Online Clinical Investigations

Diagnostic and Prognostic Value of Serum Cystatin C in Critically Ill Children With Acute Kidney Injury Leila C. Volpon, MD; Edward K. Sugo, MD; Ana P. C. P. Carlotti, MD

Objectives: We aimed to evaluate the value of serum cystatin C for detection of acute kidney injury and pediatric Risk, Injury, Failure, Loss, End-Stage Renal Disease categories in critically ill children and to investigate whether serum cystatin C was associated with outcome. Design: Prospective cohort study. Setting: PICU of a tertiary-care university hospital. Patients: A heterogeneous population of critically ill children. Interventions: None. Measurements and Main Results: Blood and 24-hour urine samples were collected daily over the first 2 days after PICU admission for measurement of serum cystatin C, serum creatinine, and creatinine clearance. Acute kidney injury was classified by pediatric Risk, Injury, Failure, Loss, End-Stage Renal Disease criteria. One hundred twentytwo children were prospectively enrolled; 40 (32.8%) developed acute kidney injury. Serum cystatin C was higher in patients with acute kidney injury compared with those who did not develop acute kidney injury at PICU admission (median, 0.90 mg/L vs 0.51 mg/L) and on the first (1.12 mg/L vs 0.57 mg/L) and second PICU days (1.15 mg/L vs 0.58 mg/L). Serum creatinine was higher in acute kidney injury group only on the first (0.50 mg/dL vs 0.40 mg/dL) and second PICU days (0.60 mg/dL vs 0.40 mg/dL). Serum cystatin C was increasingly higher according to acute kidney injury severity (Failure > Injury > Risk). Area under the receiver operating characteristic curve of cystatin C for acute kidney injury detection was 0.89. Serum cystatin C greater than 0.70 mg/L was associated with longer length of PICU stay (adjusted hazard ratio, 1.64) and prolonged duration of mechanical ventilation (adjusted hazard ratio, 1.82). Conclusions: Cystatin C is an early and accurate biomarker for acute kidney injury and pediatric Risk, Injury, Failure, Loss, EndStage Renal Disease categories, and it is associated with adverse clinical outcomes in a heterogeneous population of critically ill children. (Pediatr Crit Care Med 2015; 16:e125–e131) Key Words: biomarker; creatinine; cystatin C; glomerular filtration rate; outcome; pediatric intensive care All authors: Division of Pediatric Critical Care, Department of Pediatrics, Ribeirão Preto Medical School, University of São Paulo, São Paulo, Brazil. Dr. Sugo is employed by Hospital das Clínicas de Ribeirão Preto–USP. The remaining authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: [email protected] Copyright © 2015 by the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies DOI: 10.1097/PCC.0000000000000403

Pediatric Critical Care Medicine

A

cute kidney injury (AKI) affects up to 82% of critically ill children (1), and it is associated with longer PICU and hospital length of stay and increased mortality (1, 2). Usually, AKI occurs in the first 3 days after PICU admission (1–3) and up to 48 hours after cardiac surgery (4, 5). This highlights the importance of early detection of renal dysfunction in order to implement measures to prevent secondary insults, such as strategies for optimization of renal perfusion and dose adjustment of nephrotoxic drugs. In clinical practice, measurement of serum creatinine is used for monitoring renal function. However, serum creatinine is influenced by age, gender, and muscle mass. Furthermore, in the setting of reduced glomerular filtration rate (GFR), increased tubular secretion of creatinine leads to overestimation of renal function. In addition, serum creatinine concentrations usually do not change until the GFR has fallen by approximately 50% (6). Considering that therapeutic and preventive measures must be instituted very early to effectively impact on the high mortality rate associated with AKI, the importance of a biomarker that could provide an earlier and more accurate diagnosis of AKI becomes evident. Cystatin C (CysC) is an endogenous cysteine protease inhibitor that is synthesized by all nucleated cells and secreted into the blood at a relatively constant rate. It is freely filtered by the glomerulus, completely reabsorbed and metabolized by the proximal tubules, and does not undergo tubular secretion or extrarenal elimination (6, 7). There is good inverse correlation between CysC serum concentrations and GFR measured by radionuclide (8). In addition to changes in GFR, few situations are associated with altered serum CysC concentration, such as thyroid dysfunction (9, 10). Hence, CysC is considered a good marker of GFR (6–8). However, data on the accuracy of serum CysC to detect renal dysfunction in heterogeneous populations of critically ill children are scarce and results are controversial (11–14). We aimed to assess the diagnostic value of serum CysC for early detection of AKI and its clinical severity as determined by the pediatric Risk, Injury, Failure, Loss, End-Stage Renal Disease (pRIFLE) classification (1) in critically ill children. We also aimed to investigate whether serum CysC levels were associated with clinical outcome. www.pccmjournal.org

