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American Journal of Kidney Diseases

Cardiac and Kidney Adverse Effects of HIF Prolyl-Hydroxylase Inhibitors for Anemia in Patients With CKD Not Receiving Dialysis: A Systematic Review and Meta-analysis

  • Author Footnotes
    # Qiyan Zheng, and Yahui Wang contributed equally to this work.
    Qiyan Zheng
    Footnotes
    # Qiyan Zheng, and Yahui Wang contributed equally to this work.
    Affiliations
    Key Laboratory of Chinese Internal Medicine of Ministry of Education and Beijing, Dongzhimen Hospital Affiliated to Beijing University of Chinese Medicine, Beijing, 100700, China

    Shenzhen Key Laboratory of Hospital Chinese Medicine Preparation, Shenzhen Traditional Chinese Medicine Hospital, The Fourth Clinical Medical College of Guangzhou University of Chinese Medicine, Shenzhen, 518000, China

    Renal Research Institution of Beijing University of Chinese Medicine, Beijing, 100700, China
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  • Author Footnotes
    # Qiyan Zheng, and Yahui Wang contributed equally to this work.
    Yahui Wang
    Footnotes
    # Qiyan Zheng, and Yahui Wang contributed equally to this work.
    Affiliations
    Fangshan Hospital Affiliated to Beijing University of Chinese Medicine, Beijing, 102400, China
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  • Huisheng Yang
    Affiliations
    Shenzhen Maternity & Child Healthcare Hospital, Shenzhen, China
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  • Luying Sun
    Affiliations
    Key Laboratory of Chinese Internal Medicine of Ministry of Education and Beijing, Dongzhimen Hospital Affiliated to Beijing University of Chinese Medicine, Beijing, 100700, China

    Renal Research Institution of Beijing University of Chinese Medicine, Beijing, 100700, China

    Fangshan Hospital Affiliated to Beijing University of Chinese Medicine, Beijing, 102400, China
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  • Pingna Zhang
    Affiliations
    Key Laboratory of Chinese Internal Medicine of Ministry of Education and Beijing, Dongzhimen Hospital Affiliated to Beijing University of Chinese Medicine, Beijing, 100700, China

    Renal Research Institution of Beijing University of Chinese Medicine, Beijing, 100700, China
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  • Xueqin Zhang
    Affiliations
    Key Laboratory of Chinese Internal Medicine of Ministry of Education and Beijing, Dongzhimen Hospital Affiliated to Beijing University of Chinese Medicine, Beijing, 100700, China

    Renal Research Institution of Beijing University of Chinese Medicine, Beijing, 100700, China
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  • Jing Guo
    Affiliations
    Key Laboratory of Chinese Internal Medicine of Ministry of Education and Beijing, Dongzhimen Hospital Affiliated to Beijing University of Chinese Medicine, Beijing, 100700, China

    Renal Research Institution of Beijing University of Chinese Medicine, Beijing, 100700, China
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  • Yu Ning Liu
    Correspondence
    Prof. Yu Ning Liu, Department of Endocrinology Nephropathy of Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China.
    Affiliations
    Key Laboratory of Chinese Internal Medicine of Ministry of Education and Beijing, Dongzhimen Hospital Affiliated to Beijing University of Chinese Medicine, Beijing, 100700, China

    Renal Research Institution of Beijing University of Chinese Medicine, Beijing, 100700, China
    Search for articles by this author
  • Wei Jing Liu
    Correspondence
    Corresponding author: Prof. Wei Jing Liu, Department of Endocrinology Nephropathy of Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China.
    Affiliations
    Key Laboratory of Chinese Internal Medicine of Ministry of Education and Beijing, Dongzhimen Hospital Affiliated to Beijing University of Chinese Medicine, Beijing, 100700, China

    Renal Research Institution of Beijing University of Chinese Medicine, Beijing, 100700, China

    Zhanjiang Key Laboratory of Prevention and Management of Chronic Kidney Disease, Guangdong Medical University, Zhanjiang, Guangdong 524001, China
    Search for articles by this author
  • Author Footnotes
    # Qiyan Zheng, and Yahui Wang contributed equally to this work.
Published:November 14, 2022DOI:https://doi.org/10.1053/j.ajkd.2022.09.014

      Abstract

      Rationale & Objective

      Hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHIs) are novel, orally administered agents for anemia management in chronic kidney disease (CKD). We evaluated the cardiac and kidney-related adverse effects of HIF-PHIs among patients with CKD.

      Study Design

      Systematic review and meta-analysis of randomized controlled trials (RCTs).

      Setting & Study Populations

      Patients with anemia and CKD not receiving maintenance dialysis.

      Selection Criteria for Studies

      RCTs comparing HIF-PHIs to placebo or an erythropoiesis-stimulating agent (ESA) with primary outcomes of cardiac and kidney-related adverse events.

      Data Extraction

      Two independent reviewers evaluated RCTs for eligibility and extracted relevant data.

      Analytical Approach

      Dichotomous variables were pooled using the Mantel-Haenszel method and presented as risk ratios (RRs) with 95% confidence intervals (CI). Subgroup analyses evaluated different intervention times and HIF-PHIs, as well as phase 2 vs. phase 3 trials. The certainty of findings was rated according to GRADE criteria.

      Results

      Twenty-three studies with 15,144 participants were included. No significant difference in the risk of cardiac disorders was observed between the HIF-PHIs group and the placebo (RR=1.02; 95% CI, [0.89 to 1.16]; moderate certainty) or ESA groups (RR=1.06; 95% CI, [0.98 to 1.14]; low certainty). No significant difference in the risk of kidney-related adverse events was observed between the HIF-PHIs group and the placebo (RR=1.09; 95% CI, [0.98 to 1.20]; moderate certainty) or ESA groups (RR=1.00; 95% CI, [0.94 to 1.06]; low certainty).The occurrence of hypertension and hyperkalemia was higher in the HIF-PHIs group than in the placebo group (RR=1.35; 95% CI, [1.14 to 1.60]; high certainty and RR=1.25; 95% CI, [1.03 to 1.51]; high certainty, respectively). The occurrence of hypertension was lower in the HIF-PHIs group than in the ESA group (RR=0.89; 95% CI, [0.81 to 0.98]; moderate certainty). .

      Limitations

      The reporting criteria of cardiac and kidney-related events and dosage of HIF-PHIs were inconsistent across trials.

      Conclusions

      The occurrence of cardiac or kidney-related adverse events in the HIF-PHI groups were not different compared with placebo or ESA groups.

      Registration

      Registered at PROSPERO with record number CRD42021228243.

      Graphical abstract

      Keywords

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