title: Heparin use during dialysis sessions induces an increase in the antiangiogenic factor soluble Flt1.
abstract: BACKGROUND
  Soluble Flt1 (sFlt1) is a potent inhibitor of vascular endothelial growth factor, secreted mainly by the placenta, endothelial cells and monocytes. Increased sFlt1 serum levels correlate with endothelial dysfunction and cardiovascular complications in dialysis patients. However, the impact of dialysis by itself on sFlt1 serum levels remains unknown.
  
  
  METHODS
  We assessed sFlt1 kinetics during dialysis and the impact of different dialysis techniques [high-flux haemodialysis (HD), haemodiafiltration (HDF)] and heparinization procedures on sFlt1 serum levels in 48 patients on regular dialysis.
  
  
  RESULTS
  sFlt1 serum levels increased as early as 1 min after the start of dialysis and peaked at 15 min before returning to baseline at 4 h [mean peak level 2551 pg/mL, versus 102 before dialysis (P < 0.0001)]. sFlt1 kinetics were similar with two different dialysis membranes. In contrast, when unfractionated heparin (UH) and low-molecular-weight heparin (LMWH) were omitted during dialysis (HD or pre-dilution HDF), no significant increase in sFlt1 levels occurred. Conversely, delayed administration of LMWH (after 30 min of a heparin-free HD) induced a sharp increase in sFlt1. Similarly, when UH and LMWH were omitted and citrate-based dialysate or a heparin-coated membrane was used, sFlt1 levels remained unchanged. When heparinization procedures were the same, no difference in sFlt1 levels was noted between HD and HDF. In vitro, UH and LMWH failed to induce sFlt1 release by monocytes from controls or HD patients. These findings suggest that priming of monocytes on the extracorporeal circuit is required for heparin-induced sFlt1 release or that endothelial cells contribute to this increase.
  
  
  CONCLUSIONS
  Our results indicate that heparin-based HD induces a major sFlt1 release, which may exacerbate the anti-angiogenic state and thus endothelial dysfunction, commonly found in dialysis patients.
authors: INSERM UMR S-1064, ITUN, Université de Nantes, Nantes, France Department of Nephrology, CHU de Nantes, Nantes, France.
authors: Frédéric
authors: F
authors: Lavainne
authors: INSERM UMR S-1064, ITUN, Université de Nantes, Nantes, France.
authors: Emmanuelle
authors: E
authors: Meffray
authors: Centre for Nephrology, University College London, Royal Free Hospital, London, UK.
authors: Ruth J
authors: RJ
authors: Pepper
authors: INSERM UMR S-1064, ITUN, Université de Nantes, Nantes, France.
authors: Mélanie
authors: M
authors: Néel
authors: Department of Nephrology, CHU de Nantes, Nantes, France.
authors: Catherine
authors: C
authors: Delcroix
authors: Centre for Nephrology, University College London, Royal Free Hospital, London, UK.
authors: Alan D
authors: AD
authors: Salama
authors: INSERM UMR S-1064, ITUN, Université de Nantes, Nantes, France Department of Nephrology, CHU de Nantes, Nantes, France.
authors: Fadi
authors: F
authors: Fakhouri
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000925:Anticoagulants / Q000494:pharmacology*; D042783:Endothelial Cells / Q000378:metabolism; D004730:Endothelium, Vascular / Q000166:cytology / Q000503:physiopathology; D005260:Female; D017583:Hemodiafiltration; D006493:Heparin / Q000494:pharmacology*; D006495:Heparin, Low-Molecular-Weight / Q000494:pharmacology; D006801:Humans; D007676:Kidney Failure, Chronic / Q000097:blood* / Q000628:therapy*; D008297:Male; D008567:Membranes, Artificial; D008875:Middle Aged; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D011247:Pregnancy; D006435:Renal Dialysis / Q000379:methods; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000097:blood* / Q000187:drug effects*; D055815:Young Adult
chemical_list: D000925:Anticoagulants; D006495:Heparin, Low-Molecular-Weight; D008567:Membranes, Artificial; D006493:Heparin; C501162:FLT1 protein, human; D040281:Vascular Endothelial Growth Factor Receptor-1
keywords: VEGF; haemodialysis; heparin; sFlt1