Letter by Di Marco and Brand Regarding Article, “Reduction of Circulating Soluble fms-Like Tyrosine Kinase-1 Plays a Significant Role in Renal Dysfunction-Associated Aggravation of Atherosclerosis”
To the Editor:
In a recent issue of Circulation, Onoue et al1 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 intrigued 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 ApoE-nondeficient 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 al4 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.
Sources of Funding
This study was funded by the Stifterverband für die Deutsche Wissenschaft and Simmon-Claussen-Stiftung, grant H1405409999915626.
Onoue K, Uemura S, Takeda Y, Somekawa S, Iwama H, Imagawa K, Nishida T, Morikawa Y, Takemoto Y, Asai O, Soeda T, Okayama S, Ishigami K, Nakatani K, Kawata H, Horii M, Nakajima T, Akai Y, Iwano M, Saito Y. Reduction of circulating soluble fms-like tyrosine kinase-1 plays a significant role in renal dysfunction-associated aggravation of atherosclerosis. Circulation. 2009; 120: 2470–2477.
Di Marco GS, Reuter S, Hillebrand U, Amler S, Konig M, Larger E, Oberleithner H, Brand E, Pavenstadt H, Brand M. The soluble VEGF receptor sFlt1 contributes to endothelial dysfunction in CKD. J Am Soc Nephrol. 2009; 20: 2235–2245.
Onoue K, Uemura S, Takeda Y, Somekawa S, Iwama H, Nishida T, Morikawa Y, Nakagawa H, Tsutsumi T, Sung JH, Takemoto Y, Soeda T, Okayama S, Ishigami K, Kawata H, Horii M, Nakajima T, Saito Y. Usefulness of soluble Fms-like tyrosine kinase-1 as a biomarker of acute severe heart failure in patients with acute myocardial infarction. Am J Cardiol. 2009; 104: 1478–1483.
Guo Q, Carrero JJ, Yu X, Barany P, Qureshi AR, Eriksson M, Anderstam B, Chmielewski M, Heimburger O, Stenvinkel P, Lindholm B, Axelsson J. Associations of VEGF and its receptors VEGFR-1 and -2 with cardiovascular disease and survival in prevalent haemodialysis patients. Nephrol Dial Transplant. 2009; 24: 3468–3473.