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Background In the first part of this study, a variable power-functional creatinine correction (V-PFCRC), normalizing results to 1 g/L creatinine (uCR) was established for total weight spot-urinary arsenic (TWuAs) as an adequate method of urinary dilution. In this second part, the impact of age and sex on TWuAs, V-PFCRC functions, and fluid regulation was investigated in the identical dataset of the first part based on a comprehensive literature review. Methods All samples with age indication, uAsUC <= 500 mcg/L and uCR < 4.5 g/L (n=5585, females n= 2967, males n = 2618) were classified into seven age groups, for which sex-aggregate and disaggregate means (SEs), medians, and ICRs were calculated for uCR and TWuAs in uncorrected (uAsUC), classical CR corrected (CCRC, uAsC), and V-PFCRC (uAsN) results mode. In addition, Pearson correlation analyses were performed for uCR and TWuAs with age. In addition, sex-aggregated - and disaggregated V-PFCRC functions were compared between three numerically similar age groups. Finally, the efficacy of creatinine correction error (CRCE) compensation was assessed by simple power-functional regression analysis (PFRA) in both sexes and seven age bands. Findings The clear male dominance uAsUC (p < 0.001) in aggregate age data and all five adult subgroups separately was found inverted by CCRC (uAsC, p = 0.011) and neutralized by V-PFCRC (uAsN, p = 0.19). Children and adolescents did not exhibit significant sex variations of TWuAs or uCR. A continuous rise of TWuAs with age from adolescence to the beginning of the seventh decade of life was observed in uAsUC, uAsC, and uAsN (0.28 mcg/1g uCR/year). Conversely, TWuAs decreased from childhood to adolescence and in the highest age group. Pearson analysis for all patients between 14 - 72 years and uAsUC < 500 mcg/L revealed significant weak positive correlations (p < 0.001) between TWuAs and age. The log curves between the coefficient a (= uAsN) and exponent b ran higher in younger men and both sexes among seniors, in broad analogy with reportedly higher baseline renal vasopressor activities of Angiotensin II (ATII) and Arginine-Vasopressin (AVP, V1) in these subgroups. The efficacy of V-PFCRC was established based on minimized residual biases of uCR on uAsN in both sexes and all seven age bands (R2 0.0029 - 7.0E-09). Interpretation Sex differences in uAsUC and uAsC are primarily attributable to differentiate urinary dilution and thus are compensated by V-PFCRC. In contrast, age-dependent increases of TWuAs, evident in all results modes, are genuine and should be further accounted for in exposure studies and normal range determinations. While sex and age affect V-PFCRC formulas analog to baseline vasopressor activities of ATII/AVP, they only negligibly affect the correction validity. Adequate perception of power-functional relations between uCR and uAsUC alone, even neglecting these minor sex- and age-specific differences in V-PFCRC correction formulas, results in substantial improvement of dilution adjustment.

