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Gao Z, Gao Y, Wang Q, Wang Q, Lu P, Lv H, Xue H, Ma X, Li S, Hu Z. Study on HIF-PHI combined with iron supplement in treatment of renal anemia in rats. BMC Nephrol 2025; 26:125. [PMID: 40050784 PMCID: PMC11887227 DOI: 10.1186/s12882-025-04045-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2024] [Accepted: 02/25/2025] [Indexed: 03/09/2025] Open
Abstract
BACKGROUND 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. OBJECTIVES 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. MATERIALS AND METHODS 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. RESULTS 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). CONCLUSIONS 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.
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Affiliation(s)
- Zhaoli Gao
- Department of Nephrology, Qilu Hospital of Shandong University (Qingdao), 758 Hefei Road, Qingdao, Shandong, 266035, China
| | - Yanxia Gao
- Department of Nephrology, Qilu Hospital of Shandong University (Qingdao), 758 Hefei Road, Qingdao, Shandong, 266035, China
| | - Qiang Wang
- Department of Nephrology, Qilu Hospital of Shandong University (Qingdao), 758 Hefei Road, Qingdao, Shandong, 266035, China
| | - Qi Wang
- Department of Nephrology, Qilu Hospital of Shandong University (Qingdao), 758 Hefei Road, Qingdao, Shandong, 266035, China
| | - Peng Lu
- Department of Nephrology, Qilu Hospital of Shandong University (Qingdao), 758 Hefei Road, Qingdao, Shandong, 266035, China
| | - Hailin Lv
- Department of Nephrology, Qilu Hospital of Shandong University (Qingdao), 758 Hefei Road, Qingdao, Shandong, 266035, China
| | - Haoran Xue
- Department of Medicine Experimental Center, Qilu Hospital of Shandong University (Qingdao), 758 Hefei Road, Qingdao, Shandong, 266035, China
| | - Xiaotian Ma
- Department of Medicine Experimental Center, Qilu Hospital of Shandong University (Qingdao), 758 Hefei Road, Qingdao, Shandong, 266035, China
| | - Shuen Li
- Department of Pathology, Qilu Hospital of Shandong University (Qingdao), 758 Hefei Road, Qingdao, Shandong, 266035, China
| | - Zhao Hu
- Department of Nephrology, Qilu Hospital of Shandong University, 107 Wenhuaxi Road, Jinan, Shandong, 250012, P.R. China.
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Virtanen N, Saarela U, Karpale M, Arffman RK, Mäkelä KA, Herzig KH, Koivunen P, Piltonen T. Roxadustat alleviates metabolic traits in letrozole-induced PCOS mice. Biochem Pharmacol 2024; 229:116522. [PMID: 39245394 DOI: 10.1016/j.bcp.2024.116522] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2024] [Revised: 08/02/2024] [Accepted: 09/05/2024] [Indexed: 09/10/2024]
Abstract
Polycystic ovary syndrome (PCOS) is a highly prevalent disorder in women that is commonly accompanied by metabolic syndrome. Activation of the hypoxia-inducible factor (HIF) pathway is known to alleviate metabolic defects. Hence, this study utilized a preclinical PCOS mouse model to investigate the effects of chemically induced HIF activation on the metabolic traits of PCOS. Prepubertal letrozole treatment was used to generate a PCOS mouse model in the C57Bl6/J strain, and PCOS mice were orally treated with vehicle or roxadustat for six weeks from age 12 weeks onwards to induce HIF activation. Although the PCOS mice showed impaired glucose tolerance, increased insulin resistance, elevated blood lipids, and reduced muscle glycogen content, there was no difference in histological evaluations of white adipose tissue (WAT) or liver or in organ weights. Roxadustat treatment resulted in significant improvement in glucose tolerance (27 % reduction in area under the curve (AUC) values, p < 0.0001), fasting glucose levels (4.59 ± 0.83 mmol/l vs 3.05 ± 0.62 mmol/l, p < 0.0001) and insulin resistance (46 % reduction in homeostasis model assessment-insulin resistance (HOMA-IR) values, 6.76 ± 3.72 vs 3.64 ± 2.44, p = 0.019) compared to vehicle-treated mice without altering the body weight. Gene expression analyses with real-time quantitative polymerase chain reaction (RT-qPCR) and RNA sequencing revealed significant differences in gene expression in the tissues of PCOS mice compared to control mice, whereas the transcriptomic effects of roxadustat were mainly transient. However, immunohistochemistry revealed increased uncoupling protein 1 (UCP1) expression in WAT, which may indicate WAT browning related to HIF pathway activation.
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Affiliation(s)
- Nikke Virtanen
- Department of Obstetrics and Gynecology, Medical Research Centre, Research Unit of Clinical Medicine, University of Oulu, Oulu University Hospital, Oulu, Finland; Research Unit of Extracellular Matrix and Hypoxia, Biocenter Oulu, Faculty of Biochemistry and Molecular Medicine, Oulu Center for Cell-Matrix Research, University of Oulu, Oulu, Finland
| | - Ulla Saarela
- Department of Obstetrics and Gynecology, Medical Research Centre, Research Unit of Clinical Medicine, University of Oulu, Oulu University Hospital, Oulu, Finland
| | - Mikko Karpale
- Research Unit of Extracellular Matrix and Hypoxia, Biocenter Oulu, Faculty of Biochemistry and Molecular Medicine, Oulu Center for Cell-Matrix Research, University of Oulu, Oulu, Finland
| | - Riikka K Arffman
- Department of Obstetrics and Gynecology, Medical Research Centre, Research Unit of Clinical Medicine, University of Oulu, Oulu University Hospital, Oulu, Finland
| | - Kari A Mäkelä
- Research Unit of Biomedicine and Internal Medicine, Biocenter Oulu, Medical Research Center, Oulu University Hospital, University of Oulu, Oulu, Finland
| | - Karl-Heinz Herzig
- Research Unit of Biomedicine and Internal Medicine, Biocenter Oulu, Medical Research Center, Oulu University Hospital, University of Oulu, Oulu, Finland; Department of Gastroenterology and Metabolism, Poznan University of Medical Sciences, Poznan, Poland
| | - Peppi Koivunen
- Research Unit of Extracellular Matrix and Hypoxia, Biocenter Oulu, Faculty of Biochemistry and Molecular Medicine, Oulu Center for Cell-Matrix Research, University of Oulu, Oulu, Finland
| | - Terhi Piltonen
- Department of Obstetrics and Gynecology, Medical Research Centre, Research Unit of Clinical Medicine, University of Oulu, Oulu University Hospital, Oulu, Finland.
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Zhong JJ, Wang ML, Zheng GF, Li MP, Chen DZ. The clinical efficacy of combined ESA and Roxadustat treatment for renal anemia in hemodialysis patients with secondary hyperparathyroidism: A case series. Medicine (Baltimore) 2024; 103:e39083. [PMID: 39151521 PMCID: PMC11332787 DOI: 10.1097/md.0000000000039083] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/12/2024] [Revised: 07/02/2024] [Accepted: 07/04/2024] [Indexed: 08/19/2024] Open
Abstract
RATIONALE Pharmacological mechanism of Roxadustat in the treatment of renal anemia. PATIENT CONCERNS To investigate the efficacy and safety of combined Roxadustat and erythropoiesis stimulator (ESA) treatment of renal anemia in hemodialysis patients with secondary hyperparathyroidism. DIAGNOSES A retrospective analysis was conducted on hemodialysis patients with renal anemia and secondary hyperparathyroidism treated with ESAs alone, who were admitted to our hospital from March 2022 to December 2022. INTERVENTIONS The patients were treated with Roxadustat combined with ESAs for 3 months, during which oral iron supplementation was given, and the changes in Hb levels and laboratory-related indicators before and after the combined treatment were analyzed. OUTCOMES The results showed that a total of 13 patients received combination therapy, with a significant increase in Hb compared to ESAs alone (t = -3.955, P = .002). The Hb qualification rate was 38.46%, and the ∆Hb response rate was 76.92%. The parathyroid hormone significantly decreased with a statistically significant difference (Z = -2.062b, P = .039). Hemoglobin (RBC), total iron binding capacity, and serum ferritin (male) were significantly increased compared to ESAs alone. Total cholesterol and low-density lipoprotein were significantly lower than ESAs alone. The differences in the changes in the above indicators were statistically significant (P < .05). There was no statistically significant difference in changes in other laboratory-related indicators (P > .05). No adverse reactions were observed during the combined treatment of 13 patients. LESSONS SUBSECTIONS The combination of Roxadustat and ESAs can effectively improve renal anemia in hemodialysis patients with secondary hyperparathyroidism, as well as improve indicators of hyperparathyroidism and blood lipid levels with high levels of safety. This combined treatment thus provides a new and safe treatment method for these patients.
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Affiliation(s)
- Jing-jing Zhong
- Department of pharmacy, The People’s Hospital of JianYang City, Jianyang, Sichuan, China
| | - Ming-li Wang
- Department of pharmacy, The People’s Hospital of JianYang City, Jianyang, Sichuan, China
| | - Gao-feng Zheng
- Department of pharmacy, The People’s Hospital of JianYang City, Jianyang, Sichuan, China
| | - Ming-peng Li
- Department of pharmacy, The People’s Hospital of JianYang City, Jianyang, Sichuan, China
| | - De-zheng Chen
- Department of pharmacy, The People’s Hospital of JianYang City, Jianyang, Sichuan, China
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Akbarian M, Kianpour M, Tayebi L. Fabricating Multiphasic Angiogenic Scaffolds Using Amyloid/Roxadustat-Assisted High-Temperature Protein Printing. ACS APPLIED MATERIALS & INTERFACES 2024; 16:36983-37006. [PMID: 38953207 DOI: 10.1021/acsami.4c06207] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/03/2024]
Abstract
Repairing multiphasic defects is cumbersome. This study presents new soft and hard scaffold designs aimed at facilitating the regeneration of multiphasic defects by enhancing angiogenesis and improving cell attachment. Here, the nonimmunogenic, nontoxic, and cost-effective human serum albumin (HSA) fibril (HSA-F) was used to fabricate thermostable (up to 90 °C) and hard printable polymers. Additionally, using a 10.0 mg/mL HSA-F, an innovative hydrogel was synthesized in a mixture with 2.0% chitosan-conjugated arginine, which can gel in a cell-friendly and pH physiological environment (pH 7.4). The presence of HSA-F in both hard and soft scaffolds led to an increase in significant attachment of the scaffolds to the human periodontal ligament fibroblast (PDLF), human umbilical vein endothelial cell (HUVEC), and human osteoblast. Further studies showed that migration (up to 157%), proliferation (up to 400%), and metabolism (up to 210%) of these cells have also improved in the direction of tissue repair. By examining different in vitro and ex ovo experiments, we observed that the final multiphasic scaffold can increase blood vessel density in the process of per-vascularization as well as angiogenesis. By providing a coculture environment including PDLF and HUVEC, important cross-talk between these two cells prevails in the presence of roxadustat drug, a proangiogenic in this study. In vitro and ex ovo results demonstrated significant enhancements in the angiogenic response and cell attachment, indicating the effectiveness of the proposed design. This approach holds promise for the regeneration of complex tissue defects by providing a conducive environment for vascularization and cellular integration, thus promoting tissue healing.
