http://informahealthcare.com/rnf ISSN: 0886-022X (print), 1525-6049 (electronic) Ren Fail, 2014; 36(10): 1497–1503 ! 2014 Informa Healthcare USA, Inc. DOI: 10.3109/0886022X.2014.949759
CLINICAL STUDY
Preoperative serum cystatin C combined with dipstick proteinuria predicts acute kidney injury after cardiac surgery Xudong Wang1, Miaolin Che2, Bo Xie1, Song Xue1, and Yucheng Yan2 Department of Cardiovascular Surgery, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China and 2Department of Nephrology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China
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1
Abstract
Keywords
Background: Acute kidney injury (AKI) is common following cardiac surgery and is associated with poor outcomes. However, the detection of those preoperative patients who will develop AKI is still difficult. In this study, we compared serum cystatin C combined with dipstick proteinuria as early markers to predict AKI available before surgery. Methods: We prospectively followed 616 patients undergoing cardiac surgery and identified 179 that developed AKI, defined as an increase in serum creatinine (SCr) of 0.3 mg/dL or 50% increase in creatinine level. Preoperative values for cystatin C were categorized into quartiles. We defined proteinuria, measured with a dipstick, as mild (trace to 1+) or heavy (2 + to 4+). Univariate as well as multivariate regression was performed. Cystatin C combined with dipstick proteinuria before surgery was assessed for its’ predictive value of AKI using receiver operating characteristic (ROC) curves. Results: The final cohort consisted of 616 patients aged 60.7 ± 13.2 years, and baseline SCr was 75.8 ± 26.4 mmol/L, estimated glomerular filtration rate (eGFR) 96.3 ± 29.0 mL/min/ 1.73 m2 and cystatin C 1.05 ± 0.33 mg/L. Patients in higher cystatin C quartiles were older (p50.001), more often to have heavy proteinuria (p ¼ 0.021), hyperuricemia (p50.001), heart failure (p50.001) and recent myocardial infarction (p ¼ 0.002). Those with heavy proteinuria were more often to have diabetes mellitus (p ¼ 0.010), hyperuricemia (p ¼ 0.043), worse cardiac function (p50.05), higher creatinine levels (p50.001) and lower eGFR levels (p50.001). In a multiple logistic regression model, preoperative heavy proteinuria [OR: 3.14, 95% confidence interval (CI): 1.26–7.77] and preoperative cystatin C quartiles (Q2:OR: 1.60, 95% CI: 0.72–3.60; Q3:OR: 1.87, 95% CI: 0.85–4.14; Q4:OR: 3.10, 95% CI: 1.37–7.02) each associated with an increased odds of AKI, independent of advanced age (OR: 1.04, 95% CI: 1.01–1.06), hypertension (OR: 1.88, 95% CI: 1.13–3.12) and combined surgery (OR: 3.47, 95% CI: 1.35–8.89). The risk for adverse outcomes such as postoperative AKI, persistent AKI, severe AKI, dialysis and mortality were highest in patients with highest quartile of cystatin C (p50.05, respectively) and heavy proteinuria (p50.05, respectively). The area under the ROC curve for preoperative cystatin C combined with proteinuria to detect AKI, persistent AKI and severe AKI were 0.695 (p50.001; 95% CI ¼ 0.637–0.754), 0.753 (p50.001; 95% CI ¼ 0.693–0.812) and 0.718 (p50.001; 95% CI ¼ 0.642–0.795), respectively. Conclusion: These data suggest that preoperative serum cystatin C combined with dipstick proteinuria may improve prediction of AKI among patients undergoing cardiac surgery.
Acute kidney injury, serum cystatin C, dipstick proteinuria, prognosis
Introduction Acute kidney injury (AKI) is a major complication after cardiac surgery and associated with increases in mortality, morbidity and intensive care unit (ICU) length-of-stay.1–4 While recent advances have improved our understanding of the pathogenesis of AKI, this has so far not translated into better clinical diagnostics or treatments.5 Meanwhile, early detection of these patients may contribute to improving their outcomes.5–7
Address correspondence to Yucheng Yan, MD, PhD, Department of Nephrology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China. Tel.: +86-21-68383139; Fax: + 86-2163260745; E-mail: [email protected]
History Received 12 April 2014 Revised 2 July 2014 Accepted 15 July 2014 Published online 21 August 2014
Patient’s renal reserve before surgery has been confirmed as an important determinants for both mortality and AKI outcomes.8,9 Serum cystatin C has been validated as a better marker to estimate glomerular filtration rate for chronic kidney disease (CKD) relative to creatinine and creatininebased estimated glomerular filtration rate (eGFR).10 Although several studies have focused on the diagnostic accuracy of preoperative cystatin C in predicting AKI,11,12 the capability remain elusive.13,14 Moreover, proteinuria has been shown to be strongly associated with adverse outcomes, including renal disease progression, cardiovascular events and long-term mortality.15–17 Recent reports from large epidemiologic studies have shown that patients with proteinuria have a higher risk of adverse outcomes than those without proteinuria within the same CKD stage.18,19 Data on the application
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of preoperative serum cystatin C combined with proteinuria to predict AKI are scarce in Chinese patients following cardiac surgery but are of great usefulness.
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preoperative laboratory data (hemoglobin concentration and brain natriuretic peptide concentration). Outcomes
Materials and methods
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Patients A total of 616 patients (18–85 years of age) who underwent cardiac surgery (including coronary artery bypass grafting (CABG), valve surgery, combined coronary artery bypass graft and valve procedures, and other cardiac surgeries such as congenital heart disease repair, aorta aneurysm and others) at Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China, between 1 June 2011 and 31 March 2013 were prospectively enrolled. Exclusion criteria include patients younger than 18 years, patients with preexisting end-stage kidney disease, patients receiving any form of dialysis therapy before surgery and patients who had died during or after surgery within 24 hours. We recorded preoperative clinical data, including serum creatinine (SCr) to estimate GFR [according to the Modification of Diet in Renal Disease (MDRD) equation (National Kidney Foundation 2002)] as well as clinical data during hospitalization. Informed consent was obtained from each patient prior to enrollment, and the ethical review board of the Shanghai Renji Hospital approved this study. Predictors At the preoperative visit, a blood sample was collected, centrifuged at 2000 g for 5 min, and the supernatants were aliquoted and stored at –80 C. Serum cystatin C was measured by immunonephelometry (Dade Behring, Marburg, Germany). SCr was measured by a modified Jaffe method with protein precipitation using an alkaline picrate reaction. The eGFR was calculated with MDRD equation. Proteinuria was measured using a dipstick within two days before surgery. To classify the severity of proteinuria, we defined negative as ‘‘no proteinuria’’, trace to 1+ as ‘‘mild proteinuria’’ and 2+ to 4+ as ‘‘heavy proteinuria’’.20 The test strips were measured by an automatic dipstick autoanalyzer (Cobas u 411; F. Hoffmann-La Roche, Ltd., Basel, Switzerland). Risk factors Preoperative variables known to be or who could potentially be associated with AKI or other adverse outcomes were collected. These included age, gender, hypertension (systolic blood pressure 140 mmHg and/or diastolic blood pressure 90 mmHg), diabetes mellitus (DM; using oral hypoglycemic agents or insulin), peripheral arterial disease21 (determined by clinical diagnosis or imaging results), cerebral vascular accident21 (previous cerebral vascular accident such as ischemic or hemorrhagic), New York Heart Association functional class III or IV congestive heart failure (CHF), chronic obstructive pulmonary disease, recent myocardial infarction (MI; i.e.,530 days before surgery) and hyperuricemia (a serum uric acid 46.6 in women and 47.0 mg/dL in men), left ventricular ejection fraction (assessed preoperatively by echocardiography), emergency surgery and
The outcome of AKI was determined using the daily SCr measurements during the first five hospital days. Our primary outcomes were AKI,13 defined as an increase of SCr levels of more than 0.3 mg/dL or a 50% relative increase in the first 48 hours postoperatively. We evaluated a secondary outcome of persistent AKI,13 defined as having AKI for 48 hours or longer. We further evaluated severe AKI13 [Acute Kidney Injury Network (AKIN) stage 2], defined as either doubling of SCr level or requirement of acute hemodialysis. Total duration of ventilator-assisted respiration during postoperative hospitalization, the length of stay in ICU and hospital were recorded. Patients were followed until discharge [median observation time was 15 (7–95) days] and all-cause in-hospital mortality was recorded. Statistical analysis To improve precision for some analyses, we categorized our cohort into quartiles by preoperative serum cystatin C. To compare continuous variables, we used the Student’s t-test or the non-parametric Mann–Whitney U-test, and to compare categorical variables, we used the 2 or Fisher’s exact test, as appropriate. A multivariate logistic regression model incorporating all factors associated with AKI in univariate analysis as well as the factors showing a univariate p value50.05 was performed to identify associated risk factors with AKI. Risk data are presented as odds ratios with 95% confidence intervals (CI). We calculated the receiver operating characteristic (ROC) curve of biomarkers for predicting AKI. We also used a fitted multiple logistic regression model to combine preoperative serum cystatin C and dipstick proteinuria and calculated ROC data. A p value of 50.05 was considered statistically significant for all comparisons. SPSS version 16.0 for windows software (SPSS Inc., Chicago, IL) was used for the statistical analysis.
