抗HBV药物富马酸替诺福韦二吡呋酯长期低剂量灌胃大鼠的肾脏毒性观察OACSTPCD

Objective To observe the renal injury in rats after long-term low-dose intragastric administration of teno-fovir disoproxil fumarate(TDF)in order to evaluate the safety of this drug.Methods Thirty SD rats were randomly di-vided into the control group,normal saline group,TDF-0w group,TDF-4w group,and TDF-8w group,with 6 rats in each group.Rats in the TDF-0w,TDF-4w,and TDF-8W groups were given TDF 1 mg/(kg·d)by gavage for 6 weeks,and the drug withdrawal time was 0,4,and 8 weeks,respectively.Rats in the normal saline group were given the same volume of normal saline by gavage for 6 weeks,and rats in the blank control group were allowed to eat and drink freely for 6 weeks.Blood phosphorus,blood calcium,blood β2-microglobulin(β2-MG),serum creatinine(Scr),urine β2-MG and urine β-N-acetylglucosaminidase(NAG)were detected by Sunrise microplate analyzer.After the rats were sacrificed,the kidney tis-sues were taken for HE staining and Massion staining to observe the pathological changes of kidney tissues.The relative ex-pression levels of kidney injury molecule 1(Kim-1)antibody,anion transporter 1(Oat1),anion transporter 2(Oat2)and multidrug resistanence-associated protein 4(Mrp4)mRNA in the renal tissues were detected by real-time fluorescence quantitative PCR.Western blotting was used to detect the relative expression of Kim-1 and Mrp4 protein in kidney tissues.Results There were no significant differences in serum phosphorus,serum calcium,serum β2-MG,serum Scr or urine β2-MG among these groups(all P>0.05).The urinary NAG water in the TDF-4w group was significantly lower than that in the blank control,saline,TDF-0w,and TDF-8w groups(all P<0.05).In the blank control group and the normal saline group,the glomerular structure was intact,the renal tubular epithelial cells were arranged neatly,and the renal basement membrane was intact without lesions.Compared with the blank control group and the saline group,the TDF-0w group showed mild/moderate swelling,degeneration and degranulation of some renal tubular epithelial cells,obvious renal fibro-sis and inflammatory cell infiltration,but the overall glomerular structure was intact,and no obvious renal tubular necrosis was observed.Compared with the TDF-0w group,the TDF-4w group and TDF-8w group had improved glomerular patholog-ical morphology,reduced renal fibrosis and inflammatory cell infiltration.Compared with the blank control group and the normal saline group,the relative expression of Kim-1,Oat1,Oat2 and Mrp4 mRNA and Kim-1 and Mrp4 protein in kid-ney tissue of the TDF-0w group and the TDF-4w group increased;the above indexes in the TDF-0w group,TDF-4w group and TDF-8w group decreased in turn(all P<0.05).Conclusion Long-term low-dose intragastric administration of TDF can cause pathological damage of renal tubules in rats,which can be alleviated over the withdrawal time of TDF.