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Therapeutic Apheresis and Dialysis 2014; 18(1):57–67 doi: 10.1111/1744-9987.12054 © 2013 The Authors Therapeutic Apheresis and Dialysis © 2013 International Society for Apheresis
Serum Cystatin-C as a Marker of Acute Kidney Injury in the Newborn After Perinatal Hypoxia/Asphyxia Milena Treiber,1 Maksimiljan Gorenjak,2 and Breda Pecovnik Balon3 1
Clinical Department of Gynecology and Perinatology, Unit of Neonatology, 2Department of Clinical Chemistry, University Medical Center Maribor, and 3Faculty of Medicine, University of Maribor, Maribor, Slovenia
Abstract: We evaluated cystatin-C (cysC) in the umbilical blood as a predictor of acute kidney injury (AKI) after perinatal hypoxia/asphyxia compared with creatinine (Cr). One hundred full-term newborns were enrolled in the study (50 in a group affected by perinatal hypoxia/asphyxia [AS] and 50 controls). CysC and Cr were measured in blood samples from the umbilical cord at birth (cysC-umb and Cr-umb) and from a peripheral vein 3 days later (cysC-3 and Cr-3).At birth, the mean level of cysC in healthy term babies was found to be 1.39 ⫾ 0.19 mg/L and 1.34 ⫾ 0.21 mg/L after 3 days of life, not significantly decreased (P = 0.137). The mean of cysC in the AS group was 2.12 ⫾ 0.53 mg/L in cord blood and 1.56 ⫾ 0.32 g/L in day 3 blood samples, also decreased (P < 0.001) and different from the control (P < 0.001). Cr levels, determined simultaneously at birth
were different (P = 0.001) between the control (62.74 ⫾ 12.84 mmol/L) and AS (72.60 ⫾ 15.55 mmol/L) group, significantly decreased after 3 days in both groups (P < 0.001). The receiver-operating characteristic curve analysis, comparing AS and the control group, showed area under the curve for cysC-umb, cysC-3, Cr-umb and Cr-3 (0.918; 0.698; 0.692; 0.660). The highest diagnostic accuracy was achieved with a chosen cut-off for cysC-umb of 1.67 mg/L (sensitivity of 84.0%, specificity of 90.0%) or 1.69 mg/L (sensitivity of 82.0%, specificity of 94.0%). Our results indicate serum CysC is a more sensitive marker of glomerular filtration rate than Cr in the newborns. Key Words: Acute kidney injury, Asphyxia, Creatinine, Cystatin C, Glomerular filtration rate, Hypoxia, Newborn.
Acute kidney injury (AKI) is a common consequence of perinatal asphyxia, a complex disorder with clinical manifestations ranging from mild dysfunction to complete anuric kidney failure. The incidence of asphyxia is estimated to be between 1 and 10 per 1000 live births and is influenced by the local availability of medical resources. Asphyxia can lead to multiple organ dysfunction and a redistribution of cardiac output to maintain cerebral, cardiac, and adrenal perfusion, while potentially compromising renal, gastrointestinal and skin perfusion. There is no consensus on the definition of AKI in the neonate, making estimations of its incidence and studies of its management difficult (1). Acute kidney injury is defined as a sudden, severe derangement of glomerular filtration and tubular function. On the basis of serum creatinine values
(Cr), it is diagnosed when Cr is greater than 1.5 mg/dL (132.5 mmol/L), regardless of the rate of urine output. AKI should also be suspected in the newborn if Cr fails to decline below maternal levels by the fifth to seventh days postnatally or is rising by 0.3 mg/dL per day (ⱖ26.4 mmol/L per day) or faster. In neonates, renal failure can occur in more than 50% of cases in the absence of oliguria (2). In 2007 the Acute Kidney Injury Network (AKIN), a collaborative group of investigators from all major critical care and nephrology societies, proposed a staging system that uses mild AKI (stage 1), moderate AKI (stage 2), and severe AKI (stage 3) in a way similar to the RIFLE classification (risk, injury, failure, loss, and end-stage renal disease). In children a modified pediatric RIFLE classification was proposed (3). These classification systems for defining AKI in neonatal populations have not been implemented, owing to the lack of research. The ideal marker for detecting AKI should be upregulated shortly after an injury and independent of glomerular filtration rate (GFR) level. Using Cr as
Received December 2012; revised February 2013. Address correspondence and reprint requests to Professor Breda Pecovnik-Balon, Faculty of Medicine, University of Maribor, Slomskov trg 15, Maribor 2000, Slovenia. Email: breda.balon@ guest.arnes.si
