# Incidence of new-onset HFpEF across CKD stages and Its association with cardio-renal, inflammatory, and fibrotic biomarkers

## TL;DR

This study shows that heart failure with preserved ejection fraction (HFpEF) becomes more common as kidney disease worsens, and adding biomarker data improves risk prediction.

## Contribution

The study introduces a biologically anchored, multimarker approach to improve HFpEF risk prediction in CKD patients beyond clinical factors.

## Key findings

- HFpEF incidence increases with CKD stage and albuminuria severity.
- Biomarker domains like cardiac stretch and fibrosis significantly predict HFpEF risk.
- Adding biomarker domains improves risk model discrimination and reclassification.

## Abstract

Chronic kidney disease (CKD) substantially increases the risk of heart failure with preserved ejection fraction (HFpEF). In this study, we quantified prospective, stage-specific incidence and evaluated whether biologically anchored, multimarker domains improve prediction beyond clinical factors.

We conducted a single-center, prospective cohort study (2019–2024) of adults with CKD G1–G5 (not on dialysis) with a 36-month follow-up. Incident HFpEF was adjudicated by two cardiologists using Heart Failure Association—Pre-test assessment, Echocardiography and natriuretic peptide score, Functional testing, Final aetiology (HFA-PEFF) criteria with atrial fibrillation–adjusted natriuretic peptide thresholds, and death was treated as a competing event. Baseline biomarkers were grouped into five domains—cardiac stretch, myocyte injury, fibrosis/remodeling, renal injury/function, and inflammation—and standardized to domain z-scores. We estimated incidence per 100 person-years and adjusted associations using Cox and Fine–Gray models. Incremental value was assessed with changes in the C-statistic (ΔC), continuous net reclassification improvement (NRI), integrated discrimination improvement (IDI), and calibration, with all metrics bootstrap-validated and false discovery rate control applied for domain tests.

Among 920 participants (mean age 64 ± 12 years; 43% women), 68 HFpEF events occurred over 2,582 person-years, corresponding to 2.63 [95% confidence intervals (CI) 2.01–3.26] events per 100 person-years. Incidence increased with CKD stage—G1 0.29%, G2 1.16%, G3a 1.76%, G3b 3.14%, G4 4.46%, and G5 6.93%—and with albuminuria—A1 1.32%, A2 2.42%, and A3 4.87%. Adjusted hazard ratios were 1.32 (1.17–1.49) per CKD stage and 1.41 (1.20–1.66) per albuminuria category. Per 1 SD, domains associated with higher risk were stretch 1.45 (1.23–1.72), fibrosis/remodeling 1.34 (1.13–1.59), injury 1.26 (1.07–1.48), renal 1.22 (1.04–1.43), and inflammation 1.17 (0.99–1.37). Adding biomarker domains improved discrimination from 0.72 to 0.79 (ΔC 0.07, 95% CI 0.03–0.10), with continuous NRI 0.20 and IDI 0.055.

In CKD, HFpEF incidence increases stepwise with CKD stage and albuminuria. Domain-based biomarker profiling, particularly cardiac stretch and fibrosis/remodeling, provides prognostic information beyond clinical factors, supporting a biologically anchored and parsimonious approach to risk stratification.

CKD severity, biomarker domains, and incident HFpEF.Flowchart illustrating the progression from CKD severity to cardiac response. It details stages including kidney barrier injury, systemic pathways, and cardiac response leading to HFpEF. Incident HFpEF rates are given overall and by CKD stage and albuminuria. Biomarker domains impact HR with cardiac stretch, fibrosis/remodeling, myocyte injury, renal injury/function, and inflammation affecting values. Incremental prediction shows improvements in C-statistic, continuous NRI, IDI, and calibration slope.

CKD severity, biomarker domains, and incident HFpEF.