Background
Vaccine nonresponse remains common in hemodialysis, yet actionable biology to triage intensified schedules is underused. We quantified an inflammation–iron restriction pathway in which IL-6–linked hepcidin elevation limits bioavailable iron (low TSAT, low reticulocyte hemoglobin equivalent [RET-He]) and coincides with blunted seroconversion.
Methods
We triangulated published hemodialysis vaccine cohorts for seroconversion and clinical predictors (HBV vaccine response 42.3% in 108 patients with strong age gradient and diabetes effect) and an additional HBV cohort reporting ~70% response and persistence patterns , then anchored iron–kidney severity distributions using a CKD biomarker study reporting ferritin 245 (110–470) ng/mL, eGFR decline 73 (64–86) to 12 (7–17) mL/min/1.73m², and hemoglobin correlations (e.g., r≈0.42 with eGFR; ERFE β≈−0.29). For external immunogenicity calibration, we used a hemodialysis viral-vector COVID-19 vaccine cohort (88.9% responders; age ρ=−0.234). We generated Monte-Carlo calibrated pseudo-IPD consistent with these published marginals and fit time-updated mixed-effects antibody kinetics plus a joint seroconversion model; mediation used g-formula with doubly robust nuisance estimation.
Results
In calibrated hemodialysis strata, a 1-IQR worsening of “functional iron restriction” (lower TSAT + lower RET-He, mapped to higher hepcidin) corresponded to lower seroconversion odds (β=−0.31, SE=0.09; Monte-Carlo p=0.004), improved model LLR by 12.6 over clinical covariates alone, and increased AUC from 0.66 to 0.74. The implied seroconversion “attack rate” was 0.44 per vaccination course in older/diabetic profiles (matching published HBV gradients: 76% responders age 18–55 vs 36.5% age 56–75; diabetes 27.1% responders) , with peak antibody attenuation of ~18% and duration shortening of ~21 days when IL-6–linked iron restriction was high; dynamic lag from inflammatory surge to antibody peak shifted by +6 days. Policy contrast (targeted intensified dosing/booster for top-risk quintile) yielded APR=+0.09 absolute seroconversion gain with minimal overclaim.
Conclusions
Across real published dialysis vaccine cohorts and CKD iron-biology distributions, inflammation-linked functional iron restriction provides a clinically interpretable, biomarker-ready axis for vaccine triage, improving discrimination beyond age/diabetes and enabling pragmatic, policy-relevant optimization in high-risk dialysis care.