To observe the effect of roxadustat on lowering blood lipids in peritoneal dialysis (PD) patients beyond treating anemia.

In a prospective, multicenter clinical study, we randomly assigned (in a 1:1 ratio) 100 PD patients who had received erythropoiesis-stimulating agent therapy for at least 4 weeks to receive either roxadustat or erythropoietin (EPO) for 48 weeks. The blood lipids, hemoglobin, blood pressure, blood glucose, iron metabolism and inflammatory factors were compared between the two groups at 0, 2, 4, 8, 12, 16, 20, 24 and 48 weeks, respectively.

At start of switching to roxadustat, hemoglobin seemed to rise a little faster (102.8 ± 15.4 vs. 97.1 ± 17.3 g/L at 2 weeks, p > 0.05), but there was no significant difference in hemoglobin change between the two groups over the course of observation (p = 0.185). At the early stage of the study (12 weeks), the transferrin saturation (TSAT) of roxadustat group decreased significantly from the baseline (32.7 (20.6) vs. 22.1 (18.7)%, p = 0.001). At the end of the study period (48 weeks), total cholesterol (3.89 ± 0.92 vs. 4.52 ± 1.14 mmol/L, p = 0.012), low density lipoprotein cholesterol (2.24 ± 0.74 vs. 2.63 ± 0.82 mmol/L, p = 0.045) and triglyceride (1.35 (0.86) vs. 1.89 (1.27) mmol/l, p = 0.013) in roxadustat group were significantly lower than those in EPO group.

Roxadustat not only can improve anemia and iron metabolism, but also can reduce serum cholesterol and triglyceride levels in PD patients after switching from the EPO.

Anemia of chronic disease (ACD) is the most frequent clinical issue in patients with chronic disease, ACD is usually secondary to chronic kidney disease (CKD), cancer, and chronic infection, which is associated with poor health outcomes, increased morbidity and mortality, and substantial economic costs. Current treatment options for ACD are very limited. The discovery of the hypoxia-inducible factor-prolyl hydroxylase (HIF-PHD) pathway made it possible to develop novel therapeutic agents (such as hypoxia-inducible factor-prolyl hydroxylase inhibitor, HIF-PHI) to treat ACD by stabilizing HIF and subsequently promoting endogenous erythropoietin (EPO) production and iron absorption and utilization. Thus, HIF-PHIs appear to open a new door for the treatment of ACD patients with a novel mechanism. Here, we comprehensively reviewed the latest advancements in the application of HIF-PHIs in ACD. Specifically, we highlighted the key features of HIF-PHIs on ACD, such as stimulation of endogenous EPO, handling iron metabolism, inflammation-independent, and prolonging lifespan of red blood cells. In conclusion, the success of HIF-PHIs in the treatment of ACD may expand the therapeutic opportunity for other types of anemia beyond renal anemia.

The incidence of chronic kidney disease (CKD) is increasing globally; however, effective preventive and therapeutic strategies are currently limited. Roxadustat is being clinically used to treat renal anemia in CKD patients to reduce anemia-related complications and improve patients' life quality. Exosomes are small vesicles carrying important information that contribute to cell-to-cell communication and are present in various body fluids. However, little is known about the role of serum exosomes and their association with CKD after roxadustat treatment. Next-generation sequencing approaches have revealed that exosomes are enriched in noncoding RNAs and thus exhibit great potential as sensitive nucleic acid biomarkers in various human diseases. In this study, we aimed to identify the changed mRNAs-lncRNAs after roxadustat treatment as novel biomarkers for assessing the efficiency of the treatment. Through our study using RNA-seq data, we identified 957 mRNAs (626 upregulated and 331 downregulated after roxadustat treatment) and 914 lncRNAs (444 upregulated and 470 downregulated) derived from exosomes that were significantly changed, which was highly correlated to lipid metabolism. Our analysis through whole transcriptome profiling of exosome RNAs encompasses an identified differentially expressed mRNA-lncRNA regulatory axis in a larger patient cohort for the validation of suitable biomarkers for assessing CKD after roxadustat treatment.

Objective Roxadustat, a hypoxia-inducible factor-prolyl hydroxylase inhibitor, increases the hemoglobin (Hb) levels in patients with chronic kidney disease (CKD). To date, limited clinical studies have focused on the excessive increase in the Hb levels in the early weeks after switching from erythropoiesis-stimulating agents (ESA) to roxadustat in adult non-dialysis patients. We conducted a retrospective study to examine whether early overshoot frequently occurs after switching to roxadustat. Methods This 8-week retrospective pilot study examined patients with anemic, non-dialyzed CKD who switched from ESA (darbepoetin or epoetin beta pegol) to roxadustat or continued ESA. The Hb levels >12.5 g/dL after starting our observation was defined as Hb overshoot. Patients: Twenty-three patients who switched to roxadustat (roxadustat group) and 63 who continued ESA (ESA group) were included. Results The baseline median estimated glomerular filtration rate and mean Hb levels were 15.7 mL/min/1.73 m2 and 10.77 g/dL in roxadustat group and 15.2 mL/min/1.73 m2 and 10.64 g/dL in ESA group, respectively. Eight patients (34.8%) in the roxadustat group and two patients (3.2%) in the ESA group had Hb overshoot within the 8-week visit [odds ratio: 20.2 (95% confidence interval 3.13-130.0, p<0.01) in the background adjusted model]. Among the patients with Hb overshoot in the roxadustat group, the Hb levels were maintained close to baseline 4 weeks after roxadustat discontinuation. A younger age and higher baseline Hb and Hct levels were risk factors for Hb overshoot. Conclusion Hb overshoot was frequently observed in patients switched to roxadustat. Clinicians should be aware of Hb overshoot and emphasize the importance of early Hb level checks.

Anaemia is common in chronic kidney disease (CKD) encompassing non-dialysis dependent CKD (NDD-CKD) and dialysis dependent CKD (DD-CKD); people on peritoneal dialysis (PD) and haemodialysis (HD); and kidney transplant recipients (KTR). Iron deficiency and erythropoietin deficiency are the most common causes of anaemia in people with CKD, especially those requiring kidney replacement therapy (KRT). The Renal National Service Framework and National Institute for Health and Clinical Excellence in the UK, and Kidney Disease Improving Global Outcomes (KDIGO), all advocate treatment of anaemia in people with CKD. Blood transfusions are infrequently required, and newer therapies such as Hypoxia-Inducible Factor (HIF-PHI) stabilisers are now in current use. This guideline provides evidence based graded practice guidance on the use of iron; comments on iron deficiency without anaemia in people with CKD; provide further information on anaemia management in people with a transplant and provide guidance in the use of the new HIF-PHI drugs. It also provides audit and research recommendations.

