[Efficacy and safety analysis of hypoxia-inducible factor prolyl hydroxylase inhibitors for anemia in low-risk myelodysplastic syndromes patients].

Myelodysplastic syndromes is a heterogeneous group of myeloid neoplastic disorders originating from hematopoietic stem cells and manifesting as pathological bone marrow hematopoiesis and a high risk of transformation to acute myeloid leukemia. In low-risk patients, the therapeutic goal is to improve hematopoiesis and quality of life. Roxadustat is the world's first oral small-molecule hypoxia-inducible factor prolyl hydroxylase inhibitor, which, unlike conventional erythropoietin, corrects anemia through various mechanisms. In this study, we retrospectively analyzed the changes in anemia, iron metabolism, lipids and inflammatory indexes in patients with low-risk myelodysplastic syndromes to evaluate its therapeutic efficacy and safety, and to provide theoretical and practical data for the application of roxadustat in myelodysplastic syndromes.

Consensus commentary and position of the Italian Society of Nephrology on KDIGO controversies conference on novel anemia therapies in chronic kidney disease.

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.

Discovery of DS44470011: An oral hypoxia-inducible factor prolyl hydroxylase inhibitor for the treatment of renal anemia.

Inhibition of the hypoxia-inducible factor prolyl hydroxylase (HIF-PHD) represents a promising strategy for discovering next-generation treatments for renal anemia. We identified a pyrimidine core with HIF-PHD inhibitory activity based on scaffold hopping of FG-2216 using crystal structures of HIF-PHD2 in complex with compound. By optimizing the substituents at the 2- and 6- positions of the pyrimidine core, we discovered DS44470011, which improves the effectiveness of erythropoietin (EPO) release in cells. Oral administration of DS44470011 to cynomolgus monkeys increased plasma EPO levels.

The drug-specific properties of hypoxia-inducible factor-prolyl hydroxylase inhibitors in mice reveal a significant contribution of the kidney compared to the liver to erythropoietin induction.

AIMS: Kidney disease often leads to anemia due to a defect in the renal production of the erythroid growth factor erythropoietin (EPO), which is produced under the positive regulation of hypoxia-inducible transcription factors (HIFs). Chemical compounds that inhibit HIF-prolyl hydroxylases (HIF-PHs), which suppress HIFs, have been developed to reactivate renal EPO production in renal anemia patients. Currently, multiple HIF-PH inhibitors, in addition to conventional recombinant EPO reagents, are used for renal anemia treatment. This study aimed to elucidate the therapeutic mechanisms and drug-specific properties of HIF-PH inhibitors. METHODS AND KEY FINDINGS: Gene expression analyses and mass spectrometry revealed that HIF-PH inhibitors (daprodustat, enarodustat, molidustat, and vadadustat) alter Epo gene expression levels in the kidney and liver in a drug-specific manner, with different pharmacokinetics in the plasma and urine after oral administration to mice. The drug specificity revealed the dominant contribution of EPO induction in the kidneys rather than in the liver to plasma EPO levels after HIF-PH inhibitor administration. We also found that several HIF-PH inhibitors directly induce duodenal gene expression related to iron intake, while these drugs indirectly suppress hepatic hepcidin expression to mobilize stored iron for hemoglobin synthesis through induction of the EPO-erythroferrone axis. SIGNIFICANCE: Renal EPO induction is the major target of HIF-PH inhibitors for their therapeutic effects on erythropoiesis. Additionally, the drug-specific properties of HIF-PH inhibitors in EPO induction and iron metabolism have been shown in mice, providing useful information for selecting the proper HIF-PH inhibitor for each renal anemia patient.

A retrospective study on the efficacy of Roxadustat in peritoneal dialysis patients with erythropoietin hyporesponsiveness.

