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, g-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.

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IntroductionThe urine output criterion of 0.5 ml/kg/hour for 6 hours for acute kidney injury (AKI) has not been prospectively validated. Urine output criteria for AKI (AKIUO) as predictors of in-hospital mortality or dialysis need were compared.MethodsAll admissions to a general ICU were prospectively screened for 12 months and hourly urine output analysed in collection intervals between 1 and 12 hours. Prediction of the composite of mortality or dialysis by urine output was analysed in increments of 0.1 ml/kg/hour from 0.1 to 1 ml/kg/hour and the optimal threshold for each collection interval determined. AKICr was defined as an increase in plasma creatinine ≥26.5 μmol/l within 48 hours or ≥50% from baseline.ResultsOf 725 admissions, 72% had either AKICr or AKIUO or both. AKIUO (33.7%) alone was more frequent than AKICr (11.0%) alone (P <0.0001). A 6-hour urine output collection threshold of 0.3 ml/kg/hour was associated with a stepped increase in in-hospital mortality or dialysis (from 10% above to 30% less than 0.3 ml/kg/hour). Hazard ratios for in-hospital mortality and 1-year mortality were 2.25 (1.40 to 3.61) and 2.15 (1.47 to 3.15) respectively after adjustment for age, body weight, severity of illness, fluid balance, and vasopressor use. In contrast, after adjustment AKIUO was not associated with in-hospital mortality or 1-year mortality. The optimal urine output threshold was linearly related to duration of urine collection (r2 = 0.93).ConclusionsA 6-hour urine output threshold of 0.3 ml/kg/hour best associated with mortality and dialysis, and was independently predictive of both hospital mortality and 1-year mortality. This suggests that the current AKI urine output definition is too liberally defined. Shorter urine collection intervals may be used to define AKI using lower urine output thresholds.

IntroductionFluid resuscitation in the critically ill often results in a positive fluid balance, potentially diluting the serum creatinine concentration and delaying diagnosis of acute kidney injury (AKI).MethodsDilution during AKI was quantified by combining creatinine and volume kinetics to account for fluid type, and rates of fluid infusion and urine output. The model was refined using simulated patients receiving crystalloids or colloids under four glomerular filtration rate (GFR) change scenarios and then applied to a cohort of critically ill patients following cardiac arrest.ResultsThe creatinine concentration decreased during six hours of fluid infusion at 1 litre-per-hour in simulated patients, irrespective of fluid type or extent of change in GFR (from 0% to 67% reduction). This delayed diagnosis of AKI by 2 to 9 hours. Crystalloids reduced creatinine concentration by 11 to 19% whereas colloids reduced concentration by 36 to 43%. The greatest reduction was at the end of the infusion period. Fluid dilution alone could not explain the rapid reduction of plasma creatinine concentration observed in 39 of 49 patients after cardiac arrest. Additional loss of creatinine production could account for those changes. AKI was suggested in six patients demonstrating little change in creatinine, since a 52 ± 13% reduction in GFR was required after accounting for fluid dilution and reduced creatinine production. Increased injury biomarkers within a few hours of cardiac arrest, including urinary cystatin C and plasma and urinary Neutrophil-Gelatinase-Associated-Lipocalin (biomarker-positive, creatinine-negative patients) also indicated AKI in these patients.ConclusionsCreatinine and volume kinetics combined to quantify GFR loss, even in the absence of an increase in creatinine. The model improved disease severity estimation, and demonstrated that diagnostic delays due to dilution are minimally affected by fluid type. Creatinine sampling should be delayed at least one hour following a large fluid bolus to avoid dilution. Unchanged plasma creatinine post cardiac arrest signifies renal injury and loss of function.Trial registrationAustralian and New Zealand Clinical Trials Registry ACTRN12610001012066.

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