Title: 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. 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. Acute kidney injury (AKI) is a common and serious complication of cardiothoracic surgery;1.Wijeysundera D.N. Karkouti K. Dupuis J.Y. et al.Derivation and validation of a simplified predictive index for renal replacement therapy after cardiac surgery.JAMA. 2007; 297: 1801-1809Crossref PubMed Scopus (282) Google Scholar depending on the definition of AKI used, it may occur in over 40% of adults, with 1–5% requiring renal replacement therapy (RRT).2.Abel R. Buckley M. Austen W. et al.Etiology, incidence and prognosis of renal failure following cardiac operations. Results of a prospective analysis of 500 consecutive patients.J Thorac Cardiovasc Surg. 1976; 71: 323-333PubMed Google Scholar,3.Andersson L. Ekroth R. 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Similarly, if such a biomarker panel could also predict AKI severity, and in particular whether RRT is likely required, then accurate stratification of patients to receive pharmacotherapy or early RRT in randomized trials would be possible. Serum creatinine, the currently accepted ‘gold standard’ to diagnose AKI, is a delayed and inadequate marker of acute changes in renal function. In AKI, serum creatinine elevation that reflects the development and severity of kidney damage does not occur until days after renal tubular injury has begun.14.Rosner M.H. Okusa M.D. Acute kidney injury associated with cardiac surgery.Clin J Am Soc Neprol. 2006; 1: 19-32Crossref PubMed Scopus (759) Google Scholar,22.Murray P. Le Gall J. 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Brocker-Preuss M. et al.Increased urinary cystatin C reflects structural and functional renal tubular impairment independent of glomerular filtration rate.Clin Biochem. 2007; 40: 946-951Crossref PubMed Scopus (80) Google Scholar NGAL, a 25 kDa member of the lipocalin family, is markedly upregulated in the early postischemic mouse and rat kidney.39.Mishra J. Ma Q. Prada A. et al.Identification of neutrophil gelatinase-associated lipocalin as a novel early urinary biomarker for ischemic renal injury.J Am Soc Nephrol. 2003; 14: 2534-2543Crossref PubMed Scopus (1329) Google Scholar Serum and urine NGAL levels are elevated earlier than serum creatinine in the setting of delayed graft function following kidney transplantation40.Parikh C.R. Jani A. 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Kim M. et al.Association between increases in urinary neutrophil gelatinase-associated lipocalin and acute renal dysfunction after adult cardiac surgery.Anesthesiology. 2006; 105: 485-491Crossref PubMed Scopus (453) Google Scholar similarly found that urinary NGAL is useful in the early diagnosis of AKI in adults after cardiac surgery, although the test performance was significantly inferior in this population to the seminal pediatric study (area under the curve (AUC) under the receiver operating characteristic (ROC) curve for urinary NGAL was 0.8 at 18 h, but only 0.68 at 1 h and 0.74 at 3 h postoperation, whereas it was 0.998 at 2 h and 1.0 at 4 h in the Mishra study). Taken together with the fact that only limited numbers of cardiac surgery patients (adult or pediatric) have been studied, it is clear that the role of NGAL in the diagnosis of perioperative AKI requires further investigation. A total of 262 patients were screened for study enrollment. Of them 162 were excluded because they met one or more exclusion criteria and 49 declined to participate. In total 81 subjects consented for the study, of whom 73 subjects completed the protocol; the most common reason for failure to complete the protocol despite informed consent was an unanticipated preoperative cardiac catheterization within 24 h of surgery. Of these 73 individuals, 1 died in the operating