BACKGROUND/AIMS: Roxadustat, an oral medication for treating renal anemia, is a hypoxia-inducible factor prolyl hydroxylase inhibitor used for regulating iron metabolism and promoting erythropoiesis. To investigate the efficacy and safety of roxadustat in patients undergoing peritoneal dialysis (PD) with erythropoietin hyporesponsiveness. METHODS: Single-center, retrospective study, 81 PD patients (with erythropoietin hyporesponsiveness) were divided into the roxadustat group (n = 61) and erythropoiesis-stimulating agents (ESAs) group (n = 20). Hemoglobin (Hb), total cholesterol, intact parathyroid hormone (iPTH), brain natriuretic peptide (BNP), related indicators of cardiac function and high-sensitivity C-reactive protein (hs-CRP) were collected. Additionally, adverse events were also recorded. The follow-up period was 16 weeks. RESULTS: The two groups exhibited similar baseline demographic and clinical characteristics. At baseline, the roxadustat group had a mean Hb level of 89.8 ± 18.9 g/L, while the ESAs group had a mean Hb level of 95.2 ± 16.0 g/L. By week 16, the Hb levels had increased to 118 ± 19.8 g/L (p < 0.05) in the roxadustat group and 101 ± 19.3 g/L (p > 0.05) in the ESAs group. The efficacy of roxadustat in improving anemia was not influenced by baseline levels of hs-CRP and iPTH. Cholesterol was decreased in the roxadustat group without statin use. An increase in left ventricular ejection fraction and stabilization of BNP were observed in the roxadustat group. CONCLUSION: For PD patients with erythropoietin hyporesponsiveness, roxadustat can significantly improve renal anemia. The efficacy of roxadustat in improving renal anemia was not affected by baseline levels of hs-CRP0 and iPTH.

Factors affecting responsiveness of vadadustat in patients with anemia associated with chronic kidney disease: a post-hoc subgroup analysis of Japanese phase 3 randomized studies.

BACKGROUND: Vadadustat is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor developed for treating anemia in chronic kidney disease (CKD). The purpose of this post-hoc analysis was to investigate the factors affecting the responsiveness to vadadustat in anemia patients with nondialysis-dependent (NDD) or hemodialysis-dependent (HDD) CKD in two Japanese phase 3 studies. METHODS: Of 151 and 162 patients enrolled in NDD-CKD and HDD-CKD studies, 136 and 140 patients, respectively, were included and divided into subgroups for the analysis. To assess vadadustat responsiveness, the resistance index was defined as the mean body weight-adjusted dose of vadadustat (mg/kg) at weeks 20-24 divided by the mean hemoglobin (g/dL) at weeks 20-24. Multivariate analysis was performed to identify the variables affecting the resistance index. RESULTS: Independent factors identified as determinants for better response to vadadustat were as follows: high baseline hemoglobin, low baseline eGFR, high week-20-24 ferritin, and CKD not caused by autoimmune disease/glomerulonephritis/vasculitis in NDD-CKD; and male sex, high baseline C-reactive protein, and low baseline erythropoiesis-stimulating agent resistance index (ERI) in HDD-CKD. CONCLUSIONS: In this post-hoc analysis, several factors were identified as affecting the response to vadadustat. These results may provide useful information leading to an appropriate dose modification for vadadustat. CLINICAL TRIAL REGISTRATION: NCT03329196 (MT-6548-J01) and NCT03439137 (MT-6548-J03).

Prolyl hydroxylase inhibitor FG-4592 alleviates neuroinflammation via HIF-1/BNIP3 signaling in microglia.