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the most common method to monitor renal function and to diagnose AKI is not ideal for many reasons: (i) the Cr value in a neonate reflects maternal Cr; (ii) Cr is a measure of function (not injury), and it is a late marker for an acute injury; (iii) >50% of nephrons must be compromised before changes in the Cr level become evident, so it is a late marker of significant renal dysfunction; (iv) at lower GFR, serum Cr will overestimate renal function, owing to tubular secretion of creatinine; (v) Cr varies by muscle mass, hydration status, age and gender; (vi) bilirubin and medications can affect Cr measurement by the Jaffe method (4–6). Human cystatin C (cysC) is a low molecular mass protein belonging to the cystatin superfamily, a protease inhibitor found in several human body fluids. It is produced at a constant rate in all nucleated cells, freely filtrated through the glomerular membrane without significant peritubular uptake and then completely reabsorbed and degraded by the proximal tubule. Unlike Cr, cysC does not appear to be affected by body muscle mass, age, gender, inflammatory state or nutritional conditions (7). CysC does not cross the placental barrier, as Cr does, and the high serum levels of cysC after birth probably reflect the degree of maturation of glomerular filtration capacity (8). Studies have shown that serum cysC is a more specific and sensitive marker of GFR in both adults and children (7,9,10) To date, only limited evaluations of cysC as an AKI biomarker have been performed in neonates. The aim of this study was first to clarify the reference values of cysC in a population of normal term newborns by taking the umbilical cord and 3-day blood samples in comparison with Cr determined from the same blood samples. The values of cysC and Cr were also measured in a group of newborns with mild to moderate perinatal hypoxia/asphyxia, and cysC was analyzed as a marker of impaired GFR and an AKI predictor. PATIENTS AND METHODS Patients The study is designed as a case-control study including a total of 100 full-term neonates, born at the University Medical Centre Maribor, Department of Gynecology and Perinatology between January 2008 and December 2011. The study protocol was in conformity with ethical guidelines and informed consent was obtained from the parents. The study group (AS group) comprised 50 fullterm neonates with clinical and laboratory signs of perinatal hypoxia/asphyxia (Apgar score 0.3 mg/dL or >26 mmol/L). In the control group, the level of cysC-3 was frequently but minimally higher than cysC-umb (21/50 cases) compared to the AS group. Such value fluctuations are normal over a short time interval of 3 days.
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The average values in the control group are insignificantly lower by 6% after 3 days, compared to 38% in the AS group. Our results are in accordance with the results from Sarafidis, who also registered no increase of cysC in asphyxiated newborns 3 days after birth compared to day 1 after birth; not even in cases of reduced renal function (24). Sarafidis used the findings of his recent study to recommend urine biomarkers for monitoring renal dysfunction in those asphyxiated newborns with increased values of serum cysC on day 1 after birth. The AUC area of diagnostic effectiveness of biomarkers as early predictors of AKI is as follows: 0.73 for serum cysC; 0.94 for serum NGAL; 0.92 for urine cysC; 0.89 for urine NGAL and 0.60 for urine KIM-1. His study included only 13 asphyxiated, normal term newborns, eight of which met the criteria for AKI regarding the values of Cr, with 22 healthy subjects in the control group. The small sample size represents the main drawback in evaluating his results. In comparison with his results, serum cysC-umb has even greater diagnostic effectiveness in our study regarding the AUC area (0.73 vs. 0.91); however, Sarafidis made calculations on the basis of cysC measurements on day 1 after birth and not in cord blood. It appears that the predictive value of serum cysC as an early predictor of renal dysfunction decreases with each day subsequent to the hypoxic/ asphyxia injury. Urine biomarkers point more to the level of tubular dysfunction after asphyxia that is not always related to the level of AKI, which explains the decreased sensitivity of serum cysC. Initial glomerular dysfunction improves faster than tubular dysfunction, which leads to a decrease in the value of serum cysC and an increase in urine cysC. Results of a study on an animal model have also confirmed that, following asphyxia, GFR normalizes after 3 days and that tubules are the primary location of injury (25). CysC in urine was not measured in our study, which proved a shortcoming of our study, in addition to the need for monitoring renal function markers over a longer period of time. CONCLUSIONS The cystatin-C values in cord blood in neonates after perinatal hypoxia/asphyxia correlate well with the severity of the asphyxia; the value of cysC in cord blood is an indicator of the level of perinatal hypoxia/ asphyxia as well as of a decrease in glomerular filtration rate. The serum creatinine is not a suitable indicator of reduced renal function during the first 3 days after birth, regardless of the cause. Unlike Cr,
