The utility of biomarker excretion rates in acute kidney injury

INTRODUCTION: The concentration of urinary biomarkers of acute kidney injury (AKI) is influenced by variation in urinary concentration within and between individuals.1 Normalisation to urine creatinine concentration is commonly used to account for this variation.2 The accuracy of this method is compromised by tubular secretion of creatinine, and variations in urine creatinine excretion in non-steady state when glomerular filtration rate (GFR) changes.1 Alternatives to normalisation to creatinine include using the absolute biomarker concentration or quantifying the biomarker excretion rate. Intuitively, the excretion rate may also account for variation in water reabsorption and urine flow rate. In addition, total biomarker excretion in AKI might more accurately reflect the mass of injured tubular cells, a function of both severity and duration, parameters associated with long-term mortality.3 OBJECTIVE: To compare the performance of biomarker excretion rate and the absolute and normalized biomarker concentration in diagnosis of AKI, prediction of AKI, death and the need for renal replacement therapy (RRT) in adult intensive care patients. This will assists in the comparison of biomarkers between trials and guide clinicians on how it should be utilized in clinical practice. METHODS: Urinary concentrations of alkaline phosphatase (AP), γ-glutamyl transpeptidase (GGT), cystatin C (CysC), neutrophil gelatinase-associated-lipocalin (NGAL), kidney-injury molecule-1 (KIM 1), and interleukin-18(IL-18) were measured on ICU admission, at 12 and 24 hours in the EARLYARF trial.4, 5 The average urine flow rate was calculated from 4-hour creatinine clearance measurements obtained at the same time points, which allowed calculation of biomarker excretion rate. The normalised biomarker concentrations were derived by dividing the biomarker concentration by the urinary creatinine concentration. The total excretion over 24 hours for each biomarker (i.e. integration of excretion rate with respect to time) was determined using the trapezoidal rule. The performance of absolute and normalised biomarker concentration, and biomarker excretion rate on admission to the ICU in diagnosis or prediction of outcome was assessed by comparison of the area under the curve (AUC) of receiver-operator characteristic curves (ROC) for each parameter using the DeLong method.6, 7 The association of total biomarker excretion with AKI severity (maximum AKIN stages within 48 hours), and 1-year survival were assessed with one-way ANOVA and Kaplan Meier survival analysis. RESULTS: Of 528 recruited patients, 484 had 4h-creatinine clearance measurements on ICU admission from which urine output volumes could be obtained for the calculation of biomarker excretion rates. For diagnosis of AKI on ICU admission, biomarker concentration performed better than normalised concentration or excretion rate. Normalised concentrations performed best in prediction of 7-day mortality and the need of RRT. Excretion rate did not diagnose or predict outcomes better than absolute or normalised concentration. In the cohort of patients without AKI on ICU admission (n=339), there were no differences in performance between absolute and normalised biomarker concentration in prediction of development of AKI within 48 hours (AKIN48) or sustained AKI within 7 days of admission (RIFLE 24). However, here also the normalised concentrations had higher AUCs than excretion rates (Figure 1). The total biomarker excretion in the first 24 hours increased with severity of injury for all biomarkers except AP. For NGAL alone, post-hoc analysis also demonstrated significant differences between successive AKIN stages of increasing severity AKI (p≤0.02) (Figure 2). Patient survival was assessed according to extent of biomarker excretion ranked by tertiles Only NGAL demonstrated a significant association between total excretion and survival over 365 days (log-rank test, p=0.04). After adjusting for age, gender, sepsis, APACHE II and SOFA scores, patients with higher excretion of NGAL (higher tertile, total excretion >184µg) had a higher 1-year mortality compared to those with a lower tertile of NGAL excretion (total excretion of <40µg) (Hazard ratio of 2.15 (95% CI: 1.23 to 3.73), p=0.007) (Figure 3). . CONCLUSIONS: Normalisation to urine creatinine provides no advantage in diagnosis of AKI, but improves prediction of AKI and outcome. Periodic excretion rates did not improve performance, but total excretion in the first 24hr was strongly associated with AKI severity, and for NGAL with survival. The ideal method for standardizing urinary AKI biomarkers depends on the outcome being assessed

Test characteristics of urinary biomarkers depend on quantitation method in acute kidney injury

The concentration of urine influences the concentration of urinary biomarkers of AKI. Whether normalization to urinary creatinine concentration, as commonly performed to quantitate albuminuria, is the best method to account for variations in urinary biomarker concentration among patients in the intensive care unit is unknown. Here, we compared the diagnostic and prognostic performance of three methods of biomarker quantitation: absolute concentration, biomarker normalized to urinary creatinine concentration, and biomarker excretion rate. We measured urinary concentrations of alkaline phosphatase, gamma-glutamyl transpeptidase, cystatin C, neutrophil gelatinase–associated lipocalin, kidney injury molecule–1, and IL-18 in 528 patients on admission and after 12 and 24 hours. Absolute concentration best diagnosed AKI on admission, but normalized concentrations best predicted death, dialysis, or subsequent development of AKI. Excretion rate on admission did not diagnose or predict outcomes better than either absolute or normalized concentration. Estimated 24-hour biomarker excretion associated with AKI severity, and for neutrophil gelatinase–associated lipocalin and cystatin C, with poorer survival. In summary, normalization to urinary creatinine concentration improves the prediction of incipient AKI and outcome but provides no advantage in diagnosing established AKI. The ideal method for quantitating biomarkers of urinary AKI depends on the outcome of interest