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Affiliation(s)
- Mohsen Akbarian
- Marquette University School of Dentistry, Milwaukee, Wisconsin 53233, United States
| | - Maryam Kianpour
- Marquette University School of Dentistry, Milwaukee, Wisconsin 53233, United States
| | - Lobat Tayebi
- Marquette University School of Dentistry, Milwaukee, Wisconsin 53233, United States
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Yang Y, Chen Y, Yang Y, Bai H, He B, Liu D. Compassionate use of roxadustat for treatment of refractory renal anemia in an infant. Pediatr Nephrol 2024; 39:911-914. [PMID: 38086983 PMCID: PMC10817834 DOI: 10.1007/s00467-023-06240-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/31/2023] [Revised: 11/18/2023] [Accepted: 11/20/2023] [Indexed: 01/27/2024]
Abstract
BACKGROUND Erythropoiesis-stimulating agents (ESAs) have played an important role in the treatment of renal anemia in children, but cannot improve hemoglobin to target level in some cases. Roxadustat, a hypoxia-inducible factor prolyl hydroxylase inhibitor, can stimulate endogenous erythropoietin production and regulate iron metabolism even in patients with kidney failure. However, roxadustat has not yet been approved for use in children. CASE-DIAGNOSIS/TREATMENT We report a case of refractory renal anemia in an 80-day-old boy, who was hyporesponsive to ESAs even in combination with iron supplementation and transfusion. Compassionate use of roxadustat successfully corrected the intractable anemia. Hyperkalemia is a manageable adverse event of concern during follow-up. CONCLUSION The successful experience in this case may inform the clinical utility of roxadustat for refractory renal anemia in children, which should be further confirmed by well-designed prospective clinical trials.
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Affiliation(s)
- Yan Yang
- Department of Pediatrics, The First Affiliated Hospital of Xiamen University, Xiamen, Fujian, China
- Pediatric Key Laboratory of Xiamen, Xiamen, Fujian, China
- Institute of Pediatrics, School of Medicine, Xiamen University, Xiamen, Fujian, China
| | - Yan Chen
- Department of Pediatrics, The First Affiliated Hospital of Xiamen University, Xiamen, Fujian, China
- Pediatric Key Laboratory of Xiamen, Xiamen, Fujian, China
- Institute of Pediatrics, School of Medicine, Xiamen University, Xiamen, Fujian, China
| | - Yang Yang
- Department of Pediatrics, The First Affiliated Hospital of Xiamen University, Xiamen, Fujian, China
- Pediatric Key Laboratory of Xiamen, Xiamen, Fujian, China
- Institute of Pediatrics, School of Medicine, Xiamen University, Xiamen, Fujian, China
| | - Haitao Bai
- Department of Pediatrics, The First Affiliated Hospital of Xiamen University, Xiamen, Fujian, China.
- Pediatric Key Laboratory of Xiamen, Xiamen, Fujian, China.
- Institute of Pediatrics, School of Medicine, Xiamen University, Xiamen, Fujian, China.
| | - Bizi He
- Department of Pediatrics, The First Affiliated Hospital of Xiamen University, Xiamen, Fujian, China
- Pediatric Key Laboratory of Xiamen, Xiamen, Fujian, China
- Institute of Pediatrics, School of Medicine, Xiamen University, Xiamen, Fujian, China
| | - Dengli Liu
- Department of Pediatrics, The First Affiliated Hospital of Xiamen University, Xiamen, Fujian, China
- Pediatric Key Laboratory of Xiamen, Xiamen, Fujian, China
- Institute of Pediatrics, School of Medicine, Xiamen University, Xiamen, Fujian, China
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Ren S, Yao X, Li Y, Zhang Y, Tong C, Feng Y. Efficacy and safety of hypoxia-inducible factor-prolyl hydroxylase inhibitor treatment for anemia in chronic kidney disease: an umbrella review of meta-analyses. Front Pharmacol 2023; 14:1296702. [PMID: 38099145 PMCID: PMC10720324 DOI: 10.3389/fphar.2023.1296702] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2023] [Accepted: 11/20/2023] [Indexed: 12/17/2023] Open
Abstract
The objective was to provide a comprehensive summary of existing evidence on the efficacy and safety of hypoxia-inducible factor-prolyl hydroxylase inhibitors (HIF-PHIs) for the treatment of anemia in chronic kidney disease (CKD). A systematic search was conducted in the Medline, Embase, and Cochrane databases. Only meta-analyses that evaluated the efficacy and safety of HIF-PHI treatment for anemia in CKD were included. The efficacy outcomes included hemoglobin levels and iron metabolism indices, while the safety outcomes were assessed by examining adverse events. The qualities of methodologies and evidence were assessed using the AMSTAR 2 system and the NutriGrade tool, respectively. Fourteen meta-analyses, comprising 105 distinct comparisons, were included. The comparisons were backed by evidence of high, moderate, and low levels, distributed in approximately equal proportions. None of the studies were deemed to possess a high level of confidence. In both the overall and individual treatment groups of HIF-PHI, there was an increase in the levels of hemoglobin, transferrin, and transferrin saturation, while the levels of hepcidin and total iron binding capacity decreased. Serum ferritin exhibited a reduction to some extent, while serum iron did not show significant alterations following HIF-PHI treatments. There were no notable disparities in safety outcomes between the HIF-PHI and erythropoietin stimulating agents or placebo groups. This umbrella review suggests that HIF-PHI treatment can effectively increase hemoglobin levels in CKD patients and enhance iron metabolism by decreasing hepcidin levels and improving iron transport. The safety profiles of HIF-PHIs were generally comparable to those of ESA therapies or placebos.
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Affiliation(s)
- Song Ren
- Department of Nephrology, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, China
| | - Xiaoxiu Yao
- Department of Health Management, Damian Honghe Community Health Service Center of Longquanyi District, Chengdu, China
| | - Yi Li
- Department of Nephrology, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, China
| | - Ying Zhang
- Department of Ophthalmology, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, China
| | - Chao Tong
- State Key Laboratory of Maternal and Fetal Medicine of Chongqing Municipality, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Yunlin Feng
- Department of Nephrology, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, China
- Renal Division, The George Institute for Global Health, University of New South Wales, Sydney, NSW, Australia
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Chen D, Niu Y, Liu F, Yang Y, Wang X, Li P, Chen X. Safety of HIF prolyl hydroxylase inhibitors for anemia in dialysis patients: a systematic review and network meta-analysis. Front Pharmacol 2023; 14:1163908. [PMID: 37292157 PMCID: PMC10244523 DOI: 10.3389/fphar.2023.1163908] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2023] [Accepted: 05/09/2023] [Indexed: 06/10/2023] Open
Abstract
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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Affiliation(s)
- Dinghua Chen
- Department of Nephrology, First Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Yue Niu
- Department of Nephrology, First Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Fei Liu
- Department of Urology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yue Yang
- Department of Nephrology, First Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Xue Wang
- Department of Nephrology, First Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Ping Li
- Department of Nephrology, First Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Xiangmei Chen
- Department of Nephrology, First Medical Center of Chinese PLA General Hospital, Beijing, China
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Chen J, Shou X, Xu Y, Jin L, Zhu C, Ye X, Mei Z, Chen P. A network meta-analysis of the efficacy of hypoxia-inducible factor prolyl-hydroxylase inhibitors in dialysis chronic kidney disease. Aging (Albany NY) 2023; 15:2237-2274. [PMID: 36988549 PMCID: PMC10085583 DOI: 10.18632/aging.204611] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2023] [Accepted: 03/11/2023] [Indexed: 03/29/2023]
Abstract
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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Affiliation(s)
- Jun Chen
- Zhejiang Chinese Medical University, First Clinical Medical College, Hangzhou, Zhejiang 310000, China
| | - Xinyang Shou
- Zhejiang Chinese Medical University, First Clinical Medical College, Hangzhou, Zhejiang 310000, China
| | - Yanyan Xu
- Department of Pharmaceutical, Lishui Municipal Central Hospital, The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui, Zhejiang 323000, China
| | - Lie Jin
- Department of Nephrology, Lishui Municipal Central Hospital, The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui, Zhejiang 323000, China
| | - Chaoyong Zhu
- Department of Nephrology, Lishui Municipal Central Hospital, The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui, Zhejiang 323000, China
| | - Xiaolan Ye
- Department of Pharmaceutical, Zhejiang Provincial People’s Hospital, Hangzhou, Zhejiang 310000, China
| | - Ziwei Mei
- Department of Pharmaceutical, Lishui Municipal Central Hospital, The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui, Zhejiang 323000, China
| | - Peipei Chen
- Department of Pharmaceutical, Lishui Municipal Central Hospital, The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui, Zhejiang 323000, China
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Liu J, Yang F, Waheed Y, Li S, Liu K, Zhou X. The role of roxadustat in chronic kidney disease patients complicated with anemia. Korean J Intern Med 2023; 38:147-156. [PMID: 36588451 PMCID: PMC9993099 DOI: 10.3904/kjim.2022.318] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/12/2022] [Accepted: 12/13/2022] [Indexed: 01/03/2023] Open
Abstract
The incidence of chronic kidney disease (CKD) is increasing worldwide and the current prevalence rate is 13.4%. There are > 120 million CKD patients in China and this number is expected to increase. One of the main abnormalities in patients with CKD and kidney impairment is decreased synthesis of erythropoietin (EPO), which causes anemia and affects iron metabolism. The probability of developing is higher in anemia patients with CKD than in the general population, and the incidence increases as kidney function decreases. Deficient EPO production by the kidney is the most important cause of renal anemia. Notably, anemia in patients with CKD has multiple causes, such as bleeding caused by platelet dysfunction, iron deficiency due to digestive and absorption disorders of the gastrointestinal tract, and shorter red blood cell life. Anemia is also a leading cause of hospitalization in patients with CKD. A new oral medication to treat renal anemia, the hypoxia-inducible factor prolyl hydroxylase inhibitor called roxadustat (FG-4592), regulates iron metabolism and promotes erythropoiesis. This drug has a therapeutic effect on patients with CKD. Roxadustat showed advantages over EPO in clinical experiments. This review summarizes the mechanisms of action, clinical applications, effectiveness, and safety of roxadustat.
