Dose of doxorubicin determines severity of renal damage and responsivenessto ACE-inhibition in experimental nephrosis

Nephrosis induced by doxorubicin (adriamycin) is an experimental model of g lomerulosclerosis with relative stable proteinuria which is commonly used f or pharmacological intervention studies. It is induced by a single or a dou ble dose of doxorubicin, with doses that vary considerably among investigat ors from 2 to 7.5 mg/kg. Intervention studies with ACE-inhibitors in this m odel have provided conflicting results. We hypothesized that these discrepa ncies might be due to different properties of the doxorubicin model, relate d to the dose of doxorubicin used to induce proteinuria. We tested this hyp othesis by inducing doxorubicin nephrosis with 1, 2 and 3 mg/kg, and evalua ting the response to intervention with lisinopril. The 1-mg/kg doxorubicin dose did not induce significant proteinuria. The 2- and the 3-mg/kg dose re sulted in a proteinuria of 684+/-215 mg/24 h and 736+/-277 mg/24 h 6 weeks after induction, respectively (Mean+/-SD). Treatment with lisinopril 2 mg/k g/day reduced proteinuria to 160+/-170 mg/24 h(p<0.01) in the 2-mg/kg doxor ubicin group, whereas in the 3-mg/kg doxorubicin group, proteinuria did not respond to lisinopril (529+/-264 mg/24 h). In time control rats, proteinur ia remained stable. Renal damage developed in both time control groups, wit h a glomerulosclerosis score of 29+/-22 in the 2-mg/kg group and 84+/-41 in the 3-mg/kg doxorubicin group. Lisinopril resulted in a significantly lowe r glomerulosclerosis score in the 2-mg/kg doxorubicin group only (16+/-15, p<0.05), whereas the 3-mg/kg group showed no significant reduction (56+/-29 , NS). In conclusion, the dose of doxorubicin used to induce nephrosis is a n important determinant not only of the severity of the ensuring renal dama ge, but also of the response to intervention by ACE-inhibition. These findi ngs have an impact on the interpretation of intervention studies in this mo del. (C) 1999 Elsevier Science Inc.