Early detection of ketoprofen-induced acute kidney injury in sheep as determined by evaluation of urinary enzyme activities

Abstract

Objective-To evaluate early indicators of renal tissue destruction and changes in urinary enzyme activities in sheep during the first hours after acute kidney injury induced by administration of an overdose of an NSAID. Animals-12 adult female sheep. Procedures-Acute kidney injury was induced in 6 sheep by administration of ketoprofen (30 mg/kg, IV) and detected by evaluation of urinary protein concentration, iohexol clearance, and results of histologic examination. Six sheep served as control animals. Blood and urine samples were collected for up to 24 hours after administration of ketoprofen. Plasma concentrations of urea, creatinine, albumin, and total protein; plasma activities of alkaline phosphatase, acid phosphatase, γ-glutamyl transpeptidase (GGT), matrix metalloproteinase (MMP)-2, and MMP-9; and urinary creatinine and protein concentrations, specific gravity, and activities of alkaline phosphatase, acid phosphatase, GGT, lactate dehydrogenase, N-acetyl-β-D-glucosaminidase (NAG), MMP-2, and MMP-9 were measured. Urinary protein concentration and enzyme activities were normalized on the basis of urinary creatinine concentrations and reported as ratios. Results-Many urinary enzyme-to-creatinine ratios increased before the plasma creatinine concentration exceeded the reference value. Urine NAG, lactate dehydrogenase, and acid phosphatase activities were increased beginning at 2 hours after ketoprofen administration, and alkaline phosphatase, GGT, and MMP-2 activities were increased beginning at 4 hours after ketoprofen administration. Most peak urinary enzyme-to-creatinine ratios were detected earlier than were the highest plasma creatinine and urea concentrations. Conclusions and Clinical Relevance-Urinary enzyme activities were sensitive early indicators of acute kidney injury induced by an overdose of an NSAID in sheep. (Am J Vet

Activation of complement system in kidney after ketoprofen-induced kidney injury in sheep

“…As reported in our previous publication and further shown in Table 1 , proteinuria was detected in sheep after ketoprofen induced AKI by an elevated urine protein to creatinine ratio [ 32 ]. Proteinuria is usually a consequence of protein leakage in the glomeruli that leads to tubular injury [ 34 , 35 ].…”

“…At the end of the study (24 h after treatment), the treatment animals and their controls were euthanized and the last urine samples were collected via cystocentesis and autopsies were performed. AKI was confirmed later by increased plasma urea and creatinine concentrations, proteinuria, enzymuria (Table 1 ) and histopathology indicative of acute tubular injury (ATI) as described in our previous report [ 32 ]. Tissue samples from kidneys were collected immediately after euthanasia and snap-frozen in liquid nitrogen and stored in −80°C freezer for later preparation and analysis.…”

Renal biomarkers in domestic species

“…Other nephrotoxic drugs evaluated in the context of tubular enzymes include polymyxin B (dogs), methyl cantharidimide (dogs), sulfonamide (a cat), neomycin (horses), ketoprofen (sheep), and mercuric chloride and potassium dichromate (ponies), all of which resulted in early increases in uNAG/c, uGGT/c, or both. One study reported early increases in uNAG/c and uGGT/c in dogs administered a therapeutic dose of ketoprofen long‐term, but noted that these enzyme indices returned to clinically normal values in both dogs despite continued drug administration .…”

“…Other urinary enzymes noted to be increased in AKI but not included in Table include: glutathione‐S‐transferase, lactate dehydrogenase, acid phosphatase, MMP/pro‐MMP 2 in sheep, and MMP/pro‐MMP 9 in horses …”

Avaliação clínica, laboratorial e anatomopatológica do sistema urinário de ovinos confinados com ou sem suplementação de cloreto de amônio

“…As demais alterações microscópicas, como dilatação e degeneração tubular, e fibrose cortical mostraram pouca importância, em razão da baixa prevalência encontrada. A congestão vascular (Fig.4) observada pode estar relacionada a processos inflamatórios (Maxie & Newman 2007, Raekallio et al 2010. Visualizou-se infiltrado inflamatório mononuclear (Fig.5), com predomínio de linfócitos e plasmócitos.…”