scholarly journals Iron Therapy in Chronic Kidney Disease: Days of Future Past

2021 ◽  
Vol 22 (3) ◽  
pp. 1008
Author(s):  
Kuo-Hua Lee ◽  
Yang Ho ◽  
Der-Cherng Tarng
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Fibroblast Growth Factor 23 ◽  
Hypoxia Inducible Factor ◽  
Reticuloendothelial System ◽  
Deficiency Anemia ◽  
Ferric Carboxymaltose ◽  
High Dose ◽  
Ferric Pyrophosphate ◽  
Infusion Reactions

Anemia affects millions of patients with chronic kidney disease (CKD) and prompt iron supplementation can lead to reductions in the required dose of erythropoiesis-stimulating agents, thereby reducing medical costs. Oral and intravenous (IV) traditional iron preparations are considered far from ideal, primarily due to gastrointestinal intolerability and the potential risk of infusion reactions, respectively. Fortunately, the emergence of novel iron replacement therapies has engendered a paradigm shift in the treatment of iron deficiency anemia in patients with CKD. For example, oral ferric citrate is an efficacious and safe phosphate binder that increases iron stores to maintain hemoglobin levels. Additional benefits include reductions in fibroblast growth factor 23 levels and the activation of 1,25 dihydroxyvitamin D. The new-generation IV iron preparations ferumoxytol, iron isomaltoside 1000, and ferric carboxymaltose are characterized by a reduced risk of infusion reactions and are clinically well tolerated as a rapid high-dose infusion. In patients undergoing hemodialysis (HD), ferric pyrophosphate citrate (FPC) administered through dialysate enables the replacement of ongoing uremic and HD-related iron loss. FPC transports iron directly to transferrin, bypassing the reticuloendothelial system and avoiding iron sequestration. Moreover, this paper summarizes recent advancements of hypoxia-inducible factor prolyl hydroxylase inhibitors and future perspectives in renal anemia management.

scholarly journals Jian-Pi-Yi-Shen Regulates EPO and Iron Recycling Protein Expressions in Anemic Rats with Chronic Kidney Disease: Accumulation of Hypoxia Inducible Factor-2α via ERK Signaling

2020 ◽  
Vol 2020 ◽  
pp. 1-11
Author(s):  
Fochang Wang ◽  
Huimin Yu ◽  
Shiying Huang ◽  
Lin Zheng ◽  
Ping Zheng ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Protein Expression ◽  
Translational Control ◽  
Periodic Acid ◽  
Hypoxia Inducible Factor ◽  
Erk Signaling ◽  
High Dose ◽  
Protein Accumulation ◽  
Protein Expressions

Jian-Pi-Yi-Shen (JPYS), the traditional Chinese medicine (TCM) decoction, has been commonly used to treat chronic kidney disease (CKD) and its complications such as anemia. JPYS has been previously found to induce erythropoietin (EPO) production in HEK293T cells and CKD rats. However, the mechanism of JPYS in treating anemia of CKD rats has remained largely unknown. Here, we further extend our effort to investigate the translational control of hypoxia inducible factor- (HIF-) α protein via ERK signaling and the effect on iron recycling-related protein expression by JPYS, thus revealing the mechanism of JPYS in correcting anemia in CKD. Experimental CKD rats with anemia were induced by 5/6 nephrectomy. Rats were administrated orally with high dose (6.0 g/kg/d) and low dose (1.5 g/kg/d) of JPYS for 90 days. Serum hepcidin level was determined to evaluate iron homeostasis. The protein expressions of HIF-2α, erythropoietin (EPO), ferritin, and ferroportin (FPN) and the phosphorylation level of extracellular signal-regulated kinase 1/2 (ERK1/2) were detected by Western blot. The results showed that JPYS treatment significantly ameliorated kidney function by reducing increased levels of blood urea nitrogen (BUN), serum creatinine (Scr), and urine protein (UPRO). Periodic acid-Schiff (PAS) and Masson staining observation showed that the renal pathological damage was restored in JPYS-treated CKD rats. In parallel, JPYS markedly improved CKD anemia through upregulation of red blood cell (RBC), hemoglobin (HGB), and hematocrit (HCT). JPYS stimulated EPO and HIF-2α protein expressions in both the kidney and liver of CKD rats. Furthermore, JPYS induced the phosphorylation of ERK1/2 protein. In addition, JPYS regulated protein expression of ferritin and FPN in both the liver and spleen of CKD rats and the serum level of hepcidin. In conclusion, JPYS induces the expression of EPO through ERK-mediated HIF-2α protein accumulation and regulates systemic iron recycling, supporting its role in promoting erythropoiesis and improvement of anemia in CKD.

