Treatment Of Renal Anemia Research Articles

Receptor-mediated mitophagy regulates EPO production and protects against renal anemia.

Erythropoietin (EPO) drives erythropoiesis and is secreted mainly by the kidney upon hypoxic or anemic stress. The paucity of EPO production in renal EPO-producing cells (REPs) causes renal anemia, one of the most common complications of chronic nephropathies. Although mitochondrial dysfunction is commonly observed in several renal and hematopoietic disorders, the mechanism by which mitochondrial quality control impacts renal anemia remains elusive. In this study, we showed that FUNDC1, a mitophagy receptor, plays a critical role in EPO-driven erythropoiesis induced by stresses. Mechanistically, EPO production is impaired in REPs in Fundc1-/- mice upon stresses, and the impairment is caused by the accumulation of damaged mitochondria, which consequently leads to the elevation of the reactive oxygen species (ROS) level and triggers inflammatory responses by up-regulating proinflammatory cytokines. These inflammatory factors promote the myofibroblastic transformation of REPs, resulting in the reduction of EPO production. We therefore provide a link between aberrant mitophagy and deficient EPO generation in renal anemia. Our results also suggest that the mitochondrial quality control safeguards REPs under stresses, which may serve as a potential therapeutic strategy for the treatment of renal anemia.

Structural Basis of Prolyl Hydroxylase Domain Inhibition by Molidustat.

Human prolyl‐hydroxylases (PHDs) are hypoxia‐sensing 2‐oxoglutarate (2OG) oxygenases, catalysis by which suppresses the transcription of hypoxia‐inducible factor target genes. PHD inhibition enables the treatment of anaemia/ischaemia‐related disease. The PHD inhibitor Molidustat is approved for the treatment of renal anaemia; it differs from other approved/late‐stage PHD inhibitors in lacking a glycinamide side chain. The first reported crystal structures of Molidustat and IOX4 (a brain‐penetrating derivative) complexed with PHD2 reveal how their contiguous triazole, pyrazolone and pyrimidine/pyridine rings bind at the active site. The inhibitors bind to the active‐site metal in a bidentate manner through their pyrazolone and pyrimidine nitrogens, with the triazole π‐π‐stacking with Tyr303 in the 2OG binding pocket. Comparison of the new structures with other PHD inhibitor complexes reveals differences in the conformations of Tyr303, Tyr310, and a mobile loop linking β2–β3, which are involved in dynamic substrate binding/product release.

Significance of Levocarnitine Treatment in Dialysis Patients.

Carnitine is a naturally occurring amino acid derivative that is involved in the transport of long-chain fatty acids to the mitochondrial matrix. There, these substrates undergo β-oxidation, producing energy. The major sources of carnitine are dietary intake, although carnitine is also endogenously synthesized in the liver and kidney. However, in patients on dialysis, serum carnitine levels progressively fall due to restricted dietary intake and deprivation of endogenous synthesis in the kidney. Furthermore, serum-free carnitine is removed by hemodialysis treatment because the molecular weight of carnitine is small (161 Da) and its protein binding rates are very low. Therefore, the dialysis procedure is a major cause of carnitine deficiency in patients undergoing hemodialysis. This deficiency may contribute to several clinical disorders in such patients. Symptoms of dialysis-related carnitine deficiency include erythropoiesis-stimulating agent-resistant anemia, myopathy, muscle weakness, and intradialytic muscle cramps and hypotension. However, levocarnitine administration might replenish the free carnitine and help to increase carnitine levels in muscle. This article reviews the previous research into levocarnitine therapy in patients on maintenance dialysis for the treatment of renal anemia, cardiac dysfunction, dyslipidemia, and muscle and dialytic symptoms, and it examines the efficacy of the therapeutic approach and related issues.

