Association of iron status with all-cause and cardiovascular mortality in individuals with Cardiovascular-Kidney-Metabolic syndrome stages 0-3

Technical Summary: Association of Iron Status with All-Cause and Cardiovascular Mortality in Individuals with Cardiovascular-Kidney-Metabolic Syndrome Stages 0-3

Problem Statement
Cardiovascular-Kidney-Metabolic (CKM) syndrome is a systemic disorder integrating metabolic diseases, chronic kidney disease (CKD), and cardiovascular disease (CVD). While the American Heart Association (AHA) has stratified CKM into five stages, individuals in stages 0–3 are often asymptomatic yet at high risk of progression to clinical CVD, kidney failure, and death. Although dysregulated iron metabolism is known to correlate with obesity, diabetes, CKD, and CVD, the specific relationship between iron status and mortality risks within the CKM stages 0–3 population remains under-investigated. This study addresses the gap in identifying easily obtainable clinical indicators to predict mortality in this specific high-risk cohort.

Methodology
The study utilized data from the National Health and Nutrition Examination Survey (NHANES) spanning 1999 to 2018.

• Population: The initial cohort included 101,316 participants. After applying exclusion criteria (age <20 or >79, pregnancy, cancer, missing CKM data, stage 4 CKM, absolute iron deficiency defined as ferritin <30 ng/mL, and missing iron indices), the final sample consisted of 7,663 individuals with ferritin data, 6,441 with total iron binding capacity (TIBC) data, and 6,440 with transferrin saturation (Tsat) data.
• Definitions: CKM stages 0–3 were defined according to AHA criteria, ranging from no risk factors (Stage 0) to subclinical CVD (Stage 3).
• Iron Indicators: Serum ferritin, TIBC, and Tsat were measured using various assays across survey cycles, with ferritin values linearly converted to a common standard (Roche e601 equivalent).
• Outcomes: Mortality data were linked to the National Death Index (NDI) as of December 31, 2019. Outcomes included all-cause mortality and CVD mortality (defined by specific underlying cause of death codes).
• Statistical Analysis: The researchers employed univariate and multivariate Cox regression models to calculate hazard ratios (HRs) and 95% confidence intervals (CIs). Three adjustment models were constructed, progressively controlling for demographics, lifestyle factors, and clinical covariates (blood pressure, lipids, HbA1c, BMI). Restricted cubic spline (RCS) regression with three knots was used to assess non-linear dose-response relationships. Kaplan-Meier survival analysis and subgroup analyses were also performed.

Key Results
The study identified distinct non-linear associations between specific iron indices and mortality risks:

1. Ferritin and All-Cause Mortality: A significant J-shaped association was observed (inflection point = 53.0 ng/mL; P for non-linearity = 0.009).

   • Below 53.0 ng/mL, each unit decrease in ferritin significantly increased all-cause mortality risk.
   • Above 53.0 ng/mL, each unit increase in ferritin significantly increased all-cause mortality risk.
   • In categorical analysis, the highest ferritin tertile had a significantly higher all-cause mortality risk compared to the middle tertile (HR: 1.2928).

2. Ferritin and CVD Mortality: An L-shaped association was found (inflection point = 100.0 ng/mL; P for non-linearity < 0.001).

   • Below 100.0 ng/mL, lower ferritin levels were significantly associated with higher CVD mortality risk.
   • Above 100.0 ng/mL, no significant relationship was observed between increasing ferritin and CVD mortality.
   • The lowest ferritin tertile had the highest CVD mortality risk compared to the middle tertile (HR: 1.6649).

3. TIBC and Mortality: A significant non-linear correlation existed between TIBC and all-cause mortality (inflection point = 67.1 µmol/L; P for non-linearity = 0.028).

   • Below 67.1 µmol/L, lower TIBC levels were associated with increased all-cause mortality risk.
   • The lowest TIBC tertile showed significantly elevated all-cause mortality risk compared to the middle tertile (HR: 1.2931).
   • No significant association was found between TIBC and CVD mortality.

4. Transferrin Saturation (Tsat): No significant associations were found between Tsat and either all-cause or CVD mortality (P > 0.05).

Significance and Claims
The authors claim that their study provides evidence that iron status is a predictor of mortality in individuals with CKM syndrome stages 0–3. Specifically:

• Dual Risk of Ferritin: Both excessively low and high ferritin levels are associated with increased all-cause mortality, while only low ferritin levels (<100 ng/mL) are associated with increased CVD mortality.
• TIBC as a Marker: Low serum TIBC (<67.1 µmol/L) serves as an indicator for higher all-cause mortality risk.
• Clinical Utility: The authors suggest that these findings offer a straightforward and practical tool for early risk assessment. They propose that maintaining ferritin within a favorable range (avoiding <53 ng/mL and >53 ng/mL for all-cause risk, and <100 ng/mL for CVD protection) and avoiding TIBC levels below 67.1 µmol/L could be beneficial for clinical management in this population.

The study acknowledges limitations, including its observational nature (precluding causal inference), potential residual confounding, and the use of single-point measurements for iron status, which may not capture dynamic fluctuations. The authors conclude that further research is needed to explore these relationships further.