Effect of hypoxia-inducible factor-prolyl hydroxylase inhibitors on anemia in patients with CKD: a meta-analysis of randomized controlled trials including 2804 patients

Wang, Bin; Yin, Qian; Han, Yu‐Chen; Wu, Min; Li, Zuo‐Lin; Tu, Yan; Zhou, Le-Ting; Wei, Qingyang; Liu, Hong; Tang, Ri‐Ning; Cao, Jun; Lv, Lin‐Li; Liu, Bi‐Cheng

doi:10.1080/0886022x.2020.1811121

Cited by 24 publications

(40 citation statements)

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“…By inhibiting PHD, the agents stabilize HIF‐α that results in increased HIF transcriptional activity, which can stimulate the synthesis of endogenous EPO from native kidneys or the liver and regulate iron metabolism 12 . Previous systematic reviews and meta‐analyses based on small‐sample clinical data proved that short‐term use of HIF‐PHD inhibitors increased haemoglobin levels in anaemic patients with CKD and reached different conclusions on iron parameters and adverse event profiles 13,14 . Now, we performed a comprehensive meta‐analysis to further assess the long‐term efficacy and safety of HIF‐PHD inhibitors for the treatment of anaemia in CKD.…”

Section: What Is Known and Objectivementioning

confidence: 99%

Long‐term efficacy and safety of hypoxia‐inducible factor prolyl hydroxylase inhibitors in anaemia of chronic kidney disease: A meta‐analysis including 13,146 patients

et al. 2021

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What is known and objective Previous studies based on small‐sample clinical data proved that short‐term use of hypoxia‐inducible factor prolyl hydroxylase (HIF‐PHD) inhibitors increased haemoglobin levels in anaemic patients with chronic kidney disease (CKD). However, these studies reached conflicting conclusions on iron parameters and adverse event profiles. Our meta‐analysis aimed to evaluate the long‐term efficacy and safety of HIF‐PHD inhibitors in renal anaemia. Methods Randomized controlled trials comparing treatment with HIF‐PHD inhibitors versus placebo or erythropoiesis‐stimulating agents (ESAs) were thoroughly searched in the PubMed, Embase, Cochrane Library and international clinical trial registries. Meta‐analysis was performed on main outcomes with random effects models. Results and discussion A total of 30 studies comprising 13,146 patients were included. The HIF‐PHD inhibitors used included roxadustat, daprodustat, vadadustat, molidustat, desidustat and enarodustat. HIF‐PHD inhibitors significantly increased haemoglobin levels in comparison with placebo [weighted mean difference (WMD) 1.53, 95% confidence interval (CI) 1.39 to 1.67] or ESAs (WMD 0.13, 95% CI 0.03 to 0.22). Hepcidin, ferritin and serum iron levels were decreased, while total iron binding capacity and transferrin levels were increased in the HIF‐PHD inhibitor group versus those in placebo or ESAs group. Additionally, HIF‐PHD inhibitors medication was associated with cholesterol‐lowering effects. As for safety, the risk of serious adverse events in the HIF‐PHD inhibitor group was increased in comparison with placebo group [risk ratio (RR) 1.07, 95% CI 1.01 to 1.13], but comparable to the ESAs group (RR 1.02, 95% CI 0.94 to 1.10). Compared with placebo, the agents increased the risk of diarrhoea (1.21, 1.00 to 1.47), nausea (1.46, 1.09 to 1.97), oedema peripheral (1.32, 1.01 to 1.59), hyperkalemia (1.27, 1.05 to 1.54) and hypertension (1.34, 1.02 to 1.76). Compared with ESAs, the drugs increased the risk of vomiting (1.30, 1.02 to 1.65), headache (1.27, 1.05 to 1.53) and thrombosis events (1.31, 1.05 to 1.63). What is new and conclusion HIF‐PHD inhibitors treatment effectively increased haemoglobin levels and promoted iron utilization in anaemic patients with CKD, and they were well tolerated for long‐term use. In order to avoid unfavourable effects of excessive iron consumption, it was appropriate to administer HIF‐PHD inhibitors in combination with iron supplements for long‐term treatment.

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Section: What Is Known and Objectivementioning

confidence: 99%

Long‐term efficacy and safety of hypoxia‐inducible factor prolyl hydroxylase inhibitors in anaemia of chronic kidney disease: A meta‐analysis including 13,146 patients

et al. 2021

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“…The hypoxia response pathway, when activated by hypoxia, minimizes such damage; however, long-term adaptations and tissue remodeling triggered by the hypoxia response pathway itself can also cause damage 5,6 . The pathway can also be activated to promote anaerobic glycolysis (i.e., the Warburg effect) even under aerobic conditions, including in some cancers, in dividing stem cells, in the proliferation of activated T lymphocytes, during endometrial decidualization, and presumably in patients receiving prolyl hydroxylase inhibitors to treat anemia associated with chronic kidney disease 1,[7][8][9][10][11][12][13][14][15][16][17] . HIF-1 clearly upregulates enzymes that mediate anaerobic glycolysis, but our understanding of the complete adaptive response mobilized by pathway activation has largely focused on gene expression changes in cultured cells [18][19][20][21] .…”

Section: Main Textmentioning

confidence: 99%

The Hypoxia Response Pathway Promotes PEP Carboxykinase Expression And Gluconeogenesis

