000 (first-year), U=10407, p=0.000 (sixth-year)}. A greater percentage of female students would choose career options based on the possibility of marriage and childbirth {U=10689, p=0.000 (first-year), U=10930, p=0.000 (sixth-year)}. Among first-year students, a greater percentage of female students expected to work part-time. Also among first-year students, greater percentages of female students expected to work part-time or leave their jobs temporarily while raising their children. Compared with first-year male students, first-year female students expected to undertake larger portions of the childcare and housework burden than their partners. However, gender differences in work-life balance and childcare leave vanished in the sixth-year students. CONCLUSIONS: Female medical students accepted childcare and housework burdens as inevitable; the work environment they choose might affect their career development. While support from male partners and institutions must be increased, voluntary actions and change in mentality of female students need to be promoted through medical education to prevent them from waiting passively for the situation to change.

The association of alcohol and smoking with CKD in a Japanese nationwide cross-sectional survey.

Chronic kidney disease (CKD) is characterized by a reduced glomerular filtration rate (GFR) and proteinuria. Modifiable lifestyle factors such as smoking and alcohol contribute to CKD. Recent cohort studies have shown that moderate alcohol consumption attenuates the decline of the GFR and smoking has been previously shown to be associated with CKD. However, the association of smoking and alcohol consumption on CKD is not entirely clear. To examine whether there is evidence to assume that smoking is an effective modifier of the association between CKD and alcohol consumption, we conducted a cross-sectional study of a population of people who presented for a health checkup under a program that targets the insured population aged ≧40 years using data from the Specific Health Check and Guidance in Japan between April 2008 and March 2009. Of the 506 807 participants aged ⩾40 years, 292 013 (57.6%) were included in the present analysis. Outcomes were kidney dysfunction, as an eGFR of <60 ml/min/1.73 m2, and proteinuria. In nonsmokers, drinking a small amount was associated with a lower prevalence of proteinuria, but in smokers, the association between alcohol and proteinuria was not observed. The analysis regarding eGFR <60 ml/min/1.73 m2 revealed that in both smokers and nonsmokers, alcohol consumption was inversely associated with the risk of CKD. Mild to moderate alcohol consumption might be associated with a lower risk of CKD (proteinuria and eGFR), especially among nonsmokers, because smoking might have modified the potential benefits of alcohol to prevent CKD.

Serum Uric Acid Level Predicts Progression of IgA Nephropathy in Females but Not in Males.

BACKGROUND: Immunoglobulin A nephropathy (IgAN) is one of most common forms of glomerulonephritis. At this point, the clinical impact of hyperuricemia on IgAN is not clear. The aim of the present study was to explore the clinical impact of hyperuricemia on the progression of IgAN. STUDY DESIGN: Multicenter retrospective cohort study. SETTING & PARTICIPANTS: 935 IgAN patients who were diagnosed by kidney biopsy at Osaka University Hospital, Osaka General Hospital, and Osaka Rosai Hospital. were included in this study. PREDICTOR: Uric acid levels at renal biopsy. OUTCOMES: The outcome of interest was the time from the kidney biopsy to the time when a 50% increase in the baseline serum creatinine level was observed, which was defined as "progression". MEASUREMENTS: The baseline characteristics according to the kidney biopsy at the time of diagnosis were collected from the medical records, and included age, gender, body mass index, hypertension, diabetes (use of antidiabetic drugs), serum levels of creatinine, urinary protein, smoking status, RAAS blockers and steroid therapy. RESULTS: An elevated serum uric acid level was an independent risk factor for progression in female patients (per 1.0 mg/dL, multivariate-adjusted incident rate ratio 1.33 [95% confidence interval 1.07, 1.64], P = 0.008) but not in male patients (1.02 [0.81, 1.29], P = 0.855). To control a confounding effect of renal function on an association between serum uric acid level and progression in female patients, age- and serum creatinine-matched and propensity score-matched analyses were performed, and these results also supported the effect by uric acid on kidney disease progression independent of basal kidney function. LIMITATIONS: A cohort analyzed retorospectively. CONCLUSIONS: This study revealed that an elevated uric acid level was an independent risk factor for ESKD in female IgAN patients. Therefore, uric acid might be a treatable target in female IgAN patients.

Iron Localization and Infectious Disease in Chronic Kidney Disease Patients.

For patients on dialysis, infection is the second leading cause of mortality. Iron metabolism should be considered in the pathogenesis of infectious disease, as high local iron concentrations favor the growth of many microbes. This review is intended to provide information regarding iron metabolism and infection in chronic kidney disease (CKD) patients. There are 2 reasons these patients may be vulnerable to infection: (1) the excessive iron administered to treat renal anemia could be associated with impairments of the host's innate immune response, (2) CKD-associated inflammation could cause dysregulated iron metabolism. Pathogenic microorganisms can be categorized as extracellular or intracellular pathogens. The proliferation site may determine the degree of virulence. In cases of mainly extracellular microbial growth, the host's strategy of sequestering iron in cells may efficiently inhibit proliferation. However, the same strategy may favor the intracellular growth of microorganisms. The administration of excessive amounts of iron may modify iron localization by an increase in the hepcidin concentration. We conclude that there is a need for large multicenter randomized controlled trials to evaluate the long-term safety of different iron administration patterns that allow for a lower infection rate while still producing efficient erythropoiesis in CKD patients.