Effects of molidustat, a hypoxia-inducible factor prolyl hydroxylase inhibitor, on sodium dynamics in hypertensive subtotally nephrectomized rats

Hypoxia-inducible factor prolyl hydroxylase (HIF-PHD) inhibitors were developed for treatment of renal anemia. Patients applicable for HIF-PHD inhibitor treatment experience complications such as chronic kidney disease, whereby water and electrolyte homeostasis is disrupted. The effects of hypoxia-inducible factor stabilization on salt accumulation in the setting of reduced renal function remain unclear. In the present study, we investigated the effect of a HIF-PHD inhibitor, molidustat, on salt distribution and excretion in rats with subtotal nephrectomy-induced chronic kidney disease. Male Wistar rats were subjected to 5/6 nephrectomy. After confirming blood pressure elevation (>150 mmHg, at 4 weeks after surgery), rats were treated with molidustat. After 1 week of treatment, molidustat did not significantly improve blood cell volume or blood pressure. Distribution of sodium, potassium, and water in skin, carcass, and bone samples was not affected by molidustat. Furthermore, molidustat had no significant effect on urinary sodium excretion or concentration in response to acute oral salt loading (1 g/kg). In conclusion, molidustat did not affect distribution or excretion of salt in rats subjected to a model of nephron loss.

Suppression of thyrotropin secretion during roxadustat treatment for renal anemia in a patient undergoing hemodialysis

BackgroundInhibition of hypoxia-inducible factor prolyl hydroxylase (HIF-PH) is a novel choice for the treatment of renal anemia, and an oral HIF-PH inhibitor roxadustat was approved for renal anemia. Roxadustat has high affinity to thyroid hormone receptor beta, which may affect thyroid hormone homeostasis.Case presentationWe present here a patient undergoing hemodialysis with primary hypothyroidism receiving levothyroxine replacement, who showed decreased free thyroxine (FT4) and thyroid stimulating hormone (TSH) after starting roxadustat. Pituitary stimulation test revealed selective suppression of TSH secretion. Recovery of TSH and FT4 levels after stopping roxadustat suggested the suppression of TSH was reversible.ConclusionsPhysicians should pay special attention to thyroid hormone abnormalities in treatment with roxadustat.

Effect of L-carnitine supplementation on renal anemia in patients on hemodialysis: a meta-analysis.

L-carnitine is an amino acid derivative that is thought to be helpful for treating renal anemia in hemodialysis patients. However, the mechanism remains to be fully elucidated. A literature search was performed on PubMed, Embase, and Cochrane Central Register of Controlled Trials to identify randomized controlled trials (RCTs) and conduct a meta-analysis for investigating the effect of L-carnitine in the treatment of renal anemia in participants receiving hemodialysis. A total of 18 eligible trials with 1090 participants were included in this study. L-carnitine can significantly increase plasma free L-carnitine levels (mean difference [MD]: 140.53, 95% confidence interval [CI] 102.22-178.85; P < 0.00001), decrease the erythropoietin responsiveness index (ERI; MD: -2.72, 95% CI -3.20 to -2.24; P < 0.00001) and the required erythropoiesis-stimulating agent (ESA) doses (MD: -1.70, 95% CI -2.04 to -1.36; P < 0.00001). However, the use of L-carnitine was not associated with a higher hemoglobin level (MD: 0.18, 95% CI -0.20 to 0.55; P = 0.35) and hematocrit level (MD: 1.07, 95% CI -0.73 to 2.87; P = 0.24). In subgroup analyses, the effects of L-carnitine supplementation on renal anemia in patients on hemodialysis were independent of the treatment duration and intervention routes. The present meta-analysis indicated that L-carnitine therapy significantly increased plasma L-carnitine concentrations, improved the response to ESA, decreased the required ESA doses in patients receiving hemodialysis, and maintained hemoglobin and hematocrit levels. L-carnitine supplementation should be supported in hemodialysis patients. However, the relationship between L-carnitine treatment and long-term outcomes is still unclear. Further high-quality RCTs are needed to verify our findings.