room, had no postoperative data, and was excluded from the analysis. The clinical characteristics of the remaining 72 subjects are listed in Table 1.Table 1Clinical characteristics of subjects (n=72)VariableNo AKI (n=38)AKI (n=34)P-valuePreoperative factors Age65.0 (51.0–73.0)64.5 (50.0–76.0)NS Female sex11 (28.9)10 (29.4)NS Race Caucasian26 (68.4)26 (76.5)NS Afr. Am.7 (18.4)5 (14.7) Hispanic4 (10.6)2 (5.9) Other1 (2.6)1 (2.9) Baseline eGFR (MDRD) ml/min per 1.73 m270.1±4.571.2±4.8NS Cleveland Clinic score3 (2–6)4 (3–6)NS Wijeysundera JAMA score2 (1–3)2 (1–3)NS Diabetes mellitus8 (21.1)9 (26.5)NS Ejection fraction52.0 (30.0–60.0)50.0 (31.5–58.9)NS(n=31)(n=27) Surgery type CABG alone7 (18.4)6 (17.6)NS Valve alone10 (26.3)5 (14.7) CABG+valve15 (39.5)10 (29.4) CABG+other1 (2.6)2 (5.9) Valve+other2 (5.3)7 (20.6) Other3 (7.9)4 (11.8) Reoperation11 (28.9)9 (26.5)NSOperative factors Cardiopulmonary bypass time (min)180.2±10.8220.4±18.4NS (0.065) Off-pump surgeries4 (10.5)4 (11.8)NS Cross-clamp time (minutes)144.2±8.6158.6±8.8NS No cross-clamp surgeries9 (23.7)7 (20.6)NSOutcomes ICU days4 (3–5)5 (3.75–10)0.038 Postoperative hospital days7 (6–9)10 (7.75–19)0.003 Mortality in hospital0 (0.0)4 (11.8)0.045Data are expressed as mean±s.e., median (25–75%), or number (percentage).AKI, acute kidney injury; Afr. Am., African American; CABG, coronary artery bypass graft surgery; eGFR, estimated glomerular filtration rate; NS, not significant (P>0.05); MDRD, Modification of Diet in Renal Disease. Open table in a new tab Data are expressed as mean±s.e., median (25–75%), or number (percentage). AKI, acute kidney injury; Afr. Am., African American; CABG, coronary artery bypass graft surgery; eGFR, estimated glomerular filtration rate; NS, not significant (P>0.05); MDRD, Modification of Diet in Renal Disease. Of the 72 study subjects, 34 (47.2%, 95% confidence interval (CI, 35.3, 59.3%)) of patients developed postoperative AKI (the primary study end point) as defined by a peak increase of plasma creatinine of greater than or equal to 25% (from preoperative baseline) (Figure 1a) or need for RRT (Table 2) within 3 days of the surgery. The mean preoperative plasma creatinine for all 72 subjects was 1.25 mg/100 ml (median=1.08 mg/100 ml), consistent with their mean preoperative Modification of Diet in Renal Disease-estimated glomerular filtration rate (eGFR) of 70.6 ml/min per 1.73 m2 body surface area. Baseline plasma creatinine (mg/100 ml; median (interquartile range)) was 1.05 (0.90–1.50) in the group that did not develop AKI (n=38), not significantly different than the AKI group (1.14 (0.92–1.24), n=34, P=0.86). There was also no significant difference in baseline eGFR values between the two groups (P=0.87; Table 1).Table 2RRT cases, indications, and outcomesAge/sex/racePlasma creatinine at RRT start (mg/100 ml)Hours in ICU postoperation prior to RRTIndicationsOutcome40/M/AA5.425.3Refractory hyperkalemia (6 mEq/l), oliguriaCurrently receiving outpatient RRT74/M/Cauc.3.4851.2Anuria, elevated creatinine, shockOff RRT prior to hospital discharge78/F/Cauc.1.4221.6Volume overload, hypoxia, oliguria, shockDied POD no. 2868/M/Cauc.3.7926.8Lactic acidosis, oliguria, shock, elevated creatinineDischarged on RRT—lost to follow up after 4 months.62/M/AA1.745.3Anuria, shock, volume overload, acidosisOff RRT after 2.5 months31/F/Hisp.1.283.0Lactic acidosis, anuria, shockDied POD no. 862/M/Cauc.2.8081.0Volume overload, shock, hypoxiaDied POD no. 10AA, African American; Cauc., Caucasian; F, female; Hisp., Hispanic; ICU, intensive care unit; M, male; POD, postoperative day; RRT, renal replacement therapy. Open table in a new tab AA, African American; Cauc., Caucasian; F, female; Hisp., Hispanic; ICU, intensive care unit; M, male; POD, postoperative day; RRT, renal replacement therapy. The peak plasma creatinine (mg/100 ml) within 