Assessing and Predicting Drug‐Induced Kidney Injury, Functional Change, and Safety in Preclinical Studies in Rats

Chen, Yafei

doi:10.1002/9781119053248.ch28

Cited by 2 publications

(2 citation statements)

References 70 publications

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“…Current clinical methods, such as SCr and estimated glomerular filtration rate (eGFR), require a substantial decline in kidney function in order to detect clinical AKI. 14 However, there has been a recent surge of research activity aimed at testing the utility of urinary protein biomarkers as a noninvasive and sensitive means of diagnosing drug-induced nephrotoxicity in patients. In 2008, the U.S. Food and Drug Administration (FDA) approved seven urinary protein biomarkers for use in preclinical submissions for regulatory decision-making.…”

Section: Introductionmentioning

confidence: 99%

Urinary protein biomarkers of kidney injury in patients receiving cisplatin chemotherapy

George

Joy²,

Aleksunes

2017

Exp Biol Med (Maywood)

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Despite recent progress in the development of novel approaches to treat cancer, traditional antineoplastic drugs, such as cisplatin, remain a mainstay of regimens targeting solid tumors. Use of cisplatin is limited by acute kidney injury, which occurs in approximately 30% of patients. Current clinical measures, such as serum creatinine and estimated glomerular filtration rate, are inadequate in their ability to detect acute kidney injury, particularly when there is only a moderate degree of injury. Thus, there is an urgent need for improved diagnostic biomarkers to predict nephrotoxicity. There is also interest by the U.S. Food and Drug Administration to validate and implement new biomarkers to identify clinical and subclinical acute kidney injury in patients during the drug approval process. This minireview provides an overview of the current literature regarding the utility of urinary proteins (albumin, beta-2-microglobulin, N-acetyl-D-glucosaminidase, kidney injury molecule-1, neutrophil gelatinase-associated lipocalin, and cystatin C) as biomarkers for cisplatin-induced AKI. Many of the well-studied urinary proteins (KIM-1, NGAL, B2M, albumin) as well as emerging biomarkers (calbindin, monocyte chemotactic protein-1, and trefoil factor 3) display distinct patterns of time-dependent excretion after cisplatin administration. Implementation of these biomarker proteins in the oncology clinic has been hampered by a lack of validation studies. To address these issues, large head-to-head studies are needed to fully characterize time-dependent responses and establish accurate cutoff values and ranges, particularly in cancer patients. Impact statement There is growing interest in using urinary protein biomarkers to detect acute kidney injury in oncology patients prescribed the nephrotoxic anticancer drug cisplatin. We aim to synthesize and organize the existing literature on biomarkers examined clinically in patients receiving cisplatin-containing chemotherapy regimens. This minireview highlights several proteins (kidney injury molecule-1, beta-2-microglobulin, neutrophil gelatinase-associated lipocalin, calbindin, monocyte chemotactic protein-1, trefoil factor 3) with the greatest promise for detecting cisplatin-induced acute kidney injury in humans. A comprehensive review of the existing literature may aid in the design of larger studies needed to implement the clinical use of these urinary proteins as biomarkers of kidney injury.

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Section: Introductionmentioning

confidence: 99%

Urinary protein biomarkers of kidney injury in patients receiving cisplatin chemotherapy

George

Joy²,

Aleksunes

2017

Exp Biol Med (Maywood)

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“…The 8 urinary biomarkers analyzed in this study have been previously categorized into 3 general classes based on the type of renal injury they respond to, 41 and all 3 classes are affected in a cisplatin-induced renal injury. These 3 classes include kidney filtration and/or tubular reabsorption functional markers (TP, albumin, B2M), kidney tissue injury leakage markers (RPA-1), and kidney tissue injury and repair response markers (clusterin, OPN, NGAL, and KIM-1).…”

Section: Discussionmentioning

confidence: 99%

Investigating the Value of Urine Volume, Creatinine, and Cystatin C for Urinary Biomarkers Normalization for Drug Development Studies

et al. 2019

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Novel urinary protein biomarkers have recently been identified and qualified in rats for the early detection of renal injury in drug development studies. However, there seems to be no standardized normalization method for analyzing these urinary biomarkers, as some users normalize with urinary creatinine (uCr), urine volume (uVol), or leave biomarker un-normalized. More recently, urinary cystatin C is also emerging as a urinary biomarker normalizer, given some of its characteristics as a glomerular filtration marker. The purpose of this study was to identify an optimal drug-induced kidney injury biomarker normalization method that can be adopted more uniformly in the field. To this end, we compared the variability of uVol, urinary cystatin C, and Cr in healthy rats; we evaluated the sensitivity of the renal biomarkers to renal injury after normalization with uVol, uCr, and cystatin C in rats with cisplatin-induced renal injury. We showed that, over time, uCr was less variable than urinary cystatin C and uVol. When the renal biomarkers were normalized with the 3 normalizing end points, the biomarkers showed (1) least variability following normalization with Cr in healthy animals and (2) poor sensitivity when normalized with urinary cystatin C in animals with renal injury. Overall, the results suggested that uCr is better than urinary cystatin C and uVol for normalizing renal biomarkers in rats under controlled preclinical conditions. To our knowledge, this is the first report that compared the variability of uVol, cystatin C, and Cr in the context of renal biomarkers’ normalization.

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Assessing and Predicting Drug‐Induced Kidney Injury, Functional Change, and Safety in Preclinical Studies in Rats

Cited by 2 publications

References 70 publications

Urinary protein biomarkers of kidney injury in patients receiving cisplatin chemotherapy

Urinary protein biomarkers of kidney injury in patients receiving cisplatin chemotherapy

Investigating the Value of Urine Volume, Creatinine, and Cystatin C for Urinary Biomarkers Normalization for Drug Development Studies

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