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Regardless of anemia, iron deficiency in patients with late-stage chronic kidney disease (CKD) was linked with adverse health outcomes, an observational study found.

In 5,145 patients with stage 3-5 CKD not on dialysis, a transferrin saturation (TSAT) of 15% or less was associated with a higher risk for all-cause mortality before reaching dialysis or kidney transplant, as compared to TSAT levels of 26-35% (HR 1.44, 95% CI 1.03-2.01), according to Roberto Pecoits-Filho, MD, PhD, of the Arbor Research Collaborative for Health in Ann Arbor, Michigan, and colleagues.

A TSAT of 15% or less was also tied to a higher risk for major adverse cardiac events (MACE), including myocardial infarction and stroke (HR 1.77, 95% CI 1.12-2.81), even after adjusting for confounders such as age, sex, race, body mass index, and estimated glomerular filtration rate (eGFR).

A TSAT of 40% was linked to the lowest level of risk, the group wrote in the . During the median 3-year follow-up, each 5-unit decrease in TSAT was linked with a 10% increase in mortality risk (HR 1.10, 95% CI 1.02-1.19) and 16% increase in cardiovascular risk (HR 1.16, 95% CI 1.05-1.28).

On the other side of this U-shaped association, high TSAT levels were also associated with all-cause mortality. The highest risks were seen at each ends of the extremes: a TSAT of 15% or below and 46% or above, with the lowest risk seen in the 36-45% range.

However, the association between TSAT and MACE was linear, with the highest risk seen at levels of 15% or below, without any excess risk for those with a TSAT of 46% or higher.

"Interventional studies evaluating the impact of iron supplementation and alternative targets on clinical outcomes are needed to better inform strategies for administration of exogenous iron," Pecoits-Filho's group suggested.

They added that for managing anemia in non-dialysis CKD patients suggest screening and monitoring of iron stores, although this recommendation is only for patients with anemia already being considered for erythropoiesis stimulating agents.

"Despite these evidence-based recommendations published almost a decade ago, our reported that non-dialysis CKD patients with clear indications for iron replacement therapy remain considerably under-treated," wrote Pecoits-Filho and co-authors.

The group also noted that in previous studies of patients with heart failure, iron supplementation -- particularly intravenous iron -- was associated with improvements in measures of cardiac function, such as ejection fraction. Iron supplementation also has demonstrated mortality benefits, even in non-anemic patients.

The study included patients from Brazil, France, Germany, and the U.S. enrolled in the Chronic Kidney Disease Outcomes and Practice Patterns Study () from 2013 to 2017. Participants were at least 18 years old and had an eGFR under 60 mL/min/1.73² at enrollment. Individuals with a kidney transplant or on maintenance dialysis were excluded. Study participants had an average age of 69 years, 59% were male, and they had a mean eGFR of 28 mL/min/1.73².

Iron deficiency was assessed using the first available TSAT and ferritin measurements. Anemia was defined as a hemoglobin level less than 12 g/dL. Among those without anemia, about 12% had a TSAT of 15% or below. As for those with anemia, about 25% had a TSAT of 15% or below.

The researchers also examined ferritin laboratory measurements but found no association between low levels with either of the study outcomes. They did however find a higher all-cause mortality risk linked with high ferritin levels of 300 ng/mL or more (HR 1.29, 95% CI 1.03-1.61).

The concept of tissue iron deficiency may explain how low iron levels could affect clinical outcomes independent of anemia, the researchers said.

"Tissues involved in high metabolic demand, such as muscles, are particularly affected by such tissue iron deficiency," they said. "This framework may explain improvements in functional status followed by iron administration in heart failure patients."

They continued, referencing that showed non-dialysis CKD patients with iron deficiency had reduced overall physical health-related quality of life even after adjusting for hemoglobin levels, "which further reinforces the concept that tissue iron deficiency results in lower functionality."

On top of the observational design, a chief limitation of the study was the exclusion of patients with missing TSAT or ferritin measurements -- as 36% of those in CKDopps were missing these measurements -- possibly introducing a selection bias. In addition, because cause-specific mortality data were missing from some countries, the cardiovascular outcomes analysis was performed in only a subset of patients.

"Particularly, the exclusion of data from Germany for this outcome may have reduced the power to detect associations, particularly for ferritin," Pecoits-Filho's group noted.

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