BACKGROUND: Neuroinflammation is responsible for neuropsychiatric dysfunction following acute brain injury and neurodegenerative diseases. This study describes how a hypoxia-inducible factor prolyl hydroxylase (HIF-PHD) inhibitor FG-4592 prevents the lipopolysaccharide (LPS)-induced acute neuroinflammation in microglia. METHODS: The distribution of FG-4592 in mouse brain tissues was determined by collision-induced dissociation tandem mass spectrometry. Microglial activation in the hippocampus was analyzed by immunofluorescence. Moreover, we determined the activation of HIF-1 and nuclear factor-κB (NF-κB) signaling pathways, proinflammatory responses using molecular biological techniques. Transcriptome sequencing and BNIP3 silencing were conducted to explore signaling pathway and molecular mechanisms underlying FG-4592 anti-inflammatory activity. RESULTS: FG-4592 was transported into the brain tissues and LPS increased its transportation. FG-4592 promoted the expression of HIF-1α and induced the downstream gene transcription in the hippocampus. Administration with FG-4592 significantly inhibited microglial hyperactivation and decreased proinflammatory cytokine levels following LPS treatment in the hippocampus. The LPS-induced inflammatory responses and the NF-κB signaling pathway were also downregulated by FG-4592 pretreatment in microglial cells. Mechanistically, Venn diagram analysis of transcriptomic changes of BV2 cells identified that BNIP3 was a shared and common differentially expressed gene among different treatment groups. FG-4592 markedly upregulated the protein levels of BNIP3 in microglia. Importantly, BNIP3 knockdown aggravated the LPS-stimulated inflammatory responses and partially reversed the protection of FG-4592 against microglial inflammatory signaling and microglial activation in the mouse hippocampus. CONCLUSIONS: FG-4592 alleviates neuroinflammation through facilitating microglial HIF-1/BNIP3 signaling pathway in mice. Targeting HIF-PHD/HIF-1/BNIP3 axis is a promising strategy for the development of anti-neuroinflammation drugs.

Impact of HIF prolyl hydroxylase inhibitors in heart failure patients with renal anemia.

OBJECTIVE: Hypoxia-inducible factor prolyl hydroxylase (HIF-PH) inhibitors are a new class of anti-anemia agents. We retrospectively evaluated the safety and efficacy of HIF-PH inhibitors in patients with heart failure (HF) complicated by anemia associated with chronic kidney disase. HIF-PH inhibitor treatment was initiated in 32 patients with chronic HF complicated by renal anemia and were followed up for 3 months. RESULTS: Hematocrit and hemoglobin levels markedly improved 3 months after HIF-PH inhibitor treatment. However, levels of NT-proBNP, which is an indicator of HF, did not decrease considerably. Based on the rate of change in NT-proBNP, we divided the patients into "responder" and "non-responder" groups. The results showed that considerably more patients had a ferritin level of less than 100 ng/mL in the non-responder group at baseline. There were substantially more patients with TSAT of less than 20% in the non-responder group at 1 month after HIF-PH inhibitor treatment. The cut-off values to maximize the predictive power of ferritin level at baseline and TSAT value at 1 month after treatment were 41.8 ng/ml and 20.75. HIF-PH inhibitor treatment can be expected to be effective for improving both anemia and HF if ferritin≥41.8 ng/ml at baseline or TSAT≥20.75 at 1 month after treatment.

Prolyl hydroxylase domain inhibitor is an effective pre-hospital pharmaceutical intervention for trauma and hemorrhagic shock.

Pre-hospital potentially preventable trauma related deaths are mainly due to hypoperfusion-induced tissue hypoxia leading to irreversible organ dysfunction at or near the point of injury or during transportation prior to receiving definitive therapy. The prolyl hydroxylase domain (PHD) is an oxygen sensor that regulates tissue adaptation to hypoxia by stabilizing hypoxia inducible factor (HIF). The benefit of PHD inhibitors (PHDi) in the treatment of anemia and lactatemia arises from HIF stabilization, which stimulates endogenous production of erythropoietin and activates lactate recycling through gluconeogenesis. The results of this study provide insight into the therapeutic roles of MK-8617, a pan-inhibitor of PHD-1, 2, and 3, in the mitigation of lactatemia in anesthetized rats with polytrauma and hemorrhagic shock. Additionally, in an anesthetized rat model of lethal decompensated hemorrhagic shock, acute administration of MK-8617 significantly improves one-hour survival and maintains survival at least until 4 h following limited resuscitation with whole blood (20% EBV) at one hour after hemorrhage. This study suggests that pharmaceutical interventions to inhibit prolyl hydroxylase activity can be used as a potential pre-hospital countermeasure for trauma and hemorrhage at or near the point of injury.