Kidney Mesenchymal Stem Cell‐derived Extracellular Vesicles Engineered to Express Erythropoietin Improve Renal Anemia in Mice with Chronic Kidney Disease

Extracellular vesicles (EVs) shed from kidney mesenchymal stem cells (KMSCs) show protective effects against acute kidney injury and progressive kidney fibrosis via mRNA transfer. Previous studies report improvement of renal anemia following administration of genetically modified MSCs or peritoneal mesothelial cells that secrete erythropoietin (EPO). Here, we determined whether EPO-secreting KMSC-derived EVs (EPO(+)-EVs) can improve renal anemia in mouse models of chronic kidney disease (CKD). The mouse CKD and renal anemia model was induced by electrocoagulation of the right renal cortex and sequential left nephrectomy. At six weeks post-nephrectomy, we observed significantly lower hemoglobin (10.4 ± 0.2 vs. 13.2 ± 0.2g/dL) and significantly higher blood urea nitrogen and serum creatinine levels in CKD mice relative to controls (60.5 ± 0.5 and 0.37 ± 0.09mg/dL vs. 19.9 ± 0.5 and 0.12 ± 0.02mg/dL, respectively). Genetically engineered EPO(+)-KMSCs secreted 71 IU/mL EPO/106 cells/24h in vitro, and EPO(+)-EVs isolated by differential ultracentrifugation expressed EPO mRNA and horizontally transferred EPO mRNA into target cells in vitro and in vivo. Furthermore, at two weeks post-injection of EPO(+)-KMSCs or EPO(+)-EVs into CKD mice with renal anemia, we observed significant increases in hemoglobin levels (11.7 ± 0.2 and 11.5 ± 0.2 vs. 10.1 ± 0.2g/dL, respectively) and significantly lower serum creatinine levels at eight weeks in comparison to mice receiving vehicle control (0.30 ± 0.00 and 0.23 ± 0.03vs. 0.43 ± 0.06mg/dL, respectively). These results demonstrate that intraperitoneal administration of EPO(+)-EVs significantly increased hemoglobin levels and renal function in CKD mice, suggesting the efficacy of these genetically engineered EVs as a promising novel strategy for the treatment of renal anemia.

Factors affecting pre-end-stage kidney disease haemoglobin control and outcomes following dialysis initiation: a nationwide study.

BackgroundAttaining the narrow haemoglobin (Hb) range recommended by European Renal Best Practice Guidelines renal anaemia guidelines may be difficult, and whether this leads to better outcomes following dialysis initiation is not known.MethodsThis was an observational study from the Swedish Renal Registry 2012–16, including all patients with non-dialysis-dependent chronic kidney disease (CKD) initiating renal anaemia treatment. We evaluated factors associated with off-target Hb attainment (<10 and >12 g/dL). For those who initiated dialysis, we explored associations between the pre-end-stage kidney disease (pre-ESKD) time in which Hb was within or above range, and pre-ESKD Erythropoietin Resistance Index (ERI) with the 1-year risk of death or major adverse cardiovascular events + (MACE+).ResultsAbout 5000 patients initiated anaemia treatment, contributing to 25 431 consecutive visits over time. Patients with polycystic kidney disease, diabetic nephropathy and nephrosclerosis, with recent bleeding/transfusion, with higher C-reactive protein or abnormal phosphate had higher odds of maintaining Hb below range. Conversely, patients with older age, CKD Stages 3b–4, pyelonephritis, kidney transplant, iron medication, higher ESA doses or abnormal serum calcium and albumin had higher odds of maintaining Hb above range. A total of 1361 patients initiated dialysis, among whom 220 deaths and 453 MACE+ occurred. A greater time spent with a pre-ESKD Hb >12 g/dL was associated with a lower risk of MACE+ (hazard ratio = 0.76; 95% confidence interval 0.61–0.94) after dialysis initiation, and a lower pre-ESKD Erythropoietin Resistance Index (ERI) was associated with improved survival (1.39; 1.02–1.90).ConclusionsOur study identified populations that require additional efforts to control their Hb. Our outcome analysis supports the value of pre-ESKD anaemia care while illustrating the problems of ESA hyporesponsiveness in clinical practice.

