EFFECT OF URETERAL LIGATION AND NEPHRECTOMY ON GRANULOCYTE-MACROPHAGE PROGENITOR CELLS AND AZATHIOPRINE TOXICITY

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Abstract
Using an in vitro quantitative clonal culture technique of bone marrow granulocyte-macrophage progenitor cells (colony-forming units culture (CFU-c)), the hematopoietic toxicity of azathioprine was studied after unilateral and bilateral ureteral ligation, unilateral and bilateral nephrectomy and splenectomy in C57BL/6 mice. Analysis of femoral bone marrow 18 h after i.p. injection of azathioprine (300 mg/m2) revealed increased CFU-c toxicity in comparison to controls as follows: bilateral ureteral ligation, P < 0.01; bilateral nephrectomy, P < 0.01; unilateral ureteral ligation, P > 0.05 < 0.1; unilateral nephrectomy, P, not significant; and splenectomy, P, not significant. Extrapolation from a dose-response curve for the toxicity of azanthioprine on the bone marrow CFU-c indicated that bilateral ureteral ligation and bilateral nephrectomy had the effect of a 25-50% 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, increased sensitivity to azathioprine is apparently related to the increased proliferative rate of the CFU-c. A rationale for a clinical policy of azathioprine reduction when there is depressed renal function was provided.