Serum Biomarkers of Iron Stores Are Associated with Increased Risk of All-Cause Mortality and Cardiovascular Events in Nondialysis CKD Patients, with or without Anemia

J Am Soc Nephrol. 2021 Aug;32(8):2020-2030. doi: 10.1681/ASN.2020101531. Epub 2021 Jul 8.


Background: Approximately 30%-45% of patients with nondialysis CKD have iron deficiency. Iron therapy in CKD has focused primarily on supporting erythropoiesis. In patients with or without anemia, there has not been a comprehensive approach to estimating the association between serum biomarkers of iron stores, and mortality and cardiovascular event risks.

Methods: The study included 5145 patients from Brazil, France, the United States, and Germany enrolled in the Chronic Kidney Disease Outcomes and Practice Patterns Study, with first available transferrin saturation (TSAT) and ferritin levels as exposure variables. We used Cox models to estimate hazard ratios (HRs) for all-cause mortality and major adverse cardiovascular events (MACE), with progressive adjustment for potentially confounding variables. We also used linear spline models to further evaluate functional forms of the exposure-outcome associations.

Results: Compared with patients with a TSAT of 26%-35%, those with a TSAT ≤15% had the highest adjusted risks for all-cause mortality and MACE. Spline analysis found the lowest risk at TSAT 40% for all-cause mortality and MACE. Risk of all-cause mortality, but not MACE, was also elevated at TSAT ≥46%. Effect estimates were similar after adjustment for hemoglobin. For ferritin, no directional associations were apparent, except for elevated all-cause mortality at ferritin ≥300 ng/ml.

Conclusions: Iron deficiency, as captured by TSAT, is associated with higher risk of all-cause mortality and MACE in patients with nondialysis CKD, with or without anemia. Interventional studies evaluating the effect on clinical outcomes of iron supplementation and therapies for alternative targets are needed to better inform strategies for administering exogenous iron.

Keywords: anemia; chronic kidney disease; mortality.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Aged, 80 and over
  • Anemia, Iron-Deficiency / blood*
  • Anemia, Iron-Deficiency / etiology
  • Biomarkers / blood
  • Brazil / epidemiology
  • Cardiovascular Diseases / epidemiology*
  • Female
  • Ferritins / blood*
  • France / epidemiology
  • Germany / epidemiology
  • Humans
  • Male
  • Mortality
  • Proportional Hazards Models
  • Renal Insufficiency, Chronic / blood*
  • Renal Insufficiency, Chronic / complications
  • Risk Factors
  • Transferrin / metabolism*
  • United States / epidemiology


  • Biomarkers
  • Transferrin
  • Ferritins