Annals of Clinical & Laboratory Science 37:233-240 (2007)
© 2007 Association of Clinical Scientists
Is Serum Cystatin-C a Suitable Marker of Renal Function in Children?
Marco Zaffanello1,
Massimo Franchini2 and
Vassilios Fanos3
1 Department of Mother-Child and Biology-Genetics, University of Verona, Verona,2 Immunohematology and Transfusion Service, Verona Hospital, Verona, and3 Neonatal Intensive Care Unit, University of Cagliari, Cagliari, Italy
Address orrespondence to Marco Zaffanello, M.D., Department of Mother-Child and Biology-Genetics, University of Verona, Piazzale L. Scuro 10, Verona 37134, Italy; tel 39 045 812 4895; fax 39 045 820 0993; e-mail: marco.zaffanello{at}univr.it.
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Abstract
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Cystatin C (Cys-C) is a low-molecular weight (13 kDa) protein that is a member of the cysteine protease family and is produced by all nucleated cells. In normal conditions, serum Cys-C is almost completely filtered by the renal glomerulus and largely catabolized by proximal tubular cells. Since serum Cys-C levels are closely correlated with the glomerular filtration rate (GFR), serum Cys-C assay has been introduced as a marker of renal function in patients with kidney diseases. In this review, we focus on studies reported during the past decade in which serum Cys-C levels have been compared to serum creatinine levels as a marker of GFR in pediatric populations. All but one of these studies showed diagnostic superiority or equivalence of serum Cys-C levels vs serum creatinine levels in children. The recent evidence from clinical trials generally supports the use of serum Cys-C assays as a renal function test in pediatric patients. However, clinicians should be cognizant of extrarenal conditions and pharmacological factors that can influence the results of serum Cys-C assays.
Keywords: cystatin-C, renal function test, glomerular filtration rate, kidney disease, pediatric nephrology
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Introduction
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Cystatin C (Cys-C), a protein of the cysteine protease inhibitor family, is produced by all nucleated cells and is measurable in body fluids. Cys-C has regulatory roles in protein catabolism, antigen presentation, bone reabsorbtion, and hormone processing. It is also involved in tissue remodeling, cancer cell invasion, and tumor metastasis [1].
Cys-C is a low molecular weight protein (13-kDa) that is almost completely filtered by the glomerulus and largely catabolized by proximal tubular cells. In adults, serum Cys-C concentration is closely correlated with the glomerular filtration rate (GFR) [2,3]. Serum Cys-C assay has been introduced as a marker of GFR in children as well as adults. This article reviews the literature published during the past decade on serum Cys-C levels as a marker of GFR in pediatric populations.
We used PUBMED and EMBASE computer databases to identify the clinical studies that have used serum Cys-C assays in pediatric nephrology. In particular, we focused on (a) comparisons of serum Cys-C and creatinine levels as markers of renal function, (b) renal and extrarenal factors that can affect the diagnostic sensitivity of Cys-C, (c) predictive formulas that are used to estimate GFR from serum Cys-C levels, and (d) age-related reference values. We also evaluated the reliability of serum Cys-C as a marker of renal function in several pediatric kidney diseases.
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Marker of Renal Function
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In clinical research, GFR is measured by reference methods that use exogenous markers, including inulin [4–6], 51Cr-EDTA [7–9], and 99mTc-DTPA. For routine clinical practice, such methods are seldom required [10]; the markers of GFR that are frequently employed are endogenous: serum creatinine or, more recently, serum Cys-C.
Studies in pediatric populations have compared GFR estimations, based on endogenous markers (ie, serum Cys-C and creatinine levels), with those measured by reference methods with exogenous markers (ie, inulin clearance [Cin] and 51Cr-EDTA clearance (Table 1
). These studies yielded somewhat disparate results [8–29]. In most reports, serum Cys-C was either superior or equivalent to serum creatinine in estimating GFR; in only one report was it worse [11]. The endogenous markers were both able to differentiate normal and reduced GFR [12,13]. In children with renal diseases, GFR values calculated from serum Cys-C or creatinine levels were similar to those measured by Cin [5,12,14]. Consequently, serum Cys-C has been introduced as an alternative to serum creatinine to monitor GFR [15].
Several authors found that serum Cys-C is a better marker of GFR than creatinine [16–20,78], even in cases of sub-clinical renal dysfunction [21]. Since the classic Schwartz formula for estimating GFR from serum creatinine concentration shows considerable bias in children and GFR values derived from serum Cys-C are only slightly overestimated, some authors have suggested replacing the Schwartz GFR formula with GFR calculated from serum Cys-C [12,24,25]. A similar Cys-C-based approach yielded better estimates of GFR in children when compared to those obtained by the Cockcroft-Gault formula [26]. The urinary Cys-C/creatinine ratio in childhood also showed high sensitivity and might serve as a marker of renal disease [27,28].