scholarly journals Hypoxia-inducible factor-prolyl hydroxylase inhibitor ameliorates myopathy in a mouse model of chronic kidney disease

2019 ◽  
Vol 317 (5) ◽  
pp. F1265-F1273 ◽  
Author(s):  
Fang-Yuan Qian ◽  
Zuo-Lin Li ◽  
Yu-Dong Guo ◽  
Han-Chao Gao ◽  
Li-Hua Gu ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Hypoxia Inducible Factor ◽  
Prolyl Hydroxylase ◽  
Vehicle Group ◽  
Acute Ischemia ◽  
High Dose ◽  
Dependent Manner ◽  
Prolyl Hydroxylase Inhibitor

Muscle wasting and diminished physical performance contribute to the morbidity and mortality of chronic kidney disease (CKD), for which no curative therapy exists. Accumulating evidence indicates that impaired angiogenesis occurs in the muscles of CKD models. Therefore, proangiogenesis therapy is considered a potentially effective strategy for limiting CKD-associated myopathy. Hypoxia-inducible factor (HIF)-prolyl hydroxylase inhibitor (HIF-PHI) stabilizes HIF and enhances muscle angiogenesis during acute ischemia; however, little evidence was available from CKD models. Here, we assessed whether pharmacological activation of HIF by MK-8617 (MK), a novel orally active HIF-PHI, improves CKD-associated myopathy. Mice were divided into sham or CKD groups, and CKD mice were subdivided into CKD + vehicle or MK treatment groups (1.5, 5, or 12.5 mg/kg for 12 wk). In CKD mice, skeletal muscle mass, mitochondrial amount, and exercise capacity decreased compared with sham mice. Compared with the CKD + vehicle group, low (1.5 mg/kg) and medium (5 mg/kg) doses of MK, but not the high dose (12.5 mg/kg), significantly restored these changes and was accompanied by incremental increases in HIF-1α. Furthermore, increased capillary density and area were observed in a MK dose-dependent manner, which is likely related to an improved VEGF response in the skeletal muscle of CKD mice. In addition, macrophage and proinflammatory cytokines, including monocyte chemoattractant protein 1, TNF-α, and IL-6, significantly increased in the high-dose MK group. These results indicate that HIF-PHI provides a potential therapeutic strategy to improve CKD-associated myopathy.

scholarly journals Jian-Pi-Yi-Shen Regulates EPO and Iron Recycling Protein Expressions in Anemic Rats with Chronic Kidney Disease: Accumulation of Hypoxia Inducible Factor-2α via ERK Signaling

2020 ◽  
Author(s):  
Fochang Wang ◽  
Huimin Yu ◽  
Shiying Huang ◽  
Lin Zheng ◽  
Ping Zheng ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Protein Expression ◽  
Translational Control ◽  
Periodic Acid ◽  
Hypoxia Inducible Factor ◽  
Erk Signaling ◽  
High Dose ◽  
Protein Accumulation ◽  
Protein Expressions

Abstract Background: Jian-Pi-Yi-Shen (JPYS), the traditional Chinese medicine (TCM) decoction has been commonly used to treat chronic kidney disease (CKD) and its complications such as anemia. JPYS has been previously found to induce erythropoietin (EPO) production in HEK293T cells and CKD rats. However, the mechanism of JPYS in treating anemia of CKD rats has remained largely unknown. Here, we further extend our effort to investigate the translational control of hypoxia inducible factor (HIF)-α protein via ERK signaling and the effect on iron recycling related protein expression by JPYS, thus revealing the mechanism of JPYS in correcting anemia in CKD. Methods: Experimental CKD rats with anemia were induced by 5/6 nephrectomy. Rats were administrated orally with high dose (6.0 g/kg/d) and low dose ( 1.5 g/kg/d ) of JPYS for 90 days. Serum hepcidin level was determined to evaluate iron homeostasis. Protein expressions of HIF-2α, erythropoietin (EPO), ferritin and ferroportin (FPN), as well as the phosphorylation level of extracellular signal regulated kinase 1/2 (RK1/2) were detected by Western blot. Results: Our data showed that JPYS treatment significantly ameliorated kidney function by reducing increased levels of blood urea nitrogen (BUN), serum creatinine (Scr) and the urine protein (UPRO). Periodic acid-Schiff (PAS) and Masson staining observation showed that the renal pathological damage was restored in JPYS-treated CKD rats. In parallel, JPYS markedly improved CKD anemia through up-regulation of red blood cell (RBC), hemoglobin (HGB) and haematocrit (HCT). JPYS stimulated EPO and HIF-2α protein expression in both kidney and liver of CKD rats. Furthermore, JPYS induced the phosphorylation of ERK1/2 protein. In addition, JPYS regulated protein expressions of ferritin and FPN in both liver and spleen of CKD rats, as well as serum level of hepcidin. Conclusions: JPYS induces the expression of EPO through ERK-mediated HIF-2α protein accumulation, and regulates systemic iron recycling, supporting its role in promoting erythropoiesis and improvement of anemia in CKD.

