Normalization of urinary biomarkers to creatinine during changes in glomerular filtration rate

Abstract

Urinary biomarkers, such as albumin and other markers of kidney injury, are frequently reported as a normalized ratio to urinary creatinine (UCr) concentration [UCr] to control for variations in urine flow rate. The implicit assumption is that UCr excretion is constant across and within individuals, such that changes in the ratio will reflect changes in biomarker excretion. Using computer simulations of creatinine kinetics, we found that normalized levels of a biomarker reflecting tubular injury can be influenced by dynamic changes in the UCr excretion rate when the glomerular filtration rate changes. Actual timed urine collections from hospitalized patients with changing glomerular filtration rates and/or critical illness exhibited variability in UCr excretion rates across and within individuals. Normalization by [UCr] may, therefore, result in an underestimation or overestimation of the biomarker excretion rate depending on the clinical context. Lower creatinine excretion in the setting of acute kidney injury or poor renal allograft function may amplify a tubular injury biomarker signal, thereby increasing its clinical utility. The variability of creatinine excretion, however, will complicate the determination of a threshold value for normalized biomarkers of acute or chronic kidney disease, including albumin. Thus, we suggest that the most accurate method to quantify biomarkers requires the collection of timed urine specimens to estimate the actual excretion rate, provided that the biomarker is stable over the period of collection. This ideal must be balanced, however, against practical considerations.

Day-to-day variation of urinary NGAL and rational for creatinine correction

“…Excretion of creatinine may vary with changes in glomerular filtration rate, thus the results may not be extrapolated to patients with acute kidney diseases [16]. To further evaluate the clinical importance and prognostic utility of U-NGAL versus U-NGAL/Cr ratio large prospective cohort studies are needed.…”

Metabolic profiles of placenta in preeclampsia using HR-MAS MRS metabolomics

“…Creatinine normalization in urine is common in clinical chemistry, but is not ideal because metabolic processes and individual factors may alter creatinine excretion. 110,111,203 In paper I, creatinine normalization was used in the quanti ed urinary metabolite levels, and was not signi cantly di erent between preeclamptic and normal pregnant women. In paper II, creatinine excretion was found to be increased in preeclampsia, and although it was not signi cant alone (p=0.09), it contributed to the multivariate prediction model and also to the signi cance of the hippurate / creatinine marker.…”

Methodologic Issues in the Measurement of Urinary Renin

“…Remarkably, the urinary renin-to-creatinine ratios in that study, involving patients between 58 and 79 years old, ranged from 114 to 2894 pg/mg. Given the urinary creatinine concentration in such patients (approximately 1 mg/ml), these results would translate to urinary renin levels of 114-2894 pg/ml (5,6). Such levels are several orders of magnitude higher than the urinary renin levels reported by others (approximately 1-2 pg/ml; range=0.03-157 pg/ml) (7-9) and even substantially higher than the plasma renin levels in cardiac patients (10).…”