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Affiliation(s)
- Jie Liu
- Department of Nephrology, The Second Affiliated Hospital of Xuzhou Medical University, Xuzhou,
China
| | - Fan Yang
- Department of Nephrology, Beijing Aerospace General Hospital, Beijing,
China
| | - Yousuf Waheed
- Department of Nephrology, Affiliated Hospital of Xuzhou Medical University, Xuzhou,
China
| | - Shulin Li
- Department of Nephrology, Affiliated Hospital of Xuzhou Medical University, Xuzhou,
China
| | - Kun Liu
- Department of Nephrology, The Second Affiliated Hospital of Xuzhou Medical University, Xuzhou,
China
| | - Xinglei Zhou
- Department of Nephrology, The Second Affiliated Hospital of Xuzhou Medical University, Xuzhou,
China
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10
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Fang T, Ma C, Zhang Z, Sun L, Zheng N. Roxadustat, a HIF-PHD inhibitor with exploitable potential on diabetes-related complications. Front Pharmacol 2023; 14:1088288. [PMID: 36843948 PMCID: PMC9950780 DOI: 10.3389/fphar.2023.1088288] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2022] [Accepted: 01/26/2023] [Indexed: 02/12/2023] Open
Abstract
Diabetes mellitus (DM) is a group of metabolic diseases caused by absolute or relative deficiency of insulin secretion and characterized by chronic hyperglycemia. Its complications affect almost every tissue of the body, usually leading to blindness, renal failure, amputation, etc. and in the final stage, it mostly develops into cardiac failure, which is the main reason why diabetes mellitus manifests itself as a high clinical lethality. The pathogenesis of diabetes mellitus and its complications involves various pathological processes including excessive production of mitochondrial reactive oxygen species (ROS) and metabolic imbalance. Hypoxia-inducible Factor (HIF) signaling pathway plays an important role in both of the above processes. Roxadustat is an activator of Hypoxia-inducible Factor-1α, which increases the transcriptional activity of Hypoxia-inducible Factor-1α by inhibiting hypoxia-inducible factor prolyl hydroxylase (HIF-PHD). Roxadustat showed regulatory effects on maintaining metabolic stability in the hypoxic state of the body by activating many downstream signaling pathways such as vascular endothelial growth factor (VEGF), glucose transporter protein-1 (GLUT1), lactate dehydrogenase (LDHA), etc. This review summarizes the current research findings of roxadustat on the diseases of cardiomyopathy, nephropathy, retinal damage and impaired wound healing, which also occur at different stages of diabetes and greatly contribute to the damage caused by diabetes to the organism. We attempts to uncover a more comprehensive picture of the therapeutic effects of roxadustat, and inform its expanding research about diabetic complications treatment.
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Affiliation(s)
- Tingting Fang
- Department of Pathophysiology, College of Basic Medical Science, China Medical University, Shenyang, Liaoning, China
| | - Congcong Ma
- Department of Pathophysiology, College of Basic Medical Science, China Medical University, Shenyang, Liaoning, China
| | - Zhanming Zhang
- Pharmaceutical Sciences, China Medical University-The Queen’s University of Belfast Joint College, Shenyang, Liaoning, China
| | - Luning Sun
- Department of Pathophysiology, College of Basic Medical Science, China Medical University, Shenyang, Liaoning, China
| | - Ningning Zheng
- Department of Pathophysiology, College of Basic Medical Science, China Medical University, Shenyang, Liaoning, China,*Correspondence: Ningning Zheng,
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11
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Future perspectives of anemia management in chronic kidney disease using hypoxia-inducible factor-prolyl hydroxylase inhibitors. Pharmacol Ther 2022; 239:108272. [DOI: 10.1016/j.pharmthera.2022.108272] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2022] [Revised: 08/07/2022] [Accepted: 08/22/2022] [Indexed: 11/23/2022]
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12
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Zhu X, Jiang L, Wei X, Long M, Du Y. Roxadustat: Not just for anemia. Front Pharmacol 2022; 13:971795. [PMID: 36105189 PMCID: PMC9465375 DOI: 10.3389/fphar.2022.971795] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2022] [Accepted: 08/12/2022] [Indexed: 11/13/2022] Open
Abstract
Roxadustat is a recently approved hypoxia-inducible factor prolyl hydroxylase inhibitor that has demonstrated favorable safety and efficacy in the treatment of renal anemia. Recent studies found it also has potential for the treatment of other hypoxia-related diseases. Although clinical studies have not yet found significant adverse or off-target effects of roxadustat, clinicians must be vigilant about these possible effects. Hypoxia-inducible factor regulates the expression of many genes and physiological processes in response to a decreased level of oxygen, but its role in the pathogenesis of different diseases is complex and controversial. In addition to increasing the expression of hypoxia-inducible factor, roxadustat also has some effects that may be HIF-independent, indicating some potential off-target effects. This article reviews the pharmacological characteristics of roxadustat, its current status in the treatment of renal anemia, and its possible effects on other pathological mechanisms.
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Affiliation(s)
- Xiaoyu Zhu
- Department of Nephrology, The First Hospital of Jilin University, Changchun, Jilin, China
| | - Lili Jiang
- Physical Examination Center, The First Hospital of Jilin University, Changchun, Jilin, China
| | - Xuejiao Wei
- Department of Nephrology, The First Hospital of Jilin University, Changchun, Jilin, China
| | - Mengtuan Long
- Department of Nephrology, The First Hospital of Jilin University, Changchun, Jilin, China
| | - Yujun Du
- Department of Nephrology, The First Hospital of Jilin University, Changchun, Jilin, China
- *Correspondence: Yujun Du,
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13
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Roxadustat regulates iron metabolism in dialysis-dependent and non-dialysis-dependent chronic kidney disease patients: A meta-analysis. J Formos Med Assoc 2022; 121:2288-2299. [PMID: 35871036 DOI: 10.1016/j.jfma.2022.06.008] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2022] [Revised: 06/03/2022] [Accepted: 06/15/2022] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND/PURPOSE The effect of roxadustat on iron homeostasis in patients with chronic kidney disease (CKD) is unclear. This study aimed to evaluate the efficacy of roxadustat for the treatment of iron metabolism disorders in dialysis-dependent (DD) and non-dialysis-dependent (NDD) CKD patients. METHODS We searched the PubMed, Embase, China National Knowledge Internet and Web of Science databases for randomized controlled trials (RCTs). The primary outcomes were changes in serum iron, total iron binding capacity (TIBC), transferrin saturation (TSAT), ferritin, transferrin, and hepcidin. The secondary outcomes included the changes in hemoglobin (Hb) and the incidences of adverse events (AEs) and severe adverse events (SAEs). RESULTS Twelve RCTs comprising 4976 participants were included. Compared to the control group, increases in the serum iron (SMD = 0.21, 95% CI: 0.15 to 0.27, P < 0.00001), TIBC (SMD = 1.02, 95% CI: 0.82 to 1.22, P < 0.00001) and transferrin levels (WMD = 0.55, 95% CI: 0.41 to 0.69, P < 0.00001) were found in the roxadustat group. Compared to the control group, decreases in the ferritin levels (WMD = -37.82, 95% CI: -59.89 to -15.74, P = 0.0008) and hepcidin levels (WMD = -24.04, 95% CI: -36.28 to -11.79, P = 0.0001) were observed in the roxadustat group. The meta-analysis showed that roxadustat significantly increases Hb levels (WMD = 0.77, 95% CI: 0.42 to 1.12, P < 0.0001). The incidences of AEs and SAEs in the roxadustat group was significantly higher than that in the control group (RR = 1.03, 95% CI: 1.00 to 1.07, P = 0.04; RR = 1.08, 95% CI: 1.00 to 1.15, P = 0.04). CONCLUSION Our findings suggest that roxadustat could effectively improve iron metabolism in patients with CKD.
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14
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Affiliation(s)
- Ondřej Píša
- Zentiva k.s., U kabelovny 130, 102 00 Prague, Czech Republic
| | - Stanislav Rádl
- Zentiva k.s., U kabelovny 130, 102 00 Prague, Czech Republic
| | - Igor Čerňa
- Zentiva k.s., U kabelovny 130, 102 00 Prague, Czech Republic
| | - Filip Šembera
- Zentiva k.s., U kabelovny 130, 102 00 Prague, Czech Republic
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15
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Miao M, Wu M, Li Y, Zhang L, Jin Q, Fan J, Xu X, Gu R, Hao H, Zhang A, Jia Z. Clinical Potential of Hypoxia Inducible Factors Prolyl Hydroxylase Inhibitors in Treating Nonanemic Diseases. Front Pharmacol 2022; 13:837249. [PMID: 35281917 PMCID: PMC8908211 DOI: 10.3389/fphar.2022.837249] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2021] [Accepted: 01/19/2022] [Indexed: 12/19/2022] Open
Abstract
Hypoxia inducible factors (HIFs) and their regulatory hydroxylases the prolyl hydroxylase domain enzymes (PHDs) are the key mediators of the cellular response to hypoxia. HIFs are normally hydroxylated by PHDs and degraded, while under hypoxia, PHDs are suppressed, allowing HIF-α to accumulate and transactivate multiple target genes, including erythropoiesis, and genes participate in angiogenesis, iron metabolism, glycolysis, glucose transport, cell proliferation, survival, and so on. Aiming at stimulating HIFs, a group of small molecules antagonizing HIF-PHDs have been developed. Of these HIF-PHDs inhibitors (HIF-PHIs), roxadustat (FG-4592), daprodustat (GSK-1278863), vadadustat (AKB-6548), molidustat (BAY 85-3934) and enarodustat (JTZ-951) are approved for clinical usage or have progressed into clinical trials for chronic kidney disease (CKD) anemia treatment, based on their activation effect on erythropoiesis and iron metabolism. Since HIFs are involved in many physiological and pathological conditions, efforts have been made to extend the potential usage of HIF-PHIs beyond anemia. This paper reviewed the progress of preclinical and clinical research on clinically available HIF-PHIs in pathological conditions other than CKD anemia.
