J Am Soc Nephrol. 2015 Nov;26(11):2871-81.

Placental Growth Factor as a Predictor of Cardiovascular Events in Patients with CKD from the NARA-CKD Study.

Matsui M1, Uemura S1, Takeda Y1, Samejima K2, Matsumoto T1, Hasegawa A1, Tsushima H3, Hoshino E4, Ueda T1, Morimoto K1, Okamoto K1, Okada S1, Onoue K1, Okayama S1, Kawata H1, Kawakami R1, Maruyama N5, Akai Y1, Iwano M6, Shiiki H7, Saito Y8; NARA-CKD Investigators.
  • 1First Department of Internal Medicine and.
  • 2First Department of Internal Medicine and Department of Medicine, Ohyodo Town Hospital, Nara, Japan;
  • 3Department of Medicine, Ohyodo Town Hospital, Nara, Japan;
  • 4Department of Medicine, Saisei-kai Nara City Hospital, Nara, Japan;
  • 5Department of Cardiology, Nara City General Hospital, Nara, Japan;
  • 6Department of Nephrology, Fukui University, Fukui, Japan; and.
  • 7Department of Medicine, Uda City General Hospital, Nara, Japan.
  • 8First Department of Internal Medicine and Department of Regulatory Medicine for Blood Pressure, Nara Medical University, Nara, Japan; saitonaramed@gmail.com.




Placental growth factor (PlGF) contributes to atherogenesis through vascular inflammation and plaque destabilization. High levels of PlGF may be associated with mortality and cardiovascular disease, but the relationship between PlGF level and adverse outcomes in patients with CKD is unclear. We conducted a prospective cohort study of 1351 consecutive participants with CKD enrolled in the Novel Assessment of Risk management for Atherosclerotic diseases in CKD (NARA-CKD) study between April 1, 2004, and December 31, 2011. During a median follow-up of 3 years, 199 participants died and 383 had cardiovascular events, defined as atherosclerotic disease or heart failure requiring hospitalization. In adjusted analyses, mortality and cardiovascular risk increased in each successive quartile of serum PlGF level; hazard ratios (HRs) (95% confidence intervals [95% CIs]) for mortality and cardiovascular risk, respectively, were 1.59 (0.83 to 3.16) and 1.55 (0.92 to 2.66) for the second quartile, 2.97 (1.67 to 5.59) and 3.39 (2.20 to 5.41) for the third quartile, and 3.87 (2.24 to 7.08) and 8.42 (5.54 to 13.3) for the fourth quartile. The composite end point of mortality and cardiovascular events occurred during the study period in 76.4% of patients in both the highest PlGF quartile (≥19.6 pg/ml) and the lowest eGFR tertile (<30 ml/min per 1.73 m(2)). The association between PlGF and mortality or cardiovascular events was not attenuated when participants were stratified by age, sex, traditional risk factors, and eGFR. These data suggest elevated PlGF is an independent risk factor for all-cause mortality and cardiovascular events in patients with CKD.

KEYWORDS: VEGF; cardiovascular disease; cardiovascular events

PMID: 25788536



Placental growth factor (PlGF), a member of vascular endothelial growth factor (VEGF) family acts via fms-like tyrosine kinase receptor-1 (Flt-1) to stimulate angiogenesis and induce atherosclerotic lesions through recruitment and activation of macrophages. PlGF is originally identified from a human placental cDNA library, but along with other studies, we found its expression in lung, aorta and vein (Figure1). PlGF protein were highly expressed in atherosclerotic lesions in ApoE deficient mice which have impaired clearing of plasma lipoproteins and develop atherosclerosis in a short time (1).



VEGF and its receptor, Flt-1 are key regulators of angiogenic and atherogenic process, whereas PlGF is not needed for a healthy cardiovascular system in adults. However, PlGF expression is highly upregulated in pathological condition such as chronic kidney disease (CKD), heart failure and cancer. Elevations in PlGF have been attracting attention due to clinical utility.


PlGF has recently been reported as a potential predictor of survive and cardiovascular events, but the relationship between PlGF and adverse events was not fully understood in CKD patients. We have recently found increased plasma levels of PlGF in CKD model mice and elevated expression levels of PlGF mRNA in human vascular endothelial cells treated with serum from patients with advanced CKD (2, 3). These findings suggest PlGF is partly involved in the pathogenesis of CKD-associated atherosclerosis.


In the current study, we focused on 1351 CKD patients, all of whom serum levels of PlGF were measured with ELISA kit (R&D Systems, Minneapolis, MN). PlGF is inversely and significantly correlated with renal function (Figure 2), and multivariately associated with eGFR, hypoalbuminemia, C-reactive protein and hypo-HDL-emia. In adjusted analyses, hazard ratios of both mortality and cardiovascular events are consistently increased with increasing levels of PlGF. Subgroup and sensitivity analyses confirmed the robustness of our main results.


This study has three important implications. First, PlGF alone and combination with other biomarkers is used to identify and stratify CKD patients at high risk of mortality and cardiovascular events. Second, this risk stratification enables clinical physicians to allow earlier intervention for atherosclerotic disease. Third, PlGF may provide a novel therapeutic target for the treatment of cardiovascular diseases. Aflibercept and anti-PlGF antibody, novel anti-angiogenic and anti-atherogenic drugs with antagonizing PlGF signal, potentially improve the risk of cardiovascular morbidity and mortality in CKD patients.





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