People with chronic kidney disease (CKD) who are not dependent on dialysis and have iron deficiency show significant increases in the risk of major adverse cardiovascular events (MACE) and death, regardless of whether or not they have anemia, new research from a multinational cohort shows.

The results suggest that a “paradigm shift” in care might be necessary that involves “treating iron deficiency in patients without anemia with the aim of reducing mortality risk, particularly from cardiovascular causes,” first author Roberto Pecoits-Filho, MD, PhD, of Arbor Research Collaborative for Health, in Ann Arbor, Michigan, told Medscape Medical News.

“The motivation at the present is purely to correct anemia,” he noted.

“To our knowledge, this is the first observational study to evaluate MACE outcomes in nondialysis CKD patients exposed to iron deficiency,” Pecoits-Filho and colleagues write in their article, published online July 8 in the Journal of the American Society of Nephrology.

Heart Failure Studies Show Benefits of Iron Correction

Iron deficiency can occur with or without decreased hemoglobin (anemia) and kidney disease guidelines currently only recommend monitoring iron stores in patients with overt anemia who are being considered to start or are receiving maintenance therapy with erythropoiesis-stimulating agents, the researchers note.

But there is compelling evidence for the effects of correcting iron deficiency on clinical outcomes independent of hemoglobin levels from randomized controlled trials in patients with heart failure, say the authors. Several such trials have shown improvements in measures including cardiac function and mortality with treatment, particularly IV iron formulations, even among patients who are not anemic.

To investigate the relationship between iron deficiency and mortality and cardiovascular events among nondialysis-dependent patients with kidney disease regardless of anemia status, Pecoits-Filho and colleagues evaluated data on 5145 patients enrolled in the Chronic Kidney Disease Outcomes and Practice Patterns Study (CKDopps) in 2013-2017, an observational study of patients with advanced nondialysis CKD.

Patients in the multinational cohort, from Brazil, France, the United States, and Germany, were a mean age of 69; 59% were male, and their mean estimated glomerular filtration rate (eGFR) was 28 mL/min/1.73m².

Over a median follow-up of 3 years, there were 47 deaths and 48 MACE per 1000 patients each year.

Patients with the greatest levels of iron deficiency, with iron saturation levels of 15% or lower on the transferrin saturation index (TSAT), showed the highest risks for all-cause mortality (hazard ratio [HR], 1.44) and MACE (HR, 1.77) compared to those with iron levels of 26%-35% on the TSAT.

Randomized Controlled Trials Needed

Importantly, those results were independent of anemia status in the multivariate analysis that also adjusted for factors including age, sex, race, body mass index (BMI), eGFR, and comorbidities.

The lowest risk for all-cause mortality and MACE were observed with TSAT levels of 40%, while the risks for mortality and MACE increased by HR 1.10 and 1.16, respectively, for each 5-unit decrease in TSAT under 40%.

“In our study, we found that TSAT levels around 36%-45% were associated with lowest risks of both all-cause mortality and MACE,” the authors write.

The risk of all-cause mortality, but not MACE, was also increased with excessive iron, starting at TSAT levels that exceeded 46%.

Pecoits-Filho concludes that intervention studies addressing the impact of iron deficiency treatment beyond its erythropoietic effects “are necessary to challenge the anemia-focused paradigm of iron deficiency management in CKD, potentially fostering more optimal strategies for improving patient outcomes.”

Pecoits-Filho has received research grants from Fresenius Medical Care, the National Council for Scientific and Technological Development, honorarium (paid to employer) for participation in advisory boards and educational activities from AstraZeneca, Boehringer-Lilly, Novo Nordisk, Akebia, and Bayer.

J Am Soc Nephrol. Published online July 8, 2021. Full text

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