Impact of chronic kidney disease on the association of vascular endothelial growth factor D with cardiovascular mortality in patients with suspected or known coronary artery disease: the ANOX study
Authors: Wada H , Suzuki M , Matsuda M , Ajiro Y , Shinozaki T , Sakagami S , Yonezawa K , Shimizu M , Funada J , Takenaka T , Nakayama T , Iguchi M , Abe M , Akao M , Hasegawa K 
Published: November 2023

Abstract

Background
Vascular endothelial growth factor D (VEGF-D) is a secreted glycoprotein that can induce lymphangiogenesis and angiogenesis. We recently demonstrated that serum levels of VEGF-D are independently associated with all-cause mortality in patients with suspected or known coronary artery disease (CAD). However, the impact of chronic kidney disease (CKD) on the associations of VEGF-D with cardiovascular (CV) events and mortality in those patients is unclear.

Methods
Serum VEGF-D levels were measured in 2,418 patients with suspected or known CAD undergoing elective coronary angiography. The primary outcome was CV death. The secondary outcomes were all-cause death, major adverse CV events (MACE) defined as a composite of CV death, nonfatal myocardial infarction, and nonfatal stroke, and heart failure (HF) hospitalization. Patients were divided into 2 groups according to the presence (CKD, n=999) or absence (non-CKD, n=1,419) of CKD, and followed up over a 6-year period.

Results
During the follow-up, 325 CKD and 211 non-CKD patients died from any cause, 116 CKD and 49 non-CKD patients died from CV disease, 173 CKD and 124 non-CKD patients developed MACE, and 169 CKD and 99 non-CKD patients developed HF hospitalization. After adjustment for potential clinical confounders and established CV biomarkers (i.e., N-terminal pro-brain natriuretic peptide, high-sensitivity cardiac troponin I, and high-sensitivity C-reactive protein), VEGF-D levels were significantly associated with CV death (hazard ratio [HR] for 1-SD increase, 1.20; 95% confidence interval [CI], 1.06–1.37), all-cause death (HR, 1.15; 95% CI, 1.05–1.25), MACE (HR, 1.15; 95% CI, 1.03–1.29), and HF hospitalization (HR, 1.15; 95% CI, 1.02–1.29) in CKD, while VEGF-D levels were significantly associated with HF hospitalization (HR, 1.27; 95% CI, 1.09–1.49), but not with CV death (HR, 0.98; 95% CI, 0.68–1.43), all-cause death (HR, 1.10; 95% CI, 0.94–1.28), or MACE (HR, 0.94; 95% CI, 0.74–1.20) in non-CKD patients. The addition of VEGF-D levels to the model with potential clinical confounders and established CV biomarkers significantly improved the prediction of CV death (P&lt;0.001 for continuous net reclassification improvement [NRI], P= 0.046 for integrated discrimination improvement [IDI]) and all-cause death (P&lt;0.001 for NRI, P=0.004 for IDI), but not that of MACE (P=0.001 for NRI, P= 0.080 for IDI) or HF hospitalization (P=0.542 for NRI, P=0.605 for IDI) in CKD, whereas the addition of VEGF-D levels did not improve the prediction of CV death (P=0.769 for NRI, P=0.717 for IDI), all-cause death (P=0.089 for NRI, P=0.485 for IDI), MACE (P=0.876 for NRI, P=0.313 for IDI) or HF hospitalization (P=0.532 for NRI, P=0.155 for IDI) in non-CKD patients.

Conclusions
The VEGF-D level independently predicted CV and all-cause mortality in CKD, but not in non-CKD patients with suspected or known CAD. The associations of VEGF-D with CV and all-cause mortality may depend on the presence of CKD.