Effect of iron administration on the aortic iron content and vascular calcification in phosphorus-loaded chronic kidney disease rats.

BACKGROUND: Cardiovascular disease (CVD) is a major cause of morbidity and mortality in patients with chronic kidney disease (CKD) and could be related to oxidative stress. Vascular calcification (VC) has been established as a critical risk factor for accelerated CVD. In CKD, phosphorus (Pi), iron (Fe) and Nrf2 are modulators of VC and important agonists and antagonists of oxidative stress. The aim of this study was to determine whether Fe administration, which is commonly used to treat renal anemia, affects aortic Fe overload and VC, and whether Nrf2 and its related genes, ferritin H and HIF-1α, are involved in the development of VC. METHODS: A CKD model was created in rats by administering adenine and simultaneously feeding a high-Pi diet. In addition to control and CKD rats without Fe administration (No-Fe group), Fe was administered orally (PO-Fe group) or intraperitoneally (IP-Fe group) to CKD animals to clarify the effects of Fe administration on the aortic Fe and calcium (Ca) contents and the involvement of Nrf2 and its induced antioxidative proteins, ferritin H and HIF-1α, in VC. RESULTS: The aortic Fe content increased significantly in the IP-Fe group, which was closely correlated with liver HAMP (hepcidin) expression in all animals. Fe administration had no significant effect on the aortic Ca and Pi contents regardless of the route of Fe administration. The aortic mRNA level of Nrf2 was significantly increased in the IP-Fe group and correlated with serum Pi levels and aortic Fe contents, which could respond to oxidative stress. Notably, the mRNA level of Nrf2 was also significantly correlated with the mRNA levels of ferritin H and HIF-1α. Since we could not measure Nrf2 protein levels in this study, we confirmed the upregulation of HMOX1 and NQO1 mRNA expression in parallel with Nrf2 mRNA. CONCLUSION: Parenteral Fe administration increased aortic Fe in parallel with the liver HAMP mRNA level but did not affect VC. Aortic Nrf2 mRNA levels correlated significantly with aortic Fe and serum Pi levels and with aortic mRNA levels of ferritin H and HIF-1α as well as HMOX1 and NQO1.

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 ).

Construction of a circularly connected VHH bispecific antibody (cyclobody) for the desirable positioning of antigen-binding sites.

A bispecific antibody (bsAb) is an emerging class of next-generation biological therapeutics. BsAbs are engineered antibodies possessing dual antigen-binding paratopes in one molecule. The circular backbone topology has never been demonstrated, although an enormous number of bispecific constructs have been proposed. The circular topology is potentially beneficial for fixing the orientation of two paratopes and protection from exopeptidase digestion. We construct herein a circularly connected bispecific VHH, termed cyclobody, using the split-intein circular ligation of peptides and proteins. The constructed cyclobodies are protected from proteolysis with a retained bispecificity. The anti-EGFR × anti-GFP cyclobody can specifically stain EGFR-positive cells with GFP. The anti-EGFR × anti-CD16 cyclobody shows cytotoxic activity against EGFR-positive cancer cells with comparative activity of a tandem VHH construct. Successful demonstration of a new topology for the bispecific antibody will expand the construction strategy for developing antibody-based drugs and reagents.

Functional Domain Order of an Anti-EGFR × Anti-CD16 Bispecific Diabody Involving NK Cell Activation.

