title: Predictive usefulness of urinary biomarkers for the identification of cyclosporine A-induced nephrotoxicity in a rat model.
abstract: The main side effect of cyclosporine A (CsA), a widely used immunosuppressive drug, is nephrotoxicity. Early detection of CsA-induced acute nephrotoxicity is essential for stop or minimize kidney injury, and timely detection of chronic nephrotoxicity is critical for halting the drug and preventing irreversible kidney injury. This study aimed to identify urinary biomarkers for the detection of CsA-induced nephrotoxicity. We allocated salt-depleted rats to receive CsA or vehicle for 7, 14 or 21 days and evaluated renal function and hemodynamics, microalbuminuria, renal macrophage infiltration, tubulointerstitial fibrosis and renal tissue and urinary biomarkers for kidney injury. Kidney injury molecule-1 (KIM-1), tumor necrosis factor-alpha (TNF-α), interleukin 6 (IL-6), fibronectin, neutrophil gelatinase-associated lipocalin (NGAL), TGF-β, osteopontin, and podocin were assessed in urine. TNF-α, IL-6, fibronectin, osteopontin, TGF-β, collagen IV, alpha smooth muscle actin (α -SMA) and vimentin were assessed in renal tissue. CsA caused early functional renal dysfunction and microalbuminuria, followed by macrophage infiltration and late tubulointerstitial fibrosis. Urinary TNF-α, KIM-1 and fibronectin increased in the early phase, and urinary TGF-β and osteopontin increased in the late phase of CsA nephrotoxicity. Urinary biomarkers correlated consistently with renal tissue cytokine expression. In conclusion, early increases in urinary KIM-1, TNF-α, and fibronectin and elevated microalbuminuria indicate acute CsA nephrotoxicity. Late increases in urinary osteopontin and TGF-β indicate chronic CsA nephrotoxicity. These urinary kidney injury biomarkers correlated well with the renal tissue expression of injury markers and with the temporal development of CsA nephrotoxicity.
authors: Division of Nephrology, São José do Rio Preto Medical School, São José do Rio Preto, SP, Brazil; Department of Biology, Instituto de Biociências, Letras e Ciências Exatas, São Paulo State University, São José do Rio Preto, SP, Brazil.
authors: Carla Patrícia
authors: CP
authors: Carlos
authors: Department of Biology, Instituto de Biociências, Letras e Ciências Exatas, São Paulo State University, São José do Rio Preto, SP, Brazil.
authors: Nathália Martins
authors: NM
authors: Sonehara
authors: Department of Biology, Instituto de Biociências, Letras e Ciências Exatas, São Paulo State University, São José do Rio Preto, SP, Brazil.
authors: Sonia Maria
authors: SM
authors: Oliani
authors: Division of Nephrology, São José do Rio Preto Medical School, São José do Rio Preto, SP, Brazil; LIM 12, Division of Nephrology, University of São Paulo Medical School, São Paulo, SP, Brazil.
authors: Emmanuel A
authors: EA
authors: Burdmann
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000652:urine*; D015815:Cell Adhesion Molecules / Q000652:urine; D016572:Cyclosporine / Q000633:toxicity*; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005353:Fibronectins / Q000652:urine; D005919:Glomerular Filtration Rate; D007150:Immunohistochemistry; D007166:Immunosuppressive Agents / Q000633:toxicity*; D015850:Interleukin-6 / Q000652:urine; D007668:Kidney / Q000473:pathology; D007674:Kidney Diseases / Q000209:etiology* / Q000473:pathology / Q000652:urine; D053495:Osteopontin / Q000652:urine; D051381:Rats; D017208:Rats, Wistar; D016212:Transforming Growth Factor beta / Q000652:urine; D014409:Tumor Necrosis Factor-alpha / Q000652:urine; D014746:Vimentin / Q000378:metabolism
chemical_list: D015415:Biomarkers; D015815:Cell Adhesion Molecules; D016572:Cyclosporine; D005353:Fibronectins; D007166:Immunosuppressive Agents; D015850:Interleukin-6; D053495:Osteopontin; D016212:Transforming Growth Factor beta; D014409:Tumor Necrosis Factor-alpha; D014746:Vimentin; C110936:Havcr1 protein, rat