Tissue Kim-1 and Urinary Clusterin as Early Indicators of Cisplatin-Induced Acute Kidney Injury in Rats

Vinken, Petra; Starckx, Sofie; Barale-Thomas, Erio; Looszova, Adriana; Sonee, Manisha; Goeminne, Nick; Versmissen, Loes; Buyens, Kristel; Lampo, Ann

doi:10.1177/0192623312444765

Cited by 85 publications

(62 citation statements)

References 22 publications

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“…In agreement with other groups (de Borst et al 2007;Vinken et al 2012), we detected low levels of KIM-1 immunoreactivity in some control rat kidneys; a finding likely to reflect low levels of naturally occurring tubular injury/regeneration. In animals dosed with cisplatin, all animals with KIM-1-positive immunoreactivity showed histopathological changes.…”

Section: Discussionsupporting

confidence: 92%

Tissue Expression and Correlation of a Panel of Urinary Biomarkers Following Cisplatin-induced Kidney Injury

et al. 2013

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In recent years, there has been considerable activity to identify urinary biomarkers of nephrotoxicity as noninvasive measurements with greater sensitivity and specificity than traditional biomarkers, such as serum creatinine and blood urea nitrogen. Our study aimed to use cisplatin-treated rats to evaluate the use of immunohistochemistry directed at multiple urinary biomarkers in kidney tissue. Tissue levels were compared to urinary levels of these biomarkers to demonstrate tissue specificity and sensitivity. These techniques could also be used in studies where urine samples are not available, such as retrospective studies in drug safety testing, to demonstrate the potential utility of using these biomarkers in future preclinical or clinical studies. All of the biomarkers investigated showed either an increase (kidney injury molecule [KIM-1], osteopontin [OPN], and, clusterin) or a decrease (alpha-glutathione S-transferase and trefoil factor 3) except beta 2 microglobulin (b2MG) that showed no significant changes 5 days after 1.0 mg/kg or 2.5 mg/kg cisplatin treatment. All of the biomarkers except b2MG showed utility as tissue biomarkers, but KIM-1 and OPN expression correlated closely with urinary biomarker measurements and reflect tissue damage. Future studies are needed to determine the wider application of these two markers for detecting renal toxicity following administration of other nephrotoxicants.

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Section: Discussionsupporting

confidence: 92%

Tissue Expression and Correlation of a Panel of Urinary Biomarkers Following Cisplatin-induced Kidney Injury

et al. 2013

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“…Support for this notion comes from numerous clinical studies in which plasma KIM-1 and NGAL or urinary excretion of these biomarkers increased a few hours after the induction of AKI of various etiologies, including kidney transplant rejection [21,22], nephron sparing surgery [23] and nephrotoxic drugs induced nephropathy [24].…”

Section: Discussionmentioning

confidence: 99%

Evaluation of KIM-1 and NGAL as Early Indicators for Assessment of Gentamycin-Induced Nephrotoxicity In Vivo and In Vitro

Luo

Chen

et al. 2016

Kidney Blood Press Res

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Background/Aims: The aminolycoside Gentamicin is a widely used antibiotic, applied in equine medicine. Despite its clinical use, concerns remain regarding the potential toxic side-effects, such as nephrotoxicity. Early detection of renal damage is critical in preclinical drug development. This study was aimed to determine whether kidney injury molecule-1 (KIM-1) and neutrophil gelatinase-associated lipocalin (NGAL) may be early indicators in the assessment of Gentamycin-induced nephrotoxicity. Methods: In our study, a model of Gentamicin-induced nephrotoxicity in male Sprague Dawley rats treated for up to 7 days at 50 or 100mg/kg/day was used to monitor the expressions of novel biomarkers of renal toxicity during the progression of acute kidney injury (AKI). Additionally, biomarkers were assessed in human kidney proximal epithelial cells (HK-2) treated with Gentamicin for 2, 6, 12, 24, 36 or 48h in vitro. Results: Repeated administration of Gentamicin to rats for 1, 3, or 7 days resulted in a dose- and time-dependent increase in the expression of KIM-1 and NGAL. The expressions of the two biomarkers changed prior to renal tubule damage and increases in serum creatinine (SCr) and blood urea nitrogen (BUN) levels, suggesting their usefulness for predicting Gentamicin-induced acute kidney injury (AKI) in vivo. Conclusions: In contrast, no significant increase in the expression of the biomarker genes and proteins were evident in HK-2 cells after treated by Gentamycin for up to 48h, suggesting that they may not be suitable endpoints for sensitive detection of nephrotoxic effects in vitro.