Bispecific antibodies (bsAbs) have emerged as promising therapeutics. A bispecific diabody (bsDb) is a small bsAb consisting of two distinct chimeric single-chain components, with two possible arrangements of the domains. We previously reported the effect of domain order on the function of a humanized bsDb targeting the epidermal growth factor receptor (EGFR) on cancer cells, and CD3 on T cells. Notably, the co-localization of a T-cell receptor (TCR) with CD3 is bulky, potentially affecting the cross-linking ability of bsDbs, due to steric hindrance. Here, we constructed and evaluated humanized bsDbs, with different domain orders, targeting EGFR and CD16 on natural killer (NK) cells (hEx16-Dbs). We predicted minimal effects due to steric hindrance, as CD16 lacks accessory molecules. Interestingly, one domain arrangement displayed superior cytotoxicity in growth inhibition assays, despite similar cross-linking abilities for both domain orders tested. In hEx16-Dbs specifically, domain order might affect the agonistic activity of the anti-CD16 portion, which was supported by a cytokine production test, and likely contributed to the superiority of one of the hEx16-Dbs. Our results indicate that both the target antigen and mode of action of an antibody must be considered in the construction of highly functional bsAbs.

Chemically Crosslinked Bispecific Antibodies for Cancer Therapy: Breaking from the Structural Restrictions of the Genetic Fusion Approach.

Antibodies are composed of structurally and functionally independent domains that can be used as building blocks to construct different types of chimeric protein-format molecules. However, the generally used genetic fusion and chemical approaches restrict the types of structures that can be formed and do not give an ideal degree of homogeneity. In this study, we combined mutation techniques with chemical conjugation to construct a variety of homogeneous bivalent and bispecific antibodies. First, building modules without lysine residues-which can be chemical conjugation sites-were generated by means of genetic mutation. Specific mutated residues in the lysine-free modules were then re-mutated to lysine residues. Chemical conjugation at the recovered lysine sites enabled the construction of homogeneous bivalent and bispecific antibodies from block modules that could not have been so arranged by genetic fusion approaches. Molecular evolution and bioinformatics techniques assisted in finding viable alternatives to the lysine residues that did not deactivate the block modules. Multiple candidates for re-mutation positions offer a wide variety of possible steric arrangements of block modules, and appropriate linkages between block modules can generate highly bioactive bispecific antibodies. Here, we propose the effectiveness of the lysine-free block module design for site-specific chemical conjugation to form a variety of types of homogeneous chimeric protein-format molecule with a finely tuned structure and function.

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.

Effect of Progression in Malnutrition and Inflammatory Conditions on Adverse Events and Mortality in Patients on Maintenance Hemodialysis.

BACKGROUND/AIM: In maintenance hemodialysis (MHD), protein-energy malnutrition and chronic inflammation can be critical and are two of the main causes of mortality. METHOD: We compared the change in nutrition and inflammatory conditions between younger and older MHD patients during a 2-year period. Furthermore, using Kaplan-Meier analysis, we evaluated the correlations between changes in each parameter and any adverse events. RESULT: During the observational period, body mass index (BMI) and serum albumin levels decreased significantly in older patients. In Kaplan-Meier analysis, patients who showed a decline in BMI had an associated elevated risk for cerebro-cardiovascular disease and hospitalization. Moreover, patients who showed a decline in albumin also had an associated higher risk for infectious disease and hospitalization. CONCLUSION: This study revealed that the downward trend in nutritional status was prominent in elderly patients. Furthermore, changes in nutritional and inflammatory conditions during MHD were associated with adverse events in MHD patients.

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.

Predilution On-Line Hemodiafiltration Improves Albumin Redox in Maintenance Hemodialysis Patients.

BACKGROUND/AIM: In this study, we compared the dialysis efficiency, oxidative stress, and nutritional conditions between predilution on-line hemodiafiltration (pre-OL-HDF) and conventional hemodialysis (HD) using a super-flux dialyzer (CHD). METHOD: This was a crossover study of 38 maintenance HD patients. All patients were treated with CHD for the first 4 months (1st CHD period), then were switched to pre-OL-HDF for 4 months (pre-OL-HDF period), and were returned to CHD for the next 4 months (2nd CHD period). RESULTS: We found no significant difference in the removal ratio of small uremic substances or the indices of inflammation or nutritional states between the pre-OL-HDF and CHD periods. However, we found higher removal of ß2 micro-globulin in the pre-OL-HDF period, and the human mercapto-albumin (Alb)/human serum Alb ratio was significantly higher in the pre-OL-HDF period. CONCLUSION: Treatment with pre-OL-HDF enabled enhanced removal of middle molecule uremic toxins and better Alb redox than did CHD.