Vora

et al. 2021

Preprint

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Actively dividing cells, including some cancers, rely on aerobic glycolysis rather than oxidative phosphorylation to generate energy, a phenomenon termed “the Warburg effect1.” Constitutive activation of the Hypoxia Inducible Factor (HIF-1), a transcription factor known for mediating an adaptive response to oxygen deprivation (hypoxia), is a hallmark of the Warburg effect2. HIF-1 is thought to promote glycolysis and suppress oxidative phosphorylation. Here, we show instead that HIF-1 can promote gluconeogenesis. Using a multiomics approach, we determined the genomic, transcriptomic, and metabolomic landscapes regulated by constitutively active HIF-1 in C. elegans. We performed RNA-seq and ChIP-seq under aerobic conditions in mutants lacking EGL-9, a key negative regulator of HIF-1, and then integrated these approaches to identify over a hundred genes directly and functionally upregulated by HIF-1. We show that HIF-1 directly promotes the expression of PCK-1, a PEP carboxykinase that is a rate-limiting mediator of gluconeogenesis3. This activation of PCK-1 by HIF-1 promotes survival in response to both oxidative and hypoxic stress. Our work is the first to identify functional direct targets of HIF-1 in vivo, and it describes the first complete metabolome induced by constitutive HIF-1 activation in any organism.

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“…However, patients treated with ESAs are exposed to supraphysiologic EPO concentrations, potentially leading to adverse events [ 5 , 37 , 43 , 44 ]. Some studies have found an increased risk of cardiovascular events and stroke in both hemodialysis-dependent and nonhemodialysis-dependent patients targeted at higher Hb levels [ 45 , 46 ].…”

Section: Erythropoiesis-stimulating Agentsmentioning

confidence: 99%

“…The prevalence of renal anemia gradually rises as the estimated glomerular filtration rate (eGFR) decreases [ 3 ]. Anemia occurs in approximately half of patients with CKD stage G4 and in more than 90% of the end-stage renal disease patients who undergo dialysis [ 3 , 4 , 5 ]. Correcting renal anemia can decrease mortality, hospitalization, risk of CKD progression, and improve the health-related quality of life [ 5 , 6 , 7 , 8 , 9 , 10 ].…”

Section: Introductionmentioning

confidence: 99%

“…Anemia occurs in approximately half of patients with CKD stage G4 and in more than 90% of the end-stage renal disease patients who undergo dialysis [ 3 , 4 , 5 ]. Correcting renal anemia can decrease mortality, hospitalization, risk of CKD progression, and improve the health-related quality of life [ 5 , 6 , 7 , 8 , 9 , 10 ]. The principial mechanism implicated in the development of renal anemia is a combination of inadequate erythropoietin (EPO) synthesis and EPO resistance [ 11 , 12 ].…”

Section: Introductionmentioning

confidence: 99%

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Current Status of Renal Anemia Pharmacotherapy—What Can We Offer Today

Borawski

Małyszko

Kwiatkowska

et al. 2021

JCM

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Chronic kidney disease (CKD) is one of the fastest-growing major causes of death internationally. Better treatment of CKD and its complications is crucial to reverse this negative trend. Anemia is a frequent complication of CKD and is associated with unfavorable clinical outcomes. It is a devastating complication of progressive kidney disease, that negatively affects also the quality of life. The prevalence of anemia increases in parallel with CKD progression. The aim of this review is to summarize the current knowledge on therapy of renal anemia. Iron therapy, blood transfusions, and erythropoietin stimulating agents are still the mainstay of renal anemia treatment. There are several novel agents on the horizon that might provide therapeutic opportunities in CKD. The potential therapeutic options target the hepcidin–ferroportin axis, which is the master regulator of iron homeostasis, and the BMP-SMAD pathway, which regulates hepcidin expression in the liver. An inhibition of prolyl hydroxylase is a new therapeutic option becoming available for the treatment of anemia in CKD patients. This new class of drugs stimulates the synthesis of endogenous erythropoietin and increases iron availability. We also summarized the effects of prolyl hydroxylase inhibitors on iron parameters, including hepcidin, as their action on the hematological parameters. They could be of particular interest in the out-patient population with CKD and patients with ESA hyporesponsiveness. However, current knowledge is limited and still awaits clinical validation. One should be aware of the potential risks and benefits of novel, sophisticated therapies.

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Effect of hypoxia-inducible factor-prolyl hydroxylase inhibitors on anemia in patients with CKD: a meta-analysis of randomized controlled trials including 2804 patients

Abstract: (2020) Effect of hypoxia-inducible factor-prolyl hydroxylase inhibitors on anemia in patients with CKD: a metaanalysis of randomized controlled trials including 2804 patients,

Cited by 24 publications

References 56 publications

Long‐term efficacy and safety of hypoxia‐inducible factor prolyl hydroxylase inhibitors in anaemia of chronic kidney disease: A meta‐analysis including 13,146 patients

Long‐term efficacy and safety of hypoxia‐inducible factor prolyl hydroxylase inhibitors in anaemia of chronic kidney disease: A meta‐analysis including 13,146 patients

The Hypoxia Response Pathway Promotes PEP Carboxykinase Expression And Gluconeogenesis

Current Status of Renal Anemia Pharmacotherapy—What Can We Offer Today

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