Zinc Supplementation Enhances the Hematopoietic Activity of Erythropoiesis-Stimulating Agents but Not Hypoxia-Inducible Factor-Prolyl Hydroxylase Inhibitors.

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.

Hypoxia-inducible Factor Prolyl Hydroxylase Inhibitors and Hypothyroidism: An Analysis of the Japanese Pharmacovigilance Database.

BACKGROUND/AIM: Hypothyroidism induced by roxadustat, a hypoxia-inducible factor prolyl hydroxylase (HIF-PH) inhibitor, was recently reported; however, information regarding roxadustat-associated hypothyroidism is still lacking. We explored the risk and time to onset of hypothyroidism associated with HIF-PH inhibitors using the Japanese Adverse Drug Event Report (JADER), a pharmacovigilance database. PATIENTS AND METHODS: The participants of this study were registered in the JADER database between April 2004 and March 2023. The association between HIF-PH inhibitors and hypothyroidism was evaluated using the reporting odds ratio (ROR) and information component (IC). We also calculated the period from the start of drug administration to the onset of hypothyroidism and determined the onset pattern using Weibull distribution. RESULTS: Roxadustat had positive signals for hypothyroidism among the HIF-PH inhibitors based on the ROR [31.03, 95% confidence interval (CI)=27.81-34.62] and IC (4.51, 95%CI=4.36-4.67) values, and a strong relationship was confirmed. In addition, the median time to roxadustat-associated hypothyroidism onset was 92 days, and over 50% of cases occurred within 100 days of starting treatment. Furthermore, the onset pattern was an early failure type. CONCLUSION: There is a possible association between roxadustat and hypothyroidism. Therefore, enhanced thyroid function testing within 100 days of treatment initiation may help detect roxadustat-associated hypothyroidism. However, further research is required to confirm these findings, considering study limitations using databases of spontaneous adverse event reports.

Cardiovascular and renal safety outcomes of hypoxia-inducible factor prolyl-hydroxylase inhibitor roxadustat for anemia patients with chronic kidney disease: a systematic review and meta-analysis.

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.

Discovery of Novel and Potent Prolyl Hydroxylase Domain-Containing Protein (PHD) Inhibitors for The Treatment of Anemia.

Stabilization of hypoxia-inducible factor (HIF) by inhibiting prolyl hydroxylase domain enzymes (PHDs) represents a breakthrough in treating anemia associated with chronic kidney disease. Here, we identified a novel scaffold for noncarboxylic PHD inhibitors by utilizing structure-based drug design (SBDD) and generative models. Iterative optimization of potency and solubility resulted in compound 15 which potently inhibits PHD thus stabilizing HIF-α in vitro. X-ray cocrystal structure confirmed the binding model was distinct from previously reported carboxylic acid PHD inhibitors by pushing away the R383 and Y303 residues resulting in a larger inner subpocket. Furthermore, compound 15 demonstrated a favorable in vitro/in vivo absorption, distribution, metabolism, and excretion (ADME) profile, low drug-drug interaction risk, and clean early safety profiling. Functionally, oral administration of compound 15 at 10 mg/kg every day (QD) mitigated anemia in a 5/6 nephrectomy rat disease model.

HIF-PHD inhibitor desidustat ameliorates iron deficiency anemia.

