Kidney Week

Abstract: FR-PO0536

Proteomic Determinants of Diastolic Dysfunction and the Mediating Role of Kidney Function

Session Information

• CKM: Clinical - Trials, Epidemiology, and Biomarkers
  October 23, 2026 | Location: Exhibit Hall A, Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Cardiovascular-Kidney-Metabolic Health

• 602 Cardiovascular-Kidney-Metabolic Health: Clinical

Authors

• Liu, Chenyu, Case Western Reserve University, Cleveland, Ohio, United States

Chenyu Liu, MS

• Pillai, Gargi Vijayan, Case Western Reserve University, Cleveland, Ohio, United States

Gargi Vijayan Pillai

• Liu, Ruitao, Case Western Reserve University, Cleveland, Ohio, United States

Ruitao Liu, MSc

• Viswanath, Satish E., Case Western Reserve University, Cleveland, Ohio, United States

Satish E. Viswanath, PhD

• Iyengar, Sudha K., Case Western Reserve University, Cleveland, Ohio, United States

Sudha K. Iyengar, PhD

• Zhang, Liangliang, Case Western Reserve University, Cleveland, Ohio, United States

Liangliang Zhang, PhD

• Schelling, Jeffrey R., Case Western Reserve University, Cleveland, Ohio, United States

Jeffrey R. Schelling, MD

• Dobre, Mirela A., Case Western Reserve University, Cleveland, Ohio, United States

Mirela A. Dobre, MD, MPH, FASN

Background

Heart failure with preserved ejection fraction (EF) is highly prevalent in CKD, yet the biological pathways linking reduced eGFR to diastolic dysfunction (DD) remain incompletely understood. We investigated plasma proteins associated with DD and evaluated the mediating role of eGFR in the UK Biobank cohort.

Methods

We analyzed 4,987 UK Biobank participants with 1,459 available baseline plasma proteins (2006–2010) and follow-up cardiac MRI (2014-2019). The primary outcome was a composite of DD, defined as left ventricular (LV) EF > 50%, and one or more of the following: left atrium (LA) volume maximum index > 34 mL/m², LV hypertrophy, or LA ejection fraction ≤ 36%. Protein-outcome associations were assessed using logistic regression adjusted for age, sex, BMI, assay batch, diabetes, smoking, systolic blood pressure, and eGFR, with false discovery rate control at q<0.10. Mediation analyses evaluated eGFR as a mediator between protein levels and DD. Pathway enrichment analysis was performed using ranked signed statistics derived from fully adjusted models.

Results

Among 281 proteins associated with DD in models excluding eGFR, all demonstrated significant indirect effects through eGFR after q-value correction, with several showing >80% mediation. After eGFR adjustment, 107 proteins remained significantly associated with DD, whereas 174 lost significance, supporting a dominant eGFR-mediated pathway. Proteins with the highest mediation effects included COL6A3, insulin-like growth factor-binding protein 4 (IGFBP4), HSPG2, CD59, and tumor necrosis factor receptor superfamily member 1A (TNFRSF1A), with additional mediation-supported associations observed for natriuretic peptide precursor C (NPPC), WFDC2/HE4, fatty acid-binding protein 4 (FABP4), leptin, IL1RN, and agrin. Pathway analysis showed negative enrichment of complement and immune-regulatory pathways, with leading proteins involved in fibrinolysis, proteolytic remodeling, and immune regulation.

Conclusion

Diastolic dysfunction demonstrated a strong kidney function–linked proteomic signature, with eGFR mediating a substantial proportion of protein associations, supporting kidney dysfunction as a major upstream determinant of biological pathways associated with impaired diastolic function.