Body Mass Index Modifies an Association between Self-Reported Regular Exercise and Proteinuria.

AIM: Regular exercise habits are well-known to exert a favorable effect on the metabolic syndrome, which may cause proteinuria and chronic kidney disease (CKD). However, it remains unknown if exercise exerts a favorable effect on proteinuria and kidney dysfunction. The aim of this study was to reveal the association between exercise and the prevalence of proteinuria and kidney dysfunction and the attenuation by obesity. METHODS: This study was a cross-sectional cohort study that included 292,013 participants who underwent the Specific Health Check and Guidance in Japan. The exercise score (range 0-3) was based on the number of positive answers to three questions regarding exercise habits. The outcome was defined as urinary protein detected by a dipstick test and kidney dysfunction [estimated glomerular filtration rate (GFR) less than 45 ml/min/1.73 m(2)]. RESULTS: The exercise score was significantly associated with the prevalence of proteinuria in both males [vs. exercise score 0; exercise score 1, multivariate-adjusted odds ratio 0.86 (95% confidence interval 0.81-0.92), P<0.001; exercise score 2, 0.84 (0.79-0.90), P<0.001; exercise score 3, 0.77 (0.72-0.82), P<0.001] and females (same as in males). After the male subjects were divided into quintiles according to body mass index (BMI) in more than three groups (22.9

Novel iron-containing phosphate binders and anemia treatment in CKD: oral iron intake revisited.

Recent reports have shown that novel phosphate binders containing iron are not only efficacious for the treatment of hyperphosphatemia but also may reduce the need for erythropoiesis-stimulating agents and intravenous (IV) iron for anemia management in patients on maintenance hemodialysis (MHD). Possible healthcare cost savings, which have not been demonstrated in a long-term study, may be an additional advantage of using such multi-pronged treatment strategies for the control of both hyperphosphatemia and iron needs. It is currently assumed that oral iron supplementation is less efficient than the IV route in patients with chronic kidney disease (CKD). The unexpected efficacy of novel iron-containing phosphate binders, such as ferric citrate, in repleting insufficient iron stores and improving the anemia of CKD could change this view. Previous assumptions of self-controlled iron uptake by 'mucosal block' or hepcidin, or else by impaired intestinal iron absorption due to CKD-associated inflammation cannot be reconciled with recent observations of the effects of ferric citrate administration. Citrate in the intestinal lumen may partly contribute to the acceleration of iron absorption. Animal experiments and clinical studies have also shown that oral iron overload can cause excessive iron accumulation despite high hepcidin levels, which are not able to block iron absorption completely. However, like with IV iron agents, no long-term safety data exist with respect to the effects of iron-containing phosphate binders on 'hard' patient outcomes. Future randomized prospective studies in patients with CKD are necessary to establish the safety of oral iron-containing phosphate binders for the control of both hyperphosphatemia and renal anemia.

Dysregulated iron metabolism in patients on hemodialysis.

The two main causes of death in patients on maintenance hemodialysis (MHD) are cardiovascular disease and infection. In the current report, we discuss the association of the iron-catalyzed Fenton reaction and iron sequestration with complications in MHD patients. In particular, we have studied the deregulation of several iron transport systems of polymorphonuclear leukocytes (PMNLs) and the effects of TNF-α on human umbilical vein endothelial cells or PMNLs obtained from MHD patients and controls, and the following results were obtained. (1) Iron was sequestered in MHD-PMNLs, in which the protein governing iron transport was dysregulated. (2) TNF-α accelerated iron accumulation and oxidative stress in human umbilical vein endothelial cells in a manner similar to that in MHD-PMNLs. (3) An endosomal iron transport protein, or natural resistance-associated macrophage protein 1, was decreased in PMNLs from MHD patients, and TNF-α caused a decline in this protein's expression in control PMNLs. (4) The mitochondrial iron chaperone protein frataxin was decreased in MHD-PMNLs, which was linked to the acceleration of oxidative stress and hypercytokinemia. (5) The index of arterial stiffness was aggravated in MHD patients and was associated with serum hepcidin and TNF-α levels, which could inhibit iron exit from cells. With regard to bacterial infections, iron availability to these intracellular pathogens is critical for their growth. In particular, iron accumulation in cells and endosomes may accelerate the spread of infection. Cardiovascular disease has been shown to be linked to oxidative stress caused by iron sequestration in vascular cells and macrophages as well as by the alteration of iron metabolism in mitochondria, and the observed increase in hepcidin and TNF-α may accelerate these crucial steps of oxidative stress in vascular disease. Thus, because surplus iron in the body may escalate the dysregulation of iron metabolism, as observed in MHD patients, iron supplementation for renal anemia treatment should be prudent.