Long-term intervention with heparins in a rat model of peritoneal dialysis.
BACKGROUND
Peritoneal dialysis (PD) is associated with functional and structural alterations of the peritoneal membrane, particularly new vessel formation and fibrosis. In addition to anticoagulant effects, heparin displays anti-inflammatory and angiostatic properties. Therefore, the effects of administration of heparins on function and morphology of the peritoneal membrane were studied in a rat PD model.


METHODS
Rats received 10 mL conventional PD fluid (PDF) daily, with or without the addition of unfractionated heparin (UFH) or low molecular weight heparin (LMWH) in the PDF (1 mg/10 mL intraperitoneally) via a mini access port. Untreated rats served as controls. After 5 weeks, a 90-minute functional peritoneal transport test was performed and tissues and peritoneal leukocytes were taken.


RESULTS
PD treatment induced loss of ultrafiltration (p<0.01), a twofold increase in glucose absorption (p<0.03), increased urea transport (p<0.02), and loss of sodium sieving (p<0.03), which were also found in the PDF+heparin groups. Increased peritoneal cell influx and hyaluronan production (p<0.02) as well as an exchange of mast cells and eosinophils for neutrophils after PD treatment were observed in PD rats; addition of heparin did not affect those changes. Mesothelial regeneration, submesothelial blood vessel and matrix formation, and accumulation of tissue macrophages were seen in PD animals. Spindle-shaped vimentin-positive and cytokeratin-negative cells indicated either partial injury and denudation of mesothelial cells or epithelial-to-mesenchymal transition. Neither UFH nor LMWH affected any of these morphological changes.


CONCLUSIONS
Within 5 weeks, PD treatment induces a chronic inflammatory condition in the peritoneum, evidenced by high transport, leukocyte recruitment, tissue remodeling, and induction of spindle-shaped cells in the mesothelium. Addition of LMWH or UFH to the PDF did not prevent these adverse PDF-induced peritoneal changes.
Schilte
Margot N
MN
Department of Molecular Cell Biology and Immunology, VU University Medical Center, Amsterdam, The Netherlands. m.schilte@vumc.nl
Loureiro
Jesus
J
Keuning
Eelco D
ED
ter Wee
Piet M
PM
Celie
Johanna W A M
JW
Beelen
Robert H J
RH
van den Born
Jacob
J
D000818:Animals; D000925:Anticoagulants / Q000008:administration & dosage* / Q000493:pharmacokinetics; D001692:Biological Transport / Q000502:physiology; D004195:Disease Models, Animal; D005355:Fibrosis / Q000209:etiology / Q000473:pathology / Q000517:prevention & control; D005500:Follow-Up Studies; D006493:Heparin / Q000008:administration & dosage* / Q000493:pharmacokinetics; D007676:Kidney Failure, Chronic / Q000378:metabolism / Q000628:therapy; D008297:Male; D008643:Mesentery / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000473:pathology / Q000517:prevention & control; D009852:Omentum / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D010530:Peritoneal Dialysis / Q000009:adverse effects / Q000379:methods*; D010537:Peritoneum / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D051381:Rats; D017208:Rats, Wistar; D013997:Time Factors
D000925:Anticoagulants; D006493:Heparin