Soluble Flt-1 links microvascular disease with heart failure in CKD.

Chronic kidney disease (CKD) is associated with an increased risk of heart failure (HF). Elevated plasma concentrations of soluble Flt-1 (sFlt-1) have been linked to cardiovascular disease in CKD patients, but whether sFlt-1 contributes to HF in CKD is still unknown. To provide evidence that concludes a pathophysiological role of sFlt-1 in CKD-associated HF, we measured plasma sFlt-1 concentrations in 586 patients with angiographically documented coronary artery disease and renal function classified according to estimated glomerular filtration rate (eGFR). sFlt-1 concentrations correlated negatively with eGFR and were associated with signs of heart failure, based on New York Heart Association functional class and reduced left ventricular ejection fraction (LVEF), and early mortality. Additionally, rats treated with recombinant sFlt-1 showed a 15 % reduction in LVEF and a 29 % reduction in cardiac output compared with control rats. High sFlt-1 concentrations were associated with a 15 % reduction in heart capillary density (number of vessels/cardiomyocyte) and a 24 % reduction in myocardial blood volume. Electron microscopy and histological analysis revealed mitochondrial damage and interstitial fibrosis in the hearts of sFlt-1-treated, but not control rats. In 5/6-nephrectomised rats, an animal model of CKD, sFlt-1 antagonism with recombinant VEGF121 preserved heart microvasculature and significantly improved heart function. Overall, these findings suggest that a component of cardiovascular risk in CKD patients could be directly attributed to sFlt-1. Assessment of patients with CKD confirmed that sFlt-1 concentrations were inversely correlated with renal function, while studies in rats suggested that sFlt-1 may link microvascular disease with HF in CKD.

Bone marrow-derived cells and their conditioned medium induce microvascular repair in uremic rats by stimulation of endogenous repair mechanisms.

The reduced number of circulating stem/progenitor cells that is found in chronic kidney disease (CKD) patients may contribute to impaired angiogenic repair and decreased capillary density in the heart. Cell therapy with bone marrow-derived cells (BMDCs) has been shown to induce positive effects on the microvasculature and cardiac function, most likely due to secretion of growth factors and cytokines, all of which are present in the conditioned medium (CM); however, this is controversial. Here we showed that treatment with BMDC or CM restored vascular density and decreased the extent of fibrosis in a rat model of CKD, the 5/6 nephrectomy. Engraftment and differentiation of exogenous BMDCs could not be detected. Yet CM led to the mobilization and infiltration of endogenous circulating cells into the heart. Cell recruitment was facilitated by the local expression of pro-inflammatory factors such as the macrophage chemoattractant protein-1, interleukin-6, and endothelial adhesion molecules. Consistently, in vitro assays showed that CM increased endothelial adhesiveness to circulating cells by upregulating the expression of adhesion molecules, and stimulated angiogenesis/endothelial tube formation. Overall, our results suggest that both treatments exert vasculoprotective effects on the heart of uremic rats by stimulating endogenous repair mechanisms.