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Background: Several treatment options are available for anemia associated with chronic kidney disease (CKD); however, there remains a lack of awareness of physician and patient preferences regarding these treatments. We aimed to explore physicians' and patients' perceptions and preferences regarding the management of anemia of CKD in Japan. Methods: A web-based survey, including best-worst scaling (BWS), was conducted with physicians who had treated ≥1 patient with anemia of CKD in the preceding year, and with patients with CKD who self-reported a clinical diagnosis of anemia of CKD or low hemoglobin levels. A three-step approach was used comprising cognitive interviews, a pilot survey, and a main survey. The BWS survey results were analyzed using multinomial logit and hierarchical Bayesian models. Results: The survey was completed by 906 participants: 103 patients (average age 60.6 years; 77.7% male) and 803 physicians (166 nephrologists, 214 cardiologists, 137 diabetologists, and 286 general internists). Almost all (96.0%) physicians surveyed considered anemia of CKD to be an important condition to treat. Hypoxia-inducible factor prolyl hydroxylase (HIF-PH) inhibitors had the highest treatment satisfaction among physicians, whereas patients had the highest satisfaction with both erythropoietin-stimulating agent therapy and HIF-PH inhibitors. Approximately one-third (35.9%) of patients surveyed indicated that they were receiving treatment. When comparing the relative importance of attributes and levels, physicians favored efficacy (particularly improvement in hemoglobin levels), whereas patients favored safety (particularly a lower rate of severe adverse events). Conclusion: Although a majority of physicians consider treatment of CKD-related anemia important, differences in the perceptions and usage of medications exist between medical specialties. Preferences for the management of anemia of CKD vary between physicians and patients; therefore, patient involvement in treatment decisions may help optimize outcomes.

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INTRODUCTION: Erythropoiesis-stimulating agents (ESAs) together with iron supplementation had been the standard treatment for anemia in chronic kidney disease (CKD) for the past decades. Recently, hypoxia-inducible factor-prolyl hydroxylase inhibitors (HIF-PHIs) have attracted attention as a novel treatment option. AREAS COVERED: This review summarizes the effectiveness and the safety of HIF-PHIs based on previous clinical trials and discusses points to consider for their clinical use. EXPERT OPINION: The results from clinical trials demonstrate that HIF-PHIs are non-inferior to ESAs in terms of the efficacy to maintain or improve blood hemoglobin levels. However, concerns about adverse events including cardiovascular outcomes, thrombotic events, and tumor progression have prevented HIF-PHIs from being widely approved for clinical use. Also, long-term safety has not been demonstrated yet. Practically, HIF-PHIs should be used with caution in patients with a history of thrombosis or active malignancy. Patients without them may be preferable for HIF-PHIs if those are bothered with regular injections of ESAs or are hyporesponsive to ESAs without obvious reasons, provided that the drugs were approved in the country. Even so, clinicians must take caution for signs of adverse events such as heart failure after prescribing the drugs.

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Hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHIs) are new drugs developed for the treatment of anemia associated with chronic kidney disease (CKD). This class of drugs stimulates endogenous erythropoietin production and, at the same time, improves iron absorption and mobilization of iron stores (less evident with daprodustat, vadadustat and enarodustat). Several studies have been published in the last few years showing that these agents are not inferior to standard therapy in correcting anemia associated with CKD. The efficacy of HIF-PHIs is coupled with a safety profile comparable to that of standard erythropoiesis stimulating agent (ESA) treatment. However, studies with HIF-PHIs were not long enough to definitively exclude the impact of new drugs on adverse events, such as cancer, death and possibly cardiovascular events, that usually occur after a long follow-up period. Kidney Disease: Improving Global Outcomes (KDIGO) recently reported the conclusions of the Controversies Conference on HIF-PHIs held in 2021. The goal of the present position paper endorsed by the Italian Society of Nephrology is to better adapt the conclusions of the latest KDIGO Conference on HIF-PHIs to the Italian context by reviewing the efficacy and safety of HIF-PHIs as well as their use in subpopulations of interest as emerged from more recent publications not discussed during the KDIGO Conference.

