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

Abstract

BackgroundApproximately 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.MethodsThe 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.ResultsCompared 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.ConclusionsIron 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.

Safety and effectiveness of ferric citrate hydrate in serum phosphorus management of patients with chronic kidney disease: a long-term, real-world, observational, post-marketing surveillance study

“…In these PD patients, median ferritin levels did not exceed 300 ng/mL (262.1 ng/mL) and the hemoglobin level was well maintained within the target range recommended in the JSDT guidelines [17]. The importance of treating anemia and iron deficiency in CKD patients has recently been receiving increasing attention, as several studies have demonstrated that these conditions are associated with an increased risk of hospitalizations, cardiovascular events, or all-cause mortality [18,19]. FC is expected to contribute to the treatment of anemia and iron deficiency in CKD patients, but caution regarding iron overload is required, especially in PD patients.…”

Characteristics and predictors of mortality on haemodialysis in Brazil: a cohort of 5,081 incident patients

“…It is interesting the association between TSAT ≥ 20% and the lower risk of death seen in the present study. Such association was found and well explored in a recent CKDopps study with pre-dialysis chronic kidney disease (CKD) patients [ 15 ]. However, whether low TSAT was just a marker of inflammation/malnutrition [ 16 , 17 ] or iron replacement would be effective to improve outcomes is a question that could only be answered through interventional studies.…”

Iron deficiency screening is a key issue in chronic inflammatory diseases: A call to action

“…A recent international (Brazil, France, Germany, and United States) observational study included 1545 nondialyzed CKD patients with and without anemia [27]. Patients with TSAT ≤15% had the highest risks of all‐cause mortality and major adverse cardiovascular events, compared with patients with TSAT 26%–35%.…”