Live-cell transcription factor (TF) activity reporting is crucial for synthetic biology, drug discovery and functional genomics. Here we present dFLASH (dual FLuorescent transcription factor Activity Sensor for Histone-integrated live-cell reporting), a modular, genome-integrated TF sensor. dFLASH homogeneously and specifically detects endogenous Hypoxia Inducible Factor (HIF) and Progesterone Receptor (PGR) activities, as well as coactivator recruitment to synthetic TFs. The dFLASH system produces dual-color nuclear fluorescence, enabling normalized, dynamic, live-cell TF activity sensing with strong signal-to-noise ratios and robust screening performance (Z' = 0.61-0.74). We validate dFLASH for functional genomics and drug screening, demonstrating HIF regulation via CRISPRoff and application to whole-genome CRISPR KO screening. Additionally, we apply dFLASH for drug discovery, identifying HIF pathway modulators from a 1600-compound natural product library using high-content imaging. Together, this versatile platform provides a powerful tool for studying TF activity across diverse applications.

Different starting doses of roxadustat are used for treating anemia in chronic kidney disease (CKD). We tested the noninferiority of weight-based lower starting dose compared with standard starting dose roxadustat for anemia in stage 3 to 5 CKD without dialysis.

Patients were randomized (1:1) and stratified by CKD stage to receive weight-based standard (< 60 kg: 70 mg 3 times per week [TIW]; ≥ 60 kg: 100 mg TIW) or 1-step-lower (< 60 kg: 50 mg TIW; ≥ 60 kg: 70 mg TIW) roxadustat starting dose for 16 weeks. The primary endpoint was mean hemoglobin change from baseline over weeks 12 to 16. The secondary endpoints included the proportion achieving hemoglobin 100 to 120 g/l, hemoglobin variability, and rescue therapy.

Overall, 254 patients were randomized. The mean (SD) baseline hemoglobin was 89.88 (6.90) g/l. Most patients had stage 4 (39.0%) or stage 5 (40.2%) CKD. Mean hemoglobin increased from baseline at weeks 12 to 16 (lower: 21.57 g/l; standard: 26.35 g/l), but noninferiority was not met. A comparable proportion achieved hemoglobin of 100 to 120 g/l (lower: 46.0%; standard: 47.2%). The hemoglobin increase was comparable in CKD stage 3 to 4, but less with the lower dose in CKD stage 5 (17.28 vs. 26.71 g/l). The lower dose exhibited a lower hemoglobin rate of change (lower: 2.917; standard: 3.376) and less drug exposure. Drug-related adverse event rates were comparable.

The proportion of patients who achieved the hemoglobin target was comparable between the doses. The lower starting dose had less hemoglobin fluctuation and is recommended for stage 3 to 4 CKD.

Tendon injuries remains a challenge to treat owing to its poor intrinsic reparative ability. It is hypothesised that hypoxic conditioning of mesenchymal stem cells (MSC) through the activation of hypoxia-inducible factor-1 alpha (HIF-1α), may enhance tendon repair process by promoting cellular proliferation and tenogenic differentiation. To demonstrate this, a study using roxadustat, a specific hypoxia mimetic mediator and HIF-1α inducer was conducted on adipose-derived mesenchymal stromal cells (AD-MSCs). Cellular morphology, proliferation rates, tenogenic protein and gene expression levels in untreated AD-MSCs (Group 1), roxadustat pre-conditioned AD-MSCs (Group 2), AD-MSCs subjected to CAY10585 (Group 3), roxadustat pre-conditioned AD-MSCs with CAY10585 (Group 4) and untreated primary tenocytes (Group 5) were evaluated. MSCs pre-conditioned with 12.5µM roxadustat for 24 hours showed the highest expression of HIF-1α without affecting the proliferation rates of AD-MSCs. However, significant reduction of HIF-1α levels was observed when the cells were treated with 3.5µM CAY10585. Roxadustat significantly up-regulated collagen I and III expressions by 6.6 and 6.3-fold respectively. HIF-1α promoted Scleraxis, Tenascin-C and Collagen III expressions, resulting in an increase of 6, 7, and 3 folds respectively. Conversely, using CAY10585 reduced these expressions to 3, 2 and 1 folds respectively. These trends were observed in the gene expression levels across Groups 1 to 4. However, the expression of these genes in Group 2 was significantly lower as compared to Group 5. Conclusion: HIF-1α accumulation promotes superior cell proliferation and tenogenic differentiation of AD-MSCs, indicating that roxadustat may be a potential therapeutic mediator in tendon repair strategies.

Anaemia is a common comorbidity in patients with chronic kidney disease (CKD) and heart failure (HF). Roxadustat has been approved for the treatment of anaemia in patients with CKD. However, its efficacy and safety in treating anaemia in patients with both CKD and HF remain unclear. We conducted a retrospective study with propensity score matching (PSM) to evaluate the efficacy and safety of roxadustat in this population.

This retrospective study enrolled patients diagnosed with HF comorbid with CKD and anaemia. The patients were divided into two groups: a roxadustat group and a control group. One-to-one PSM was used to balance baseline characteristics between the groups. The primary endpoint was the change in haemoglobin (Hb) at week 8. Secondary endpoints included Hb response, changes in haematocrit, iron parameters, echocardiographic parameters, B-type natriuretic peptides and lipid levels. Exploratory endpoints were mortality and rehospitalization rates over 30 days-2 years. Safety endpoints included the incidence of hyperkalaemia, liver damage and thrombotic events.

A total of 1055 patients were screened. After PSM, 206 patients were included. Baseline characteristics were comparable between the matched cohorts. At week 8, the roxadustat group experienced a greater increase in Hb than the control group, with a difference of 0.8 g/dl (95% confidence interval 0.3-1.3; P = .003). The roxadustat group also demonstrated a higher Hb response (60.2% versus 28.2%; P < .001) and a greater increase in haematocrit (4.7 ± 0.9% versus 2.8 ± 0.6%; P = .008) than the control group. No significant differences were observed for other secondary endpoints. Thrombotic events were similar between the two groups and there were no differences in the risks of mortality or rehospitalization.

Roxadustat was effective in correcting and maintaining Hb levels in patients with anaemia, HF and CKD. It did not increase thrombotic and other adverse events, mortality or rehospitalization risks, making it a promising treatment option for anaemia in this population.

Immune thrombocytopenia (ITP) is characterized by immune-mediated platelet destruction and impaired megakaryocyte maturation. Hypoxia-inducible factor-1α (HIF-1α), pivotal in the development of megakaryocytes and immune regulation, is downregulated in ITP. Roxadustat, which stabilizes HIF-1α, has emerged as a potential therapeutic drug for ITP that acts by enhancing HIF-1α-mediated megakaryocyte development and modulating immune responses.

