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.

Figure 1. Change in serum creatinine concentration (gray) and urine creatinine-normalized biomarker concentration (black) after severe acute kidney injury (acute decrease in creatinine clearance at time 0 from 100 to 10 ml/min)

The urinary biomarker production and excretion rates are assumed not to change; the effect on the normalized biomarker level is due to changes in urinary creatinine excretion rate.

Figure 2. Change in serum creatinine concentration (gray) and urine creatinine-normalized biomarker concentration (black) after mild acute kidney injury (acute decrease in creatinine clearance at time 0 from 100 to 40 ml/min)

The urinary biomarker production and excretion rates are assumed not to change; the effect on the normalized biomarker level is due to changes in urinary creatinine excretion rate.

Figure 3. Change in serum creatinine concentration (gray) and urine creatinine-normalized biomarker concentration (black) after severe acute kidney injury (acute decrease in creatinine clearance at time 0 from 100 to 10 ml/min, followed 5 days later by a linear increase to 100 ml/min over 24 h (diagonal arrow))

The urinary biomarker production and excretion rates are assumed not to change; the effect on the normalized biomarker level is due to changes in urinary creatinine excretion rate.

Figure 4. Changes in the urine creatinine-normalized biomarker concentration after prompt graft function and delayed graft function

The urinary biomarker production and excretion rates are assumed not to change; the effect on the normalized biomarker level is due to changes in urinary creatinine excretion rate.

Figure 5. Graphical comparison of extrapolated 24 h urinary KIM-1 excretion rate (y axis) versus normalized urinary KIM-1/ creatinine ratio

The solid diagonal line represents the line of identity. Three outlier measurements from subject #31 are excluded (see Table 3). KIM-1, kidney injury molecule-1.