Comparative profile of commercially available urinary biomarkers in preclinical drug-induced kidney injury and recovery in rats

Rouse, Rodney; Zhang, Jun; Stewart, Sharron; Rosenzweig, Barry A.; Espandiari, Parvaneh; Sadrieh, Nakissa

doi:10.1038/ki.2010.463

Cited by 69 publications

(66 citation statements)

References 36 publications

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“…In our study, marked increases NGAL was observed in urine, and necrosis and swelling of proximal epithelium and regeneration of proximal and distal epithelium were noted in the dog given the high dose of gentamicin. Although immunohistochemistry of frozen and paraffin section in the dog kidney using commercially available anti-NGAL antibodies was failed to identify NGAL expression and its distribution in this study, it was reported that NGAL mRNA was highly upregulated after kidney injury such as renal ischemia-reperfusion, and cisplatin or gentamicin nephropathy in rodents (Mishra, 2003;Rouse et al, 2011). In the high dose treatment of this study, reabsorption of NGAL in the proximal epithelium was considered to be the main reason for the increase in urinary NGAL due to severe proximal tubular lesions, and elevation of NGAL synthesis and/or secretion in injured tubular epithelium may also contribute to the changes.…”

Section: Discussionmentioning

confidence: 80%

Neutrophil gelatinase-associated lipocalin, a sensitive urinary biomarker of acute kidney injury in dogs receiving gentamicin

et al. 2013

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-A sensitive urinary biomarker for acute kidney injury (AKI) was investigated in beagle dogs with nephrotoxicity induced by gentamicin. Gentamicin sulphate at 25 or 50 mg/kg was injected (s.c.) for 9 days, and conventional urinalysis, ELISA assay of neutrophil gelatinase-associated lipocal (NGAL) in urine, blood chemistry, and pathological examinations were performed. The dog given gentamicin at 25 mg/kg only showed slight deposition of lysosomal granules in the proximal tubular epithelium of the kidneys without any other significant changes even though urinary NGAL was elevated on Day 10 (day of necropsy). In the dog receiving gentamicin at 50 mg/kg, increases in urinary NGAL were observed on Days 3 and 5, and absence of urination, marked increases in serum urea nitrogen and creatinine, enlargement and discoloration of the kidneys with marked necrosis, and swelling of proximal epithelium were observed. In conclusion, urinary NGAL is considered to be a candidate as a sensitive predictable biomarker of AKI in the gentamicin-induced nephrotoxicity model in dogs.Key words: NGAL, Dogs, Acute kidney injury, Urinary biomarker, Gentamicin Correspondence: Kiyonori Kai (E-mail: kai.kiyonori.xb@daiichisankyo.co.jp) LetterThe Journal of Toxicological Sciences (J. Toxicol. Sci.) Vol.38, No.2, 269-277, 2013 Vol. 38 No. 2 269 addition to these biomarkers, neutrophil gelatinase-associated lipocal (NGAL), a member of the lipocalin superfamily, has been proposed as a candidate for a sensitive urinary biomarker to detect AKI Mori, 2005;Mori and Nakao, 2007). Unfortunately, in part due to the lack of commercially available assays for non-rodents, limited data comparing the performance of the exploratory and approved markers are publicly available so far.In this study, we selected gentamicin, a well-known nephrotoxic agent that induces AKI in experimental animals and humans, and injected it subcutaneously to beagle dogs for 9 days and evaluated urinary NGAL using a commercial ELISA kit as a sensitive urinary biomarker in comparison with conventional blood and urinary toxicity makers and pathological examinations. MATERIALS AND METHODS Test articleELTACIN injection, an injectable product of gentamicin sulfate was purchased from FujiPharma (Shizuoka, Japan). Animals and housing conditionsTwo male beagle dogs were purchased from Narc Corporation (Chiba, Japan) for gentamicin treatment, and 6 males and 6 females were additionally obtained from Marshall BioResources, Japan (Ibaraki, Japan) for collection background data of urinalysis. The dogs were individually housed in stainless steel cages (W93.5 cm × W80 cm × H78.5 cm) in an air-conditioned room (temperature, 18 to 28°C; relative humidity, 30 to 70%). A light/dark cycle of 12 hr and ventilation rate of 10 to 20 air changes/ hr were used in the animal rooms. Two hundred and twenty grams of basal diet (Certified Canine Diet 5007, PMI Nutrition International, Inc., St. Louis, MO, USA) was given to each dog in the morning and tap water was available ad libitum. All experimen...