Results Patients’ characteristics By excluding patients whose complete clinical data were not available (n ¼ 68) and those with pre-existing end-stage kidney disease (n ¼ 1), a total of 616 patients [393 men, mean age 60.7 ± 13.2 years (range 18–85 years)] were included in the final analysis. Baseline characteristics of these patients are summarized in Table 1. Briefly, the preoperative cystatin C was 1.05 ± 0.33 mg/L, SCr level was 75.8 ± 26.4 mmol/L and eGFR was 96.3 ± 29.0 mL/min. The most frequent cardiac surgery was valve surgery (46.3%), followed by CABG (37.9%) and CABG combined with valve (8.3%; Table 1). We compared baseline characteristics across quartiles of cystatin C. The most striking differences across quartiles were that patients in higher cystatin C quartiles were older, have more often heavy proteinuria and hyperuricemia, more likely to have heart failure and recent MI (Table 1). As expected, creatinine levels were higher and eGFR levels were lower in the higher cystatin C quartiles. A total of 190 (30.8%)
60.8 ± 17.3 118.2 ± 28.9 13.1 ± 1.6 162.3 ± 231.3 11 (7.1%) 0.70 ± 0.09
75.8 ± 26.4 96.3 ± 29.0 12.8 ± 1.8 267.6 ± 340.7
59 (9.6%) 1.05 ± 0.33
(37.0%) (53.2%) (3.9%) (1.9%) (1.3%) (2.6%)
57 82 6 3 2 4
(37.9%) (46.3%) (8.3%) (2.7%) (0.8%) (1.7%)
239 292 52 17 5 11
(25.3%) (17.5%) (0.6%) (2.6%) (7.8%) (1.3%) (14.3%) (3.9%) (6.5%)
7 (3.9%) 0 (0%) 51 (33.1%)
39 27 1 4 12 2 22 6 10
17 (2.8%) 4 (0.6%) 230 (37.3%)
(31.8%) (18.2%) (1.8%) (3.6%) (19.3%) (1.6%) (25.5%) (8.9%) (9.1%)
53.7 ± 13.4 89 (57.8%)
60.7 ± 13.2 393 (62.4%)
196 112 11 22 119 10 157 55 56
154
616
Quartile 1 (0.38–0.83 mg/L)
(31.2%) (13.6%) (1.9%) (1.3%) (14.9%) (1.9%) (20.8%) (5.8%) (9.1%)
(43.6%) (46.1%) (4.5%) (1.9%) (0.6%) (1.9%)
13 (8.4%) 0.92 ± 0.04
67.3 ± 15.1 105.5 ± 25.7 12.8 ± 1.8 200.8 ± 212.3
69 71 7 3 1 3
2 (1.9%) 1 (0.6%) 66 (42.9%)
48 21 3 2 23 3 32 9 14
59.6 ± 12.8 98 (63.6%)
154
Quartile 2 (0.83–1.00 mg/L)
(32.9%) (20.3%) (1.9%) (4.4%) (23.4%) (0.6%) (27.8%) (10.8%) (8.9%)
(36.1%) (51.3%) (7.6%) (3.2%) (0.6%) (1.3%)
11 (7.0%) 1.10 ± 0.06
73.4 ± 17.6 95.4 ± 24.7 12.9 ± 2.0 295.3 ± 385.9
57 81 12 5 1 2
4 (2.5%) 1 (0.6%) 59 (37.3%)
52 32 3 7 37 1 44 17 14
61.6 ± 13.5 102 (64.5%)
158
Quartile 3 (1.00–1.21 mg/L)
(38.0%) (21.3%) (2.7%) (6.0%) (31.3%) (2.7%) (39.3%) (15.3%) (12.0%)
(37.3%) (38.7%) (18.0%) (4%) (0.7%) (1.3%)
24 (16%) 1.48 ± 0.32
101.3 ± 41.2 71.6 ± 25.0 12.4 ± 2.0 396.0 ± 444.2
56 58 27 6 1 2
4 (2.7%) 2 (1.3%) 54 (36.0%)
57 32 4 9 47 4 59 23 18
65.2 ± 11.2 104 (69.3%)
150
Quartile 4 (1.21–2.95 mg/L)
0.021 50.001
50.001 50.001 0.061 50.001
0.369 0.051 50.001 0.666 0.939 0.823
0.378 0.476 0.351
0.124 0.303 0.608 0.130 50.001 0.447 50.001 0.002 0.423
50.001 0.218
p Value
(29.2%) (15.8%) (1.4%) (3.3%) (13.1%) (1.1%) (24.3%) (7.6%) (6.0%)
(40.6%) (47.4%) (7.6%) (1.9%) (0.5%) (2.5%)
– 1.01 ± 0.28
73.2 ± 23.5 97.7 ± 27.7 12.9 ± 1.7 237.7 ± 320.3
149 174 28 7 2 9
10 (2.7%) 2 (0.5%) 148 (40.3%)
107 58 5 12 48 4 89 28 22
61.4 ± 12.3 235 (64%)
367
None
(36.3%) (18.4%) (2.1%) (3.2%) (27.4%) (2.6%) (23.7%) (11.6%) (14.2%)
(36.3%) (49.5%) (8.4%) (3.7%) (1.1%) (1.6%)
– 1.03 ± 0.29
75.3 ± 23.5 97.3 ± 28.5 12.7 ± 1.7 294.6 ± 350.9
69 94 16 7 2 3
6 (3.2%) 2 (1.1%) 68 (35.8%)
69 35 4 6 52 5 45 22 27
59.2 ± 13.3 124 (65.3%)
190
Mild
(33.9%) (32.2%) (3.4%) (6.8%) (32.2%) (1.7%) (38.9%) (8.5%) (11.9%)
21 24 8 3 1 0
(35.6%) (40.7%) (13.6%) (5.1%) (1.7%) (0%)
1 (1.7%) 0 (0%) 14 (23.7%)
20 19 2 4 19 1 23 5 7
61.4 ± 15.8 34 (57.6%)
59
Heavy
– 1.38 ± 0.55
95.9 ± 53.4 80.6 ± 32.0 12.5 ± 2.2 418.9 ± 427.1
Proteinuria on dipstick
– 0.000
0.000 0.000 0.346 0.019
0.542 0.497 0.325 0.248 0.546 0.679
0.819 0.739 0.046
0.218 0.010 0.764 0.387 50.001 0.321 0.043 0.318 0.005
0.179 0.556
p Value
Notes: Data are expressed as mean ± SD or number (percentage). PAD ¼ peripheral arterial disease; CVA ¼ cerebral vascular accident; CHF ¼ congestive heart failure; COPD ¼ chronic obstructive pulmonary disease; MI ¼ myocardial infarction; LVEF ¼ left ventricular ejection fraction; CABG ¼ coronary artery bypass grafting; CHD ¼ congenital heart disease; SCr ¼ serum creatinine; eGFR ¼ estimated glomerular filtration rate; and BNP ¼ brain natriuretic peptide.