scholarly journals Ferric carboxymaltose vs. ferrous sulfate for the treatment of anemia in advanced chronic kidney disease: an observational retrospective study and cost analysis

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Luigi Cirillo ◽  
Chiara Somma ◽  
Marco Allinovi ◽  
Alfredo Bagalà ◽  
Giuseppe Ferro ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Iron Deficiency ◽  
Iron Deficiency Anemia ◽  
Outpatient Clinic ◽  
Intravenous Infusion ◽  
Ferrous Sulfate ◽  
Treatment Costs ◽  
Deficiency Anemia ◽  
Ferric Carboxymaltose

AbstractIn non-dialysis-dependent chronic kidney disease (NDD-CKD), erythropoiesis-stimulating agents (ESAs) and iron supplementation are essential for anemia management. Ferric carboxymaltose (FCM) is a relatively novel intravenous iron formulation used in different clinical settings, although scarce data exist in NDD-CKD patients. Primary objective of this study was to retrospectively evaluate the efficacy of FCM compared with oral ferrous sulfate for the treatment of iron-deficiency anemia in a cohort of NDD-CKD patients, considering also the treatment costs. This was a monocentric, retrospective observational study reviewing 349 NDD-CKD patients attending an outpatient clinic between June 2013 and December 2016. Patients were treated by either FCM intravenous infusion or oral ferrous sulfate. We collected serum values of hemoglobin, ferritin and transferrin saturation (TSAT) and ESAs doses at 12 and 18 months. The costs related to both treatments were also analysed. 239 patients were treated with FCM intravenous infusion and 110 patients with oral ferrous sulfate. The two groups were not statistically different for age, BMI and eGFR values. At 18 months, hemoglobin, serum ferritin and TSAT values increased significantly from baseline in the FCM group, compared with the ferrous sulfate group. ESAs dose and rate of infusion decreased only in the FCM group. At 18 months, the treatment costs, analysed per week, was higher in the ferrous sulfate group, compared with the FCM group, and this was mostly due to a reduction in ESAs prescription in the FCM group. Routine intravenous FCM treatment in an outpatient clinic of NDD-CKD patients results in better correction of iron-deficiency anemia when compared to ferrous sulfate. In addition to this, treating NDD-CKD patients with FCM leads to a significant reduction of the treatment costs by reducing ESAs use.

The problem with transferrin saturation as an indicator of iron ‘sufficiency’ in chronic kidney disease

2020 ◽  
Author(s):  
Anatole Besarab ◽  
Tilman B Drueke
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Iron Deficiency ◽  
Iron Metabolism ◽  
Iron Status ◽  
Hypoxia Inducible Factor ◽  
Transferrin Saturation ◽  
Deficiency Anemia ◽  
Iron Availability ◽  
Inflammatory State

Abstract After a brief review of physiological iron metabolism, we describe diagnostic tests for iron status and iron deficiency anemia in patients without chronic kidney disease (CKD) or inflammation. Thereafter we review the dysregulation of iron metabolism in CKD. Specific emphasis is placed on the role of the ‘inflammatory’ state that develops with the progression of CKD. It invokes changes in iron metabolism that are the exact opposite of those occurring during pure iron deficiency. As a result, transferrin saturation (TSAT) becomes a poorer index of iron availability to the bone marrow and serum ferritin no longer represents iron that can be used during erythropoiesis. We argue that serum iron may provide more information to guide iron therapy than TSAT. In other words, the emphasis on TSAT is misplaced. With the development of a number of hypoxia-inducible factor prolyl hydroxylase inhibitors, which restore iron metabolism toward the ‘physiologic state’, the iron indices indicating sufficient iron availability to avoid functional iron deficiency during therapy of CKD-associated anemia are likely to change. We summarize these changes in the section ‘A peek into things to come!’, citing the available data.

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