A Clinical Significance of Intermittent Infusion Hemodiafiltration Using Backfiltration of Ultrapure Dialysis Fluid Compared to Hemodialysis: A Multicenter Randomized Controlled Crossover Trial.

BACKGROUND: Intermittent infusion hemodiafiltration -(I-HDF) using repeated infusion of ultrapure dialysis fluid through a dialysis membrane or sterile nonpyrogenic substitution fluid was developed to prevent a rapid decrease in blood pressure by increasing the patient's circulating blood volume, to enhance the plasma refilling rate by improving peripheral circulation, and to enhance solute transfer from the extravascular space to the intravascular space by enhancing the plasma refilling rate. Furthermore, the effect of fouling caused by attachment of proteins to the membrane as a result of ultrafiltration can be reduced by backflushing of the membrane with the purified dialysate in I-HDF. Although there have been several clinical trials of I-HDF, there have been no comparisons of the clinical significance of and indications for -I-HDF with those of conventional hemodialysis (HD). OBJECTIVE: The aim of this multicenter randomized controlled crossover trial was to compare the clinical significance of -I-HDF with that of HD in Japan. METHOD: Patients were randomized to receive HD, I-HDF, and HD (group A) or I-HDF, HD, and I-HDF (group B) in that order for 14 weeks each. The sample size of 70 was determined based on the operability and patient availability. Treatment outcomes were evaluated 5 and 14 weeks after the start of each treatment period. The patients received 4-h treatment sessions with no changes in session duration or anticoagulant therapy during the study. I-HDF was performed using a GC-110N dialysis machine. Two hundred milliliters of ultrapure dialysis fluid were infused at a rate of 150 mL/min by backfiltration every 30 min during treatment. The first and last infusions were performed 30 min after the start and 30 min before the end of treatment, respectively. The total estimated infusion volume per session was 1.4 L (i.e., 200 mL × 7 infusions). I-HDF is a type of online HDF with a small fluid replacement volume. An ABH-P polysulfone membrane hemodiafilter was used for -I-HDF and a class 1 or 2 hemodialyzer with a polysulfone membrane not coated with vitamin E and approved by the Japanese reimbursement system was used for HD. The primary outcomes were the Short Form-36 version 2 summary scores for quality of life and the visual analog scale scores for clinical symptoms. Secondary outcomes were vital signs, number of interventions, and pre-treatment blood test results. These variables were evaluated 1 week before at the start of the study, and at 5 and 14 weeks after the start of each treatment period. The removal characteristics of the various solutes were evaluated when possible on the first day of each treatment period. All patients provided written informed consent to participate. RESULTS: Thirty-two patients in group A and 32 patients in group B completed the trial. There were no differences in the primary or secondary outcomes between I-HDF and HD. Serum α1-microglobulin (MG) levels at 14 weeks were significantly lower for I-HDF than for HD. During treatment, the removal rates for urea and creatinine, which are low molecular weight substances, were significantly lower during I-HDF than during HD. In contrast, the ß2-MG and α1-MG removal rates were significantly higher during I-HDF than during HD. Furthermore, there was significantly less albumin leak during I-HDF than during HD. The solute removal results reflect the difference in pore size between the hemodiafilter used for I-HDF and the hemodialyzer used for HD and the difference in convective transport attributable to filtration between the 2 methods. CONCLUSIONS: These findings show that the removal rates of low molecular weight substances are significantly lower and those of medium to high molecular weight substances are significantly higher with I-HDF than with HD. They also indicate that there is significantly less albumin leak during I-HDF than during HD, meaning that I-HDF may be a particularly suitable dialysis modality for patients with malnutrition and the elderly in Japan.