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Affiliation(s)
- Mengqiu Miao
- Department of Nephrology, Children's Hospital of Nanjing Medical University, Nanjing, China.,Nanjing Key Laboratory of Pediatrics, Children's Hospital of Nanjing Medical University, Nanjing, China.,Jiangsu Key Laboratory of Pediatrics, Nanjing Medical University, Nanjing, China
| | - Mengqiu Wu
- Department of Nephrology, Children's Hospital of Nanjing Medical University, Nanjing, China.,Nanjing Key Laboratory of Pediatrics, Children's Hospital of Nanjing Medical University, Nanjing, China.,Jiangsu Key Laboratory of Pediatrics, Nanjing Medical University, Nanjing, China
| | - Yuting Li
- Department of Nephrology, Children's Hospital of Nanjing Medical University, Nanjing, China.,Nanjing Key Laboratory of Pediatrics, Children's Hospital of Nanjing Medical University, Nanjing, China.,Jiangsu Key Laboratory of Pediatrics, Nanjing Medical University, Nanjing, China
| | - Lingge Zhang
- Department of Nephrology, Children's Hospital of Nanjing Medical University, Nanjing, China.,Nanjing Key Laboratory of Pediatrics, Children's Hospital of Nanjing Medical University, Nanjing, China.,Jiangsu Key Laboratory of Pediatrics, Nanjing Medical University, Nanjing, China
| | - Qianqian Jin
- Department of Nephrology, Children's Hospital of Nanjing Medical University, Nanjing, China.,Nanjing Key Laboratory of Pediatrics, Children's Hospital of Nanjing Medical University, Nanjing, China.,Jiangsu Key Laboratory of Pediatrics, Nanjing Medical University, Nanjing, China
| | - Jiaojiao Fan
- Department of Nephrology, Children's Hospital of Nanjing Medical University, Nanjing, China.,Nanjing Key Laboratory of Pediatrics, Children's Hospital of Nanjing Medical University, Nanjing, China.,Jiangsu Key Laboratory of Pediatrics, Nanjing Medical University, Nanjing, China.,School of Medicine, Southeast University, Nanjing, China
| | - Xinyue Xu
- Department of Nephrology, Children's Hospital of Nanjing Medical University, Nanjing, China.,Nanjing Key Laboratory of Pediatrics, Children's Hospital of Nanjing Medical University, Nanjing, China.,Jiangsu Key Laboratory of Pediatrics, Nanjing Medical University, Nanjing, China.,School of Medicine, Southeast University, Nanjing, China
| | - Ran Gu
- Department of Nephrology, Children's Hospital of Nanjing Medical University, Nanjing, China.,Nanjing Key Laboratory of Pediatrics, Children's Hospital of Nanjing Medical University, Nanjing, China.,Jiangsu Key Laboratory of Pediatrics, Nanjing Medical University, Nanjing, China
| | - Haiping Hao
- State Key Laboratory of Natural Medicines, Key Laboratory of Drug Metabolism, China Pharmaceutical University, Nanjing, China
| | - Aihua Zhang
- Department of Nephrology, Children's Hospital of Nanjing Medical University, Nanjing, China.,Nanjing Key Laboratory of Pediatrics, Children's Hospital of Nanjing Medical University, Nanjing, China.,Jiangsu Key Laboratory of Pediatrics, Nanjing Medical University, Nanjing, China
| | - Zhanjun Jia
- Department of Nephrology, Children's Hospital of Nanjing Medical University, Nanjing, China.,Nanjing Key Laboratory of Pediatrics, Children's Hospital of Nanjing Medical University, Nanjing, China.,Jiangsu Key Laboratory of Pediatrics, Nanjing Medical University, Nanjing, China
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16
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Zheng L, Tian J, Liu D, Zhao Y, Fang X, Zhang Y, Liu Y. Efficacy and safety of roxadustat for anaemia in dialysis-dependent and non-dialysis-dependent chronic kidney disease patients: A systematic review and meta-analysis. Br J Clin Pharmacol 2022; 88:919-932. [PMID: 34428860 DOI: 10.1111/bcp.15055] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2021] [Revised: 08/08/2021] [Accepted: 08/12/2021] [Indexed: 12/29/2022] Open
Abstract
AIMS Renal anaemia is a common complication of chronic kidney disease (CKD). Roxadustat is the first-in-class oral hypoxia-inducible factor prolyl hydroxylase inhibitor for the treatment of anaemia. In this systematic review, we aimed to investigate the efficacy and safety of roxadustat in the treatment of anaemia in CKD patients. METHODS PubMed, Cochrane Library, Embase, and ClinicalTrials.gov databases were searched from their inception to February 2021 for randomised controlled trials (RCTs) that compared the efficacy and safety of roxadustat to those of an erythropoiesis-stimulating agent (ESA) or a placebo in treating anaemia in CKD patients. RESULTS Nine RCTs involving 2743 patients were found. The meta-analysis showed that roxadustat increased haemoglobin (Hb) level by 0.91 g/dL (95% confidence interval [CI]: 0.47-1.34, P < .05), transferrin level by 0.50 mg/dL (95% CI: 0.34-0.65, P < .05), and total iron-binding capacity by 50.64 μg/dL (95% CI: 36.21-65.07, P < .05) in CKD patients. Decreases in hepcidin (mean difference [MD] = -23.16, 95% CI: -37.12 to -9.19, P < .05) and ferritin (MD = -38.35, 95% CI: -67.41 to -9.29, P < .05) levels were also observed. There was no significant difference in the incidence of adverse events (AEs) (OR: 1.12, 95% CI: 0.95-1.32, P = .17) between the roxadustat and control groups; however, the incidence of serious AEs in the roxadustat group was significantly higher than that in the ESA group (OR: 1.33, 95% CI: 1.06-1.68, P < .05). CONCLUSION Roxadustat can significantly improve renal anaemia in CKD patients by increasing Hb level and iron metabolism. However, attention must be paid to the risk of SAEs during treatment.
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Affiliation(s)
- Li Zheng
- Evidence-Based Medicine Center, School of Basic Medical Sciences, Lanzhou University, Lanzhou, China
- Department of Pharmacy, China Aerospace Science & Industry Corporation 731 Hospital, Beijing, China
| | - Jinhui Tian
- Evidence-Based Medicine Center, School of Basic Medical Sciences, Lanzhou University, Lanzhou, China
| | - Deping Liu
- Department of Cardiovascular Medicine, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, China
| | - Yan Zhao
- Department of Pharmacy, China Aerospace Science & Industry Corporation 731 Hospital, Beijing, China
| | - Xiaoyong Fang
- Department of Pharmacy, China Aerospace Science & Industry Corporation 731 Hospital, Beijing, China
| | - Yatong Zhang
- Department of Pharmacy, Beijing Hospital, Beijing, China
| | - Yuming Liu
- Department of Endocrinology and Metabolism and Nephropathy, China Aerospace Science & Industry Corporation 731 Hospital, Beijing, China
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17
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Xiong L, Zhang H, Guo Y, Song Y, Tao Y. Efficacy and Safety of Vadadustat for Anemia in Patients With Chronic Kidney Disease: A Systematic Review and Meta-Analysis. Front Pharmacol 2022; 12:795214. [PMID: 35115942 PMCID: PMC8804247 DOI: 10.3389/fphar.2021.795214] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2021] [Accepted: 12/20/2021] [Indexed: 11/13/2022] Open
Abstract
Background: Vadadustat is a novel drug for treating anemia patients with chronic kidney disease (CKD), but its effect and safety remain uncertain. This study aimed to summarize the evidence for vadadustat in the treatment of CKD patients with anemia.Methods: PubMed, Ovid Medline, Embase, Cochrane CENTRAL, Wanfang Data, China National Knowledge Infrastructure and an international trial register were searched from their inception to June 2021 for randomized controlled trials (RCTs) comparing the efficacy and safety of vadadustat to those of placebo or erythropoiesis-stimulating agents (ESAs) in treating anemia in CKD patients. Data were pooled in a meta-analysis, with results expressed as the mean difference for continuous outcomes and relative risk for categorical outcomes with 95% confidence intervals (95% CIs). The certainty of evidence was rated according to Cochrane methods and the GRADE approach.Results: Ten RCTs comparing vadadustat with placebo (4 RCTs) or darbepoetin alfa (6 RCTs) were included (n = 8,438 participants). Compared with placebo, vadadustat increased the hemoglobin (Hb) response rate (risk ratio 5.27; 95% CI: 2.69 to 10.31; p < 0.001; high certainty of evidence) and Hb level from baseline (∆Hb) (mean difference (MD) 1.28; 95% CI: 0.83 to 1.73; p < 0.001; low certainty of evidence). Compared with placebo or darbepoetin alfa, vadadustat decreased hepcidin (MD -36.62; 95% CI: −54.95 to −18.30; p < 0.001) and ferritin (MD −56.24; 95% CI: −77.37 to −35.11; p < 0.001) levels and increased iron-binding capacity (MD 24.38; 95% CI: 13.69 to 35.07; p < 0.001), with a low to moderate certainty of evidence. Moderate to high certainty evidence suggested that compared with placebo or darbepoetin alfa, vadadustat significantly increased the risk of nausea and diarrhea but did not significantly increase the risk of serious adverse events, especially all-cause mortality, cardiac events and nonfatal stroke.Conclusion: Vadadustat may safely improve Hb levels and promote iron utilization in CKD patients with anemia without increasing the incidence of serious adverse events.
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Affiliation(s)
- Limei Xiong
- Division of Nephrology, Department of Pediatrics, West China Second University Hospital, Sichuan University, Chengdu, China
- Key Laboratory of Birth Defects and Related Diseases of Women and Children, Ministry of Education, Sichuan University, Chengdu, China
| | - Hui Zhang
- Division of Nephrology, Department of Pediatrics, West China Second University Hospital, Sichuan University, Chengdu, China
| | - Yannan Guo
- Division of Nephrology, Department of Pediatrics, West China Second University Hospital, Sichuan University, Chengdu, China
| | - Yue Song
- Division of Nephrology, Department of Pediatrics, West China Second University Hospital, Sichuan University, Chengdu, China
- Key Laboratory of Birth Defects and Related Diseases of Women and Children, Ministry of Education, Sichuan University, Chengdu, China
| | - Yuhong Tao
- Division of Nephrology, Department of Pediatrics, West China Second University Hospital, Sichuan University, Chengdu, China
- Key Laboratory of Birth Defects and Related Diseases of Women and Children, Ministry of Education, Sichuan University, Chengdu, China
- Department of Pediatrics, Meishan Women and Children’s Hospital, Alliance Hospital of West China Second University Hospital, Sichuan University, Meishan, China
- *Correspondence: Yuhong Tao,
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18
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Alnuwaysir RIS, Hoes MF, van Veldhuisen DJ, van der Meer P, Beverborg NG. Iron Deficiency in Heart Failure: Mechanisms and Pathophysiology. J Clin Med 2021; 11:125. [PMID: 35011874 PMCID: PMC8745653 DOI: 10.3390/jcm11010125] [Citation(s) in RCA: 51] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2021] [Revised: 12/17/2021] [Accepted: 12/22/2021] [Indexed: 12/15/2022] Open
Abstract
Iron is an essential micronutrient for a myriad of physiological processes in the body beyond erythropoiesis. Iron deficiency (ID) is a common comorbidity in patients with heart failure (HF), with a prevalence reaching up to 59% even in non-anaemic patients. ID impairs exercise capacity, reduces the quality of life, increases hospitalisation rate and mortality risk regardless of anaemia. Intravenously correcting ID has emerged as a promising treatment in HF as it has been shown to alleviate symptoms, improve quality of life and exercise capacity and reduce hospitalisations. However, the pathophysiology of ID in HF remains poorly characterised. Recognition of ID in HF triggered more research with the aim to explain how correcting ID improves HF status as well as the underlying causes of ID in the first place. In the past few years, significant progress has been made in understanding iron homeostasis by characterising the role of the iron-regulating hormone hepcidin, the effects of ID on skeletal and cardiac myocytes, kidneys and the immune system. In this review, we summarise the current knowledge and recent advances in the pathophysiology of ID in heart failure, the deleterious systemic and cellular consequences of ID.
