Profiling of Kidney Injury Biomarkers in Patients Receiving Cisplatin: Time‐dependent Changes in the Absence of Clinical Nephrotoxicity

George, Blessy; Wen, Xiaozhong; Mercke, Nickie; Gomez, Madeleine; O’Bryant, Cindy L.; Bowles, Daniel W.; Hu, Yichun; Hogan, Susan L.; Joy, Melanie S.; Aleksunes, Lauren M.

doi:10.1002/cpt.606

Cited by 36 publications

(58 citation statements)

References 47 publications

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“…There have been several reports suggesting that uB2MG concentrations elevated three folds by day 3 of UTI, whereas NGAL levels increased earlier (12 hours to 3 days). 31) …”

Section: Discussionmentioning

confidence: 99%

Diagnostic accuracy of urinary biomarkers in infants younger than 3 months with urinary tract infection

et al. 2018

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PurposeThe aim of this study was to evaluate the diagnostic accuracy of urinary biomarkers, such as neutrophil gelatinase-associated lipocalin (uNGAL) and β-2 microglobulin (uB2MG), in early detection of urinary tract infection (UTI) in infants aged <3 months with fever.MethodsA total of 422 infants aged <3 months (male:female=267:155; mean age, 56.4 days), who were admitted for fever, were retrospectively included in this study. We compared uNGAL and uB2MG between the UTI and non-UTI groups at the time of admission. The sensitivity, specificity, accuracy, and area under the curve (AUC) of uNGAL and uB2MG for use in diagnosing UTI were assessed.ResultsAmong 422 patients, 102 (24.2%) were diagnosed with UTI. Levels of uNGAL were higher in the UTI group than in the non-UTI group (366.6 ng/mL vs. 26.9 ng/mL, P<0.001). Levels of uB2MG were not different between the 2 groups. Multivariate analysis revealed that uNGAL was an independent predictive factor for UTI (P=0.033). The sensitivity, specificity, and accuracy were 90.2%, 92.5%, and 91.9% for uNGAL, and 48.0%, 43.8%, and 44.8% for uB2MG, respectively. AUC of uNGAL was 0.942 and that of uB2MG was 0.407.ConclusionAccuracy of uNGAL in the diagnosis of UTI is high in febrile infants aged <3 months. uNGAL can help in the early diagnosis and treatment of UTI in infants.

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“…There have been several reports suggesting that uB2MG concentrations elevated three folds by day 3 of UTI, whereas NGAL levels increased earlier (12 hours to 3 days). 31) …”

Section: Discussionmentioning

confidence: 99%

Diagnostic accuracy of urinary biomarkers in infants younger than 3 months with urinary tract infection

et al. 2018

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“…The eGFR was obtained from the medical record at baseline and after the first cisplatin dose and calculated using the CKD-EPI equation [ 33 ]. Additional details on biomarker analysis methods was previously published [ 57 ]. Biomarker data was not normalized to urinary creatinine as our previous study demonstrated similar findings with absolute and normalized data [ 57 ].…”

Section: Methodsmentioning

confidence: 99%

“…Additional details on biomarker analysis methods was previously published [ 57 ]. Biomarker data was not normalized to urinary creatinine as our previous study demonstrated similar findings with absolute and normalized data [ 57 ]. Biomarker data was assayed at baseline, and Day 3 and Day 10 post cisplatin administration.…”

Section: Methodsmentioning

confidence: 99%

Pharmacogenomic Variants May Influence the Urinary Excretion of Novel Kidney Injury Biomarkers in Patients Receiving Cisplatin

Chang

Hogan

et al. 2017

IJMS

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Nephrotoxicity is a dose limiting side effect associated with the use of cisplatin in the treatment of solid tumors. The degree of nephrotoxicity is dictated by the selective accumulation of cisplatin in renal tubule cells due to: (1) uptake by organic cation transporter 2 (OCT2) and copper transporter 1 (CTR1); (2) metabolism by glutathione S-transferases (GSTs) and γ-glutamyltransferase 1 (GGT1); and (3) efflux by multidrug resistance-associated protein 2 (MRP2) and multidrug and toxin extrusion protein 1 (MATE1). The purpose of this study was to determine the significance of single nucleotide polymorphisms that regulate the expression and function of transporters and metabolism genes implicated in development of acute kidney injury (AKI) in cisplatin treated patients. Changes in the kidney function were assessed using novel urinary protein biomarkers and traditional markers. Genotyping was conducted by the QuantStudio 12K Flex Real-Time PCR System using a custom open array chip with metabolism, transport, and transcription factor polymorphisms of interest to cisplatin disposition and toxicity. Traditional and novel biomarker assays for kidney toxicity were assessed for differences according to genotype by ANOVA. Allele and genotype frequencies were determined based on Caucasian population frequencies. The polymorphisms rs596881 (SLC22A2/OCT2), and rs12686377 and rs7851395 (SLC31A1/CTR1) were associated with renoprotection and maintenance of estimated glomerular filtration rate (eGFR). Polymorphisms in SLC22A2/OCT2, SLC31A1/CTRI, SLC47A1/MATE1, ABCC2/MRP2, and GSTP1 were significantly associated with increases in the urinary excretion of novel AKI biomarkers: KIM-1, TFF3, MCP1, NGAL, clusterin, cystatin C, and calbindin. Knowledge concerning which genotypes in drug transporters are associated with cisplatin-induced nephrotoxicity may help to identify at-risk patients and initiate strategies, such as using lower or fractionated cisplatin doses or avoiding cisplatin altogether, in order to prevent AKI.

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“…The power of these and other biomarkers to detect subtle renal injury has been well illustrated with cisplatin …”

Section: Today and The Near Termmentioning

confidence: 99%

Evaluating the Renal Safety of Investigational New Drugs: Where Should We Be Going?

Stockbridge

Blank

Hausner

et al. 2017

Clin Pharma and Therapeutics

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We the authors work in the US Food and Drug Administration (FDA) review division responsible for the therapeutic agents for primary renal disease. We also field consultative inquiries regarding off-target adverse renal effects of drugs intended to treat other diseases. We do neither basic science research on renal diseases nor clinical studies of new drugs, but we are professional spectators of both. We offer here our thoughts on the challenge of identifying renal safety signals in the preclinical space and in the earliest phases of clinical development.

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Profiling of Kidney Injury Biomarkers in Patients Receiving Cisplatin: Time‐dependent Changes in the Absence of Clinical Nephrotoxicity

Cited by 36 publications

References 47 publications

Diagnostic accuracy of urinary biomarkers in infants younger than 3 months with urinary tract infection

Diagnostic accuracy of urinary biomarkers in infants younger than 3 months with urinary tract infection

Pharmacogenomic Variants May Influence the Urinary Excretion of Novel Kidney Injury Biomarkers in Patients Receiving Cisplatin

Evaluating the Renal Safety of Investigational New Drugs: Where Should We Be Going?

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