Response by Ma et al . to the letter ‘Therapy gaps in HFrEF with CKD: time to close the loopholes’

We thank Dr Mei Li and colleagues for their insightful letter regarding our article ‘Therapy gaps for patients with heart failure and reduced kidney function: a prospective cohort study’.1 Their letter points to three methodological concerns that we aim to clarify. Li et al. correctly noted that we did not distinguish among the different cardiorenal syndromes in our analysis. This was an intentional decision aligned with the primary aim of our study to characterize how patients with chronic heart failure were managed in the ambulatory setting, where steady-state kidney function is assessed to inform treatment decisions. Our study's strength in excluding creatinine measurements during acute illness reduces the influence of transient kidney injury and better reflects chronic kidney function, which guides heart failure therapy initiation, as supported by major international guidelines.2 Indeed, as Dr Li suggested, understanding the trajectory of kidney function and cardiorenal phenotypes has important prognostic value, particularly around the time of heart failure hospitalization. However, the use of kidney function trajectory, particularly the eGFR (estimated glomerular filtration rate) slope, in the chronic heart failure setting requires further study to address challenges such as acute haemodynamic effects on GFR following initiation of guideline-directed medical therapy, changes in body composition, and heterogeneity in the heart failure population.3 Secondly, the exclusion of female sex from our final multivariable model for hyperkalaemia, once it did not reach predefined thresholds in univariable analysis, follows a commonly used approach in cardiovascular, epidemiologic, and clinical research to reduce the risk of overfitting. However, we agree that sex is biologically and clinically relevant in both heart failure and kidney disease, and that more detailed sex-stratified analyses and formal interaction testing between sex and kidney function would be valuable in larger cohorts or pooled datasets. Our findings should therefore be interpreted as demonstrating a strong, clinically meaningful association between reduced kidney function and increased hyperkalaemia risk, while acknowledging that a more definitive assessment of sex-specific differences will require studies with greater statistical power and a design specifically tailored to that question. Lastly, although we did not centrally adjudicate clinical outcomes, we used validated ICD (International Classification of Disease) based definitions within a province-wide administrative database to ensure data accuracy and completeness.4 Previously, we demonstrated that improvement in echocardiographic markers of cardiac remodelling through serial assessment is linked to persistent recovery in left ventricular ejection fraction and the ability to up-titrate medications such as renin–angiotensin system inhibitors and mineralocorticoid receptor antagonists.5 Nevertheless, the link between changes in heart failure parameters with the evolution of chronic kidney disease and patient-reported outcome measures represents another important and active avenue of research to improve heart failure and kidney care. All authors declare no disclosure of interest for this contribution. No new data were generated or analysed in support of this research. None.