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Section: Discussionmentioning

confidence: 80%

Neutrophil gelatinase-associated lipocalin, a sensitive urinary biomarker of acute kidney injury in dogs receiving gentamicin

et al. 2013

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“…Potential biomarkers also have to be considered in the type of evaluation offered. (50,51) Kidney injury assessments may be made via measurements of kidney function, oxidative stress, cellular and structural injury, immune responses, and fibrosis. Clearly, a panel of biomarkers is attractive in that it is able to provide a more holistic assessment of kidney injury, be it AKI or CKD; however, the research methodology, analysis, interpretation, and clinical application will be challenging.…”

Section: Disease Acuity and Type Of Biomarkermentioning

confidence: 99%

Normalisation of urinary biomarkers to creatinine for clinical practice and research – when and why

Tang¹,

Toh²,

Teo³

2015

smedj

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Acute kidney injury (AKI) and chronic kidney disease (CKD) are major health problems. Urinary biomarkers have both diagnostic and prognostic utility in AKI and CKD. However, how biomarker excretion rates should be reported, especially whether they should be normalised to urinary creatinine concentration (uCr), is controversial. Some studies suggest that normalisation to uCr may be inappropriate at times, as urinary creatinine excretion rate may vary greatly, depending on the situation. Notably, recent studies suggest that while normalisation of values to UCr may be valid for the evaluation of CKD and prediction of AKI sequelae and occurrences, it could be inappropriate for the diagnosis of AKI, or in the presence of certain acute kidney disease states.

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“…Both of these proteins have compelling preclinical data as early indicators of AKI and appear promising in initial translation experiments in humans (9)(10)(11)(12)(13). In addition, KIM-1 was recently approved by the US Food and Drug Administration as an AKI biomarker for preclinical drug development (14,15) and L-FABP is approved as a diagnostic test for human AKI in Japan. This study represents the first large-scale validation of these two biomarkers and offers comparisons with other novel biomarkers of AKI.…”

Section: Introductionmentioning

confidence: 99%

Performance of Kidney Injury Molecule-1 and Liver Fatty Acid-Binding Protein and Combined Biomarkers of AKI after Cardiac Surgery

Parikh¹,

Thiessen-Philbrook²,

Garg³

et al. 2013

Clinical Journal of the American Society of Nephrology

205

179

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SummaryBackground and objectives AKI is common and novel biomarkers may help provide earlier diagnosis and prognosis of AKI in the postoperative period.Design, setting, participants, & measurements This was a prospective, multicenter cohort study involving 1219 adults and 311 children consecutively enrolled at eight academic medical centers. Performance of two urine biomarkers, kidney injury molecule-1 (KIM-1) and liver fatty acid-binding protein (L-FABP), alone or in combination with other injury biomarkers during the perioperative period was evaluated. AKI was defined as doubling of serum creatinine or need for acute dialysis.Results KIM-1 peaked 2 days after surgery in adults and 1 day after surgery in children, whereas L-FABP peaked within 6 hours after surgery in both age groups. In multivariable analyses, the highest quintile of the first postoperative KIM-1 level was associated with AKI compared with the lowest quintile in adults, whereas the first postoperative L-FABP was not associated with AKI. Both KIM-1 and L-FABP were not significantly associated with AKI in adults or children after adjusting for other kidney injury biomarkers (neutrophil gelatinaseassociated lipocalin and IL-18). The highest area under the curves achievable for discrimination for AKI were 0.78 in adults using urine KIM-1 from 6 to 12 hours, urine IL-18 from day 2, and plasma neutrophil gelatinaseassociated lipocalin from day 2 and 0.78 in children using urine IL-18 from 0 to 6 hours and urine L-FABP from day 2.Conclusions Postoperative elevations of KIM-1 associate with AKI and adverse outcmes in adults but were not independent of other AKI biomarkers. A panel of multiple biomarkers provided moderate discrimination for AKI.

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Comparative profile of commercially available urinary biomarkers in preclinical drug-induced kidney injury and recovery in rats

Cited by 69 publications

References 36 publications

Neutrophil gelatinase-associated lipocalin, a sensitive urinary biomarker of acute kidney injury in dogs receiving gentamicin

Neutrophil gelatinase-associated lipocalin, a sensitive urinary biomarker of acute kidney injury in dogs receiving gentamicin

Normalisation of urinary biomarkers to creatinine for clinical practice and research – when and why

Performance of Kidney Injury Molecule-1 and Liver Fatty Acid-Binding Protein and Combined Biomarkers of AKI after Cardiac Surgery

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