Radiation-induced glomerular thrombus formation and nephropathy are not prevented by the ADP receptor antagonist clopidogrel.
OBJECTIVE
To assess the effects of kidney irradiation on glomerular adenosine diphosphatase (ADPase) activity and intraglomerular microthrombus formation, and their correlation to the development of renal functional impairment.


METHODS
C3H/HenAf-nu(+) mice were given single-dose or fractionated kidney irradiations. Glomerular ADPase activity was measured using a cerium-based histochemical method. Microthrombus formation within the glomeruli was assessed by a semiquantitative immunohistochemical analysis of fibrinogen/fibrin deposits. Renal function was assessed by the [(51)Cr]EDTA retention assay.


RESULTS
The ADPase activity was significantly reduced, to approximately 50% of pretreatment value, 4--40 weeks after 10--16 Gy single-dose irradiation and at 44 weeks after 20 x 2 Gy. No dose--effect relationship was found. An approximately fourfold increase in glomerular fibrinogen/fibrin staining was observed at 1 year after irradiation. This increase was not influenced by treating the mice with daily, oral clopidogrel, a platelet ADP receptor antagonist, which reduced platelet aggregation by more than 75%. Radiation-induced impairment of glomerular filtration was also not affected by the clopidogrel treatment.


CONCLUSIONS
These data indicate that irradiation significantly reduced glomerular ADPase activity, which correlated with an increased glomerular fibrinogen/fibrin deposition. We were not able to reduce these prothrombotic changes, nor to protect against radiation nephropathy, by pharmacological intervention with an ADP-receptor antagonist.
te Poele
J A
JA
Division of Experimental Therapy, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
van Kleef
E M
EM
van der Wal
A F
AF
Dewit
L G
LG
Stewart
F A
FA
D000818:Animals; D001081:Apyrase / Q000037:antagonists & inhibitors*; D000077144:Clopidogrel; D019583:Dose Fractionation, Radiation; D004307:Dose-Response Relationship, Radiation; D004353:Drug Evaluation, Preclinical; D004492:Edetic Acid / Q000493:pharmacokinetics; D005260:Female; D005338:Fibrin Fibrinogen Degradation Products / Q000032:analysis; D005343:Fibrinolytic Agents / Q000627:therapeutic use*; D005919:Glomerular Filtration Rate / Q000528:radiation effects; D007091:Image Processing, Computer-Assisted; D007677:Kidney Function Tests; D007678:Kidney Glomerulus / Q000528:radiation effects*; D051379:Mice; D008809:Mice, Inbred C3H; D008819:Mice, Nude; D058919:Purinergic P2 Receptor Antagonists; D011833:Radiation Injuries, Experimental / Q000188:drug therapy / Q000517:prevention & control*; D011836:Radiation Tolerance; D013927:Thrombosis / Q000188:drug therapy / Q000209:etiology / Q000517:prevention & control*; D013988:Ticlopidine / Q000031:analogs & derivatives / Q000627:therapeutic use*
D005338:Fibrin Fibrinogen Degradation Products; D005343:Fibrinolytic Agents; D058919:Purinergic P2 Receptor Antagonists; D004492:Edetic Acid; D000077144:Clopidogrel; D001081:Apyrase; D013988:Ticlopidine