No. of patients Patient characteristics Age, mean ± SD, years Male, n Comorbidities Hypertension, n DM, n PAD, n CVA, n CHF, n COPD, n Hyperuricemia, n recent MI, n LVEF545%, n Surgical characteristics Prior cardiac surgery, n Non elective surgery, n Preoperative use of statins, n Surgery types CABG, n Valve, n CABG + valve, n Aortic, n CHD, n Others, n Preoperative laboratory data SCr, mean ± SD, mmol/L eGFR, mean ± SD, mL/min Hemoglobin (g/dL) BNP, ng/L Preoperative biomarker Heavy proteinuria, n Serum cystatin C (mg/L)
All
Cystatin C Quartiles
Table 1 Basic patient demographic characteristics, classified with cystatin C or proteinuria in 616 patients undergoing cardiac surgery.
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patients had mild proteinuria before surgery and 59 (9.6%) patients had heavy proteinuria. Those with heavy proteinuria were more likely to have DM, hyperuricemia, worse cardiac function, higher creatinine levels and lower eGFR levels. The percentage of patients with proteinuria in each quartile of cystatin C is listed in Table 2. In patients with quartile 1–3, 6.9–8.4% patients had heavy proteinuria. In quartile 4, 16% patients had heavy proteinuria. Adverse outcomes
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The unadjusted odds for adverse outcomes such as postoperative AKI, persistent AKI, severe AKI, dialysis and mortality were highest in patients with highest quartile of cystatin C (Figure 1A) or heavy proteinuria (Figure 1B). The risk stepped up for each corresponding classification. In addition, higher cystatin C quartiles were associated with
longer stay in the ICU, and heavier proteinuria was associated with longer durations of mechanical ventilation (Table 3). Multivariate stepwise logistic regression model for postoperative AKI We included variables listed in Table 1 into regression analysis to identify important factors associated with postoperative AKI. As presented in Table 4, multivariable stepwise logistic regression model revealed that after adjustment for advanced age (OR: 1.04, 95% CI: 1.01–1.06), hypertension (OR: 1.88, 95% CI: 1.13–3.12) and combined surgery (OR: 3.47, 95% CI: 1.35–8.89), preoperative heavy proteinuria (OR: 3.14, 95% CI: 1.26–7.77) and preoperative cystatin C quartiles (Q2:OR: 1.60, 95% CI: 0.72–3.60; Q3:OR: 1.87, 95% CI: 0.85–4.14; Q4:OR: 3.10, 95% CI: 1.37–7.02) remained significantly associated with development of AKI.
Table 2 Percentage of patients with proteinuria in groups stratified by quartiles of cystatin C.
ROC analysis comparing evaluated biomarkers as predictors of AKI
Cystatin C Quartiles
We combined preoperative serum cystatin C and dipstick proteinuria with fitted multiple logistic regression model. The results showed that the area under the ROC curve (AUC) for AKI occurrence was 0.695 (p50.001; 95% CI: 0.637–0.754) by combination of cystatin C and proteinuria, higher than cystatin C (0.682, p50.001; 95% CI: 0.625–0.745) alone or
Quartile Quartile Quartile Quartile
1 2 3 4
Normal 96 99 93 79
(62.3%) (64.3%) (58.9%) (52.7%)
Mild proteinuria
Heavy proteinuria
47 42 54 47
11 13 11 24
(30.5%) (27.3%) (33.5%) (32.0%)
Figure 1. Unadjusted risk for postoperative AKI, persistent AKI, severe AKI, dialysis and hospital mortality in patients with quartiles of cystatin C (A) and different severities of proteinuria (B). Comparison on patients with quartiles 1 of cystatin C or normal proteinuria. *p50.05 and #p50.001.
(7.1%) (8.4%) (6.9%) (16.0%)
Subtotal 154 154 158 150
Serum cystatin C combined with dipstick proteinuria to predict AKI 0.048 2 (1.1%) 4 (2.7%) 0 (0.0%) 8 (1.3%)
2 (1.3%)
3 (1.9%)
0.196
3 (0.8%)
3 (5.1%)
0.027 0.008 50.001 0.008 0.093 0.035 59 26 (44.1%) 17 (28.8%) 16 (27.1%) 3 (5.1%) 4 (3.5) 19 (15.28) 190 54 (28.4%) 27 (14.2%) 20 (10.5%) 2 (1.1%) 3 (2.4) 17 (12.20) 367 99 (27.0%) 49 (13.4%) 33 (9.0%) 1 (0.3%) 3 (2.4) 17 (11.20) 150 75 (50.0%) 43 (28.7%) 28 (18.7%) 5 (3.3%) 3 (3.4) 18 (13.24) 154 20 (13.0%) 10 (6.5%) 4 (2.6%) 0 (0.0%) 3 (2.3) 15 (10.19)
No. of patients AKI Persistent AKI Severe AKI Dialysis Length of ICU stay (days) Duration of mechanical ventilation (hours) Mortality
616 179 (28.4%) 93 (15.1%) 69 (11.2%) 6 (1.0%) 3 (2.4) 17 (12.20)
154 36 (23.4%) 22 (14.3%) 18 (11.7%) 0 (0.0%) 3 (2.4) 17 (11.20)
158 48 (30.4%) 18 (11.4%) 19 (12.0%) 1 (0.6%) 3 (2.4) 17 (12.20)
50.001 50.001 50.001 0.005 50.001 0.073
Mild None p Value Quartile 4 (1.21–2.95 mg/L) Quartile 3 (1.00–1.21 mg/L) Quartile 2 (0.83–1.00 mg/L) Quartile 1 (0.38–0.83 mg/L) All
Cystatin C quartiles
Table 3 Adverse outcomes in 616 patients with various quartiles of cystatin C and degree of proteinuria.
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Proteinuria on dipstick
Heavy
p Value
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Table 4 Multivariate logistic regression analysis of risk factors for the development of AKI in 616 cardiac surgery patients. Covariate
OR
95% CI
p Value
Age (years) Hypertension Combined surgery Heavy proteinuria Cystatin C quartile Quartile 1 Quartile 2 Quartile 3 Quartile 4
1.04 1.88 3.47 3.14
1.01–1.06 1.13–3.12 1.35–8.89 1.26–7.77
0.002 0.015 0.010 0.014
1 1.60 1.87 3.10
0.72–3.60 0.85–4.14 1.37–7.02
0.276 0.119 0.006
proteinuria (0.562, p ¼ 0.022; 95% CI: 0.507–0.614). However, the AUCs for preoperative eGFR and SCr to detect AKI were 0.621 (p50.001) and 0.595 (p50.001), respectively (Figure 2). For the persistent AKI outcome, the AUC was 0.753 (p50.001; 95% CI: 0.693–0.812) for cystatin C combined with dipstick proteinuria [0.737 (p50.001; 95% CI: 0.677–0.797) for cystatin C and 0.572 (p ¼ 0.018; 95% CI: 0.509–0.684) for proteinuria], remained significantly stronger than eGFR (AUC ¼ 0.652, p50.001) and SCr (AUC ¼ 0.627, p50.001). Results for severe AKI were similar, 0.718 (p50.001; 95% CI: 0.642–0.795) for combination of cystatin C and proteinuria [0.692 (p50.001; 95% CI: 0.617–0.767) for cystatin C and 0.594 (p ¼ 0.016; 95% CI: 0.511–0.677) for proteinuria], versus 0.586 (p ¼ 0.027) for eGFR and 0.563 (p ¼ 0.105) for SCr.
