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Background <p>Anemia is a common complication of chronic kidney disease (CKD), partly driven by IL-6–mediated chronic inflammation. Targeting this pathway represents a novel therapeutic strategy for patients with insufficient response to standard therapies. Ziltivekimab, the only IL-6 inhibitor being evaluated in CKD populations, is currently in phase III development; however, its specific effects on anemia have not been quantified to date. To address this critical gap, we conducted an exploratory meta-analysis of randomized controlled trials (RCTs) to assess the early-phase evidence for IL-6 inhibition in CKD-associated anemia.</p> Methods <p>Following PRISMA 2020 guidelines, we systematically searched PubMed, Cochrane Library, Europe PMC, ClinicalTrials.gov, and Google Scholar. Of 80 records, three RCTs (<i>N</i> = 337) met the inclusion criteria. The primary outcome was change in hemoglobin; secondary outcomes included adverse events and iron-related parameters. Data were pooled using a random-effects model, with sensitivity analysis (fixed-effects model) and GRADE certainty assessment.</p> Results <p>Ziltivekimab significantly increased hemoglobin versus placebo (MD = 0.87&#xa0;g/dL; 95% CI: 0.70–1.04; high certainty) over 12 weeks. Adverse events were similar between groups (RR = 0.95; 95% CI: 0.77–1.18; moderate certainty). Serum iron showed a borderline increase (MD = 22.36&#xa0;µg/dL; 95% CI: − 0.88 to 45.60), while ferritin showed no significant change (MD = − 3.44 ng/mL; 95% CI: − 25.10 to 18.22; low certainty). However, all outcomes were surrogate biomarkers, and findings should be interpreted as exploratory and hypothesis-generating.</p> Conclusion <p>These early-phase results suggest IL-6 inhibition with ziltivekimab may improve anemia in CKD, but larger, long-term trials are required to confirm efficacy, evaluate clinically meaningful outcomes, and establish safety.</p> <p><b>PROSPERO Registration</b>: CRD420251126701.</p> Graphical Abstract <p></p>

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Interleukin-6 Inhibition with Ziltivekimab in Chronic Kidney Disease–Associated Anemia: A Hypothesis-Generating Systematic Review and Meta-Analysis of Early-Phase Randomized Trials

  • 期刊论文

  • 发表日期：

    2026年3月30日

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  • Hafiz M. Ahmed,
  • Ubaid ur Rehman,
  • Muhammad Owais

摘要

Background

Anemia is a common complication of chronic kidney disease (CKD), partly driven by IL-6–mediated chronic inflammation. Targeting this pathway represents a novel therapeutic strategy for patients with insufficient response to standard therapies. Ziltivekimab, the only IL-6 inhibitor being evaluated in CKD populations, is currently in phase III development; however, its specific effects on anemia have not been quantified to date. To address this critical gap, we conducted an exploratory meta-analysis of randomized controlled trials (RCTs) to assess the early-phase evidence for IL-6 inhibition in CKD-associated anemia.

Methods

Following PRISMA 2020 guidelines, we systematically searched PubMed, Cochrane Library, Europe PMC, ClinicalTrials.gov, and Google Scholar. Of 80 records, three RCTs (N = 337) met the inclusion criteria. The primary outcome was change in hemoglobin; secondary outcomes included adverse events and iron-related parameters. Data were pooled using a random-effects model, with sensitivity analysis (fixed-effects model) and GRADE certainty assessment.

Results

Ziltivekimab significantly increased hemoglobin versus placebo (MD = 0.87 g/dL; 95% CI: 0.70–1.04; high certainty) over 12 weeks. Adverse events were similar between groups (RR = 0.95; 95% CI: 0.77–1.18; moderate certainty). Serum iron showed a borderline increase (MD = 22.36 µg/dL; 95% CI: − 0.88 to 45.60), while ferritin showed no significant change (MD = − 3.44 ng/mL; 95% CI: − 25.10 to 18.22; low certainty). However, all outcomes were surrogate biomarkers, and findings should be interpreted as exploratory and hypothesis-generating.

Conclusion

These early-phase results suggest IL-6 inhibition with ziltivekimab may improve anemia in CKD, but larger, long-term trials are required to confirm efficacy, evaluate clinically meaningful outcomes, and establish safety.

PROSPERO Registration: CRD420251126701.

Graphical Abstract