Abstract
Chronic kidney disease is common in heart failure with preserved ejection fraction (HFpEF). However, the biologic correlates and the prognostic significance of kidney injury (KI), above and beyond estimated glomerular filtration rate (eGFR) are not well understood. We evaluated the proteomic correlates and prognostic significance of KI assessed with a combination of plasma protein biomarkers in HFpEF.
Using baseline frozen plasma samples from the TOPCAT trial, we measured the following KI biomarkers using an aptamer-based assay (SomaScan®): cystatin-C (CST-C), fatty acid-binding protein-3 (FABP3), Beta-2 microglobulin (B2M), neutrophil gelatinase-associated lipocalin (NGAL), and kidney injury molecule-1 (KIM1). Factor analysis was used to extract the common variability underlying these biomarkers. We assessed the relationship between the KI factor score and the composite of death and heart failure hospital admission (DHFA). We used linear regression to assess the relationship between KI factor score and ∼5,000 plasma proteins, followed by pathway analysis, to assess proteomic correlates of KI. HFpEF participants enrolled in the Penn heart failure study (PHFS) were used as a validation cohort.
A single underlying KI factor underlying the variability of KI biomarkers was found. KI factor score was associated with diabetes, higher meta‐analysis global group in chronic HF (MAGGIC) risk scores, higher N-terminal B-type natriuretic peptide levels, lower estimated glomerular filtration rate (eGFR) and lower diastolic blood pressure. In Cox models (Figure) adjusted for the MAGGIC risk score and eGFR, KI was significantly and independently associated with the risk of DHFA (Standardized hazard ratio=1.98; 95%CI=1.1.59-2.47; P<0.0001). KI was predominantly associated to proteins and biologic pathways related to inflammation, complement activation, cholesterol homeostasis and fibrosis. KI was associated with 140 proteins which reproduced across cohorts after correction for multiple comparisons. Findings regarding clinical correlates, biologic associations, and prognostic significance of KI were also reproduced in the validation cohort.
KI, assessed with a combination of plasma proteins, is associated with adverse outcomes in HFpEF. This relationship is independent of baseline eGFR, suggesting that ongoing KI is related to adverse outcomes. Patients with HFpEF and ongoing KI exhibit a plasma proteomic signature indicative of inflammation, complement activation, fibrosis, and impaired cholesterol homeostasis.