Discussion In a prospective study of 616 cardiac surgery patients, we compared the ability of preoperative measurement of serum cystatin C, an alternative marker of glomerular filtration rate, combined with dipstick proteinuria, with the clinical standard of SCr to predict postoperative AKI. The results demonstrated that patients with higher cystatin C quartiles and heavy proteinuria were significantly more likely to suffer postoperative complications and had a prolonged ICU stay and durations of mechanical ventilation. The combination of preoperative cystatin C and dipstick proteinuria may be useful for identifying patients at risk before cardiac surgery in the Chinese hospital setting. Responding to the need for early and sensitive identification of patients with surgery-associated AKI, several predictive models and biomarkers have been proposed over the past few years.9,13,20 Serum cystatin C is a 13-kDa protein produced in all nucleated cells at a relatively constant rate. It has been validated as a better marker to estimate GFR for CKD relative to creatinine and creatinine-based eGFR.10 Recently, pre-existing kidney insufficiency generally has been accepted as among the strongest risk factors for AKI and death in cardiac surgery.22,23 Our previous study also found that serum cystatin C may have value both for detection of early changes in GFR and as a marker of acute injury to the kidney.4 Therefore, we compared preoperative cystatin C as an assessment of preoperative kidney function, with SCr and eGFR, to detect preoperative CKD or AKI, both of which are independent risk factors for postoperative AKI.
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Figure 2. ROC analysis curve showing the predictive value of cystatin C combined with proteinuria, eGFR and Scr.
Proteinuria has been shown to be strongly associated with adverse outcomes, including renal disease progression, cardiovascular events and long-term mortality.15,16 Huang et al. indicated that preoperative proteinuria is a predictor of AKI following cardiac surgery,20 and Coca et al.24 found the similar results. Moreover, recent reports from large epidemiologic studies have shown that patients with proteinuria have a higher risk of adverse outcomes than those without proteinuria within the same CKD stage.18,19 These reports suggested that GFR and proteinuria should be used together to identify patients at risk. Thus, in our study, we combined the two biomarkers to improve the accuracy of the early detection and risk discrimination for postoperative AKI. We divided the dipstick proteinuria into groups according to Huang et al.’s definition to improve the sensitivity of the prediction.20 Proteinuria has been identified as a marker of renal damage, regardless of whether the etiology of the primary disease is DM, hypertension, another form of glomerulopathy or tubulointerstitial damage. In our analysis, those with heavy proteinuria were more likely to have DM, hyperuricemia, higher creatinine levels and lower eGFR levels. There were also more patients with heavy proteinuria in the CHF or EF545% group, which implies that these patients may actually have acute proteinuria secondary to cardiac insults. A multivariate logistic regression model was performed to identify associated risk factors with AKI. We confirmed previous findings in non-Chinese populations,20,21 that patients developing AKI were older and had more often combined surgeries. Among the other predictors, hypertension is consistent with prior studies indicating the untoward effect of reduced renal function. Quartiles of cystatin C was
also found to be associated with the development of AKI with an approximately 1.6–3.1-fold increase in the risk of AKI. Preoperative proteinuria within two days before surgery is highly predictive of postoperative AKI, irrespective of acute or chronic insults, which is finally in the multivariate logistic equation. It is therefore reasonable to use proteinuria as an independent factor to better detect patients at risk of AKI. DM, which was significantly higher in patients who developed AKI in other studies,25,26 dropped out of multivariate analysis in our analysis. Finally, our study found cystatin C combined with dipstick proteinuria provided a moderate and significant incremental increase in AUC, higher than cystatin C and proteinuria, respectively. Combination measurement of cystatin C and dipstick proteinuria proved to be a modest predictor of AKI before surgery obtaining an AUC of nearly 70 75%. A study13 of 1147 patients reported an AUC of 72% for cystatin C combined with SCr when predicting AKI following cardiac surgery, while a study of 288 children undergoing cardiac surgery found that preoperative cystatin C was not associated with AKI.14 The reason was possible that because few young children had preoperative CKD, the preoperative serum cystatin C failed to detect a CKD-AKI association. Several limitations of this study should be acknowledged. First, we had few patients with either dialysis-requiring AKI (n ¼ 6) or who died (n ¼ 8). Therefore, the ability of the biomarkers to predict risk of these outcomes could not be reliably assessed in our study. In future, we will assess longterm survival and kidney function after cardiac surgery in this cohort. Second, proteinuria detection was performed with dipsticks. Although urine albumin-to-creatinine ratio is preferred for the detection of CKD and more accurate
DOI: 10.3109/0886022X.2014.949759
Serum cystatin C combined with dipstick proteinuria to predict AKI
quantification of albuminuria, the urine dipstick examination is inexpensive and readily performed and interpreted. In conclusion, we found that preoperative cystatin C level combined with proteinuria had a stronger association with AKI risk than SCr level or eGFR based on SCr level. The inclusion of cystatin C and dipstick proteinuria in risk scoring systems may lead to improved patient outcomes.
Declaration of interest None of the authors have any conflict of interest to declare. This study was supported by a Shanghai Medical Development Grant (2003ZD001).
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References 1. Thakar CV, Worley S, Arrigain S, Yared JP, Paganini EP. Improved survival in acute kidney injury after cardiac surgery. Am J Kidney Dis. 2007;50:703–711. 2. Schrier RW, Wang W, Poole B, Mitra A. Acute renal failure: definitions, diagnosis, pathogenesis, and therapy. J Clin Invest. 2004;114:5–14. 3. Chertow GM, Burdick E, Honour M, Bonventre JV, Bates DW. Acute kidney injury, mortality, length of stay, and costs in hospitalized patients. J Am Soc Nephrol. 2005;16:3365–3370. 4. Che M, Li Y, Liang X, et al. Prevalence of acute kidney injury following cardiac surgery and related risk factors in Chinese patients. Nephron Clin Pract. 2011;117:c305–c311. 5. Coca SG, Yalavarthy R, Concato J, Parikh CR. Biomarkers for the diagnosis and risk stratification of acute kidney injury: A systematic review. Kidney Int. 2008;73:1008–1016. 6. Coca SG, Parikh CR. Urinary biaomarkers for acute kidney injury: perspectives on translation. Clin J Am Soc Nephrol. 2008;3: 481–490. 7. Ponce D, Zorzenon Cde P, dos Santos NY, Balbi AL. Early nephrology consultation can have an impact on outcome of acute kidney injury patients. Nephrol Dial Transplant. 2011;26: 3202–3206. 8. Wijeysundera DN, Karkouti K, Dupuis JY, et al. Derivation and validation of a simplified predictive index for renal replacement therapy after cardiac surgery. JAMA. 2007;297:1801–1809. 9. Thakar CV, Arrigain S, Worley S, Yared JP, Paganini EP. A clinical score to predict acute renal failure after cardiac surgery. J Am Soc Nephrol. 2005;16:162–168. 10. Filler G, Bokenkamp A, Hofmann W, Le Bricon T, Martı´nez-Bru´ C, Grubb A. Cystatin C as a marker of GFR-history, indications, and future research. Clin Biochem. 2005;38:1–8.