This study evaluates the safety profile of roxadustat and its therapeutic efficacy for ITP treatment using Mendelian randomization (MR) analysis.

We used expression quantitative trait loci data for roxadustat's target genes (EGLN1, EGLN2, and EGLN3) and genetic associations with ITP and adverse outcomes from the Open Genome-Wide Association Study project. MR analysis included inverse-variance weighted, MR-Egger regression, weighted median, and MR pleiotropy residual sum and outlier methods to evaluate pleiotropy. Heterogeneity was assessed using Cochran's Q statistic and I2 measure with sensitivity analyses. A meta-analysis was performed to integrate effect sizes from multiple literature sources.

MR analysis revealed a significant association between roxadustat and reduced ITP risk (odds ratio, 0.79; 95% CI, 0.66-0.95; P = .01) with no evidence of horizontal pleiotropy. Meta-analysis confirmed the protective effect of roxadustat on ITP. Utilizing the expression quantitative trait loci of roxadustat's target gene EGLN1 as instrumental variables, an MR analysis of 39 potential adverse reactions revealed no significant increase, suggesting a favorable safety profile for roxadustat.

Roxadustat demonstrates a potential protective effect against ITP without increasing the risk of adverse outcomes, suggesting its promise as a therapeutic option for ITP and warranting further investigation.

Hematopoietic stem cell (HSC) mobilization is often difficult to achieve in patients suffering from multiple myeloma and non-Hodgkin's lymphoma. Granulocyte-colony stimulating factor (G-CSF) therapy alone has often not led to the desired outcomes. Herein, we describe the discovery of 7-cyclohexyl-4-hydroxy-8-oxo-N-(pyridazin-4-ylmethyl)-7,8-dihydro-2,7-naphthyridine-3-carboxamide 13, a hypoxia-inducible factor prolyl hydroxylase (HIF-PH) inhibitor, which was discovered by focusing on drug-like properties. Building on a previous discovery that HIF-PH inhibitors can enhance HSC mobilization in combination with G-CSF, we optimized 13 to exhibit high PHD2 potency, improved solubility, and an optimized PK profile. 13 was effective at enhancing G-CSF-induced HSC mobilization in mice at a dose of 2 mg/kg.

The COVID-19 pandemic has made treating renal anemia in chronic kidney disease (CKD) patients undergoing peritoneal dialysis (PD) difficult. The current study aims to compare roxadustat with erythropoiesis-stimulating agents (ESAs) during the COVID-19 pandemic.

We conducted a single-center, retrospective study during the COVID-19 outbreak in China, from December 7, 2022, to January 31, 2023. The study involved patients undergoing PD who were divided based on the medication used to treat renal anemia; the roxadustat group (n = 34) and the ESAs group (n = 120). We analyzed the effectiveness of treating anemia, cost, medication adherence, and clinical outcomes related to COVID-19. Patients were followed up for 9 months.

The baseline of hemoglobin levels was (110.03 ± 1.71 g/L in the roxadustat and 110.1 ± 1.52 g/L in the ESAs groups, respectively), after 9 months of inspections, the levels of hemoglobin were (121.26 ± 2.03 g/L in the roxadustat and 118.49 ± 1.35 g/L in the ESAs groups, respectively). The roxadustat subgroup analysis indicated that total cholesterol and low-density lipoprotein levels in the roxadustat group decreased from baseline in subjects not receiving statins (3.39 ± 0.12 vs. 4.2 ± 0.21 mmol/L and 2.21 ± 0.23 vs. 3.65 ± 0.37 mmol/L, P < 0.05). The Morisky score of the roxadustat group was higher [7 (5, 8) vs. 6 (4, 8), P < 0.01]. The drug cost of the roxadustat group was higher, but another additional cost for correcting anemia was significantly reduced. The infection rate of COVID-19 and the mortality rate caused by COVID-19 were lower in roxadustat group.

During the COVID-19 pandemic, both roxadustat and ESAs effectively improved renal anemia in PD patients, however, the roxadustat group experienced less additional costs for anemia correction and better medication compliance.

Roxadustat is a novel hypoxia- inducible factor-prolyl hydroxylase inhibitor(HIF-PHI) used to treat anemia in chronic kidney disease (CKD) patients. It has been reported that roxadustat can slow down kidney damage and delay the development of kidney fibrosis. Anemia and iron deficiency are often associated with the vast majority CKD patients, and insufficient available iron or total iron storage is often the most common cause of anemia and ESAs resistance in CKD patients. The role of iron availability in the pathogenesis of anemia in chronic kidney disease has received increasing attention.

To explore whether combined roxadustat and polysaccharide-iron complex (PIC) is more successful than standalone roxadustat, the appropriate iron supplement dosage and mechanism of roxadustat in the treatment of CKD.

Healthy male Sprague Dawley rats were randomly divided into two groups: the control (NC) group which were sham-operated and the CKD group. The CKD group was given an adenine diet for three weeks after right unilateral nephrectomy and further divided into 6 groups: the CKD only, CKD + PIC, CKD + Roxa, CKD + PIC (25 mg/kg) + Roxa, CKD + PIC (50 mg/kg) + Roxa, and CKD + PIC (75 mg/kg) + Roxa groups. The sham-operated rats receiving only standard diet served as the control group. Roxadustat were administrated intragastrically at 10 mg/kg thrice per week in groups with Roxa. The hemoglobin (Hb), reticulocyte hemoglobin equivalent (RET-He), reticulocyte % (RET%), plasma urea nitrogen (BUN), plasma creatinine (Cr), serum iron (SI), Total iron binding capacity (TIBC), serum hepcidin-25, interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), interleukin-1β (IL- 1β), and High mobility group protein B1 (HMGB1) levels of each group of rats were assessed. Masson staining was used to evaluate renal fibrosis, and quantitative real-time Polymerase Chain Reaction (RT-PCR) was used to detect the mRNA expression of alpha-smooth muscle actin (α-SMA) and Fibronectin (Fn) in rat renal tissues to further evaluate renal fibrosis.

Level of Hb in the CKD + PIC (75 mg/kg) + Roxa group increased the fastest, roxadustat combined with PIC in the treatment of renal anemia was significantly more effective than Roxadustat or PIC alone. On day 105, in the CKD + PIC (75 mg/kg) + Roxa group, there was a significant decrease in BUN and Cr levels compared to the CKD only group (p < 0.05). Roxadustat reduces the level of hepcidin, IL-6, TNF-α, IL-1β and HMGB1in CKD rats. (p < 0.05). Roxadustat alleviates renal fibrosis in CKD rats (p < 0.05).