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Affiliation(s)
| | | | | | | | - Niels Grote Beverborg
- Department of Cardiology, University Medical Center Groningen, University of Groningen, P.O. Box 30.001, 9700 RB Groningen, The Netherlands; (R.I.S.A.); (M.F.H.); (D.J.v.V.); (P.v.d.M.)
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19
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Abstract
The pharmacokinetics of roxadustat are well characterized, with an apparent volume of distribution after oral administration of 22–57 L, apparent clearance of 1.2–2.65 L/h, and renal clearance of 0.030–0.026 L/h in healthy volunteers; the elimination half-life is 9.6–16 h. Plasma binding is 99% and the fraction eliminated by hemodialysis is 2.34%. As an interpretation of the pharmacodynamics of roxadustat, we proposed a concept with a hypothetical cascade of two subsequent effects, first on erythropoetin (EPO) and second on hemoglobin (delta Hb). The primary effect on EPO is observed within a few hours after roxadustat administration and can be modeled using the sigmoidal Hill equation. The concentration at half-maximum effect can be inferred at 10–36 µg/mL, the Hill coefficient at 3.3, and the effect bisection time at 10–17 h, corresponding to EPO half-life. The subsequent effect on hemoglobin (delta Hb) is observed after several weeks and can be interpreted as an irreversible, dose proportional, unsaturable effect, continuing in agreement with the lifespan of red blood cells of 63–112 days.
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20
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Crugliano G, Serra R, Ielapi N, Battaglia Y, Coppolino G, Bolignano D, Bracale UM, Pisani A, Faga T, Michael A, Provenzano M, Andreucci M. Hypoxia-Inducible Factor Stabilizers in End Stage Kidney Disease: "Can the Promise Be Kept?". Int J Mol Sci 2021; 22:12590. [PMID: 34830468 PMCID: PMC8618724 DOI: 10.3390/ijms222212590] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2021] [Revised: 11/12/2021] [Accepted: 11/19/2021] [Indexed: 12/13/2022] Open
Abstract
Anemia is a common complication of chronic kidney disease (CKD). The prevalence of anemia in CKD strongly increases as the estimated Glomerular Filtration Rate (eGFR) decreases. The pathophysiology of anemia in CKD is complex. The main causes are erythropoietin (EPO) deficiency and functional iron deficiency (FID). The administration of injectable preparations of recombinant erythropoiesis-stimulating agents (ESAs), especially epoetin and darbepoetin, coupled with oral or intravenous(iv) iron supplementation, is the current treatment for anemia in CKD for both dialysis and non-dialysis patients. This approach reduces patients' dependence on transfusion, ensuring the achievement of optimal hemoglobin target levels. However, there is still no evidence that treating anemia with ESAs can significantly reduce the risk of cardiovascular events. Meanwhile, iv iron supplementation causes an increased risk of allergic reactions, gastrointestinal side effects, infection, and cardiovascular events. Currently, there are no studies defining the best strategy for using ESAs to minimize possible risks. One class of agents under evaluation, known as prolyl hydroxylase inhibitors (PHIs), acts to stabilize hypoxia-inducible factor (HIF) by inhibiting prolyl hydroxylase (PH) enzymes. Several randomized controlled trials showed that HIF-PHIs are almost comparable to ESAs. In the era of personalized medicine, it is possible to envisage and investigate specific contexts of the application of HIF stabilizers based on the individual risk profile and mechanism of action.
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Affiliation(s)
- Giuseppina Crugliano
- Department of Health Sciences, “Magna Graecia” University, I-88100 Catanzaro, Italy; (G.C.); (G.C.); (D.B.); (T.F.); (A.M.)
| | - Raffaele Serra
- Department of Medical and Surgical Sciences, University Magna Graecia of Catanzaro, Viale Europa, I-88100 Catanzaro, Italy;
- Interuniversity Center of Phlebolymphology (CIFL), “Magna Graecia” University, I-88100 Catanzaro, Italy
| | - Nicola Ielapi
- Department of Public Health and Infectious Disease, “Sapienza” University of Rome, I-00185 Roma, Italy;
| | - Yuri Battaglia
- Division of Nephrology and Dialysis, St. Anna University-Hospital, I-44121 Ferrara, Italy;
| | - Giuseppe Coppolino
- Department of Health Sciences, “Magna Graecia” University, I-88100 Catanzaro, Italy; (G.C.); (G.C.); (D.B.); (T.F.); (A.M.)
| | - Davide Bolignano
- Department of Health Sciences, “Magna Graecia” University, I-88100 Catanzaro, Italy; (G.C.); (G.C.); (D.B.); (T.F.); (A.M.)
| | - Umberto Marcello Bracale
- Vascular Surgery Unit, Department of Public Health, University Federico II of Naples, I-80131 Naples, Italy;
| | - Antonio Pisani
- Department of Public Health, University Federico II of Naples, I-80131 Naples, Italy;
| | - Teresa Faga
- Department of Health Sciences, “Magna Graecia” University, I-88100 Catanzaro, Italy; (G.C.); (G.C.); (D.B.); (T.F.); (A.M.)
| | - Ashour Michael
- Department of Health Sciences, “Magna Graecia” University, I-88100 Catanzaro, Italy; (G.C.); (G.C.); (D.B.); (T.F.); (A.M.)
| | - Michele Provenzano
- Department of Medical and Surgical Sciences, University Magna Graecia of Catanzaro, Viale Europa, I-88100 Catanzaro, Italy;
| | - Michele Andreucci
- Department of Health Sciences, “Magna Graecia” University, I-88100 Catanzaro, Italy; (G.C.); (G.C.); (D.B.); (T.F.); (A.M.)
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21
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Barratt J, Sulowicz W, Schömig M, Esposito C, Reusch M, Young J, Csiky B. Efficacy and Cardiovascular Safety of Roxadustat in Dialysis-Dependent Chronic Kidney Disease: Pooled Analysis of Four Phase 3 Studies. Adv Ther 2021; 38:5345-5360. [PMID: 34523074 PMCID: PMC8478753 DOI: 10.1007/s12325-021-01903-7] [Citation(s) in RCA: 47] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2021] [Accepted: 08/26/2021] [Indexed: 12/15/2022]
Abstract
INTRODUCTION This integrated phase 3 analysis examined efficacy and cardiovascular safety for roxadustat vs erythropoiesis-stimulating agents (ESAs) in dialysis-dependent patients. METHODS Efficacy and safety results from four phase 3, randomized, open-label studies comparing roxadustat to ESAs (PYRENEES, SIERRAS, HIMALAYAS, ROCKIES) in dialysis-dependent patients with anemia of chronic kidney disease (CKD) were evaluated by study, pooled population and in two subgroups: incident dialysis and stable dialysis. The primary efficacy endpoint per study was hemoglobin change from baseline (CFB) to weeks 28-36 using least-squares mean difference (LSMD) without rescue therapy. Pooled safety endpoints included time to major adverse cardiovascular event (MACE; myocardial infarction, stroke, and all-cause mortality [ACM]) and MACE+ (MACE plus congestive heart failure or unstable angina requiring hospitalization), ACM, and treatment-emergent adverse events (TEAEs). MACE and MACE+ were evaluated for non-inferiority at 1.8 and 1.3 margins using hazard ratios (HRs) and 95% confidence intervals (CIs). TEAEs were descriptively summarized. RESULTS In total, 4714 patients were randomized (2354 roxadustat; 2360 ESA). Hemoglobin CFB to weeks 28-36 achieved non-inferiority for roxadustat vs ESA in each study. Roxadustat was non-inferior to ESA for risks for MACE and MACE+ in the entire cohort (MACE: HR 1.09, 95% CI 0.95-1.26; MACE+ : HR 0.98, 95% CI 0.86-1.11) and similar to the incident dialysis and stable dialysis subgroups; ACM results were consistent with MACE and MACE+ (HR 1.13, 95% CI 0.95-1.34). TEAEs were generally comparable between groups. CONCLUSION Roxadustat improved hemoglobin similarly to ESA while demonstrating comparable cardiovascular and overall safety profiles in a wide spectrum of dialysis-dependent patients with anemia of CKD. Roxadustat represents an oral alternative to ESAs for achieving a target hemoglobin for anemia of CKD in dialysis-dependent patients.
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Affiliation(s)
- Jonathan Barratt
- Cardiovascular Sciences, University of Leicester, Leicester, UK.
| | - Wladyslaw Sulowicz
- Department of Nephrology, Collegium Medicum of the Jagiellonian University, Kraków, Poland
| | | | - Ciro Esposito
- Unit of Nephrology and Dialysis, ICS Maugeri, University of Pavia, Pavia, Italy
| | | | | | - Botond Csiky
- 2nd Department of Medicine and Nephrology-Diabetes Center, University of Pécs, FMC Dialysis Centers, Pécs, Hungary
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22
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Bellelli A, Tame JRH. Hemoglobin allostery and pharmacology. Mol Aspects Med 2021; 84:101037. [PMID: 34600771 DOI: 10.1016/j.mam.2021.101037] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2021] [Revised: 09/24/2021] [Accepted: 09/27/2021] [Indexed: 10/20/2022]
Abstract
The oxygen demands of the human body require the constant circulation of blood carrying an enormous concentration of hemoglobin (Hb). Oxygen transport depends not only on the amount of Hb, but also on the control over the affinity of the protein for the gas, which can be optimized for the environmental conditions by changes in the concentration of effectors (hydrogen ions, chloride, CO2, and DPG) inside the red cell. Some pathological conditions affecting Hb may benefit from pharmacological interventions to increase or decrease its affinity for oxygen, or otherwise modify its properties, or alter its biosynthesis. Examples of such conditions include sickle cell anemia, thalassemias and inherited hemoglobinopathies. Effective and safe drugs such as voxelotor, bezafibrate and efaproxiral are available that significantly increase or decrease Hb oxygen affinity. Some medical conditions not directly affecting the blood or its oxygen carrying capacity may also be relieved by the manipulation of Hb. For example, the standard treatment of acute cyanide poisoning requires the oxidation of a fraction of the Hb in the bloodstream so that it efficiently scavenges cyanide. Tumors are often extremely hypoxic and therefore strongly resistant to radiotherapy; the sensitivity of cancerous tissue to X-rays may be increased by improved oxygenation through drugs binding Hb. This review attempts to provide a systematic exploration of the pharmacology of Hb, its molecular basis, and its intended and possible uses.