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Anaemia is a common complication of chronic kidney disease (CKD) and is associated with poor long-term outcomes and quality of life. The use of supplemental iron, erythropoiesis stimulating agents (ESAs) and blood transfusions has been the mainstay of treatment of anaemia in CKD for more than three decades. Despite available treatments, CKD patients with anaemia are undertreated and moderate-to-severe anaemia remains prevalent in the CKD population. Anaemia has consistently been associated with greater mortality, hospitalisation, cardiovascular events, and CKD progression in patients with CKD, and the risk increases with anaemia severity. Hypoxia-inducible factor (HIF) prolyl hydroxylase (PH) inhibitors have a novel mechanism of action by mimicking the body's response to hypoxia and have emerged as an alternative to ESAs for the treatment of anaemia in CKD. Their efficacy in correcting and maintaining haemoglobin has been demonstrated in over 30 phase 3 clinical trials. Additionally, HIF activation results in various pleiotropic effects beyond erythropoiesis with cholesterol reduction and improved iron homeostasis and potential anti-inflammatory effects. The long-term safety of these agents, particularly with respect to cardiovascular and thromboembolic events, and their possible effect on tumor growth requires to be fully elucidated. This document presents in detail the effects of HIF-PH inhibitors, describes their mechanisms of action and pharmacologic properties, and discusses their place in the treatment of anaemia in CKD according to the available evidence.

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Background: Anemia is one of the common complications of chronic kidney disease (CKD), and its prevalence has been arising globally. The key cause of anemia in CKD patients is the diseased kidney's reduced ability to synthesize endogenous erythropoietin (EPO), yet this is not the sole reason. Inflammatory elements, functional iron deficiency, and uremic toxins together participate in the development of anemia. According to research data, anemia is an independent risk factor for cardiovascular events, all-cause mortality, and worsening renal function and affects the clinical prognosis and quality of life of CKD patients. Regular treatments for anemia in CKD patients include the use of erythropoiesis-stimulating agents (ESAs), iron supplements, and blood transfusions. Summary: Hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHIs) are novel and small-molecule pharmacological compounds that target the hypoxia-inducible factor (HIF) pathway and are another option for improving anemia in CKD patients. HIF-PHIs simulate hypoxia, stabilize HIF protein, stimulate EPO synthesis, reduce hepcidin level, boost iron utilization, induce the creation of red blood cells, and alleviate anemia. The results of several HIF-PHI phase III trials indicated that HIF-PHIs are similarly effective as ESA at raising hemoglobin concentration. Key Messages: This article summarizes the structure of HIF and the mechanism of stabilizing HIF to improve anemia, discusses the efficacy of HIF-PHIs in CKD patients with or without dialysis, as well as emphasizes the potential safety concerns with HIF-PHIs.

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Since zinc is involved in many aspects of the hematopoietic process, zinc supplementation can reduce erythropoiesis-stimulating agents (ESAs) in patients undergoing hemodialysis. However, it remains unclear whether hypoxia-inducible factor-prolyl hydroxylase inhibitors (HIF-PHIs) have similar reduction effects. HIF-PHI stabilizes HIF, which promotes hematopoiesis, although HIF-1α levels are downregulated by zinc. This study aimed to investigate the effect of zinc supplementation on the hematopoietic effect of HIF-PHI in patients undergoing hemodialysis. Thirty patients undergoing maintenance hemodialysis who underwent periods of treatment with roxadustat or darbepoetin alfa during the past 3 years were retrospectively observed. Participants who underwent periods with and without zinc supplementation were selected, with nine treated with darbepoetin alfa and nine treated with roxadustat. Similarly to the ESA responsiveness index (ERI), the hematopoietic effect of zinc supplementation was determined by the HIF-PHI responsiveness index (HRI), which was calculated by dividing the HIF-PHI dose (mg/week) by the patient's dry weight (kg) and hemoglobin level (g/L). Zinc supplementation significantly increased ERI (p < 0.05), but no significant change was observed (p = 0.931) in HRI. Although zinc supplementation did not significantly affect HRI, adequate zinc supplementation is required to alleviate concerns such as vascular calcification and increased serum copper during the use of HIF-PHI.