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“…In one study, Ur RPA-1 levels showed a gradual increase in control male SD rats during the 14 day period (Vinken et al, 2012). Conversely, another study showed stable baseline concentration of Ur RPA-1 in naïve male and female SD rats or variations at different time points over a 44 day period (Rouse et al, 2011).…”

Section: Discussionmentioning

confidence: 98%

“…To date, most investigations of DIKI biomarkers in rat preclinical studies (Xie et al, 2013) were in male rats (Xie et al, 2001;Gautier et al, 2010;Hoffmann et al, 2010;Betton et al, 2012;Vlasakova et al, 2014;Vinken et al, 2012). Common characteristics of AmpB nephrotoxicity in animal models and humans has been reviewed elsewhere (Fanos and Cataldi, 2000;Bagnis and Deray, 2002).…”

Section: Discussionmentioning

confidence: 99%

Acute biomarker panel changes associated with amphotericin B nephrotoxicity in female Sprague-Dawley rats

et al. 2016

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-To date, eight next-generation urinary protein kidney safety biomarkers have been qualified to enable monitoring for subclinical drug-induced kidney injury (DIKI) in rat preclinical studies; however, most DIKI biomarker studies have included only male rats. The objective of this study was to assess the utility of novel DIKI biomarkers, including but not limited to urinary total protein, albumin, cystatin C and osteopontin in female Sprague-Dawley rats (8/group) that received repeated intravenous injections of amphotericin B (AmpB, 3 mg/kg/day) or vehicle for 10 consecutive days. Serial serum/urine samples were collected on study day (D)4, D8, and D11. Surviving animals were necropsied on D11. The AmpB-induced kidney histopathology findings were characterized by cortical and medullary tubular alterations, interstitial inflammation, intratubular granular and inflammatory cell casts, acute pelvic inflammation and tubular mineralization. Significant elevations in urinary clusterin on D4, D8 and D11 (3.5 fold, 2.2 fold and 3.3 fold respectively) were observed (versus concurrent controls) following repeated injections of AmpB. In addition, significantly elevated (fold changes) in biomarkers, neutrophil gelatinase-associated lipocalin (14.6 fold), albumin (13.5 fold), cystatin C (13.5 fold), total protein (3.5 fold), kidney injury molecule 1 (3.0 fold) and osteopontin (2.3 fold) were detected in urine as early as D4. These findings demonstrate the value of early elevations in nephron-specific DIKI biomarkers for detecting subclinical AmpB nephrotoxicity in female Sprague-Dawley rats. These findings are anticipated to provide the basis for inclusion of female rats on a case-by-case basis in preclinical toxicology studies designed to detect DIKI.

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Tissue Kim-1 and Urinary Clusterin as Early Indicators of Cisplatin-Induced Acute Kidney Injury in Rats

Cited by 85 publications

References 22 publications

Tissue Expression and Correlation of a Panel of Urinary Biomarkers Following Cisplatin-induced Kidney Injury

Tissue Expression and Correlation of a Panel of Urinary Biomarkers Following Cisplatin-induced Kidney Injury

Evaluation of KIM-1 and NGAL as Early Indicators for Assessment of Gentamycin-Induced Nephrotoxicity <b><i>In Vivo</i></b> and <b><i>In Vitro</i></b>

Acute biomarker panel changes associated with amphotericin B nephrotoxicity in female Sprague-Dawley rats

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