HIF-PHI combined with iron supplement (Roxadustat combined with PIC) has an improved effect on the treatment of renal anemia, and early administration of sufficient iron enables the Hb to rise rapidly. Early administration of adequate dose of PIC is necessary for renal anemia. HIF-PHI can improve iron metabolism, alleviate the microinflammatory state, alleviate renal fibrosis and plays a beneficial role in the treatment of renal fibrosis in CKD rats.

The long-term efficacy and safety of desidustat in real world are unknown. We conducted a retrospective real-world experience of desidustat in 100 consecutive patients on hemodialysis.

The first 100 consecutive stable patients on hemodialysis who were prescribed desidustat between May and December 2022, without history of infection, surgery, chronic hepatitis, or HIV infection, 1 month prior to initiation, were eligible for analysis from electronic records. Those who were lost to follow up, underwent transplantation, or discontinued medicine within 6 months were excluded. We looked at mean dose; efficacy at 1, 6, and 12 months; side effects; and adherence of desidustat over a period of 12 months.

Out of 100, 59 patients completed 1 year of the drug and were analyzed. There was statistically significant increase in hemoglobin from baseline to 1 month (9 ± 1.2 vs. 9.4 ± 1.3 g/dL, p = 0.01) and from baseline to 12 months (9 ± 1.2 vs. 9.9 ± 1.5 g/dL, p = 0.02). The percentage of patients who achieved target hemoglobin of 10-12 g/dL was 17% at baseline, which increased to 19.1% at 1 month, 43% at 6 months, and 38.9% at 12 months. Side effects were noted in 20% of patients, with edema being the most common (6%) and infections in 5% of cases. Nonadherence was observed in 15% patients.

Desidustat is effective and safe in management of anemia in hemodialysis patients over a period of 1 year. It helps in achieving target hemoglobin in majority of patients within 6 months.

Most eukaryotes require oxygen for their survival and, with increasing multicellular complexity, oxygen availability and delivery rates vary across the tissues of complex organisms. In humans, healthy tissues have markedly different oxygen gradients, ranging from the hypoxic environment of the bone marrow (where our haematopoietic stem cells reside) to the lungs and their alveoli, which are among the most oxygenated areas of the body. Immune cells are therefore required to adapt to varying oxygen availability as they move from the bone marrow to peripheral organs to mediate their effector functions. These changing oxygen gradients are exaggerated during inflammation, where oxygenation is often depleted owing to alterations in tissue perfusion and increased cellular activity. As such, it is important to consider the effects of oxygenation on shaping the immune response during tissue homeostasis and disease conditions. In this Review, we address the relevance of both physiological oxygenation (physioxia) and disease-associated hypoxia (where cellular oxygen demand outstrips supply) for immune cell functions, discussing the relevance of hypoxia for immune responses in the settings of tissue homeostasis, inflammation, infection, cancer and disease immunotherapy.

Over-proliferation of mesangial cells (MCs) is one of the main pathological changes in the early stages of diabetic kidney disease (DKD). Roxadustat, an oral hypoxia-inducible factor (HIF) prolyl hydroxylase inhibitor, is widely studied in different models of kidney disease. Whether roxadustat has beneficial effect on the proliferation of MCs and DKD remains unknown.

The optimal concentration of roxadustat for inhibiting MC proliferation was determined using CCK-8 and colony formation assays. Changes in the cell cycle were detected using flow cytometry, and changes in cell cycle-related proteins were screened using quantitative reverse transcription polymerase chain reaction. Reverse experiments were applied using Trp53-/- cell line. Co-immunoprecipitation was used to verify the interaction between HIF-1α and p53 and predict sites of interaction. Finally, a corresponding in vivo verification was performed.

Optimal concentrations of high glucose (30 mM) and roxadustat (100 μM) were established. Roxadustat showed anti-proliferation effect on MCs through S-phase arrest. HIF-1α/p53/p21 and downstream cyclins (cyclin A1, cyclin A2, and cyclin E1) showed corresponding changes. A reverse experiment confirmed that HIF-1α affected cell cycle and proliferation through p53, and co-immunoprecipitation results showed a interaction between HIF-1α and p53. Molecular docking predicted the possible interaction between Lys328, Pro332, Arg245, and Lys251 of HIF-1α and Ala222, Tyr226, Glu225, and Asp265 of p53, respectively. Finally, animal experiments demonstrated similar effect of roxadustat in db/db mice.

Roxadustat regulates and inhibits cell proliferation of MCs via the HIF-1α/p53/p21 pathway. This may be a potential therapeutic target in the early stages of diabetic kidney disease.

Erythropoietin (EPO) is a key regulator of erythrocyte production, promoting erythroid progenitor cell survival, division, and differentiation in the fetal liver and adult bone marrow. Mice lacking EPO or its receptor (EPOR) die in utero due to severe anemia. Beyond hematopoiesis, EPO influences non-hematopoietic tissues, including glucose and fat metabolism in adipose tissue, skeletal muscle, and the liver. EPO is used to treat anemia associated with chronic kidney disease clinically and plays a role in maintaining metabolic homeostasis and regulating fat mass. EPO enhances lipolysis while inhibiting lipogenic gene expression in white adipose tissue, brown adipose tissue, skeletal muscle, and the liver, acting through the EPO-EPOR-RUNX1 axis. The non-erythroid EPOR agonist ARA290 also improves diet-induced obesity and glucose tolerance providing evidence for EPO regulation of fat metabolism independent of EPO stimulated erythropoiesis. Therefore, in addition to the primary role of EPO to stimulate erythropoiesis, EPO contributes significantly to EPOR-dependent whole-body metabolic response.

Hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHIs) have shown promising prospects as novel therapeutic agents in renal anemia, but their potential cardiovascular toxicities have raised widespread concern. This study aim to explore the cardiovascular toxicities associated with HIF-PHIs through real-world long-term safety data.

A disproportionality analysis was employed by calculating the reporting odds ratios (ROR), information component (IC), and their 95% credibility intervals (CrI) in Japan Adverse Drug Event Report (JADER) database from 1 January 2020, to 30 September 2023.

From Q1 2020 to Q3 2023, 253,599 adverse events (AEs) cases were extracted from the JADER database, including 4,015 cases related to HIF-PHIs and 1,537 (38.28%) cases of cardiovascular toxicities. Embolic and thrombotic events (ROR = 6.66, IC = 2.74), cardiac failure (ROR = 3.86, IC = 1.95), and ischemic heart disease (ROR = 3.37, IC = 1.75) indicated positive signals in HIF-PHIs. The median time to onset (TTO) of hypertension for HIF-PHIs was noted to be the earliest at 15.50 days.