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Meta-analyses offer an estimate of the overall effect size and help address the inconsistency in findings across studies. The risk is the overemphasis on statistical significance while underrepresenting or misinterpreting clinical significance. There's also a lack of standardized methods for quantifying and reporting clinical significance and these measures are often missing or inconsistently reported in many meta-analyses, making it difficult for readers to determine the clinical relevance of the findings. A major merit of Minutolo's meta-analysis is to formally evaluate efficacy and safety of Hypoxia Inducible Factor Prolyl Hydroxylase Inhibitors (HIF-PHI) as class and as single agents in comparison with ESA, by selecting from only phase-3 randomised clinical trials (RCTs) that compared HIF-PHIs with erythropoiesis-stimulating agents (ESAs) in dialysis and non-dialysis patients. From a clinical perspective, the primary evaluation in this meta-analysis should have been the percentage of patients able to reach and maintain the target haemoglobin (Hb) levels throughout the trials but only a few RCTs selected this primary end point. Any claimed superiority of one drug over another should consider the selected doses. The amount of iron administered to patients, their iron stores and level of inflammation are important confounding factors that affect the reliability of any comparison.

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Background: Hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHIs) are oral alternatives to current standard-of-care treatments for anaemia in chronic kidney disease (CKD). We conducted network meta-analyses to indirectly compare clinical outcomes for three HIF-PHIs in dialysis and non-dialysis populations with anaemia in CKD. Methods: The evidence base comprised phase III, randomised, controlled trials evaluating daprodustat, roxadustat, or vadadustat. Three outcomes were evaluated: efficacy [change from baseline in haemoglobin (Hgb)], cardiovascular safety [time to first major adverse cardiovascular event (MACE)] and quality of life [change from baseline in 36-Item Short Form Health Survey (SF-36) Vitality score]. Analyses were performed separately for all patients and for erythropoiesis-stimulating agent (ESA) non-users at baseline (non-dialysis population) or prevalent dialysis patients (dialysis population). Bayesian Markov Chain Monte Carlo methods with non-informative priors were used to estimate the posterior probability distribution and generate pairwise treatment comparisons. Point estimates (medians of posterior distributions) and 95% credible intervals (CrI) were calculated. Results: Seventeen trials were included. In non-dialysis patients, there were no clinically meaningful differences between the three HIF-PHIs with respect to Hgb change from baseline [all patients analysis (total n = 7907): daprodustat vs. roxadustat, 0.09 g/dL (95% CrI -0.14, 0.31); daprodustat vs. vadadustat, 0.09 g/dL (-0.04, 0.21); roxadustat vs. vadadustat, 0.00 g/dL (-0.22, 0.22)] or risk of MACE [all patients analysis (total n = 7959): daprodustat vs. roxadustat, hazard ratio (HR) 1.16 (95% CrI 0.76, 1.77); daprodustat vs. vadadustat, 0.88 (0.71, 1.09); roxadustat vs. vadadustat, 0.76 (0.50, 1.16)]. Daprodustat showed a greater increase in SF-36 Vitality compared with roxadustat [total n = 4880; treatment difference 4.70 points (95% CrI 0.08, 9.31)]. In dialysis patients, Hgb change from baseline was higher with daprodustat and roxadustat compared with vadadustat [all patients analysis (total n = 11 124): daprodustat, 0.34 g/dL (0.22, 0.45); roxadustat, 0.38 g/dL (0.27, 0.49)], while there were no clinically meaningful differences in the risk of MACE between the HIF-PHIs [all patients analysis (total n = 12 320): daprodustat vs. roxadustat, HR 0.89 (0.73, 1.08); daprodustat vs. vadadustat, HR 0.99 (0.82, 1.21); roxadustat vs. vadadustat, HR 1.12 (0.92, 1.37)]. Results were similar in analyses of ESA non-users and prevalent dialysis patients. Conclusions: In the setting of anaemia in CKD, indirect treatment comparisons suggest that daprodustat, roxadustat, and vadadustat are broadly clinically comparable in terms of efficacy and cardiovascular safety (precision was low for the latter), while daprodustat may be associated with reduction in fatigue to a greater extent than roxadustat.