Ther Apher Dial, Vol. 18, No. 1, 2014
serum cysC registers even mild forms of glomerular dysfunction, which for everyday clinical practice in the neonatal period means that acute kidney injury would have to be redefined on the basis of cysC or combinations of larger and newer biomarkers of renal failure that would also reflect tubular dysfunction. REFERENCES 1. Durkan AM, Todd Alexander CB. Acute kidney injury post neonatal asphyxia. J Pediatr 2011;158:e29–33. 2. Karlowicz MG, Adelman RD. Nonoliguric and oliguric acute renal failure in asphyxiated term neonates. Pediatr Nephrol 1995;9:718–22. 3. Akcan-Arikan A, Zappitelli M, Loftis LL, Washburn KK, Jefferson LS, Goldstein SL. Modified RIFLE criteria in critically ill children with acute kidney injury. Kidney Int 2007;71:1028– 35. 4. Drukker A, Guignard JP. Renal aspects of the term and preterm infant: a selective update. Curr Opin Pediatr 2002;14: 175–82. 5. Askenazi DJ, Ambalavanan N, Goldstein SL. Acute kidney injury in critically ill newborns: what do we know? What do we need to learn? Pediatr Nephrol 2009;24:265–74. 6. Feldman H, Guignard JP. Plasma creatinine in the first month of life. Arch Dis Child 1982;57:123–6. 7. Randers E, Erlandsen EJ. Serum cystatin C as an endogenous marker of the renal function-a review. Clin Chem Lab Med 1999;37:389–95. 8. Bökenkamp A, Dieterich C, Dressler F. Fetal serum concentrations of cystatin C and b2-microglobulin as predictors of postnatal kidney function. Am J Obstet Gynecol 2001;185:468– 75. 9. Hojs R, Bevc S, Ekart R, Gorenjak M, Puklavec L. Serum cystatin C as an endogenous marker of renal function in patients with mild to moderate impaired kidney function. Nephrol Dial Transplant 2006;21:1855–62. 10. Andersen TB, Jensen AE, Frokiaer J, Mortensen JB. Measuring glomerular filtration rate in children; can cystatin C replace established methods? A review. Pediatr Nephrol 2009;24:929– 41. 11. Finney H, Newman DJ, Thakkar H, Fell JME, Price CP. Reference ranges for plasma cystatin C and creatinine measurements in premature infants, neonates and older children. Arch Dis Child 2000;82:71–5. 12. Bahar A, Ylmaz Y, Unver S, Gocmen I, Karademir F. Reference values of umbilical cord and third-day cystatin C levels for determining glomerular filtration rates in newborns. J Int Med Res 2003;31:231–5. 13. Albuquerque Cavalcanti Ferreira Novo AC, Santos Rodrigues Sadeck L, Suely Okay T, Rodrigues Leone C. Longitudinal study of cystatin C in healthy term newborns. Clinics 2011;66: 2017–220. 14. Parvex P, Combescure C, Rodriguez M, Girardin E. Is cystatin C a promising marker of renal function, at birth, in neonates prenatally diagnosed with congenital kidney anomaly? Nephrol Dial Transplant 2012;27:3477–82. 15. Treiber M, Pecˇovnik Balon B, Gorenjak M. Cystatin C versus creatinine as a marker of glomerular filtration rate in the newborn. Wien Klin Wochenschr 2006;118:66–70. 16. Dorum S, Silfeler I, Dorum BA, Silfeler DB, Canbak Y, Say A. Reference values of serum cystatin-C for full-term and preterm neonates in Istanbul. Indian J Pediatr 2012;79:1037– 42. 17. Cataldi L, Mussap M, Bertelli L, Ruzzante N, Fanos V, Plebani M. Cystatin C in healthy women at term pregnancy and in their infant newborns: relationship between maternal and neonatal serum levels and reference values. Am J Perinatol 1999;16:287– 95. © 2013 The Authors Therapeutic Apheresis and Dialysis © 2013 International Society for Apheresis
Cystatin-C in the Newborn 18. Armangil D, Yurdakok M, Canpolat FE. Determination of reference values for plasma cystatin C and comparison with creatinine in premature infants. Pediatr Nephrol 2008;23:2081– 83. 19. Aggarwal A, Kumar P, Chowdhary G, Majumdar S, Nurang A. Evaluation of renal function in asphyxiated newborns. J Trop Pediatr 2005;51:295–9. 20. Gupta BD, Sharma P, Bagla J, Parakh M, Soni JP. Renal failure in asphyxiated neonates. Indian Pediatr 2005;42:928–34. 21. Kaur S, Jain S, Saha A et al. Evaluation of glomerular and tubular renal function in neonates with birth asphyxia. Ann Trop Paediatr 2011;31:129–34.
