Urinary enzymes as biomarkers of renal injury in experimental nephrotoxicity of immunosuppressive drugs

Urinary excretion of N-acetyl-βD-glucosaminidase (NAG) and of alanine-aminopeptidase (A AP) was studied after administration of cyclosporine A (CSA A), FK 506, or the corresponding vehicles to salt-depleted rats. On days 7, 14, and 28 after treatment for CSA and day 14 after treatment for FK 506, measurements of the urinary enzymes, serum creatinine (S_cr), creatinine clearance (Cl_Cr), and blinded renal histology were done. After 1 week on CSA there was a dramatic increase of 489% in the urinary excretion of AAP (162.6 IU/g Cr, CSA vs. 27.6 IU/g Cr control, p <03), a significant decrease of 32% in Cl_Cr, a significant increase of 41% in S_Cr, and mild proximal tubular atrophy and vacuolization. After 2 or 4 weeks of CSA treatment there were no more differences in the urinary AAP between CSA and control rats, but the urinary excretion of NAG was increased: 29.6 IU/g Cr, CSA vs. 20.9 IU/g Cr, control, p <03 on day 14 and 26.9 IU/g Cr, CSA vs. 21.5 IU/g Cr, control, p < 008 on day 28. At the same time there was a progressive decline of the Cl_Cr, a progressive increase in the S_Cr, and an increase in the severity of the histological lesion. After 14 days of treatment with FK 506 we observed a striking elevation in urinary AAP (62.6 IU/g Cr, FK 506 vs. 36.0 IU/g Cr, control, p <01) consistent with a significant decrease in Cl_Cr, a significant increase in S_Cr, and a moderate proximal tubular vacuolization and atrophy. Thus, there was an early and significant increase in enzymuria after treatment with both drugs, even in the presence of mild histological lesion, pointing to the values of AAP and NAG as markers of renal injury in CSA and FK experimental nephrotoxicity.