Albumin urinary biomarkers

In humans, there seems to be a dose-dependent association between compound A exposure and the appearance of urinary biomarkers such as albumin, glucose, and the enzymes NAG or a-GST. These findings appear in studies when the compound A exposure exceeds 160 ppm/ hour [71-74], while they are absent in studies with lower compound A exposure [75-77]. In all studies associated with higher exposure of compound A, the urinary markers are transient, lasting 3-5 days with total normalization within one week. There is no correlation between serum creatinine and the urinary markers. 

Urinary Total Protein and Albumin Urinary total protein and albumin have been nsed for decades as glomerular injury biomarkers and, more recently, were qualified as measurements of glomerular filtration and tubular reabsorption function (Ferguson et al., 2008 Bonventre et al., 2010). Compared with blood concentrations of protein/albumin, a small amount of protein and albumin (microalbumin, which is below the albumin detection threshold by the conventional urinary dipstick 30-300 mg/L) enters the filtrate by the glomerulus and is reabsorbed and subsequently catabolized in the normal kidney proximal tubnle (Vaidya et al., 2008 Charlton et al., 2014). Therefore, increased urinary protein/albumin can reflect glomerular injury, tubular injury, or combined effects, though albuminuria can be observed in rats secondary to other effects such as dehydration or hypertensive conditions (Haschek et al., 2013). 

Between 2008 and 2010, the FDA (2008), the EMA (2008), and the PMDA (2010) qualified the use of seven urinary biomarkers for GLP rat studies to support the safe conduct of early-phase clinical trials KlM-1, CLU, TFF-3, p2-microglobulin, CysC, albumin, and total protein. These are detailed below. 

Wilson PD (2009) In vitro methods in renal research. In Avner ED, Harmon WE, Niaudet P, Yoshikawa N (eds) Pediatric nephrology, 6th edn. Springer, Berlin, pp 379-396 Yu Y, Jin H, Holder D, Ozer JS, Villarreal S (2010) Urinary biomarkers trefoil factor 3 and albumin enable early detection of kidney tubular injury. Nat Biotechnol 28 470-477 Zhu HY, Liu MY, Hong Q, Zhang D, Geng WJ, Xie YS, Chen XM (2012) Role of microRNA-181a in the apoptosis of tubular epithelial cell induced by cisplatin. Chin Med J (Engl) 125(3) 523-526... 

The urinary excretion of DNOC was also studied in these volunteers (King and Harvey 1953b). The 5 volunteers excreted about 7% of the total DNOC dose in the urine over 13 days after exposure. However, only 0.016% of the dose was excreted within 5 hours after exposure and 1.3% within 24 hours after exposure. In the first 24 hours after a single exposure of 75 mg per person, 35.2-46.6% of the dose could be accounted for by blood levels and 0.8-2.0% could be accounted for by urinary levels. Thus, 51.7-64.0% of the oral dose was unaccounted for. These data suggest that DNOC is stored longer in the human body than in the animal body. Since DNOC binds to albumin, the chief internal stores may be extracellular fluids containing albumin. Therefore, urinary levels of DNOC may not be useful biomarkers to quantitate exposure. 

Analysis of Blood Samples. Urinary metabolites undergo relatively rapid elimination from the body, whereas blood components offer biomarkers that have the potential to be used for verification of sulfur mustard exposure long after the exposure incident. Three different approaches have been used for blood biomarker analysis. The intact macromolecule such as protein or DNA with the sulfur mustard adducts still attached can be analyzed. To date, this approach has only been demonstrated for hemoglobin using in vitro experiments. For proteins, an alternate approach is to enzymatically digest them to produce a smaller peptide with the sulfur mustard adduct still attached. Methods of this type have been developed for both hemoglobin and albumin. A third approach has been to cleave the sulfur mustard adduct from the macromolecule and analyze in a fashion similar to that used for free metabolites found in the urine. The later two approaches have both been successfully used to verify human exposure of sulfur mustard. 

Diagnosis of cardiac muscle injury relies on the detection of biomarkers such as troponin I (Tnl), troponin C (TnC), myoglobin, fatty acid binding protein (FABP), glycogen phosporylase isoenzyeme BB (GPBB), C-reactive protein (CP), urinary albumin, creatine kinase myocardial band (CK-MB), and brain (B-type) natriuretic peptide in blood and urine [28-30]. 

Contamination Exogenous feeal, food, bacteria, environmental, for example, chemical environmental cleaning agents (e.g., Clidox) Blood (cystocentesis) and lower urinary tract cells (catheterization) introduced by collection method Intrinsic sample differences crystals, casts, epithelial, and blood cells physicochemical properties (pH, albumin, hemoglobin) Collection procedure Addition or dilution of biomarkers biomarker stability assay interference... 

There are several biomarkers used to assess the internal exposure to PAHs after exposure in the environment and workplaces. These include the urinary metabolite, genetoxic end points, and adducts of benz o(a)pyrene with the DNA in peripheral lymphocytes and other tissues with proteins such as albumin [15]. The urinary metabolite mainly used is 1-hydroxypyrene (Figure 22.4). Hydroxylated phenanthrene is also used but not as commonly used as 1-hydroxypyrene. The drawback of this method is that the concentration or excretion of parent PAH or metabolites in the body fluids or urine is not only dependent on the exposure but also on absorption, biotransformation, and excretion, which vary considerably between individuals. 

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