© 2013 The Authors Therapeutic Apheresis and Dialysis © 2013 International Society for Apheresis
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22. Willis F, Summers J, Minutillo C, Hewitt I. Indices of renal tubular function in perinatal asphyxia. Arch Dis Child Fetal Neonatal Ed 1997;77:57–60. 23. Bhat MA, Shah ZA, Makhdoomi MS, Mufti MH. Theophylline for renal function in term neonates with perinatal asphyxia: a randomized placebo-controlled trial. J Pediatr 2006;149:180–4. 24. Sarafidis K, Tsepkentzi E, Agakidou E. Serum and urine acute kidney injury biomarkers in asphyxiated neonates. Pediatr Nephrol 2012;27:1575–82. 25. O’Connell AE, Boyce AC, Lumbers ER, Gibson KJ. The effects of asphyxia on renal function in fetal sheep at midgestation. J Physiol 2003;552:933–43.
Ther Apher Dial, Vol. 18, No. 1, 2014
Therapeutic Apheresis and Dialysis 2014; 18(1):57–67 doi: 10.1111/1744-9987.12054 © 2013 The Authors Therapeutic Apheresis and Dialysis © 2013 International Society for Apheresis
Serum Cystatin-C as a Marker of Acute Kidney Injury in the Newborn After Perinatal Hypoxia/Asphyxia Milena Treiber,1 Maksimiljan Gorenjak,2 and Breda Pecovnik Balon3 1
Clinical Department of Gynecology and Perinatology, Unit of Neonatology, 2Department of Clinical Chemistry, University Medical Center Maribor, and 3Faculty of Medicine, University of Maribor, Maribor, Slovenia
Abstract: We evaluated cystatin-C (cysC) in the umbilical blood as a predictor of acute kidney injury (AKI) after perinatal hypoxia/asphyxia compared with creatinine (Cr). One hundred full-term newborns were enrolled in the study (50 in a group affected by perinatal hypoxia/asphyxia [AS] and 50 controls). CysC and Cr were measured in blood samples from the umbilical cord at birth (cysC-umb and Cr-umb) and from a peripheral vein 3 days later (cysC-3 and Cr-3).At birth, the mean level of cysC in healthy term babies was found to be 1.39 ⫾ 0.19 mg/L and 1.34 ⫾ 0.21 mg/L after 3 days of life, not significantly decreased (P = 0.137). The mean of cysC in the AS group was 2.12 ⫾ 0.53 mg/L in cord blood and 1.56 ⫾ 0.32 g/L in day 3 blood samples, also decreased (P < 0.001) and different from the control (P < 0.001). Cr levels, determined simultaneously at birth
were different (P = 0.001) between the control (62.74 ⫾ 12.84 mmol/L) and AS (72.60 ⫾ 15.55 mmol/L) group, significantly decreased after 3 days in both groups (P < 0.001). The receiver-operating characteristic curve analysis, comparing AS and the control group, showed area under the curve for cysC-umb, cysC-3, Cr-umb and Cr-3 (0.918; 0.698; 0.692; 0.660). The highest diagnostic accuracy was achieved with a chosen cut-off for cysC-umb of 1.67 mg/L (sensitivity of 84.0%, specificity of 90.0%) or 1.69 mg/L (sensitivity of 82.0%, specificity of 94.0%). Our results indicate serum CysC is a more sensitive marker of glomerular filtration rate than Cr in the newborns. Key Words: Acute kidney injury, Asphyxia, Creatinine, Cystatin C, Glomerular filtration rate, Hypoxia, Newborn.
