# Erythropoiesis-stimulating agent hyporesponsiveness and malignancy development in patients with non-dialysis chronic kidney disease: a prospective cohort study

## TL;DR

This study finds that poor response to ESA treatment in CKD patients may indicate a higher risk of developing cancer.

## Contribution

The study introduces ESA hyporesponsiveness as a potential clinical marker for undiagnosed malignancy in non-dialysis CKD patients.

## Key findings

- Poor ESA response at 12 weeks was linked to a 2.07-fold higher malignancy risk.
- Patients with declining ESA responsiveness after 12 weeks had a 2.01-fold higher malignancy risk.
- ESA hyporesponsiveness is suggested as a marker for increased cancer risk in NDD-CKD patients.

## Abstract

Erythropoiesis-stimulating agents (ESA) hyporesponsiveness may be linked to malignancy, but studies examining this association are limited. We investigated whether initial ESA hyporesponsiveness and changes in responsiveness may serve as clinical markers reflecting undiagnosed malignancy in patients with non-dialysis-dependent chronic kidney disease (NDD-CKD).

We used data from the BRIGHTEN, a prospective study of NDD-CKD patients with anemia. Initial ESA responsiveness was assessed using the erythropoietin resistance index (ERI-1B), calculated as the ratio of darbepoetin-alfa dose (μg) to hemoglobin concentration (g/dL) at 12 weeks after darbepoetin-alfa initiation. ESA responsiveness trends after 12 weeks were analyzed using a joint latent class model (JLCM). The associations of both initial ESA responsiveness and ESA responsiveness trends after 12 weeks with malignancy development were analyzed using a Cox proportional hazards model.

Of the 1641 patients analyzed, 44 developed new malignancies. Patients with poor ESA response at 12 weeks (ERI-1B > 3.8 μg/g/dL) had a higher incidence of malignancy compared to those with better ESA response (adjusted hazard ratio [HR]: 2.07; 95% confidence interval [CI]: 1.07–4.00). Furthermore, based on the JLCM, patients in the poor response group, characterized by a faster decline in ESA responsiveness after 12 weeks, had a higher risk of malignancy than the good response group (adjusted HR: 2.01; 95% CI: 1.08–3.72).

Both initial ESA hyporesponsiveness and subsequent declines in responsiveness were significantly associated with the development of malignancy in patients with NDD-CKD. ESA hyporesponsiveness may serve as a clinical marker that reflects an increased risk of undiagnosed malignancy.

The online version contains supplementary material available at 10.1007/s10157-025-02769-7.