Creatinine urinary biomarkers

The risk interpretation of biomonitoring results will tend to have additional uncertainties. That is because, in addition to the standard uncertainties encountered in risk assessment, there is the uncertainty of extrapolating from a blood or urinary concentration to an external dose. There will be variability both in the timing between sample draw and most recent exposure and in the relationship between blood concentration and dose. Those kinds of variability are compounded by uncertainty in the ability of a PK calculation or model to convert biomarker to dose accurately. For example, reliance on urinary biomarker results expressed per gram of urinary creatinine leads to an uncertain calculation of total chemical excretion per day because of the considerable variability in creatinine clearance per day. That complicates an otherwise simple approach to estimating dose. Furthermore, the conversion requires knowledge of fractional excretion via various pathways, which may not be present for a large sample of humans. The uncertainties created by these factors can be bounded via sensitivity and Monte... 

Carlo analysis, but ultimately the variability in fractional excretion and creatinine clearance needs to be understood to characterize population exposure to urinary biomarkers. 

Urinary biomarkers can be related to exposure dose in a straightforward manner for chemicals that are excreted rapidly in urine. This approach requires the collection of data describing the percentage of dose excreted each day in urine and percentages excreted by different metabolic and elimination pathways. There can be important variability and uncertainty in those factors and in the normalization of the biomarker result (per gram of creatinine). Furthermore, there may be environmental sources of the urinary biomarker that can confound an estimation of parent-chemical dose based on the metabolite in urine. It is also possible that the urinary metabolites may exist as breakdown products in the environment. 

How uncertainties and variability in creatinine clearance can affect urinary biomarker results and their extrapolation to external dose. 

Cystatin C is nearly completely metabolized by proximal renal tubular cells. As a consequence, under ordinary circumstances there is little to no detectable cystatin C present in the urine. Thus, a true clearance of cystatin C cannot be determined. However, in the presence of tubular damage, cystatin C may be detected in the urine [147,148] and may be more sensitive to early and mild changes of kidney function compared with creatinine [149,150]. In this regard, elevation in serum cystatin C consistent with AKI, defined by at least a 50% increase from baseline, was evident 1-2 days prior to changes in SCr [151]. Finally, in patients with AKI, elevated urinary cystatin C was highly predictive of subsequent need for acute renal replacement therapy and outperformed several other urinary biomarkers in some studies [152]., but not in others [152a]... 

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 excretion of total phenol (free and conjugates) is considered a biomarker of exposure for phenol. The biological exposure index (BEI) for phenol, for exposure to 5 ppm in air, is 250 mg/g creatinine when measured at the end of the shift (ACGIH 1991). 

Biomarkers for decreased function include increases in urinary proteins and elevation of serum creatinine or 2-microglobulin. Biomarkers for renal cytotoxicity include increases in urinary excretion of antigens and enzymes located within renal tissues. Biomarkers for biochemical changes occurring within the kidneys include eicosanoids, fibronectin, kallikrein activity, and glycosaminoglycans in urine. 

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