Iron deficiency anemia is caused by many pathological conditions like chronic kidney disease (CKD), inflammation, malnutrition and gastrointestinal abnormality. Current treatments that are erythropoiesis stimulating agents (ESAs) and iron supplementation are inadequate and often lead to tolerance and/or toxicity. Desidustat, a prolyl hydroxylase (PHD) inhibitor, is clinically used for the treatment of anemia with CKD. In this study, we investigated the effect of desidustat on iron deficiency anemia (IDA). IDA was induced in C57BL6/J mice by iron deficient diet feeding. These mice were then treated with desidustat (15 mg/kg, PO) and FeSO4 (20 mg/kg) for five weeks and effect of the treatment on hematology, iron homeostasis, and bone marrow histology was observed. Effect of desidustat on iron metabolism in inflammation (LPS)-induced iron deficiency was also assessed. Both, Desidustat and FeSO4, increased MCV (mean corpuscular volume), MCH (mean corpuscular hemoglobin), hemoglobin, and HCT (hematocrit) in blood and increased iron in serum, liver, and spleen. Desidustat increased MCHC (mean corpuscular hemoglobin concentration) while FeSO4 treatment did not alter it. FeSO4 treatment significantly increased iron deposition in liver, and spleen, while desidustat increased iron in circulation and demonstrated efficient iron utilization. Desidustat increased iron absorption, serum iron and decreased hepcidin without altering tissue iron, while FeSO4 increased serum and tissue iron by increasing hepcidin in LPS-induced iron deficiency. Desidustat increased erythroid population, especially iron-dependent polychromatic normoblasts and orthochromatic normoblasts, while FeSO4 did not improve cell architecture. PHD inhibition by desidustat improved iron utilization in iron deficiency anemia, by efficient erythropoiesis.

Efficacy of Hypoxia-Inducible Factor Prolyl Hydroxylase Inhibitor on Clinical Parameters in Patients with Heart Failure.

Background and Objectives: Hypoxia-inducible factor prolyl hydroxylase (HIF-PH) inhibitors have been approved as an oral drug for treating anemia in chronic kidney disease (CKD). However, the clinical effect of HIF-PH inhibitors in patients with heart failure (HF) is unclear. Thus, this study investigated the effect of HIF-PH inhibitors in patients with HF and CKD. Materials and Methods: Thirteen patients with HF complicated by renal anemia who were started on vadadustat were enrolled. Clinical parameters were compared before and 1 month after vadadustat was started. Results: The mean left ventricular ejection fraction was 49.8 ± 13.9%, and the mean estimated glomerular filtration rate was 29.4 ± 10.6 mL/min/1.73 m2. The hemoglobin level was significantly increased (9.7 ± 1.3 mg/dL vs. 11.3 ± 1.3 mg/dL, p < 0.001), and the N-terminal prohormone of B-type natriuretic peptide was significantly decreased after the introduction of vadadustat [4357 (2651-15182) pg/mL vs. 2367 (1719-9347) pg/mL, p = 0.002]. Furthermore, the number of patients with New York Heart Association functional class ≥ 3 was also decreased after the introduction of vadadustat [8 (61.5%) vs. 1 (7.7%), p = 0.008]. No thromboembolic adverse events or new tumors were observed in any patient during the study period. Conclusions: The introduction of vadadustat in patients with HF complicated by renal anemia led to improvements in anemia and symptoms of HF.

Tubular Endogenous Erythropoietin Protects Renal Function against Ischemic Reperfusion Injury.

Many large-scale studies show that exogenous erythropoietin, erythropoiesis-stimulating agents, lack any renoprotective effects. We investigated the effects of endogenous erythropoietin on renal function in kidney ischemic reperfusion injury (IRI) using the prolyl hydroxylase domain (PHD) inhibitor, Roxadustat (ROX). Four h of hypoxia (7% O2) and 4 h treatment by ROX prior to IRI did not improve renal function. In contrast, 24-72 h pretreatment by ROX significantly improved the decline of renal function caused by IRI. Hypoxia and 4 h ROX increased interstitial cells-derived Epo production by 75- and 6-fold, respectively, before IRI, and worked similarly to exogenous Epo. ROX treatment for 24-72 h increased Epo production during IRI by 9-fold. Immunohistochemistry revealed that 24 h ROX treatment induced Epo production in proximal and distal tubules and worked similarly to endogenous Epo. Our data show that tubular endogenous Epo production induced by 24-72 h ROX treatment results in renoprotection but peritubular exogenous Epo production by interstitial cells induced by hypoxia and 4 h ROX treatment did not. Stimulation of tubular, but not peritubular, Epo production may link to renoprotection.