Acute kidney injury (AKI) is a common consequence of perinatal asphyxia, a complex disorder with clinical manifestations ranging from mild dysfunction to complete anuric kidney failure. The incidence of asphyxia is estimated to be between 1 and 10 per 1000 live births and is influenced by the local availability of medical resources. Asphyxia can lead to multiple organ dysfunction and a redistribution of cardiac output to maintain cerebral, cardiac, and adrenal perfusion, while potentially compromising renal, gastrointestinal and skin perfusion. There is no consensus on the definition of AKI in the neonate, making estimations of its incidence and studies of its management difficult (1). Acute kidney injury is defined as a sudden, severe derangement of glomerular filtration and tubular function. On the basis of serum creatinine values
(Cr), it is diagnosed when Cr is greater than 1.5 mg/dL (132.5 mmol/L), regardless of the rate of urine output. AKI should also be suspected in the newborn if Cr fails to decline below maternal levels by the fifth to seventh days postnatally or is rising by 0.3 mg/dL per day (ⱖ26.4 mmol/L per day) or faster. In neonates, renal failure can occur in more than 50% of cases in the absence of oliguria (2). In 2007 the Acute Kidney Injury Network (AKIN), a collaborative group of investigators from all major critical care and nephrology societies, proposed a staging system that uses mild AKI (stage 1), moderate AKI (stage 2), and severe AKI (stage 3) in a way similar to the RIFLE classification (risk, injury, failure, loss, and end-stage renal disease). In children a modified pediatric RIFLE classification was proposed (3). These classification systems for defining AKI in neonatal populations have not been implemented, owing to the lack of research. The ideal marker for detecting AKI should be upregulated shortly after an injury and independent of glomerular filtration rate (GFR) level. Using Cr as
Received December 2012; revised February 2013. Address correspondence and reprint requests to Professor Breda Pecovnik-Balon, Faculty of Medicine, University of Maribor, Slomskov trg 15, Maribor 2000, Slovenia. Email: breda.balon@ guest.arnes.si
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the most common method to monitor renal function and to diagnose AKI is not ideal for many reasons: (i) the Cr value in a neonate reflects maternal Cr; (ii) Cr is a measure of function (not injury), and it is a late marker for an acute injury; (iii) >50% of nephrons must be compromised before changes in the Cr level become evident, so it is a late marker of significant renal dysfunction; (iv) at lower GFR, serum Cr will overestimate renal function, owing to tubular secretion of creatinine; (v) Cr varies by muscle mass, hydration status, age and gender; (vi) bilirubin and medications can affect Cr measurement by the Jaffe method (4–6). Human cystatin C (cysC) is a low molecular mass protein belonging to the cystatin superfamily, a protease inhibitor found in several human body fluids. It is produced at a constant rate in all nucleated cells, freely filtrated through the glomerular membrane without significant peritubular uptake and then completely reabsorbed and degraded by the proximal tubule. Unlike Cr, cysC does not appear to be affected by body muscle mass, age, gender, inflammatory state or nutritional conditions (7). CysC does not cross the placental barrier, as Cr does, and the high serum levels of cysC after birth probably reflect the degree of maturation of glomerular filtration capacity (8). Studies have shown that serum cysC is a more specific and sensitive marker of GFR in both adults and children (7,9,10) To date, only limited evaluations of cysC as an AKI biomarker have been performed in neonates. The aim of this study was first to clarify the reference values of cysC in a population of normal term newborns by taking the umbilical cord and 3-day blood samples in comparison with Cr determined from the same blood samples. The values of cysC and Cr were also measured in a group of newborns with mild to moderate perinatal hypoxia/asphyxia, and cysC was analyzed as a marker of impaired GFR and an AKI predictor. PATIENTS AND METHODS Patients The study is designed as a case-control study including a total of 100 full-term neonates, born at the University Medical Centre Maribor, Department of Gynecology and Perinatology between January 2008 and December 2011. The study protocol was in conformity with ethical guidelines and informed consent was obtained from the parents. The study group (AS group) comprised 50 fullterm neonates with clinical and laboratory signs of perinatal hypoxia/asphyxia (Apgar score 0.3 mg/dL or >26 mmol/L). In the control group, the level of cysC-3 was frequently but minimally higher than cysC-umb (21/50 cases) compared to the AS group. Such value fluctuations are normal over a short time interval of 3 days.
