Elsevier

Cytokine

Volume 43, Issue 1, July 2008, Pages 98-101
Cytokine

Oxidative stress, phosphate and creatinine levels are independently associated with vascular endothelial growth factor levels in patients with chronic renal failure

https://doi.org/10.1016/j.cyto.2008.03.011Get rights and content

Abstract

Elevated VEGF levels has been reported in patients with chronic renal failure (CRF), but the reasons for its higher level in renal insufficiency remain unknown. We assessed VEGF, SOX markers: total peroxide, Cu/Zn superoxide dismutase (Cu/Zn SOD), the levels of autoantibodies against oxidized LDL (OxLDL-Ab), and inflammation markers: high sensitivity C-reactive protein (hs CRP), interleukine-6 (IL-6) and tumor necrosis factor α (TNF-α) in 55 CRF patients and 18 controls. The patients with CRF showed a significant increase in plasma levels of VEGF, markers of inflammation, total peroxide and Cu/Zn SOD levels compared with controls. The strong positive associations were between VEGF and creatinine, urea, phosphate and CaxP product (all p < 0.0001), Cu/Zn SOD (p < 0.001) and hs CRP levels (p < 0.01). VEGF showed a strong inverse relationship with eGFR (p < 0.0001). In multiple regression analysis increased Cu/Zn SOD, phosphate and creatinine levels were found to be independent factors affecting VEGF. This study documented significant elevation in plasma values of VEGF in patients with CRF, which appears early during the progression of renal insufficiency. Increased oxidative stress, phosphate levels and impaired elimination by kidney were the main factors affecting the plasma levels of this growth factor in CRF patients.

Introduction

Atherosclerosis and consequent cardiovascular disease (CVD) are recognized as leading reasons of the increased morbidity and mortality observed in patients with chronic renal failure (CRF). Accelerated atherosclerosis in this population appears to be caused by a synergism of different mechanisms, such as metabolic syndrome, anemia, inflammation, oxidative stress (SOX) and abnormal calcium and phosphate metabolism [1]. These non-traditional risk factors seem to appear early during the progression of kidney damage and probably are responsible for the large difference in cardiovascular mortality between patients with CRF and the general population [2].

Oxidative stress as well as inflammation are present in patients with CRF [3], [4], [5], [6], [7], and may contribute to enhanced cardiovascular complications in this population [1], [2]. On the other hand, atherosclerosis is also associated with increased expression of adhesion molecules, cytokines and growth factors—including vascular endothelial growth factor (VEGF), produced by cells participating in this process [8]. VEGF is a main regulator of blood vessel growth, it plays an important role in the maintenance of endothelial integrity and vascular permeability to serum proteins. Its level is increased in conditions associated with increased risk of vascular disease, for example in cardiac allografts atherosclerosis [9] or in patients with diabetic nephropathy [10]. However, controversy remains as to whether VEGF has vasoprotective [11] or atherosclerogenic effects [12]. Recently, Doi et al. [13] reported the contribution of VEGF to CRF progression, especially in males.

To our knowledge, there is only one report demonstrating elevated VEGF levels in non-diabetic predialysis uraemia [14] but the reasons for higher level of this growth factor in renal insufficiency are unknown. In our previous study, we have demonstrated the association between VEGF levels and oxidative stress in hemodialysis patients [15]. The aim of the present study was to determine VEGF levels across the whole range of renal function and the possible relationship between oxidative stress, inflammation and this growth factor level in uraemia.

Section snippets

Subjects

Fifty-five adult patients with CRF, who were clinically stable and free of active infection, and autoimmune diseases, participated in the study. None of the patients received immunosuppressive treatment, lipid-lowering agents, non-steroidal anti-inflammatory drugs or antioxidants such as vitamin E, C or allopurinol at the time of the study. End stage renal disease was attributed to glomerulonephritis in 22 cases, interstitial nephritis in 6, polycystic kidney disease in 9, hypertensive

Results

The demographic, biochemical and clinical characteristics of controls and CRF patients are shown in Table 1. There was no difference among CRF groups in age, BMI, total cholesterol, triglycerides, platelets, leukocytes, total protein, albumin, calcium, blood pressure and antihypertensive medication. Serum creatinine, urea, phosphate, and CaxP increased, as expected, whereas eGFR and hemoglobin levels decreased significantly as CRF advanced. Creatinine, urea, triglycerides, phosphate, and CaxP

Discussion

In this study, we have determined the plasma VEGF levels in patients with CRF stage 1 to 5, and we have tried to find the factors affecting its level in this population. This is the first study that shows an association between plasma VEGF levels, markers of renal function, oxidative stress and inflammation in patients with CRF. We also showed, that this effect is linear and is present already in patients with mild renal insufficiency. However, in the multiple regression analysis model the

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