Mechanistic and Clinical Comparison of the Erythropoietic Effects of SGLT2 Inhibitors and Prolyl Hydroxylase Inhibitors in Patients with Chronic Kidney Disease and Renal Anemia.

Renal anemia is treated with erythropoiesis-stimulating agents (ESAs), even though epoetin alfa and darbepoetin increase the risk of cardiovascular death and thromboembolic events, including stroke. Hypoxia-inducible factor prolyl hydroxylase domain (HIF-PHD) inhibitors have been developed as an alternative to ESAs, producing comparable increases in hemoglobin. However, in advanced chronic kidney disease, HIF-PHD inhibitors can increase the risk of cardiovascular death, heart failure, and thrombotic events to a greater extent than that with ESAs, indicating that there is a compelling need for safer alternatives. Sodium-glucose cotransporter 2 (SGLT2) inhibitors reduce the risk of major cardiovascular events, and they increase hemoglobin, an effect that is related to an increase in erythropoietin and an expansion in red blood cell mass. SGLT2 inhibitors increase hemoglobin by ≈0.6-0.7 g/dL, resulting in the alleviation of anemia in many patients. The magnitude of this effect is comparable to that seen with low-to-medium doses of HIF-PHD inhibitors, and it is apparent even in advanced chronic kidney disease. Interestingly, HIF-PHD inhibitors act by interfering with the prolyl hydroxylases that degrade both HIF-1α and HIF-2α, thus enhancing both isoforms. However, HIF-2α is the physiological stimulus to the production of erythropoietin, and upregulation of HIF-1α may be an unnecessary ancillary property of HIF-PHD inhibitors, which may have adverse cardiac and vascular consequences. In contrast, SGLT2 inhibitors act to selectively increase HIF-2α, while downregulating HIF-1α, a distinctive profile that may contribute to their cardiorenal benefits. Intriguingly, for both HIF-PHD and SGLT2 inhibitors, the liver is likely to be an important site of increased erythropoietin production, recapitulating the fetal phenotype. These observations suggest that the use of SGLT2 inhibitors should be seriously evaluated as a therapeutic approach to treat renal anemia, yielding less cardiovascular risk than other therapeutic options.

Hypoxia-inducible factor-prolyl hydroxylase inhibitor Roxadustat (FG-4592) reduces renal fibrosis in Dahl salt-sensitive rats.

OBJECTIVE: Although hypoxia-inducible factor-prolyl hydroxylase (HIF-PH) inhibitors have been developed for the treatment of renal anemia, their effects on cardiac and renal dysfunction remain unknown. We previously reported on Dahl salt-sensitive rats, in a rat model of salt-sensitive hypertension, that exhibited anemia and impaired expression of duodenal iron transporters after the development of hypertensive cardiac and renal dysfunction. Therefore, we investigated the effects of Roxadustat (FG-4592), an HIF-PH inhibitor, on anemia, iron regulation, and cardiac and renal dysfunction in Dahl salt-sensitive rats. METHODS: Six-week-old male Dahl salt-sensitive rats were fed a normal or high-salt diet for 8 weeks. A further subset of Dahl salt-sensitive rats, that were fed a high-salt diet, was administered Roxadustat for 8 weeks. RESULTS: Dahl salt-sensitive rats fed a high-salt diet developed hypertension, cardiac and renal dysfunction, and anemia after 8 weeks of feeding. Roxadustat increased hemoglobin and serum erythropoietin levels in Dahl salt-sensitive rats fed a high-salt diet. With regard to the iron-regulating system, Roxadustat lowered hepatic hepcidin gene expression and increased the gene expression of duodenal iron transporters, such as cytochrome b and divalent metal transporter 1 , in Dahl salt-sensitive rats fed a high-salt diet. Roxadustat did not affect the development of hypertension and cardiac hypertrophy in Dahl salt-sensitive rats with a high-salt diet; however, Roxadustat treatment attenuated renal fibrosis in these rats. CONCLUSIONS: Roxadustat ameliorated anemia with affecting the gene expression of the iron-regulating system, and did not affect cardiac hypertrophy but attenuated renal fibrosis in Dahl salt-sensitive rats fed a high-salt diet.

