Available online http://ccforum.com/content/11/3/R59 ResearchVol 11 No 3 Open Access Cystatin C and beta2-microglobulin: markers of glomerular filtration in critically ill children José David Herrero-Morín1, Serafín Málaga1, Nuria Fernández2, Corsino Rey3, María Ángeles Diéguez4, Gonzalo Solís2, Andrés Concha3 and Alberto Medina3 1Section of Paediatric Nephrology, Hospital Universitario Central de Asturias, Celestino Villamil Street, 33006, Oviedo, Spain and University of Oviedo, Julian Claveria Street, 33006, Oviedo, Spain 2Paediatrics Service, Hospital Cabueñes, Camino de los Prados Street, 395, 33204, Gijón, Spain 3Paediatric Intensive Care Unit, Department of Paediatrics, Hospital Universitario Central de Asturias, Celestino Villamil Street, 33006, Oviedo, Spain and University of Oviedo, Julian Claveria Street, 33006, Oviedo, Spain 4Immunology Unit, Department of Clinical Chemistry, Hospital Universitario Central de Asturias, Celestino Villamil Street, 33006, Oviedo, Spain and University of Oviedo, Julian Claveria Street, 33006, Oviedo, Spain Corresponding author: José David Herrero-Morín, [email protected] Received: 29 Dec 2006 Revisions requested: 24 Jan 2007 Revisions received: 27 Apr 2007 Accepted: 22 May 2007 Published: 22 May 2007 Critical Care 2007, 11:R59 (doi:10.1186/cc5923) This article is online at: http://ccforum.com/content/11/3/R59 © 2007 Herrero-Morín et al.; licensee BioMed Central Ltd. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Abstract Introduction Parameters allowing regular evaluation of renal Results Mean age was 2.9 years (range, 0.1 to 13.9 years). CrC function in a paediatric intensive care unit (PICU) are not was less than 80 ml/minute per 1.73 m2 in 14 children, and optimal. The aim of the present study was to analyse the utility of Schwartz was less than 80 ml/minute per 1.73 m2 in 9 children. serum cystatin C and beta2-microglobulin (B2M) in detecting Correlations between inverse of B2M and CrC (r = 0.477) and decreased glomerular filtration rate in critically ill children. between inverse of B2M and Schwartz (r = 0.697) were better than correlations between inverse of cystatin C and CrC (r = Methods This was a prospective, observational study set in an 0.390) or Schwartz (r = 0.586) and better than correlations eight-bed PICU. Twenty-five children were included. The between inverse of creatinine and CrC (r = 0.104) or Schwartz inverses of serum creatinine, cystatin C, and B2M were (r = 0.442). The ability of serum cystatin C and B2M to identify correlated with creatinine clearance (CrC) using a 24-hour urine a CrC rate and a Schwartz CrC rate under 80 ml/minute per sample and CrC estimation by Schwartz formula (Schwartz). 1.73 m2 was better than that of creatinine (areas under the ROC The diagnostic value of serum creatinine, cystatin C, and B2M curve: 0.851 and 0.792 for cystatin C, 0.802 and 0.799 for to identify a glomerular filtration rate under 80 ml/minute per B2M, and 0.633 and 0.625 for creatinine). 1.73 m2 was evaluated using receiver operating characteristic (ROC) curve analysis. Conclusion Serum cystatin C and B2M were confirmed as easy and useful markers, better than serum creatinine, to detect acute kidney injury in critically ill children. Introduction [2,4,5,7,8], although not the most accurate. However, there Glomerular filtration rate (GFR) is difficult to measure in clinical are limitations to their use. Cr could be affected by factors practice [1-4]. The ideal laboratory marker should be of other than renal function (for example, muscle mass, protein endogen synthesis, regular production rate, eliminated only by intake, inflammatory illness, or hepatic disease) [2,4,9-12]. glomerular filtration, and without tubular secretion or reabsorp- Moreover, Cr is partially secreted by renal tubules [2,4,10,13] tion [4-6]. Creatinine clearance (CrC) using a 24-hour urine and frequently overestimates GFR [1,2,4,5,13]. On the other sample and serum creatinine (Cr) are the most commonly hand, CrC requires urine collection over a 24-hour period with used parameters to estimate GFR in clinical practice a steady-state situation [1,2,4,11,14]. Mathematical formulas B2M = beta2-microglobulin; CI = confidence interval; Cr = serum creatinine; CrC = creatinine clearance; GFR = glomerular filtration rate; NS = not significant; PICU = paediatric intensive care unit; PRISM = paediatric risk of mortality; ROC = receiver operating characteristic; Schwartz = creatinine clearance estimation by Schwartz formula; SD = standard deviation. Page 1 of 7 (page number not for citation purposes) Critical Care Vol 11 No 3 Herrero-Morín