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11. Ahlstro¨m A, Tallgren M, Peltonen S, Pettila¨ V. Evolution and predictive power of serum cystatin C in acute renal failure. Clin Nephrol. 2004;62:344–350. 12. Herget-Rosenthal S, Marggraf G, Husing J, et al. Early detection of acute renal failure by serum cystatin C. Kidney Int. 2004;66: 1115–1122. 13. Shlipak MG, Coca SG, Wang Z, et al. Presurgical serum cystatin C and risk of acute kidney injury after cardiac surgery. Am J Kidney Dis. 2011;58:366–373. 14. Zappitelli M, Krawczeski CD, Devarajan P, et al. Early postoperative serum cystatin C predicts severe acute kidney injury following pediatric cardiac surgery. Kidney Int. 2011;80:655–662. 15. Klausen K, Borch-Johnsen K, Feldt-Rasmussen B, et al. Very low levels of microalbuminuria are associated with increased risk of coronary heart disease and death independently of renal function, hypertension, and diabetes. Circulation. 2004;110:32–35. 16. Mann JF, Gerstein HC, Pogue J, Bosch J, Yusuf S. Renal insufficiency as a predictor of cardiovascular outcomes and the impact of ramipril: The HOPE randomized trial. Ann Intern Med. 2001;134:629–636. 17. Hillege HL, Fidler V, Diercks GF, et al. Urinary albumin excretion predicts cardiovascular and noncardiovascular mortality in general population. Circulation. 2002;106:1777–1782. 18. Hallan SI, Ritz E, Lydersen S, Romundstad S, Kvenild K, Orth SR. Combining GFR and albuminuria to classify CKD improves prediction of ESRD. J Am Soc Nephrol. 2009;20:1069–1077. 19. Hemmelgarn BR, Manns BJ, Lloyd A, et al. Relation between kidney function, proteinuria, and adverse outcomes. JAMA. 2010; 303:423–429. 20. Huang TM, Wu VC, Young GH, et al. Preoperative proteinuria predicts adverse renal outcomes after coronary artery bypass grafting. J Am Soc Nephrol. 2011;22:156–163. 21. Thakar CV, Liangos O, Yared JP, et al. ARF after open-heart surgery: influence of gender and race. Am J Kidney Dis. 2003;41: 742–751. 22. Cooper WA, O’Brien SM, Thourani VH, et al. Impact of renal dysfunction on outcomes of coronary artery bypass surgery: Results from the Society of Thoracic Surgeons National Adult Cardiac Database. Circulation. 2006;13:1063–1070. 23. Howell NJ, Keogh BE, Bonser RS, et al. Mild renal dysfunction predicts in-hospital mortality and post-discharge survival following cardiac surgery. Eur J Cardiothorac Surg. 2008;34:390–395. 24. Coca SG, Jammalamadaka D, Sint K, et al. Preoperative proteinuria predicts acute kidney injury in patients undergoing cardiac surgery. J Thorac Cardiovasc Surg. 2012;143:495–502. 25. Chertow GM, Lazarus JM, Christiansen CL, et al. Preoperative renal risk stratification. Circulation. 1997;95:878–884. 26. Schmekal B, Pichler R, Biesenbach G. Causes and prognosis of nonstraumatic acute renal failure requiring dialysis in adult patients with and without diabetes. Ren Fail. 2004;26:39–43.
CLINICAL STUDY
Preoperative serum cystatin C combined with dipstick proteinuria predicts acute kidney injury after cardiac surgery Xudong Wang1, Miaolin Che2, Bo Xie1, Song Xue1, and Yucheng Yan2 Department of Cardiovascular Surgery, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China and 2Department of Nephrology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China
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1
Abstract
Keywords
Background: Acute kidney injury (AKI) is common following cardiac surgery and is associated with poor outcomes. However, the detection of those preoperative patients who will develop AKI is still difficult. In this study, we compared serum cystatin C combined with dipstick proteinuria as early markers to predict AKI available before surgery. Methods: We prospectively followed 616 patients undergoing cardiac surgery and identified 179 that developed AKI, defined as an increase in serum creatinine (SCr) of 0.3 mg/dL or 50% increase in creatinine level. Preoperative values for cystatin C were categorized into quartiles. We defined proteinuria, measured with a dipstick, as mild (trace to 1+) or heavy (2 + to 4+). Univariate as well as multivariate regression was performed. Cystatin C combined with dipstick proteinuria before surgery was assessed for its’ predictive value of AKI using receiver operating characteristic (ROC) curves. Results: The final cohort consisted of 616 patients aged 60.7 ± 13.2 years, and baseline SCr was 75.8 ± 26.4 mmol/L, estimated glomerular filtration rate (eGFR) 96.3 ± 29.0 mL/min/ 1.73 m2 and cystatin C 1.05 ± 0.33 mg/L. Patients in higher cystatin C quartiles were older (p50.001), more often to have heavy proteinuria (p ¼ 0.021), hyperuricemia (p50.001), heart failure (p50.001) and recent myocardial infarction (p ¼ 0.002). Those with heavy proteinuria were more often to have diabetes mellitus (p ¼ 0.010), hyperuricemia (p ¼ 0.043), worse cardiac function (p50.05), higher creatinine levels (p50.001) and lower eGFR levels (p50.001). In a multiple logistic regression model, preoperative heavy proteinuria [OR: 3.14, 95% confidence interval (CI): 1.26–7.77] and preoperative cystatin C quartiles (Q2:OR: 1.60, 95% CI: 0.72–3.60; Q3:OR: 1.87, 95% CI: 0.85–4.14; Q4:OR: 3.10, 95% CI: 1.37–7.02) each associated with an increased odds of AKI, independent of advanced age (OR: 1.04, 95% CI: 1.01–1.06), hypertension (OR: 1.88, 95% CI: 1.13–3.12) and combined surgery (OR: 3.47, 95% CI: 1.35–8.89). The risk for adverse outcomes such as postoperative AKI, persistent AKI, severe AKI, dialysis and mortality were highest in patients with highest quartile of cystatin C (p50.05, respectively) and heavy proteinuria (p50.05, respectively). The area under the ROC curve for preoperative cystatin C combined with proteinuria to detect AKI, persistent AKI and severe AKI were 0.695 (p50.001; 95% CI ¼ 0.637–0.754), 0.753 (p50.001; 95% CI ¼ 0.693–0.812) and 0.718 (p50.001; 95% CI ¼ 0.642–0.795), respectively. Conclusion: These data suggest that preoperative serum cystatin C combined with dipstick proteinuria may improve prediction of AKI among patients undergoing cardiac surgery.
Acute kidney injury, serum cystatin C, dipstick proteinuria, prognosis
Introduction Acute kidney injury (AKI) is a major complication after cardiac surgery and associated with increases in mortality, morbidity and intensive care unit (ICU) length-of-stay.1–4 While recent advances have improved our understanding of the pathogenesis of AKI, this has so far not translated into better clinical diagnostics or treatments.5 Meanwhile, early detection of these patients may contribute to improving their outcomes.5–7
Address correspondence to Yucheng Yan, MD, PhD, Department of Nephrology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China. Tel.: +86-21-68383139; Fax: + 86-2163260745; E-mail: [email protected]
History Received 12 April 2014 Revised 2 July 2014 Accepted 15 July 2014 Published online 21 August 2014
Patient’s renal reserve before surgery has been confirmed as an important determinants for both mortality and AKI outcomes.8,9 Serum cystatin C has been validated as a better marker to estimate glomerular filtration rate for chronic kidney disease (CKD) relative to creatinine and creatininebased estimated glomerular filtration rate (eGFR).10 Although several studies have focused on the diagnostic accuracy of preoperative cystatin C in predicting AKI,11,12 the capability remain elusive.13,14 Moreover, proteinuria has been shown to be strongly associated with adverse outcomes, including renal disease progression, cardiovascular events and long-term mortality.15–17 Recent reports from large epidemiologic studies have shown that patients with proteinuria have a higher risk of adverse outcomes than those without proteinuria within the same CKD stage.18,19 Data on the application
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of preoperative serum cystatin C combined with proteinuria to predict AKI are scarce in Chinese patients following cardiac surgery but are of great usefulness.