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Affiliation(s)
- Andrea Bellelli
- Department of Biochemical Sciences "A. Rossi Fanelli", Sapienza University of Rome, Rome, Italy.
| | - Jeremy R H Tame
- Drug Design Laboratory, Graduate School of Medical Life Science, Yokohama City University, Tsurumi, Yokohama, 230-0045, Japan
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Liu C, Fu Z, Jiang J, Chi K, Geng X, Mao Z, Song C, Sun G, Hong Q, Cai G, Chen X, Sun X. Safety and Efficacy of Roxadustat for Anemia in Patients With Chronic Kidney Disease: A Meta-Analysis and Trial Sequential Analysis. Front Med (Lausanne) 2021; 8:724456. [PMID: 34532333 PMCID: PMC8438137 DOI: 10.3389/fmed.2021.724456] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2021] [Accepted: 08/12/2021] [Indexed: 12/19/2022] Open
Abstract
Background: Roxadustat, a hypoxia-inducible factor prolyl-hydroxylase inhibitor (HIF-PHI), has been used to treat anemia in patients with chronic kidney disease (CKD). However, its safety and efficacy remain controversial. Methods: The PubMed, EMBASE, Science Citation Index, Cochrane Central Register of Controlled Trials, and Clinical Trial Registries databases were searched for relevant studies published up to April 2021. We identified randomized controlled trials (RCTs) comparing roxadustat with placebo or erythropoiesis-stimulating agents (ESAs) in anemia patients with CKD with or without dialysis. Results: Eleven studies including 6,631 patients met the inclusion criteria. In non-dialysis-dependent (NDD-) and dialysis-dependent (DD-) CKD patients, the total adverse events were not significantly different between the roxadustat and control (placebo for NDD-CKD patients and ESA for DD-CKD patients) groups [relative risk (RR) = 1.02, 95% confidence interval (CI) = 1.00, 1.04, P = 0.08, and RR = 1.22, 95% CI = 0.91, 1.64, P = 0.18, respectively], and the trial sequential analysis (TSA) confirmed the result in the NDD-CKD groups. No significant differences in hyperkalemia and infection incidences were found between roxadustat and placebo in the DD-CKD groups. The pooled results showed that roxadustat significantly increased the hemoglobin response rate compared with placebo in the NDD-CKD group and had an effect similar to that of ESA in the DD-CKD group. However, iron metabolism parameters did not seem to be obviously optimized by roxadustat. Conclusion: Roxadustat can be safely used in CKD patients. Oral roxadustat was more effective than placebo as a therapy for anemia in NDD-CKD patients and non-inferior to ESA in correcting anemia in DD-CKD patients. However, additional clinical trials are still needed to further prove whether roxadustat can optimize iron metabolism.
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Affiliation(s)
- Chao Liu
- Department of Nephrology, Chinese PLA General Hospital, Chinese PLA Institute of Nephrology, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing, China
| | - Zhangning Fu
- Department of Nephrology, Chinese PLA General Hospital, Chinese PLA Institute of Nephrology, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing, China
| | - Jiawei Jiang
- Department of Critical Care Medicine, Tianjin Medical University First Center Clinical College, Tianjin, China
| | - Kun Chi
- Department of Nephrology, Chinese PLA General Hospital, Chinese PLA Institute of Nephrology, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing, China
| | - Xiaodong Geng
- Department of Nephrology, Chinese PLA General Hospital, Chinese PLA Institute of Nephrology, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing, China
| | - Zhi Mao
- Department of Critical Care Medicine, Chinese PLA General Hospital, Beijing, China
| | - Chengcheng Song
- Department of Nephrology, Chinese PLA General Hospital, Chinese PLA Institute of Nephrology, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing, China
| | - Guannan Sun
- Department of Nephrology, Chinese PLA General Hospital, Chinese PLA Institute of Nephrology, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing, China
| | - Quan Hong
- Department of Nephrology, Chinese PLA General Hospital, Chinese PLA Institute of Nephrology, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing, China
| | - Guangyan Cai
- Department of Nephrology, Chinese PLA General Hospital, Chinese PLA Institute of Nephrology, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing, China
| | - Xiangmei Chen
- Department of Nephrology, Chinese PLA General Hospital, Chinese PLA Institute of Nephrology, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing, China
| | - Xuefeng Sun
- Department of Nephrology, Chinese PLA General Hospital, Chinese PLA Institute of Nephrology, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing, China
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24
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Zhu XW, Zhang CX, Xu TH, Jiang GN, Yao L. Efficacy of roxadustat in treatment of peritoneal dialysis patients with renal anaemia. World J Clin Cases 2021; 9:7682-7692. [PMID: 34621819 PMCID: PMC8462256 DOI: 10.12998/wjcc.v9.i26.7682] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/23/2021] [Revised: 04/02/2021] [Accepted: 07/27/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND There are no studies on the use of roxadustat in patients on regular peritoneal dialysis in China.
AIM To observe the efficacy and safety of roxadustat in treating renal anaemia in peritoneal dialysis patients.
METHODS Patients with renal anaemia who were regularly followed at the Peritoneal Dialysis Center of the First Affiliated Hospital of China Medical University from November 1, 2019 to June 30, 2020 were selected. A before-and-after self-control design was performed to retrospectively analyse the treatment effects on anaemia in patients treated with recombinant human erythropoietin (EPO) and roxadustat.
RESULTS A total of 31 patients with renal anaemia on long-term peritoneal dialysis treated with roxadustat were included. Haemoglobin (Hb) levels were maintained or increased in all patients (100%), and no patients had a decrease in Hb compared with the previous phase. Patients had a mean Hb of 86.2 ± 14.8 g/L with Hb compliance (Hb ≥ 110 g/L) of 16.1% during the EPO phase and a mean Hb of 112.4 ± 18.5 g/L with Hb compliance of 67.7% during the roxadustat phase. No major adverse cardiovascular events occurred in any patient.
CONCLUSION The application of roxadustat in peritoneal dialysis patients with renal anaemia can effectively improve the Hb compliance rate.
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Affiliation(s)
- Xin-Wang Zhu
- Department of Nephrology, The First Affiliated Hospital of China Medical University, Shenyang 110001, Liaoning Province, China
| | - Cong-Xiao Zhang
- Blood Purification Center, The Fourth People’s Hospital of Shenyang, Shenyang 110031, Liaoning Province, China
| | - Tian-Hua Xu
- Department of Nephrology, The First Affiliated Hospital of China Medical University, Shenyang 110001, Liaoning Province, China
| | - Guan-Nan Jiang
- Department of Nephrology, The First Affiliated Hospital of China Medical University, Shenyang 110001, Liaoning Province, China
| | - Li Yao
- Department of Nephrology, The First Affiliated Hospital of China Medical University, Shenyang 110001, Liaoning Province, China
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Tang M, Zhu C, Yan T, Zhou Y, Lv Q, Chuan J. Safe and Effective Treatment for Anemic Patients With Chronic Kidney Disease: An Updated Systematic Review and Meta-Analysis on Roxadustat. Front Pharmacol 2021; 12:658079. [PMID: 34276361 PMCID: PMC8283176 DOI: 10.3389/fphar.2021.658079] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2021] [Accepted: 06/22/2021] [Indexed: 12/14/2022] Open
Abstract
Background: Roxadustat is a new oral drug for anemia in chronic kidney disease (CKD). This study aimed to synthesize the evidence from randomized controlled trial (RCT)-based studies that estimated the efficacy and safety of roxadustat in anemia patients with non-dialysis-dependent (NDD) and dialysis-dependent (DD) CKD. Methods: We searched the PubMed, Web of Science, and Cochrane Central Register of Controlled Trials (CENTRAL) databases for related published studies. Moreover, we manually searched relevant pharmaceutical company websites and two international clinical trial registers to search for published and unpublished RCTs comparing roxadustat with erythropoietin-stimulating agents (ESAs) or placebo. Results: Fifteen RCTs (seven for DD-CKD patients, eight for NDD-CKD patients) were included in the meta-analysis, with 10,189 patients, 4,810 DD-CKD patients, and 5,379 NDD-CKD patients enrolled. Compared with ESAs (epoetin alfa or darbepoetin alfa) and placebo, roxadustat raised the hemoglobin level [weighted mean difference (WMD): 0.82 g/dL; 95% confidence interval (CI): 0.43–1.21], transferrin level (WMD: 0.5 g/L; 95% CI: 0.34–0.65), and TIBC level (WMD: 41.79 μg/dL; 95% CI: 38.67–44.92) and lowered the hepcidin level (WMD: −37.38 ng/ml; 95% CI: −46.63– −28.12) in both the DD-CKD and NDD-CKD patients with renal anemia. Roxadustat improved hemoglobin response and lowered the ferritin and TAST levels in the NDD-CKD patients but not in the DD-CKD patients. Furthermore, there was no difference between the treatment-emergent adverse events (TEAEs) of roxadustat and that of ESAs or placebo. But the incidence of serious TEAEs in the roxadustat group was significantly higher with NDD-CKD patients (OR: 1.15; 95% CI: 1.02–1.29). Conclusion: This study confirmed that roxadustat therapy could alleviate the anemia of DD-CKD and NDD-CKD patients by raising the hemoglobin level and regulating iron metabolism, but increased serious incidences of treatment-emergent adverse events (TEAEs) in NDD-CKD patients.