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PATIENTS AND METHODS This is a prospective cohort study conducted in a PICU of a tertiary-care university hospital in Brazil. The study was approved by the Research Ethics Board of Hospital das Clínicas of Ribeirão Preto Medical School, University of São Paulo (#2447/2011) and written informed consent was obtained from the patients’ parents. All consecutive patients admitted to the PICU from August 2011 to April 2012 who had a urinary catheter inserted were eligible for the study. Exclusion criteria were length of PICU stay of less than 24 hours, a previous diagnosis of chronic kidney disease or thyroid disease, and refusal to participate. Blood samples were collected daily over the first 2 days after PICU admission for measurement of serum concentrations of CysC and creatinine, and 24-hour urine samples were collected for measurement of creatinine to calculate creatinine clearance. CysC serum concentrations were measured by immunonephelometric assay in a BN II system (Dade Behring Marburg GmbH, Germany). Serum and urine creatinine concentrations were determined by Jaffe’s method. Measured creatinine clearance (in mL/min/1.73 m2) was calculated according to the following formula: [(urine creatinine × urine volume)/(serum creatinine × time in minutes)] × (1.73/patient’s body surface area). Estimated creatinine clearance was calculated using the Schwartz formula (15). In patients requiring renal replacement therapy, all measurements were performed before initiation of dialysis. Demographic and clinical data were collected from patients’ health records, including age, gender, weight, height, and diagnosis. Severity of illness was assessed by Pediatric Risk of Mortality (PRISM) score between 8 and 24 hours following PICU admission (16). Patients were grouped according to the presence or absence of AKI defined as estimated creatinine clearance of less than 75 mL/min/1.73 m2 within the first 72 hours after PICU admission. AKI was classified by the pRIFLE criteria (1). The pRIFLE stratum (R, I, or F) was determined based on the lowest score for estimated creatinine clearance. Patients were classified according to the maximum pRIFLE stratum (pRIFLEmax) reached over the first 72 hours of PICU stay. Clinical outcomes, such as PICU length of stay, duration of mechanical ventilation, need for renal replacement therapy, and mortality, were recorded. Statistical Analysis Analysis was made using SAS 9.2, R 2.15.1 (SAS/STAT User’s Guide, Version 9.2, 2008; SAS Institute, Cary, NC) and Graphpad Prism 6.0 (GraphPad Software, La Jolla, CA). Data were expressed as median (range) or number (%). Continuous variables were compared by Mann-Whitney U test and categorical variables by Fisher exact test. Comparisons between more than two groups were made by Kruskal-Wallis test with Dunn posttest. Association between variables was assessed by Spearman correlation test. Receiver operating characteristic (ROC) curves were constructed for determination of cutoff values of CysC for estimated and measured creatinine clearance less than 75 mL/min/1.73 m2 and for categories R, I, and F of pRIFLE criteria. Because CysC has been independently associated e126

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with cardiovascular disease (17) and its serum concentrations can be impacted by significant changes in basal metabolic rate (18), which can occur in septic shock, a multiple linear regression analysis was performed to address this potential confounding, with serum CysC as the dependent variable and postoperative cardiac surgery and septic shock as independent variables. Product-limit Kaplan-Meier method and Cox proportional hazard model were performed to verify the association of serum CysC concentration with PICU length of stay and duration of mechanical ventilation. A Cox proportional hazard model, adjusted for age, gender, and PRISM, was used for comparison between AKI and non-AKI groups. Crude and adjusted relative risks (RRs) for death were obtained by adjusting a log-binomial regression model. A 5% significance level was considered.

RESULTS One hundred twenty-two patients were enrolled in the study. Of these, 40 (32.8%) developed AKI within the first 72 hours after PICU admission. Patients in the AKI group were younger (median age, 5.8 mo; range, 0–163 mo) compared with those who did not develop AKI (median age, 65 mo; range, 5–215 mo) (p < 0.0001). There was a significant male predominance in the non-AKI group (68% vs 48% in the non-AKI and AKI groups, respectively; p = 0.03). In the AKI group, PRISM score was significantly higher (median, 10; range, 0–27) compared with the non-AKI group (median, 4; range, 0–32) (p < 0.0001). The most common diagnosis in the AKI group was postoperative cardiac surgery, whereas in the non-AKI group, trauma was the main diagnostic category (Table 1). Blood samples for measurement of CysC and creatinine serum concentrations were collected on three occasions: at a median time of 1 hour (range, 0–12 hr) after PICU admission, on the first PICU day (median time, 17 hr; range, 8–40 hr), and on the second PICU day (median time, 40 hr; range, 31–60 hr). CysC serum concentrations were significantly Table 1. Diagnostic Categories in Acute Kidney Injury and Non–Acute Kidney Injury Groups