Profile of Daprodustat in the Treatment of Renal Anemia Due to Chronic Kidney Disease.

Anemia is a major complication of chronic kidney disease (CKD), which mainly results from appropriate erythropoietin production impairment. Prolyl hydroxylase domain (PHD) inhibitors are currently being developed and approved in some countries as a new treatment for CKD patients with anemia due to the stabilization of intracellular hypoxia-inducible factor (HIF) 1α and HIF2α by PHD inhibition. Daprodustat is one of the orally administrated small-molecule HIF-PH inhibitors, leading to an increase in erythropoietin production, which is regulated by HIF. Also, daprodustat is expected to improve iron metabolism. Recently, several clinical trials showed its efficacy and safety in both hemodialysis- and non-hemodialysis- dependent CKD patients. In addition, some international Phase 3 studies are underway to confirm these effects and reveal the safety profile. This article summarizes the development process and results of each clinical trial.

Relationship between red cell distribution width, mean corpuscular hemoglobin level, and the treatment of renal anemia in hemodialysis patients

Relationship between red cell distribution width, mean corpuscular hemoglobin level, and the treatment of renal anemia in hemodialysis patients

Roxadustat (Evrenzo® tablet), a therapeutic drug for renal anemia: pharmacological characteristics and clinical evidence in Japan

Roxadustat (Evrenzo® tablet) is an oral hypoxia-inducible factor prolyl hydroxylase (HIF-PH) inhibitor. Roxadustat has been approved for the treatment of renal anemia in patients on dialysis in September 2019 in Japan. By inhibiting HIF-PH, roxadustat suppresses the degradation of HIF-α, a subunit of the heterodimeric transcription factor HIF, leading to its accumulation and activation of the HIF pathway. Similar to activation of the HIF pathway in response to hypoxia, the production of endogenous erythropoietin is increased and erythropoiesis is stimulated. Moreover, roxadustat stimulates erythropoiesis efficiently by improving iron bioavailability. The efficacy and mechanism of action of roxadustat have been detailed in non-clinical pharmacology studies. Rat models of anemia demonstrated efficacy of roxadustat in correcting anemia and changes in gene expression leading to increased iron bioavailability. Four phase 3 clinical studies in Japan clearly demonstrated the efficacy of roxadustat in patients with renal anemia on dialysis. Roxadustat showed an acceptable safety profile, and the incidences and types of adverse events and serious adverse events reported in the clinical studies were similar with those predicted to occur in these patient population. Since roxadustat is an oral drug, concerns present with erythropoiesis-stimulating agents (ESAs) such as the risk of infection to the medical staff due to accidental needle-stick, pain during ESA injection in patients and burden on patients to visit a hospital, can be avoided or reduced. In November 2020, roxadustat has also been approved for the treatment of renal anemia in patients not on dialysis (data not shown in this article).

Recommendations by the Asian Pacific society of nephrology (APSN) on the appropriate use of HIF-PH inhibitors.

Renal anaemia is a common and important complication in patients with chronic kidney disease (CKD). The current standard‐of‐care treatment for renal anaemia in CKD patients involves ensuring adequate iron stores and administration of erythropoietin stimulating agents (ESA). Hypoxia inducible factor (HIF) is a key transcription factor primarily involved in the cellular regulation and efficiency of oxygen delivery. Manipulation of the HIF pathway by the use of HIF‐prolyl hydroxylase inhibitors (HIF‐PHI) has emerged as a novel approach for renal anaemia management. Despite it being approved for clinical use in various Asia‐Pacific countries, its novelty mandates the need for nephrologists and clinicians generally in the region to well understand potential benefits and harms when prescribing this class of drug. The Asian Pacific society of nephrology HIF‐PHI Recommendation Committee, formed by a panel of 11 nephrologists from the Asia‐Pacific region who have clinical experience or have been investigators in HIF‐PHI studies, reviewed and deliberated on the clinical and preclinical data concerning HIF‐PHI. This recommendation summarizes the consensus views of the committee regarding the use of HIF‐PHI, taking into account both available data and expert opinion in areas where evidence remains scarce.

