Comparison of the course of biomarker changes and kidney injury in a rat model of drug-induced acute kidney injury

Sasaki, Daisuke; Yamada, Atsushi; Umeno, Hitomi; Kojima, Hiroshi; Nakatsuji, Shunji; Fujihira, Shiro; Tsubota, Kenjiro; Ono, Mihoko; Moriguchi, Akira; Watanabe, Kouji; Seki, Jiro

doi:10.3109/1354750x.2011.613123

Cited by 65 publications

(46 citation statements)

References 37 publications

(37 reference statements)

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“…In fact, doxorubicin 3D tissues had a greater increase in NGAL secretion over time than did the same treatment groups in 2D. Sasaki et al has shown that rats dosed with cisplatin or gentamicin can take up to 7 days to have increased expression of Kim-1 and NGAL in their urine at high doses [38], indicating that our time course may be relevant to in vivo situations. Our data also shows the usefulness of our 3D model over 2D culture for the interpretation of biomarker data as the 3D tissues do not have as high a level of background expression as the 2D cultures.…”

Section: Resultsmentioning

confidence: 66%

Bioengineered 3D Human Kidney Tissue, a Platform for the Determination of Nephrotoxicity

et al. 2013

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The staggering cost of bringing a drug to market coupled with the extremely high failure rate of prospective compounds in early phase clinical trials due to unexpected human toxicity makes it imperative that more relevant human models be developed to better predict drug toxicity. Drug–induced nephrotoxicity remains especially difficult to predict in both pre-clinical and clinical settings and is often undetected until patient hospitalization. Current pre-clinical methods of determining renal toxicity include 2D cell cultures and animal models, both of which are incapable of fully recapitulating the in vivo human response to drugs, contributing to the high failure rate upon clinical trials. We have bioengineered a 3D kidney tissue model using immortalized human renal cortical epithelial cells with kidney functions similar to that found in vivo. These 3D tissues were compared to 2D cells in terms of both acute (3 days) and chronic (2 weeks) toxicity induced by Cisplatin, Gentamicin, and Doxorubicin using both traditional LDH secretion and the pre-clinical biomarkers Kim-1 and NGAL as assessments of toxicity. The 3D tissues were more sensitive to drug-induced toxicity and, unlike the 2D cells, were capable of being used to monitor chronic toxicity due to repeat dosing. The inclusion of this tissue model in drug testing prior to the initiation of phase I clinical trials would allow for better prediction of the nephrotoxic effects of new drugs.

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Section: Resultsmentioning

confidence: 66%

Bioengineered 3D Human Kidney Tissue, a Platform for the Determination of Nephrotoxicity

et al. 2013

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“…In 300,000 IU/kg/day of colistin dose received by second group, we found a significant uNGAL increase, suggesting that this parameter is more sensitive than pCysC for the detection of renal damage induced by treatment with colistin. Several studies either experimental in rats 22,23 or clinical in patients with different pathologies 24,25 revealed the importance of early detection of kidney lesions induced by drug or other nephrotoxic factors. Urine NGAL has also been shown to predict the severity of AKI and over-expressed in response to injury.…”

Section: Discussionmentioning

confidence: 99%

Evaluation of colistin nephrotoxicity administered at different doses in the rat model

et al. 2013

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Objective: This study evaluated the usefulness of plasma Cystatin C (pCysC) along with urinary neutrophil gelatinase-associated lipocalin (NGAL), g-glutamyltransferase (GGT), lactate dehydrogenase (LDH), alkaline phosphatase (ALP), aspartate (AST) and alanine (ALT) aminotransferase to monitor colistin nephrotoxicity. Method: Male rats were given intramuscular (i.m.) injections of colistin in doses of 150,000 (G 1 ), 300,000 (G 2 ) and 450,000 IU/kg/day (G 3 ) or normal saline (Control), every 12 h for 7 days. After the 14th injection, animals were placed in metabolic cages and urine samples were collected in the next 12 h. Thereafter, animals were euthanized, blood samples were collected and kidneys were removed for histological assessment. Results: Nephrotoxicity was completely dose-dependent according to pathologic findings. The major insults were acute tubular necrosis in the tubules of G 3 . No significant change in pCr was observed in all treated groups, but pCysC increased in the G 3 compared to the control. In urinary markers, uNGAL level showed a dose dependant increase with significant change in the G2 and G3 groups compared to the control. However, there was no significant change in the AST, ALT, LDH or ALP activities but only GGT increased in the G 3 compared to the control. Conclusion: Based on colistin doses used in our experimental study on rat model, histopathologic assessment remains the most accurate way to diagnose colistin nephrotoxicity. pCysC appears to be more reliable than pCr, and uNGAL seems to be the most sensitive factor of colistin nephrotoxicity.

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“…There currently are no biomarkers that can accurately track, correlate, or predict the occurrence of renal injury, particularly when related to drug-related toxicity [1–3]. There is a growing interest in the role of micro Ribonucleic Acids (miRNAs) in the pathogenesis of renal diseases [4, 5] and a growing number of investigations are directed to characterizing their potential as biomarkers [6–9].…”

Section: Introductionmentioning

confidence: 99%

Identification of tubular injury microRNA biomarkers in urine: comparison of next-generation sequencing and qPCR-based profiling platforms

et al. 2014

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BackgroundMicroRNAs (miRNAs) are small, non-coding RNAs that regulate protein levels post-transcriptionally. miRNAs play important regulatory roles in many cellular processes and have been implicated in several diseases. Recent studies have reported significant levels of miRNAs in a variety of body fluids, raising the possibility that miRNAs could serve as useful biomarkers. Next-generation sequencing (NGS) is increasingly employed in biomedical investigations. Although concordance between this platform and qRT-PCR based assays has been reported in high quality specimens, information is lacking on comparisons in biofluids especially urine. Here we describe the changes in miRNA expression patterns in a rodent model of renal tubular injury (gentamicin). Our aim is to compare RNA sequencing and qPCR based miRNA profiling in urine specimen from control and rats with confirmed tubular injury.ResultsOur preliminary examination of the concordance between miRNA-seq and qRT-PCR in urine specimen suggests minimal agreement between platforms probably due to the differences in sensitivity. Our results suggest that although miRNA-seq has superior specificity, it may not detect low abundant miRNAs in urine samples. Specifically, miRNA-seq did not detect some sequences which were identified by qRT-PCR. On the other hand, the qRT-PCR analysis was not able to detect the miRNA isoforms, which made up the majority of miRNA changes detected by NGS.ConclusionsTo our knowledge, this is the first time that miRNA profiling platforms including NGS have been compared in urine specimen. miRNAs identified by both platforms, let-7d, miR-203, and miR-320, may potentially serve as promising novel urinary biomarkers for drug induced renal tubular epithelial injury.

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Comparison of the course of biomarker changes and kidney injury in a rat model of drug-induced acute kidney injury

Abstract: These data suggested that establishment of a suitable biomarker panel would facilitate detection of site-specific kidney injury with high sensitivity.

Cited by 65 publications

References 37 publications

Bioengineered 3D Human Kidney Tissue, a Platform for the Determination of Nephrotoxicity

Bioengineered 3D Human Kidney Tissue, a Platform for the Determination of Nephrotoxicity

Evaluation of colistin nephrotoxicity administered at different doses in the rat model

Identification of tubular injury microRNA biomarkers in urine: comparison of next-generation sequencing and qPCR-based profiling platforms

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