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preoperative laboratory data (hemoglobin concentration and brain natriuretic peptide concentration). Outcomes
Materials and methods
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Patients A total of 616 patients (18–85 years of age) who underwent cardiac surgery (including coronary artery bypass grafting (CABG), valve surgery, combined coronary artery bypass graft and valve procedures, and other cardiac surgeries such as congenital heart disease repair, aorta aneurysm and others) at Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China, between 1 June 2011 and 31 March 2013 were prospectively enrolled. Exclusion criteria include patients younger than 18 years, patients with preexisting end-stage kidney disease, patients receiving any form of dialysis therapy before surgery and patients who had died during or after surgery within 24 hours. We recorded preoperative clinical data, including serum creatinine (SCr) to estimate GFR [according to the Modification of Diet in Renal Disease (MDRD) equation (National Kidney Foundation 2002)] as well as clinical data during hospitalization. Informed consent was obtained from each patient prior to enrollment, and the ethical review board of the Shanghai Renji Hospital approved this study. Predictors At the preoperative visit, a blood sample was collected, centrifuged at 2000 g for 5 min, and the supernatants were aliquoted and stored at –80 C. Serum cystatin C was measured by immunonephelometry (Dade Behring, Marburg, Germany). SCr was measured by a modified Jaffe method with protein precipitation using an alkaline picrate reaction. The eGFR was calculated with MDRD equation. Proteinuria was measured using a dipstick within two days before surgery. To classify the severity of proteinuria, we defined negative as ‘‘no proteinuria’’, trace to 1+ as ‘‘mild proteinuria’’ and 2+ to 4+ as ‘‘heavy proteinuria’’.20 The test strips were measured by an automatic dipstick autoanalyzer (Cobas u 411; F. Hoffmann-La Roche, Ltd., Basel, Switzerland). Risk factors Preoperative variables known to be or who could potentially be associated with AKI or other adverse outcomes were collected. These included age, gender, hypertension (systolic blood pressure 140 mmHg and/or diastolic blood pressure 90 mmHg), diabetes mellitus (DM; using oral hypoglycemic agents or insulin), peripheral arterial disease21 (determined by clinical diagnosis or imaging results), cerebral vascular accident21 (previous cerebral vascular accident such as ischemic or hemorrhagic), New York Heart Association functional class III or IV congestive heart failure (CHF), chronic obstructive pulmonary disease, recent myocardial infarction (MI; i.e.,530 days before surgery) and hyperuricemia (a serum uric acid 46.6 in women and 47.0 mg/dL in men), left ventricular ejection fraction (assessed preoperatively by echocardiography), emergency surgery and
The outcome of AKI was determined using the daily SCr measurements during the first five hospital days. Our primary outcomes were AKI,13 defined as an increase of SCr levels of more than 0.3 mg/dL or a 50% relative increase in the first 48 hours postoperatively. We evaluated a secondary outcome of persistent AKI,13 defined as having AKI for 48 hours or longer. We further evaluated severe AKI13 [Acute Kidney Injury Network (AKIN) stage 2], defined as either doubling of SCr level or requirement of acute hemodialysis. Total duration of ventilator-assisted respiration during postoperative hospitalization, the length of stay in ICU and hospital were recorded. Patients were followed until discharge [median observation time was 15 (7–95) days] and all-cause in-hospital mortality was recorded. Statistical analysis To improve precision for some analyses, we categorized our cohort into quartiles by preoperative serum cystatin C. To compare continuous variables, we used the Student’s t-test or the non-parametric Mann–Whitney U-test, and to compare categorical variables, we used the 2 or Fisher’s exact test, as appropriate. A multivariate logistic regression model incorporating all factors associated with AKI in univariate analysis as well as the factors showing a univariate p value50.05 was performed to identify associated risk factors with AKI. Risk data are presented as odds ratios with 95% confidence intervals (CI). We calculated the receiver operating characteristic (ROC) curve of biomarkers for predicting AKI. We also used a fitted multiple logistic regression model to combine preoperative serum cystatin C and dipstick proteinuria and calculated ROC data. A p value of 50.05 was considered statistically significant for all comparisons. SPSS version 16.0 for windows software (SPSS Inc., Chicago, IL) was used for the statistical analysis.
Results Patients’ characteristics By excluding patients whose complete clinical data were not available (n ¼ 68) and those with pre-existing end-stage kidney disease (n ¼ 1), a total of 616 patients [393 men, mean age 60.7 ± 13.2 years (range 18–85 years)] were included in the final analysis. Baseline characteristics of these patients are summarized in Table 1. Briefly, the preoperative cystatin C was 1.05 ± 0.33 mg/L, SCr level was 75.8 ± 26.4 mmol/L and eGFR was 96.3 ± 29.0 mL/min. The most frequent cardiac surgery was valve surgery (46.3%), followed by CABG (37.9%) and CABG combined with valve (8.3%; Table 1). We compared baseline characteristics across quartiles of cystatin C. The most striking differences across quartiles were that patients in higher cystatin C quartiles were older, have more often heavy proteinuria and hyperuricemia, more likely to have heart failure and recent MI (Table 1). As expected, creatinine levels were higher and eGFR levels were lower in the higher cystatin C quartiles. A total of 190 (30.8%)
60.8 ± 17.3 118.2 ± 28.9 13.1 ± 1.6 162.3 ± 231.3 11 (7.1%) 0.70 ± 0.09
75.8 ± 26.4 96.3 ± 29.0 12.8 ± 1.8 267.6 ± 340.7
59 (9.6%) 1.05 ± 0.33
(37.0%) (53.2%) (3.9%) (1.9%) (1.3%) (2.6%)
57 82 6 3 2 4
(37.9%) (46.3%) (8.3%) (2.7%) (0.8%) (1.7%)
239 292 52 17 5 11
(25.3%) (17.5%) (0.6%) (2.6%) (7.8%) (1.3%) (14.3%) (3.9%) (6.5%)
7 (3.9%) 0 (0%) 51 (33.1%)
39 27 1 4 12 2 22 6 10
17 (2.8%) 4 (0.6%) 230 (37.3%)
(31.8%) (18.2%) (1.8%) (3.6%) (19.3%) (1.6%) (25.5%) (8.9%) (9.1%)
53.7 ± 13.4 89 (57.8%)
60.7 ± 13.2 393 (62.4%)
196 112 11 22 119 10 157 55 56
154
616
Quartile 1 (0.38–0.83 mg/L)
(31.2%) (13.6%) (1.9%) (1.3%) (14.9%) (1.9%) (20.8%) (5.8%) (9.1%)
(43.6%) (46.1%) (4.5%) (1.9%) (0.6%) (1.9%)
13 (8.4%) 0.92 ± 0.04
67.3 ± 15.1 105.5 ± 25.7 12.8 ± 1.8 200.8 ± 212.3
69 71 7 3 1 3
2 (1.9%) 1 (0.6%) 66 (42.9%)
48 21 3 2 23 3 32 9 14
59.6 ± 12.8 98 (63.6%)
154
Quartile 2 (0.83–1.00 mg/L)
(32.9%) (20.3%) (1.9%) (4.4%) (23.4%) (0.6%) (27.8%) (10.8%) (8.9%)
(36.1%) (51.3%) (7.6%) (3.2%) (0.6%) (1.3%)
11 (7.0%) 1.10 ± 0.06