High Erythropoiesis Resistance Index Is a Significant Predictor of Cardiovascular and All-Cause Mortality in Chinese Maintenance Hemodialysis Patients.

Background Renal anemia is a common complication of hemodialysis patients. Erythropoietin (EPO) hyporesponsiveness has been recognized as an important factor to poor efficacy of recombinant human erythropoietin in the treatment of renal anemia. More importantly, increased erythropoiesis resistance index (ERI) may be associated with inflammation and increased mortality. Objective The objective of this research was to investigate correlated factors of EPO responsiveness and to clarify the relationships between EPO hyporesponsiveness and cardiovascular mortality and all-cause mortality among maintenance hemodialysis patients. Methods This prospective cohort study enrolled 276 maintenance hemodialysis patients for a 55-month follow-up to investigate the factors related to ERI and its relationship to all-cause mortality and cardiovascular mortality. Results ERI was positively correlated with predialysis serum high-sensitivity C-reactive protein (r = 0.234, p < 0.001), alkaline phosphatase (r = 0.134, p = 0.028), and ferritin (r = 0.155, p = 0.010) and negatively correlated with albumin (r = −0.206, p < 0.001) and creatinine (r = −0.232, p < 0.001). As multiple linear regression showed, predialysis serum albumin, high-sensitivity C-reactive protein, ferritin, and creatinine were independent correlated factors of ERI (p < 0.05). Kaplan–Meier curves showed that the cumulative incidences of both cardiovascular mortality and all-cause mortality were significantly higher in patients with ERI > 11.04 IU/kg/w/g/dL (both p < 0.01). The high ERI group was significantly associated with higher risk for all-cause mortality (OR 1.781, 95% CI 1.091 to 2.910, p = 0.021) and cardiovascular mortality (OR 1.972, 95% CI 1.139 to 3.417, p = 0.015) after adjusting for confounders. Conclusions Predialysis serum albumin, high-sensitivity C-reactive protein, ferritin, and creatinine were independent correlated factors of EPO responsiveness among maintenance hemodialysis patients. Patients with higher ERI values had a higher all-cause mortality rate and cardiovascular mortality rate.

Hypoxia inducible factor stabilizers: a promising treatment for chronic kidney disease

Anemia in chronic kidney disease (CKD) is a very common complication. The two main factors contributing to the development of anemia in CKD is decreased erythropoietin production and iron deficiency. Other factors that might play a role in the pathogenesis of renal anemia are: chronic inflammation leading to increased hepcidin, uremic toxins, and shorter red blood cell life span. The mainstay of treatment is iron supplementation, blood transfusion and erythropoietin stimulating agents (ESA). The discovery of hypoxia inducible factor (HIF) pathway has opened a new chapter in the treatment of anemia in CKD. The oxygen-sensitive HIF pathway plays a prominent role in the control of erythropoiesis and iron metabolism. HIF stabilizers are a new set of drugs that inhibits prolyl hydroxylase domain (PHD) proteins which are key regulators of HIF activity. Several such compounds are being developed to revolutionize the treatment of renal anemia.

In Mixed Lymphocyte Reaction, the Hypoxia-Inducible Factor Prolyl-Hydroxylase Inhibitor Roxadustat Suppresses Cellular and Humoral Alloimmunity.