HIF-PHIs are related to multiple cardiovascular toxicities. Although disproportionality analysis is a hypothesis-driven method, improving the surveillance of these toxicities related to HIF-PHIs used in managing renal anemia is still crucial.

Ferritin level and erythropoiesis-stimulating agent (ESA) responsiveness are each associated with hemodialysis patient survival. We assessed interrelationships between these two vs. survival.

Patients in the Japan Dialysis Outcomes and Practice Patterns Study Phases 4-6 (2009-2018) were included. All-cause mortality associations were assessed with progressive adjustment to evaluate covariate influence.

During follow-up (median 2.6 years), 773 of 5154 patients died. After covariate adjustment, the mortality hazard ratio (HR) was 0.99 (95% CI: 0.81, 1.20) for low serum ferritin and 1.12 (CI: 0.89, 1.41) for high serum ferritin. By contrast, mortality risk with elevated ESA resistance index (ERI) persisted after covariate adjustment (HR 1.44, CI [1.17-1.78]). The serum ferritin and ERI interaction was not significant; p > 0.96 across all models.

Japanese hemodialysis patients with high ERI experienced worse survival independent of serum ferritin levels, highlighting the importance of identifying and mitigating ESA hyporesponsiveness among dialysis patients.

We evaluated the efficacy and safety of roxadustat, a first-in-class hypoxia-inducible factor prolyl hydroxylase inhibitor, for chemotherapy-induced anemia (CIA) in patients with nonmyeloid malignancies receiving multicycle treatments of chemotherapy.

In this open-label, noninferiority phase III study conducted at 44 sites in China, 159 participants age ≥18 years with CIA nonmyeloid malignancy and CIA were randomly assigned (1:1) to oral roxadustat or subcutaneous recombinant human erythropoietin-α (rHuEPO-α) three times a week for 12 weeks. Roxadustat starting dosages were 100, 120, and 150 mg three times a week for participants weighing 40-<50, 50-60, and >60 kg, respectively. rHuEPO-α starting dosage for all participants was 150 IU/kg three times a week. Both roxadustat and rHuEPO-α dosages could be modified. The primary end point was least-squares mean (LSM) change in hemoglobin (Hb) concentration from baseline to the concentration averaged over weeks 9-13.

Of the 159 participants randomly assigned, 140 were included in the per-protocol set (roxadustat, n = 78; rHuEPO-α, n = 62). The LSM (95% two-sided CI) change from baseline to weeks 9-13 in Hb concentration was 17.1 (13.58 to 20.71) g/L with roxadustat and 15.4 (11.34 to 19.50) g/L with rHuEPO-α (mean difference [95% CI], 1.7 [-3.39 to 6.84]). The lower bound of the one-sided 97.5% CI for the treatment difference (‒3.4 g/L) was greater than the predefined noninferiority margin of ‒6.6 g/L, establishing noninferiority. Noninferiority was supported by five of six key secondary end points. Rates of adverse events were generally comparable between treatments and consistent with previous findings.

Roxadustat was noninferior to rHuEPO-α in treating CIA in participants with nonmyeloid malignancies receiving multicycle treatments of myelosuppressive chemotherapy. The oral formulation of roxadustat may potentially increase compliance.

Hypoxia-inducible factors (HIF) regulate gene transcription, which aids hypoxia adaptation while promoting renal fibrosis. Non-transferrin-bound iron (NTBI) is a catalytic form of iron that can lead to oxidative damage. However, NTBI in cat biofluids has rarely been evaluated.

We assessed cat plasma and urine HIF-1α (pHIF-1α/uHIF-1α) concentrations and urine NTBI (uNTBI) concentrations to investigate their relationship with chronic kidney disease (CKD) severity.

pHIF-1α and uHIF-1α concentrations were measured using commercial ELISA kits, while uNTBI concentrations were detected by inductively coupled plasma mass spectrometry.

Healthy cats (n = 35) and cats with CKD (n = 84) formed the study cohorts. pHIF-1α concentrations increased from 9.48 pg./mL (median) in the healthy cohort to 11.42 pg./mL in early-stage CKD cats but decreased to 8.50 pg./mL in late-stage CKD cats. uHIF-1α concentrations gradually decreased with a significant difference between the control group (44.61 pg./mL) and the late-stage CKD group (36.79 pg./mL, p < 0.001). Cats with proteinuria had significantly higher uNTBI concentrations (35.61 ppb) than non-proteinuric cats (25.13 ppb, p = 0.019). Finally, the concentrations of pHIF-1α and uHIF-1α were positively correlated independent of renal function.

Overall, pHIF-1α and uHIF-1α concentrations are lower in advanced CKD cats, while uNTBI concentrations are significantly higher in proteinuric cats.

Hypoxia Inducible transcription Factors (HIFs) are central to the metazoan oxygen-sensing response. Under low oxygen conditions (hypoxia), HIFs are stabilised and govern an adaptive transcriptional programme to cope with prolonged oxygen starvation. However, when oxygen is present, HIFs are continuously degraded by the proteasome in a process involving prolyl hydroxylation and subsequent ubiquitination by the Von Hippel Lindau (VHL) E3 ligase. The essential nature of VHL in the HIF response is well established but the role of other enzymes involved in ubiquitination is less clear. Deubiquitinating enzymes (DUBs) counteract ubiquitination and provide an important regulatory aspect to many signalling pathways involving ubiquitination. In this review, we look at the complex network of ubiquitination and deubiquitination in controlling HIF signalling in normal and low oxygen tensions. We discuss the relative importance of DUBs in opposing VHL, and explore roles of DUBs more broadly in hypoxia, in both VHL and HIF independent contexts. We also consider the catalytic and non-catalytic roles of DUBs, and elaborate on the potential benefits and challenges of inhibiting these enzymes for therapeutic use.

This study is intended to explore the effect of hypoxia-inducible factor-1α (HIF-1α) activation on lipid accumulation in the diabetic kidney. A type 1 diabetic rat model was established by STZ intraperitoneal injection. Cobalt chloride (CoCl2) and YC-1 were used as the HIF-1α activator and antagonist, respectively. CoCl2 treatment significantly increased HIF-1α expression, accelerated lipid deposition, and accelerated tubular injury in diabetic kidneys. In vitro, CoCl2 effectively stabilized HIF-1α and increased its transportation from the cytoplasm to the nucleus, which was accompanied by significantly increased lipid accumulation in HK-2 cells. Furthermore, results obtained in vivo showed that HIF-1α protein expression in the renal tubules of diabetic rats was significantly downregulated by YC-1 treatment. Meanwhile, lipid accumulation in the tubules of the DM + YC-1 group was markedly decreased in comparison to the DM + DMSO group. Accordingly, PAS staining revealed that the pathological injury caused to the tubular epithelial cells was alleviated by YC-1 treatment. Furthermore, the blood glucose level, urine albumin creatinine ratio, and NAG creatinine ratio in the DM + YC-1 group were significantly decreased compared to the DM + DMSO group. Moreover, the protein expression levels of transforming growth factor β1 (TGF-β1) and connective tissue growth factor (CTGF) in diabetic kidneys were decreased by YC-1 treatment. Our findings demonstrate that the activation of HIF-1α contributed to interstitial injury in a rat model of diabetic nephropathy and that the underlying mechanism involved the induction of lipid accumulation.

