Iron Therapy May Help Broader Group of Patients With Kidney Disease

A study published this week found that iron deficiency in patients with chronic kidney disease (CKD) was linked with a higher risk of death and cardiovascular events, whether they had anemia or not.

The results were drawn from the long-running Chronic Kidney Disease Outcomes and Practice Patterns Study (CKDopps), an observational study of patients with advanced CKD. Iron deficiency occurs in 30% to 45% of patients with CKD, so managing iron deficiency focuses on improving erythropoiesis, the production of red blood cells.

In this study, published in the Journal of the American Society of Nephrology, researchers studied patients in nephrology clinics in Brazil, France, the United States, and Germany in order to evaluate a possible anemia-independent association of iron stores in patients with or without the condition and not on dialysis on the risk of death and cardiovascular events.

The authors noted that patients with CKD not on dialysis with clinical factors pointing to the need for iron replacement therapy are typically undertreated. In addition, studies of patients with heart failure and similar iron deficiency status found improvement in cardiovascular outcomes when iron deficiency was treated, regardless of the presence of anemia.

The study included 5145 patients from CKDopps, using their first available iron saturation (TSAT) and ferritin levels as exposure variables. Cox models were used to estimate hazard ratios for all-cause mortality (ACM) and major adverse cardiovascular events (MACE), with progressive adjustment confounding variables. Further analysis using linear spline models were used to evaluate exposure-outcome associations.

Patients were followed for a median of 3 years; 59% were male, with a mean age of 69 years, and 45% had diabetes, 28% had coronary artery disease, and 15% had heart failure. The cohort had a mean eGFR 28 ml/min per 1.73 m2 and mean TSAT and ferritin of 24% and 196 ng/ml, respectively. Mean hemoglobin Hgb was 12.3 g/dl. Erythropoiesis stimulating agents were prescribed at baseline for 13% and 21% were prescribed iron.

The researchers found that low TSAT levels were linked with an increase in the risk of ACM and incidence of MACE, regardless of anemia status, with 47 deaths per 1000 patients each year, and 48 major cardiovascular events per 1000 patients.

Patients with low TSAT and high ferritin showed the highest risk of adverse clinical events.

Compared with patients with a TSAT of 26%–35%, those with a TSAT ≤15% had the highest adjusted risks for ACM and MACE.

Further analysis found that patients with a TSAT of 40% had the lowest risk for ACM and MACE.

Patients with TSAT ≥46% or ferritin ≥300 ng/ml had higher risks of ACM but not MACE, although the authors said that the results should be “cautiously interpreted” for several reasons. One hypothesis is that this subgroup has an increased risk of infectious disease, although this was not an endpoint in the study. It is also possible that TSAT levels above 45% “may be indicative of iron overload and iron-mediated oxidative stress, which may cause organ dysfunction and increased risks of adverse clinical events.”

Effect estimates were similar after adjustment for hemoglobin.

"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," said one of the authors, Roberto Pecoits-Filho, MD, PhD, of the Arbor Research Collaborative for Health, in Ann Arbor, Michigan, in a statement. He also said randomized controlled clinical trials are needed to establish the role of iron treatment in these patients.

Reference

Guedes M, Muenz D, Zee J, et al. Serum biomarkers of iron stores are associated with an increased risk of all-cause mortality and cardiovascular events in non-dialysis chronic kidney disease patients, with or without anemia. J Am Soc Nephrol. Published online July 8, 2021. doi:10.1681/ASN.2020101531