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Background: Anemia is a common and important complication in patients with chronic kidney disease (CKD). Accordingly, the current treatment is based on erythropoiesis-stimulating agents (ESAs) and iron. Hypoxia-inducible factor (HIF) prolyl hydroxylase domain inhibitors (HIF-PHIs) have been developed to treat renal anemia through a novel mechanism. HIF-PHIs increase erythropoietin at physiologic blood concentrations and also improve the supply of hematopoietic iron. Iron is the main component of hemoglobin, and ensuring efficient iron metabolism is essential in the treatment of anemia. Summary: HIF-PHIs may have advantages in improving iron utilization and mobilization compared to ESAs. Most HIF-PHI trials revealed a significant decline of hepcidin, increase in transferrin level and total iron binding capacity in patients. From a clinical point of view, improvements in iron metabolism should translate into reductions in iron supplementation. There are differences in the iron treatment regimentation currently used, so it is important to evaluate and timely iron supplementation across studies. Key Messages: This review summarizes the mechanism of HIF-PHIs on improved iron metabolism and the route of iron usage in the trials for dialysis-dependent CKD and non-dialysis CKD. And this review also makes an interpretation of the clinical practice guidelines in China and recommendation by Asia Pacific Society of Nephrology.

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INTRODUCTION: Erythropoiesis-stimulating agents (ESAs) are the standard of treatment for anemia in chronic kidney disease. Hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHI) are small molecules that stimulate endogenous erythropoietin synthesis. AREAS COVERED: The cardiovascular safety of ESAs and HIF-PHIs. We performed a PubMed search using several key words, including anemia, chronic kidney disease, safety, erythropoiesis stimulating agents, HIF-PH inhibitors. EXPERT OPINION: ESAs are well-tolerated drugs with a long history of use; there are safety concerns, especially when targeting high hemoglobin levels. HIF-PHIs have comparable efficacy to ESAs in correcting anemia. Contrary to expectations, randomized phase 3 clinical trials have shown that overall HIF-PHIs were non-inferior to ESA or placebo with respect to the risk of cardiovascular endpoints. In addition, some phase 3 trials raised potential safety concerns regarding cardiovascular and thrombotic events, particularly in non-dialysis patients.Today, HIF-PHIs represent an additional treatment option for anemia in patients with chronic kidney disease. This has made the management of anemia in CKD more complex and heterogeneous. A better understanding of the mechanisms causing hypo-responsiveness to ESAs, combined with an individualized approach that balances ESAs, HIF-PHIs and iron doses, could increase the benefits while reducing the risks.

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BACKGROUND: Roxadustat is an oral hypoxia inducing factor-prolyl hydroxylase inhibitor (HIF-PHI) that regulates iron metabolism in patients with chronic kidney disease (CKD) primarily by reducing hepcidin levels and mobilizing internal iron stores. More data are needed to demonstrate the efficacy of roxadustat in regulating iron metabolism in patients with peritoneal dialysis (PD) compared with erythropoiesis stimulating agents (ESAs). METHODS: This prospective cohort study enrolled PD patients with a mean hemoglobin level of 60-100 g/L. All subjects were randomized into two groups at a ratio of 2:1 the roxadustat group (106 cases), and the ESA group (53 cases). The primary endpoint was the change in the iron biomarker levels and the proportion of patients with absolute iron deficiency and functional iron deficiency. RESULTS: Compared with ESAs, roxadustat significantly decreased hepcidin level (difference, - 20.09 ng/mL; 95% CI, - 30.26 to - 9.92), attenuated the increase in serum soluble transferrin receptor (sTFR) level (difference, - 7.87 nmol/L; 95% CI, - 12.11 to - 3.64), and reduced the proportion of patients with functional iron deficiency (roxadustat, 11.43%; ESA, 33.33%). There was no significant difference in safety of the two groups over the duration of the study. CONCLUSIONS: Compared with ESA group, roxadustat group showed significant differences in all iron biomarker levels except serum ferritin (sFt) and transferrin saturation (TSAT). These results suggest that roxadustat was superior to ESAs as a therapy for iron metabolism in PD patients. TRIAL REGISTRATION: This study completed Chinese Clinical Trial Registration on March 4, 2022 (registration number: ChiCTR2200057231).