Diagnoses

Postoperative cardiac surgery

AKI (n = 40) (%)

Non-AKI (n = 82) (%)

17 (42.5)

14 (17.1)

Septic shock

9 (22.5)

6 (7.3)

Respiratory disease

5 (12.5)

10 (12.2)

Neurologic disease

1 (2.5)

7 (8.5)

Trauma

2 (5)

Postoperative general surgery

3 (7.5)

Postoperative neurosurgery

0 (0)

Others

3 (7.5)

22 (26.8) 8 (9.8) 11 (13.4) 4 (4.9)

AKI = acute kidney injury.

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Online Clinical Investigations

higher in patients with AKI compared with those without AKI at PICU admission and on the first and second PICU days. However, serum creatinine concentrations were significantly higher in the AKI group only on the first and second PICU days (Table 2). In patients without AKI, there was a significant positive correlation between serum creatinine on PICU admission and age (r = 0.75; p < 0.0001). Nevertheless, no correlation was observed between serum CysC on PICU admission and age (r = 0.016; p = 0.89). In addition, no significant differences were observed in serum concentrations of CysC or creatinine at PICU admission between male and female patients (p = 0.12 and p = 0.87, respectively). No significant difference in mean values of serum CysC was observed between postoperative and nonpostoperative cardiac surgery patients adjusted for the presence or absence of AKI (adjusted p = 0.48). Also, there was no significant difference in mean values of serum CysC between septic shock and nonseptic shock patients adjusted for the presence or absence of AKI (adjusted p = 0.45) (Table 3). A significant positive correlation was observed between measured and estimated creatinine clearance on the first and second days after PICU admission (r = 0.74; 95% CI, 0.63–0.82;

p < 0.0001 and r = 0.72; 95% CI, 0.54–0.84; p 0.70 mg/L and ≤ 0.70 mg/L.

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Our data also showed that the performance of serum CysC to diagnose AKI defined as creatinine clearance of less than 75 mL/min/1.73 m2 was very good. A serum CysC level of 0.70 mg/L had sensitivity of 0.83, specificity of 0.86, and positive likelihood ratio of 6.44 for detecting estimated creatinine clearance less than 75 mL/min/1.73 m2. In addition, a significant negative correlation was observed between serum CysC and creatinine clearance at all time points. Furthermore, serum CysC was accurate in stratifying AKI severity according to pRIFLE classification, with a progressive rise in serum CysC concentration with worsening of pRIFLE category, which is in accordance with recent studies of pediatric cardiac surgical patients (19, 21). Approximately one third of our study population had AKI and about 60% of them reached pRIFLEmax I or F. Patients in the AKI group were younger and had higher PRISM score compared with those who did not develop AKI, as previously shown (12, 27, 28). In our study, the development of AKI was associated with worse clinical outcomes. In the AKI group, length of PICU stay and duration of mechanical ventilation were longer and mortality was higher, which corroborates previously published data (1, 2, 28). Furthermore, a cutoff value of 0.70 mg/L of serum CysC concentration was associated with dialysis need, longer length of PICU stay, and prolonged duration of mechanical ventilation. A few studies have shown that serum levels of CysC predicted dialysis requirement and death in adults (29, 30) and longer duration of mechanical ventilation and PICU length of stay in children following cardiac surgery (31). Our results suggest that serum CysC has also a prognostic value in a heterogeneous group of critically ill children with AKI for prediction of adverse clinical outcomes. The main limitation of our study is the lack of a gold standard method for measuring GFR. However, creatinine clearance or estimates of creatinine clearance based on serum creatinine concentration are used in clinical practice to measure GFR.

CONCLUSIONS In critically ill children, serum CysC is an early and accurate diagnostic marker of AKI, is useful for stratification of AKI severity, and is associated with poor clinical outcomes.

ACKNOWLEDGMENTS We thank Davi Casale Aragon for his help with statistical analysis and the nursing staff of the PICU of Hospital das Clínicas of Ribeirão Preto Medical School, University of São Paulo, for blood and urine sample collection.

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Diagnostic and prognostic value of serum cystatin C in critically ill children with acute kidney injury.

We aimed to evaluate the value of serum cystatin C for detection of acute kidney injury and pediatric Risk, Injury, Failure, Loss, End-Stage Renal Dis...
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