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Affiliation(s)
- Mei Tang
- Department of Pharmacy, Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, Chengdu, China.,Personalized Drug Therapy Key Laboratory of Sichuan Province, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
| | - Changyu Zhu
- Department of Pharmacy, Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, Chengdu, China.,Personalized Drug Therapy Key Laboratory of Sichuan Province, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
| | - Ting Yan
- Department of Pharmacy, Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, Chengdu, China.,Personalized Drug Therapy Key Laboratory of Sichuan Province, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
| | - Yanglin Zhou
- Department of Pharmacy, Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, Chengdu, China.,Personalized Drug Therapy Key Laboratory of Sichuan Province, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
| | - Qin Lv
- Department of Respiratory and Critical Care Medicine, Sichuan Academy of Medical Science and Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
| | - Junlan Chuan
- Department of Pharmacy, Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, Chengdu, China.,Personalized Drug Therapy Key Laboratory of Sichuan Province, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
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26
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Zhang Y, Ren S, Xue H, Wang AY, Zou Y, Cai Y, He J, Yuan X, Jiang F, Wei J, Yang D, He D, Hu S, Lei M, Deng F, Chen J, Wang X, He Q, Li G, Hong D. Roxadustat in treating anemia in dialysis patients (ROAD): protocol and rationale of a multicenter prospective observational cohort study. BMC Nephrol 2021; 22:28. [PMID: 33441103 PMCID: PMC7805134 DOI: 10.1186/s12882-021-02229-w] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2020] [Accepted: 01/01/2021] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND Roxadustat has been shown effective in treating patients with anemia due to chronic kidney disease. However, its long-term effect on clinical outcomes and socioeconomic burden and safety remains unclear. METHODS/DESIGN This is a multicenter, prospective, longitudinal observational cohort study assessing if Roxadustat improves prognosis in dialysis patients. Primary outcomes will be major adverse cardiovascular events (MACE), defined as composites of cardiovascular death, myocardial infarction, cerebral infarction, hospitalization because of heart failure; all-cause mortality, and annual economic costs in two years. The data will be collected via Research electronic data capture (REDCap) based database as well as software-based dialysis registry of Sichuan province. The primary outcomes for the ROAD study participants will be compared with those in the dialysis registry cohort. Data at baseline and study follow up will also be compared to assess the association between Roxadustat and long-term clinical outcomes. DISCUSSION The main objective of this study is to the assess long-term association of Roxadustat on MACE, all-cause mortality, socio-economic burden, safety in dialysis patients, which will provide guidance for designing further large randomized controlled trials to investigate this clinic question. STUDY REGISTRATION The study has been registered in Chinese Clinical Trials Registry (ROAD, ROxadustat in treating Anemia in Dialysis patients, registration number ChiCTR1900025765) and provincial observational cohort database (Renal disEAse observational CoHort database, REACH, ChiCTR1900024926), registered 07 September 2019, http://www.chictr.org.cn .
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Affiliation(s)
- Yaling Zhang
- Renal Department and Nephrology Institute, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, No. 32, West 2nd Duan, 1st Circle Road, Qingyang District, Chengdu, Sichuan, China
| | - Song Ren
- Renal Department and Nephrology Institute, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, No. 32, West 2nd Duan, 1st Circle Road, Qingyang District, Chengdu, Sichuan, China
| | - Hen Xue
- Department of Nephrology, Ya'an People's Hospital, 625000, Ya'an, Sichuan, China
| | - Amanda Y Wang
- The Renal and Metabolic Division, The George Institute for Global Health, University of New South Wales, Sydney, 2042, Australia.
- Concord Clinical School, The University of Sydney, Sydney, 2042, Australia.
- Department of Renal Medicine, Concord Repatriation General Hospital, Beijing Friendship Hospital, Beijing, China.
| | - Yang Zou
- Renal Department and Nephrology Institute, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, No. 32, West 2nd Duan, 1st Circle Road, Qingyang District, Chengdu, Sichuan, China
| | - Yanrong Cai
- Department of Nephrology, 610000, Gao Xin Boli Hospital,Chengdu, China
| | - Jingdong He
- Department of Nephrology, The Second Affiliated Hospital of Chengdu Medical College, National Nuclear Corporation 416 Hospital, 610000, Chengdu, China
| | - Xiaoling Yuan
- Department of Nephrology, Sichuan Science City Hospital, 621000, Mianyang, China
| | - Feifei Jiang
- Department of Nephrology, Chengdu Jinniu District People's Hospital, 610036, Chengdu, China
| | - Jinxi Wei
- Hemodialysis center,Pidu District People's Hospital, 611730, Chengdu, China
| | - Dongmei Yang
- Department of Nephrology, Mianyang Anzhou People's Hospital, 621000, Mianyang, China
| | - Dong He
- Department of Nephrology, The People's Hospital of Mianyang, 621000, Mianyang, China
| | - Shide Hu
- Department of Nephrology, Sichuan Mianyang 404 Hospital, 621000, Mianyang, China
| | - Min Lei
- Department of Nephrology, Affiliated Hospital of Chengdu University, 610081, Chengdu, China
| | - Fei Deng
- Renal Department and Nephrology Institute, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, No. 32, West 2nd Duan, 1st Circle Road, Qingyang District, Chengdu, Sichuan, China
| | - Jin Chen
- Renal Department and Nephrology Institute, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, No. 32, West 2nd Duan, 1st Circle Road, Qingyang District, Chengdu, Sichuan, China
| | - Xia Wang
- The George Institute for Global Health, Faculty of Medicine, University of New South Wales, Sydney, NSW, Australia
| | - Qiang He
- Renal Department and Nephrology Institute, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, No. 32, West 2nd Duan, 1st Circle Road, Qingyang District, Chengdu, Sichuan, China.
| | - Guisen Li
- Renal Department and Nephrology Institute, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, No. 32, West 2nd Duan, 1st Circle Road, Qingyang District, Chengdu, Sichuan, China.
| | - Daqing Hong
- Renal Department and Nephrology Institute, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, No. 32, West 2nd Duan, 1st Circle Road, Qingyang District, Chengdu, Sichuan, China.
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Musio F. Revisiting the treatment of anemia in the setting of chronic kidney disease, hematologic malignancies, and cancer: perspectives with opinion and commentary. Expert Rev Hematol 2020; 13:1175-1188. [PMID: 33028115 DOI: 10.1080/17474086.2020.1830371] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2020] [Accepted: 09/27/2020] [Indexed: 12/17/2022]
Abstract
INTRODUCTION Anemia has and will continue to be a central theme in medicine particularly as clinicians are treating a burgeoning population of complex multi-organ system processes. As a result of multiple randomized controlled trials (RCTs), meta-analyses, and societal recommendations overly restrictive paradigms and under-administration of erythropoiesis stimulating agents (ESAs) have likely been followed by clinicians among all specialties. AREAS COVERED A review of anemia in the context of chronic kidney disease, hematologic malignancies, and cancer is presented with focus on the establishment of ESAs as integral in the treatment of anemia. Multiple RCTs and meta-analyses studying the use of ESAs are presented with focus upon their application to clinical practice. A 'compendium' is proffered describing the evolution, establishment, and implications of ESA administration initially among those with CKD with rapid subsequent application to the Hematology-Oncology population of patients. Literature search methodologies have included MEDLINE (1985-2020), PubMed (1996-2020), Cochrane Central Trials (1985-2020), EMBASE (2000-2020), and ClinicalTrials.gov (2000-2020). EXPERT OPINION Upon evaluation of risks and benefits of ESAs focused opinion and commentary is made supporting more liberal use of these agents and strongly suggesting that the current underlying treatment 'pendulum' has perhaps shifted too far to the 'under-treatment' side in many cases.
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Affiliation(s)
- Franco Musio
- Senior Partner, Nephrology Associates of Northern Virginia , VA, Fairfax, Virginia, USA
- Nephrology Division Chief, Inova Fairfax Hospital, Department of Medicine, Falls Church , Virginia, VA, USA
- Associate Professor of Medicine, Virginia Commonwealth University (Inova Fairfax Hospital Campus) , Richmond, Virginia, USA
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Hypoxia Pathway Proteins are Master Regulators of Erythropoiesis. Int J Mol Sci 2020; 21:ijms21218131. [PMID: 33143240 PMCID: PMC7662373 DOI: 10.3390/ijms21218131] [Citation(s) in RCA: 39] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2020] [Revised: 10/21/2020] [Accepted: 10/28/2020] [Indexed: 02/06/2023] Open
Abstract
Erythropoiesis is a complex process driving the production of red blood cells. During homeostasis, adult erythropoiesis takes place in the bone marrow and is tightly controlled by erythropoietin (EPO), a central hormone mainly produced in renal EPO-producing cells. The expression of EPO is strictly regulated by local changes in oxygen partial pressure (pO2) as under-deprived oxygen (hypoxia); the transcription factor hypoxia-inducible factor-2 induces EPO. However, erythropoiesis regulation extends beyond the well-established hypoxia-inducible factor (HIF)-EPO axis and involves processes modulated by other hypoxia pathway proteins (HPPs), including proteins involved in iron metabolism. The importance of a number of these factors is evident as their altered expression has been associated with various anemia-related disorders, including chronic kidney disease. Eventually, our emerging understanding of HPPs and their regulatory feedback will be instrumental in developing specific therapies for anemic patients and beyond.
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Li J, Xie QH, You L, Xu NX, Hao CM. Effects of hypoxia-inducible factor prolyl hydroxylase inhibitors on iron regulation in non-dialysis-dependent chronic kidney disease patients with anemia: A systematic review and meta-analysis. Pharmacol Res 2020; 163:105256. [PMID: 33086081 DOI: 10.1016/j.phrs.2020.105256] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/01/2020] [Revised: 09/11/2020] [Accepted: 10/13/2020] [Indexed: 02/06/2023]
Abstract
Phase 2 and phase 3 clinical studies showed that hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHIs) efficiently increased hemoglobin levels in both dialysis-dependent and non-dialysis-dependent chronic kidney disease (CKD) patients. However, the effects of HIF-PHIs on iron regulation have not been consistent among clinical trials. We performed a systematic review and meta-analysis of randomized controlled trials to evaluate the effects of six HIF-PHIs on iron regulation in non-dialysis CKD patients. Electronic databases were searched from inception to April 20, 2020, for eligible studies. Changes from baseline in transferrin saturation (TSAT), total iron-binding capacity (TIBC), iron, ferritin, and hepcidin levels were pooled using the inverse-variance method and presented as the mean difference (MD) or standardized MD (SMD) with 95 % confidence intervals (CIs). Meta-analysis of the included studies showed that, in non-dialysis-dependent CKD patients, HIF-PHIs decreased TSAT (MD, -4.51; 95 % CI, -5.81 to -3.21), ferritin (MD, -47.29; 95 % CI, -54.59 to -40.00) and hepcidin (SMD, -0.94; 95 % CI, -1.25 to -0.62), increased TIBC (MD, 9.15; 95 % CI, 7.08-11.22), and did not affect serum iron (MD, -0.31; 95 % CI, -2.05 to 1.42) despite enhanced erythropoiesis. This systematic review suggests that HIF-PHIs promote iron utilization in non-dialysis-dependent CKD patients. Importantly, HIF-PHIs are associated with increased transferrin levels (and TIBC), leading to reduced TSAT. Therefore, the reduction of TSAT after HIF-PHIs should not be interpreted as iron deficiency.
