Kidney-on-a-Chip Technology for Drug-Induced Nephrotoxicity Screening

The analysis of tissue-specific expression at both the gene and protein levels is vital for understanding human biology and disease. Antibody-based proteomics provides a strategy for the systematic generation of antibodies against all human proteins to combine with protein profiling in tissues and cells using tissue microarrays, immunohistochemistry and immunofluorescence. The Human Protein Atlas project was launched in 2003 with the aim of creating a map of protein expression patterns in normal cells, tissues and cancer. At present, 11,200 unique proteins corresponding to over 50% of all human protein-encoding genes have been analysed. All protein expression data, including underlying high-resolution images, are published on the free and publically available Human Protein Atlas portal (http://www.proteinatlas.org). This database provides an important source of information for numerous biomedical research projects, including biomarker discovery efforts. Moreover, the global analysis of how our genome is expressed at the protein level has provided basic knowledge on the ubiquitous expression of a large proportion of our proteins and revealed the paucity of cell- and tissue-type-specific proteins.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.1365-2796.2011.02427.x

The Human Protein Atlas as a proteomic resource for biomarker discovery

Neutrophil gelatinase-associated lipocalin (NGAL), a 25 kDa protein produced by injured nephron epithelia, is one of the most promising new markers of renal epithelial injury. In contrast to serum creatinine and urinary output, which are the measures of kidney function, NGAL is specifically induced in the damaged nephron and then released into blood and urine, where it can be readily measured. Careful proof-of-concept studies using defined animal models have uncovered the sources and trafficking of NGAL in acute kidney injury (AKI) and have addressed the contributions of renal and non-renal sources. Clinical studies indicate that NGAL, unlike creatinine, is a marker responsive to tissue stress and nephron injury, but less so to adaptive hemodynamic responses. In certain clinical settings, NGAL is an earlier marker compared with serum creatinine. In addition, clinical studies have shown that NGAL is a powerful predictor of poor clinical outcomes, which can be used to risk stratify patients when combined with serum creatinine. NGAL has important limitations, including its responsiveness in systemic inflammation, which is partially uncoupled from its response to kidney injury and which needs to be considered when interpreting NGAL results clinically. This review covers the biology and pathophysiology of NGAL and summarizes the results of the growing body of clinical studies that have addressed the utility of NGAL in the early diagnosis of AKI, in the distinction of intrinsic AKI and in the prognostic assessment of broad patient populations.

Neutrophil gelatinase‐associated lipocalin: pathophysiology and clinical applications

Blood urea nitrogen and serum creatinine are imperfect markers of kidney function because they are influenced by many renal and nonrenal factors independent of kidney function. A biomarker that is released directly into the blood or urine by the kidney in response to injury may be a better early marker of drug-induced kidney toxicity than blood urea nitrogen and serum creatinine. Urine albumin and urine protein, as well as urinary markers kidney injury molecule-1 (KIM-1), β2-microglobulin (B2M), cystatin C, clusterin, and trefoil factor-3 (TFF-3) have been accepted by the Food and Drug Administration and European Medicines Agency as highly sensitive and specific urinary biomarkers to monitor drug-induced kidney injury in preclinical studies and on a case-by-case basis in clinical trials. Other biomarkers of drug-induced kidney toxicity that have been detected in the urine of rodents or patients include IL-18, neutrophil gelatinase-associated lipocalin, netrin-1, liver-type fatty acid-binding protein (L-FABP), urinary exosomes, and TIMP2 (insulin-like growth factor-binding protein 7)/IGFBP7 (insulin-like growth factor-binding protein 7), also known as NephroCheck, the first Food and Drug Administration-approved biomarker testing platform to detect acute kidney injury in patients. In the future, a combined use of functional and damage markers may advance the field of biomarkers of drug-induced kidney toxicity. Earlier detection of drug-induced kidney toxicity with a kidney-specific biomarker may result in the avoidance of nephrotoxic agents in clinical studies and may allow for earlier intervention to repair damaged kidneys.

Biomarkers of Drug-Induced Kidney Toxicity.

http://www.parallexbio.com/wordpress/wp-content/uploads/2015/06/Dark-Side-of-Multiplexing-CurrOpinionChemBio-2014-review.pdf

Cross-reactivity in antibody microarrays and multiplexed sandwich assays: shedding light on the dark side of multiplexing

Evaluation of a urinary kidney biomarker panel in rat models of acute and subchronic nephrotoxicity

Sequential Multiplex Analyte Capturing for Phosphoprotein Profiling

Receptor tyrosine kinases (RTK) are important targets in drug discovery processes. Studying the phosphorylation pattern of RTKs enables the determination of their activation and inactivation states. Multiplex bead-based sandwich immunoassays are powerful tools for measuring the phosphorylation state of key regulators within cellular signalling networks. Here, we describe the analysis of the phosphorylation state of receptor tyrosine kinases using the epidermal growth factor receptor (EGFR) as an example. We provide a protocol for a bead-based sandwich immunoassay that enables a relative quantification of the EGFR and its generic tyrosine phosphorylation. We also present data from a kinase inhibitor experiment using 96-well cell-culture plates and a commercially available kit for the analysis of seven receptor tyrosine kinases.

Receptor tyrosine kinase inhibitor profiling using bead-based multiplex sandwich immunoassays.

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Evaluation of a urinary kidney biomarker panel in rat models of acute and subchronic nephrotoxicity

Sequential Multiplex Analyte Capturing for Phosphoprotein Profiling

Receptor tyrosine kinase inhibitor profiling using bead-based multiplex sandwich immunoassays.