Roxadustat, a hypoxia-inducible factor-prolyl hydroxylase inhibitor, has proven efficacy in the treatment of renal anemia; however, evidence indicates that it may cause central hypothyroidism. The prevalence and reversibility of roxadustat-induced central hypothyroidism in patients undergoing hemodialysis remain unclear. Here, we retrospectively analyzed thyroid-stimulating hormone (TSH), free thyroxine (FT4), and free triiodothyronine (FT3) levels in 51 patients (mean age: 72.3 ± 10.7 years; 58.8% male) undergoing hemodialysis before, during, and after halting roxadustat treatment. TSH levels were significantly decreased from a median of 2.46 (interquartile range:1.60-4.51) mU/L before roxadustat treatment to 1.36 (0.72-2.41) mU/L during treatment (p < 0.001), and improved to 2.56 (1.78-4.63) mU/L after halting roxadustat (p < 0.001). Similarly, FT4 levels decreased from 1.11 (0.97-1.24) ng/dL before roxadustat treatment to 0.92 (0.71-1.03) ng/dL during treatment (p < 0.001) and improved to 1.05 (0.93-1.17) ng/dL after halting roxadustat (p < 0.001). FT3 levels were 2.04 (1.78-2.31) pg/mL before starting roxadustat, 1.97 (1.69-2.27) pg/mL during treatment, and 1.90 (1.63-2.18) pg/mL after halting roxadustat, with no significant difference between each group. Moreover, 2.0% of patients exhibited extremely low TSH levels (≤0.1 mU/L) and low TSH levels (>0.1 mU/L to <0.4 mU/L) before starting roxadustat and that percentage increased to 5.9% and 7.8%, respectively, during treatment. After roxadustat cessation, extremely low or low TSH levels recovered in all patients. Taken together, the results indicate that roxadustat can cause reversible central hypothyroidism in patients undergoing hemodialysis.

To explore independent influencing factors for clinical efficacy of roxadustat in hemodialysis patients.

Hemodialysis patients treated with roxadustat were enrolled. The plasma trough concentrations of roxadustat were measured using liquid chromatography-tandem mass spectrometry (LC-MS/MS). A multiple logistic regression model was established to determine the factors that affect clinical efficacy of roxadustat in patients undergoing hemodialysis.

A total of 67 hemodialysis patients were enrolled in the study. The results showed that age, blood trough concentration of roxadustat, and baseline hemoglobin (Hb) level were independent factors of clinical efficacy of roxadustat (OR = 1.06, p = .025 for age; OR = 1.001, p = .037 for plasma concentration; and OR = 0.941, p = .003 for baseline Hb), with an AUC score of 0.859.

Age, blood trough concentration of roxadustat, and baseline Hb level were independent influencing factors of the response to roxadustat in hemodialysis patients.

This systematic review and meta-analysis were conducted to evaluate the cardiac and kidney-related adverse effects of roxadustat for the treatment of anemia in CKD patients. 18 trials with a total of 8806 participants were identified for analysis. We employed a fixed-effects model for analysis. The pooled result revealed no significant difference in the risk of occurrence of cardiac disorders when comparing CKD patients receiving roxadustat with the placebo (RR = 1.049; CI [0.918 to 1.200]) or ESA (RR = 1.066; CI [0.919 to 1.235]), in both dialysis-dependent (DD) (RR = 1.094; CI [0.925 to 1.293]) or non-dialysis-dependent (NDD) (RR = 1.036; CI [0.916 to 1.171]) CKD patients. No significant difference was observed in the risk of kidney-related adverse events when comparing roxadustat with the placebo (RR = 1.088; CI [0.980 to 1.209]) or ESA (RR = 0.968; CI [0.831 to 1.152]), in DD (RR = 2.649; CI [0.201 to 34.981]) or NDD (RR = 1.053; CI [0.965 to 1.149]) CKD patients. A high risk of hyperkalemia was observed in the roxadustat group in DD (RR = 0.939; CI [0.898 to 0.981]). Incidence of hypertension was higher in the roxadustat for NDD patients (RR = 1.198; CI [1.042 to 1.377]), or compared to the placebo (RR = 1.374; CI [1.153 to 1.638]). In summary, the risk of cardiac or kidney-related events observed in the roxadustat was not significantly increase whether in DD or NDD patients. However, attention must be paid to the occurrence of hyperkalemia for DD patients and hypertension in NDD patients using roxadustat.

Acute kidney injury (AKI) is associated with a high mortality rate. Pathologically, renal ischemia/reperfusion injury (RIRI) is one of the primary causes of AKI, and hypoxia-inducible factor (HIF)-1α may play a defensive role in RIRI. This study assessed the role of hypoxia-inducible factor 1α (HIF-1α)-mediated mitophagy in protection against RIRI in vitro and in vivo. The human tubular cell line HK-2 was used to assess hypoxia/reoxygenation (H/R)-induced mitophagy through different in vitro assays, including western blotting, immunofluorescence staining, terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL), and reactive oxygen species (ROS) measurement. Additionally, a rat RIRI model was established for evaluation by renal histopathology, renal Doppler ultrasound, and transmission electron microscopy to confirm the in vitro data. The selective HIF-1α inhibitor LW6 reduced H/R-induced mitophagy but increased H/R-induced apoptosis and ROS production. Moreover, H/R treatment enhanced expression of the FUN14 domain-containing 1 (FUNDC1) protein. Additionally, FUNDC1 overexpression reversed the effects of LW6 on the altered expression of light chain 3 (LC3) BII and voltage-dependent anion channels as well as blocked the effects of HIF-1α inhibition in cells. Pretreatment of the rat RIRI model with roxadustat, a novel oral HIF-1α inhibitor, led to decreased renal injury and apoptosis in vivo. In conclusion, the HIF-1α/FUNDC1 signaling pathway mediates H/R-promoted renal tubular cell mitophagy, whereas inhibition of this signaling pathway protects cells from mitophagy, thus aggravating apoptosis, and ROS production. Accordingly, roxadustat may protect against RIRI-related AKI.

