Higher Transferrin Saturation Levels Linked to Fewer CV Events in CKD

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A transferrin saturation (TSAT) level lower than 30% was linked to a significantly higher incidence of cardiovascular (CV) events in patients with chronic kidney disease (CKD) receiving an erythropoiesis-stimulating agent (ESA), according to analysis of the BRIGHTEN Trial.¹

By comparison, TSAT levels of 30–40% were associated with a better cardiovascular prognosis, independent of ferritin levels, in this population with CKD, even after multivariate adjustment for potential confounders.

“Therefore, this study is considered a vital report in real-life clinical practice showing the association between TSAT and patient prognosis in treating anemia with ESAs in patients with CKD,” wrote the investigative team, led by Kentaro Nakai, division of nephrology and dialysis center at Japanese Red Cross Fukuoka Hospital.

Anemia has been associated with renal prognosis and life expectancy, with decreased renal function leading to anemia and contributing to a cycle of worsening prognosis.² ESAs are widely used to treat anemia in patients with CKD, without the need for blood transfusions.

However, there are lingering concerns about the paradoxical association between therapeutic interventions and cardiovascular disease (CVD) with increasing dosing of ESAs.³

The BRIGHTEN trial is a multi-center, prospective, observational study assessing ESA resistance to darbepoetin alfa in treating anemia in non-dialysis-dependent CKD.⁴ For this analysis, Nakai and colleagues sought to evaluate the target TSAT levels to reduce CV events in patients with CKD treated for anemia with long-acting ESA therapy.¹

This analysis evaluated 1040 of the original 1980 patients with non-dialysis-dependent CKD, who were aged ≥20 years with an estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2 and hemoglobin <11 g/dL. Patients were treated with darbepoetin alfa for 96 weeks.

Study endpoints were categorized as the occurrence of cardiovascular events, including fatal and non-fatal events. Nakai and colleagues assessed the association between transferrin saturation and the cumulative incidence of CV events using the Kaplan-Meier method.

Patients had a mean age of 69.9 years and 58.8% of the population was male, with an average body mass index (BMI) of 23.2. Iron was administered to 14.5% of the population at study initiation. TSAT levels gradually increased until approximately 12 weeks, rapidly increasing and reaching a plateau at 24 weeks.

After the exclusion of 684 patients without sufficient TSAT data, the 1040 patients experienced 103 events, including 35 hospitalizations for congestive heart failure, 18 for cerebrovascular disease, 12 for angina pectoris, and 8 for ischemic heart disease requiring invasive intervention.

Survival curve analysis for cardiovascular events revealed those with TSAT ≥30% experienced significantly better prognosis, than those with TSAT 20–30%, which remained significant after adjustment (adjusted hazard ratio [aHR], 0.34; 95% CI, 0.22 - 0.52; P <.001).

Moreover, in the stratified analysis, patients with TSAT 30–40% experienced a significantly lower risk of CV events, than those with TSAT 20–30%, even after adjusting for multivariate covariates (aHR, 0.33; 95% CI, 0.21 - 0.54; P <.001).

Survival curve analysis, specifically for heart failure events, also showed those with TSAT ≥30% had a significantly better prognosis than TSAT <30%, which remained significant after adjustment (aHR, 0.26; 95% CI, 0.13 – 0.53; P <.001).

“Although future studies, including RCTs, are needed to determine whether higher TSAT can improve prognosis, this study indicates that a higher threshold of 30% TSAT may change the prognosis,” Nakai and colleagues wrote.

References

1. _{Nakai K, Nishino T, Kagimura T, Narita I. Impact of transferrin saturation on cardiovascular events in non-dialysis-dependent chronic kidney disease patients treated with darbepoetin alfa. J Nephrol. Published online June 28, 2024. doi:10.1007/s40620-024-02000-y}
2. _{Shaikh H, Hashmi MF, Aeddula NR. Anemia of Chronic Renal Disease. [Updated 2023 Feb 24]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK539871/}
3. _{Gergal Gopalkrishna Rao SR, Bugazia S, Dhandapani TPM, et al. Efficacy and Cardiovascular Adverse Effects of Erythropoiesis Stimulating Agents in the Treatment of Cancer-Related Anemia: A Systematic Review of Randomized Controlled Trials. Cureus. 2021;13(9):e17835. Published 2021 Sep 8. doi:10.7759/cureus.17835}
4. _{Kato H, Nangaku M, Hirakata H, et al. Rationale and design of oBservational clinical Research In chronic kidney disease patients with renal anemia: renal proGnosis in patients with Hyporesponsive anemia To Erythropoiesis-stimulating agents, darbepoetiN alfa (BRIGHTEN Trial) [published correction appears in Clin Exp Nephrol. 2018 Feb;22(1):85-86. doi: 10.1007/s10157-017-1461-2]. Clin Exp Nephrol. 2018;22(1):78-84. doi:10.1007/s10157-017-1427-4}