Background Dilution adjustment of spot-urinary biomarkers by conventional creatinine correction (CCRC) remains controversial. Apart from unaccounted confounders like age, sex, muscle mass, or diet, the misperception of constant mass ratios between analyte and creatinine (uCR) over a wide hydration range entails deceptive creatinine correction errors (CRCE), foremost at both ends of the uCR-spectrum. Mitigating CRCE by restricting uCR-ranges to 0.3(0.4)-3 g/L generates high numbers of sample rejects and allows for misleading fluctuations within presumably tolerable uCR-ranges. Methods The CRCE for exemplary total weight Arsenic (TWuAs) was analyzed in a large set of n= 5,599 unselected spot urine samples. After confining data to 14 - 80 years, uncorrected arsenic (uAsUC) < 500 mcg/l, and uCR < 4.5g/L, the remaining 5,400 samples were partitioned, and a calculation method to standardize uAsUC to 1 g/L uCR developed based on uAsUC-stratified power functional regression analysis (PFRA). Findings The obtained standardizing method of variable power-functional creatinine correction (V-PFCRC) represents a progression of reportedly proven simple power-functional modifications of CCRC (S-PFCRC). In contrast to CCRC and S-PFCRC, standardization to 1g/L uCR by V-PFCRC yielded constant uAsN-values over the entire uCR-range in all sextiles. Residual bias was largely neutralized in all sextiles of uAsN (R2 9E-06 - 0.04), compared to uAsUC (R2 0.93 - 0.99) and CCRC (R2 0.42 - 0.89). The efficacy of CRCE compensation was confirmed by simple PFRA in both sexes and seven age bands. The strongest %CRCEs were found in samples at low concentrations of uCR (SBC -0.96) and/or uAsUC (SBC -0.11). Interpretation Standardization to 1g/L uCR by V-PFRA allows for more reliable dilution adjustment of spot urinary results than CCRC and S-PFCRC. As an easily adoptable, novel approach, the calculation method developed in this study can minimize residual dilution bias in urinary biomarkers adjusted by uCR, SG, and osmolality. While minimizing sample rejects, V-PFCRC will improve the reliability and comparability, particularly of lower concentrated urinary biomarkers in both conventional results and multiple linear regression models. Funding Self-funded.

Background In the first part of this study, a variable power-functional creatinine correction (V-PFCRC), normalizing results to 1 g/L creatinine (uCR), was established for total weight spot-urinary arsenic (TWuAs) as an adequate method of urinary dilution. In this second part, the impact of age and sex on TWuAs, V-PFCRC functions, and fluid regulation was investigated in the identical dataset of the first part based on a comprehensive literature review. Methods All samples with age indication, uAsUC ≤ 500 mg/L, and uCR < 4.5 g/L (n=5585, females n= 2967, males n = 2618) were classified into seven age groups, for which sex-aggregate and disaggregate means ± SEs, medians, and ICRs were calculated for uCR and TWuAs in uncorrected (uAsUC), classical CR corrected (CCRC, uAsC), and V-PFCRC (uAsN) results mode. In addition, Pearson correlation analyses were performed for uCR and TWuAs with age. In addition, sex-aggregated and disaggregated V-PFCRC functions were compared between three numerically similar age groups. Finally, the efficacy of creatinine correction error (CRCE) compensation was assessed by simple power-functional regression analysis (PFRA) in both sexes and seven age bands. Findings The clear male dominance of uAsUC (p < 0.001) in aggregate age data and all five adult subgroups separately was inverted by CCRC (uAsC, p = 0.011) and neutralized by V-PFCRC (uAsN, p = 0.19). Children and adolescents did not exhibit significant sex variations in TWuAs or uCR. A continuous rise in TWuAs with age from adolescence to the beginning of the seventh decade of life was observed in uAsUC, uAsC, and uAsN (0.28 µg/1 g uCR/year). Conversely, TWuAs decreased from childhood to adolescence and in the highest age group. Pearson analysis for all patients between 14 - 72 years and uAsUC ≤ 500 mg/L revealed significant weak positive correlations (p < 0.001) between TWuAs and age. The log curves between the coefficient a (= uAsN) and exponent b ran higher in younger men and both sexes among seniors, in broad analogy with reportedly higher baseline renal vasopressor activities of angiotensin II (ATII) and arginine vasopressin (AVP, V1) in these subgroups. The efficacy of V-PFCRC was established based on minimized residual biases of uCR on uAsN in both sexes and all seven age bands (R2 0.0029 - 7.0E-09). Interpretation Sex differences in uAsUC and uAsC are primarily attributable to distinct urinary dilution and thus are compensated by V-PFCRC. In contrast, age-dependent increases in TWuAs, evident in all results modes, are genuine and should be further accounted for in exposure studies and normal range determinations. While sex and age affect V-PFCRC formulas analog to baseline vasopressor activities of ATII/AVP, they only negligibly affect the correction validity. Adequate perception of power-functional relations between uCR and uAsUC alone, even neglecting these minor sex- and age-specific differences in V-PFCRC correction formulas, results in substantial improvement of dilution adjustment.

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