Progression of chronic adriamycin nephropathy in leukopenic rats

In this study, we examined the progression of chronic Adriamycin (ADR) nephropathy in mild leukopenic rats and tried to define the possible relationship between tubulointerstitial lesions and proteinuria in this model. Chronic ADR nephropathy was induced by 2 doses of ADR (2mg/kg) in 32 Sprague-Dawley rats. Eight of these were randomly assigned to cyclophosphamide treatment (50mg/kg), given intravenously every week, to keep the blood leukocyte count constantly lower than 5,000/mm³. Serial parameters were followed for 16 weeks including clearance studies with iothalamate and p-aminohippurate and the analysis of urinary protein composition by: (a) an enzymatic assay for β-glucosidase; (b) specific ELISA using antibodies against rat albumin and RBP, and finally (c) two-dimensional electrophoresis. ADR-treated rats rapidly (within 2 weeks) developed massive proteinuria which was in constant increment throughout the disease evolution in each single component (i.e., high and low molecular weight proteinuria, enzymuria) and developed renal insufficiency. At week 8, in ADR rats, glomerulosclerosis was mild whereas tubulointerstitial infiltrates predominated, characterized mainly by CD4 + T lymphocytes while CD8 + T lymphocytes were inconspicuous, and macrophages were only occasionally present. All such alterations had worsened after 16 weeks when the tubulointerstitial infiltration was associated with marked interstitial fibrosis and tubular atrophy. Leukopenia induced by cyclophosphamide was in all cases associated with a net amelioration of renal histopathology reducing tubulointerstitial infiltrates (by 40%) and glomerulosclerosis (33±5 vs. 52.2±7.5% sclerotic glomeruli) and also ameliorated glomerular filtration indexes (C(I) 780±40 vs. 447±66μl/min/kg^-1). In spite of these differences, albuminuria and urinary-retinol-binding protein were comparable at weeks 4, 8 and 16 in this group, while urinary β-glucosidase was decreased at week 16 (p