Iron deficiency is associated with higher risks for death and major adverse cardiovascular events (MACE) in patients with nondialysis-dependent chronic kidney disease (NDD-CKD) — even in those without anemia, a new study finds.

Investigators led by Roberto Pecoits-Filho, MD, of Pontificia Universidade Catolica do Parana in Curitiba, Brazil, performed an international cohort study of 5145 patients (mean age 69 years; 59% male) from Brazil, France, the United States, and Germany enrolled in the Chronic Kidney Disease Outcomes and Practice Patterns Study (CKDopps).

According to results published in the Journal of the American Society of Nephrology, patients with a transferrin saturation (TSAT) of 15% or less (the lowest TSAT category) had the highest risks for death and MACE prior to renal replacement therapy, using TSAT 26%-35% as a reference range. Among patients with a TSAT of 15% or less, those with and without anemia had an adjusted 59% and 47% increased risk for all-cause mortality, respectively. Patients in the lowest TSAT category also had an adjusted 2.7- and 1.4-fold increased risk for MACE. The MACE outcome was defined as any cardiovascular event leading to death, as well as nonfatal acute myocardial infarction, stroke, and heart failure hospitalization. Of the cohort, 18% of patients had TSAT 15% or less, 45% had diabetes, 28% had coronary artery disease, and 15% had heart failure. Erythropoiesis-stimulating agents (ESAs) were prescribed at baseline for 13%, and intravenous (IV) or oral iron for 21%.

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TSAT and mortality displayed a U-shaped association, with that highest risks at TSAT 15% or less and 46% or more, according to the investigators. Spline analysis found the lowest risk for all-cause mortality and MACE at TSAT 40%. No relationship was observed for ferritin, except an elevated risk for all-cause mortality at 300 ng/mL or greater.

Iron therapy in CKD has focused primarily on supporting erythropoiesis, the investigators stated.

“This study provides observational support to the hypothesis that [iron deficiency], regardless of anemia status, may affect clinical outcomes in patients with ND[D]-CKD,” Dr Pecoits-Filho’s team wrote.

They noted that well-designed randomized controlled trials are needed to assess the clinical benefits of iron supplementation for patients with iron deficiency, with and without anemia, and thereby confirm their study’s findings.

“Proactive iron interventions, particularly IV iron, may lead to better tissue iron delivery and therefore better outcomes,” the investigators wrote.

Disclosure: This research was supported by Vifor-Fresenius Medical Care Renal Pharma Ltd. Please see the original reference for a full list of disclosures.


Guedes M, Muenz DG, Zee J, et al; on behalf of CKDopps investigators. 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. Published online July 8, 2021. doi:10.1681/ASN.2020101531