73.4 ± 17.6 95.4 ± 24.7 12.9 ± 2.0 295.3 ± 385.9
57 81 12 5 1 2
4 (2.5%) 1 (0.6%) 59 (37.3%)
52 32 3 7 37 1 44 17 14
61.6 ± 13.5 102 (64.5%)
158
Quartile 3 (1.00–1.21 mg/L)
(38.0%) (21.3%) (2.7%) (6.0%) (31.3%) (2.7%) (39.3%) (15.3%) (12.0%)
(37.3%) (38.7%) (18.0%) (4%) (0.7%) (1.3%)
24 (16%) 1.48 ± 0.32
101.3 ± 41.2 71.6 ± 25.0 12.4 ± 2.0 396.0 ± 444.2
56 58 27 6 1 2
4 (2.7%) 2 (1.3%) 54 (36.0%)
57 32 4 9 47 4 59 23 18
65.2 ± 11.2 104 (69.3%)
150
Quartile 4 (1.21–2.95 mg/L)
0.021 50.001
50.001 50.001 0.061 50.001
0.369 0.051 50.001 0.666 0.939 0.823
0.378 0.476 0.351
0.124 0.303 0.608 0.130 50.001 0.447 50.001 0.002 0.423
50.001 0.218
p Value
(29.2%) (15.8%) (1.4%) (3.3%) (13.1%) (1.1%) (24.3%) (7.6%) (6.0%)
(40.6%) (47.4%) (7.6%) (1.9%) (0.5%) (2.5%)
– 1.01 ± 0.28
73.2 ± 23.5 97.7 ± 27.7 12.9 ± 1.7 237.7 ± 320.3
149 174 28 7 2 9
10 (2.7%) 2 (0.5%) 148 (40.3%)
107 58 5 12 48 4 89 28 22
61.4 ± 12.3 235 (64%)
367
None
(36.3%) (18.4%) (2.1%) (3.2%) (27.4%) (2.6%) (23.7%) (11.6%) (14.2%)
(36.3%) (49.5%) (8.4%) (3.7%) (1.1%) (1.6%)
– 1.03 ± 0.29
75.3 ± 23.5 97.3 ± 28.5 12.7 ± 1.7 294.6 ± 350.9
69 94 16 7 2 3
6 (3.2%) 2 (1.1%) 68 (35.8%)
69 35 4 6 52 5 45 22 27
59.2 ± 13.3 124 (65.3%)
190
Mild
(33.9%) (32.2%) (3.4%) (6.8%) (32.2%) (1.7%) (38.9%) (8.5%) (11.9%)
21 24 8 3 1 0
(35.6%) (40.7%) (13.6%) (5.1%) (1.7%) (0%)
1 (1.7%) 0 (0%) 14 (23.7%)
20 19 2 4 19 1 23 5 7
61.4 ± 15.8 34 (57.6%)
59
Heavy
– 1.38 ± 0.55
95.9 ± 53.4 80.6 ± 32.0 12.5 ± 2.2 418.9 ± 427.1
Proteinuria on dipstick
– 0.000
0.000 0.000 0.346 0.019
0.542 0.497 0.325 0.248 0.546 0.679
0.819 0.739 0.046
0.218 0.010 0.764 0.387 50.001 0.321 0.043 0.318 0.005
0.179 0.556
p Value
Notes: Data are expressed as mean ± SD or number (percentage). PAD ¼ peripheral arterial disease; CVA ¼ cerebral vascular accident; CHF ¼ congestive heart failure; COPD ¼ chronic obstructive pulmonary disease; MI ¼ myocardial infarction; LVEF ¼ left ventricular ejection fraction; CABG ¼ coronary artery bypass grafting; CHD ¼ congenital heart disease; SCr ¼ serum creatinine; eGFR ¼ estimated glomerular filtration rate; and BNP ¼ brain natriuretic peptide.
No. of patients Patient characteristics Age, mean ± SD, years Male, n Comorbidities Hypertension, n DM, n PAD, n CVA, n CHF, n COPD, n Hyperuricemia, n recent MI, n LVEF545%, n Surgical characteristics Prior cardiac surgery, n Non elective surgery, n Preoperative use of statins, n Surgery types CABG, n Valve, n CABG + valve, n Aortic, n CHD, n Others, n Preoperative laboratory data SCr, mean ± SD, mmol/L eGFR, mean ± SD, mL/min Hemoglobin (g/dL) BNP, ng/L Preoperative biomarker Heavy proteinuria, n Serum cystatin C (mg/L)
All
Cystatin C Quartiles
Table 1 Basic patient demographic characteristics, classified with cystatin C or proteinuria in 616 patients undergoing cardiac surgery.
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DOI: 10.3109/0886022X.2014.949759
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patients had mild proteinuria before surgery and 59 (9.6%) patients had heavy proteinuria. Those with heavy proteinuria were more likely to have DM, hyperuricemia, worse cardiac function, higher creatinine levels and lower eGFR levels. The percentage of patients with proteinuria in each quartile of cystatin C is listed in Table 2. In patients with quartile 1–3, 6.9–8.4% patients had heavy proteinuria. In quartile 4, 16% patients had heavy proteinuria. Adverse outcomes
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The unadjusted odds for adverse outcomes such as postoperative AKI, persistent AKI, severe AKI, dialysis and mortality were highest in patients with highest quartile of cystatin C (Figure 1A) or heavy proteinuria (Figure 1B). The risk stepped up for each corresponding classification. In addition, higher cystatin C quartiles were associated with
longer stay in the ICU, and heavier proteinuria was associated with longer durations of mechanical ventilation (Table 3). Multivariate stepwise logistic regression model for postoperative AKI We included variables listed in Table 1 into regression analysis to identify important factors associated with postoperative AKI. As presented in Table 4, multivariable stepwise logistic regression model revealed that after adjustment for advanced age (OR: 1.04, 95% CI: 1.01–1.06), hypertension (OR: 1.88, 95% CI: 1.13–3.12) and combined surgery (OR: 3.47, 95% CI: 1.35–8.89), preoperative heavy proteinuria (OR: 3.14, 95% CI: 1.26–7.77) and preoperative cystatin C quartiles (Q2:OR: 1.60, 95% CI: 0.72–3.60; Q3:OR: 1.87, 95% CI: 0.85–4.14; Q4:OR: 3.10, 95% CI: 1.37–7.02) remained significantly associated with development of AKI.
Table 2 Percentage of patients with proteinuria in groups stratified by quartiles of cystatin C.
ROC analysis comparing evaluated biomarkers as predictors of AKI
Cystatin C Quartiles
We combined preoperative serum cystatin C and dipstick proteinuria with fitted multiple logistic regression model. The results showed that the area under the ROC curve (AUC) for AKI occurrence was 0.695 (p50.001; 95% CI: 0.637–0.754) by combination of cystatin C and proteinuria, higher than cystatin C (0.682, p50.001; 95% CI: 0.625–0.745) alone or
Quartile Quartile Quartile Quartile
1 2 3 4
Normal 96 99 93 79
(62.3%) (64.3%) (58.9%) (52.7%)
Mild proteinuria
Heavy proteinuria
47 42 54 47
11 13 11 24
(30.5%) (27.3%) (33.5%) (32.0%)
Figure 1. Unadjusted risk for postoperative AKI, persistent AKI, severe AKI, dialysis and hospital mortality in patients with quartiles of cystatin C (A) and different severities of proteinuria (B). Comparison on patients with quartiles 1 of cystatin C or normal proteinuria. *p50.05 and #p50.001.
(7.1%) (8.4%) (6.9%) (16.0%)
Subtotal 154 154 158 150
Serum cystatin C combined with dipstick proteinuria to predict AKI 0.048 2 (1.1%) 4 (2.7%) 0 (0.0%) 8 (1.3%)
2 (1.3%)
3 (1.9%)
0.196
3 (0.8%)
3 (5.1%)
0.027 0.008 50.001 0.008 0.093 0.035 59 26 (44.1%) 17 (28.8%) 16 (27.1%) 3 (5.1%) 4 (3.5) 19 (15.28) 190 54 (28.4%) 27 (14.2%) 20 (10.5%) 2 (1.1%) 3 (2.4) 17 (12.20) 367 99 (27.0%) 49 (13.4%) 33 (9.0%) 1 (0.3%) 3 (2.4) 17 (11.20) 150 75 (50.0%) 43 (28.7%) 28 (18.7%) 5 (3.3%) 3 (3.4) 18 (13.24) 154 20 (13.0%) 10 (6.5%) 4 (2.6%) 0 (0.0%) 3 (2.3) 15 (10.19)
No. of patients AKI Persistent AKI Severe AKI Dialysis Length of ICU stay (days) Duration of mechanical ventilation (hours) Mortality
616 179 (28.4%) 93 (15.1%) 69 (11.2%) 6 (1.0%) 3 (2.4) 17 (12.20)
154 36 (23.4%) 22 (14.3%) 18 (11.7%) 0 (0.0%) 3 (2.4) 17 (11.20)
158 48 (30.4%) 18 (11.4%) 19 (12.0%) 1 (0.6%) 3 (2.4) 17 (12.20)
50.001 50.001 50.001 0.005 50.001 0.073
Mild None p Value Quartile 4 (1.21–2.95 mg/L) Quartile 3 (1.00–1.21 mg/L) Quartile 2 (0.83–1.00 mg/L) Quartile 1 (0.38–0.83 mg/L) All
Cystatin C quartiles
Table 3 Adverse outcomes in 616 patients with various quartiles of cystatin C and degree of proteinuria.