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Extrarenal Factors That May Affect Cys-C Levels
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Serum Cys-C concentration is rarely influenced by extrarenal variables or associated conditions (Table 2). In newborns, the Cys-C levels are independent of gender, height, gestational age, lean body mass, and bilirubin serum level [30]. In children, Cys-C levels reflect renal function independent of age, gender, height, and body composition [31], pre-renal factors, extra-renal diseases [32], or prednisone therapy of nephrotic syndrome [33].
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Table 2. Factors that are independent of serum Cyc-C level or dependently related to serum Cys-C level in children.
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Serum creatinine, when compared to Cys-C, is a poor marker of kidney function in early neonates, since the mother clears fetal creatinine that may cross through the placenta. Consequently creatinine levels in neonatal serum may not reflect the neonatal renal function [34]. Since fetal Cys-C levels do not show any relationship to maternal Cys-C levels, serum Cys-C appears to be a good marker of GFR in neonates [35].
In children with nephrotic syndrome, Cys-C is freely cleared from the kidney. Therefore, the serum Cys-C may overestimate the true renal function during nephrotic syndrome [36]. Furthermore, serum Cys-C levels can be modified by certain conditions and drugs. For example, Cys-C levels are influenced by ketonuria in diabetic children. High blood ketone levels have been associated with reduced serum Cys-C and overestimation of kidney function [37]. In patients with mild thyroid dysfunction, serum Cys-C levels may be increased or decreased, respectively, as a result of sub-clinical hypo- or hyperthyroidism [38]. Administration of methylprednisolone pulses or cyclosporin A can respectively over- or under-estimate serum Cys-C levels [39].
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Predictive GFR Formulas Based on Cys-C Levels
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Several predictive formulas to estimate GFR (ml/ min/1.73 m2) from serum Cys-C levels (mg/L) have been published (Table 3). The Bokenkamp formula, adapted for a wide age-range of pediatric patients, estimates the GFR from reciprocal serum Cys-C levels [40]. The Filler formula calculates the logarithm of GFR (mL/min/1.73 m2) from the logarithm of reciprocal serum Cys-C concentration [41]. The Larsson formulas are adapted for a wide age-range of patients, not exclusively pediatric [42]. In prepubertal children, the GFR calculated from serum Cys-C levels by the Grubb formula seems better than GFR estimates by the Schwartz and Counahan-Barratt formulas that are based on serum creatinine levels [43]. Two formulas have been proposed for GFR estimation in children that are based on serum Cys-C, serum creatinine, and other covariates [44,79]. GFR estimates by these equations are more precise than by the classic Schwartz formula, but complexity of the equations may reduce their feasibility in clinical practice.
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Reference Values for Serum Cys-C
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Serum Cys-C concentration is generally measured by latex-particle enhanced immunonephelometric methods [22,45,46]. Table 4 lists reference intervals for healthy infants and children, reported in different ways (ie, mean ± SD; 5th–95th percentiles; or 2.5th–97.5th percentiles). The serum Cys-C concentration is influenced by age. Cys-C levels are higher in preterm infants than at-term infants. Most premature neonates have low GFR due to kidney immaturity [47]. The serum Cys-C concentration is high on the first day of life and declines during the first 4 mo of life. Under the age of 1.5 yr, healthy children have higher Cys-C levels than older children [48]. After the 1st year of life, the Cys-C levels [49] approach those of older children [50]. Serum Cys-C concentration is considered stable after 3 yr of age [51]. Harmoinen et al [52] summarized reference intervals for serum Cys-C levels at all ages.
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Serum Cys-C and Kidney Diseases
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In pediatric patients with nephrotic syndrome, serum proteins (eg, albumin, transferrin) leak into the urine through the glomeruli, resulting in hypoproteinemia, hyperproteinuria, and edema. Cys-C is detectable in the urine of children with proteinuria. The Cys-C concentration in urine correlates with both proteinuria and serum albumin levels [36].
Kidney malformations may be detected by imaging during fetal life. The finding of bilateral hyperechogenic enlarged kidneys suggests future development of renal failure in postnatal life. However, it is difficult to predict the postnatal kidney outcome solely on the basis of imaging techniques. Serum Cys-C level has been suggested as a predictor of renal failure in fetuses with renal hypoplasia and/or dysplasia. For example, fetuses with cystic dysplasia of the kidney showed high Cys-C levels in fetal serum [53]. Another example is polycystic kidney disease (PKD) where the serum Cys-C level is significantly lower and GFR higher than normal, reflecting early hyperfiltration of PKD kidneys [54]. Finally, serum Cys-C is increased in children =12 yr of age who have a solitary kidney and the serum Cys-C level is correlated with kidney overgrowth [55].
Serum Cys-C level has been investigated in critically ill septic patients with kidney failure. However, Cys-C was not a better marker than creatinine and did not help to identify acute kidney failure earlier [56].
In children with chronic kidney disease (CKD), Mitsnefes et al [57] observed good correlation between serum Cys-C and GFR, but serum Cys-C measurement was not superior to serum creatinine [57]. In kidney donors, serum Cys-C was found to be superior to serum creatinine as an index of the rapid GFR decrease following uninephrectomy [58]. In cases of terminal kidney failure, dialysis is the most important therapeutic measure prior to kidney transplant. The significance of serum Cys-C levels differs with the method of dialysis. With peritoneal dialysis, solute clearance decreases from high to low molecular weight. Hence, these patients show a disproportionate accumulation of serum Cys-C [59]. On the other hand, in hemodialysis patients, GFR values calculated from serum Cys-C show less variability than those calculated from serum creatinine [60].
