A multiplexed UPLC-MS/MS assay for the simultaneous measurement of urinary safety biomarkers of drug-induced kidney injury and phospholipidosis

Tengstrand, Elizabeth; Zhang, Hannah; Liu, Nanjun; Dunn, Kelly E.; Hsieh, F.

doi:10.1016/j.taap.2019.01.012

Cited by 10 publications

(6 citation statements)

References 34 publications

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“…There continues to be intensive research in urinary biomarkers for kidney disease, given the inadequacy of current markers, both in Lupus and other diseases. [7,[19][20][21] As shown by Devarajan et al, serum creatinine was a problematic and often inaccurate measure of renal injury, and urine NGAL was introduced as a biologically appropriate marker of injury. [22] It has since been instituted clinically, successfully detecting acute kidney injury (AKI) prior to increase J o u r n a l P r e -p r o o f in serum creatinine.…”

Section: Discussionmentioning

confidence: 99%

“…Future directions would be working towards configuring the panel towards human analysis. [19] Urinary biomarkers in LN specifically are also an active field of study. Landolt-Marticorena et al published on urinary biomarkers distinguishing active lupus nephritis patients and patients with SLE without nephritis, which were identified using multiplex technology and had excellent correlation with biopsy activity.…”

Section: Discussionmentioning

confidence: 99%

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Successful Urine Multiplex Bead Assay to Measure Lupus Nephritis Activity

Cody

Bennett

Gulati

et al. 2021

Kidney International Reports

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Successful Urine Multiplex Bead Assay to Measure Lupus Nephritis Activity

Cody

Bennett

Gulati

et al. 2021

Kidney International Reports

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“…Previous studies demonstrated that the phospholipid di-22:6-BMP, usually strongly elevated in phospholipidosis (Tengstrand et al, 2010;Liu et al, 2014;Tengstrand et al, 2019), is reduced in the urine of LRRK2 knockout mice and non-human primates treated with the LRRK2 inhibitor GNE-7915 (Fuji et al, 2015). We wondered whether the same effect could be obtained in exosome-depleted urine used for simultaneous measures of exosomal-LRRK2 protein.…”

Section: Urine Markers Of Lrrk2 Kinase Inhibitionmentioning

confidence: 93%

“…Di-docosahexaenoyl (22:6) bis (monoacylglycerol) phosphate (di-22:6-BMP) was measured in plasma and exosome-depleted urine and CSF by ultra-performance liquid chromatographytandem mass spectrometry (UPLC-MS/MS). The analyses were performed as previously described (Tengstrand et al, 2019). Standard curves were prepared using an authentic di-22:6-BMP reference standard.…”

Section: Di-docosahexaenoyl (22:6) Bis (Monoacylglycerol) Phosphate Mmentioning

confidence: 99%

“…pS1292-LRRK2 and pT73-Rab10 are direct substrates of LRRK2, although the phosphatases that affect these sites are likely different in cells and tissues, potentially affecting pharmacodynamic marker kinetics (Berndsen et al, 2019). Apart from protein pharmacodynamic markers, levels of didocosahexaenoyl (22:6) bis (monoacylglycerol) phosphate (di-22:6-BMP) which are usually elevated in phospholipidosis and lysosomal storage diseases (Meikle et al, 2008;Liu et al, 2014;Tengstrand et al, 2019), appear decreased in urine from LRRK2-inhibitor treated nonhuman primates (Fuji et al, 2015). The mechanisms behind LRRK2-inhibitor induced decreases in di-22:6-BMP in urine have yet to be defined.…”

Section: Introductionmentioning

confidence: 99%

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Pharmacodynamic Markers of LRRK2 Inhibition in Biofluids

Wang

Kelly

Schussler

et al. 2020

Preprint

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AbstractHyper-activated LRRK2 is linked to Parkinson’s disease susceptibility and progression. Quantitative measures of LRRK2 inhibition, especially in the brain, may be critical in the clinical development of successful LRRK2-targeting therapeutics. In this study, three different brain-penetrant and selective LRRK2 small-molecule kinase inhibitors (PFE-360, MLi2, and RA283) were orally administered to groups of cynomolgus macaques at different doses. Biofluid markers with proposed pharmacodynamic properties for assessing LRRK2 inhibition were measured from samples of blood, urine, and cerebral-spinal fluid (CSF). LRRK2 kinase inhibition led to consistent reduced pS935-LRRK2 and pRab10 proteins in blood mononuclear cells, reduced exosome LRRK2 protein and di-docosahexaenoyl (22:6) bis (monoacylglycerol) phosphate in urine, and reduced exosome LRRK2 and autophosphorylated pS1292-LRRK2 protein in CSF. Incomplete LRRK2 kinase inhibition reduced LRRK2 protein secretion in exosomes whereas high drug exposures may reduce both exosome and tissue levels of LRRK2 protein. These orthogonal markers for LRRK2 inhibition in urine and CSF can be used in combination with blood markers to non-invasively monitor the potency of LRRK2-targeting therapeutics in the brain and periphery.

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Circulating microRNAs as promising testicular translatable safety biomarkers: current state and future perspectives

et al. 2023

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Drug-induced testicular injury (DITI) is one of the often-observed and challenging safety issues seen during drug development. Semen analysis and circulating hormones currently utilized have significant gaps in their ability to detect testicular damage accurately. In addition, no biomarkers enable a mechanistic understanding of the damage to the different regions of the testis, such as seminiferous tubules, Sertoli, and Leydig cells. MicroRNAs (miRNAs) are a class of non-coding RNAs that modulate gene expression post-transcriptionally and have been indicated to regulate a wide range of biological pathways. Circulating miRNAs can be measured in the body fluids due to tissue-specific cell injury/damage or toxicant exposure. Therefore, these circulating miRNAs have become attractive and promising non-invasive biomarkers for assessing drug-induced testicular injury, with several reports on their use as safety biomarkers for monitoring testicular damage in preclinical species. Leveraging emerging tools such as 'organs-on-chips' that can emulate the human organ's physiological environment and function is starting to enable biomarker discovery, validation, and clinical translation for regulatory qualification and implementation in drug development.

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A multiplexed UPLC-MS/MS assay for the simultaneous measurement of urinary safety biomarkers of drug-induced kidney injury and phospholipidosis

Cited by 10 publications

References 34 publications

Successful Urine Multiplex Bead Assay to Measure Lupus Nephritis Activity

Successful Urine Multiplex Bead Assay to Measure Lupus Nephritis Activity

Pharmacodynamic Markers of LRRK2 Inhibition in Biofluids

Circulating microRNAs as promising testicular translatable safety biomarkers: current state and future perspectives

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