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La anemia es una complicación frecuente de la enfermedad renal cuya prevalencia aumenta a medida que progresa la enfermedad, empeora la calidad de vida de pacientes y aumenta la morbimortalidad. El fundamento actual para tratar la anemia renal se basa en empleo de agentes estimuladores de eritropoyesis, la suplementación con hierro y en menor medida, el uso de trasfusiones. La estimulación de la síntesis endógena de eritropoyetina y la mejora de la disponibilidad del hierro, a través de la inhibición de prolil-hidroxilasa del factor inducible por la hipoxia (PH-HIF), representa una nueva alternativa oral de tratamiento de la anemia renal. Los ensayos clínicos con inhibidores PH-HIF han demostrado su eficacia en mantener niveles de hemoglobina objetivo. Sin embargo, aspectos concernientes a la seguridad a largo plazo se encuentran pendientes de clarificar. En conclusión, los avances en la patogenia de anemia renal permiten disponer de tratamientos actuales para tratar la anemia renal y el desarrollo de nuevas moléculas, basadas en la inhibición de PH-HIF, representa una nueva alternativa eficaz para anemia asociada con enfermedad renal, especialmente en pacientes con resistencia a agentes estimuladores de eritropoyesis (AU)

Anemia is a common complication of kidney disease and the prevalence increases as the disease progresses. It worsens the quality of life of patients and increases morbidity and mortality. The current rationale for treating renal anemia is based on the use of erythropoiesis-stimulating agents, iron supplementation and, to a lesser extent, the use of transfusions. Stimulation of endogenous erythropoietin synthesis and improvement of iron availability, through inhibition of prolyl-hydroxylase-hypoxia-inducible factor (PH-HIF), represents a new oral alternative for renal anemia treatment. Clinical trials with PH-HIF inhibitors have demonstrated their efficacy in maintaining target hemoglobin levels. However, aspects concerning long-term safety are pending a clarification. In conclusion, advances in the pathogenesis of renal anemia make it possible to have current treatments to treat renal anemia. The development of new molecules, based on the inhibition of PH-HIF, represents a new effective alternative for anemia associated with kidney disease, especially in patients with resistance to erythropoiesis-stimulating agents (AU)

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Hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHIs) are a new class of medications for managing renal anemia in patients with chronic kidney disease (CKD). In addition to their erythropoietic activity, HIF-PHIs exhibit multifaceted effects on iron and glucose metabolism, mitochondrial metabolism, and angiogenesis through the regulation of a wide range of HIF-responsive gene expressions. However, the systemic biological effects of HIF-PHIs in CKD patients have not been fully explored. In this prospective, single-center study, we comprehensively investigated changes in plasma metabolomic profiles following the switch from an erythropoiesis-stimulating agent (ESA) to an HIF-PHI, daprodustat, in 10 maintenance hemodialysis patients. Plasma metabolites were measured before and three months after the switch from an ESA to an HIF-PHI. Among 106 individual markers detected in plasma, significant changes were found in four compounds (erythrulose, n-butyrylglycine, threonine, and leucine), and notable but non-significant changes were found in another five compounds (inositol, phosphoric acid, lyxose, arabinose, and hydroxylamine). Pathway analysis indicated decreased levels of plasma metabolites, particularly those involved in phosphatidylinositol signaling, ascorbate and aldarate metabolism, and inositol phosphate metabolism. Our results provide detailed insights into the systemic biological effects of HIF-PHIs in hemodialysis patients and are expected to contribute to an evaluation of the potential side effects that may result from long-term use of this class of drugs.