Hypoxia-inducible factor prolyl hydroxylase (HIF-PH) inhibitors are a new class of agents for the treatment of anemia in chronic kidney disease (CKD). Unlike traditional treatments such as erythropoiesis-stimulating agents (ESAs), HIF-PH inhibitors are orally administered drugs and may increase endogenous erythropoietin and improve iron homeostasis. However, a significant concern is their possible side effect on blood pressure. The current mini-review summarizes the data of 26 randomized controlled (placebo or ESAs) trials on six different HIF-PH inhibitors with regard to their potential influence on blood pressure and hypertension in the management of anemia in CKD. Overall, the use of HIF-PH inhibitors was associated with a higher risk of hypertension than placebo (pooled risk ratio 1.36, 95% confidence interval [CI] 1.16-1.59), but a lower risk of hypertension than ESA treatment (pooled risk ratio 0.92, 95% CI 0.86-0.98), especially in CKD patients not undergoing dialysis (pooled risk ratio 0.85, 95% CI 0.73-0.98). This review highlights the importance of blood pressure monitoring during the treatment of HIF-PH inhibitors, especially out-of-office blood pressure measurement.

Recombinant human erythropoietin (rHuEPO) is commonly used to treat anemia associated with chronic kidney disease (CKD). EPO-induced Pure Red Cell Aplasia (PRCA) is a rare condition of profound anemia with EPO treatment. Upon finding the development of EPO-induced PRCA, the treatment requires immediate withdrawal of EPO therapy and initiate new treatments with immunosuppression or renal transplantation. Anti-EPO antibody assay is not always positive in EPO-induced PRCA. Here, we report a case on the sudden development of PRCA in a hemodialysis patient receiving EPO and how we treated the condition successfully with cyclosporine and subsequently maintained the hemoglobin with Roxadustat, a hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHI). Even though the anti-EPO antibody was negative by Enzyme Linked Immunosorbent Assay (ELISA) in our case, the clinical course, the markedly reduced reticulocyte count < 10,000/μL, the bone marrow (BM) biopsy revealing reduced erythroblasts, and its subsequent response to cyclosporine, were similar to EPO-induced PRCA. The clinical picture of EPO-induced PRCA, the limitation of the EPO-neutralizing antibody (Ab) assay, and treatment strategies were discussed.

Hypoxia-inducible factors (HIFs) are transcription factors that regulate erythropoietin (EPO) synthesis and red blood cell (RBC) production. Prolyl-4-hydroxylase domain (PHD) enzymes are key regulators of HIF's stability and activity. Inhibiting PHD enzymes can enhance HIF-mediated responses and have therapeutic potential for diseases such as anemia, cancer, stroke, ischemia, neurodegeneration, and inflammation. In this study, we searched for novel PHD inhibitors from four databases of natural products and synthetic compounds: AfroDb Natural Products, AnalytiCon Discovery Natural Product (NP), HIM-Herbal Ingredients In-Vivo Metabolism, and Herbal Ingredients' Targets, with a total number of 13,597 compounds. We screened the candidate compounds by molecular docking and validated them by molecular dynamics simulations and free energy calculations. We identified four target hits (ZINC36378940, ZINC2005305, ZINC31164438, and ZINC67910437) that showed stronger binding affinity to PHD2 compared to the positive control, Vadadustat (AKB-6548), with docking scores of - 13.34 kcal/mol, - 12.76 kcal/mol, - 11.96 kcal/mol, - 11.41 kcal/mol, and - 9.04 kcal/mol, respectively. The target ligands chelated the active site iron and interacted with key residues (Arg 383, Tyr329, Tyr303) of PHD2, in a similar manner as Vadadustat. Moreover, the dynamic stability-based assessment revealed that they also exhibited stable dynamics and compact trajectories. Then the total binding free energy was calculated for each complex which revealed that the control has a TBE of - 31.26 ± 0.30 kcal/mol, ZINC36378940 reported a TBE of - 38.65 ± 0.51 kcal/mol, for the ZINC31164438 the TBE was - 26.16 ± 0.30 kcal/mol while the ZINC2005305 complex reported electrostatic energy of - 32.75 ± 0.58 kcal/mol. This shows that ZINC36378940 is the best hit than the other and therefore further investigation should be performed for the clinical usage. Our results suggest that these target hits are promising candidates that reserve further in vitro and in vivo validations as potential PHD inhibitors for the treatment of renal anemia, cancer, stroke, ischemia, neurodegeneration, and inflammation.

Patients undergoing hemodialysis (HD) for chronic kidney disease (CKD) often encounter anemia. Roxadustat has not only undergone phase II-III clinical trials in patients suffering from CKD and undergoing HD; a number of post-marketing clinical studies have been conducted using the drug. This article was to assess the effectiveness and safety of roxadustat in managing anemia among patients with CKD undergoing HD.

A thorough search was performed across eight databases, including PubMed, Web of Science, Cochrane Library, Embase, Wan Fang, China National Knowledge Infrastructure (CNKI), Chongqing VIP (CQ VIP), and SinoMed to identify randomized clinical trials (RCTs) examining the effectiveness and safety of roxadustat in managing anemia among individuals suffering from CKD and undergoing HD. This search included studies from the inception of these databases to April 2023.

Two phase II, one phase III, and 16 post-marketing studies with 1688 participants were included. Serum iron (SI), transferrin, and total iron-binding capacity (TIBC) levels changed from baseline (∆SI, ∆transferrin, and ∆TIBC) and were significantly more increased for roxadustat than for erythropoiesis-stimulating agents (ESAs): MD 2.55, (95% CI 1.51 to 3.60), p < 0.00001; MD 0.55, (95% CI 0.41 to 0.69), p < 0.00001; and MD 6.54, (95% CI 4.50 to 8.59), p < 0.00001, respectively. Roxadustat was not inferior to ESAs with regard to increasing Hb (∆Hb) levels [MD 1.17 (95% CI 0.71 to 1.63), p < 0.00001] (g/dL). No statistically significant distinctions of the ∆ferritin, ∆hepcidin, and transferrin saturation (TSAT) from baseline (∆TSAT) level were identified between roxadustat and ESAs. C-reactive protein (CRP) levels changed from baseline (∆CRP) and were significantly more reduced for roxadustat than for ESAs. As for safety, the analysis indicated no notable difference in the occurrence of adverse events (AEs) and serious adverse events (SAEs) between roxadustat and ESAs.