Hypoxia-inducible factor (HIF) prolyl-hydroxylase inhibitors are currently used for the treatment of renal anemia. Since HIF affects immune cells, we evaluated the effect of such a drug, the roxadustat, on adaptive immunity. Cell proliferation was assessed in a two-way mixed lymphocyte reaction (MLR) with BrdU assay. In CD4+ T cells isolated from the two-way MLRs, western blotting was performed to detect the impact of roxadustat on HIF-1α and HIF-2α, the apoptotic marker cleaved caspase-3, and the master transcription factors of CD4+ T cells differentiation towards Th1, Th2, Th17, Treg and Tfh subsets. The signature cytokines of the above CD4+ T-cell subsets IFN-γ, IL-4, IL-17, IL-10, and IL-21 were measured in the supernatants. For assessing humoral immunity, we developed a suitable antibody-mediated complement-dependent cytotoxicity assay. Roxadustat stabilized HIF-1α and HIF-2α, suppressed cell proliferation, inhibited CD4+ T-cell differentiation into Th1 and Th17 subsets, while it favored differentiation towards Th2, Treg and Tfh. Roxadustat suppressed humoral immunity too. These immunosuppressive properties of roxadustat indicate that the recently introduced HIF prolyl-hydroxylase inhibitors in medical therapeutics may render the patients vulnerable to infections. This possibility should be further evaluated in clinical trials.

Molecular regulatory mechanisms of hypoxia-inducible factor and interventional effect of Chinese herbal medicine

Hypoxia-inducible factors(HIFs)are the key transcription factors that sense and regulate cellular oxygen concentration in vivo. HIF-1 is composed of 2 subunits,α and β,in which,the molecular regulatory mechanism of HIF-1α involves the main processes of its degradation and activation. The degradation of HIF-1α is regulated by oxygen-dependent pathways,including &quot;von hippel-lindau protein(pVHL)-dependent pathway&quot; and &quot;pVHL-independent pathway&quot;. The activation of HIF-1α is regulated by oxygen-independent pathways,including mammalian target of rapamycin(mTOR)/eukaryotic initiation factor 4 E-binding protein 1(4 EBP1)/HIF-1α pathway,phosphatidylinositol 3-kinase(PI3 K)/proteirrserinc-threonine kinases(Akt)/HIF-1α pathway and silent information regulator1(Sirt1)/HIF-1α pathway. In recent years,based on the molecular regulatory mechanism of HIFs,Roxadustat,a new drug for the treatment of renal anemia has been developed. Besides, some macromolecular substances with similar pharmacological effect to HIFs have been found in the extracts from Chinese herbal medicine(CHM),such as emodin,notoginseng triterpenes,honokiol and clematichinenoside. These natural macromolecular substances play the regulatory roles in inflammatory response,epigenetic modification and auto-phagy. It is worth noting that,for common hypoxic-related diseases including diabetic kidney disease,HIFs-mediated &quot;pyroptosis&quot; may be a new target of CHMs for clearing dampness and heat and its representative classical prescriptions(Ermiao Pills)in treating inflammatory injury in cells and tissues.

Collagen Hydrolysate Corrects Anemia in Chronic Kidney Disease via Anti-Inflammatory Renoprotection and HIF-2α-Dependent Erythropoietin and Hepcidin Regulation.

Anemia is a common chronic kidney disease (CKD) complication contributing to increased morbidity and mortality. Collagen-based traditional Chinese nutraceuticals have long been used in antianemic therapies. This study aims to investigate the therapeutic effectiveness of porcine collagen hydrolysate (CH) and its underlying mechanism in the treatment of renal anemia by using adenine-induced CKD mice, RAW264.7 macrophages, and HepG2 hepatoma cells, with prolyl-hydroxyproline as a reference compound for collagen-derived hydroxyproline-containing di-/tripeptides. CH was found to alleviate renal filtering dysfunction, systemic and kidney inflammation, liver hepcidin overproduction and anemia and to increase erythropoietin production and hypoxia inducible factor (HIF)-2α stability in liver and kidney in CKD mice. Prolyl-hydroxyproline exerted direct anti-inflammatory effects on lipopolysaccharide-activated macrophages and elicited stimulating and inhibiting activities on erythropoietin expression and hepcidin overproduction, respectively, in HepG2 cells by HIF-2α activation. Overall, CH was effective in correcting renal anemia via anti-inflammatory renoprotection and HIF-2α-dependent erythropoietin and hepcidin regulation.