Ther Apher Dial, Vol. 18, No. 1, 2014
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M Treiber et al.
The average values in the control group are insignificantly lower by 6% after 3 days, compared to 38% in the AS group. Our results are in accordance with the results from Sarafidis, who also registered no increase of cysC in asphyxiated newborns 3 days after birth compared to day 1 after birth; not even in cases of reduced renal function (24). Sarafidis used the findings of his recent study to recommend urine biomarkers for monitoring renal dysfunction in those asphyxiated newborns with increased values of serum cysC on day 1 after birth. The AUC area of diagnostic effectiveness of biomarkers as early predictors of AKI is as follows: 0.73 for serum cysC; 0.94 for serum NGAL; 0.92 for urine cysC; 0.89 for urine NGAL and 0.60 for urine KIM-1. His study included only 13 asphyxiated, normal term newborns, eight of which met the criteria for AKI regarding the values of Cr, with 22 healthy subjects in the control group. The small sample size represents the main drawback in evaluating his results. In comparison with his results, serum cysC-umb has even greater diagnostic effectiveness in our study regarding the AUC area (0.73 vs. 0.91); however, Sarafidis made calculations on the basis of cysC measurements on day 1 after birth and not in cord blood. It appears that the predictive value of serum cysC as an early predictor of renal dysfunction decreases with each day subsequent to the hypoxic/ asphyxia injury. Urine biomarkers point more to the level of tubular dysfunction after asphyxia that is not always related to the level of AKI, which explains the decreased sensitivity of serum cysC. Initial glomerular dysfunction improves faster than tubular dysfunction, which leads to a decrease in the value of serum cysC and an increase in urine cysC. Results of a study on an animal model have also confirmed that, following asphyxia, GFR normalizes after 3 days and that tubules are the primary location of injury (25). CysC in urine was not measured in our study, which proved a shortcoming of our study, in addition to the need for monitoring renal function markers over a longer period of time. CONCLUSIONS The cystatin-C values in cord blood in neonates after perinatal hypoxia/asphyxia correlate well with the severity of the asphyxia; the value of cysC in cord blood is an indicator of the level of perinatal hypoxia/ asphyxia as well as of a decrease in glomerular filtration rate. The serum creatinine is not a suitable indicator of reduced renal function during the first 3 days after birth, regardless of the cause. Unlike Cr,
Ther Apher Dial, Vol. 18, No. 1, 2014
serum cysC registers even mild forms of glomerular dysfunction, which for everyday clinical practice in the neonatal period means that acute kidney injury would have to be redefined on the basis of cysC or combinations of larger and newer biomarkers of renal failure that would also reflect tubular dysfunction. REFERENCES 1. Durkan AM, Todd Alexander CB. Acute kidney injury post neonatal asphyxia. J Pediatr 2011;158:e29–33. 2. Karlowicz MG, Adelman RD. Nonoliguric and oliguric acute renal failure in asphyxiated term neonates. Pediatr Nephrol 1995;9:718–22. 3. Akcan-Arikan A, Zappitelli M, Loftis LL, Washburn KK, Jefferson LS, Goldstein SL. Modified RIFLE criteria in critically ill children with acute kidney injury. Kidney Int 2007;71:1028– 35. 4. Drukker A, Guignard JP. Renal aspects of the term and preterm infant: a selective update. Curr Opin Pediatr 2002;14: 175–82. 5. Askenazi DJ, Ambalavanan N, Goldstein SL. Acute kidney injury in critically ill newborns: what do we know? What do we need to learn? Pediatr Nephrol 2009;24:265–74. 