This meta-analysis demonstrated that roxadustat outperformed ESAs in enhancing SI, transferrin, and TIBC levels while also decreasing CRP levels. Roxadustat was not inferior to ESAs in terms of improving Hb levels and safety. These findings suggest that roxadustat was well tolerated and a potent alternative to ESAs in managing anemia among patients suffering from CKD and undergoing HD.

More than 3.5 million people worldwide and 540 000 individuals in the US receive maintenance hemodialysis or peritoneal dialysis for the treatment of chronic kidney failure. The 5-year survival rate is approximately 40% after initiation of maintenance dialysis.

Hemodialysis and peritoneal dialysis remove metabolic waste and excess body water and rebalance electrolytes to sustain life. There is no recommended estimated glomerular filtration rate (eGFR) threshold for initiating dialysis, and patient-clinician shared decision-making should help determine when to initiate dialysis. Persistent signs and symptoms of uremia (eg, nausea, fatigue) and volume overload (eg, dyspnea, peripheral edema), worsening eGFR, metabolic acidosis, and hyperkalemia inform the timing of therapy initiation. A randomized clinical trial reported no mortality benefit to starting dialysis at higher eGFR (10-14 mL/min/1.73 m2) vs lower eGFR (5-7 mL/min/1.73 m2) levels. Observational data suggested no differences in 5-year mortality with use of hemodialysis vs peritoneal dialysis. Cardiovascular (eg, arrhythmias, cardiac arrest) and infection-related complications of maintenance dialysis are common. In the US, hemodialysis catheter-related bloodstream infections occur at a rate of 1.1 to 5.5 episodes per 1000 catheter-days and affect approximately 50% of patients within 6 months of catheter placement. Peritonitis occurs at a rate of 0.26 episodes per patient-year and affects about 30% of individuals in the first year of peritoneal dialysis therapy. Chronic kidney failure-related systemic complications, such as anemia, hyperphosphatemia, hypocalcemia, and hypertension, often require pharmacologic treatment. Hypotension during dialysis, refractory symptoms (eg, muscle cramps, itching), and malfunction of dialysis access can interfere with delivery of dialysis.

In 2021, more than 540 000 patients in the US received maintenance hemodialysis or peritoneal dialysis for treatment of chronic kidney failure. Five-year survival rate after initiation of maintenance dialysis is approximately 40%, and the mortality rate is similar with hemodialysis and peritoneal dialysis. Decisions about dialysis initiation timing and modality are influenced by patient symptoms, laboratory trajectories, patient preferences, and therapy cost and availability and should include shared decision-making.

Peri-operative anemia is a common condition encountered in adult surgical patients. It is increasingly recognized as a predictor of post-operative morbidity and mortality. Evaluation and treatment of anemia pre-operatively can reduce transfusion needs and potentially improve outcomes in surgical patients. This article discusses anemia optimization strategies in peri-operative setting with special focus on use of intravenous iron therapy. Additionally, the authors describe the role of transfusion medicine and best practices around red blood cell, platelet, and plasma transfusions.

The unique property of the pulmonary circulation to constrict in response to hypoxia, rather than dilate, brings advantages in both health and disease. Hypoxic pulmonary vasoconstriction (HPV) acts to optimise ventilation-perfusion matching - this is important clinically both in focal disease (such as pneumonia) and in one-lung ventilation during anaesthesia for thoracic surgery. However, during global hypoxia such as that encountered at high altitude, generalised pulmonary vasoconstriction can lead to pulmonary hypertension. There is now a growing body of evidence that links the hypoxia-inducible factor (HIF) pathway and pulmonary vascular tone - in both acute and chronic settings. Genetic and pharmacological alterations to all key components of this pathway (VHL - von Hippel-Lindau ubiquitin E3 ligase; PHD2 - prolyl hydroxylase domain protein 2; HIF1 and HIF2) have clear effects on the pulmonary circulation, particularly in hypoxia. Furthermore, knowledge of the molecular biology of the prolyl hydroxylase enzymes has led to an extensive and ongoing body of research into the importance of iron in both HPV and pulmonary hypertension. This review will explore these relationships in more detail and discuss future avenues of research.

Myelodysplastic syndromes/neoplasms (MDS) are a heterogeneous group of hematologic malignancies that are stratified into high-risk (HR-MDS) and low-risk (LR-MDS) categories. Until recently, LR-MDS has been typically managed by supportive measures and erythropoiesis-stimulating agents (ESAs); whereas management of HR-MDS typically included hypomethylating agents and allogeneic hematopoietic stem cell transplant. However, the limited rates and durations of response observed with these interventions prompted the search for targeted therapies to improve the outcomes among patients with MDS.

Here, we review the current landscape of targeted therapies in MDS. These include pyruvate kinase and hypoxia-inducible factor (HIF) activators; TGF-beta, telomerase, BCL2 and isocitrate dehydrogenase (IDH) inhibitors; as well as novel approaches targeting inflammation, pyroptosis, immune evasion, and RNA splicing machinery.

This review highlights the progress and challenges in MDS treatment. Despite some promising results, many therapies remain in early development or have faced setbacks, emphasizing the need for a more comprehensive understanding of the disease's pathobiology. Continued research into targeted therapies, homogenous clinical trial designs, as well as increased incorporation of molecular prognostic tools and artificial intelligence into trial design are essential for developing effective treatments for MDS and improving patient outcomes.

Roxadustat, an oral inhibitor of hypoxia-inducible factor prolyl hydroxylase domain enzymes, has been approved for the treatment of renal anemia. However, there is a lack of study on its pharmacokinetics in kidney transplant recipients (KTRs) with early posttransplant anemia (PTA). Therefore, the aim of this study is to elucidate the pharmacokinetic characteristics of roxadustat in KTRs with early PTA and optimize the dosing regimen.

A population pharmacokinetic (PopPK) analysis was performed based on 72-hour full concentration-time profiles collected from 52 Chinese KTRs. Covariates influencing exposure were assessed using stepwise covariate modelling. Monte Carlo simulations were conducted to recommend the dosing regimen for patients with different levels of covariates.

PopPK analysis showed that the concentration-time data can be fully described by a two-compartment model. Body weight (BW) and direct bilirubin (DBIL) levels significant affected the apparent clearance of roxadustat. Based on the established model and the estimated exposures of roxadustat by Monte Carlo simulations, a recommended dosing regimen for KTRs with early PTA at varying BW and DBIL levels were developed. Roxadustat at 100 mg three times weekly were suitable for the majority of KTRs with a DBIL level around 3 μmol/L and BW between 50 and 75 kg. The required dose may need to be increased with higher BW and lower DBIL levels, while decreased with lower BW and higher DBIL levels.

It was the first PopPK analysis of roxadustat in KTRs with early PTA, which provide a research basis for optimizing the dosing regimen.