Use of molidustat, a hypoxia-inducible factor prolyl hydroxylase inhibitor, in chronic kidney disease-associated anemia in cats.

BACKGROUND: Erythropoietic effects of molidustat, a hypoxia-inducible factor prolyl hydroxylase (HIF-PH) inhibitor, were previously demonstrated in healthy cats. OBJECTIVE: To evaluate the safety and erythropoietic effects of daily PO administration of molidustat in anemic cats with chronic kidney disease (CKD). ANIMALS: Twenty-one client-owned CKD cats (4-17 years old) with anemia. METHODS: Multicenter field study; randomized, masked, and placebo-controlled. Cats were treated PO once daily for 28 days with suspensions of control product (CP; n = 6) or 5 mg/kg of molidustat (n = 15). Hematocrit (HCT) was evaluated at weekly intervals. Individual cat treatment success was defined as a ≥4% point increase in HCT compared to baseline. RESULTS: Control group mean HCT remained low throughout the study (20.1%-23.4%). Mean HCT of molidustat-treated cats increased weekly, and a significant increase compared to baseline (23.6%) was first observed on Day 21 (27.3%; P < .001; 95% confidence interval [CI], 1.69-5.67). Compared to CP group, mean HCT was significantly higher on Day 21 (27.3% vs 20.1%; P < .001; 95% CI, 2.91-10.75) but not significantly higher on Day 28 (27.8% vs 23.4%; P = .06; 95% CI, -0.23 to 9.88). The number of individual treatment successes on Day 28 was higher among remaining molidustat-treated cats (7/14) compared to remaining control cats (1/5), but there was no significant difference between groups. CONCLUSIONS AND CLINICAL IMPORTANCE: Daily PO molidustat administration may stimulate a clinically relevant erythropoietic response in anemic cats with CKD. This HIF-PH inhibitor may be an alternative for managing anemia in cats compared to recombinant EPO treatment.

[New Therapeutic Strategies in the Treatment of CKD Anemia: Hypoxia-Induced Factor Prolyl-Hydroxylase Inhibitors].

The link between chronic renal failure and anemia has been known for more than 180 years, negatively impacting the quality of life, cardiovascular risk, mortality, and morbidity of patients with chronic kidney disease (CKD). Traditionally, the management of anemia in CKD has been based on the use of replacement martial therapy, vitamin therapy, and the use of erythropoiesis-stimulating agents (ESAs). In recent years, alongside these consolidated therapies, new molecules known as hypoxia-induced factor prolyl-hydroxylase inhibitors (HIF-PHIs) have appeared. The mechanism of action is expressed through an increased transcriptional activity of the HIF gene with increased erythropoietin production. The drugs currently produced are roxadustat, daprodustat, vadadustat, molidustat, desidustat, and enarodustat; among these only roxadustat is currently approved and usable in Italy. The possibility of oral intake, pleiotropic activity on martial and lipidic metabolism, and the non-inferiority compared to erythropoietins make these drugs a valid alternative to the treatment of anemia associated with chronic kidney disease in the nephrologist practice.