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.

Fludrocortisone stimulates erythropoietin production in the intercalated cells of the collecting ducts.

Erythropoietin has been thought to be secreted to plasma soon after the production because of the difficulty of Western blot analysis and immunohistochemistry. We established the new methods of Western blot analysis and immunohistochemistry. Using the new methods, we investigated the effects of aldosterone and fludrocortisone, an analogue of aldosterone on erythropoietin mRNA and protein production by the kidneys. Aldosterone stimulated Epo and HIF2α mRNA expressions in tubule suspensions and microdissected medullary thick ascending limbs and outer medullary collecting ducts. Western blot analysis showed a recombinant erythropoietin at 34-45 kDa and kidney erythropoietin at 36-40 and 42 kDa, both of which shifted to 22 kDa by deglycosylation. Erythropoietin protein expression was observed in the nephrons but not in the interstitial cells in control condition. Fludrocortisone stimulated erythropoietin mRNA and protein expressions in the distal nephrons, particularly in the intercalated cells of the collecting ducts. These data show that erythropoietin is produced by the nephrons by the regulation of renin-angiotensin-aldosterone system and not by the renal interstitial cells in control condition.

Impact of Lesion Morphology on Durability After Angioplasty of Failed Arteriovenous Fistulas in Hemodialysis Patients.

PURPOSE: To investigate if morphological patterns of arteriovenous fistula (AVF) venous lesions affect primary patency after percutaneous transluminal angioplasty (PTA). METHODS: From July 2014 to June 2015, 262 patients underwent PTA for failed AVFs. A total of 104 patients were excluded owing to (1) calcification or AVF occlusion precluding ultrasound examination, (2) central venous or arterial lesions, and (3) no follow-up, leaving 158 patients (mean age 71±12; 96 men) for analysis. More than half of the patients had one or more previous PTAs for the failed AVF. Prior to PTA the stenotic lesions were assessed using ultrasonography to determine stenotic patterns at the minimum lumen area site and to evaluate the flow volume in the brachial artery. Three stenotic patterns were identified: intimal hyperplasia (IH) stenosis (n=110), shrinking lumen stenosis (n=32), and venous valve-related stenosis (n=16). The main outcome measure was primary patency after PTA estimated using Kaplan-Meier analysis. Predictors for loss of primary patency were determined using a multivariate Cox proportional hazards model; the results are presented as the adjusted hazard ratio (HR) and 95% confidence interval (CI). RESULTS: Median follow-up after PTA was 6.3 months (interquartile range 3.3, 10.5). The 6-month primary patency estimates were 56%±5% in the IH group, 40±9% in the shrinking lumen group, and 100% in the valve stenosis group (IH vs shrinking, p=0.013; IH vs valve, p=0.003). In multivariate analysis, shrinking lumen morphology had a negative impact on primary patency (HR 2.05, 95% CI 1.25 to 3.36, p=0.005), while venous valve-related stenosis had a positive impact (HR 0.19, 95% CI 0.04 to 0.79, p=0.023). Flow volume (10-mL/min increments; HR 0.97, 95% CI 0.96 to 0.99, p=0.004) and history of PTA (HR 1.66, 95% CI 1.06 to 2.60, p=0.029) were also independently associated with primary patency after PTA. CONCLUSION: The patterns of AVF stenosis as determined by ultrasound can affect the outcome of treatment with balloon dilation.

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.

Predicting loss of patency after forearm loop arteriovenous graft.

