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.
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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•Misdistribution of iron causes cardiovascular disease in CKD.•Sequestration of iron in cells by proinflammatory cytokines and hepcidin;•Reduction in frataxin increases “free” iron in mitochondria.•Elevated aminolevulinate has toxic effects on iron and mitochondrial metabolism.•Elevated leptin level promotes hepatic hepcidin production.
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.
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 (greater than or equal to100 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 beta2 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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Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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.
•Plasma levels of hepcidin in ob/ob mice is significantly higher than those of control mice.•Leptin administration to ob/ob mice significantly increase in plasma and liver expression of Hanmp mRNA and iron content in the liver.•As well as the expression of Hanmp mRNA, hepcidin related genes (BMP6 mRNA, STAT3 mRNA) and iron transporters (DMT1 mRNA, TfR mRNA) in the liver also increased after administration of leptin to ob/ob mice.
Renal anemia is a complication of chronic kidney disease. Guidelines for safe and effective treatment in patients with renal anemia are needed. The Japanese Society for Dialysis Therapy (JSDT) ...published guidelines for the treatment of renal anemia in chronic hemodialysis patients in 2004 and in hemodialysis, peritoneal dialysis, predialysis, and pediatric patients in 2008. These two publications provide excellent guidance with respect to clinical practice issues, including the definition and diagnosis of renal anemia, the criteria for the initiation of treatment, target hemoglobin levels, iron supplementation therapy, blood transfusion, and side effects. The guidelines significantly improved the treatment of renal anemia in Japan. However, since 2008, many studies have assessed the treatment of renal anemia, and erythropoiesis-stimulating agents (ESAs) are now available. Therefore, the Executive Board of the JSDT decided that it was time to revise the guidelines to make them more appropriate to the situation of chronic kidney disease patients in Japan. This is the third edition of the guidelines for renal anemia published by the JSDT. The purpose is to improve the prognosis of chronic kidney disease patients, including after renal transplantation, through the treatment of renal anemia. The intended users of the guidelines are all healthcare professionals engaged in the treatment of chronic kidney disease. Regarding the treatment of adult dialysis and predialysis patients, statements and commentary are provided in the context of answers to clinical questions in Chapter 2 (Target Hb level and criteria for starting renal anemia treatment) and Chapter 4 (Evaluation of iron status and iron therapy). Furthermore, the essential information is provided alongside the critical issues in Chapter 1 (Diagnosis of renal anemia), Chapter 3 (Administration of ESAs—administration route and dose), Chapter 5 (ESA hyporesponsiveness), Chapter 6 (Side effects and concomitant symptoms of ESAs), and Chapter 7 (Red blood cell transfusion). In addition, the treatment of pediatric patients and post-renal transplant patients is discussed in Chapter 8 and Chapter 9, respectively.
Abstract Background TAFRO syndrome is a rare disorder that causes thrombocytopenia, generalized oedema, fever, organ enlargement, and renal impairment. Few reports have suggested an association with ...vaccines, and few cases have undergone renal biopsy. TAFRO syndrome is often severe and fatal, and its cause is unknown. We report a case of TAFRO syndrome that occurred after vaccination with the coronavirus disease 2019 (COVID-19) vaccine. Case presentation An 82-year-old woman received two doses of the BNT162b2 mRNA vaccine 3 weeks apart. Two weeks later, she was admitted to the hospital with oedema, accompanied with renal failure and thrombocytopenia. After close examination, she was diagnosed with TAFRO syndrome. She was treated with steroids, cyclosporine, and thrombopoietin receptor agonists. The patient was discharged after several months in remission. Conclusions Although an incident of TAFRO syndrome after COVID-19 vaccination has been previously reported, this is a rare case in which the patient went into remission and was discharged. A renal biopsy was also performed in this case, which was consistent with previous reports. The favorable treatment course for TAFRO syndrome provides valuable insights.
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.
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.
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.
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.
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