Attribute based cross classification analyses from the BRIGHTEN study reveal that therapeutic responsiveness to erythropoiesis stimulating agents predicts cardiorenal prognosis in renal anemia

Abstract

Abstract Renal anemia outcomes are influenced by sex and age; however, current guidelines for renal anemia lack sex- or age-specific standards for initiating treatment. Recently, the concept of attribute-based medicine has gained attention, with an emphasis on personalized approaches based on patient characteristics. As prognostic factors for renal and cardiovascular outcomes may vary between men and women, as well as between younger and older patients with chronic kidney disease (CKD), we aimed to investigate anemia treatment-related indicators influencing kidney disease progression and cardiovascular events across four age and sex attributes (cross-classified by sex and age < or ≥ 65 years). A total of 1,671 patients with CKD and renal anemia from the BRIGHTEN study, who were initiated on an erythropoiesis-stimulating agent (ESA) according to Japanese guidelines for renal anemia recommending initiating treatment when the hemoglobin (Hb) level is 11 g/dL), were analyzed using the ESA resistance index-1B (ERI-1B) and the initial ESA response index (iEResI). Baseline Hb levels were similar across all sub-groups (9.7–9.9 g/dL), and kidney function was lowest in younger men (estimated glomerular filtration rate, 15.6 ml/min/1.73 m2) and highest in older women (estimated glomerular filtration rate, 19.4 ml/min/1.73 m2). Darbepoetin alfa doses during 12 weeks were lowest in younger men (0.79 μg/kg) and highest in older women (1.08 μg/kg). Renal outcomes were the poorest in younger men and the best in older women. Cardiovascular outcomes were the poorest in older men and the best in younger women. Multivariable Cox analyses showed that baseline hemoglobin levels (hazard ratio [HR], 0.77; P < 0.001) and the iEResI (HR, 0.76; P < 0.001) were associated with kidney prognosis across the cohort, whereas ERI-1B was not. When stratified by cross-classification, kidney prognosis correlated with iEResI (HR, 0.63; P = 0.019) in younger men and with ERI-1B (HR, 1.10; P < 0.001) in older women. Renal outcomes were linked to hemoglobin levels and ESA responsiveness in younger men with the poorest outcomes and to ESA resistance in older women with the best outcomes. This study revealed that renal outcomes correlated with Hb levels and ESA responsiveness in patients with CKD and anemia, especially in younger men with poor renal outcomes and with ESA resistance in older women with the best renal outcomes. Cross-classification helps identify specific patient attributes that should be targeted for optimizing anemia treatment in CKD.