OBJECTIVE: Although arteriovenous grafts (AVGs) for dialysis access have been applied to patients who were poor candidates for an arteriovenous fistula, durability after AVGs has been clinically suboptimal. This retrospective study investigated whether forearm AVGs based on radial artery inflow would have superior patency to those with brachial artery inflow and evaluated the operative predictors for loss of patency after AVG. METHODS: This multicenter retrospective study included 156 upper limbs in 150 consecutive patients (50% male; age, 70.5 ± 12.8 years) who underwent forearm loop AVG formation from January 2010 to October 2013. The outcome measures were the primary and secondary functional graft patency rates and factors related to primary patency. Primary and secondary patency of AVGs was evaluated by Kaplan-Meier analysis, and predictors for loss of primary patency of AVGs were determined using a Cox proportional hazards model. RESULTS: The median observation period was 10 months (interquartile range, 6-18 months). The 1-year primary patency rate was 32.4%, and the secondary patency rate was 83.4%. Use of the radial artery as the inflow arteriovenous anastomosis (hazard ratio, 0.56; 95% confidence interval, 0.30-0.99) was independently associated as an operative predictor for primary patency after AVG. The primary patency rate was significantly different between radial artery inflow and brachial artery inflow at 1 year (53.8% vs 24.4%; P = .032). CONCLUSIONS: Radial artery selection as inflow artery was independently associated with primary patency after AVG.

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.

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.

Hemodialysis restored iron distribution that was sequestered in the spleen by bilateral nephrectomy.

Acute kidney injury (AKI) is associated with dysregulated iron metabolism, which may play a significant role in cellular injury. The effect of hemodialysis (HD) on iron metabolism in AKI therapy has not been well defined. The effects of HD on iron parameters were tested in control rats and bilateral nephrectomy (BNx) rats. The BNx rats were divided into the following three groups: 1) the sham-operated group (BNx-Sham), 2) the BNx group, and 3) the HD group (BNx-HD), which received HD therapy 40-45 h after BNx. Sections of the liver or spleen were stained with Berlin blue to examine the accumulation of iron. The mRNA levels of hepcidin and ferroportin 1 in the spleen and liver were also quantified using RT-PCR. In the BNx group, the plasma iron and hematocrit levels were decreased, and hepcidin levels were increased. The iron staining in the spleen in the BNx group was significantly more intense than that in the BNx-Sham group; however, after an HD session, splenic iron staining diminished to the level of the sham group along with an increase in plasma iron and a decrease in hepcidin. BNx moved iron from hemoglobin and the plasma to the spleen, which is associated with an increase in plasma hepcidin. A single HD session accelerated the release of iron from the spleen, and the increased plasma iron was linked to the removal of hepcidin. Our data suggested that hepcidin might dynamically modulate the iron metabolism in BNx as well as in HD.

Association between hemoglobin variability, serum ferritin levels, and adverse events/mortality in maintenance hemodialysis patients.

In recent times, therapy for renal anemia has changed dramatically in that iron administration has increased and doses of erythropoiesis-stimulating agents (ESAs) have decreased. Here we used a prospective, observational, multicenter design and measured the serum ferritin and hemoglobin levels every 3 months for 2 years in 1086 patients on maintenance hemodialysis therapy. The associations of adverse events with fluctuations in ferritin and hemoglobin levels and ESA and iron doses were measured using a Cox proportional hazards model for time-dependent variables. The risks of cerebrovascular and cardiovascular disease (CCVD), infection, and hospitalization were higher among patients who failed to maintain a target-range hemoglobin level and who exhibited high-amplitude fluctuations in hemoglobin compared with patients who maintained a target-range hemoglobin level. Patients with a higher compared with a lower ferritin level had an elevated risk of CCVD and infectious disease. Moreover, the risk of death was significantly higher among patients with high-amplitude ferritin fluctuations compared with those with a low ferritin level. The risks of CCVD, infection, and hospitalization were significantly higher among patients who were treated with high weekly doses of intravenous iron compared with no intravenous iron. Thus, there is a high risk of death and/or adverse events in patients with hemoglobin levels outside the target range, in those with high-amplitude hemoglobin fluctuations, in those with consistently high serum ferritin levels, and in those with high-amplitude ferritin fluctuations.