Effects of hypoxia-inducible factor-prolyl hydroxylase inhibitors vs. erythropoiesis-stimulating agents on iron metabolism in non-dialysis-dependent anemic patients with CKD: A network meta-analysis

Front Endocrinol (Lausanne). 2023 Mar 16:14:1131516. doi: 10.3389/fendo.2023.1131516. eCollection 2023.

Abstract

Objective: To compare the effects of five hypoxia-inducible factor-prolyl hydroxylase domain inhibitors (HIF-PHIs), two erythropoiesis-stimulating agents (ESAs), and placebo on iron metabolism in renal anemia patients with non-dialysis-dependent chronic kidney disease (NDD-CKD).

Method: Five electronic databases were searched for studies. Randomized controlled clinical trials comparing HIF-PHIs, ESAs, and placebo in NDD-CKD patients were selected. The statistical program used for network meta-analysis was Stata/SE 15.1. The main outcomes were the change in hepcidin and hemoglobin (Hb) levels. The merits of intervention measures were predicted by the surface under the cumulative ranking curve method.

Results: Of 1,589 original titles screened, data were extracted from 15 trials (3,228 participants). All HIF-PHIs and ESAs showed greater Hb level-raising ability than placebo. Among them, desidustat demonstrated the highest probability of increasing Hb (95.6%). Hepcidin [mean deviation (MD) = -43.42, 95%CI: -47.08 to -39.76], ferritin (MD= -48.56, 95%CI: -55.21 to -41.96), and transferrin saturation (MD = -4.73, 95%CI: -5.52 to -3.94) were decreased, while transferrin (MD = 0.09, 95%CI: 0.01 to 0.18) and total iron-binding capacity (MD = 6.34, 95%CI: 5.71 to 6.96) was increased in HIF-PHIs versus those in ESAs. In addition, this study observed heterogeneity in the ability of HIF-PHIs to decrease hepcidin. Compared with darbepoetin, only daprodustat (MD = -49.09, 95% CI: -98.13 to -0.05) could significantly reduce hepcidin levels. Meanwhile, daprodustat also showed the highest hepcidin-lowering efficacy (84.0%), while placebo was the lowest (8.2%).

Conclusion: For NDD-CKD patients, HIF-PHIs could ameliorate functional iron deficiency by promoting iron transport and utilization, which may be achieved by decreasing hepcidin levels. Interestingly, HIF-PHIs had heterogeneous effects on iron metabolism.

Systematic review registration: https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=242777, Identifier CRD42021242777.

Keywords: erythropoiesis-stimulating agent; hepcidin; hypoxia-inducible factor prolyl hydroxylase inhibitor; iron metabolism; renal anemia.

Publication types

  • Meta-Analysis
  • Systematic Review
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anemia* / drug therapy
  • Anemia* / etiology
  • Erythropoiesis
  • Hematinics* / pharmacology
  • Hematinics* / therapeutic use
  • Hepcidins / metabolism
  • Hepcidins / pharmacology
  • Hepcidins / therapeutic use
  • Humans
  • Hypoxia / drug therapy
  • Hypoxia-Inducible Factor-Proline Dioxygenases / metabolism
  • Hypoxia-Inducible Factor-Proline Dioxygenases / pharmacology
  • Hypoxia-Inducible Factor-Proline Dioxygenases / therapeutic use
  • Iron
  • Network Meta-Analysis
  • Prolyl Hydroxylases / metabolism
  • Prolyl Hydroxylases / pharmacology
  • Prolyl-Hydroxylase Inhibitors* / pharmacology
  • Prolyl-Hydroxylase Inhibitors* / therapeutic use
  • Randomized Controlled Trials as Topic
  • Renal Insufficiency, Chronic* / complications
  • Renal Insufficiency, Chronic* / drug therapy
  • Renal Insufficiency, Chronic* / metabolism
  • Transferrin

Substances

  • Hepcidins
  • Hematinics
  • Prolyl-Hydroxylase Inhibitors
  • Prolyl Hydroxylases
  • Hypoxia-Inducible Factor-Proline Dioxygenases
  • Transferrin
  • Iron

Grants and funding

This study was supported by grants from the National Natural Science Foundation of China (No. 81570612 and No. 81870497) and Jiangsu Province Key Research and Development Program-Social Development (BE2021737), which were awarded to Prof. XLZ.