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Aim: We performed a systematic review and network meta-analysis evaluating the safety and efficacy of hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHIs) among dialysis chronic kidney disease patients. Methods: Safety was evaluated with any adverse events (AEs), serious adverse events (SAEs), and 12 common events. Efficacy was mainly analyzed with hemoglobin response. All reported results were summarized using mean difference and risk ratio (RR) with 95% confidence interval (CI). Publication bias was assessed through funnel plots. Results: Twenty trials (19 studies) with 14,947 participants were included, comparing six HIF-PHIs with erythropoiesis-stimulating agents (ESAs). No significant differences were indicated in overall AEs and SAEs between each HIF-PHI and ESA. The occurrence of gastrointestinal disorder was higher in enarodustat and roxadustat than in ESAs (RR: 6.92, 95% CI: 1.52-31.40, p = 0.01; RR: 1.30, 95% CI: 1.04-1.61, p = 0.02). The occurrence of hypertension was lower in vadadustat than in ESAs (RR: 0.81, 95% CI: 0.69-0.96, p = 0.01). The occurrence of vascular-access complications was higher in roxadustat (RR: 1.15, 95% CI: 1.04-1.27, p<0.01) and lower in daprodustat (RR: 0.78, 95% CI: 0.66-0.92, p<0.01) than in ESAs. In the risk of the other nine events, including cardiovascular events, no significant differences were observed between HIF-PHIs and ESAs. For hemoglobin response, network meta-analysis showed that compared with ESAs, significant increases were shown in roxadustat (RR: 1.04, 95% CI: 1.01-1.07, p<0.01) and desidustat (RR: 1.22, 95% CI: 1.01-1.48, p = 0.04), whereas noticeable reductions were indicated in vadadustat (RR: 0.88, 95% CI: 0.82-0.94, p<0.01) and molidustat (RR: 0.83, 95% CI: 0.70-0.98, p = 0.02). There was no significant difference between daprodustat and ESAs (RR: 0.97, 95% CI: 0.89-1.06, p = 0.47). Conclusion: Although HIF-PHIs did not show significant differences from ESAs in terms of overall AEs and SAEs, statistical differences in gastrointestinal disorder, hypertension, and vascular-access complications were observed between HIF-PHIs, which deserved to be noted in clinical decision making. Systematic review registration: This study is registered with PROSPERO (registration number CRD42022312252).

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Anemia is a common complication of kidney disease and the prevalence increases as the disease progresses. It worsens the quality of life of patients and increases morbidity and mortality. The current rationale for treating renal anemia is based on the use of erythropoiesis-stimulating agents, iron supplementation and, to a lesser extent, the use of transfusions. Stimulation of endogenous erythropoietin synthesis and improvement of iron availability, through inhibition of prolil-hydroxilase-hypoxia-inducible factor (PH-HIF), represents a new oral alternative for renal anemia treatment. Clinical trials with PH-HIF inhibitors have demonstrated their efficacy in maintaining target hemoglobin levels. However, aspects concerning long-term safety are pending a clarification. In conclusion, advances in the pathogenesis of renal anemia make it possible to have current treatments to treat renal anemia. The development of new molecules, based on the inhibition of PH-HIF, represents a new effective alternative for anemia associated with kidney disease, especially in patients with resistance to erythropoiesis-stimulating agents.

