Radiation-induced glomerular thrombus formation and nephropathy are not prevented by the ADP receptor antagonist clopidogrel.

PURPOSE: 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 AND MATERIALS: 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. CONCLUSION: 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.

Radiation nephropathy--the link between functional damage and vascular mediated inflammatory and thrombotic changes.

The extent of radiation-induced nephropathy, which develops progressively over periods of months to years after treatment, is strongly influenced by both total dose and dose per fraction. In this study we examined the relationship between the early expression of various thrombotic and inflammatory markers of endothelial cell (EC) damage in irradiated mouse kidneys and the subsequent development of nephropathy. Decreased levels of glomerular ADPase and increased levels of glomerular Vwf were seen from 4 or 20 weeks after irradiation, respectively. These pro-thrombotic changes were associated with increased fibrin/fibrinogen deposits, indicative of microthrombus formation, at later times. These events were, however, not sensitive to changes in total dose or dose per fraction, therefore they cannot be quantitatively linked to the development of radiation nephropathy. Increased leucocyte invasion of the renal cortex was also seen after irradiation; this was quantitatively dependent on both total dose and dose per fraction. Linear quadratic analysis of the leucocyte dose-response curves yielded an alpha/beta ratio of 7.7 Gy, which is significantly greater than the alpha/beta ratio or 2.7 Gy determined for nephropathy, indicating less fractionation sensitivity for the inflammatory response. We conclude that inflammatory changes contribute to, but do not entirely explain, radiation nephropathy. The role of thrombotic changes is less clear.

Influence of acetylsalicylic acid on development of radiation-induced nephropathy.

PURPOSE: Previous studies have demonstrated that long-term treatment with acetylsalicylic acid (ASA) can significantly reduce the renal functional impairment that develops after high doses of irradiation. The effect is hypothesized to be mediated by selective inhibition of thromboxane A2 synthesis and inhibition of platelet aggregation. The present study was undertaken to investigate this phenomenon further using more clinically relevant fractionated and re-irradiation schedules. METHODS AND MATERIALS: Groups of mice were given bilateral renal irradiation with a series of four or 20 daily fractions of X-rays, or 10 daily fractions with a single dose of re-irradiation (0-10 Gy) after 27 weeks. Half the mice received ASA in drinking water (2.4 g x l(-1)) from 1 week before the start of irradiation and continuously throughout the follow-up period. Renal function was assessed by clearance of [51Cr]EDTA, about every 4 weeks for up to 80 weeks after the start of treatment. Histological damage in representative groups of mice was also assessed. RESULTS: Oral administration of ASA caused inhibition of thromboxane A2 synthesis (to < 36% of controls) and a strong inhibition of platelet aggregation in whole mouse blood (ex vivo). Prolonged treatment with ASA also resulted in a small, non-significant reduction of radiation-induced renal functional damage. No reduction in histological damage was seen in the ASA treated mice. CONCLUSION: Long-term oral administration of ASA gave only a modest, non-significant reduction of renal radiation injury after clinically relevant fractionated irradiation schedules.