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Affiliation(s)
- Jing Li
- Division of Nephrology, Huashan Hospital, Fudan University, Shanghai, China
| | - Qiong-Hong Xie
- Division of Nephrology, Huashan Hospital, Fudan University, Shanghai, China
| | - Li You
- Division of Nephrology, Huashan Hospital, Fudan University, Shanghai, China
| | - Ning-Xin Xu
- Division of Nephrology, Huashan Hospital, Fudan University, Shanghai, China
| | - Chuan-Ming Hao
- Division of Nephrology, Huashan Hospital, Fudan University, Shanghai, China.
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Zhang S, Guo J, Xie S, Chen J, Yu S, Yu Y. Efficacy and safety of hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHI) on anemia in non-dialysis-dependent chronic kidney disease (NDD-CKD): a systematic review and meta-analysis. Int Urol Nephrol 2020; 53:1139-1147. [PMID: 33026571 DOI: 10.1007/s11255-020-02671-z] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2020] [Accepted: 09/28/2020] [Indexed: 12/17/2022]
Abstract
PURPOSE HIF-PHI (hypoxia-inducible factor prolyl hydroxylase inhibitor) was developed to improve renal anemia. This study was to evaluate the efficiency and safety of HIF-PHI in patients with non-dialysis-dependent chronic kidney disease (NDD-CKD). METHODS The literature was extracted from PubMed, EMBASE, the Cochrane Central Register of Controlled Trials, and the Wanfang database. Statistical tests and forest plots were depicted by Review Manager Version 5.3. The primary outcome was a change in hemoglobin level from baseline (ΔHb). Secondary outcomes were changes in ferritin (ΔFerritin), hepcidin (ΔHepcidin), and transferrin saturation from baseline (ΔTSAT), and adverse events (AEs). This study is registered with PROSPERO (registration number CRD42020199656). RESULTS Ten trials were included. The results showed that HIF-PHI improved the ΔHb [SMD 3.03 (95% CI 2.10, 3.96), P < 0.00001] in NDD patients. HIF-PHI reduced hepcidin levels in the NDD patients [SMD - 1.44 (95% CI - 2.19-0.70), P = 0.0002]. ΔFerritin values were reduced significantly in the HIF-PHI group [SMD - 1.08 (95% CI - 1.63-0.53), P = 0.0001]. However, ΔTSAT values showed no significant difference in the HIF-PHI group compared to the placebo group [SMD - 0.23 (95% CI - 0.66-0.21), P = 0.31]. In the safety assessment, HIF-PHI did not increase adverse events significantly [RR 0.98 (95% CI 0.88-1.10), P = 0.74]. CONCLUSION HIF-PHI improves renal anemia and iron utilization disorder in NDD-CKD patients, without significantly more adverse events.
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Affiliation(s)
- Siliang Zhang
- Department of Nephrology, The Second Affiliated Hospital, Chongqing Medical University, Lingjiang Road, Yuzhong District, Chongqing, 400010, China
| | - Jing Guo
- Radiation Oncology Center, Chongqing University Cancer Hospital, Chongqing, 400030, China
| | - Shuqin Xie
- Department of Nephrology, The Second Affiliated Hospital, Chongqing Medical University, Lingjiang Road, Yuzhong District, Chongqing, 400010, China
| | - Jianwei Chen
- Department of Nephrology, The Second Affiliated Hospital, Chongqing Medical University, Lingjiang Road, Yuzhong District, Chongqing, 400010, China
| | - Shenrun Yu
- Center of Urology and Nephrology, Yongchuan People's Hospital of Chongqing, Chongqing, 402160, China
| | - Yuan Yu
- Department of Nephrology, The Second Affiliated Hospital, Chongqing Medical University, Lingjiang Road, Yuzhong District, Chongqing, 400010, China.
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31
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Zheng Q, Yang H, Sun L, Wei R, Fu X, Wang Y, Huang Y, Liu YN, Liu WJ. Efficacy and safety of HIF prolyl-hydroxylase inhibitor vs epoetin and darbepoetin for anemia in chronic kidney disease patients not undergoing dialysis: A network meta-analysis. Pharmacol Res 2020; 159:105020. [PMID: 32561478 DOI: 10.1016/j.phrs.2020.105020] [Citation(s) in RCA: 49] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/06/2020] [Revised: 06/05/2020] [Accepted: 06/10/2020] [Indexed: 12/12/2022]
Abstract
Hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHIs) are a new class of oral medicines being developed for the treatment of anemia in chronic kidney disease (CKD) patients. This study aimed to compare the efficacy and safety of HIF-PHI vs epoetin and darbepoetin in CKD patients with anemia not undergoing dialysis. The PubMed, Embase, Cochrane Library, Web of Science, and clinicaltrials.gov databases were searched from inception to October 2019 for randomized controlled trials investigating different agents (six HIF-PHIs, epoetin, darbepoetin, and placebo) for treating CKD patients with anemia that did not undergo dialysis. The outcomes included a change in hemoglobin (Hb) levels and all-cause mortality. A total of 19 studies were included. Compared with the placebo, except for vadadustat (mean differences: 1.12, 95 % confidence interval [CI]: ‒0.11-2.35), the other drugs significantly increased Hb levels, with mean differences of 2.46 (95 % CI: 0.93-3.99) for desidustat, 1.81 (0.87-2.75) for enarodustat, 1.68 (0.64-2.72) for molidustat, 1.66 (0.89-2.44) for epoetin, 1.63 (0.69-2.56) for darbepoetin, 1.61 (0.99-2.22) for roxadustat, and 1.55 (0.74-2.36) for daprodustat. No differences were found in the Hb level elevations among these eight drugs. Compared with the placebo, there also was no significant association between the drugs and all-cause mortality (molidustat of RR, 0.39 [95 % CI, 0.06-2.59]; roxadustat, 0.40 (0.06-2.84); enarodustat, 0.33 (0.01-16.25); desidustat, 0.34 (0.01-17.00); epoetin, 0.50 (0.18-1.42); daprodustat, 0.54 (0.09-3.31); darbepoetin, 1.03 (0.65-1.65); and vadadustat, 1.43 (0.15-13.27)). No differences were observed in the all-cause mortality among the drugs. In conclusion, these HIF-PHIs are effective and relatively tolerant for treating anemia patients with CKD not undergoing dialysis. Further research should consider the limitations of our study to evaluate the value of these HIF-PHIs in clinical settings.
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Affiliation(s)
- Qiyan Zheng
- Beijing University of Chinese Medicine, Beijing, 100029, China; Key Laboratory of Chinese Internal Medicine of Ministry of Education and Beijing, Beijing, 100700, China
| | - Huisheng Yang
- Institute of Acupuncture and Moxibustion, China Academy of Chinese Medical Sciences, Beijing, 100700, China
| | - Luying Sun
- Beijing University of Chinese Medicine, Beijing, 100029, China; Key Laboratory of Chinese Internal Medicine of Ministry of Education and Beijing, Beijing, 100700, China
| | - Ruojun Wei
- Beijing University of Chinese Medicine, Beijing, 100029, China; Key Laboratory of Chinese Internal Medicine of Ministry of Education and Beijing, Beijing, 100700, China
| | - Xinwen Fu
- Beijing University of Chinese Medicine, Beijing, 100029, China; Key Laboratory of Chinese Internal Medicine of Ministry of Education and Beijing, Beijing, 100700, China
| | - Yahui Wang
- Beijing University of Chinese Medicine, Beijing, 100029, China; Key Laboratory of Chinese Internal Medicine of Ministry of Education and Beijing, Beijing, 100700, China
| | - Yishan Huang
- Beijing University of Chinese Medicine, Beijing, 100029, China; Key Laboratory of Chinese Internal Medicine of Ministry of Education and Beijing, Beijing, 100700, China
| | - Yu Ning Liu
- Beijing University of Chinese Medicine, Beijing, 100029, China; Key Laboratory of Chinese Internal Medicine of Ministry of Education and Beijing, Beijing, 100700, China.
| | - Wei Jing Liu
- Beijing University of Chinese Medicine, Beijing, 100029, China; Key Laboratory of Chinese Internal Medicine of Ministry of Education and Beijing, Beijing, 100700, China; Zhanjiang Key Laboratory of Prevention and Management of Chronic Kidney Disease, Guangdong Medical University, Zhanjiang, Guangdong 524001, China.
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Souza E, Cho KH, Harris ST, Flindt NR, Watt RK, Pai AB. Hypoxia-inducible factor prolyl hydroxylase inhibitors: a paradigm shift for treatment of anemia in chronic kidney disease? Expert Opin Investig Drugs 2020; 29:831-844. [PMID: 32476498 DOI: 10.1080/13543784.2020.1777276] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
INTRODUCTION The hypoxia-inducible factor prolyl hydroxylase (HIF-PH) pathway is responsible for regulating the biosynthesis of erythropoietin (EPO) and maintaining iron homeostasis. Investigational drugs that target the HIF-PH pathway are promising alternatives for treating anemia in Chronic Kidney Disease (CKD). AREAS COVERED This review summarizes recent advances focused on the clinical development of HIF-PH inhibitors (HIF-PHIs) as potentially novel therapies in the treatment of anemia in CKD based on publications available on PubMed and restricted Google searches. We provide a comparison between HIF-PHIs regarding their pharmacokinetics, dosing regimens and safety concerns, structure-activity relationships, and alterations in key laboratory parameters observed in animal models and clinical trials. EXPERT OPINION HIF-PHIs may be advantageous in some aspects compared to the conventional erythropoiesis-stimulating agents (ESAs). While ESAs could increase the risk of cardiovascular events due to rapid rises in ESA blood levels, HIF-PHIs have been reported to maintain EPO concentrations at levels that are closer to the normal physiological ranges. Although HIF-PHIs have been demonstrated to be relatively safe and effective in clinical trials, long-term safety data are needed in order to establish whether these therapeutic agents will lead to a major paradigm change in the treatment of anemia of CKD.
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Affiliation(s)
- Ernane Souza
- Department of Clinical Pharmacy, University of Michigan , Ann Arbor, MI, USA
| | - Katherine H Cho
- Department of Clinical Pharmacy, University of Michigan , Ann Arbor, MI, USA
| | - Shelby T Harris
- Department of Chemistry and Biochemistry, Brigham Young University , Provo, UT, USA
| | - Naomi R Flindt
- Department of Chemistry and Biochemistry, Brigham Young University , Provo, UT, USA
| | - Richard K Watt
- Department of Chemistry and Biochemistry, Brigham Young University , Provo, UT, USA
| | - Amy Barton Pai
- Department of Clinical Pharmacy, University of Michigan , Ann Arbor, MI, USA
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