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Aims: This study aimed to evaluate the effects of hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHIs) on iron metabolism and inflammation in dialysis-dependent chronic kidney disease (DD-CKD) patients. Methods: PubMed, Embase, Web of Science, Cochrane Library, and ClinicalTrials.gov websites were searched for randomized controlled trials (RCTs) investigating HIF-PHIs versus ESAs for DD-CKD patients. Key findings: Twenty studies with 14,737 participants were included in the meta-analysis, which demonstrated no significant difference in the effect of transferrin saturation and ferritin between HIF-PHIs and the ESAs group (MD, 0.65; 95%CI, -0.45 to 1.75; very low certainty; SMD, -0.03; 95% CI, -0.13 to 0.07; low certainty). However, HIF-PHIs significantly increased the iron (MD, 2.30; 95% CI, 1.40 to 3.20; low certainty), total iron-binding capacity (SMD, 0.82; 95% CI, 0.66 to 0.98; low certainty), and transferrin (SMD, 0.90; 95%CI, 0.74 to 1.05; moderate certainty) levels when compared with the ESAs group. In contrast, the hepcidin level and dosage of intravenous iron were significantly decreased in the HIF-PHIs group compared with the ESAs group (MD, -15.06, 95%CI, -21.96 to -8.16; low certainty; MD, -18.07; 95% CI, -30.05 to -6.09; low certainty). The maintenance dose requirements of roxadustat were independent of baseline CRP or hsCRP levels with respect to the effect on inflammation. Significance: HIF-PHIs promote iron utilization and reduce the use of intravenous iron therapy. Furthermore, HIF-PHIs, such as roxadustat, maintain the erythropoietic response independent of the inflammatory state. Thus, HIF-PHIs may be an alternative treatment strategy for anemia in DD-CKD patients, where ESA is hyporesponsive due to iron deficiency and inflammation.

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Anemia is common in patients with chronic kidney disease and is associated with a high burden of morbidity and adverse clinical outcomes. In 2012, Kidney Disease: Improving Global Outcomes (KDIGO) published a guideline for the diagnosis and management of anemia in chronic kidney disease. Since then, new data from studies assessing established and emerging therapies for the treatment of anemia and iron deficiency have become available. Beginning in 2019, KDIGO planned 2 Controversies Conferences to review the new evidence and its potential impact on the management of anemia in clinical practice. Here, we report on the second of these conferences held virtually in December 2021, which focused on a new class of agents-the hypoxia-inducible factor-prolyl hydroxylase inhibitors (HIF-PHIs). This report provides a review of the consensus points and controversies from this second conference and highlights areas that warrant prioritization for future research.

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BACKGROUND: Five types of HIF-PHIs have been authorized for anemia treatment in CKD patients in China and Japan. These are enarodustat, roxadustat, daprodustat, vadadustat, and molidustat. How effectively they compare to ESAs about clinical results in CKD-DD patients is uncertain. This study examined the RCT evidence about the benefits and risks of HIF-PHIs and ESAs in dialysis CKD patients. METHODS: We conducted an extensive investigation and network meta-analysis of RCTs. In these RCTs, patients with CKD-DD received one of five different HIF-PHI or ESAs, a placebo, and no medical intervention. Outcomes included hemoglobin, iron parameters, and adverse events, and there were four weeks of follow-up at least. A frequentist framework for multivariate random effects meta-analyzed the results. The effect sizes of categorical variables were displayed as odds ratios. Mean differences were employed for computing continuous outcomes with common units; otherwise, standardized mean differences were applied. The Cochrane tool evaluated the bias risk in RCTs. RESULTS: 26 RCTs with 14945 patients were qualified for inclusion. Compared to the placebo, HIF-PHIs and ESAs dramatically boosted hemoglobin without affecting serum iron. Roxadustat performed better hemoglobin levels than ESAs (MD 0.32, 95% CI 0.10 to 0.53) and daprodustat (0.46, 0.09 to 0.84). Roxadustat (91.8%) was the top hemoglobin treatment among all medical interventions, as determined by the SUCRA ranking. However, roxadustat caused more thrombosis and hypertension than ESAs (1.61, 1.22 to 2.12) and vadadustat (1.36, 1.01 to 1.82). The lowest rates of hypertension and thrombosis were seen in molidustat (80.7%) and ESAs (88.5%). Compared with a placebo, ESAs and HIF-PHIs all affected TSAT levels. Except for molidustat, the other four HIF-PHIs impact different iron parameters. Regarding ferritin reduction, roxadustat (90.9%) and daprodustat (60.9%) came out on top. Enarodustat (80.9%) and roxadustat (74%) placed best and second in lowering hepcidin levels. The former two medicines for TIBC improvement were vadadustat (98.7%) and enarodustat (80.9%). CONCLUSION: The most effective treatment for hemoglobin correction is roxadustat. The superior efficacy of reducing hepcidin makes roxadustat and enarodustat appropriate for patients with inflammation. However, the increased risk of hypertension and thrombosis associated with roxadustat should be noted. In patients at risk for hypertension and thrombosis, molidustat and ESAs may be preferable options. When administering roxadustat and daprodustat, clinicians should check ferritin to assess iron storage. Lower TSAT in patients receiving HIF-PHIs and ESAs treatment suggests intravenous iron supplements are needed.

