Abstract
The analysis of protein biomarkers in urine is expected to lead to advances in a variety of clinical settings. Several characteristics of urine including a low-protein matrix, ease of testing and a demonstrated proteomic stability offer distinct advantages over current widely used biofluids, serum and plasma. Improvements in our understanding of the urine proteome and in methods used in its evaluation will facilitate the clinical development of urinary protein biomarkers. Multiplexed bead-based immunoassays were utilized to evaluate 211 proteins in urines from 103 healthy donors. An additional 25 healthy donors provided serial urine samples over the course of two days in order to assess temporal variation in selected biomarkers. Nearly one-third of the evaluated biomarkers were detected in urine at levels greater than 1ng/ml, representing a diverse panel of proteins with respect to structure, function and biological role. The presence of several biomarkers in urine was confirmed by western blot. Several methods of data normalization were employed to assess impact on biomarker variability. A complex pattern of correlations with urine creatinine, albumin and beta-2-microglobulin was observed indicating the presence of highly specific mechanisms of renal filtration. Further investigation of the urinary protein biomarkers identified in this preliminary study along with a consideration of the underlying proteomic trends suggested by these findings should lead to an improved capability to identify candidate biomarkers for clinical development.
Highlights
Protein biomarkers represent the myriad aspects of cellular physiology altered in response to disease
Tamm-Horsfall protein (THP) demonstrated the greatest abundance of all evaluated proteins with other glycoproteins and high abundance plasma proteins predominating in class 1
The observed abumin to urine creatinine (ACR) and protein to urine creatinine (PCR) for Set I individuals fell within normal levels, 10 mg/g and 0.15 mg/mg, respectively [20,21]
Summary
Protein biomarkers represent the myriad aspects of cellular physiology altered in response to disease. The measurement of protein biomarkers through proteomics, immunoassays, immunohistochemistry or various other novel techniques has formed the basis for the development of tools currently utilized in numerous clinical settings. Realized and potential applications include early detection, disease monitoring, prognostication, and evaluation of treatment response. Protein biomarkers have emerged as important tools within the arena of pharmaceutical development, serving as companion diagnostics to novel therapeutics which aid in patient selection, treatment monitoring, adverse event risk assessment, and the extension of indications for established drugs. The vast majority of protein biomarkers currently in use or under investigation do not represent novel pathological entities, but merely dysregulated aspects of normal physiology. Biomarker development requires extensive preclinical characterization in order to overcome inherent limitations in sensitivity and specificity
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