In a recent issue of Circulation, Onoue et al 1 described that circulating soluble fms-like tyrosine kinase-1 (sFlt-1), a soluble form of the vascular endothelial growth factor receptor 1, is reduced in patients with renal dysfunction as well as in an animal model of kidney disease, the 5/6 nephrectomized mice. In addition, they suggested that replacement therapy with recombinant human sFlt-1 ameliorates renal dysfunction-induced exacerbation of atherosclerosis in this model. We are extremely

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... trigued by these results because we also recently reported on this subject. 2 However, we have shown the opposite results. In our study, patients with decreased renal function (decreased glomerular filtration rate) presented increased plasma levels of sFlt-1, evidencing a significant negative correlation between them. Moreover, increased sFlt-1 levels correlated positively with proteinuria, endothelial dysfunction, and, even more interesting, the Framingham risk score. Increased cardiovascular events were also increased at high-plasma sFlt-1 levels. By using the rat 5/6 nephrectomy model, we confirmed the results found in humans by showing again that increased sFlt-1 levels are directly associated with the impairment of renal function. Two differences in our clinical study design could be relevant for the discrepancy between our results: the genetic background of the studied populations (Asians versus whites) and the blood sample (aortic versus peripheral). Concerning the experimental model, there are 2 open questions: what happens with sFlt-1 levels after nephrectomy in ApoEnondeficient mice? Are the authors sure that the human sFlt-1 protein can bind to the endogenous placental growth factor/vascular endothelial growth factor? We are surprised by the complete absence of sFlt-1 effects on blood pressure and renal function. As also described by the authors elsewhere, 3 sFlt-1 levels are not only increased in patients with acute myocardial infarction, but they serve as a promising biomarker for the development of severe acute heart failure after myocardial infarction. These results are in agreement with ours, which have shown a positive association between sFlt-1 levels and myocardial infarction in renal patients. Moreover, Guo et al 4 also showed that, in these patients, a high level of sFlt-1 is an independent risk factor for all-cause mortality. In our opinion, these findings suggest that increased sFlt-1 may constitute a surrogate marker as well as a novel cardiovascular risk factor in renal patients. Y. Reduction of circulating soluble fms-like tyrosine kinase-1 plays a significant role in renal dysfunction-associated aggravation of atherosclerosis. Usefulness of soluble Fms-like tyrosine kinase-1 as a biomarker of acute severe heart failure in patients with acute myocardial infarction. of VEGF and its receptors VEGFR-1 and -2 with cardiovascular disease and survival in prevalent haemodialysis patients.