72 h postoperatively (‘72 h Max’) was significantly greater, by definition, in the AKI group than in the group that did not develop AKI (1.65 (1.28–2.22) vs 1.15 (1.06–1.48), respectively; P<0.001). Furthermore, peak plasma creatinine increased with increasing AKI severity (P<0.001): no AKI (1.15, 1.06–1.48), AKI without RRT (1.56, 1.26–1.84), and RRT (2.84, 1.42–5.41). Of the 34 AKI subjects, 13 (38.2%) had a ≥50% increase in their plasma creatinine without receiving RRT. Of these 34 patients, 7 (20.6%) went on to require RRT, all initiated with continuous venovenous hemodialysis. Clinical features, indications, and timing of initiation of the RRT cases are in listed in Table 2. Four (11.8%) of these AKI subjects died during their postoperative hospital course, with three of the four deaths in those requiring RRT; none of the cohort without AKI died during their hospitalization (P=0.045). Similarly, there were significantly longer intensive care unit (ICU) stays and duration of hospitalization in the AKI group (Table 1). Finally, the AKI group had a trend towards longer mean cardiopulmonary bypass pump (CPB) times than those without AKI (220.4 vs 180.2 min, respectively; P=0.065; Table 1). Similar to plasma creatinine (Figure 1a), plasma CyC decreased from preoperative values at the initial postoperative time points (Figure 1b). There was no difference between the preoperative baseline plasma CyC values of those with and without AKI (P=0.92; Table 3), or in a three-group comparison (no AKI, AKI without RRT, RRT; P=0.55). There was no significant difference between the maximum plasma CyC values of those with and without AKI in the early postoperative period (post-CPB, ICU arrival, and 6 h ICU time points: the ‘early composite’ period), although there was a trend toward higher values in the AKI group (P=0.071; Table 3). This composite time point represents a period approximately 24 h prior to the diagnosis of AKI. The trend toward higher plasma CyC values in the AKI group continued subsequently, so that there was a significantly higher 72 h peak value for plasma CyC in those who developed AKI compared to those without AKI (Table 3), and evidence for an overall difference in plasma CyC change over time (interaction P< 0.01 from repeated-measures analysis of variance, ANOVA).Table 3Plasma and urinary cystatin and NGAL values in the perioperative periodVariableNo AKI (n=38)AKI (n=34)P-valuePlasma CyC (mg/l) Baseline1.23 (1.05–1.52)1.36 (1.03–1.61)NS(0.71–3.75)(0.71–5.10) Maximum 72 h1.31 (1.11–1.73)1.90 (1.31–2.55)0.019(0.64–3.75)(0.78–8.39) Maximum early composite1.17 (0.96–1.36)1.29 (1.06–1.87)NS(0.64–3.31)(0.78–3.90)Urine CyC/urine creatinine (mg/g) Baseline0.05 (0.03–0.07)0.06 (0.04–0.09)NS(0.01–0.30)(0.001–1.01) Maximum 72 h0.29 (0.10–0.78)1.30 (0.54–3.52)<0.001(0.02–5.06)(0.12–12.92) Maximum early composite0.18 (0.09–0.46)0.92 (0.23–1.76)<0.001(0.02–5.06)(0.06–10.64)Plasma NGAL (ng/ml) Baseline104.2 (63.9–225.1)116.5 (57.9–193.6)NS(7.9–698.9)(10.0–588.7) Maximum 72 h392.0 (251.5–599.9)393.9 (300.7–731.8)NS(17.7–2137.8)(12.5–1663.7) Maximum early composite371.2 (195.5–597.3)378.8 (210.3–731.8)NS(13.9–1810.5)(12.5–1663.7)Urine NGAL/urine creatinine (ng/mg) Baseline3.2 (1.7–8.0)3.0 (2.3–7.2)NS(0.2–119.3)(0.6–196.7) Maximum 72 h157.3 (29.8–1068.8)1136.1 (243.6–4226.8)0.002(9.7–6029.7)(17.9–25725.3) Maximum early composite147.2 (24.2–1068.8)1136.1 (176.6–4226.8)0.006(1.6–6029.7)(3.0–24289.6)Data are expressed as median (25–75%) (min–max).AKI, acute kidney injury; Cr, creatinine; CyC, cystatin C; NGAL, neutrophil gelatinase-associated lipocalin; NS, not significant (P>0.05).Maximum 72 h is the maximum value during the first 72 postoperative hours.Maximum early composite is the maximum value during the first 6 postoperative hours (time points post-CPB, ICU, and 6 h ICU). Open table in a