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Proteinuria on dipstick
Heavy
p Value
DOI: 10.3109/0886022X.2014.949759
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Table 4 Multivariate logistic regression analysis of risk factors for the development of AKI in 616 cardiac surgery patients. Covariate
OR
95% CI
p Value
Age (years) Hypertension Combined surgery Heavy proteinuria Cystatin C quartile Quartile 1 Quartile 2 Quartile 3 Quartile 4
1.04 1.88 3.47 3.14
1.01–1.06 1.13–3.12 1.35–8.89 1.26–7.77
0.002 0.015 0.010 0.014
1 1.60 1.87 3.10
0.72–3.60 0.85–4.14 1.37–7.02
0.276 0.119 0.006
proteinuria (0.562, p ¼ 0.022; 95% CI: 0.507–0.614). However, the AUCs for preoperative eGFR and SCr to detect AKI were 0.621 (p50.001) and 0.595 (p50.001), respectively (Figure 2). For the persistent AKI outcome, the AUC was 0.753 (p50.001; 95% CI: 0.693–0.812) for cystatin C combined with dipstick proteinuria [0.737 (p50.001; 95% CI: 0.677–0.797) for cystatin C and 0.572 (p ¼ 0.018; 95% CI: 0.509–0.684) for proteinuria], remained significantly stronger than eGFR (AUC ¼ 0.652, p50.001) and SCr (AUC ¼ 0.627, p50.001). Results for severe AKI were similar, 0.718 (p50.001; 95% CI: 0.642–0.795) for combination of cystatin C and proteinuria [0.692 (p50.001; 95% CI: 0.617–0.767) for cystatin C and 0.594 (p ¼ 0.016; 95% CI: 0.511–0.677) for proteinuria], versus 0.586 (p ¼ 0.027) for eGFR and 0.563 (p ¼ 0.105) for SCr.
Discussion In a prospective study of 616 cardiac surgery patients, we compared the ability of preoperative measurement of serum cystatin C, an alternative marker of glomerular filtration rate, combined with dipstick proteinuria, with the clinical standard of SCr to predict postoperative AKI. The results demonstrated that patients with higher cystatin C quartiles and heavy proteinuria were significantly more likely to suffer postoperative complications and had a prolonged ICU stay and durations of mechanical ventilation. The combination of preoperative cystatin C and dipstick proteinuria may be useful for identifying patients at risk before cardiac surgery in the Chinese hospital setting. Responding to the need for early and sensitive identification of patients with surgery-associated AKI, several predictive models and biomarkers have been proposed over the past few years.9,13,20 Serum cystatin C is a 13-kDa protein produced in all nucleated cells at a relatively constant rate. It has been validated as a better marker to estimate GFR for CKD relative to creatinine and creatinine-based eGFR.10 Recently, pre-existing kidney insufficiency generally has been accepted as among the strongest risk factors for AKI and death in cardiac surgery.22,23 Our previous study also found that serum cystatin C may have value both for detection of early changes in GFR and as a marker of acute injury to the kidney.4 Therefore, we compared preoperative cystatin C as an assessment of preoperative kidney function, with SCr and eGFR, to detect preoperative CKD or AKI, both of which are independent risk factors for postoperative AKI.
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Figure 2. ROC analysis curve showing the predictive value of cystatin C combined with proteinuria, eGFR and Scr.
Proteinuria has been shown to be strongly associated with adverse outcomes, including renal disease progression, cardiovascular events and long-term mortality.15,16 Huang et al. indicated that preoperative proteinuria is a predictor of AKI following cardiac surgery,20 and Coca et al.24 found the similar results. Moreover, recent reports from large epidemiologic studies have shown that patients with proteinuria have a higher risk of adverse outcomes than those without proteinuria within the same CKD stage.18,19 These reports suggested that GFR and proteinuria should be used together to identify patients at risk. Thus, in our study, we combined the two biomarkers to improve the accuracy of the early detection and risk discrimination for postoperative AKI. We divided the dipstick proteinuria into groups according to Huang et al.’s definition to improve the sensitivity of the prediction.20 Proteinuria has been identified as a marker of renal damage, regardless of whether the etiology of the primary disease is DM, hypertension, another form of glomerulopathy or tubulointerstitial damage. In our analysis, those with heavy proteinuria were more likely to have DM, hyperuricemia, higher creatinine levels and lower eGFR levels. There were also more patients with heavy proteinuria in the CHF or EF545% group, which implies that these patients may actually have acute proteinuria secondary to cardiac insults. A multivariate logistic regression model was performed to identify associated risk factors with AKI. We confirmed previous findings in non-Chinese populations,20,21 that patients developing AKI were older and had more often combined surgeries. Among the other predictors, hypertension is consistent with prior studies indicating the untoward effect of reduced renal function. Quartiles of cystatin C was
also found to be associated with the development of AKI with an approximately 1.6–3.1-fold increase in the risk of AKI. Preoperative proteinuria within two days before surgery is highly predictive of postoperative AKI, irrespective of acute or chronic insults, which is finally in the multivariate logistic equation. It is therefore reasonable to use proteinuria as an independent factor to better detect patients at risk of AKI. DM, which was significantly higher in patients who developed AKI in other studies,25,26 dropped out of multivariate analysis in our analysis. Finally, our study found cystatin C combined with dipstick proteinuria provided a moderate and significant incremental increase in AUC, higher than cystatin C and proteinuria, respectively. Combination measurement of cystatin C and dipstick proteinuria proved to be a modest predictor of AKI before surgery obtaining an AUC of nearly 70 75%. A study13 of 1147 patients reported an AUC of 72% for cystatin C combined with SCr when predicting AKI following cardiac surgery, while a study of 288 children undergoing cardiac surgery found that preoperative cystatin C was not associated with AKI.14 The reason was possible that because few young children had preoperative CKD, the preoperative serum cystatin C failed to detect a CKD-AKI association. Several limitations of this study should be acknowledged. First, we had few patients with either dialysis-requiring AKI (n ¼ 6) or who died (n ¼ 8). Therefore, the ability of the biomarkers to predict risk of these outcomes could not be reliably assessed in our study. In future, we will assess longterm survival and kidney function after cardiac surgery in this cohort. Second, proteinuria detection was performed with dipsticks. Although urine albumin-to-creatinine ratio is preferred for the detection of CKD and more accurate
DOI: 10.3109/0886022X.2014.949759
Serum cystatin C combined with dipstick proteinuria to predict AKI
quantification of albuminuria, the urine dipstick examination is inexpensive and readily performed and interpreted. In conclusion, we found that preoperative cystatin C level combined with proteinuria had a stronger association with AKI risk than SCr level or eGFR based on SCr level. The inclusion of cystatin C and dipstick proteinuria in risk scoring systems may lead to improved patient outcomes.
Declaration of interest None of the authors have any conflict of interest to declare. This study was supported by a Shanghai Medical Development Grant (2003ZD001).
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