In kidney transplant recipients, preliminary results indicate that serum Cys-C is better than [61] or similar to [62] serum creatinine as a marker of GFR in children. In the immediate and early post-transplant periods, Cys-C showed good sensitivity to estimate renal function. However, its value as a marker of GFR diminished by the end of the first week post-transplant [63]. Sidlova et al [64] reported that serum Cys-C level is a valuable indicator of GFR in pediatric patients before kidney transplantation. Since children having one kidney transplant, or kidney plus liver combined transplant, showed higher variability of serum Cys-C than of creatinine, Cys-C appears useful in the post-transplant period mainly for intra-individual follow-up [65]. The serum Cys-C level has been recommended as a marker of GFR in pediatric transplant recipients with immunosuppression and viral renal infection [66]. Filler et al [67] advised that in kidney transplant clinical trials the better diagnostic sensitivity of radiolabeled markers cannot be replaced by serum Cys-C levels alone. Serum Cys-C level can serve as an early indicator of allograft dysfunction following kidney transplantation in children, but it does not seem superior to creatinine. Although Bokenkamp et al initially reported that Cys-C was better than creatinine as a marker of GFR in transplanted children, further data did not support their preliminary results [68].
Cys-C is a good marker of GFR for an early identification of fetuses and children with urinary tract malformations [69,70], in particular as a marker of renal tube damage. Fetal bilateral obstructive uropathy causes higher urine Cys-C levels in cases of associated renal failure [71]. Serum Cys-C may be a better marker than serum creatinine in estimating GFR in children <3 years old with renal malformations and mild impairment [70]. Bladder dysfunctions are frequently associated with occult spina bifida. In a prospective study, serum Cys-C and creatinine were used to estimate kidney function in subjects with nervous system malformation. In these children, the estimation of GFR from Cys-C was superior to that from creatinine [72].
The detection and follow-up of early renal dysfunction is important in children with diabetes mellitus. Serum Cys-C was suggested as an early marker of renal malfunction during this condition. Peczynska et al [73] found that the concentration of serum Cys-C was higher and was related to disease length in non-compliant diabetic patients, particularly if there were also vascular complications. However, Holmquist et al [37] cautioned that the serum Cys-C level may be affected by acute metabolic status in newly diagnosed diabetic children [37].
Chemotherapy for malignant diseases is frequently associated with nephrotoxic side effects. Such children can develop significant reduction in GFR during the induction phase of chemotherapy. In a study of children with various types of malignancy, serum Cys-C and creatinine levels were measured before and at 1 mo after initiation of chemotherapy. Cys-C was shown to be more sensitive than creatinine as a marker to assess GFR and to predict those at risk of renal impairment during the induction phase of chemotherapy [74]. In another group of children, serum Cys-C level was measured before and after antineoplastic treatment with cisplatin, methotrexate, cyclophos-phamide, and ifosfamide, singly or in combinations. The treatments all led to increased Cys-C levels in serum [75]. Other studies used serum Cys-C levels to monitor mild-to-moderate sub-clinical glomerular and tubular damage during chemotherapy [76], particularly in children with acute lymphoblastic leukemia [77]. In young pediatric cancer patients (<3 yr old), serum Cys-C appears to have somewhat better diagnostic value than serum creatinine as an index of renal function [78].
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Conclusions
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Although serum Cys-C levels are unaffected by many variables, age seems to be the most important variability factor. Serum Cys-C levels show a progressive decline after birth and reach a plateau only after 1.5 yr of age, which is actually a young age for a metabolite to reach stable adult levels.
Serum Cys-C is a good marker of kidney function in various renal conditions (eg, nephrotic syndrome, renal malformations, and kidney transplantation). Nevertheless, serum Cys-C does not seem superior to serum creatinine in patients with acute kidney failure, acute allograft dysfunction, and chronic renal insufficiency. Furthermore Cys-C is not cleared efficiently by peritoneal dialysis in anuric patients, which may be a limitation in monitoring these patients.
Serum Cyc-C levels are influenced by some extra-renal conditions, including spina bifida, diabetic ketosis, and thyroid dysfunction, as well as by cancer chemotherapy, methylprednisolone pulses, and cyclosporin A.
Several studies have shown that serum Cys-C levels are superior, or at least equivalent, to serum creatinine levels as an index of renal function. Clinical trials have provided encouraging evidence for the superiority of Cys-C over creatinine as a marker of GFR in children. However, clinicians and laboratorians should be cognizant of the pathophysiological and pharmacological factors that can influence serum Cys-C results.
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J. R. Delanghe
How to estimate GFR in children
Nephrol. Dial. Transplant.,
March 1, 2009;
24(3):
714 - 716.
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Abstract
Introduction
