Effect of ureteral ligation and nephrectomy on granulocyte-macrophage progenitor cells and azathioprine toxicity.
Using an in vitro quantitative clonal culture technique of bone marrow granulocyte-macrophage progenitor cells (colony-forming units culture (CFU-c)), we studied the hematopoietic toxicity of azathioprine after unilateral and bilateral ureteral ligation, unilateral and bilateral nephrectomy, and splenectomy in C57BL/6 mice. Analysis of femoral bone marrow 18 hr after i.p. injection of azathioprine (300 mg/m2) revealed increased CFU-c toxicity in comparison to controls as follows: (1) bilateral ureteral ligation, P less than 0.01; (2) bilateral nephrectomy, P less than 0.01; (3) unilateral ureteral ligation, P greater than 0.05 less than 0.1; (4) unilateral nephrectomy, P, not significant; and (5) splenectomy, P, not significant. Extrapolation from a dose-response curve for the toxicity of azathioprine on the bone marrow CFU-c indicated that bilateral ureteral ligation and bilateral nephrectomy had the effect of a 25 to 50% increase in the azathioprine dose. After bilateral ureteral ligation, serum granulocyte-macrophage colony-stimulating factor levels were increased and in vitro tritiated thymidine suicide studies showed an increased proliferative rate of the CFU-c. Since azathioprine is a predominantly cell cycle-specific agent, we suggest that increased sensitivity to azathioprine is related to the increased proliferative rate of the CFU-c. The findings provide a rationale for a clinical policy of azathioprine reduction when there is depressed renal function.
D000818:Animals; D001379:Azathioprine / Q000633:toxicity*; D003114:Colony-Forming Units Assay; D004305:Dose-Response Relationship, Drug; D006098:Granulocytes / Q000187:drug effects*; D006412:Hematopoietic Stem Cells / Q000187:drug effects; D008026:Ligation; D008264:Macrophages / Q000187:drug effects*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009392:Nephrectomy; D014513:Ureter / Q000601:surgery*
D001379:Azathioprine