6. Feldman H, Guignard JP. Plasma creatinine in the first month of life. Arch Dis Child 1982;57:123–6. 7. Randers E, Erlandsen EJ. Serum cystatin C as an endogenous marker of the renal function-a review. Clin Chem Lab Med 1999;37:389–95. 8. Bökenkamp A, Dieterich C, Dressler F. Fetal serum concentrations of cystatin C and b2-microglobulin as predictors of postnatal kidney function. Am J Obstet Gynecol 2001;185:468– 75. 9. Hojs R, Bevc S, Ekart R, Gorenjak M, Puklavec L. Serum cystatin C as an endogenous marker of renal function in patients with mild to moderate impaired kidney function. Nephrol Dial Transplant 2006;21:1855–62. 10. Andersen TB, Jensen AE, Frokiaer J, Mortensen JB. Measuring glomerular filtration rate in children; can cystatin C replace established methods? A review. Pediatr Nephrol 2009;24:929– 41. 11. Finney H, Newman DJ, Thakkar H, Fell JME, Price CP. Reference ranges for plasma cystatin C and creatinine measurements in premature infants, neonates and older children. Arch Dis Child 2000;82:71–5. 12. Bahar A, Ylmaz Y, Unver S, Gocmen I, Karademir F. Reference values of umbilical cord and third-day cystatin C levels for determining glomerular filtration rates in newborns. J Int Med Res 2003;31:231–5. 13. Albuquerque Cavalcanti Ferreira Novo AC, Santos Rodrigues Sadeck L, Suely Okay T, Rodrigues Leone C. Longitudinal study of cystatin C in healthy term newborns. Clinics 2011;66: 2017–220. 14. Parvex P, Combescure C, Rodriguez M, Girardin E. Is cystatin C a promising marker of renal function, at birth, in neonates prenatally diagnosed with congenital kidney anomaly? Nephrol Dial Transplant 2012;27:3477–82. 15. Treiber M, Pecˇovnik Balon B, Gorenjak M. Cystatin C versus creatinine as a marker of glomerular filtration rate in the newborn. Wien Klin Wochenschr 2006;118:66–70. 16. Dorum S, Silfeler I, Dorum BA, Silfeler DB, Canbak Y, Say A. Reference values of serum cystatin-C for full-term and preterm neonates in Istanbul. Indian J Pediatr 2012;79:1037– 42. 17. Cataldi L, Mussap M, Bertelli L, Ruzzante N, Fanos V, Plebani M. Cystatin C in healthy women at term pregnancy and in their infant newborns: relationship between maternal and neonatal serum levels and reference values. Am J Perinatol 1999;16:287– 95. © 2013 The Authors Therapeutic Apheresis and Dialysis © 2013 International Society for Apheresis
Cystatin-C in the Newborn 18. Armangil D, Yurdakok M, Canpolat FE. Determination of reference values for plasma cystatin C and comparison with creatinine in premature infants. Pediatr Nephrol 2008;23:2081– 83. 19. Aggarwal A, Kumar P, Chowdhary G, Majumdar S, Nurang A. Evaluation of renal function in asphyxiated newborns. J Trop Pediatr 2005;51:295–9. 20. Gupta BD, Sharma P, Bagla J, Parakh M, Soni JP. Renal failure in asphyxiated neonates. Indian Pediatr 2005;42:928–34. 21. Kaur S, Jain S, Saha A et al. Evaluation of glomerular and tubular renal function in neonates with birth asphyxia. Ann Trop Paediatr 2011;31:129–34.
© 2013 The Authors Therapeutic Apheresis and Dialysis © 2013 International Society for Apheresis
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22. Willis F, Summers J, Minutillo C, Hewitt I. Indices of renal tubular function in perinatal asphyxia. Arch Dis Child Fetal Neonatal Ed 1997;77:57–60. 23. Bhat MA, Shah ZA, Makhdoomi MS, Mufti MH. Theophylline for renal function in term neonates with perinatal asphyxia: a randomized placebo-controlled trial. J Pediatr 2006;149:180–4. 24. Sarafidis K, Tsepkentzi E, Agakidou E. Serum and urine acute kidney injury biomarkers in asphyxiated neonates. Pediatr Nephrol 2012;27:1575–82. 25. O’Connell AE, Boyce AC, Lumbers ER, Gibson KJ. The effects of asphyxia on renal function in fetal sheep at midgestation. J Physiol 2003;552:933–43.
Ther Apher Dial, Vol. 18, No. 1, 2014
