Pharmacodynamics of local heparin infusion in a canine renal allograft model.
Inasmuch as heparin has demonstrated immunosuppressive activity in vivo and in vitro, we utilized a canine renal transplant model to estimate the first-pass extraction of heparin during renal artery infusion and to examine the effect of regional heparin delivery on the histologic features of rejection and allograft survival. Four autotransplanted mongrel dogs with programmable, implantable pump/catheter systems received a continuous intrarenal heparin infusion which was increased daily in stepwise fashion. Activated coagulation time (ACT) rose linearly with local heparin dose, indicating that heparin clearance remained constant over the dosage range studied. Comparison of these ACT values with those measured during same-dose i.v. infusion and those predicted from i.v. bolus studies revealed that there was little or no first-pass renal extraction of heparin by the transplanted kidney. In nine allografted dogs, the heparin infusion rate was adjusted according to daily ACT to maximize local heparin delivery but still maintain the ACT close to 125% of base line. There was no difference in overall survival between the heparin-treated dogs and a group of 14 untreated controls, and vascular rejection was significantly more intense in the heparin-treated animals. We conclude that intrarenal dosing of heparin to the point of producing systemic anticoagulation is limited by failure of the transplanted kidney to eliminate drug and does not prolong canine renal allograft survival.
Gruber
S A
SA
Department of Surgery, University of Minnesota, Minneapolis.
Cipolle
R J
RJ
Tzardis
P
P
Skjei
K L
KL
Jossart
G
G
Abed
J F
JF
Canafax
D M
DM
Burke
B A
BA
Matas
A J
AJ
Hrushesky
W J
WJ
D000818:Animals; D004285:Dogs; D005260:Female; D006085:Graft Survival / Q000187:drug effects; D006493:Heparin / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology; D007263:Infusions, Parenteral; D007668:Kidney / Q000378:metabolism; D016030:Kidney Transplantation; D008297:Male; D008657:Metabolic Clearance Rate; D014182:Transplantation, Autologous; D014184:Transplantation, Homologous
D006493:Heparin