Daprodustat: First Approval.

Daprodustat (DUVROQ) is a small molecule inhibitor of hypoxia-inducible factor prolyl hydroxylase (PHD) developed by GlaxoSmithKline for the treatment of anaemia in patients with chronic kidney disease (CKD). Inhibition of PHD prevents degradation of hypoxia-inducible factor (HIF), leading to the production of erythropoietin and subsequent induction of erythropoiesis. In June, daprodustat received its first approval in Japan for the treatment of renal anaemia. Clinical studies of daprodustat are underway in multiple countries worldwide. This article summarizes the milestones in the development of daprodustat leading to this first approval for the treatment of renal anaemia.

Hypoxia-Inducible Factor Prolyl Hydroxylase Inhibitors in Patients with Renal Anemia: A Meta-Analysis of Randomized Trials

Background: Hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHIs) are a new class of treatment for renal anemia in patients with chronic kidney disease (CKD). This meta-analysis was designed to evaluate their efficacy and safety. Method: Eight databases were searched for randomized controlled trials (RCTs). Information about efficacy and safety was extracted and combined using random-effects or fixed-effects models, depending on heterogeneity. Risk of bias was assessed using the method recommended by the Cochrane Centre. Results: Nineteen articles on RCTs were selected, involving 3,289 participants. We found that HIF-PHIs improved the level of hemoglobin (Hb) (weighted mean difference [WMD] 1.40; 95% CI: 0.96–1.84; p < 0.001), response rate of Hb (risk ratio [RR] 5.95; 95% CI: 3.95–8.96; p < 0.001), and total iron-binding capacity (WMD 42.94; 95% CI: 31.39–54.49; p < 0.001), while reducing the level of hepcidin (WMD −40.42; 95% CI: −50.44 to −30.39; p < 0.001), ferritin (WMD −64.60; 95% CI: −78.56 to −50.64; p < 0.001), and transferrin saturation (WMD −5.57; 95% CI: −8.53 to −2.61; p < 0.001). Meanwhile, there was no evidence of effect on serum iron (WMD 1.60; 95% CI: −3.72 to 6.93; p = 0.55), nor on the incidence of adverse events (AEs) (RR 1.06; 95% CI: 0.99–1.15; p = 0.51) or of serious adverse events (SAEs) (RR 1.14; 95% CI: 0.88–1.46; p = 0.32). Conclusion: HIF-PHIs ameliorate renal anemia and rectify iron metabolism in the short term without increasing the incidence of AEs and SAEs.

A Novel Choice to Correct Inflammation-Induced Anemia in CKD: Oral Hypoxia-Inducible Factor Prolyl Hydroxylase Inhibitor Roxadustat.

Anemia is a complication of chronic kidney disease (CKD), primarily due to insufficient secretion of erythropoietin (EPO) by the kidney. Erythropoiesis-stimulating agents (ESAs) are used to treat anemia associated with chronic kidney disease. A poor response to ESAs has been associated with inflammation. Inflammation can affect erythrocytes and its production in many ways, but mainly through the inflammatory cytokine IL-6 to stimulate the synthesis of hepcidin in the liver. Hepcidin causes iron insufficiency, which causes erythrocytes to fail to mature normally. In addition, inhibition of bone marrow erythroid precursor cells by inflammatory cytokines such as IL-1 and TNF-α also affects bone marrow hematopoiesis. These cytokines are also important factors leading to EPO resistance. Roxadustat is a new drug for the treatment of renal anemia. In addition to promoting the production of EPO, clinical trials have shown that it can significantly reduce hepcidin and can potentially be used for the treatment of inflammation-induced anemia in CKD.