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Background: Diseases such as periodontitis and osteoporosis are expected to rise tremendously by 2050. Bone formation and remodeling are complex processes that are disturbed in a variety of diseases influenced by various hormones. Objective: This study aimed to review and present the roles of various hormones that regulate bone remodeling of the craniofacial complex. Methods: A literature search was conducted on PubMed and Google Scholar for studies related to hormones and jawbone. Search strategies included the combinations ("name of hormone" + "dental term") of the following terms: "hormones", "oxytocin", "estrogen", "adiponectin", "parathyroid hormone", "testosterone", "insulin", "angiotensin", "cortisol", and "erythropoietin", combined with a dental term "jaw bone", "alveolar bone", "dental implant", "jaw + bone regeneration, healing or repair", "dentistry", "periodontitis", "dry socket", "osteoporosis" or "alveolitis". The papers were screened according to the inclusion criteria from January 1, 2000 to March 31, 2021 in English. Publications included reviews, book chapters, and original research papers; in vitro studies, in vivo animal, or human studies, including clinical studies, and meta-analyses. Results: Bone formation and remodeling is a complex continuous process involving many hormones. Bone volume reduction following tooth extractions and bone diseases, such as periodontitis and osteoporosis, cause serious problems and require a great understanding of the process. Conclusion: Hormones are with us all the time, shape our development and regulate homeostasis. Newly discovered effects of hormones influencing bone healing open the possibilities of using hormones as therapeutics to combat bone-related diseases.

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Background: Elevated Phospholipids (PLs) and sphingolipid (SM) metabolism relates to with poor clinical status and adverse outcome of end-stage kidney disease patients undergoing peritoneal dialysis (PD). Studies have suggested that the use of hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHI) (Roxadustat) is associated with altered lipid metabolism. Observing on how PLs and SMs changes after the HIF-PHI treatment in PD patients may help understand the possible effect of HIF-PHI on PD patients besides correcting of anemia. Materials and methods: Stable peritoneal dialysis (PD) patients treated with Roxadustat for over 3 months were included. Phospholipid and sphingolipid metabolism were measured before and after treatment. Results: 25 PD patients were included. Overall, phospholipid and sphingolipid metabolism showed a decreasing trend after HIF-PHI treatment. Levels of LysoPC (20:0), 1,2-dilinoleoyl-sn-glycero-3-phosphocholine [CisPC (DLPC) (18:2)], lysophosphatidylethanolamine (LysoPE) (14:0), and sphingomyelin (d18:1/17:0) (17:0) were significantly decreased (all p < 0.05). Further regression analyses confirmed the significant relationship between the increased of hemoglobin levels and the decrease in egg lyso PC: phosphatidylethanolamines (PE) (16:0-18:1), PE (16:0-18:2), PE (16:0-22:6), PE (18:0-20:4), PE (18:0-18:2), LysoPE (18:0), LysoPE (18:1), and phosphatidylcholine (PC) (18:1-18:0). Conclusion: This study demonstrated that phospholipid and sphingolipid metabolism decreased after administration of HIF-PHI and was associated with improvement of anemia.