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.

Effects of Losartan, Tempol, and Their Combination On Renal Nitric Oxide Synthases in the Animal Model of Chronic Kidney Disease

“…These data lead to the conclusion that the preexistence of hypertension in our model could not be accounted for glomerular and tubular remodeling in the early phase of ADR nephropathy. Other studies have shown that the up-regulation of vimentin expression was observed in the renal tubules and interstitial areas in cyclosporine A-induced nephrotoxicity [31,32]. Since vimentin is used as a marker of tubulointerstitial injury and epithelial-mesenchymal transition, the neoexpression of vimentin in the proximal tubules is an unequivocal signal of injury and regeneration in these areas [31,33].…”

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“…23,29,30 We aimed to ascertain the effects on these markers in CsA-treated rats given 5 ng/kg 2AMD. The Figure 4 immunoblots show ECM and lysate fractions reacted for fibronectin using histone 3 as loading control for the ECM fractions or for vimentin using GAPDH as loading control for lysates.…”

Mesenchymal Stem Cells Contribute to Improvement of Renal Function in a Canine Kidney Injury Model

“…inulin clearance test, creatinine clearance test, and analysis of urinary biomarkers (e.g. neutrophil gelatinase-associated lipocain, kidney injury molecule-1, N-acetyl-β-D-glucosaminidase) (33)(34)(35). For a more accurate evaluation of renal function, one of the supplementary methods mentioned above may be performed as well; however, monitoring serum BUN and creatinine levels alone is quite an accurate measure of renal function and a meaningful method in a clinical setting (6,36).…”