Urinary cystatin C as an early biomarker of acute kidney injury following adult cardiothoracic surgery

Abstract

There is a need to develop early biomarkers of acute kidney injury following cardiac surgery, where morbidity and mortality are increased by its presence. Plasma cystatin C (CyC) and plasma and urine Neutrophil Gelatinase Associated Lipocalin (NGAL) have been shown to detect kidney injury earlier than changes in plasma creatinine in critically ill patients. In order to determine the utility of urinary CyC levels as a measure of kidney injury, we prospectively collected plasma and urine from 72 adults undergoing elective cardiac surgery for analysis. Acute kidney injury was defined as a 25% or greater increase in plasma creatinine or renal replacement therapy within the first 72 hours following surgery. Plasma CyC and NGAL were not useful predictors of acute kidney injury within the first 6 hours following surgery. In contrast, both urinary CyC and NGAL were elevated in the 34 patients who later developed acute kidney injury, compared to those with no injury. The urinary NGAL at the time of ICU arrival and the urinary CyC level 6 hours after ICU admission were most useful for predicting acute kidney injury. A composite time point consisting of the maximum urinary CyC achieved in the first 6 hours following surgery outperformed all individual time points. Our study suggests that urinary CyC and NGAL are superior to conventional and novel plasma markers in the early diagnosis of acute kidney injury following adult cardiac surgery.

Figure 1. Plasma creatinine, cystatin C, and NGAL over time

(a) Plasma creatinine over time. This figure displays the plasma creatinine (mean ± 1 s.e.) during the perioperative period in all subjects with and without acute kidney injury (AKI). Note that the plasma creatinine generally decreased below baseline values at the first two postoperative time points; this early postoperative decrease in plasma creatinine was similarly seen in both groups. The diagnosis of AKI (≥25% increase from preoperative baseline) could generally not be made until at least the first postoperative day (diagnosed at day 1 or later in 23 of 34 patients). Similarly, note that the mean plasma creatinine does not increase by 50% in AKI subjects until day 2. (b) Plasma cystatin C (CyC) over time. The mean preoperative value was 1.47 mg/l in those with no AKI and 1.46 mg/l in those with AKI. Similar to the plasma creatinine (a), plasma CyC generally decreased below baseline values in the immediate postoperative period; this early postoperative decrease in plasma CyC was seen in both groups but persisted in those with no AKI. A 25% increase in mean CyC does not occur until postoperative day 2, and a 50% increase on day 3 in those with AKI. Mean values are displayed in the figure with error bars representing ± 1 s.e. (c) Plasma neutrophil gelatinase-associated lipocalin (NGAL) over time. This graph depicts the plasma NGAL (mean ± s.e.) at preoperative and several postoperative time points. There is no significant difference in the preoperative baseline values between those who develop AKI and those with no AKI (P = 0.83). The NGAL changes similarly in both groups throughout the early postoperative period (P = 0.93 for interaction, P = 0.79 for group main effect).

Figure 2. ROC curves for the maximum early composite

This figure displays the receiver operating characteristic (ROC) curves for the maximum early composite (maximum values from the first 6 postoperative hours) for all four biomarkers of acute kidney injury. The AUC is greatest for urine cystatin C (CyC, 0.734) followed by urine neutrophil gelatinase-associated lipocalin (NGAL, 0.691) followed by plasma CyC (0.624) and then plasma NGAL (0.536). However, these differences in the AUCs did not reach statistical significance (P = 0.11). Urine CyC (P<0.001) and urine NGAL (P = 0.006) at this early postoperative composite time point were the only two biomarkers to significantly predict the future development of acute kidney injury (AKI).

Figure 3. Urinary cystatin C excretion over time

This figure depicts urinary excretion of cystatin C (CyC, mean ± s.e.) at several preoperative and early postoperative time points in three patient groups: those who did not develop acute kidney injury (AKI, no AKI); those who developed AKI but did not receive renal replacement therapy (RRT; AKI without RRT), and those who received RRT (RRT). There is no difference in the preoperative baseline urinary CyC excretion in the three groups (P = 0.49) but a significant difference in changes over time (P<0.01), with increases in the urinary CyC concentrations correlating with severity of AKI. *P≤0.001, **P≤0.01 for three-group comparison.

Figure 4. Urinary NGAL excretion over time

Similar to urine cystatin concentrations (Figure 3), there is no difference between the preoperative urinary neutrophil gelatinase-associated lipocalin (NGAL) values across the three groups (P = 0.41). We see an early increase in urinary NGAL that correlates with severity of acute kidney injury (AKI) beginning at the intensive care unit (ICU) time point. Values displayed in the figure are mean ± s.e. *P≤0.001, **P≤0.01 for three-group comparison.