et al. using Cr serum levels to estimate GFR (Schwartz formula is Galicia, Spain, and World Health Organization, 2003) for Win- the most widely used and is based on Cr, age, and height) dows. Data are expressed as a mean value and 95% confi- have been developed [15,16]. dence interval (CI) unless indicated otherwise. Inverses of Cr, cystatin C, and B2M were correlated with CrC and with To overcome the problems of measuring GFR, an extensive Schwartz. We used the inverses of creatinine, cystatin C, and search is being conducted to find a serum marker able to B2M to obtain a direct correlation with CrC and Schwartz for- detect renal function impairment, especially at the initial phase. mula. Correlations between age and CrC, Schwartz, creati- Cystatin C and beta2-microglobulin (B2M) are low-molecular- nine, cystatin C, and B2M were performed. The diagnostic weight proteins freely filtered by the glomerulus [1,6,11,12]. value of Cr, cystatin C, and B2M for identifying CrC or Their serum concentrations, especially that of cystatin C, are Schwartz less than 80 ml/minute per 1.73 m2 was evaluated less dependent on extra renal factors than in the case of Cr using receiver operating characteristic (ROC) curve analysis. [1,5,6,10,11,13,14,17,18]. Early detection of renal function Sensitivity, specificity, and positive likelihood ratio were calcu- impairment in paediatric intensive care would be of great lated. A p value of less than 0.05 was considered statistically value, allowing accurate treatment, adjustment of drug dose, significant. Each patient's determinations were made with the and prevention of more severe renal damage [3,7,9]. Previous informed consent of their parents. studies demonstrated the superiority of serum cystatin C com- pared with creatinine in the evaluation of GFR Results [1,5,8,11,13,17-19], especially when there is a minor reduc- The mean age was 2.9 years (95% CI, 1.4 to 4.3 years) with a tion in GFR [1,5,6,8,12,13]. We have not found any medical range of 0.1 to 13.9 years and a median of 1.3 years. Male/ literature evaluating these low-molecular-weight proteins in female ratio was 1.27:1. Mean height was 86.3 cm (range, critically ill children. The aim of this study was to evaluate the 53.0 to 151.0 cm). Mean body surface area was 0.5 m2 accuracies of serum Cr, serum cystatin C, and B2M as mark- (range, 0.2 to 1.5 m2). Mean paediatric risk of mortality ers of GFR in critically ill children by comparing their results (PRISM) [20] (standard deviation [SD]) scores 24 hours after with CrC and Schwartz. admission were 15.0 (11.3). The patients' clinical conditions and the treatments they received are summarized in Table 1. Materials and methods Twenty-five children admitted to our paediatric intensive care The mean CrC was 76.3 ml/minute per 1.73 m2 (95% CI, 58.4 unit (PICU) were included in the study. All patients between to 94.1 ml/minute per 1.73 m2) and the mean Schwartz was the ages of 1 month and 14 years who were admitted due to 104.5 ml/minute per 1.73 m2 (95% CI, 88.3 to 120.8 ml/ an acute illness and who had a bladder catheter were minute per 1.73 m2). The mean serum Cr concentration was included. The presence of previous renal or thyroideal pathol- 0.42 mg/dl (95% CI, 0.36 to 0.48 mg/dl), the mean serum ogy and the need of renal replacement therapy were consid- cystatin C concentration was 0.69 mg/l (95% CI, 0.57 to 0.81 ered exclusion criteria. Demographic and clinical conditions of mg/l), and the mean serum B2M concentration was 2.12 mg/ the children were recorded. A serum sample was taken regu- l (95% CI, 1.66 to 2.57 mg/l). There were no significant differ- larly from each patient in the morning (between 7 and 8 a.m.) ences between male and female regarding CrC (79.9 versus for creatinine measurement. Cystatin C and B2M were meas- 71.7 ml/minute per 1.73 m2), Schwartz (103.7 versus 105.5 ured in this sample. A 24-hour urine sample was obtained just ml/minute per 1.73 m2), serum Cr (0.43 versus 0.42 mg/dl), before the serum sample to calculate the CrC adjusted to serum cystatin C (0.65 versus 0.75 mg/l), and serum B2M adult body surface area by means of the following formula: (2.23 versus 1.97 mg/l). CrC (in millilitres/minute per 1.73 m2) = [(urine volume × urine Cr)/(serum Cr × 1,440)] × (1.73 m2/body surface). Schwartz Fourteen out of the 25 patients enrolled in the study (56.0%) CrC rate was calculated using the following formula: (height × had a CrC less than 80 ml/minute per 1.73 m2, and 9 patients k)/Cr, where height is calculated in centimetres, k = 0.44 for (36%) had a Schwartz less than 80 ml/minute per 1.73 m2.